NZ731565B2 - Methods for treating subjects with prader-willi syndrome or smith-magenis syndrome - Google Patents

Abstract

Provided are immediate or prolonged administration of certain potassium ATP (KATP) channel openers, optionally in combination with growth hormone, to a subject to achieve novel pharmacodynamic, pharmacokinetic, therapeutic, physiological, metabolic and compositional outcomes in the treatment of diseases or conditions involving KATP channels. Also provided are pharmaceutical formulations, methods of administration and dosing of KATP channel openers that achieve these outcomes and reduce the incidence of adverse effects in treated individuals. Further provided are methods of co-administering KATP channel openers with other drugs (e.g., in combination with growth hormone) to treat diseases of humans and animals (e.g., Prader-Willi Syndrome (PWS), Smith-Magenis syndrome (SMS), and the like. ases or conditions involving KATP channels. Also provided are pharmaceutical formulations, methods of administration and dosing of KATP channel openers that achieve these outcomes and reduce the incidence of adverse effects in treated individuals. Further provided are methods of co-administering KATP channel openers with other drugs (e.g., in combination with growth hormone) to treat diseases of humans and animals (e.g., Prader-Willi Syndrome (PWS), Smith-Magenis syndrome (SMS), and the like.

Description

WO 77629 METHODS FOR TREATING SUBJECTS WITH PRADER-WILLI SYNDROME OR SMITH-MAGENIS SYNDROME FIELD OF THE INVENTION The present invention relates to pharmaceutical formulations of ium ATP (KATP) channel openers and their use for treatment of various diseases and ions such as Prader-Willi Syndrome (PWS), Smith—Magenis syndrome (SMS), and the like.

BACKGROUND OF THE INVENTION The following description of the background of the invention is provided simply as an aid in understanding the ion and is not admitted to describe or constitute prior art to the invention.

ATP—sensitive potassium (KATp) channels play important roles in a variety of tissues by coupling cellular lism to electrical activity. The KATp channel has been fied as an octameric complex of two unrelated proteins, which assemble in a 4:4 stoichiometry. The first is a pore forming subunit, Kir6.x, which forms an inwardly rectifying K+ channel; the second is an ABC (ATP binding te) transporter, also known as the sulfonylurea receptor (SURX) (Babenko, et al., Annu. Rev. Physiol, —687 (1998)). The Kir6.x pore forming subunit is common for many types of KATp channels, and has two putative transmembrane domains (identified as TMl and TM2), which are linked by a pore loop (H5). The subunit that comprises the SUR receptor includes multiple membrane- spanning domains and two nucleotide—binding folds.

According to their tissue localization, KATp channels exist in different ms or subspecies resulting from the assembly of the SUR and Kir subunits in multiple combinations. The ation of the SURl with the Kir6.2 subunits (SURl/Kir6.2) typically forms the adipocyte and pancreatic B—cell type KATp channels, whereas the SUR2A/Kir6.2 and the SUR2B/Kir6.2 or Kir6.l combinations typically form the cardiac type and the smooth muscle type KATp channels, respectively (Babenko, et al., Annu. Rev.

Physiol, 60:667—687 ). There is also evidence that the channel may include Kir2.x subunits. This class of potassium channels are inhibited by intracellular ATP and activated by intracellular nucleoside diphosphates. Such KATp ls link the metabolic status of the cells to the plasma membrane potential and in this way play a key role in regulating cellular activity. In most excitatory cells, KATp channels are closed under normal physiological conditions and open when the tissue is lically compromised (e. g. when the (ATP:ADP) ratio falls). This promotes K+ efflux and cell hyperpolarization, thereby preventing voltage—operated Ca2+ ls (VOCs) from opening. (Prog Res ch, (2001) 31:77—80).

Potassium channel openers (PCOs or KCOs) (also referred to as channel activators or channel agonists), are a structurally diverse group of nds with no apparent common pharmacophore linking their ability to antagonize the inhibition of KATp channels by intracellular nucleotides. ide is a PCO that stimulates KATp channels in pancreatic B-cells (see Trube, et al., Pfluegers Arch kEur JPhysiol, 407, 493—99 (1986)).

Pinacidil and chromakalim are PCOs that activate sarcolemmal potassium channels (see Escande, et al., Biochem Biophys Res Commun, 154, 620—625 (1988); Babenko, et al., JBiol Chem, , 717—720 (2000)). Responsiveness to diazoxide has been shown to reside in the 6th through 11th predicted transmembrane domains (TMD6-11) and the first nucleotide- binding fold (NBFl) of the SURl subunit. ide, which is a nondiuretic benzothiadiazine derivative having the formula 7-chloromethyl-2H-1,2,4-benzothiadiazine 1.1-dioxide (empirical formula C8H7C1N202S), is commercialized in three distinct formulations to treat two ent disease indications: 1) hypertensive emergencies and 2) hyperinsulinemic hypoglycemic conditions. Hypertensive emergencies are treated with tat IV, an aqueous formulation of diazoxide for intravenous use, adjusted to pH 11.6 with sodium hydroxide. Hyperstat IV is administered as a bolus dose into a peripheral vein to treat ant hypertension or sulfonylurea overdose.

In this use, diazoxide acts to open potassium channels in vascular smooth muscle, izing the membrane potential at the resting level, and preventing vascular smooth muscle ction.

Hyperinsulinemic hypoglycemic conditions are treated with Proglycem, an oral pharmaceutical version of diazoxide useful for administration to s, children and adults.

It is available as a ate mint flavored oral suspension, which includes 7.25% alcohol, sorbitol, chocolate cream flavor, propylene glycol, magnesium aluminum silicate, carboxymethylcellulose , mint flavor, sodium te, methylparaben, hydrochloric acid to adjust the pH, poloxamer 188, propylparaben and water. Diazoxide is also available as a capsule with 50 or 100 mg of diazoxide ing lactose and magnesium stearate.

Several experimental formulations of diazoxide have been tested in humans and animals. These include an oral solution tested in pharmacodynamic and pharmacokinetic WO 77629 studies and a tablet formulation under development as an anti-hypertensive, but never cialized (see Calesnick, et al., J. Pharm. Sci. 54: 1277—1280 (1965); Reddy, et al., AAPS Pharm Sci Tech 4(4):1—98, 9 (2003); US Patent 6,361,795).

Current oral formulations of diazoxide are labeled for dosing two or three times per day at 8 or 12 hour als. Most patients receiving diazoxide are dosed three times per day. Commercial and experimental formulations of diazoxide are characterized by rapid drug e following ingestion with completion of release in approximately 2 hours.

Current oral formulations of ide in therapeutic use result in a range of adverse side effects ing dyspepsia, nausea, diarrhea, fluid retention, edema, reduced rates of excretion of sodium, chloride, and uric acid, hyperglycemia, vomiting, nal pain, ileus, tachycardia, palpitations, and headache (see current ing insert for the Proglycem). Oral treatment with diazoxide is used in individuals experiencing serious disease where failing to treat results in significant morbidity and mortality. The adverse side effects from oral administration are tolerated because the benefits of treatment are substantial.

The adverse side effects profile of oral diazoxide limit the utility of the drug in treating obese patients at doses within the labeled range of 3 to 8 mg/kg per day.

The effect of diazoxide in animal models of diabetes and obesity (e. g. obese and lean Zucker rats) has been reported. See e. g. deh et al. (Endocrinology 133 :705—7 12 (1993), Alemzadeh et al. (Metabolism 45:334—341 (1996)), Alemzadeh et al. (Endocrinology 140:3197—3202 (1999)), Stanridge et al. (FASEB J 14:455-460 (2000)), Alemzadeh et al.

(Med Sci Monit 10(3): BR53—60 (2004)), Alemzadeh and Tushaus (Endocrinology 145(12):3476-3484 (2004)), Aizawa et al. (JofPharma Exp Ther 275(1): 194—199 (1995)), and Surwit et al. rinology 141:3630—3637 (2000)).

The effect of diazoxide in humans with obesity or diabetes has been reported. See e. g., Wigand and rd (Diabetes 28(4):287—291 (1979); evaluation of ide on insulin receptors), Ratzmann et al. (Int J Obesity 7(5):453—458 (1983); glucose nce and insulin sensitivity in moderately obese patients), Marugo et al. (Boll Spec It Biol Sper 53: 1860—1866 (1977); moderate dose diazoxide treatment on weight loss in obese patients), Alemzadeh et al. (J Clin Endocr Metab 83: 191 1—1915 (1998); low dose diazoxide treatment on weight loss in obese hyperinsulinemic patients), Guldstrand et al. (Diabetes and lism 28:448—456 (2002); diazoxide in obese type 11 diabetic patients), Ortqvist et al.

(Diabetes Care 27(9):2191—2197 (2004); beta—cell function ed by circulating C- peptide in children at clinical onset of type 1 diabetes), Bjork et al. (Diabetes Care 2l(3):427— 430 (1998); effect of diazoxide on residual insulin secretion in adult type I diabetes patients), and Qvigstad et al., (Diabetic Medicine 21 :73—76 (2004)).

US. Patent No. 5,284,845 describes a method for normalizing blood e and insulin levels in an individual exhibiting normal fasting blood glucose and insulin levels and exhibiting in an oral glucose tolerance test, elevated glucose levels and at least one insulin level abnormality selected from the group consisting of a delayed insulin peak, an exaggerated insulin peak and a secondary elevated n peak. According to this reference, the method includes administering diazoxide in an amount from about 0.4 to about 0.8 mg/kg body weight before each meal in an amount effective to normalize the blood glucose and insulin levels.

US. Patent No. 6,197,765 describes administration of diazoxide as a treatment for syndrome-X, and resulting complications, that include hyperlipidemia, hypertension, central obesity, hyperinsulinemia and impaired glucose rance. ing to this nce, diazoxide interferes with pancreatic islet on by ablating endogenous n ion resulting in a state of insulin deficiency and high blood glucose levels equivalent to that of diabetic patients that depend on exogenous insulin administration for normalization of their blood glucose levels.

US. Patent No. 2,986,573 bes diazoxide and alkali metal salts for the treatment of hypertension.

US. Patent no. 5,629,045 describes diazoxide for topical ophthalmic administration.

W0 98/ 10786 bes use of diazoxide in the treatment of X—syndrome including y associated therewith.

US. Patent ation no. 2003/0035106 describes diazoxide-containing compounds for reducing the consumption of fat—containing foods.

US. Patent publication no. 2004/0204472 describes the use of a Cox—2 inhibitor plus diazoxide in the treatment of obesity.

US. Patent publication no. 2002/0035106 describes the use of KATp channel openers including diazoxide and metal salts for reducing the consumption of fat containing food.

SUMNLARY OF THE INVENTION Provided herein are pharmaceutical formulations of KATp channel openers and their use (optionally in combination with growth hormone) for treatment of various diseases and conditions, including -Willi me (PWS), Smith—Magenis syndrome (SMS), and the like. Such formulations are characterized as being bioavailable. A KATp channel opener as used herein has any one or more of the following properties: (1) opening SURl/Kir6.2 ium channels; (2) binding to the SURl subunit of KATp channels; and (3) inhibiting glucose d release of insulin following administration of the compound in viva. Preferably, KATp channel s are KATp channel openers with all three properties.

KATp channel openers as defined above ably have the structure of compounds of Formulas I—VII as set forth below.

In accordance with one aspect of the present invention, it has been discovered that one or more KATp channel opener(s) (optionally in combination with growth hormone) is effective for the treatment of a subject having Prader-Willi Syndrome (PWS), Smith— Magenis syndrome (SMS), and the like, and is especially effective for increasing the lean body mass of such subjects. Therefore, in one aspect of the present invention, there are provided methods of increasing the lean body mass of a subject having Prader—Willi me (PWS), Smith—Magenis syndrome (SMS), and the like, said method sing administering to said subject for at least 4 weeks an ive amount of a KATp channel opener (optionally in combination with growth hormone).

In some embodiments, the lean body mass of said subject is sed by at least 1%. In some embodiments, the lean body mass of said subject is increased by at least 2%. In some embodiments, the lean body mass of said subject is increased by at least 3%. In some embodiments, the lean body mass of said subject is increased by at least 4%. In some embodiments, the lean body mass of said subject is increased by at least 5%.

In addition to increasing the lean body mass of a subject, in some embodiments, invention methods also reduce the hyperphagia of a subject. In some embodiments, the hyperphagia of said subject is reduced by at least 10%. In some embodiments, the hyperphagia of said subject is reduced by at least 20%. In some embodiments, the hyperphagia of said subject is reduced by at least 30%.

In on to increasing the lean body mass of a subject, in some embodiments, invention s also reduce the body fat of a subject. In some embodiments, the body fat of said subject is reduced by at least 1%. In some embodiments, the body fat of said subject is reduced by at least 3%. In some embodiments, the body fat of said subject is reduced by at least 5%.

In another aspect, the present ion provides a method of increasing the lean body mass of a subject having Prader—Willi Syndrome (PWS), Smith—Magenis syndrome (SMS), and the like, wherein said subject is already being treated by administration thereto of growth hormone, said method comprising co-administering to said subject an effective amount of a KATp channel opener in addition to said growth hormone.

In yet another aspect, the t invention provides a method of increasing the lean body mass of a t having Prader-Willi Syndrome (PWS), Smith—Magenis syndrome (SMS), and the like, wherein said subject is already being d by administration thereto of an effective amount of a KATp channel opener, said method comprising co-administering to said subject an ive amount of growth hormone in on to said KATp channel opener.

KATp l openers defined by Formula I are as follows: RN3+I:’:bR’Ib OS//\\0 Formula I wherein: R1a and Rlb, when present, are independently selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted lkyl, amino, and substituted amino; R2a and RZb, when present, are independently selected from the group consisting of hydrogen, and lower alkyl, X is a l, 2 or 3 atom chain, wherein each atom is ndently selected from carbon, sulfur or nitrogen, and each atom is ally substituted with halogen, hydroxyl, lower alkyl, substituted lower alkyl, lower , cycloalkyl, substituted cycloalkyl, substituted lower alkoxy, amino, or substituted amino; wherein rings A and B are each independently saturated, monounsaturated, polyunsaturated or aromatic; and all bioequivalents including salts, gs and isomers thereof.

In particular embodiments, compounds of Formula I may include a double bond between either positions 1 and 2 or positions 2 and 3 of Ring A. When a double bond is present between positions 1 and 2 of Ring A, R2a is absent and one of R1a and R1b are absent.

When a double bond is present between positions 2 and 3 of Ring A, R2b is absent and one of R1a and R1b are absent. In a preferred ment, R1a and R1b are not amino. In another preferred embodiment, Ring B does not include any heteroatoms.

KATp channel openers defined by Formula 11 being a era of Formula I are as follows: N R1 X/B \ | A}? S ‘R2a // \\ Formula II wherein: R1 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, amino, and substituted amino; R2a is selected from the group consisting of hydrogen, and lower alkyl, X is a l, 2 or 3 atom chain, wherein each atom is independently selected from carbon, sulfur or nitrogen, and each atom is optionally substituted with halogen, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy, cycloalkyl, substituted lkyl, substituted lower alkoxy, amino, or substituted amino; wherein ring B is saturated, monounsaturated, polyunsaturated or ic; and all bioequivalents including salts, prodrugs and isomers thereof.

In particular embodiments of Formula II, X is C(Ra)C(Rb), n R"1 and Rb are independently selected from the group consisting of en, halogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkoxy, substituted lower , amino, sulfonylamino, ulfonyl, yl, and the like. In further ments, R a and Rb are ndently selected from the group consisting of hydroxyl, substituted oxy, substituted thiol, alkylthio, substituted alkylthio, sulf1nyl, sulfonyl, substituted sulf1nyl, substituted sulfonyl, substituted sulfonylamino, substituted amino, substituted amine, alkylsulflnyl, alkylsulfonyl, alkylsulfonylamino, and the like. In a preferred embodiment, R1 is not amino. In r red ment, Ring B does not include any heteroatoms.

KATp channel openers defined by Formula III being a subgenera of Formula I are as follows: N R1 x/ B | ATNr Formula III wherein: R1 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, amino, and substituted amino; R2b is selected from the group consisting of hydrogen, and lower alkyl, X is a l, 2 or 3 atom chain, wherein each atom is independently selected from carbon, sulfur or nitrogen, and each atom is optionally substituted with n, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy, cycloalkyl, substituted lkyl, substituted lower alkoxy, amino, or tuted amino; wherein ring B is saturated, monounsaturated, polyunsaturated or aromatic; and all bioequivalents including salts, prodrugs and isomers thereof.

In particular embodiments of Formula III, X is C(Ra)C(Rb), wherein R"1 and Rb are independently selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, cycloalkyl, tuted cycloalkyl, lower , substituted lower alkoxy, amino, sulfonylamino, aminosulfonyl, sulfonyl, and the like. In further embodiments, R"1 and Rb are independently selected from the group consisting of hydroxyl, substituted oxy, substituted thiol, alkylthio, substituted alkylthio, sulf1nyl, sulfonyl, substituted sulf1nyl, substituted sulfonyl, substituted sulfonylamino, substituted amino, tuted amine, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, and the like. In a preferred ment, R1 is not amino. In another preferred embodiment, Ring B does not include any heteroatoms.

KATp channel openers defined by Formula IV being a era of Formula I are as follows: Formula IV wherein: R1 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, amino, and substituted lower amino; R221 is selected from the group consisting of hydrogen, lower alkyl, and substituted lower alkyl; R3 is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, amino, and substituted amino; R4 is selected from the group ting of hydrogen, n, lower alkyl, substituted lower alkyl, amino, and substituted amino; and all bioequivalents including salts, prodrugs and isomers thereof.

In particular embodiments of Formula IV, R1 is a lower alkyl (preferably ethyl or methyl); R23 is hydrogen; and R3 and R4 are each ndently halogen.

In a red embodiment of Formula IV, R1 is not amino.

In r embodiment of Formula IV, R1 is methyl; R2"1 is hydrogen; R3 is selected from the group consisting of en, n, lower alkyl, substituted lower alkyl, amino, substituted amino, cycloalkyl, and substituted cycloalkyl; and R4 is chlorine.

KATp channel openers defined by Formula V being a subgenera of Formula I are as follows: R3 ll\l\|rR1 Formula V wherein: R1 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, amino, and substituted lower amino; R2b is selected from the group consisting of hydrogen, lower alkyl, and substituted lower alkyl; R3 is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, amino, and tuted amino; R4 is selected from the group consisting of en, halogen, lower alkyl, substituted lower alkyl, amino, and substituted amino; and all bioequivalents including salts, prodrugs and isomers thereof.

In particular embodiments of Formula V, R1 is a lower alkyl (preferably ethyl or methyl); R2b is hydrogen; and R3 and R4 are each independently halogen.

In a preferred embodiment of Formula V, R1 is not amino.

In r embodiment of Formula V, R1 is methyl; R2b is hydrogen; R3 is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, amino, substituted amino, cycloalkyl, and substituted cycloalkyl; and R4 is chlorine.

KATp channel openers defined by Formula VI are as follows: R5 N R1 R ,s: ‘RZa Formula VI wherein: R1 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, amino, and substituted lower amino, or R1 can cooperate with R5 or R6 to form an additional ring; R221 is selected from the group ting of hydrogen, lower alkyl, and substituted lower alkyl; R5 is ed from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, substituted lower alkyl, amino, substituted amino, sulfonyl, ulfonyl, and ylamino, or R5 can cooperate with R1 or R6 to form an additional ring; R6 is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, amino, substituted amino, sulfonyl, aminosulfonyl, and sulfonylamino, or R6 can cooperate with R1 or R5 to form an additional ring; wherein the ring formed by the cooperation of R1 and R5, or R1 and R6, or R5 and R6 is saturated, monounsaturated, polyunsaturated or aromatic; wherein the ring formed by the ation of R1 and R5, or R1 and R6, or R5 and R6 is optionally tuted with halogen, hydroxyl, lower alkyl, tuted lower alkyl, amino, substituted amino, sulfonyl, aminosulfonyl, or sulfonylamino; and all bioequivalents including salts, prodrugs and isomers thereof.

In a preferred embodiment, R1 is not an amino tuent.

In another embodiment of Formula VI, R5 and R6 combine to form a 6 membered ring. In another embodiment, R5 and R6 combine to form a 6 membered ring wherein at least one nitrogen is present. Preferably, the ring formed by R5 and R6 does not include any heteroatoms.

KATp channel openers d by Formula VII are as follows: R5 N R1 R6 03‘? Formula VII wherein: R1 is selected from the group consisting of hydrogen, lower alkyl, tuted lower alkyl, cycloalkyl, substituted cycloalkyl, amino, and substituted lower amino, or R1 can ate with R5 or R6 to form an additional ring; R2b is selected from the group consisting of hydrogen, lower alkyl, and substituted lower alkyl, R5 is selected from the group consisting of hydrogen, halogen, yl, lower alkyl, substituted lower alkyl, amino, substituted amino, sulfonyl, aminosulfonyl, and sulfonylamino, or R5 can cooperate with R1 or R6 to form an additional ring; R6 is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, amino, tuted amino, yl, aminosulfonyl, and sulfonylamino, or R6 can ate with R1 or R5 to form an additional ring; wherein the ring formed by the cooperation of R1 and R5, or R1 and R6, or R5 and R6 is saturated, monounsaturated, polyunsaturated or aromatic; wherein the ring formed by the cooperation of R1 and R5, or R1 and R6, or R5 and R6 is optionally substituted with halogen, hydroxyl, lower alkyl, substituted lower alkyl, amino, tuted amino, sulfonyl, aminosulfonyl, or sulfonylamino; and all bioequivalents including salts, prodrugs and s thereof.

In a preferred embodiment, R1 is not an amino substituent.

In another embodiment of Formula VI, R5 and R6 combine to form a 6 membered ring. In another embodiment, R5 and R6 combine to form a 6 membered ring wherein at least one nitrogen is present. Preferably, the ring formed by R5 and R6 does not include any heteroatoms.

Unless otherwise indicated, reference in this application to KATp channel openers should be understood to refer to KATp channel opener(s) having one or more and preferably all three of the following properties: (1) g SURl/Kir6.2 potassium channels; (2) binding to the SURl subunit of KATp channels; and (3) inhibiting glucose induced release of insulin following administration of the nd in viva. Such KATp channel openers preferably have the structure of any of the nds of Formulae I-VII, or more preferably Formulae I-VII where R1 is not amino and also where ring B or its equivalent does not e any heteroatoms, or more preferably, any of the compounds of Formulae II or III, or more preferably, any of the compounds of Formulae II or III where R1 is not amino and also where ring B or its equivalent does not include any heteroatoms, or more preferably, the structure is diazoxide. Structural ts or bioequivalents of the compounds of any of Formulae I—VII such as derivatives, salts, prodrugs or isomers are also contemplated. Other KATp l openers that are plated for use herein include BPDZ62, BPDZ 73, NN414, BPDZ 154.

In vitro analysis of glucose induced release of insulin via KATp channel openers can be determined using rat islets as provided by De Tullio, et al., J. Med. Chem, 46:3342— 3353 (2003) or by using human islets as provided by Bjorklund, et al., Diabetes, 49: 1840— 1848 (2000). ed herein are formulations, such as controlled release pharmaceutical formulations, of KATp channel openers and bioquivalents thereof. In one embodiment, the controlled release formulations are formulated for oral administration. Such formulations contain in a single administration dosage between 10 and 100 mg, between 25 and 100 mg, between 100 and 200 mg, between 200 and 300 mg, between 300 and 500 mg or between 500 and 2000 mg of the KATp l openers. In certain ments, the dosage of the KATp l openers contained in a formulation may be determined based on the weight of the patient for which it is to be administered, i.e., the formulation may contain in a single administration dosage between 01-20 mg of the KATp channel opener per kg of the t’s body weight, or between 0.1—0.5 mg of the KATp channel opener per kg of the patient’s body weight; or between 0.5—1 mg of the KATp channel opener per kg of the patient’s body weight; or between 1-2 mg of the KATp channel opener per kg of the t’s body weight, or between 2-5 mg of the KATp channel opener per kg of the patient’s body weight, or between -10 mg of the KATp channel opener per kg of the patient’s body weight, or between 10—15 mg of the KATp channel opener per kg of the patient’s body weight, or between 15—20 mg of the KATp channel opener per kg of the patient’s body weight.

Also provided herein are controlled release pharmaceutical formulations containing KATp channel s obtained by at least one of the following: (a) particle size reduction involving comminution, spray drying, or other micronising techniques, (b) use of a pharmaceutical salt of the KATp channel opener, (c) use of an ion exchange resin, (d) use of inclusion complexes, for example extrin, (e) compaction of the KATp l opener with a lizing agent including a low viscosity hypromellose, low viscosity metylcellulose or similarly oning excipient or combinations thereof, (f) associating the KATp channel opener with a salt prior to formulation, (g) use of a solid dispersion of the KATp WO 77629 channel opener, (h) use of a self emulsifying system, (i) addition of one or more surfactants to the formulation, (j) use of nanoparticles, or (k) combinations of these ches.

Further provided herein are controlled release pharmaceutical formulations containing KATp channel openers which include at least one component that substantially inhibits release of the KATp channel activator from the formulation until after gastric transit.

As used herein, "substantially inhibits" means less than 15% release, more ably at least less than 10% release, or more preferably at least less than 5% release of the drug from the formulation during gastric transport. Release can be measured in a standard USP based in— vitro gastric ution assay in a calibrated dissolution apparatus (see, for example, US.

Pharmacopeia, Chapter 71 l (2005)).

Also provided are oral pharmaceutical formulations of KATp channel openers which include at least one component that substantially inhibits release of the KATp channel opener from the formulation until after gastric t. Substantial inhibition of drug release during gastric transit is achieved by inclusion of a component in the ation selected from the group consisting of: (a) a pH sensitive polymer or co-polymer applied as a compression coating on a tablet, (b) a pH sensitive polymer or ymer applied as a thin film on a tablet, (c) a pH sensitive polymer or co-polymer applied as a thin film to an encapsulation system, (d) a pH sensitive polymer or co—polymer applied to encapsulated microparticles, (e) a non—aqueous—soluble polymer or co—polymer applied as a ssion coating on a , (f) a non-aqueous-soluble polymer or co-polymer applied as a thin film on a tablet, (g) a non-aqueous soluble polymer applied as a thin film to an encapsulation , (h) a non—aqueous soluble r d to microparticles, (i) incorporation of the formulation in an osmotic pump system, (j) use of systems controlled by ion exchange resins, and (k) combinations of these approaches, wherein the pH sensitive polymer or co—polymer is resistant to degradation under acid conditions.

Also provided herein are controlled e pharmaceutical formulations of KATp channel openers, wherein the formulation includes at least one component that contributes to ned release of a KATp channel opener over a period of 2-4 hours following administration, or over a period of 4-8 hours following administration, or over a period of more than 8-24 hours following administration. These formulations are characterized in having one of the following ents: (a) a pH ive polymeric coating, (b) a hydrogel coating, (c) a film coating that controls the rate of diffusion of the drug from a coated matrix, (d) an le matrix that controls rate of drug release, (e) polymer coated pellets, granules or microparticles of drug which can be further encapsulated or compressed into a tablet, (f) an c pump system containing the drug, (g) a compression coated tablet form of the drug, or (h) combinations of these approaches.

As used herein, an le matrix is the core of a tablet formulation that, upon exposure to an s environment, begins a process of disintegration which tates the release of drug from the matrix. The rate of release of drug from the tablet is controlled both by the solubility of the drug and the rate of disintegration of the matrix.

The above formulations may further comprise one or more additional pharmaceutically active agents (other than KATp channel openers) useful for the treatment of a condition selected from the group consisting of obesity, prediabetes, es, hypertension, depression, ed terol, fluid retention, other obesity associated comorbidities, ischemic and reperfusion injury, epilepsy, schizophrenia, mania, or other psychotic diseases.

Further provided is a controlled release pharmaceutical formulation of a KATp channel opener wherein administration to an obese, overweight or obesity prone individual results in at least one of the following: (a) inhibition of fasting insulin secretion (b) inhibition of stimulated insulin secretion, (c) elevation of energy expenditure, (d) elevation of beta oxidation of fat, (e) tion of hyperphagia for about 24 hours, or (f) increase in lean body mass.

Additionally provided is a controlled release pharmaceutical formulation of a KATp channel opener wherein administration to an obese, overweight or obesity prone individual s in at least one of the ing: (a) inhibition of fasting insulin secretion (b) inhibition of glucose stimulated insulin secretion, (c) elevation of energy expenditure, (d) elevation of beta oxidation of fat, (e) inhibition of hyperphagia for about 18 hours, or (f) increase in lean body mass.

Still r provided is a controlled release pharmaceutical formulation of a KATp channel opener which upon administration to an obese, overweight or obesity prone individual s in at least one of the following: (a) inhibition of fasting n secretion (b) inhibition of glucose ated insulin secretion, (c) elevation of energy expenditure, (d) elevation of beta oxidation of fat, (e) inhibition of hyperphagia for about 24 hours, or (f) increase in lean body mass.

Additionally provided is a lled release ceutical formulation of a KATp l opener that upon administration to an obese, overweight or obesity prone individual s in at least one of the following: (a) inhibition of fasting insulin secretion (b) inhibition of glucose stimulated n secretion, (c) elevation of energy expenditure, (d) elevation of beta oxidation of fat, (e) inhibition of hyperphagia for about 18 hours, or (f) increase in lean body mass.

Provided herein is a method of treating hypoglycemia, the method comprising orally stering a lled e formulation of a KATp channel opener, optionally in combination with growth hormone.

Further provided herein is a method of treating obesity associated co—morbidities in an obese, overweight or obesity prone individual, the method comprising administering a therapeutically effective amount of a solid oral dosage form of a KATp channel opener, or controlled release ceutical formulation of a KATp channel opener, optionally in ation with growth hormone. In a preferred embodiment, administration is no more than two times per 24 hours, or once per 24 hours.

Yet further provided herein is a method of achieving weight loss in an obese overweight, or obesity prone individual, the method comprising administering a therapeutically effective amount of a solid oral dosage form of a KATp channel opener or controlled release pharmaceutical formulation of a KATp channel opener, optionally in combination with growth hormone. In a preferred embodiment, administration is no more than two times per 24 hours, or once per 24 hours. The daily dosage administered is preferably between 50 and 180 mg. In certain embodiments, the obese individual has a body mass index greater than 30 kg/mz, or greater than 35 kg/mz, or greater than 40 kg/mz, or greater than 50 kg/mz, or greater than 60 kg/m2 at the time the method commences.

Also ed is a method of maintaining a weight loss in an obese overweight, or y prone individual, the method comprising administering a therapeutically effective amount of a solid oral dosage form of a KATp channel opener or controlled release pharmaceutical formulation of a KATp channel opener, optionally in combination with growth hormone. It is preferable to maintain weight in an obese individual once some weight loss has ed when the alternative is to regain weight. In a preferred embodiment, administration is no more than two times per 24 hours, or once per 24 hours. 2015/060455 Further provided is a method of elevating energy expenditure in an overweight, obese or obesity prone individual, the method comprising administering an effective amount of a solid oral dosage form of a KATp l opener or controlled e pharmaceutical ation of a KATp channel opener, optionally in ation with growth hormone. In a preferred embodiment, administration is no more than two times per 24 hours, or once per 24 hours. In certain embodiments, the individual has a body mass index greater than 20 kg/mz, or greater than 25 kg/mz, or greater than 30 kg/mz, or greater than 35 kg/mz, or greater than 40 kg/mz, or greater than 50 kg/mz, or greater than 60 kg/m2 at the time the method C01’1’11’1’161’1CCS.

Additionally provided is a method of elevating beta oxidation of fat in an overweight, obese or obesity prone individual, the method comprising stering an effective amount of a solid oral dosage form of a KATp channel opener or controlled release pharmaceutical formulation of a KATp channel opener, optionally in combination with growth hormone. In a preferred embodiment, administration is no more than two times per 24 hours, or once per 24 hours. In certain embodiments, the individual has a body mass index greater than 20 kg/mz, or greater than 25 kg/mz, or greater than 30 kg/mz, or greater than 35 kg/mz, or greater than 40 kg/mz, or greater than 50 kg/mz, or greater than 60 kg/m2 at the time the method commences.

Yet further ed is a method of reducing visceral fat in an overweight, obese or obesity prone individual, the method sing administering an effective amount of a solid oral dosage form of a KATp channel opener or controlled release pharmaceutical formulation of a KATp l , optionally in combination with growth hormone. In a preferred embodiment, administration is no more than two times per 24 hours, or once per 24 hours.

Still further provided is a method of delaying or preventing the transition to diabetes of a prediabetic individual comprising administering an effective amount of a KATp channel opener or controlled release pharmaceutical formulation of a KATp channel opener, optionally in combination with growth e. In a preferred embodiment, administration is no more than two times per 24 hours, or once per 24 hours.

Additionally provided is a method of restoring normal glucose tolerance in a prediabetic dual comprising administering an effective amount of a KATp channel opener or controlled release pharmaceutical formulation of a KATp channel opener, optionally in combination with growth hormone. In a preferred ment, administration is no more than two times per 24 hours, or once per 24 hours.

Further provided is a method of restoring normal glucose tolerance in a diabetic individual comprising administering an effective amount of a KATp channel opener or controlled release pharmaceutical formulation of a KATp l opener, optionally in combination with growth hormone. In a preferred embodiment, administration is no more than two times per 24 hours, or once per 24 hours.

Still r provided is a method of delaying or preventing ssion of diabetes in an individual comprising administering an effective amount of a KATp channel opener or controlled release pharmaceutical formulation of a KATp channel opener, optionally in combination with growth hormone. In a preferred embodiment, administration is no more than two times per 24 hours, or once per 24 hours.

Also provided is a method to prevent or treat weight gain, impaired e tolerance or dyslipidemia associated with the use of anti-psychotics to treat ts comprising the co-administration of an ive amount of a KATp channel opener or controlled release pharmaceutical ation of a KATp channel opener, optionally in combination with growth hormone. In a preferred embodiment, stration is no more than two times per 24 hours, or once per 24 hours.

Further provided is a method to increase lean body mass in a Prader—Willi Syndrome patient, in a Smith—Magenis syndrome patient, in a Froelich’s Syndrome patient, in a Cohen Syndrome patient, in a Summit Syndrome patient, in an Alstrom Syndrome patient, in a Borj eson Syndrome t or in a Bardet-Biedl Syndrome patient comprising the administration of an effective amount of a KATp channel opener (optionally in combination with growth hormone) or a controlled release pharmaceutical formulation of a KATp channel opener nally in combination with growth hormone). In a preferred embodiment, administration is no more than two times per 24 hours, or once per 24 hours.

Still further provided is a method to treat obesity or elevated triglycerides in a patient suffering ipoproteinemia type I, type II, type III or type IV comprising stering an effective amount of a KATp channel opener or controlled release pharmaceutical formulation of a KATp channel opener, optionally in combination with growth e. In a preferred ment, stration is no more than two times per 24 hours, or once per 24 hours.

Also ed is a method of reducing the incidence of adverse effects from administration of a KATp channel opener in the ent of diseases of a subject achieved by any of the ing: (a) use of a dosage form that on administration reduces Cmax relative to the current Proglycem oral suspension or capsule products in order to reduce the incidence of adverse side effects that are ated with peak drug levels, (b) use of a dosage form that delays release until gastric t is complete in order to reduce the incidence of adverse side effects that are associated with the release of drug in the stomach, (c) initiating dosing at subtherapeutic levels and in a stepwise manner increasing dose daily until the therapeutic dose is achieved wherein the number of steps is 2 to 10 to reduce the incidence of adverse side effects that occur transiently at the initiation of treatment, (d) use of the lowest effective dose to achieve the desired therapeutic effect in order to reduce the nce of adverse side effects that are dose dependent, or (e) optimizing the timing of administration of dose within the day and relative to meals.

Further ed is a method of preventing weight gain, dyslipidemia or impaired glucose tolerance in a subject d with an anti-psychotic drug, the method comprising administering a pharmaceutical formulation of a KATp channel opener, ally in combination with growth hormone.

Yet further provided is a method of treating weight gain, dyslipidemia or impaired glucose tolerance in a subject treated with an anti-psychotic drug, the method comprising administering a pharmaceutical ation of a KATp channel opener, optionally in combination with growth hormone.

Also provided is a method of treating diseases characterized by obesity, hyperphagia, dyslipidemia, or decreased energy expenditure including (a) Prader Willi Syndrome, (b) Froelich’s syndrome, (c) Cohen syndrome, (d) Summit Syndrome, (e) Alstrom, Syndrome, (f) Borj esen Syndrome, (g) Bardet-Biedl Syndrome, (h) hyperlipoproteinemia type I, II, III, and IV, or (i) Smith—Magenis syndrome (SMS), said method comprising administering a pharmaceutical formulation of a KATp channel opener, optionally in combination with growth hormone.

Further provided is a pharmaceutical formulation of a KATp channel opener further comprising a pharmaceutically active agent other than the KATp channel opener. In this formulation, the other pharmaceutically active agent is an agent useful for the treatment of a condition ed from the group consisting of y, prediabetes, diabetes, hypertension, depression, elevated terol, fluid retention, or other obesity associated comorbidities, ic and reperfusion injury, epilepsy, schizophrenia, mania, and other psychotic condition.

The ations containing KATp channel openers described herein provide for improved compliance, efficacy and safety, and for co-formulations with other agents.

Included are co-formulations of KATp channel openers with one or more additional pharmaceutically active agents that have complementary or similar activities or targets.

Other pharmaceutical active agents that can be combined with KATp channel openers to treat obesity or to in weight loss in an y prone individual include, but are not limited to: amine, orlistat, phentermine, rimonabant, a diuretic, an antiepileptic, or other pharmaceutical active whose therapeutic utility includes weight loss. It is preferable to maintain weight in an obese individual once some weight loss has occurred when the alternative is to regain weight. Other pharmaceutically active agents that may be combined with KATp l openers to treat type II diabetes, or betes include acarbose, ol, metformin, repaglinide, nateglinide, rosiglitizone, proglitizone, ramipril, metaglidasen, or any other pharmaceutical active that improves insulin ivity or glucose utilization or glycemic control where the mode of action is not enhanced insulin secretion. Other pharmaceutical active agents that can be combined with KATp channel openers to treat obesity associated co—morbidities include a drug active used to lower terol, a drug active used to lower blood pressure, an anti-inflammatory drug that is not a cox-2 tor, a drug that is an antidepressant, a drug used to treat y inence, or other drug routinely used to treat disease conditions the incidence of which is elevated in overweight or obese patients as compared to normal weight individuals including, but not limited to, drugs to treat atherosclerosis, osteoarthritis, disc herniation, degeneration of knees and hips, breast, endometrium, cervical, colon, leukemia and prostate cancers, hyperlipidemia, asthma/reactive airway disease, gallstones, GERD, obstructive sleep apnea, obesity hypoventilation syndrome, recurrent ventral hernias, menstrual irregularity, infertility, and the like.

WO 77629 2015/060455 In the present context, the term "therapeutically effective" or "effective amount" indicates that the materials or amount of material is ive to prevent, alleviate, or ameliorate one or more symptoms of a disease or medical condition, and/or to prolong the survival of the subject being treated.

The term "pharmaceutically acceptable" tes that the identified material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the al to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e. g., for inj ectibles.

As used herein, the term "composition" refers to a formulation le for administration to an intended animal subject for therapeutic purposes; exemplary formulations contain at least one pharmaceutically active compound and at least one ceutically acceptable carrier or excipient. Other terms as used herein are defined below.

Adipocyte: An animal connective tissue cell specialized for the synthesis and storage of fat.

Agonist: A al compound that has affinity for and stimulates physiological ty at cell ors normally stimulated by naturally occurring nces, triggering a biochemical response. An agonist of a receptor can also be considered an tor of the receptor.

About: is used herein to mean in quantitative terms plus or minus 10%.

Adipose tissue: Tissue comprised principally of adipocytes.

Adolescent: A person between 10 and 19 years of age.

Adiponectin: A protein hormone produced and secreted exclusively by adipocytes that regulates the metabolism of lipids and glucose. Adiponectin influences the body's response to insulin. Adiponectin also has anti-inflammatory effects on the cells lining the walls of blood vessels.

Amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition: refers to any lessening, whether permanent or temporary, g or transient that can be attributed to or associated with administration of the composition.

Analog: a compound that resembles another in structure but s by at least one atom.

Antagonist: A substance that tends to nullify the action of r, as a drug that binds to a cell receptor without eliciting a biological response.

Atherosclerotic : A buildup of cholesterol and fatty material within a blood vessel due to the effects of atherosclerosis Bariatric Surgery: a range of surgical procedures which are designed to aid in the management or treatment of obesity and allied diseases.

Beta cell rest: Temporarily g beta cells in a condition in which there is reduced metabolic stress due to suppressed secretion of insulin.

Bilaminate: A ent of a pharmaceutical dosage form that consists of the lamination of two distinct materials.

Bioavailability: Refers to the amount or extent of eutically active substance that is released from the drug product and becomes available in the body at the intended site of drug action. The amount or extent of drug released can be established by the cokinetic-parameters, such as the area under the blood or plasma drug concentration— time curve (AUC) and the peak blood or plasma concentration (C max) of the drug.

Bioequivalent: Two formulations of the same active substance are ivalent when there is no significant difference in the rate and extent to which the active substance becomes available at the site of drug action when administered at the same molar dose under similar conditions. "Formulation" in this definition may include the free base of the active substance or different salts of the active substance. Bioequivalence may be demonstrated through l in vivo and in vitro methods. These methods, in descending order of preference, include pharmacokinetic, pharmacodynamic, al and in vitro studies. In particular, bioequivalence is demonstrated using pharmacokinetic measures such as the area under the blood or plasma drug concentration—time curve (AUC) and the peak blood or plasma concentration (Cmax) of the drug, using statistical criteria.

Cannabinoid Receptor: Receptors in the endocannabinoid (EC) system associated with the intake of food and tobacco dependency. Blocking the cannabinoid receptor may reduce dependence on tobacco and the craving for food.

Combination: refers to any association n or among two or more items.

The combination can be two or more separate items, such as two compositions or two collections. It can be a mixture thereof, such as a single mixture of the two or more items, or any variation thereof.

Composition: refers to any mixture. It can be a solution, a suspension, liquid, , a paste, aqueous, non—aqueous or any ation thereof.

Compression tablet: Tablet formed by the exertion of pressure to a volume of tablet matrix in a die.

Compression coated tablet: A tablet formed by the on of a coating by compression to a compressed core containing the pharmaceutical active.

Derivative: a chemical substance derived from r substance by modification or substitution.

Daily dosage: the total amount of a drug taken in a 24 hour period whether taken as a single dose or taken in multiple doses.

Diazoxide: 7-chloromethyl-2—H-l,2,4-benzothiadiazine l,l dioxide with the empirical formula C8H7ClNZOZS and a molecular weight of 230.7.

Encapsulation system: a structural feature that contains drug within such as a pharmaceutical capsule. A gel into which drug is orated also is considered an encapsulation .

] Equivalent amount: an amount of a derivative of a drug that in assays or upon stration to a subject produces an equal effect to a defined amount of the non- derivatized drug.

Fatty acid synthase: The central enzyme of a multienzyme complex that catalyses the formation of palmitate from acetylcoenzyme A, malonylcoenzyme A, and NADPH.

Gastric Lipase: An enzyme secreted into the gastrointestinal tract that catalyzes the hydrolysis of dietary triglycerides.

Glidant: An inactive component of a pharmaceutical formulation that prevents caking of the matrix during processing steps.

Growth hormone: also known as somatotropin or opin, is a peptide e that stimulates growth, cell reproduction and ration in humans and other s. It is a type of mitogen which is specific only to certain kinds of cells. Growth hormone is a l9l-amino acid, single-chain polypeptide that is synthesized, , and ed by somatotropic cells within the lateral wings of the anterior pituitary gland. GH is a stress hormone that raises the concentration of glucose and free fatty acids. It also stimulates production of IGF—1.

Hyperinsulemia: Excessively high blood insulin levels, which is differentiated from hyperinsulinism, excessive secretion of insulin by the pancreatic islets.

Hyperinsulinemia may be the result of a variety of conditions, such as obesity and pregnancy.

Hyperinsulinism: Excessive secretion of n by the pancreatic islets.

Hyperlipidemia: A general term for elevated concentrations of any or all of the lipids in the plasma, such as terol, triglycerides and lipoproteins. hagia: Ingestion of a greater than optimal quantity of food.

Ingredient of a pharmaceutical composition: refers to one or more materials used in the manufacture of a pharmaceutical composition. Ingredient can refer to an active ingredient (an agent) or to other materials in the compositions. Ingredients can e water and other solvents, salts, buffers, surfactants, water, non—aqueous solvents, and flavorings.

IGF-l, also called somatomedin C, is a protein that in humans is encoded by the IGFI gene. IGF-l is a hormone similar in molecular structure to insulin. It plays an important role in childhood growth and continues to have anabolic s in adults. IGF—l consists of 70 amino acids in a single chain with three intramolecular disulfide bridges, and has a molecular weight of 7,649 daltons.

Insulin resistance: A ion in which the tissues of the body are diminished in their response to insulin.

Ischemic injury: injury to tissue that results from a low oxygen state usually due to obstruction of the arterial blood supply or inadequate blood flow leading to hypoxia in the tissue.

Ketoacidosis: Acidosis accompanied by the lation of ketone bodies (ketosis) in the body tissue and fluids, as in diabetic acidosis.

Kit: refers to a packaged combination. A packaged ation can optionally include a label or labels, instructions and/or reagents for use with the combination.

Kir: Pore forming subunit of the KATp channel. Also known as the inwardly rectifying subunit of the KATp channel. Typically existing as Kir6.x and infrequently as Kir2.x subspecies.

K ATP channel: An ATP sensitive ium ion l across the cell membrane formed by the association of 4 copies of a ylurea receptor and 4 copies of a pore forming subunit Kir. Agonizing the channel can lead to membrane hyperpolarization.

Lean body mass: Lean Body Mass is a ent of body composition, calculated by subtracting body fat weight from total body weight: total body weight is lean plus fat. In equations: Lean Body Mass equals Body Weight minus Body Fat (LBM = BW — BF) Lean Body Mass plus Body Fat equals Body Weight (LBM + BF = BW) The percentage of total body mass that is lean is usually not quoted — it would typically be 60—90%. Instead, the body fat percentage, which is the complement, is ed, and is typically 10—40%. The Lean body mass (LBM) has been bed as an index superior to total body weight for prescribing proper levels of medications and for assessing metabolic disorders, as body fat is less relevant for metabolism.

Leptin: Product (16 kD) of the ob (obesity) locus. It is found in plasma of mammals and exerts a hormonal action, which reduces food uptake and increases energy expenditure.

Lipogenesis: The generation of new lipids, primarily lglycerides. It is ent on the action of multiple distinct s and transport molecules.

Lipolysis: The breakdown of fat by the coordinated action of multiple enzymes.

Lipoprotein lipase: An enzyme of the hydrolase class that catalyses the reaction of triacyglycerol and water to yield diacylglyerol and a fatty acid anion. The enzyme yses triacylglycerols in chylomicrons, very-low-density lipoproteins, low—density lipoproteins, and diacylglycerols.

Lubricant: An inactive component of a pharmaceutical ation that provides for the flow of als in various processing steps, ularly tableting.

Microparticle: A small particulate formed in the process of developing pharmaceutical formulations that may be coated prior to producing the final dosage from.

Obesity: An increase in body weight beyond the limitation of skeletal and physical requirement, as the result of an ive accumulation of fat in the body. Formally defined as having a body mass index greater than 30 kg/mz.

Obesity Prone: Individuals who because of genetic predisposition or prior history of y are at above average risk of becoming obese.

Obesity related co—morbidities: any disease or condition of animals or humans that are increased incidence in obese or overweight duals. Examples of such conditions include hypertension, prediabetes, type 2 diabetes, osteoarthritis and cardiovascular conditions. cally controlled release: A pharmaceutical dosage form in which the release of the active drug is pally achieved by the hydration of a swellable component of the formulation. 2015/060455 ight: an individual whose weight is above that which is ideal for their height but who fails to meet the criteria for classification as obese. In humans using Body Mass Index (kg/m2) an ight individual has a BMI between 25 and 30.

Oxidation of Fat: A series of reactions involving acyl—coenzyme A nds, whereby these undergo beta oxidation and thioclastic ge, with the formation of acetyl— coenzyme A; the major pathway of fatty acid catabolism in living tissue.

Pharmaceutical composition: refers a composition that contains an agent and one or more other ingredients that is formulated for stration to a subject. An agent refers to an active ingredient of a pharmaceutical composition. Typically active ingredients are active for treatment of a disease or condition. For e, agents that can be included in pharmaceutical compositions include agents for treating obesity or diabetes. The pharmaceutically active agent can be referred to as "a pharmaceutical active." Pharmaceutical effect: refers to an effect observed upon administration of an agent ed for treatment of a e or disorder or for amelioration of the symptoms thereof.

Pharmacodynamic: An effect mediated by drug action.

Pharmacokinetic: Relating to the absorption, distribution, metabolism and elimination of the drug in the body.

Polymorph: A compound that shares the same chemistry but a different l ure.

Pradern-Willi syndrome (PWS): A complex neurobehavioral/metalsolic disorder which is due lo lhe absence of normally active, paternally expressed genes: from the chromosome lSql l~ql3 region. PWS is an imprinted condition with 70—75% oftlie cases due to a de novo deletion in the paternally inherited chromosome 15 l l—ql3 region, 29—39% from maternal uniparental disomy 15 ('Ll'l’D), and the remaining 2- % from either microdeietions or epimutalions oftlie imprinting center (i.e., imprinting s) (Biltel and Butler, Expert Rev Mol Med 7(14): 1-20 (2005); Cassidy and Driseoll, Eur J Hum Genet 3—l3(2009)).

The clinical manifestations of the condition begin in utero with diminished fetal activity (Miller Am J Med Genet A 155A(5): 1-10 (2011)). Low lean body mass and hypotonia are universal in PWS and present throughout life illa Am J Clin Nutr 65(5): 1369—1374 (1997), —lineras Int J Obes 8—1203 (2013)). Mental retardation occurs to varying degrees with the average IQ being 70 (PWSUSA). PWS patients present with a range of behavioral complications including autistic-spectrum-disorder—like behaviors, compulsive behaviors, njurious behaviors, and aggressive, threatening and destructive behaviors. About 80% of PWS patients are growth hormone def1cient (Goldstone, Trends Endocrinol Metab 15: 12-120 (2004); Davies et 31., Front Neuroendocrinol 29:413—427 ); y and Driscoll, 2009, supra). Nearly all PWS patients are hypogonadal, requiring sex hormone supplementation (Goldstone, 2004, supra; Davies et al, 2008, supra; Cassidy and Driscoll, 2009, supra). These patients have hypothalamic insufficiency/dysfunction (Goldstone Am J Clin Nutr 75(3):468—475 (2002)).

The accumulation of excess body fat may begin about age 2 and can continue into adulthood (Miller 2011, supra). The vast majority of body fat in PWS is subcutaneous (Brambilla 1997, supra; Sode-Carlson, Growth hormone and IGF ch 20:179—184 (2010), Bedogni J Endocrinol Invest DOI 10.1007/s40618—015—0266—y (2015)). Obesity is not universal in PWS, unlike the universality of low lean body mass and nia. For example, Sode—Carlson et al. (2010), supra, evaluated 46 adult PWS patients, 25 women and 21 men. The average BMI in these adult PWS patients was 27.2 kg/mz. Thus, on average, these patients were overweight rather than obese, suggesting that more than half are not, in fact, obese by the best . Similarly, Brambilla et al. Nutr Metab Cardiovasc Dis 21(4):269-276 (2011) studied a population of 109 children with PWS. They found that 54% were n_ot classified as obese by the best metric. Thus, both in adults and in children with PWS, y is not only not universal, but may, in fact, occur in less than half of the population. Subcutaneous fat makes up a greater tage of total fat in PWS than it does in obese ls at all ages (Sode—Carlson 2010, supra).

Hyperphagia with the associated problematic food related behaviors begins on average about age 8 (Miller 2011, supra). These patients sense they are starving when they are not. Upon the onset of hyperphagia, PWS ts will eatm food in the line of sight, get up at night to eat, dig through the trash for food, steal food, consume frozen food, pet food, spoiled food and even consume non—food items (Miller 2011, supra). They will become angry or throw tantrums if denied food. At this stage and thereafter throughout life, access to food is strictly limited, with ts and refrigerators being locked. To limit food related anxiety, meal times and meal composition are strictly regimented.

The mortality rate for PWS patients is three times that of the general population at all ages (Cassidy Genet Med 14(1): 10-26 (2012)), with the average age at death being about 29 years (PWSUSA ity database, n=488). In contrast, being obese, but not morbidly obese has little impact on life expectancy (Anon (2011) National Research Council Panel on Understanding Divergent Trends in Longevity in High-Income Countries; Crimmons, EM, Preston, SH, Cohen, B, editors. National Academies Press).

Prader-Willi ts expend less energy and are more sedentary than either the l population, obese controls or patients with similar intellectual disabilities. Butler et al. Am J Med Gent A 143A(5):449-459 (2007)) compared the energy expenditure and total work of a group of 48 PWS patients with a group of 24 obese controls. Compared to the controls, PWS patients had significantly decreased total energy expenditure , g energy expenditure (-16%) and ical work (-35%). After ing for group differences in lean body mass, the difference remained significant for mechanical work.

In a study by van Mil et al., Int J Obes Relat Metab Disord 24(4):429-434 (2000), the s measured basal metabolic rate (BMR), average daily metabolic rate (ADMR), activity induced energy expenditure (AEE), and ADMlUBMR (PAL) in a group of PWS patients and matched controls. ADMR, AEE and PAL were significantly lower (P < 0.01) in the PWS group compared with the control group —28.2%, —5 8.2%, and —14.2%, respectively).

De Lind van Wijngaarden et al., J Clin inol Metab 95(4): 175 8—1766 (2010) evaluated cardiovascular and metabolic risk s in en with PWS. They showed that 63% of infants and 73% of pie—pubertal children with PWS have at least one cardiovascular risk factor, defined as dyslipidemia or hypertension. Thus, the cardiornetabolic risk in PWS is elevated even in younger children.

Preadipocyte: A progenitor cell to adipocytes.

Prediabetic: A condition that precedes diagnosis of type II diabetes. Type II diabetes is a form of diabetes mellitus which is characterized by insulin insensitivity or resistance.

Prodrug: refers to a compound which, when metabolized, yields the desired active compound. Typically, the prodrug is inactive, or less active than the active nd, but may provide ageous ng, administration, or metabolic properties. For example, some prodrugs are esters of the active compound; during metabolysis, the ester group is cleaved to yield the active drug. Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound.

] Prolonged stration (prolonged basis): stration of a pharmaceutically acceptable formulation of a drug for 7 or more days. Typically, prolonged administration is for at least two weeks, preferably at least one month, and even more preferably at least two months (i.e. at least 8 weeks).

Quick dissolving formulation: a pharmaceutical formulation which upon oral administration may release substantially all of the drug active from the formulation within 10 minutes.

Release ation (sustained), (or "sustained release formulation"): A formulation of ceutical product that, upon administration to animals, provides for release of the active pharmaceutical over an extended period of time than provided by formulations of the same ceutical active that result in rapid uptake. Similar terms are ed—release, prolonged—release, and slow—release. In all cases, the preparation, by definition, has a reduced rate of release of active nce.

Release formulation ed), (or "delayed release formulation"): Delayed— release products are modified—release, but are not extended—release. They involve the release of discrete amount(s) of drug some time after drug administration, e.g. enteric—coated products, and exhibit a lag time during which little or no absorption occurs.

Release formulation (controlled), (or "controlled release formulation"): A formulation of ceutical product that may include both delay of release of pharmaceutical active upon administration and control of release in the manner described for sustained release.

Salt: the neutral, basic or acid compound formed by the union of an acid or an acid radical and a base or basic radical.

Smith—Magenis syndrome (SMS; OMIM #182290, *607642): A complex, generally sporadic, genetic disorder caused by nsufficiency of the retinoic acid induced l (RAIl) gene. caused by either a l7pl 1.2 deletion encompassing the retinoic acid—induced l (RAIl) gene or a mutation of RAIl .(see, for example, Burns et al., in Human Molecular cs, 2010, Vol. 19, No. 20, pp. 4026—4042).

Smith—Magenis syndrome is characterized by a clinically recognizable phenotype that es physical, developmental, neurological, and behavioral features. Short stature (<5th percentile) was ed in ~67% of young ts. Short stature resolves over time with most individuals reaching the 10—25th percentile by ood (see, for example, Burns et al. supra). A ty of children with SMS also have significant early—onset obesity (see, for example, European Journal of Human Genetics (2008) 16, 412—421). Obesity in teens and adults is common, typically with broad chests and truncal obesity. RAIl haploinsufflciency represents a single-gene model of y with hyperphagia, abnormal fat distribution and altered hypothalamic gene expression associated with satiety, food intake, behavior and y.

] Hearing loss is variable and is often associated with chronic ear infections.

Ophthalmologic features are present in >60% of SMS patients and include myopia, iris anomalies, strabismus, microcomea, and, rarely, retinal detachment (often resulting from violent behaviors).

Prenatal history of SMS is notable for significantly decreased fetal movement in 50% of pregnancies. Early infancy is complicated by feeding difficulties leading to failure to thrive, marked oral sensory motor dysfunction with poor suckling reflex, gastroesophageal reflux, and hypotonia.

Most SMS individuals have mild-to-moderate mental retardation. IQ decreases as the child ages, ultimately placing the individual in the mild mental retardation range by adulthood. Delayed speech with or t hearing loss occurs in 96% of SMS patients. In addition, delayed fine/gross motor skills, problems with sensory ation, and poor adaptive function are seen. Other neurological es include pes cavus or pes planus, an abnormal ‘festinating’ gait, balance problems, and a decreased sensitivity to pain, which is often ed in association with self-injury in this disorder.

Sleep disturbance has been reported in 75—100% of SMS cases. Infants lly experience hypersomnolence during the first year of life. Sleep disturbances in older children include difficulties falling asleep, diminished REM sleep, d 24-h and night sleep, fragmented and shortened sleep cycles with frequent nocturnal and early-morning awakenings, and excessive daytime sleepiness.

Behavioral issues are one of the unique characteristic features of SMS.

Maladaptive behaviors are a cause of major concern and include frequent outbursts/temper tantrums, attention seeking, aggression, disobedience, distraction, and self—injurious behaviors. Self—injurious behaviors include head banging, skin picking, wrist biting, onychotillomania and polyembolokoilamania. The behavioral phenotype of SMS escalates with age, typically with the onset of puberty. Age, degree of developmental delay, severity of any associated systemic disorder, and degree of sleep disturbance have a strong influence on maladaptive behaviors. Individuals also have a lack of respect for personal space during a conversation and are emotionally volatile.

SMS patients share many characteristics in common with PWS patients. These include: (1) diminished fetal activity; (2) hypotonia; (3) feeding difficulties in early y; (4) short stature: (5) early onset obesity which may include hyperphagia; (6) developmental delays; (7) mental retardation; (8) temper outbursts; (9) sive behavior; (10) self— injurious behavior; (1 l) hypersomnolence in infancy and r sleep disturbances in older children and adults; (12) frequent ear infections; (13) sis; and (14) strabismus. While the underlying genetic basis for these disorders is quite distinct, the tation and natural y of the disease is very similar.

Solid oral dosage form: pharmaceutical formulations designed for oral administration including capsules and tablets.

] Subject: refers to animals, including mammals, such as human beings. ylurea receptor: A component of the KATp l responsible for interaction with sulfonylurea, other K ATP channel nists, diazoxide and other K ATP channel agonists.

Tablet: ceutical dosage form that is produced by forming a volume of a matrix containing ceutical active and excipients into a size and shape suitable for oral administration.

] Thermogenesis: The physiological process of heat production in the body.

Threshold Concentration: The minimum circulating concentration of a drug required to exert a specific metabolic, physiological or itional change in the body of a treated human or animal.

Treatment: means any manner in which the symptoms of a condition, disorder or e or other indication, are ameliorated or otherwise beneficially altered.

Triglyceride: Storage fats of animal and human adipose tissue principally consisting of ol esters of saturated fatty acids.

Type I diabetes: A chronic condition in which the pancreas makes little or no insulin because the beta cells have been destroyed.

Uncoupling protein: A family of proteins that allow oxidation in mitochondria to proceed without the usual concomitant phosphorylation to produce ATP.

Visceral fat: Human e tissues principally found below the subcutaneous fat and muscle layer in the body.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 summarizes the change in hyperphagia score for all subjects who participated in clinical study PC025.

Figure 2 summarizes the percent change in lean body mass for all subjects who participated in clinical study PC025.

Figure 3 summarizes the percent change in body fat mass for all subjects who participated in al study PC025.

Figure 4 summarizes the percent change of the lean body at mass ratio for all ts who participated in clinical study PC025.

DETAILED PTION OF THE INVENTION ] ed herein are pharmaceutical formulations of particular KATp channel s that when administered to subjects achieve novel codynamic, pharmacokinetic, therapeutic, physiological, and metabolic outcomes. Also provided are pharmaceutical formulations, methods of administration and dosing of particular KATp channel openers in combination with growth hormone, that achieve therapeutic , optionally outcomes while reducing the incidence of adverse effects.

In particular, pharmaceutical formulations formulated for oral administration exhibit advantageous properties including: facilitating consistency of absorption, pharmacokinetic and pharmacodynamic responses across d patients, contributing to patient compliance and improving the safety profile of the product, such as by reducing the frequency of serious adverse effects. Method of treatment of metabolic and other diseases of humans and s by administering the formulations are also provided.

Compounds of formulas II and III, formulas IV and V, and formulas VI and VII, such as for example, ide (shown below) can be proton tautomers. Proton tautomers are isomers that differ from each other only in the location of a hydrogen atom and a double bond. The en atom and double bond switch locations n a carbon atom and a heteroatom, such as for example N. Thus, when the nitrogen substituent is hydrogen, the two isomeric chemical structures may be used interchangeably.

N N :1 r = <1 r,NH /N (5% 6% The particular KATp channel openers that can be used in the invention formulations include any of those within ae I to VII. ary such compounds include diazoxide, BPDZ62, BPDZ 73, NN414 and BPDZ 154 (see, for example, Schou, et al., Bioorg. Med. Chem, 13, 141—155 (2005)). Compound BPDZ 154 also is an effective KATp channel activator in patients with hyperinsulinism and in patients with pancreatic insulinoma.

The synthesis of BPDZ compound is ed in Cosgrove, et al., J. Clin. Endocrinol.

Metab, 87, 4860—4868 (2002).

Analogs of diazoxide e 3—isopropylamino—7-methoxy—4H-1,2,4,— benzothiadiazine 1,1—dioxide, which is a selective Kir6.2/SUR1 channel opener (see Dabrowski, et al., Diabetes, 51, 1896—1906 ). 2—alkyl substituted diazoxides are included (see, for e, Ouedraogo, et al., Biol. Chem, 383, 768 (2002)); these channel openers show decreased activity in the inhibition of insulin release and increased activity in vascular smooth muscle tissue. Furthermore, l substituted ides generally do not function as traditional potassium channel tors, but instead show potential as Ca2+ blockers.

Other diazoxide analogs are described in Schou, et al., Bioorg. Med. Chem, 13, 141—155 (2005), and are shown below. 11:1:6,8"0 R1, R2 and R3 are: a) H, CI, NHCH(CH3)2 b) CF3, H, NHCH(CH3)2 C) H, CI, NHCH20H20H(CH3)2 d) H, CI, NH-cyclobutyl Diazoxide analogs having different alkyl substituents at the 3 position of the molecule (identified as R3 shown below) are described in Bertolino, et al., Receptors and Channels, 1, 267—278 (1993).

R6 R3 R7(I 1s’N I, \\ R3, R6 and R7 are: i) nC7H15, H, CI a) H, H, CH3 j) nC3H7, CI, H b) H, H, CI k) nC4H9. Cl. H 0) CH3, CI, H |)nCsH11, Cl. H d) CH2CI, H, CI m) "C7H15’ C" H n) nC3H7, CI, CI e) NH2, H, H 0) "C4H9’ C" C' f) CH CH2 2CI H CI ’ ’ p) nC5H11, CI, CI 9) "C4H9’ "1 C' q) , CI, CI h) nC5H11, H, CI I") H, CI: H KATp channel activity of formulae 1— VII and related compounds can be measured by membrane potential studies as described in Schou, et al., Bioorg. Med. Chem, 13, 141—155 (2005) and Dabrowski, et al., Diabetes, 51, 1896—1906 (2002).

Measurement of the tion of glucose-stimulated insulin release from BTC6 cells is bed in Schou, et al., Bioorg. Med. Chem, 13, 141—155 (2005). The ability of particular KATp channel openers to inhibit release of insulin from incubated rat pancreatic islets can be med as described by Ouedraogo, et al., Biol. Chem, 383, 768 Activation of recombinant KATp channels by KATp channel s can be examined by monitoring copic currents of inside—out ne patches from Xenopus oocytes coexpressing Kir6.2 and either SURl, SURZA or SUR2B. SUR expressing membranes can be prepared by known methods. See, for example, Dabrowski, et al., Diabetes, 51, 1896—1906 (2002).

Binding experiments can be used to determine the y of KATp channel openers to bind SURl, SURZA and SUR2B. See, for example, Schwanstecher, et al., EMBO J., 17, 535 (1998).

Preparation of SUR1 and SURZA chimeras, as described by Babenko et al., allows for comparison of pharmacologic profiles (i.e. sulfonyl sensitivity and responsiveness to diazoxide or other potassium channel openers) of the SURl/Kir6.2 and SUR2A/Kir6.2 potassium channels. See Babenko, et al., J. Biol. Chem, 275(2), 717—720 (2000). The cloning of a sulfonylurea receptor and an inwardly rectifying K+ channel is described by Isomoto, et al., J. Biol. Chem, 271 (40), 24321-24324 (1996); D’hahan, et al., PNAS, 96(21), 12162—12167 (1999).

Differences between the human SURl and human SUR2 genes are described and shown in Aguilar-Bryan, et al., Physiological Review, 78(1), 227—245 (1998).

"Halo" and "halogen" refer to all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), or iodo (I).

"Hydroxyl" and xy" refer to the group -OH.

"Substituted oxy" refers to the group —ORf, where Rf is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or tuted heterocyclyl.

"Substituted thiol" refers to the group —SR, where R is alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, cycloalkyl, tuted cycloalkyl, cyclyl, or substituted heterocyclyl.

"Alkyl" refers to an alkane-derived radical containing from 1 to 10, preferably 1 to 6, carbon atoms. Alkyl includes straight chain alkyl, branched alkyl and cycloalkyl, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like. Straight chain or ed alkyl groups contain from 1-10, preferably 1 to 6, more preferably 1-4, yet more preferably 1- 2, carbon atoms. The alkyl group is attached at any available point to produce a stable compound.

A "substituted alkyl" is an alkyl group independently substituted with l or more, e. g., l, 2, or 3, groups or substituents such as halo, hydroxy, optionally substituted alkoxy, optionally tuted alkylthio, alkylsulf1nyl, alkylsulfonyl, optionally substituted amino, optionally substituted amido, amidino, urea optionally substituted with alkyl, aminosulfonyl optionally N—mono- or N,N—di-substituted with alkyl, alkylsulfonylamino, carboxyl, heterocycle, tuted heterocycle, nitro, cyano, thiol, ylamino or the like attached at any available point to produce a stable compound. In particular, "fluro substituted" refers to substitution by l or more, e. g., l, 2, or 3 fluorine atoms. nally fluro substituted" means that substitution, if present, is fluoro.

"Lower alkyl" refers to an alkyl group having 1-6 carbon atoms.

] A ituted lower alkyl" is a lower alkyl which is substituted with l or more, e. g., l, 2, or 3, groups or substituents as defined above, attached at any available point to produce a stable compound.

"Cycloalkyl" refers to saturated or unsaturated, non-aromatic monocyclic, bicyclic or tricyclic carbon ring systems of 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and the like. "Cycloalkylene" is a divalent cycloalkyl.

"Alkoxy" denotes the group —ORf, where Rf is lower alkyl. ituted alkoxy" denotes the group —ORf, where Rf is substituted lower alkyl.

"Alkylthio" or "thioalkoxy" refers to the group -S-R, where R is lower alkyl.

] "Substituted alkylthio" or "substituted koxy" refers to the group -S-R, where R is substituted lower alkyl.

"Sulfinyl" denotes the group —S(O)—.

] "Sulfonyl" denotes the group —S(O)2—.

"Substituted sulfinyl" denotes the group —S(O)—R, where R is lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted hetereocyclylalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, aralkyl or substituted aralkyl.

"Substituted sulfonyl" denotes the group -S(O)2—R, where R is lower alkyl, substituted lower alkyl, cycloalkyl, substituted lkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted ocyclylalkyl, aryl, tuted aryl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, l or tuted aralkyl.

"Sulfonylamino" denotes the group )2— where R is hydrogen or lower alkyl.

"Substituted sulfonylamino" denotes the group —NRaS(O)2—Rb, where Ra is hydrogen or lower alkyl and Rb is lower alkyl, substituted lower alkyl, cycloalkyl, tuted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, aralkyl or substituted aralkyl.

"Amino" or "amine" s the group —NH2. A "divalent amine" denotes the group —NH—. A ituted divalent amine" denotes the group —NR— wherein R is lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl, sulfonyl or substituted sulfonyl.

"Substituted amino" or ituted amine" denotes the group —NRiRj, wherein Ri and Rj are ndently hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl, sulfonyl, substituted sulfonyl, or cycloalkyl provided, however, that at least one of Ri and Rj is not hydrogen. RiRj in ation with the nitrogen may form an optionally substituted heterocyclic or heteroaryl ring. sulfinyl" denotes the group -S(O)Rp, wherein Rp is optionally substituted alkyl.

"Alkylsulfonyl" denotes the group -S(O)2Rp, wherein Rp is optionally substituted alkyl.

"Alkylsulfonylamino" denotes the group -NRqS(O)2Rp, wherein Rp is optionally substituted alkyl, and Rq is en or lower alkyl.

Pharmaceutical formulations containing KATp channel openers include the free base of the drug or a salt of the drug. Such salts may have one or more of the following characteristics: (1) stablity in solution during synthesis and formulation, (2) stability in a solid state, (3) compatibility with excipients used in the manufacture of tablet ations, (4) quantitatively yield the KATp channel opener upon exposure to simulated or actual c and duodenal conditions, (5) release KATp channel opener from sufficiently small particles that are readily dissolved and absorbed, (6) provide, when incorporated into a pharmaceutical formulation, for absorption of greater than 80% of the administered dose, (7) present no elevated toxicological risk as compared to the free base of the KATp channel opener, (8) can be formulated into acceptable pharmaceutical formulations to treat y and other diseases of humans, (9) are acceptable to the FDA as the basis of a drug product, (10) can be recrystallized to improve purity, (l 1) can be used to form co—crystals of two or more salts of the KATp l opener, (12) have limited hygroscopicity to improve stability, or (13) synthetic and crystallization conditions under which the salt is formed can be varied resulting in different crystal structures (polymorphs) can be controlled in the synthesis of the salt.

] KATp channel s can be formulated as pharmaceutically acceptable salts.

Pharmaceutically acceptable salts are non-toxic salts in the s and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from ng its logical effect. Useful alterations in al properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering lower effective doses of the drug.

] Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p—toluene— sulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, esulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.

Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, procaine, e, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, ium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional , such as carboxylic acid or phenol are t. For example, see Remington's Pharmaceutical Sciences, 19th ed., Mack hing Co., Easton, PA, Vol. 2, p. 1457, 1995. Such salts can be prepared using the appropriate corresponding bases.

Pharmaceutically acceptable salts can be prepared, for example, by dissolving the free—base form of a compound in a suitable solvent, such as an aqueous or aqueous—alcohol in solution containing the appropriate acid and then isolated by evaporating the on. In another example, a salt is prepared by reacting the free base and acid in an organic solvent.

The pharmaceutically acceptable salt of the different compounds may be present as a complex. Examples of complexes include rotheophylline complex (analogous to, e. g., ydrinate: diphenhydramine 8-chlorotheophylline (1:1) complex; Dramamine) and various cyclodextrin inclusion xes.

Salts of KATp channel openers, and particular salts of diazoxide, may include, but are not limited to acetate, acetonide, acetyl, e, aspartate, besylate, biacetate, bitartrate, bromide, butoxide, te, calcium, ate, caproate, carbonate, citrate, cyprionate, ate, diacetate, dimegulumine, dinitrate, dipotassium, dipropionate, disodium, disulflde, ate, enanthate, estolate, etabonate, ethylsuccinate, fumarate, furoate, gluceptate,gluconate, hexacetonide, hippurate, hyclate, hydrobromide, hydrochloride, isethionate, lactobionate, malate, maleate, meglumine, methylbromide, methylsulfate, metrizoate, nafate, napsylate, nitrate, oleate, palmitate, pamoate, phenpropionate, phosphate, te, polistirex, polygalacturonate, probutate, propionate, saccharate, sodium glycinate, sodium phosphate, podium succinate, state, succinate, sulfate, sulfonate, sulfosalicylate, tartrate, tebutate, terephalate, terephthalate, tosylate, triflutate, trihydrate, trisilicate, tromethamine, te, xinafolate, or the like.

Formulations provided herein exhibit some or all the following characteristics: (1) they are stable at ambient temperatures for a minimum of one year; (2) they provide for ease of oral administration; (3) they facilitate patient compliance with dosing; (4) upon administration, they consistently facilitate high levels of absorption of the pharmaceutical active; (5) upon once or twice daily oral administration they allow release of the KATp channel opener over a sustained time frame such that the circulating concentration of the KATp channel opener or its metabolically active metabolites does not fall below a therapeutically effective concentration; (6) they achieve these results independent of the pH of the gastrointestinal tract of treated duals, and (7) they delay release until gastric transit is complete or nearly te.

Formulations designed for oral administration can be provided, for example, as capsules or tablets. e or tablet formulations include a number of distinguishing components. One is a component to improve absorption of the KATp channel opener.

Another sustains release of the drug over more than 2 hours. A third delays substantial release of the drug until gastric transit is completed.

] The formulations disclosed herein exhibit improved solubility and absorption of the KATp channel opener compared to previous ations of these drugs. These advantageous properties are achieved by any one or more of the following approaches: (1) reducing le size of the formulation by comminution, spray drying, or other micronising techniques, (2) using a pharmaceutical salt of the KATp channel opener, (3) using an ion exchange resin in the formulation, (4) using inclusion xes, for example using a extrin, (5) compaction of the KATp channel opener with a solubilizing agent including low viscosity hypromellose, low ity metylcellulose or similarly functioning excipient and ations thereof, (6) associating the KATp channel opener with a salt prior to formulation, (7) using a solid dispersion of the KATp channel opener, (8) using a self emulsifying system, (9) adding one or more tants to the formulation, (10) using nanoparticles in the formulation, or (1 l) combinations of these approaches. Preferably, when the KATp channel opener is a salt of diazoxide, the salt is not a sodium salt.

Release of KATp channel opener over a sustained period of time (2—24 hours) is achieved by the use of one or more approaches including, but not limited to: (l) the use of pH sensitive polymeric coatings, (2) the use of a hydrogel, (3) the use of a film coating that controls the rate of diffusion of the drug from a coated matrix, (4) the use of an le matrix that controls rate of drug release, (5) the use of polymer coated pellets, granules, or microparticles which can be further encapsulated or compressed into a tablet, (6) the use of an osmotic pump system, or (7) the use of a ssion coated , or (8) combinations of these approaches.

Delay of release of KATp channel openers from the formulation until c transit is te is ed in the formulations provided herein by any of several mechanisms. A pH sensitive polymer or ymer is used which when applied around the drug matrix functions as an effective barrier to release of active at pH 3.0 or lower and is unstable at pH .5 and above. This provides for control of release of the active compound in the stomach but rapidly allows release once the dosage form has passed into the small intestine. An alternative to a pH sensitive polymer or co-polymer is a polymer or co-polymer that is non- aqueous—soluble. The extent of resistance to release in the gastric environment can be lled by coating with a blend of the non—aqueous—soluble and a aqueous e polymer. In this approach neither of the blended polymers or co—polymers are pH sensitive.

One example of a pH sensitive co-polymer is the it methacrylic co-polymers, including Eudragit L100, 8100 or L100—55 solids, L30 D—55 or FS 30D dispersions, or the L12,5 or 812,5 organic ons.

Polymers that delay release can be d to a tablet either by spray coating (as a thin film) or by compression coating. If a capsule is used, then the polymer(s) may be applied over the surface of the capsule or applied to microparticles of the drug, which may then be encapsulated such as in a capsule or gel. If the capsule is coated, then it will resist disintegration until after gastric transit. If microparticles are coated, then the capsule may disintegrate in the stomach but little to no drug will be released until after the free microparticles complete gastric transit. Finally, an osmotic pump system that uses e.g., a swellable hydrogel can be used to delay drug e in the stomach. The ble hydrogel takes up moisture after administration. Swelling of the gel results in displacement of the drug from the system for absorption. The timing and rate of e of the drug depend on the gel used, and the rate at which moisture reaches the gel, which can be controlled by the size of the opening in the system through which fluid enters. See Drug ry Technologies online article Dong et al. "L—OROS® SOFTCAPTM for Controlled Release of Non—Aqueous Liquid Formulations." ] Accordingly, delay of release of KATp channel openers from the invention formulations until after gastric transit is complete is achieved in the formulations provided herein by any of several mechanisms, including, but not limited to: (a) a pH sensitive polymer or co-polymer applied as a compression coating on a tablet; (b) a pH sensitive polymer or co-polymer applied as a thin film on a tablet; (c) a pH sensitive polymer or copolymer applied as a thin film to an ulation system; (d) a pH sensitive polymer or co— polymer applied to encapsulated microparticles, (e) a non—aqueous—soluble polymer or co— polymer applied as a compression coating on a tablet; (f) a non—aqueous—soluble polymer or ymer applied as a thin film on a tablet; (g) a non-aqueous soluble polymer applied as a thin film to an encapsulation system; (h) a ueous soluble polymer applied to microparticles; (i) incorporation of the formulation in an osmotic pump system, or (j) use of s controlled by ion exchange resins, or (k) combinations of these ches, wherein the pH sensitive polymeror co-polymer is resistant to degradation under acid conditions.

Formulations are provided that are designed for administration once daily (per 24 hours). These can n between 25 and 500 mg of KATp channel openers. Formulations intended for administration twice daily (per 24 hours) are also provided. These can n between 25 and 250 mg of KATp channel openers.

The formulations provided herein exhibit improved safety of the administered drug product. This improvement in safety occurs by at least two mechanisms. First, delay of release of active drug until c transit is complete can reduce the incidence of a range of gastrointestinal adverse side s including nausea, vomiting, dyspepsia, abdominal pain, diarrhea and ileus. Second, by sustaining release of the active drug over 2 or more hours to as long as 24 hours, peak drug levels are reduced relative to the peak drug levels observed for the same administered dose using any oral formulation that does not have ned or controlled release. This reduction in peak drug levels can contribute to reductions in adverse s that are partially or completely determined by peak drug levels. These e effects include: fluid retention with the associated reduced rates of excretion of , de and uric acid, edema, hyperglycemia and the associated potential for progression to ketoacidosis, cataracts and non-ketotic hyperosmolar coma, headaches, tachycardia and palpitations.

Also ed herein are controlled release ations of KATp channel openers, which have one feature from each of A-D as shown in Table 1.

Table l: Controlled Release Formulation Characteristics and Properties A. Unit Form: Tablet or Capsule B. /unit: 10—100 mg 100—200 mg 200—300 mg 300—500 mg 500—2000mg C. Dosing Once daily (24 hours) Twice daily (24 hours) D. Release time: 2-4 hrs 4—8 hrs 8—24 hours For example, a controlled release composition can be a tablet containing 25-100 mg of a KATp channel opener, such tablet administered once daily to achieve a controlled release time of 2-4 hours. All of these formulations can further include the feature of substantially ng pharmaceutical active release until after gastric transit is complete.

In addition, any of the above formulations from Table 1 can include at least one e that improves the solubility or absorption of the KATp channel opener.

The controlled release formulations provided herein comprise the active compound (e. g., KATp channel opener, optionally in combination with growth hormone) and a matrix which comprises a gelling agent that swells upon contact with aqueous fluid. The active compound(s) entrapped within the gel is(are) slowly released into the body upon dissolution of the gel. The active compound(s) can be evenly dispersed within the matrix or can be present as pockets of drug in the matrix. For e, the drug can be formulated into small granules which are dispersed within the matrix. In on, the granules of drug also can include a matrix, thus, providing a primary and a ary matrix as described in U.S.

Pat. No. 4,880,830 to Rhodes.

The gelling agent preferably is a polymeric material, which can include, for e, any pharmaceutically acceptable water soluble or water insoluble slow releasing polymer such as xantham gum, gelatin, cellulose ethers, gum , locust bean gum, guar gum, carboxyvinyl polymer, agar, acacia gum, tragacanth, veegum, sodium alginate or alginic acid, polyvinylpyrrolidone, polyvinyl alcohol, or film forming polymers such as methyl cellulose (MC), carboxymethyl cellulose (CMC), hydroxypropyl methylcellulose, hyroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), yethyl cellulose (HEC), ethylcellulose (EC), acrylic resins or es of the above (see e.g., US.

Pat. No. 5,415,871).

The gelling agent of the matrix also can be a heterodisperse gum comprising a heteropolysaccharide component and a lysaccharide component which produces a fast—forming and rigid gel as described in US. Pat. No. 5,399,359. The matrix also can include a crosslinking agent such as monovalent or multivalent metal cations to further add rigidity and decrease dissolution of the matrix, thus further slowing release of drug. The amount of crosslinking agent to add can be determined using methods routine to the ry skilled artisan.

The matrix of the controlled release composition also can include one or more pharmaceutically able excipients ized by those d in the art, i.e. ation excipients. Such excipients include, for example, binders: polyvinylpyrrolidone, gelatin, starch paste, microcrystalline cellulose; diluents (or flllers): starch, sucrose, dextrose, lactose, fructose, xylitol, ol, sodium chloride, dextrins, calcium phosphate, calcium sulphate; and lubricants: stearic acid, magnesium stearate, m te, ol TM and flow aids for example talc or colloidal silicon dioxide.

The matrix of the controlled release composition can further include a hydrophobic material which slows the hydration of the gelling agent without disrupting the hydrophilic nature of the matrix, as bed in US. Pat. No. 5,399,3 59. The hydrophobic polymer can include, for example, alkylcellulose such as ethylcellulose, other hydrophobic cellulosic materials, polymers or co-polymers derived from acrylic or methacrylic acid esters, co-polymers of acrylic and methacrylic acid esters, zein, waxes, shellac, hydrogenated vegetable oils, waxes and waxy substances such as ba wax, spermaceti wax, candellila wax, cocoa butter, cetosteryl alcohol, beeswax, ceresin, in, myristyl alcohol, stearyl alcohol, cetylalcohol and stearic acid. and any other pharmaceutically acceptable hydrophobic material known to those skilled in the art.

The amount of hydrophobic al incorporated into the controlled release composition is that which is effective to slow the hydration of the gelling agent t disrupting the hydrophilic matrix formed upon exposure to an environmental fluid. In certain preferred embodiments, the hydrophobic material is included in the matrix in an amount from about 1 to about 20 t by weight and replaces a corresponding amount of the formulation ent. A solvent for the hobic material may be an aqueous or organic solvent, or mixtures thereof Examples of commercially available alkylcelluloses are Aquacoat ® (aqueous dispersion of ethylcellulose available from FMC) and Surelease ® us dispersion of ethylcellulose available from Colorcon). es of commercially available acrylic polymers suitable for use as the hydrophobic material include Eudragit ® RS and RL (co- rs of acrylic and methacrylic acid esters having a low content (e. g., 1:20 or 1:40) of quaternary um compounds).

] The lled release composition also can be coated to retard access of liquids to the active compound and/or retard release of the active compound through the film- coating. The film-coating can provide characteristics of gastroresistance and enterosolubility by resisting rapid dissolution of the composition in the digestive tract. The film-coating generally represents about 5—15% by weight of the controlled release composition. ably, the core by weight represents about 90% of the composition with the remaining % provided by the coating. Such coating can be a film-coating as is well known in the art and include gels, waxes, fats, emulsifiers, ation of fats and emulsifiers, polymers, starch, and the like.

Polymers and co-polymers are useful as thin film coatings. Solution coatings and dispersion coatings can be used to coat the active compound, either alone or combined with a matrix. The coating is preferably applied to the drug or drug and matrix combination as a solid core of material as is well known in the art.

A solution for coating can include polymers in both organic solvent and s t systems, and typically further including one or more compounds that act as a plasticizer. Polymers useful for coating compositions include, for example, methylcellulose (Methocel ® A; Dow Chemical Co.), ypropylmethylcellulose with a molecular weight between 1,000 and 4,000,000 (Methocel ® E; Dow Chemical Co. or Pharmacoat ®; Shin Etsu), ypropyl cellulose with a molecular weight between 2,000 and 2,000,000, ethyl cellulose, ose acetate, cellulose triacetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate an Kodak), carboxymethylethyl cellulose (Duodcel ®), hydroxypropyl methylcellulose phthalate, ethylcellulose, methylcellulose and, in general, cellulosic derivatives, hacrylic acid-methacrylic acid co-polymer (Type A 1:1 Eudragit L100; Type B 1:2 Eudragit S100; and Type C 1:1 Eudragit L100—55, aqueous dispersion 30% solids, Eudragit L30D), poly(meth)acryl ester: poly(ethyl acrylate, methyl methacrylate 2: 1), Eudragit NE30D s dispersion 30% , inomethacrylate Eudragit E100, poly(trimethylammonioethyl methacrylate chloride)ammoniomethacrylate co- polymer, it RL30D and Eudragit RS30D, carboxyvinyl polymers, polyvinylalcohols, glucans scleroglucans, mannans, and xanthans. s polymeric dispersions e Eudragit L30D and RS/RL30D, and NE30D, Aquacoat brand ethyl cellulose, Surelease brand ethyl cellulose, EC brand N—10F ethyl cellulose, Aquateric brand cellulose acetate ate, Coateric brand Poly(vinyl acetate phthalate), and Aqacoat brand ypropyl methylcellulose acetate succinate. Most of these dispersions are latex, pseudolatex powder or micronized powder mediums.

] A plasticizing agent may be included in the coating to improve the elasticity and the ity of the polymer film and to prevent changes in the polymer permeability over prolonged storage. Such changes may affect the drug release rate. Suitable conventional plasticizing agents e, for example, diethyl phthalate, glycerol triacetate, acetylated monoglycerides, acetyltributylcitrate, acetyltriethyl citrate, castor oil, citric acid esters, dibutyl phthalate, dibutyl sebacate, diethyloxalate, diethyl malate, diethylfumarate, diethylphthalate, diethylsuccinate, diethylmalonate, diethyltartarate, dimethylphthalate, glycerin, glycerol, glyceryl triacetate, glyceryltributyrate, mineral oil and lanolin alcohols, petrolatum and lanolin alcohols, phthalic acid esters, polyethylene glycols, propylene glycol, rape oil, sesame oil, triacetin, tributyl citrate, triethyl e, and triethyl acetyl citrate, or a e of any two or more of the foregoing. Plasticizers which can be used for aqueous coatings include, for example, propylene glycol, polyethylene glycol (PEG 400), triacetin, polysorbate 80, triethyl citrate, and diethyl d-tartrate.

A coating solution comprising a mixture of hydroxypropylmethylcellulose and aqueous ethylcellulose (e.g. Aquacoat brand) as the polymer and dibutyl sebacate as plasticizer can be used for coating microparticles. (Aquacoat is an aqueous polymeric dispersion of ethylcellulose and contains sodium lauryl sulfate and cetyl alcohol). Preferably, the plasticizer represents about 1—2% of the composition.

In addition to the polymers, the coating layer can include an ent to assist in ation of the g solution. Such excipients may e a lubricant or a wetting agent. Suitable lubricants as excipients for the film coating include, for example, talc, calcium te, colloidal silicon dioxide, glycerin, magnesium stearate, mineral oil, polyethylene glycol, and zinc stearate, aluminum stearate or a mixture of any two or more of the foregoing. Suitable g agents include, for example, sodium lauryl sulfate, acacia, konium chloride, cetomacrogol emulsifying wax, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, docusate sodium, sodium stearate, emulsifying wax, glyceryl monostearate, hydroxypropyl cellulose, lanolin alcohols, lecithin, mineral oil, onoethanolamine, poloxamer, polyoxyethylene alkyl , polyoxyethylene castor oil derivatives, polyoxyethylene an fatty acid esters, polyoxyethylene stearates, propylene glycol alginate, sorbitan esters, stearyl alcohol and triethanolamine, or a mixture of any two or more of the ing.

The specified tablet or capsule formulations of Table 1 may include co— formulation with an obesity treating drug (in addition to the KATp channel opener). Obesity treating drugs that may be used include, but are not limited to, sibutramine hydrochloride (5— mg/unit), at (50-360 mg/unit), phentermine hydrochloride or resin complex (15 to 40 mg/unit), zonisamide (100 to 600 mg/unit) topiramate (64 to 400 mg/unit), naltrexone hydrochloride (50 to 600 mg/unit), rimonabant (5 to 20 mg/unit), ADP356 (5 to 25 mg/unit), ATL962 (20 to 400 mg/unit), or AOD9604 (l to 10 mg/unit). These formulations are ably used once daily. For a twice daily dosing, the amount of KATp channel opener is one half the amount included in the once daily formulation and the coformulated obesity treating drug is half of the amount specified. Alternative obesity treating drugs may include: selective serotonin 2c receptor agonists, dopamine nists, cannabinoid—l receptor antagonists, leptin ues, leptin transport and/or leptin receptor promoters, neuropeptide Y and -related peptide antagonists, proopiomelanocortin and e and amine regulated ript promoters, melanocyte-stimulating hormone analogues, melanocortin-4 receptor agonists, and agents that affect insulin metabolism/activity, which include protein- tyrosine phosphatase-1B inhibitors, peroxisome proliferator activated or- receptor antagonists, short-acting bromocriptine (ergoset), somatostatin agonists (octreotide), and adiponectin, gastrointestinal-neural pathway agents, including those that increase cholecystokinin activity, increase glucagon-like peptide-l ty (extendin 4, liraglutide, dipeptidyl peptidase IV inhibitors), and increase protein YY3-36 activity and those that decrease ghrelin activity, as well as amylin analogues, agents that may increase resting metabolic rate ctive" [3-3 stimulators/agonist, uncoupling protein homologues, and thyroid or agonists), n concentrating hormone nists, tanol analogues, amylase inhibitors, growth hormone fragments, synthetic analogues of dehydroepiandrosterone e, antagonists of adipocyte llBhydroxysteroid dehydrogenase type 1 activity, corticotropin ing hormone agonists, tors of fatty acid synthesis, carboxypeptidase inhibitors, indanones/indanols, aminosterols, and other gastrointestinal lipase inhibitors.

The specified tablet or capsule formulations of Table 1 may e co- formulation with a diabetes treating drug (in addition to the KATp channel opener). Diabetes treating drugs that may be used include, but are not limited to se (50 to 300 mg/unit), miglitol (25 to 300 mg/unit), metformin hydrochloride (300 to 2000 mg/unit), repaglinide (l- 16 mg/unit), nateglinide (200 to 400 mg/unit), rosiglitizone (5 to 50 mg/unit), metaglidasen (100 to 400 mg/unit) or any drug that improves insulin sensitivity, or improves glucose utilization and uptake. These formulations are preferably used once daily. For a twice daily dosing, the amount of the the KATp channel opener is half the amount included in the once daily formulation and the co-formulated diabetes treating drug is half of the amount specified.

The specified tablet or capsule formulations of Table 1 may include co— formulation with a terol lowering drug. Cholesterol lowering drugs that may be used e, but are not limited to pravastatin or simvastatin or atorvastatin or fluvastatin or statin or lovastatin (all at 10 to 80 mg/unit). These formulations are preferably used once daily. For a twice daily dosing, the amount of KATp channel opener is preferably 25 to 200 mg/unit and the coformulated terol lowering drug is half of the amount specified.

] The specified tablet or capsule formulations of Table 1 may include co— formulation with a depression treating drug. Depression treating drugs that may be used include, but are not limited to citalopram hydrobromide (10 to 80 mg/unit), escitalopram 2015/060455 hydrobromide (5 to 40 mg/unit), fluvoxamine maleate (25 to 300 mg/unit), paroxetine hydrochloride (12.5 to 75 mg/unit), fluoxetine hydrochloride (30 to 100 mg/unit), setraline hydrochloride (25 to 200 mg/unit), amitriptyline hydrochloride (10 to 200 mg/unit), desipramine hydrochloride (10 to 300 mg/unit), nortriptyline hydrochloride (10 to 150 mg/unit), duloxetine hydrochloride (20 to 210 mg/unit), venlafaxine hloride (37.5 to 150 mg/unit), phenelzine sulfate (10 to 30 t), bupropion hydrochloride (200 to 400 t), or mirtazapine (7.5 to 90 mg/unit). These formulations are preferably used once daily. For a twice daily dosing, the amount of KATp channel opener is preferably half the amount included in the once daily formulation and the coformulated sion treating drug is half of the amount specified.

The specified tablet or capsule formulations of Table 1 may include co— ation with a hypertension treating drug. Hypertension treating drugs that may be used include, but are not limited to enalapril e (2.5 to 40 mg/unit), ril (2.5 to 150 t), lisinopril (10 to 40 mg/unit), benzaepril hydrochloride (10 to 80 mg/unit), quinapril hydrochloride (10 to 80 mg/unit), peridopril erbumine (4 to 8 mg/unit), ramipril (1.25 to 20 mg/unit), trandolapril (1 to 8 mg/unit), fosinopril sodium (10 to 80 t), moexipril hydrochloride (5 to 20 mg/unit), losartan potassium (25 to 200 mg/unit), rtan (75 to 600 mg/unit), valsartan (40 to 600 mg/unit), candesartan cilexetil (4 to 64 mg/unit), olmesartan medoxamil (5 to 80 mg/unit), telmisartan (20 to 160 mg/unit), eprosartan mesylate (75 to 600 mg/unit), atenolol (25 to 200 mg/unit), propranolol hydrochloride (10 to 180 mg/unit), metoprolol tartrate, succinate or fumarate (all at 25 to 400 mg/unit), nadolol (20 to 160 mg/unit), lol hydrochloride (10 to 40 mg/unit), acebutolol hydrochloride (200 to 800 mg/unit), pindolol (5 to 20 t), bisoprolol fumarate (5 to 20 mg/unit), nifedipine (15 to 100 mg/unit), felodipine (2.5 to 20 mg/unit), amlodipine besylate (2.5 to 20 mg/unit), nicardipine (10 to 40 mg/unit), nisoldipine (10 to 80 mg/unit), terazosin hloride (1 to mg/unit), xin mesylate (4 to 16 mg/unit), prazosin hloride (2.5 to 10 mg/unit), or alfuzosin hydrochloride (10 to 20 mg/unit). These formulations are ably used once daily. For a twice daily dosing, the amount of KATp channel opener is preferably half the amount included in the once daily formulation and the coformulated hypertension treating drug is half of the amount specified.

The specified tablet or capsule formulations of Table 1 may include co— formulation with a diuretic to treat edema. Diuretics that may be used include, but are not limited to amiloride hydrochloride (1 to 10 mg/unit), spironolactone (10 to 100 mg/unit), triamterene (25 to 200 mg/unit), bumetanide (0.5 to 4 t), furosemide (10 to 160 mg/unit), ethacrynic acid or ethacrynate sodium (all at 10 to 50 mg/unit), tosemide (5 to 100 mg/unit), chlorthalidone (10 to 200 mg/unit), indapamide (1 to 5 mg/unit), hlorothiazide (10 to 100 mg/unit), chlorothiazide (50 to 500 mg/unit), bendroflumethiazide (5 to 25 mg/unit), hydroflumethiazide (10 to 50 mg/unit), mythyclothiazide (1 to 5 mg/unit), or polythiazide (1 to 10 mg/unit). These formulations are ably used once daily. For a twice daily dosing, the amount of KATp l opener is preferably half the amount ed in the once daily formulation and the coformulated diuretic is half of the amount specified.

The specified tablet or capsule formulations of Table 1 may include co— formulation with a drug to treat inflammation or pain. Drugs for treating inflammation or pain that may be used include, but are not limited to aspirin (100 to 1000 mg/unit), tramadol hydrochloride (25 to 150 mg/unit), gabapentin (100 to 800 mg/unit), acetominophen (100 to 1000 mg/unit), carbamazepine (100 to 400 mg/unit), ibuprofen (100 to 1600 mg/unit), ketoprofen (12 to 200 t), fen sodium (100 to 600 mg/unit), flurbiprofen sodium or profen (both at 50 to 200 mg/unit), or ations of any of these with a steroid or aspirin. These formulations are preferably used once daily. For a twice daily dosing, the amount of KATp channel opener is ably half the amount included in the once daily formulation and the coformulated diuretic is half of the amount specified.

The specified tablet or capsule formulations of Table 1 may include coformulation with a drug to treat obesity associated comorbidities include those specified above for treating diabetes, cholesterol, depression, hypertension and edema, or drugs to treat atherosclerosis, osteoarthritis, disc herniation, degeneration of knees and hips, breast, endometrial, cervical, colon, leukemia and prostate cancers, ipidemia, asthma/reactive airway disease, gallstones, GERD, obstructive sleep apnea, obesity hypoventilation syndrome, recurrent ventral hernias, menstrual irregularity and infertility.

The specified tablet or capsule formulations of Table 1 may include co- formulation with an anti-psychotic drug the combination used to treat the psychotic ion and to treat or prevent weight gain, dyslipidemia or impaired glucose tolerance in the d individual. Drugs for treating s psychotic conditions that may be used include, but are not limited to, lithium or a salt thereof (250 to 2500 mg/unit), carbamazepine or a salt thereof (50 to 1200 t), valproate, valproic acid, or divalproex (125 to 2500 mg/unit), lamotrigine (12.5 to 200 mg/unit), olanzapine (5 to 20 mg/unit), clozapine (12.5 to 450 t), or risperidone (0.25 to 4 mg/unit). These coformulations are preferably intended for once per day administration. For a twice daily dosing, the amount of KATp l opener is preferably half the amount included in the once daily formulation and the coformulated anti-psychotic is half of the amount specified.

The specified tablet or capsule formulations of Table 1 may include co- formulation with a drug to treat or prevent ischemic or reperfusion . Drugs for treating or preventing ischemic or reperfusion injury that may be used include, but are not limited to: low molecular weight heparins (dalteparin, enoxaparin, nadroparin, tinzaparin or danaparoid), ancrd, pentoxifylline, nimodipine, flunarizine, ebselen, tirilazad, clomethiazole, an AMPA t (GYKI 52466, NBQX, YM90K, zonampanel, orMPQX), SYM 2081, selfotel, Cerestat, CP-101,606, dextrophan, dextromethorphan, MK-801, NPS 1502, remacemide, ACEA 1021, GV150526, eliprodil odil, lubeluzole, naloxone, nalfemene citicoline, -l-camitine, pine, resveratrol, a nitrone derivative, clopidogrel, dabigatram, prasugrel, troxoprodil, AGY—94806, or KAI—9803.

Provided are formulations administered once or twice daily to an obese or ight t continuously to result in a circulating concentration of KATp channel opener sufficient to induce weight loss. Weight loss occurs by the preferential loss of body fat. Additional weight loss can occur when the formulation is administered in combination with a reduced calorie diet.

] Provided are formulations of KATp channel openers administered as a single dose to an obese, overweight or obesity—prone subject that result in the inhibition of fasting or glucose stimulated insulin secretion for about 24 hours or for about 18 hours.

Provided are formulations of KATp channel openers administered as a single dose to an obese, overweight or obesity—prone subject that result in the elevation of energy expenditure for about 24 hours or for about 18 hours. ed are formulations of KATp channel openers administered as a single dose to an obese, overweight or obesity—prone subject that result in the elevation of beta oxidation of fat for about 24 hours or for about 18 hours. 2015/060455 Provided are ations of KATp channel openers administered as a single dose to an obese, overweight or obesity—prone hyperphagic subject that result in the inhibition of hyperphagia for about 24 hours or for about 18 hours.

] Provided are formulations administered once or twice daily (per 24 hours) to a subject continuously result in a circulating concentration of KATp channel opener sufficient to induce either ell rest or improved insulin sensitivity or both. Such ell rest and improvements in insulin sensitivity can contribute to ive treatment of type I diabetes, type II diabetes and prediabetes. Such beta—cell rest and improvements in insulin sensitivity can contribute to effective ation of normal glucose tolerance in type II diabetic and prediabetic subjects.

The various pharmaceutical KATp channel opener formulations have a variety of applications, including, but not d to: (1) treatment of obesity; (2) prevention of weight gain in duals who are predisposed to obesity; (3) treatment of hyperinsulemia or hyperinsulinism; (4) treatment of hypoglycemia; (5) treatment of hyperlipidemia, (6) treatment of type II diabetes, (7) preservation of pancreatic function in type I diabetics; (8) treatment of metabolic me (or syndrome X); (9) prevention of the transition from prediabetes to diabetes, (10) tion of the defects in n secretion and insulin ivity contributing to prediabetes and type II diabetes, (1 1) treatment of polycystic ovary syndrome, (12) prevention of ischemic or reperfusion injury, (13) treat weight gain, dyslipidemia, or impairment of e tolerance in subjects treated with antipsychotics drugs, (14) prevent weight gain, dyslipidemia, or impairment of glucose tolerance in subjects treated with antipsychotics drugs and (15) treatment of any disease where hyperlipidemia, hyperinsulemia, hyperinsulinism, hyperlipidemia, hyperphagia or obesity are contributing factors to the severity or progression of the disease, including but not limited to, Prader-Willi Syndrome, Smith—Magenis syndrome, Froelich’s syndrome, Cohen syndrome, Summit Syndrome, Alstrom, Syndrome, Borjesen Syndrome, Bardet-Biedl Syndrome, hyperlipoproteinemia type I, II, III, and IV, and the like.

In one embodiment, a KATp l opener is administered to an overweight or obese individual as a solid oral dosage once per 24 hours, optionally in combination with growth hormone, to induce weight loss. In further ments, the individual (a) is not a type I diabetic, (b) is not a type II diabetic, (c) is not experiencing chronic, recurrent or drug— induced hypoglycemia, (d) does not have metabolic syndrome, or (e) is not experiencing malignant hypertension.

In one embodiment, a KATp channel opener is administered to an overweight or obese individual as a solid oral dosage twice per 24 hours, optionally in combination with growth hormone, to induce weight loss. This ent can be the sole treatment to induce weight loss. In further embodiments, the overweight or obese dual (a) does not have an insulin secreting tumor, (b) is not suffering from Poly Cystic Ovary Syndrome, (c) is not a type I diabetic, (d) is not a type 11 diabetic, (e) does not have metabolic syndrome, (f) is not experiencing chronic recurrent or drug-induced hypoglycemia, (g) has not been treated for schizophrenia with haloperidol, or (h) is not experiencing malignant hypertension. In further embodiments, the overweight or obese adolescent (a) has not been diagnosed as being type I or type II diabetic, (b) is not experiencing chronic, recurrent or drug—induced hypoglycemia, or (c) has not been diagnosed as having metabolic syndrome.

In another embodiment, a KATp channel opener is administered to an overweight or obese individual as a solid oral dosage form three times per 24 hours, ally in combination with growth hormone, to induce weight loss. This treatment can be the sole treatment to induce weight loss. In further embodiments, the overweight or obese individual (a) does not have an insulin-secreting tumor, (b) is not ing from Poly Cystic Ovary Syndrome, (c) is not a type I diabetic, (d) is not a type 11 diabetic, (e) does not have metabolic syndrome, or (f) is not experiencing c, recurrent or drug—induced hypoglycemia.

] In another embodiment, a KATp channel opener is administered to an overweight or obese adolescent as a solid oral dosage form three times per 24 hours, ally in combination with growth hormone, to induce weight loss. This treatment can be the sole ent to induce weight loss. In further embodiments, the ight or obese adolescent is (a) is a type I or type 11 ic, (b) is not experiencing chronic, recurrent or drug—induced hypoglycemia or (c) does not have metabolic syndrome.

In another embodiment, a KATp channel opener is stered as a solid oral dosage form three times per 24 hours, optionally in combination with growth hormone, to induce weight loss to an overweight or obese adult who (a) is not simultaneously receiving glucagon injections, triiodothyroxin or furosemide, (b) is not being treated for schizophrenia with haloperidol, or (c) is not encing malignant hypertension.

In another ment, a KATp channel opener is administered to an overweight or obese individual as a solid oral dosage form four times per 24 hours, optionally in combination with growth hormone, to induce weight loss.

In another embodiment, a KATp channel opener is administered to an overweight or obese individual as a solid oral dosage form administered from one, two, three or four times per 24 hours, optionally in ation with growth hormone, to induce weight loss at a daily dose of 50 to 275 mg. In a further embodiment, the overweight or obese individual individual (a) is not type I diabetic, (b) is not type II diabetic, (c) is not suffering chronic, recurrent or drug—induced hypoglycemia, or (d) does not have metabolic syndrome.

In another embodiment, a KATp channel opener is administered to an overweight or obese dual as a solid oral dosage form administered from one, two, three or four times per 24 hours, optionally in combination with growth e, to induce weight loss at a daily dose of 130 to 275 mg. In a further ment, the overweight or obese individual (a) is not type I diabetic, (b) is not type II diabetic, (c) is not suffering chronic, recurrent or drug—induced hypoglycemia, or (d) does not have metabolic me.

In another embodiment, a KATp channel opener is administered to an overweight or obesity prone individual as a solid oral dosage form one, two, three or four times per 24 hours, ally in combination with growth hormone, to maintain a weight loss, as it is preferable to maintain weight in an obese individual once some weight loss has ed when the alternative is to regain weight. In a further embodiment, the administered daily dose of the KATp channel opener is 50 to 275 mg.

In other embodiments, a KATp channel opener is administered as a solid oral dosage form to an overweight, obese, or obesity prone dual, optionally in combination with growth hormone, to (a) elevate energy expenditure, (b) elevate beta oxidation of fat, or (c) reduce circulating triglyceride concentrations.

In other embodiments, a solid oral dosage of a KATp channel opener is administered on a prolonged basis to an individual in need thereof to induce the loss of 25%, 50%, or 75% of l body fat.

In another embodiment, a solid oral dosage of a KATp channel opener is administered on a prolonged basis to an individual in need thereof, optionally in combination with growth hormone, to induce (a) the preferential loss of body fat or (b) the preferential loss of visceral body fat.

In additional ments, a solid oral dosage of a KATp channel opener is administered on a prolonged basis one, two or three times per 24 hours at daily doses of 50 to 275 mg to an individual, optionally in combination with growth hormone, to (a) induce the loss of 25%, 50% or 75% of initial body fat, (b) induce the preferential loss of body fat, or (c) induce the preferential loss of visceral fat.

In another embodiment, a solid oral dosage of a KATp channel opener is administered to an individual, optionally in combination with growth hormone, to induce the preferential loss of body fat and to induce reduction in circulating triglycerides.

In another embodiment, a solid oral dosage of a KATp channel opener is co— administered with growth hormone.

In yet another embodiment, a solid oral dosage of a KATp channel opener is co- administered with growth hormone and ally one or more of sibutramine, orlistat, rimonabant, an appetite suppressant, an anti-depressant, an anti-epileptic, a diuretic that is not mide, a drug that induces weight loss by a mechanism that is distinct from a KATp channel opener, a drug that s weight loss by a mechanism that is distinct from a KATp channel opener but is not metformin, furosemide or triiodothyroxin, or a drug that lowers blood pressure, to induce weight loss and/or treat obesity associated comorbidities in an overweight, obese, or obesity prone individual. In further embodiments, the ight, obese, or obesity prone individual (a) is a type I diabetic, (b) is not a type 11 diabetic, (c) is not ing from chronic, recurrent or drug—induced hypoglycemia, or (d) does not have metabolic syndrome.

In r embodiment a solid oral dosage of a KATp channel opener is co- administered with growth hormone and optionally one or more of an anti-depressant, a drug that lowers blood pressure, a drug that lowers terol, a drug that raises HDL, an anti— inflammatory that is not a Cox-2 inhibitor, a drug that lowers ating triglycerides, to an ight, obese, or obesity prone individual to induce weight loss and/or treat obesity associated comorbidities. In r embodiments, the overweight, obese, or obesity prone individual (a) is not a type I diabetic, (b) is not a type II ic, (c) is not suffering from chronic, recurrent or drug—induced hypoglycemia, or (d) does not have metabolic syndrome.

In another embodiment, a solid oral dosage of a KATp channel opener is co- administered with growth hormone and optionally one or more of a drug that lowers blood pressure, a drug that lowers cholesterol, a drug that raises HDL, an anti-inflammatory that is not a Cox-2 inhibitor, a drug that lowers circulating triglycerides, to maintain weight and/or treat obesity associated comorbidities in an overweight, obese, or obesity prone individual, as it is preferable to in weight in an obese individual once some weight loss has occurred when the alternative is to regain weight. In further embodiments, the overweight, obese, or obesity prone individual (a) is not a type I diabetic, (b) is not a type II diabetic, (c) is not suffering from chronic, recurrent or drug—induced hypoglycemia, or (d) does not have metabolic syndrome.

In additional embodiments, a tablet formulation of a KATp channel opener is used to ster a therapeutically ive dose of a KATp channel opener to an obese, ight or obesity prone dual in need thereof to treat obesity, to (a) e beta cell rest, (b) treat type I or type II diabetes, or (c) prevent the occurrence of diabetes.

In additional embodiments, a solid oral dosage form or tablet formulation of a KATp channel opener is co-administered with growth hormone and optionally one or more of Phentermine or a derivative thereof to an obese adult or adolescent to induce weight loss and/or treat obesity and obesity—associated co—morbidities. In further ments, a solid oral dosage form or tablet formulation of a KATp l opener is co-administered with Phentermine or a derivative, optionally in combination with growth hormone, thereof to an obese adult or adolescent to treat lic syndrome in a patient in need thereof In further embodiments, a pharmaceutically able formulation of a KATp channel opener at doses of 50 to 275 mg/day is co—administered with growth hormone and optionally one or more of Phentermine or a derivative thereof at daily doses of 15 to 37.5 mg to an overweight or obese individual to induce weight loss, to treat metabolic syndrome, or to induce weight loss and treat obesity—associated co—morbidities. In another embodiment, a tablet ation is co-administered with growth hormone and optionally one or more of Phentermine or a derivative thereof to treat metabolic syndrome in a patient.

In another embodiment, a quick dissolving formulation of a KATp channel opener, optionally in ation with growth hormone, is used to provide a eutically effective dose to a patient in need thereof In further embodiments, a KATp channel opener is administered, optionally in combination with growth hormone, once per 24 hours at doses of 125 mg to 275 mg to an overweight or obese individual who is not type 11 diabetic and is not being treated for nighttime ycemia.

In further embodiments, a KATp channel opener is formulated as a tablet or capsule for oral stration. The tablet or capsule may be mulated with metformin. In another embodiment, a KATp channel opener is formulated as an oral sion, and the oral suspension may be further encapsulated in another embodiment.

In r embodiment, a pharmaceutical salt of a KATp channel opener is formulated as a tablet or capsule for oral administration, or as an oral sion or as an oral solution, or as an oral solution that is encapsulated. If the opener is diazoxide, the salt, is preferably not a sodium salt.

In another embodiment a KATp channel opener is co-formulated with hydrochlorothiazide, chlorothiazide, cyclothiazide, iazide, metyclothiazide, bendroflumethiazide, hydroflumethiazide, trichlormethiazide, or polythiazide in a pharmaceutical formulation le for oral administration.

Upon administration of the formulations provided herein to humans or s, some or all of the following effects are observed: (1) the production of lipoprotein lipase by adipocytes is d; (2) ed lipolysis by adipocytes; (3) expression of fatty acid synthase by adipocytes is reduced; (4) glyceraldehydes phosphate dehydrogenase activity of adipocytes is reduced; (5) little or no new triglycerides are synthesized and stored by adipocytes; (6) enhanced sion of B3 Adrenergic Receptor (B3AR) an improvement in the adrenergic function in adipocytes; (7) reduced glucose stimulated secretion of insulin by pancreatic B—cells; (8) decreased insulinemia; (9) enhanced blood glucose levels; (10) increased expression of Uncoupling Protein 1 in adipocytes; (11) enhanced thermogenesis in white and brown adipose tissue; (12) ion of plasma triglyceride concentration; (13) decrease in circulating leptin concentrations; (14) ulation of insulin receptors; (15) enhanced glucose uptake; (16) reduced adipocyte hyperplasia; (17) reduced yte hypertrophy; (18) reduced rates of conversion of preadipocytes to adipocytes; (19) reduced rates of hyperphagia, (20) increased protection of CNS, cardiac and other tissues from ischemic or reperfusion injury, (21) improved n sensitivity, (22) elevated CSF insulin 2015/060455 concentrations, (23) elevated circulating adiponectin concentrations, (25) reduced circulating triglyceride concentrations, (26) enhancement of beta-cell rest, and/or (27) increase in lean body mass.

Threshold concentrations of the current invention include those circulating trations of KATp channel openers, optionally in combination with growth hormone, resulting from the stration of the drug as an iv. formulation, an immediate release oral formulation, a controlled release formulation, a transdermal formulation, or an intranasal formulation to an overweight or obese individual which results in (l) measurable suppression of g insulin levels, (2) suppression of fasting insulin levels by at least 20% from the baseline measurement in the same individual prior to treatment with a KATp channel openers, (3) ssion of fasting insulin levels by at least 30% from the ne measurement in the same individual prior to treatment with KATp channel openers, (4) suppression of fasting insulin levels by at least 40% from the baseline measurement in the same individual prior to treatment with a KATp channel openers, (5) suppression of fasting insulin levels by at least 50% from the baseline measurement in the same individual prior to treatment with KATp channel openers, (6) suppression of fasting insulin levels by at least 60% from the baseline measurement in the same individual prior to treatment with KATp l openers, (7) suppression of fasting insulin levels by at least 70% from the baseline measurement in the same individual prior to treatment with KATp channel openers, (8) suppression of fasting insulin levels by at least 80% from the baseline measurement in the same individual prior to treatment with KATp channel openers, (9) loss of weight, (10) elevation of g energy iture, or (1 l) elevation of the oxidation of fat or fatty acids.

Threshold effects of the current invention include those ating concentrations of KATp channel openers resulting from the administration of an iv. formulation of the drug, or an immediate release oral ation of the drug, or a controlled release formulation of the drug, or a sustained release ation, or a transdermal formulation, or an intranasal formulation of the drug to an y prone individual which result in (l) the loss of weight, and (2) the maintenance of weight.

Threshold effects of the current invention include those ating concentrations of KATp channel openers resulting from the administration of an iv. formulation of the drug, or an immediate release oral formulation of the drug, or a controlled e formulation of the drug, or a sustained release formulation, or a transdermal formulation, or an intranasal 2015/060455 formulation of the drug to a prediabetic individual which result in prevention of the transition to diabetes.

Threshold effects of the current invention include those ating trations of KATp channel openers resulting from the administration of an iv. formulation of the drug, or an immediate e oral formulation of the drug, or a controlled release formulation of the drug, or a sustained e formulation, or a transdermal formulation, or an intranasal formulation of the drug to a individual with type 1 diabetes which result in beta cell rest.

The mode of action by which weight is maintained or lost resulting from the ged administration of KATp channel s to overweight, obese or obesity prone individuals as provided herein es, but is not limited to one or more of (1) enhanced energy expenditure, (2) enhanced oxidation of fat and fatty acids, (3) the enhancement of lipolysis in adipose , (4) enhanced glucose uptake by tissues, enhanced insulin sensitivity, (5) improved beta adrenergic response, and (6) increase in lean body mass. The mode of action by which weight is maintained or lost resulting from the prolonged administration of KATp channel openers to obese or obesity prone individuals as ed herein may also include the suppression of appetite.

Prolonged administration of pharmaceutical ations of KATp channel openers to overweight or obese humans or animals, optionally in combination with growth hormone, s in substantial and sustained weight loss including some or all of the following effects: (1) preferential loss of body fat; (2) loss of greater than 25% of initial body fat mass; (3) loss of greater than 50% of initial body fat mass; (4) loss of greater than 75% of initial body fat mass; (5) significant increase in resting energy expenditure; (6) increase in the oxidation of fat and fatty acids; (7) ion in blood pressure; (8) production of lipoprotein lipase by adipocytes is reduced; (9) enhanced lipolysis by adipocytes; (10) expression of fatty acid synthase by adipocytes is reduced; (11) glyceraldehydes phosphate dehydrogenase activity of adipocytes is reduced; (12) little or no new triglycerides are synthesized and stored by adipocytes; (13) enhanced expression of B3 Adrenergic Receptor (B3AR) and an ement in the adrenergic function in adipocytes; (14) reduced glucose stimulated secretion of insulin by atic B—cells; (15) decreased insulinemia; (16) enhanced blood glucose levels; (17) increased expression of Uncoupling Protein 1 in adipocytes; (18) enhanced thermogenesis in white and brown adipose tissue; (19) reduction of plasma triglyceride concentration; (20) decrease in circulating leptin concentrations; (21) up-regulation of insulin receptors; (22) enhanced glucose uptake; (23) reduced adipocyte hyperplasia; (24) reduced adipocyte hypertrophy; (25) reduced rates of conversion of preadipocytes to adipocytes; (26) reduced rates of hyperphagia; (27) the sequential loss first of the metabolically most active adipose tissue (visceral), followed by the loss of less metabolically active adipose tissue, (28) elevation of circulating adiponectin concentrations, (29) elevation of ospinal fluid insulin levels, (30) enhanced islet insulin mRNA and insulin content, (3 1) enhanced metabolic efficiency of insulin, or (32) increase in lean body mass.

Prolonged administration of ations of KATp channel openers, optionally in combination with growth hormone, to obesity prone humans or animals, including individuals who have undergone various types of ric y, s in sustained maintenance of weight including some or all of the following effects: (1) increased resting energy expenditure; (2) increase in the oxidation of fat and fatty acids; (3) reduction in blood pressure; (4) production of lipoprotein lipase by adipocytes is reduced; (5) enhanced sis by adipocytes; (6) expression of fatty acid synthase by adipocytes is reduced; (7) glyceraldehyde phosphate dehydrogenase activity of adipocytes is reduced; (8) little or no new triglycerides are synthesized and stored by adipocytes; (9) enhanced expression of B3 Adrenergic or (B3AR) and improvement in the adrenergic function in adipocytes; (10) reduced glucose stimulated secretion of insulin by pancreatic B—cells; (l 1) decreased insulinemia; (l2) ed blood glucose levels; (13) increased expression of Uncoupling Protein 1 in adipocytes; (l4) enhanced thermogenesis in white and brown e tissue; (15) ion of plasma ceride concentration; (16) decreased circulating leptin concentration; (17) up—regulation of insulin receptors; (18) enhanced glucose uptake; (19) reduced adipocyte hyperplasia; (20) reduced adipocyte hypertrophy; (2 1) reduced rates of sion of preadipocytes to adipocytes; and (22) reduced rates of hyperphagia, (23) elevated circulating adiponectin concentration, (24) elevated cerebrospinal fluid insulin levels, (25) enhanced islet insulin mRNA and insulin content, or (26) enhanced metabolic efficiency of insulin. ate or prolonged administration of formulations of KATp l openers, optionally in combination with growth hormone, to prediabetic or type 1 diabetic humans or animals results in the prevention of beta cell failure, improved glycemic l, and tion of the transition from prediabetes to diabetes including some or all of the following effects: (1) increase in resting energy expenditure; (2) increase in the oxidation of fat and fatty acids; (3) reduction in blood pressure; (4) production of otein lipase by adipocytes is reduced; (5) enhanced lipolysis by adipocytes; (6) expression of fatty acid synthase by adipocytes is reduced; (7) glyceraldehyde phosphate dehydrogenase activity of adipocytes is reduced; (8) little or no new triglycerides are synthesized and stored by adipocytes; (9) enhanced expression of B3 Adrenergic Receptor (B3AR) and an improvement in the adrenergic function in ytes; (10) reduced e stimulated secretion of insulin by pancreatic B—cells; (11) decreased insulinemia; (12) enhanced blood glucose levels; (13) increased sion of Uncoupling Protein 1 in adipocytes; (14) ed thermogenesis in white and brown adipose tissue; (15) reduction of plasma triglyceride concentration; (16) decreased circulating leptin concentrations; (17) up-regulation of insulin receptors; (18) enhanced e uptake; (19) reduced adipocyte hyperplasia; (20) reduced adipocyte rophy; (21) reduced rates of conversion of preadipocytes to adipocytes; (22) reduced rates of hyperphagia, (23) elevated circulating adiponectin concentrations, (24) elevated cerebrospinal fluid insulin levels, (25) enhanced islet insulin mRNA and insulin content, or (26) enhanced metabolic efficiency of insulin.

Immediate or prolonged administration of formulations of KATp channel openers, optionally in ation with growth hormone, to humans or animals that are at risk for myocardial infarct, or stroke or undergoing a surgical procedure that restores blood flow to heart or brain results in ed therapeutic es post-surgically, or following the occurrence of myocardial t or stroke by improving the survival of tissue after blood flow is restored, reduced stunning of tissue, and altering the nature of the inflammatory responses. ceutical formulations as provided herein are designed to be used in the treatment of y, hyperlipidemia, hypertension, weight maintenance, type I es, prediabetes, type II diabetes, or any condition where weight loss, reduction in circulating triglycerides or beta cell rest contributes to therapeutic outcomes provide for a range of critical changes in pharmacodynamic and pharmacokinetic responses to administered doses of KATP l openers, optionally in combination with growth hormone, which s include one or more of the following: (1) extending the pharmacodynamic effect of an administered dose to greater than 24 hours as measured by the suppression of insulin secretion, (2) providing for substantial uptake of the active pharmaceutical ingredient in the small intestine, (3) providing for ntial uptake of the active pharmaceutical ingredient in the large intestine, (4) result in lowered Cmax versus t oral suspension or capsule ts for the same administered dose of active pharmaceutical ingredient, (5) provide for circulating concentrations of unbound active pharmaceutical ingredient above old concentrations for 24 or more hours from a single administered dose, and (6) provide for more tent drug absorption by treated individuals as compared to existing capsule ations.

Pharmaceutical co-formulations of the current invention designed to treat a range of conditions in humans and animals e the ation of KATp channel openers with growth hormone and optionally one or more of: (l) a diuretic, (2) a drug that lowers blood pressure, (3) a drug that suppresses appetite, (4) a cannabinoid receptor antagonist, (5) a drug that suppresses that action of gastric lipases, (6) any drug that is used to induce weight loss, (7) a drug that lowers cholesterol, (8) a drug that lowers LDL bound cholesterol, (9) a drug that improves insulin ivity, (10) a drug that improves glucose utilization or uptake, (1 l) a drug that reduces incidence of atherosclerotic plaque, (12) a drug that reduces inflammation, (13) a drug that is antidepressant, (14) a drug that is an anti-epileptic, or (15) a drug that is an anti-psychotic.

Treatment of humans or animals of the current invention using pharmaceutical formulations of KATp channel openers, optionally in combination with growth hormone, result in reduced incidence of adverse side s including but not limited to edema, fluid retention, reduced rates of excretion of sodium, chloride, and uric acid, hyperglycemia, ketoacidosis, nausea, vomiting, dyspepsia, ileus and headaches. These reductions in frequency of adverse side effects are achieved by: (l) initiating dosing of individuals at subtherapeutic doses and in a step wise manner increasing the dose daily until the therapeutic dose is achieved where the number of days over which the step up in dose is effected is 2 to , (2) use of the lowest effective dose to achieve the desired therapeutic effect, (3) use of a pharmaceutical ation that delays release of active until gastric transit is complete, (4) use of a pharmaceutical formulation that delays release of active until gastric transit is complete, (5) use of a pharmaceutical formulation that results in lower ating peak drug levels as compared to an immediate release oral sion or capsule formulation for the same administered dose, and (6) optimizing the timing of administration of dose within the day and relative to meals. ent of patients suffering from Prader-Willi me, Smith—Magenis syndrome, Froelich’s syndrome, Cohen me, Summit Syndrome, Alstrom, Syndrome, Borjesen Syndrome, Bardet-Biedl Syndrome, and hyperlipoproteinemia type I, II, III, and IV with the current invention using pharmaceutical formulations of KATp channel openers, optionally in combination with growth hormone, result in some or all of the following therapeutic outcomes: (1) weight loss, (2) reduced rates of weight gain, (3) inhibition of hyperphagia, (4) reduced incidence of impaired glucose tolerance, prediabetes or es, (5) reduced incidence of congestive heart failure, (6) reduced hypertension, and (7) reduced rates of all cause mortality.

] Treatment of betic subjects with the current invention using pharmaceutical formulations of KATp channel openers, optionally in combination with growth e, result in some or all of the following eutic outcomes: (1) weight loss, (2) ation of normal glucose tolerance, (3) delayed rates of progression to diabetes, (4) reduced ension, and (5) reduced rates of all cause ity.

Treatment of diabetic subjects with the t invention using pharmaceutical formulations of KATp channel openers, optionally in combination with growth hormone, result in some or all of the following therapeutic outcomes: (1) weight loss, (2) restoration of normal glucose tolerance, (3) delayed rates of progression of diabetes, (4) improvements in glucose tolerance, (5) reduced hypertension, and (6) reduced rates of all cause mortality.

Co-administration of drugs with formulations of KATp channel openers in the treatment of diseases of overweight, obese or obesity prone human and animal subjects involves the co-administration of a pharmaceutically acceptable formulation of KATp channel openers with an acceptable formulation of growth hormone and optionally one or more of: (l) Sibutramine, (2) orlistat, (3) bant, (4) a drug that is an appetite suppressant, (5) any drug used to induce weight loss in an obese or overweight individual, (6) a non-thiazide diuretic, (7) a drug that lowers cholesterol, (8) a drug that raises HDL cholesterol, (9) a drug that lowers LDL terol, (10) a drug that lowers blood pressure, (1 l) a drug that is an anti-depressant, (12) a drug that es insulin sensitivity, (13) a drug that improves glucose utilization and uptake (14) a drug that is an anti-epileptic, (15) a drug that is an antiinflammatory , or (16) a drug that lowers circulating triglycerides.

Co-administration of drugs with formulations of KATp channel openers in the treatment or prevention of weight gain, dyslipidemia, or impaired glucose tolerance in subjects treated with antipsychotics drugs e the co-administration of a pharmaceutically acceptable formulation of KATp channel openers with growth hormone and optionally one or more of an acceptable formulation of: lithium, carbamazepine, valproic acid and divalproex, and lamotrigine, antidepressants generally classified as ine oxidase inhibitors including isocarboxazid, zine sulfate and tranylcypromine e, tricyclic antidepressants including doxepin, clomipramine, amitriptyline, line, desipromine, ptyline, desipramine, doxepin, trimipramine, imipramine and protryptyline, tetracyclic antidepressants including mianserin, mirtazapine, maprotiline, oxaprotline, delequamine, levoprotline, triflucarbine, iline, aline, azipramine, aptazapine e and pirlindole, and major tranquilizers and atypical antipsychotics including paloproxidol, perphenazine, thioridazine, idone, clozapine, olanzapine and chlorpromazine.

In one embodiment, a KATp channel opener, optionally in combination with growth hormone, is administered to an overweight or obese individual as an oral suspension, or an immediate release capsule or tablet or a controlled release formulation or a ermal ation or an intranasal ation to reach and maintain the threshold concentration required to measurably reduce g insulin levels for a prolonged period. Preferably the KATp channel opener formulation reduces fasting insulin levels by at least 20%, more preferably by at least 30%, more preferably by at least by 40%, more preferably by at least 50%, more preferably by at least by 60% more preferably by at least by 70%, and more preferably by at least 80%. Fasting insulin levels are commonly measured using the glucose tolerance test (OGTT). After an overnight fast, a patient ingests a known amount of glucose.

Initial glucose levels are determined by measuring pre—test glucose levels in blood and urine.

Blood insulin levels are measured by a blood is draw every hour after the glucose is consumed for up to three hours. In a fasting glucose assay individuals with plasma glucose values greater than 200 mg/dl at 2 hours post—glucose load indicate an impaired glucose nce.

In r embodiment, a KATp channel opener, optionally in combination with growth e, is administered to an overweight or obese individual as an oral suspension, or an immediate release capsule or tablet or a controlled release formulation or a transdermal formulation or an intranasal formulation to reach and maintain the threshold concentration required to induce weight loss for a prolonged period.

] In another embodiment, a KATp l opener, optionally in ation with growth e, is administered to an overweight or obese individual as an oral suspension, or an immediate release capsule or tablet or a controlled release formulation or a transdermal formulation or an intranasal formulation to reach and maintain the threshold concentration required to elevate resting energy expenditure for a prolonged period.

In another embodiment, a KATp l opener, optionally in ation with growth hormone, is administered to an overweight or obese individual as an oral suspension, or an immediate release capsule or tablet or a controlled release formulation or a transdermal formulation or an intranasal formulation to reach and maintain the threshold tration required to elevate fat and fatty acid oxidation for a prolonged period.

In another embodiment, a KATp channel , optionally in combination with growth hormone, is administered to an obesity prone individual as an oral suspension, or an immediate release e or tablet or a controlled release formulation or a transdermal formulation or an intranasal formulation to reach and maintain the threshold tration required to induce weight loss for a prolonged .

In another ment, a KATp channel opener, optionally in combination with growth hormone, is administered to an y prone individual as an oral suspension, or an immediate release capsule or tablet or a controlled release formulation or a transdermal formulation or an intranasal formulation to reach and maintain the threshold concentration required to maintain weight for a prolonged period.

In r embodiment, a KATp channel opener, optionally in combination with growth hormone, is administered to an overweight or obese individual as an oral suspension, or an immediate release capsule or tablet or a controlled e formulation or a transdermal formulation or an intranasal formulation to reach and maintain a drug concentration above the threshold concentration required to induce weight loss for a prolonged period.

In another embodiment, a KATp channel opener, optionally in combination with growth hormone, is administered to an overweight or obese individual as an oral suspension, or an immediate release capsule or tablet or a lled release formulation or a transdermal formulation or an intranasal formulation for a prolonged period of time to reduce body fat by more than 25%, more preferably by at least 50%, and more preferably by at least 75%.

In another embodiment, a KATp channel , optionally in combination with growth hormone, is administered to an ight or obese individual as an oral suspension, or an immediate release capsule or tablet or a controlled release formulation or a transdermal formulation or an intranasal formulation for a prolonged period of time to preferentially reduce visceral fat deposits.

In r embodiment, a KATp channel opener, ally in combination with growth e, is administered to an overweight or obese dual as an oral suspension, or an immediate release capsule or tablet or a lled release formulation or a transdermal formulation or an intranasal formulation for a prolonged period of time to reduce visceral fat depots and other fat ts.

In another embodiment, a KATp channel opener, optionally in combination with growth hormone, is administered to a normoinsulemic overweight or obese individual as an oral suspension, or an immediate release capsule or tablet or a controlled e formulation or a transdermal formulation or an intranasal formulation to reach and maintain a drug concentration above the threshold concentration required to induce weight loss for a ged period.

In another embodiment, a KATp channel opener, optionally in combination with growth hormone, is administered to a prediabetic individual as an oral suspension, or an immediate release e or tablet or a controlled release formulation or a transdermal formulation or an intranasal ation to reach and maintain a drug concentration above the threshold concentration required to prevent the transition to es for a prolonged period.

In another embodiment, a KATp channel opener, optionally in combination with growth hormone, is administered to a type 1 diabetic individual as an oral suspension, or an immediate e capsule or tablet or a controlled release formulation or a transdermal formulation or an intranasal formulation to reach and in a drug tration above the threshold concentration required to induce beta cell rest for a prolonged period.

In another embodiment, a single dose of a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, is administered to an individual in need thereof that s in circulating concentration of active drug sufficient to sh the secretion of n for 24 or more hours.

] In another embodiment, a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, is administered over a prolonged basis to an dual in need thereof no more than once per 24 hours that results in circulating concentration of active drug sufficient to diminish the secretion of n on a continuous basis.

In another embodiment, a single dose of a pharmaceutically acceptable formulation of a KATp l opener, ally in combination with growth hormone, is administered to an individual in need thereof that results in ating concentration of active drug sufficient to elevate non-esterified fatty acids in circulation for 24 or more hours.

In another embodiment, a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, is stered over a prolonged basis to an individual in need thereof no more than once per 24 hours that results in circulating concentration of active drug sufficient to elevate non-esterif1ed fatty acids in ation on a continuous basis.

In another embodiment, a single dose of a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, is administered to an individual in need thereof that results in circulating concentration of active drug sufficient to treat hypoglycemia in circulation for 24 or more hours.

In another embodiment, a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, is administered over a prolonged basis to an dual in need thereof no more than once per 24 hours that results in circulating concentration of active drug sufficient to treat hypoglycemia on a continuous basis.

In another embodiment, a ceutically acceptable formulation of a KATp channel opener, optionally in combination with growth e, is administered over a prolonged basis to an individual in need thereof no more than once per 24 hours that results in circulating concentration of active drug sufficient to induce weight loss on a continuous basis.

] In another embodiment, a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, is administered over a prolonged basis to an individual in need thereof no more than once per 24 hours that results in ating concentration of active drug sufficient to in weight on a continuous basis, as it is preferable to maintain weight in an obese individual once some weight loss has occurred when the alternative is to regain .

] In another embodiment, a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, is administered over a prolonged basis to an individual in need thereof no more than once per 24 hours that results in circulating concentration of active drug sufficient to reduce circulating triglyceride levels on a continuous basis.

In another embodiment, a single dose of a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, is stered to an individual in need thereof that s in circulating concentration of active drug sufficient to reduce or prevent ischemic or reperfusion injury in circulation for 24 or more hours.

In another embodiment, a pharmaceutically able formulation of a KATp channel , optionally in combination with growth e, is administered over a prolonged basis to an individual in need thereof no more than once per 24 hours that results in circulating concentration of active drug sufficient reduce or prevent ischemic or reperfusion injury on a continuous basis.

] In another embodiment, the adverse effects of frequent treatment with a KATp channel , optionally in ation with growth hormone, is reduced using a pharmaceutically able formulation of diazoxide or its derivatives that is administered to an individual in need thereof on a daily basis in which the first dose is known to be subtherapeutic and daily dose is subsequently increased stepwise until the therapeutic dose is reached.

In another embodiment, the adverse effects of frequent treatment with a KATp channel opener, optionally in combination with growth hormone, is reduced using a pharmaceutically acceptable formulation of a KATp channel opener that is administered to an 2015/060455 individual in need thereof on a daily basis in which the active ingredient is not released from the formulation until gastric transit is complete.

In another embodiment, the e effects of frequent treatment with a KATp channel opener, ally in combination with growth hormone, is reduced using a pharmaceutically acceptable formulation of a KATp channel opener that is administered to an individual in need thereof on a daily basis in which the active ingredient is not released from the formulation until gastric transit is te.

] In another embodiment, the adverse effects of frequent treatment with a KATp l opener, optionally in combination with growth hormone, is reduced using a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, that is stered to an individual in need thereof on a daily basis in which the maximum circulating concentration of active ingredient is lower than what would be realized by the administration of the same dose using an oral suspension or capsule formulation.

In another embodiment, the adverse effects of frequent treatment with a KATp channel opener, optionally in combination with growth hormone, is reduced using a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, that is administered to an individual in need thereof on a daily basis in which the first dose is known to be subtherapeutic and daily dose is subsequently increased stepwise until the eutic dose is reached, the active ingredient is not released from the formulation until gastric transit is complete and in which the maximum circulating concentration of active ingredient is lower than what would be realized by the administration of the same dose using an oral suspension or capsule formulation.

In another embodiment, the adverse s of nt treatment with a KATp channel opener, optionally in ation with growth hormone, is reduced using a pharmaceutically acceptable formulation of a KATp channel opener, ally in combination with growth e, that is administered to an overweight or obese individual in need thereof on a daily basis in which the first dose is known to be subtherapeutic and daily dose is subsequently sed stepwise until the therapeutic dose is reached, the active ingredient is not released from the formulation until gastric transit is complete, in which the maximum circulating concentration of active ingredient is lower than what would be realized by the administration of the same dose using an oral suspension or e formulation, and in which the maximum dose is less than 2.5 mg/kg/day.

In another embodiment, the adverse effects of nt treatment with a KATp channel , optionally in combination with growth hormone, is reduced using a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, that is administered to an overweight or obese individual in need thereof on a daily basis in which the first dose is known to be rapeutic and daily dose is subsequently increased stepwise until the therapeutic dose is reached, the active ient is not released from the formulation until gastric transit is complete, in which the maximum circulating concentration of active ingredient is lower than what would be realized by the administration of the same dose using an oral suspension or capsule formulation, and in which the maximum dose is less than 1.75 mg/kg/day.

In another embodiment, the treatment of an overweight or obese individual is optimized for weight loss by administration of a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth e, once per 24 hours in which the release of the active ingredient from the formulation has been modified to provide near zero order release for at least 12 hours.

] In another embodiment, the ent of an overweight or obese dual is optimized for weight loss by administration of a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, once per 24 hours in which the release of the active ingredient from the formulation has been modified to provide near zero order release for at least 18 hours.

In another embodiment, the treatment of an overweight or obese dual is optimized for weight loss by administration of a pharmaceutically acceptable formulation of a KATp channel , optionally in combination with growth hormone, once per 24 hours in which the release of the active ingredient from the formulation has been modified to provide a rising drug tration in circulation for at least 12 hours.

In another embodiment, the treatment of an overweight or obese individual is optimized for weight loss by administration of a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, once per 24 hours in which the release of the active ingredient from the formulation has been modified to provide a rising drug tration in circulation for at least 18 hours.

In another embodiment, the treatment of an overweight or obese individual is optimized for weight loss by administration of a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, once per 24 hours in which the release of the active ingredient from the formulation has been modified to match the pattern of basal n secretion.

In another embodiment, the frequency of adverse effects upon treatment with a KATp channel opener is reduced using a pharmaceutically acceptable ation of a KATp l opener, optionally in combination with growth hormone, that is administered to an y prone individual in need thereof on a daily basis in which the first dose is known to be subtherapeutic and daily dose is subsequently increased stepwise until the therapeutic dose is reached, the active ingredient is not released from the formulation until gastric transit is te, in which the maximum circulating concentration of active ingredient is lower than what would be ed by the administration of the same dose using an oral suspension or capsule formulation, and in which the maximum dose is less than 2.5 mg/kg/day.

In another embodiment, the frequency of adverse effects upon treatment with a KATp channel opener, optionally in ation with growth hormone, is reduced using a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, that is administered to an y prone individual in need thereof on a daily basis in which the first dose is known to be subtherapeutic and daily dose is subsequently increased stepwise until the therapeutic dose is reached, the active ingredient is not released from the formulation until gastric transit is complete, in which the maximum ating concentration of active ient is lower than what would be realized by the administration of the same dose using an oral suspension or capsule ation, and in which the maximum dose is less than 1.75 mg/kg/day.

In another embodiment, the treatment of an obesity prone individual is optimized for weight maintenance by administration of a pharmaceutically acceptable formulation of a KATp channel , optionally in combination with growth hormone, once per 24 hours in which the release of the active ingredient from the formulation has been modified to provide near zero order release for at least 12 hours.

In r embodiment, the treatment of an obesity prone individual is zed for weight maintenance by administration of a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, once per 24 hours in which the release of the active ingredient from the formulation has been modified to provide near zero order release for at least 18 hours.

In another embodiment, the treatment of an obesity prone individual is optimized for weight maintenance by administration of a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, once per 24 hours in which the e of the active ingredient from the formulation has been modified to provide a rising drug concentration in ation for at least 12 hours.

In another embodiment, the treatment of an obesity prone individual is optimized for weight nance by stration of a ceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, once per 24 hours in which the release of the active ingredient from the formulation has been modified to provide a rising drug concentration in circulation for at least 18 hours.

In another embodiment, the treatment of an obesity prone dual is optimized for weight maintenance by administration of a ceutically acceptable formulation of a KATp channel opener, optionally in ation with growth hormone, once per 24 hours in which the release of the active ient from the formulation has been modified to match the pattern of basal insulin secretion.

In another embodiment, a pharmaceutically acceptable formulation of a KATp channel opener, optionally in ation with growth hormone, is co-administered with sibutramine to an overweight or obese individual to induce weight loss.

In another embodiment, a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, is inistered with orlistat to an overweight or obese individual to induce weight loss.

In another ment, a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, is co-administered with rimonabant to an overweight or obese individual to induce weight loss.

In another embodiment, a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, is co-administered with an appetite suppressant to an overweight or obese individual to induce weight loss.

In another ment, a pharmaceutically acceptable formulation of a KATp channel opener, ally in combination with growth hormone, is co-administered with an anti—depressant to an overweight or obese individual to induce weight loss.

In another embodiment, a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, is co-administered with anti-epileptic to an overweight or obese individual to induce weight loss.

In another embodiment, a ceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, is co-administered with a iazide diuretic to an overweight or obese individual to induce weight loss.

In r embodiment, a pharmaceutically acceptable formulation of a KATp l opener, optionally in combination with growth hormone, is co-administered with a drug that induces weight loss by a mechanism that is distinct from diazoxide to an overweight or obese individual to induce weight loss.

In another embodiment, a pharmaceutically acceptable formulation of a KATp channel opener, optionally in ation with growth hormone, is co-administered with a drug that lowers blood re to an overweight, obesity prone or obese individual to induce weight loss and treat obesity associated comorbidities.

In another embodiment, a pharmaceutically able ation of a KATp channel opener, optionally in combination with growth hormone, is co-administered with a drug that lowers cholesterol to an overweight, y prone or obese individual to induce weight loss and treat y associated comorbidities.

In another embodiment, a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, is co-administered with a drug that raises HDL associated cholesterol to an overweight, y prone or obese individual to induce weight loss and treat obesity associated comorbidities.

In r embodiment, a pharmaceutically acceptable formulation of a KATp channel opener, optionally in combination with growth hormone, is co-administered with a drug that improves insulin sensitivity to an overweight, obesity prone or obese individual to induce weight loss and treat obesity associated comorbidities.

In another embodiment, a pharmaceutically able formulation of a KATp channel opener, optionally in combination with growth hormone, is co-administered with an anti—inflammatory to an overweight, obesity prone or obese dual to induce weight loss and treat obesity associated comorbidities.

In another embodiment, a pharmaceutically acceptable formulation of a KATp l opener, optionally in combination with growth hormone, is co-administered with a drug that lowers circulating triglycerides to an overweight, obesity prone or obese individual to induce weight loss and treat obesity associated idities.

In another ment, KATp l openers, optionally in combination with growth hormone, are co-formulated with sibutramine in a pharmaceutically acceptable formulation that is administered to an overweight, obesity prone or obese individual to induce weight loss and treat obesity—associated co—morbidities.

In another embodiment, KATp channel s, optionally in combination with growth hormone, are co-formulated with orlistat or other active that suppresses the action of c lipases in a ceutically acceptable formulation that is administered to an ight, obesity prone or obese individual to induce weight loss and treat obesity— associated co—morbidities.

In another embodiment, KATp channel openers, optionally in combination with growth hormone, are co-formulated with a non-thiazide diuretic in a pharmaceutically acceptable ation that is administered to an overweight, obesity prone or obese individual to induce weight loss and treat obesity—associated co—morbidities.

In another embodiment, KATp channel openers, optionally in combination with growth hormone, are co-formulated with an appetite ssant in a pharmaceutically acceptable formulation that is stered to an overweight, obesity prone or obese individual to induce weight loss and treat obesity—associated co—morbidities.

In another embodiment, KATp channel openers, optionally in combination with growth hormone, are co-formulated with a cannabinoid receptor antagonist in a pharmaceutically acceptable formulation that is administered to an overweight, obesity prone or obese individual to induce weight loss and treat obesity—associated co—morbidities.

In another embodiment, KATp l openers, optionally in combination with growth hormone, are mulated with an anti-cholesteremic active in a pharmaceutically acceptable formulation that is administered to an overweight, obesity prone or obese individual to induce weight loss and treat y—associated co—morbidities.

In another embodiment, KATp l openers, optionally in ation with growth hormone, are co-formulated with an pertensive active in a pharmaceutically acceptable formulation that is administered to an ight, obesity prone or obese individual to induce weight loss and treat obesity—associated co—morbidities In another embodiment, KATp channel openers, optionally in combination with growth hormone, are co-formulated with an insulin sensitizing active in a pharmaceutically acceptable formulation that is administered to an overweight, obesity prone or obese individual to induce weight loss and treat obesity—associated co—morbidities.

In r embodiment, KATp channel openers, optionally in ation with growth hormone, are co-formulated with an anti-inflammatory active in a ceutically acceptable formulation that is administered to an overweight, obesity prone or obese individual to induce weight loss and treat obesity—associated co—morbidities.

] In another embodiment, KATp channel openers, optionally in combination with growth hormone, are co-formulated with an anti-depressant active in a pharmaceutically acceptable formulation that is administered to an ight, obesity prone or obese individual to induce weight loss and treat obesity—associated co—morbidities.

] In another embodiment, KATp channel openers, optionally in combination with growth hormone, are co-formulated with an anti-epileptic active in a pharmaceutically acceptable formulation that is administered to an overweight, obesity prone or obese individual to induce weight loss and treat obesity—associated co—morbidities.

In r embodiment, KATp channel openers, optionally in combination with growth hormone, are co-formulated with an active that reduces the nce of atherosclerotic plaque in a pharmaceutically acceptable formulation that is administered to an ight, obesity prone or obese individual to induce weight loss and treat obesity— ated co—morbidities.

In another embodiment, KATp channel openers, optionally in combination with growth hormone, are co-formulated with an active that lowers circulating concentrations of triglycerides in a pharmaceutically acceptable formulation that is administered to an overweight, obesity prone or obese individual to induce weight loss and treat obesity— associated co—morbidities.

The reduction of circulating triglycerides in an overweight, obese or obesity prone individual is achieved by the administration of an effective amount of a solid oral dosage form of a KATp channel , optionally in combination with growth hormone.

A solid oral dosage form of KATp channel opener can be used to administer a therapeutically effective dose of KATp channel opener to an overweight or obesity prone individual in need thereof to maintain weight, as it is preferable to maintain weight in an obese dual once some weight loss has occurred when the alternative is to regain weight.

A method of ng loss of greater than 25% of initial body fat in an overweight or obese individual can be achieved by the prolonged administration of a solid oral dosage form of a KATp channel opener, optionally in combination with growth hormone.

] A method of inducing loss of greater than 50% of initial body fat in an overweight or obese dual can be achieved by the ged administration of a solid oral dosage form of a KATp channel opener, optionally in combination with growth hormone.

A method of inducing loss of greater than 75% of initial body fat in an overweight or obese individual can be achieved by the prolonged administration of a solid oral dosage form of a KATp channel opener, optionally in combination with growth hormone.

A method of inducing ential loss of visceral fat in an overweight or obese individual can be achieved by the prolonged administration of a solid oral dosage form of a KATp channel opener, optionally in ation with growth hormone.

A method of inducing loss of body fat and reductions in circulating triglycerides in an overweight or obese individual can be achieved by the prolonged administration of a solid oral dosage form of a KATp channel opener, optionally in combination with growth hormone.

The invention will now be described with reference to the following non-limiting EXAMPLES Example 1: ium ATP channel activator containing formulations l. Compressed Tablet Formulations Diazoxide or a derivative thereof at about 15-30% by weight is mixed with hydroxypropyl methylcellulose at about 55—80% by weight, ethylcellulose at about 3—10 wt/vol % and magnesium stearate (as ant) and talc (as glidant) each at less than 3% by weight. The mixture is used to produce a compressed tablet as described in Reddy et al., AAPS Pharm Sci Tech 4(4): 1—9 (2003). The tablet may be coated with a thin film as sed below for microparticles.

] A tablet containing 100 mg of diazoxide or a derivative thereof will also contain approximately 400 mg of hydroxypropyl cellulose and 10 mg of ethylcellulose. A tablet ning 50 mg of diazoxide or a derivative thereof will also contain approximately 200 mg of ypropyl cellulose and 5 mg of ethylcellulose. A tablet containing 25 mg of diazoxide or a derivative thereof will also contain approximately 100 mg of hydroxypropyl cellulose and 2.5 mg of ethylcellulose. 2. Encapsulated Coated Microparticle Formulation ofDiazoxide Diazoxide or a derivative thereof is encapsulated into microparticles in accordance with well known methods (see, e. g. US. Patent No. 6,022,562). Microparticles of n 100 and 500 microns in diameter containing diazoxide or derivative, alone or in combination with one or more suitable excipient, is formed with the assistance of a granulator and then sieved to te microparticles having the appropriate size. articles are coated with a thin film by spray drying using commercial instrumentation (e. g. Uniglatt Spray Coating Machine). The thin film ses ethylcellulose, cellulose acetate, polyvinylpyrrolidone and/or polyacrylamide. The coating solution for the thin film may include a plasticizer which may be castor oil, l phthalate, triethyl citrate and salicylic acid. The g solution may also include a lubricating agent which may be magnesium stearate, sodium , or polyoxyethylenated sorbitan laurate. The coating solution may further include an excipient such as talc, colloidal silica or of a mixture of the two added at 1.5 to 3% by weight to prevent caking of the film coated particles. 3. Formulation ofa tabletedform ofdiazoxide or a derivativefor controlled Prior to mixing, both the active ingredient and hydroxypropyl methylcellulose (Dow Methocel K4M P) are passed through an ASTM 80 mesh sieve. A mixture is formed from 1 part diazoxide or a derivative thereof to 4 parts hydroxypropyl methylcellulose. After thorough , a sufficient volume of an ethanolic solution of ethylcellulose as a granulating agent is added slowly. The quantity of ethylcellulose per tablet in the final formulation is about 1/ 10th part. The mass resulting from mixing the granulating agent is sieved through 22/44 mesh. Resulting granules are dried at 400 C for 12 hours and thereafter kept in a desiccator for 12 hours at room temperature. Once dry the granules ed on 44 mesh are mixed with 15% fines (granules that passed through 44 mesh). Talc and magnesium stearate are added as glidant and lubricant at 2% of weight each. A colorant is also added. The tablets are ssed using a single punch tablet compression machine. 4. Formulation ofa compression tabletedform ofdiazoxide or a derivative thereofthat providesfor controlled release Diazoxide or a tive thereof at 20—40% weight is mixed with 30% weight ypropyl methylcellulose (Dow Methocel K100LV P) and 20-40% weight impalpable lactose. The mixture is granulated with the addition of water. The granulated e is wet milled and then dried 12 hours at 110° C. The dried mixture is dry milled. Following milling, 25% weight ethylcellulose resin is added (Dow Ethocel 10FP or l 100FP) followed by 0.5% weight magnesium stearate. A colorant is also added. The tablets are compressed using a single punch tablet compression e (Dasbach, et a1, Poster at AAPS Annual Meeting Nov 10— 14 (2002)).

. Formulation ofa compression coated tabletedform ofdiazoxide or a derivative thereofthat providesfor controlled release. 2015/060455 The core tablet is ated by mixing either 100 mg of diazoxide or a derivative thereof with 10 mg of ethylcellulose (Dow Ethocel 10FP), or by mixing 75 mg of diazoxide or a derivative thereof with 25 mg lactose and 10 mg of ethylcellulose (Dow Ethocel 10FP), or by mixing 50 mg of diazoxide or a derivative thereof with 50 mg of lactose and 10 mg of ellulose (Dow Ethocel 10FP). The core s are formed on an automated press with concave tooling. The compression coating consisting of 400 mg of ne oxide (Union e POLYOX WSR Coagulant) is applied and compressed to 3000 psi (Dasbach, et al., Poster at AAPS Annual Meeting Oct 26—30 (2003)). 6. A controlled release dosageform ofdiazoxide or a derivative thereofusing an osmotically controlled release system Diazoxide or a derivative thereof is formulated as an osmotically regulated release system. In l, two components, and expandable hydrogel that drives release of the active drug is assembled with ide or a derivative thereof into a semipermeable bilaminate shell. Upon assembly a hole is drilled in the shell to tate release of active upon hydration of the el.

A dosage form adapted, designed and shaped as an osmotic delivery system is ctured as follows: first, a diazoxide or a derivative thereof composition is provided by blending together into a neous blend of polyethylene oxide, of diazoxide or a derivative thereof and hydroxypropyl methylcellulose. Then, a volume of denatured anhydrous ethanol weighing 70% of the dry mass is added slowly with continuous mixing over 5 minutes. The freshly prepared wet granulation is screened through a 20 mesh screen through a 20 mesh screen, dried at room temperature for 16 hours, and again screened through a 20 mesh screen. Finally, the screened granulation is mixed with 0.5% weight of magnesium stearate for 5 minutes.

A hydrogel composition is prepared as follows: first, 69% weight of polyethylene oxide weight, 25% weight of sodium chloride and 1% weight ferric oxide separately are screened through a 40 mesh screen. Then, all the screened ingredients are mixed with 5% weight of hydroxypropyl methylcellulose to e a homogeneous blend. Next, a volume of denatured anhydrous alcohol equal to 50% of the dry mass is added slowly to the blend with continuous mixing for 5 minutes. The freshly ed wet granulation is passed through a 20 mesh screen, allowed to dry at room temperature for 16 hours, and again passed through a 20 mesh screen. The screened granulation is mixed with 0.5% weight of magnesium te 5 minutes (see US. Patent No. 6,361,795 by Kuczynski, et al.).

The diazoxide or a derivative thereof composition and the hydrogel composition are compressed into nate s. First the diazoxide or a tive thereof ition is added and tamped, then, the hydrogel composition is added and the laminae are pressed under a pressure head of 2 tons into a contacting laminated arrangement.

The bilaminate arrangements are coated with a semipermeable wall (i.e. thin film).

The wall forming composition comprises 93% cellulose acetate having a 39.8% acetyl content, and 7% polyethylene glycol. The wall forming composition is sprayed onto and around the bilaminate.

Finally an exit eway is drilled through the semipermeable wall to connect the diazoxide or a derivative thereof drug lamina with the exterior of the dosage system. The residual solvent is removed by drying at 500 C and 50% humidity. Next, the c s are dried at 500 C to remove excess moisture (see US. Patent No. 6,361,795 by Kuczynski, et al.). 7. Preparation ofa salt oxide A hydrochloride salt of diazoxide is prepared by dissolving one mole of diazoxide (230.7 g) in 500 ml of EtZO. Dry HCl is passed into the solution until the weight of the container is increased by 36g. During the on of the HCl, the HCl salt of diazoxide precipitates as a powder. The salt is filtered off and washed with dry EtZO.

Example 2: In vivo Obesity Testing 1. Obesity animal model Formulations of diazoxide or derivatives prepared as described herein can be tested for efficacy in an animal model of obesity as described by Surwit et al. (Endocrinology 141:3630—3637 (2000)). Briefly, 4—week—old B6 male mice are housed 5/cage in a temperature-controlled (22°C) room with a 12-h light, 12-h dark cycle. The high fat (HF) and low fat (LF) experimental diets contain 58% and 11% of calories from fat, respectively. A group of mice are fed the HF diet for the first 4 weeks of the study; the remaining 15 mice are fed the LF diet. The mice assigned to the LF diet are maintained on this diet throughout the study as a reference group of lean control mice. At week 4, all HF—fed mice a reassigned to 2 groups of mice. The first group remains on the HF diet throughout the study as the obese control group. The remaining 3 groups of mice are fed the HF diet and stered the controlled e formulation of diazoxide or derivative at about 150 mg of active per kg per day as a single dose administered by oral gavage. Animals are weighed weekly, and food consumption is measured per cage twice weekly until the diets are changed at week 4, whereupon body weight and food intake are determined daily. The feed efficiency (grams of body weight gained per Cal consumed) is calculated on a per cage basis. Samples for analysis of insulin, glucose, and leptin are collected on day 24 (4 days before the diets are changed), on day 32 (4 days after the change), and biweekly thereafter. In all cases food is removed 8 h before samples are collected. Glucose is analyzed by the glucose oxidase . Insulin and leptin trations are determined by double antibody RIA. The insulin assay is based on a rat standard, and the leptin assay uses a mouse standard. At the termination of the study, a postprandial plasma sample is collected and analyzed for triglyceride and nonesterified fatty acid concentrations. After 4 weeks of drug treatment, a subset of 10 animals from each group is killed. The epididymal white adipose tissue , retroperitoneal (RP) fat, interscapular brown adipose tissue (IBAT) fat pads, and gastrocnemius muscle are d, trimmed, and weighed. The percent body fat is estimated from the weight of the epididymal fat pad. A subset of five animals from each group is ed ip with 0.5 g/kg glucose. At 30 min postinjection, a plasma sample is collected and analyzed for glucose content by the glucose oxidase method. 2. Treatment ofobesily in humans ations of diazoxide or derivatives prepared as described herein can be tested for efficacy in obese humans. The study is conducted as described by Alemzadeh (Alemzadeh, et al., J Clin Endocr Metal) 83: 191 1—1915 ). Subjects consist of moderate—to—morbidly obese adults with a body mass index (BMI) greater than or equal to 30 kg/mz. Each subject undergoes a complete physical examination at the initial evaluation, body weight being measured on a standard electronic scale and body composition by DEXA.

Before the initiation of the study, all ts are placed on a hypocaloric diet for a n period of 1 week. This is designed to exclude individuals who are unlikely to be compliant and to ensure stable body weight before ent. Up to 50 patients are tested at each dosage of drug. Daily dosage is set at 100, 200, and 300 mg/day. The daily dose is divided into 2 doses for administration. The dose is administered as either one, two or three 50 mg capsules or tablets at each time of administration. Individual patients are dosed daily for up to 12 months. Patients are reviewed weekly, weighed, and asked about any side s or concurrent illnesses.

Twenty—four—hour dietary recall is obtained from each patient. The dietary recalls are analyzed using a standard computer software program. All ts are placed on a hypocaloric diet and encouraged to participate in regular se.

Before commencing, and after completion of the study, the following laboratory tests are obtained: blood pressure fasting plasma glucose, insulin, cholesterol, triglycerides, free fatty acids (FFA), and glycohemoglobin and measures of rate of appearance and oxidation of plasma derived fatty acids. Additionally, e chemistry profiles and fasting plasma glucose are obtained weekly to identify those subjects with evidence of glucose intolerance and/or electrolyte abnormalities. Glucose is analyzed in plasma, by the glucose oxidase method.

Insulin concentration is ined by RIA using a -antibody kit.

Cholesterol and triglycerides concentrations are measured by an enzymatic . Plama FFA is ined by an enzymatic colorimetric method. SI was assessed by an iv glucose tolerance test (IVGTT) using the modified minimal model. After an overnight fast, a glucose bolus (300 mg/kg) was administered iv, followed (20 min later) by a bolus of insulin. Blood for determination of glucose and insulin is obtained from a contra lateral vein at -30, -15, 0, 2, 3, 4, 5, 6, 8, 10, 19, 22, 25, 30, 40, 50, 70, 100, 140, and 180 min. SI and glucose effectiveness (SG) are calculated using n’s modified minimal—model computer program before and after the completion of the study. Acute insulin response to glucose is determined over the first 19 min of the IVGTT, and the e disappearance rate (Kg) is determined from 8—19 min of the IVGTT. Body composition is measured by bioelectrical impedance before and at the tion of the study. Resting energy expenditure (REE) is measured by indirect calorimetry after an overnight l2-h fast, with subjects lying supine for a period of 30 min. Urine is collected over the corresponding 24 h, for ement of total nitrogen and determination of substrate use, before and after the study. 3. Treatment ofobesily in humans by coadministering diazoxide andphentermine Evaluation of a prolonged inistration of solid oral dosage form of diazoxide or a derivative f and phentermine in obese humans with a moderate-to- morbidly and a body mass index (BMI) r than or equal to 30 kg/mz. Each subject undergoes a complete physical examination at the initial evaluation, body weight being measured on a standard electronic scale and body composition by DEXA.

Before the initiation of the study, all subjects are placed on a hypocaloric diet for a lead—in period of 1 week. This is designed to exclude individuals who are unlikely to be compliant and to ensure stable body weight before treatment. Up to 100 patients are tested.

Daily dosage of diazoxide is set at 200 mg. The daily dose is divided into 2 doses for stration. The dose is administered as either a 100 mg capsule or a 100 mg tablet at each time of administration. Individual patients are dosed daily for up to 12 months.

Phentermine is administered as a single daily dose of 15 mg. Patients are ed every two weeks, weighed, and asked about any side effects or concurrent illnesses.

All patients are continued on a hypocaloric diet and encouraged to participate in regular exercise. Before commencing, and after completion of the study, laboratory tests as described in the example above are ed. 4. tion ofdiabetes in prediabetic humans The e describes use of diazoxide in a prediabetic individual to prevent the occurrence of diabetes. Individuals included in the study all have elevated risk of developing diabetes as measured by one of two methods. In a g glucose assay they have plasma glucose values between 100 and 125 mg/dl indicating impaired fasting glucose, or in an oral glucose tolerance test they have plasma glucose values between 140 and 199 mg/dl at 2 hours post—glucose load indicating they have impaired glucose tolerance. Treatment is initiated in any individual meeting either criteria. Treated duals receive either 200 mg diazoxide per day as a 100 mg capsule or tablet twice per day or as two 100 mg capsules or tablets once per day. Placebo treated individuals receive either one placebo capsule or tablet twice per day or two placebo es or tablets once per day.

] Treatment is ued for one year with OGTT or fasting glucose measured monthly.

. A sustained release coformulation 0fdiazoxide HCZ and metformin HCZ use to treat diabetic patients A sustained release co-formulation of diazoxide HCl and metformin HCl is produced by forming a compressed tablet matrix that es 750 mg of metformin HCl and 100 mg of diazoxide HCl. These active ients are blended with sodium carboxymethyl cellulose (about 5% (w/w)), hypromellose (about 25% (w/w), and magnesium stearate (<2% (w/w)). The compressed tablet is further coated with a combination of ethylcellulose (80% (w/w)) and methyl cellulose (20% (w/w)) as a thin film to control rate of hydration and drug release.

] Type 11 diabetic patients are treated with the oral dosage form by administration of two tablets once per day or one tablet every 12 hours. Treatment of the patient with the drug is continued until one of two therapeutic endpoints is reached, or for so long as the patient derives therapeutic benefit from administration. The two therapeutic endpoints that would serve as the basis for the decision to cease treatment include the patient reaching a Body Mass Index (BMI (kg/m2» n 18 and 25 or the re-establishment of normal glucose tolerance in the absence of treatment. The t is monitored ically for (a) glucose tolerance using an oral glucose tolerance test, (b) glycemic control using a standard blood glucose assay, (c) weight gain or loss, (d) progression of diabetic complications, and (e) adverse effects associated with the use of these active ients. 6. Prevention or treatment ofweight gain in a patient treated with olanzapine Pharmacotherapy for schizophrenia is ted for a patient g DSM III-R criteria for schizophrenia. The patient is administered 10 mg of olanzapine (Zyprexa, Lilly) once per day. Adjunctive therapy to the patient for schizophrenia includes 250 mg equivalent of valproic acid as divalproex sodium (Depakote, Abbott Labs). Weight gain, dyslipidemia and impaired glucose tolerance, and metabolic syndrome are high frequency adverse events in ts treated with this combination of anti-psychotics. Weight gain, dyslipidemia, impaired e tolerance or metabolic syndrome are d by the co-administration of a therapeutically effective dose of a KATP l opener. The patient is treated with stration of 200 mg/day of diazoxide as a once daily tablet formulation. Diazoxide administration continues until the weight gain, dyslipidemia, impaired glucose tolerance or metabolic syndrome is corrected or until treatment of the patient with olanzapine is tinued. Dyslipidemia is ed by measuring circulating concentrations of total, HDL, and LDL cholesterol, triglycerides and non—esterified fatty acids. Impaired glucose tolerance is detected through the use of oral or IV glucose tolerance tests. Metabolic syndrome is detected by measuring its key risk factors including central obesity, dyslipidemia, impaired glucose tolerance, and circulating concentrations of key proinflammatory cytokines.

Example 3: Clinical Study in Obese Pediatric and Adult PWS Patients A single-center, open-label, single-arm clinical study (PC025) with a double- blind, placebo-controlled, randomized withdrawal extension has been carried out. Patients were initiated on a DCCR dose of about 1.5 mg/kg um ng dose of 145 mg) and were titrated every 14 days to about 2.4 mg/kg, 3.3 mg/kg, and 4.2 mg/kg (maximum dose of 507.5 mg). These DCCR doses are equivalent to diazoxide doses of 1.03, 1.66, 2.28, and 2.9 mg/kg, respectively. ts were up-titrated at each visit at the discretion of the investigator. Any patient who showed an increase in resting energy expenditure and/or a reduction in hagia from Baseline through Day 27 or Day 55 was designated a Responder and eligible to be randomized in the double—blind phase. Everyone who completed the open—label phase was a Responder and was ized in and ted the double—blind phase. During the double—blind, placebo—controlled, ized withdrawal phase, Responders were randomized in a 1:1 ratio either to continue on active treatment at the dose they were treated with on Day 55 or to the placebo equivalent of that dose for an additional 4 weeks (29 days). sponders continued open label treatment with DCCR at the dose they were treated with on Day 55 for an additional 29 days. A total of 12 patients were enrolled in the study.

Screening 2 .2 Double-Blind, . (28 Days)* " j' Placebo-Controlled, j :1 ‘ Open Label Treatment Period .: Randomized (69 days) f: Withdrawal - Extension (29 days) Day -28 to Baseline Day 13 Day 27 Day 41 Day 55 Day 69 D 55 P1 2.4 3.3 4.2 5.1 .ay dose or acebo 1.5 mg/kg Equlvalent for ders and mg/kg mg/kg m /kg g mg/kg Day 55 dose for Non-Responders *All screenin rocedures must be com leted b Da -14 Inclusion Criteria: Basic requirements 0 Ability to follow verbal and written ctions with or without assistance from caregiver 0 Informed consent form signed by the subject or their legal guardian 0 Completed the screening process between 2 and 4 weeks prior to ne Visit General demographic characteristics 0 Male and female ts 10 to 22 years of age, ive at the time of dosing 0 Genetically med Prader-Willi syndrome 0 BMI exceeds the 95th percentile of the age specific BMI value on the CDC BMI charts or percent body fat 2 35% (The body fat criteria will only be used if there were a measurement made within 12 months of the Screening Visit, and the patient has not lost weight since the measurement. Under all other circumstances, the BMI criteria will apply.) 0 lly healthy as documented by the medical history, physical examination, vital sign assessments, l2-lead electrocardiogram (ECG), and clinical laboratory assessments Specific laboratory test results 0 fasting glucose 5 126 mg/dL o HbAlc S 6.5 % Endpoints and Statistical Analysis Every endpoint is measured in two timeframes: (1) during the open label treatment phase as change (or percent ) from Baseline to Day 69; and (2) during the — blind, placebo-controlled, ized withdrawal phase as change (or percent change) from Day 69 to Day 97.

Endpoints measured during the open label treatment phase were analyzed by paired t—test while those ed during the double-blind, placebo-controlled treatment phase are subjected to ANOVA and paired t—tests.

Efficacy endpoints include: hyperphagia (measured using parent/caregiver responses on a modified Dykens hyperphagia questionnaire — converted to a numeric score between 0 and 34); weight; body fat (measured by DEXA); lean body mass red by DEXA); resting energy expenditure (measured by indirect calorimetry); respiratory quotient (measured by indirect calorimetry); waist circumference; BMI; ghrelin; leptin; triglycerides; total cholesterol; HDL cholesterol; non-HDL cholesterol and LDL terol. Additional ation was collected in a behavioral questionnaire. Tables 2 and 3 summarize the visits at which each efficacy parameter was measured.

Table 2. Time points for assessment of efficacy ters during open-label phase End of Open Visit Visit Visit Visit Parameter Screening Baseline label 6 treatment Hyperphagia + + + Body fat Either at screening or + Lean body mass baseline + Weight + + + REE & RQ + + Waist + + + circumference Ghrelin, leptin + Lipids + Behavioral + + questionnaire Table 3. Time points for assessment of efficacy parameters during double-blind treatment Day 69 End of Open Day 97 End of double Parameter ing Baseline label treatment blind treatment Hyperphagia Body fat Lean body mass Weight + + REE & RQ Waist circumference n, leptin Lipids Behavioral questionnaire + + Patients in the Study Demographic information and relevant medical history for each patient are shown in Table 4. Eleven of the thirteen subjects enrolled in clinical study PC025 completed the open—label phase. All were identified as Responders and were, therefore, randomized in the double—blind phase of the study. All subjects randomized in the double-blind phase of the study completed the phase.

Baseline characteristics of patients enrolled in the study are provided in Table 5.

Table 4. Demographic ation and relevant medical history for patients enrolled in PC025 PWS Age at GH Patient Age sub--type diagnosis Relevant medical history acanthosis nigricans, obesity @ 3 yr, asthma, BN—Ol 'X—k::: undescended testes, fatty liver, sleep apnea cerebral palsy, obesity @ 2 yr, type 2 diabetes, CP-OZ M Deletion gynecomastia, undescended testicle, sleep apnea, asthma @ 1 yr obesity @ 3 yr with hyperphagia, psychiatric illness @ 2 TJ-03 186 Deletion yr, undescended le, osteopenia AC-04 17. Deletion 15 yr scoliosis, short stature, osteopenia MR-05 F Deletion sis, strabismus, amenorrhea morbid obesity @ 6 yr, sleep apnea, scoliosis, SD-06 M Deletion pulmonary hypertension, ended testes, strabismus hyperphagia @ 3 yr, dyslipidemia, opthalmoplegia, AS-08 M Deletion osteopenia, scoliosis SP-09 F 21.6 Deletion 6 Wk No scoliosis, sleep apnea, osteopenia, amenorrhea DD-10 12.5 UPD 16 wk Yes enia SM-ll F 15.4 Deletion 1 wk Yes psychiatric e, enia, scoliosis AD-13 14.7 Deletion 4 wk No y @ 5 yr, osteopenia NT-16 M 19.3 Deletion 2 wk No Scoliosis, strabismus, sleep apnea Table 5. ne characteristics of subjects who were ized in the double-blind phase of clinical study PC025.

Weight Height Percent Hyperphagia REE Sub'ect k cm bod fat BMI score %RDA RQ CP—02 97.2 166 52.0 35.3 18.5 83% 0.86 AC—04 56.9 151 46.8 25.0 7 84% 0.78 MR—05 113.1 145 59.1 53.8 20.5 83% 0.87 SD—06 133.6 145 53.5 51.5 3 102% 0.84 AS—08 60.9 140 53.4 31.0 25.5 86% 1.03 SP—09 106.8 148 60.7 48.8 10.5 84% 0.72 DD—10 70.8 155 49.3 29.5 32 101% 0.97 SM—ll 62.2 140 48.8 31.7 8 97% 0.81 AD—13 103.5 149 56.6 46.6 10 94% 0.85 JG—15 106.3 161 53.7 41.0 16 71% 0.79 NT—16 80.8 177 36.4 25.7 14 100% 0.78 e 90.4 152.5 51.8 38.2 14.95 89.6% 0.85 Dosing One subject, a treated type 2 diabetic, finished the open-label treatment period on a dose of 1.5 mg/kg. Of the remaining 10 subjects, 1 finished the open-label treatment period at a dose of 2.4 mg/kg, and 3 at 3.3 mg/kg. The last 6 subjects enrolled in the study finished the open-label treatment phase at a dose 4.2 mg/kg.

Changes in Body Composition, Waist Circumference and Weight Body fat and lean body mass were ed by DEXA at baseline and again at the end of the open label treatment. Since DEXA was not run on Day 97, the only body composition measurements made on the subjects randomized in the double—blind phase occurred in the period from Baseline to Day 69. The body composition changes are outlined in Table 6. Changes in body composition by DEXA were evaluated separately for ts who were growth hormone treated and growth hormone naive. These results are shown in Table 6.

Weight by DEXA was calculated as the sum of body fat and lean body mass. The ratio of lean body mass to body fat was also calculated.

Table 6.

Changes in body composition by DEXA from Baseline through Day 69 All sub'ects randomized in the double blind ohase ter n Percent Chane .-o—value Bod fat —3.8% _0.011 Lean bod mass j-iH 5.41% _0.001 Lean bod mass/fat mass ratio h—‘ 9.82% _0.002 Wei_o (-P h—‘ Hfi—Afi—AH 0.67% _0.150 Growth hormone treated sub'ects —-—_Parameter n Percent Chane o—value _fl—_Bodfat —3.3 1% 0.056 -—fl—_Lean bodmass 5.50% 0.005 -—fl—_Lean bodmass/fat mass ratio 9.37% 0.014 _fl—_Wei 0.90% 0.189 Growth hormone naive ts Parameter .--—value Bod fat _0.083 Lean bod mass _0.055 Lean bod mass/fat mass ratio 5 _0.043 Weight 5 0.39% 0.301 Treatment with DCCR for 10 weeks had a highly significant and clinically relevant impact on body composition including reductions in body fat, increases in lean body mass and a very marked increase in lean body mass to body fat ratio. Because these ts had almost equal lean body mass and fat mass at Baseline, parallel increases in lean body mass and reductions in body fat result in almost no net change in weight. In general, the s in body ition were of similar magnitude in both growth hormone treated and growth hormone naive subjects.

The changes in body composition were dose dependent. Those subjects who completed the open—label treatment phase at a dose of 4.2 mg/kg experienced a 6.3% decrease in fat mass, a 9.2% increase in lean body mass and a 16.6% increase in the lean body mass to fat mass ratio.

Three subjects in the study showed greater than 10% increase in lean body mass.

Every subject showed an increase in lean body mass/fat mass ratio. More than half of the ts in the study showed a > 10% se in the lean body mass/fat mass ratio, and one showed more than a 20% increase.

Figures 1-4 ize the percent change in body fat, lean body mass and lean body mass/fat mass ratio from Baseline through Day 69.

Weight and waist circumference were measured during the physical exam at each visit. This data can be used to evaluate the change from Baseline through Day 69 for all subjects randomized in the —blind phase, by arm for the period from Day 69 h Day 97 and in those who continued on DCCR in the double-blind phase from Baseline through Day 97. The results from the period ng Baseline through Day 69 are summarized in Table 7. The results from the period covering Day 69 through Day 97 are shown in Table 8. The results for subjects who continued on DCCR in the double blind phase from baseline through Day 97 are shown in Table 9.

Table 7. Changes in weight and waist ference from Baseline through Day 69 Parameter n Change/Percent p—value change Weight 11 0.53% 0.317 Waist circumference 11 —3.5 cm 0.003 Table 8. Changes in weight and waist circumference from Day 69 through Day 97 Change/Percent e Parameter Arm chan - e como arin ; arms Weight DCCR Weight Placebo Waist circumference DCCR Waist circumference Placebo UIUIOUIS Table 9. Changes in weight and waist circumference from Baseline through Day 97 for those treated with DCCR in the double-blind phase ter n Change p—value Throuh Da 97 Wei_ht ai t c1rcumference . 7cm 0.039 Interestingly, the change in weight from Baseline through day 69 by DEXA and by the standard weight measurement produces almost identical results (an increase of 0.67% by DEXA and 0.53% by the standard approach). In contrast to the lack of change in , there was a statistically significant reduction in waist circumference through Day 69 in all subjects randomized in the double—blind phase; through Day 97 for those who continued on DCCR. The comparison of change in waist circumference between arms between Day 69 and Day 97, during which the placebo treated patients showed an incremental increase in waist circumference, while those who continued on DCCR, showed a notable reduction. The reduction in waist circumference is consistent with the explanation that DCCR treated subjects are losing visceral fat. s in Hyperphagia ] The hyperphagia questionnaire was administered at all visits. This data can be used to evaluate the change from Baseline through Day 69 for all subjects randomized in the -blind phase, by arm for the period from Day 69 through Day 97 and in those who ued on DCCR in the double-blind phase from Baseline through Day 97. The s from the period covering Baseline through Day 69 are summarized in Table 10. The results from the period covering Day 69 through Day 97 are shown in Table 11. The results for subjects who continued on DCCR in the double blind phase from baseline h Day 97 are shown in Table 12.

Table 10. Changes in hyperphagia from Baseline through Day 69 Parameter Percent chane 0 —value —31.6% 0003 Table 11. s in hyperphagia from Day 69 through Day 97 p—value comparing Parameter Arm Chane arms m_-— Hyperphagia Placebo Table 12. Changes in hyperphagia from ne through Day 97 for those treated with DCCR in the double-blind phase Parameter Percent change through Day 97 —29.2% There was a statistically significant reduction in hyperphagia in all subjects randomized in the double-blind phase from Baseline through Day 69 and in those who continued on DCCR through the double-blind phase from Baseline through Day 97.

DCCR treated ts at the end of 97 days of treatment showed an improvement in hyperphagia of 29.2% while those that were treated with DCCR for 69 days followed by 28 days of placebo treatment showed only a 13.9% improvement in hyperphagia on Day 97.

Thus, at the end of the double-blind phase, DCCR treated patients showed more than twice the improvement in hyperphagia as did those who were randomized to placebo in the double— blind phase. Once patients discontinue from DCCR ent, given the long half-life of DCCR (28—32 hours) it takes about 7-10 days to completely clear from circulation. Verbatim statements were obtained from parents of subjects in the study suggesting that they had seen their children’s food related behavior deteriorate only in the last couple of weeks of the study, suggesting a longer double—blind phase might have resulted in further separation of the arms.

In general, the magnitude of impact on how upset subjects became when denied food, how easy it was to get them to think about something else if once denied food, and the impact on the frequency of stealing food, digging through the trash for food and bargaining for food were of equivalent or greater magnitude as the overall impact on the hyperphagia score.

DCCR appeared to have lesser impact on how sneaky or quick subjects were with t to food and on how often they got up at night to seek food.

Improvements in hyperphagia were observed in subjects with baseline hyperphagia g from 29 (—45%) to less than 5 (—3 3%) on a 0 to 34 point scale.

About 25% of the subjects ended the open—label phase with very low levels of hyperphagia (2 or 3 on a 0 to 34 scale). These subjects tended to be able to lose more body fat than the average. Two such subjects, both females, one growth hormone treated and one growth e , lost more than 10% of their l body fat mass through 10 weeks.

] Figure 1 shows the change in hyperphagia from Baseline through Day 69. s in Lipids A lipid panel was evaluated at Baseline, and again on Day 69 and Day 97. This data can be used to evaluate the change from Baseline h Day 69 for all ts randomized in the double-blind phase, by arm for the period from Day 69 through Day 97 and in those who continued on DCCR in the double-blind phase from Baseline through Day 97. The results from the period covering Baseline through Day 69 are ized in Table 13. The results for subjects who continued on DCCR in the double blind phase from baseline through Day 97 are shown in Table 14.

Table 13. s in Lipids from ne through Day 69 Total cholesterol _ 0.044 —21.0% 0084 —_0.030 Table 14. Median Percent Change in lipids from Baseline through Day 97 for those treated with DCCR in the double-blind phase Parameter Median Percent change from Baseline through Day 97 Total Cholesterol —1 1.0% Triglycerides —4l .8% HDL—C 25.2% LDL—C —7.9% Non-HDL-C — l 3 .4% Consistent with us studies involving DCCR, treatment of subjects randomized in the double-blind phase with DCCR from Baseline through Day 69 resulted in a number of statistically significant changes in lipids including reductions in total cholesterol, LDL cholesterol and L cholesterol. Even though the impact on triglycerides was of larger magnitude, it did not reach significance because of the smaller n and greater variability in the population. In general, greater reductions in triglycerides were seen in those with significant elevations in triglycerides at Baseline. A similar pattern was observed in those who were treated with DCCR through the end of the double—blind treatment. The decreases in total cholesterol, triglycerides, LDL-C and non-HDL-C were all larger in those who were treated with DCCR longer. s in Leptin and Ghrelin Leptin and ghrelin were measured at Baseline and again on Day 69. The results from Baseline through Day 69 for leptin and ghrelin are provided in Table 15.

Table 15. Leptin and ghrelin changes from Baseline through Day 69 Parameter n Percent chane 0 -value Ghrelin 6 —15.0% 0.052 Further evidence for loss of body fat comes from the analysis of leptin, the results of which are consistent with the DEXA data and the data on waist ference. Although not quite reaching statistical significance, leptin is down more than 20% from Baseline.

While ghrelin may or may not contribute substantially to hyperphagia in PWS, reductions in ghrelin are beneficial in PWS patients.

Behavioral Changes ] A questionnaire, adapted from the PWS natural history study, was used to nt the presence or absence of 23 PWS—associated behaviors at Baseline and again on Day 69. These behaviors generally fell into 4 categories: (1) aggressive, threatening and ctive behaviors; (2) self—injurious behaviors; (3) compulsive ors; and (4) other ors.

The questionnaire was administered at Baseline and again on Day 69. Discontinuation rates for aggressive, threatening, destructive behaviors and for all other behaviors are shown in Table 16.

Table 16. Discontinuation rates for various classes of behavior in clinical study PC025 Discontinuation rate A; ressive, enin destructive —62.5% All other PWS associated behaviors —29.8% The impact on aggressive, threatening and destructive behaviors was ndent of an impact on hyperphagia.

Changes in Resting Energy Expenditure and Respiratory quotient The measurements for resting energy expenditure and respiratory quotient were quite variable from visit to visit. Despite the variability, resting energy expenditure and atory quotient appeared to be unchanged from Baseline through Day 69.

Changes in Insulin Sensitivity ent with DCCR in other clinical studies was associated with improvements in insulin resistance as measured by changes in homeostatic model assessment of insulin ance (HOMA-IR). ements in insulin sensitivity are well documented in the ture on diazoxide. The subjects enrolled in the double—blind phase of this study were quite insulin sensitive at Baseline, which is typical of PWS patients in this age range.

Consistent with prior DCCR clinical studies and the historic diazoxide literature, treatment with DCCR for 10 weeks resulted in an improvement in HOMA-IR from .85 at Baseline to 1.46:1.36 on Day 69. The difference did not reach tical significance (p=0.095).

Example 4: Clinical Studies with Smith—Magenis syndrome Patients In a first e, a Smith-Magenis syndrome patient is treated with an oral suspension of diazoxide. The initial dose is approximately 1 mg/kg administered in divided doses. After the patient has been stably treated with 1 mg/kg for a period of l to 2 weeks, the dose is titrated to about 1.5 mg/kg. After the patient had been stably treated with 1.5 mg/kg for a period of l to 2 weeks, the dose is titrated to about 2.0 mg/kg. This process of increasing the dose by about 0.5 mg/kg at each titration step and the duration of treatment at each step of l to 2 weeks is continued until the patient displays an adequate response to treatment, or a maximal dose of 5 mg/kg is reached. Potential responses to treatment could include loss of body fat, reduction in hypotonia, an se in the lean body mass to fat mass ratio, reduction in hyperphagia, reduction in waist circumference, loss of weight, reduction in temper outbursts and sive or, and ements in cardiovascular risk factors.

Treatment with the drug is chronic and may continue for life.

In a second example, a Smith-Magenis syndrome patient is treated with a controlled release tablet formulation of diazoxide choline. The initial dose is approximately 1.5 mg/kg administered once daily. After the t has been stably treated with 1.5 mg/kg for a period of l to 2 weeks, the dose is titrated to about 2.1 mg/kg. After the patient has been stably treated with 2.1 mg/kg for a period of l to 2 weeks, the dose is titrated to about 2.7 mg/kg. This process of increasing the dose by about 0.6 mg/kg at each titration step and the duration of treatment at each step of l to 2 weeks is continued until the patient displays an adequate response to treatment, or a maximal dose of 5 mg/kg is d. Potential responses to ent could include loss of body fat, ion in hypotonia, an increase in the lean body mass to fat mass ratio, reduction in hyperphagia, reduction in waist circumference, loss of weight, reduction in temper sts and aggressive behavior and improvements in cardiovascular risk factors. Treatment with the drug is chronic and may continue for life.

In a third example, a Smith-Magenis syndrome patient is treated with a lled release tablet formulation of diazoxide choline. The initial dose is approximately 1.5 mg/kg administered once daily. After the patient has been stably treated with 1.5 mg/kg for a period of l to 2 weeks, the dose is titrated to about 2.2 mg/kg. After the patient has been stably treated with 2.2 mg/kg for a period of l to 2 weeks, the dose is titrated to about 2.9 mg/kg.

This process of increasing the dose by about 0.7 mg/kg at each titration step and the duration of treatment at each step of l to 2 weeks is continued until the t displays an adequate response to treatment or a maximal dose of 5 mg/kg is d. In parallel, the t may also be treated with beloranib. Potential responses to treatment could include loss of body fat, reduction in hypotonia, an se in the lean body mass to fat mass ratio, reduction in hyperphagia, reduction in waist circumference, loss of weight, reduction in temper sts and aggressive behavior and improvements in cardiovascular risk factors. Treatment with the drug is chronic and may continue for life.

In a fourth example, a Magenis syndrome patient is treated with a controlled release tablet formulation of diazoxide choline. The initial dose is approximately 1.5 mg/kg administered once daily. After the patient has been stably treated with 1.5 mg/kg for a period of l to 2 weeks, the dose is ed to about 2.3 mg/kg. After the patient has been stably treated with 2.3 mg/kg for a period of l to 2 weeks, the dose is titrated to about 3.0 mg/kg. This process of increasing the dose by about 0.8 mg/kg at each titration step and the duration of ent at each step of l to 2 weeks is continued until the patient displays an adequate response to treatment, or a l dose of 5 mg/kg is reached. In parallel, the patient may also be treated with an unacylated ghrelin analog. Potential responses to treatment could include loss of body fat, reduction in hypotonia, an increase in the lean body mass to fat mass ratio, reductions in hyperphagia, reductions in waist circumference, loss of weight, reductions in temper outbursts and aggressive behavior and improvements in cardiovascular risk factors. Treatment with the drug would be chronic and may continue for life.

In a fifth example, a Smith-Magenis syndrome patient is treated with a controlled release tablet formulation of diazoxide choline. The initial dose is approximately 1.5 mg/kg administered once daily. After the t had been stably treated with 1.5 mg/kg for a period of l to 2 weeks, the dose would be titrated to about 2.4 mg/kg. After the patient has been stably treated with 2.4 mg/kg for a period of l to 2 weeks, the dose is titrated to about 3.3 mg/kg. This process of increasing the dose by about 0.9 mg/kg at each titration step and the duration of treatment at each step of l to 2 weeks is continued until the patient ys an adequate response to treatment, or a maximal dose of 5 mg/kg was reached. In el, the t may also be treated with an MC4 agonist. Potential responses to treatment could include loss of body fat, reduction in hypotonia, an increase in the lean body mass to fat mass ratio, reductions in hyperphagia, reductions in waist ference, loss of , reductions in temper outbursts and aggressive behavior and improvements in cardiovascular risk factors.

Treatment with the drug would be chronic and may continue for life.

In a sixth example, a Smith-Magenis syndrome patient is treated with a controlled release tablet formulation of diazoxide choline. The l dose is approximately 1.5 mg/kg administered once daily. After the t had been stably treated with 1.5 mg/kg for a period of l to 2 weeks, the dose is titrated to about 2.5 mg/kg. After the patient has been stably treated with 2.5 mg/kg for a period of l to 2 weeks, the dose is titrated to about 3.5 mg/kg.

This process of increasing the dose by about 1.0 mg/kg at each ion step and the duration of ent at each step of l to 2 weeks is continued until the patient displays an adequate response to treatment, or a maximal dose of 5 mg/kg was d. In parallel, the patient may also be treated with an MC4 agonist. Potential responses to treatment could include loss of body fat, reduction in hypotonia, an increase in the lean body mass to fat mass ratio, reductions in hyperphagia, reductions in waist circumference, loss of weight, reductions in temper outbursts and aggressive behavior and improvements in cardiovascular risk factors.

Treatment with the drug would be chronic and may continue for life.

] All patents and other references cited in the ication are indicative of the level of skill of those skilled in the art to which the invention pertains, and are incorporated by reference in their entireties, ing any tables and figures, to the same extent as if each reference had been incorporated by reference in its entirety individually.

One skilled in the art would readily appreciate that the present invention is well adapted to obtain the ends and ages mentioned, as well as those inherent therein. The methods, ces, and compositions described herein as presently representative of red embodiments are exemplary and are not intended as limitations on the scope.

Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the ion, are defined by the scope of the claims. tions provided herein are not intended to be limiting from the meaning commonly understood by one of skill in the art unless indicated ise.

The inventions illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms "comprising", ding," containing", etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions f, but it is ized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that gh the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the inventions ed therein herein disclosed may be resorted to by those skilled in the art, and that such cations and variations are considered to be within the scope of this invention.

The invention has been described broadly and generically herein. Each of the narrower species and subgeneric ngs falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

Other embodiments are within the following claims. In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any dual member or up of members of the Markush group.

Claims (13)

1. Use of a KATP channel opener in the manufacture of a pharmaceutical formulation for treatment to reduce one or more aggressive behaviors in a subject having Prader-Willi syndrome (PWS), wherein the treatment comprises the stration to said t for at least 10 weeks of the pharmaceutical formulation comprising an effective amount of a KATP channel opener, wherein stration reduces one or more aggressive behaviors in the subject, and n the KATP channel opener is diazoxide or a pharmaceutically acceptable salt thereof.

2. The use of claim 1, wherein the treatment further comprises the administration of a second therapeutic product, wherein the second product is intended to further reduce the one or more aggressive ors.

3. Use of a KATP channel opener in the manufacture of a pharmaceutical formulation for treatment to increase by at least 2% the lean body mass or the lean body mass/fat ratio in a subject having Prader-Willi Syndrome (PWS), wherein the treatment comprises the administration to said subject for at least 10 weeks of the pharmaceutical formulation sing an effective amount of said KATP channel opener, wherein the KATP channel opener is diazoxide or a pharmaceutically able salt thereof.

4. The use of claim 3, wherein the ent is to increase the lean body mass or the lean body mass/fat ratio of the subject by at least 3%.

5. The use of claim 3, wherein the treatment is to increase the lean body mass or the lean body mass/fat ratio of the subject by at least 4% .

6. The use of claim 3, wherein the treatment is to increase the lean body mass or the lean body mass/fat ratio of the subject by at least 5%.

7. Use of a KATP l opener in the manufacture of a pharmaceutical formulation for treatment to reduce hyperghrelinemia in a t having Prader-Willi me (PWS), wherein the treatment comprises the administration to said subject for at least 10 weeks of the pharmaceutical formulation comprising an effective amount of a KATP channel opener, wherein the KATP channel opener is diazoxide or a pharmaceutically acceptable salt thereof.

8. The use of any one of claims 1-7, wherein the pharmaceutically acceptable salt is diazoxide choline.

9. The use of any one of claims 1-8, wherein said diazoxide or a pharmaceutically acceptable salt f is to be administered orally.

10. The use of any one of claims 1-9, wherein: the pharmaceutical formulation es at least one excipient which affects the rate of release of diazoxide or a pharmaceutically acceptable salt thereof; or the pharmaceutical formulation includes at least one excipient that delays release of diazoxide or a pharmaceutically acceptable salt f.

11. The use of any one of claims 1-10, wherein the formulation further comprises at least one other active ingredient.

12. The use of any one of claims 1-11, wherein said administration is to be carried out for one or more years.

13. The use of any one of claims 1-12, n the pharmaceutical formulation is to be administered twice per day, or once per day.