WO1997046239A1 - Traitement des troubles du metabolisme des lipides et du metabolisme du glucose a l'aide d'antagonistes de la dopamine et de la seratonine - Google Patents

Traitement des troubles du metabolisme des lipides et du metabolisme du glucose a l'aide d'antagonistes de la dopamine et de la seratonine Download PDF

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WO1997046239A1
WO1997046239A1 PCT/US1997/010838 US9710838W WO9746239A1 WO 1997046239 A1 WO1997046239 A1 WO 1997046239A1 US 9710838 W US9710838 W US 9710838W WO 9746239 A1 WO9746239 A1 WO 9746239A1
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agonist
dopamine
dopamine agonist
agonists
comprises administering
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PCT/US1997/010838
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Anthony H. Cincotta
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Ergo Research Corporation
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Priority to JP10500941A priority Critical patent/JP2000513337A/ja
Priority to AU34080/97A priority patent/AU3408097A/en
Priority to CA002257084A priority patent/CA2257084A1/fr
Publication of WO1997046239A1 publication Critical patent/WO1997046239A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • This invention relates to novel, improved methods for modifying or regulating in a subject (vertebrate animal or human) at least one of body weight, body fat, food consumption, lipid metabolism, and glucose metabolism.
  • obesity can be defined as a body weight exceeding 20% of the desirable body weight for individuals of the same sex, height and frame (Salans, L.B. , in Endocrinology & Metabolism. 2d Ed. , McGraw-Hill, New York 1987, pp. 1203-1244; see ajso, R.H. Williams, Textbook of Endocrinology. 1974, pp. 904-916).
  • obesity can be determined by body weight patterns correlated with prolactin profiles given that members of a species that are young, lean, and "healthy" (i.e., free of any disorders, not just metabolic disorders) have daily plasma prolactin level profiles that follow a pattern characteristic of the species.
  • Obesity, or excess fat deposits correlate with and may trigger the onset of various lipid and/or glucose metabolism disorders, e.g. hypertension, Type II diabetes, atherosclerosis, retinopathy etc.
  • body fat stores notably visceral fat stores
  • body fat stores in domestic animals (as well as pets), especially on a long-term or permanent basis would also obviously be of considerable economic benefit to man, particularly since farm animals supply a major portion of man's diet; and the animal fat may end up as de novo fat deposits in man.
  • Hyperlipoproteinemia is a condition in which the concentration of one or more of cholesterol- or triglyceride-carrying lipoproteins (such as chylomicrons, very low density lipoproteins (“VLDL”), and low-density lipoproteins (“LDL”) in plasma exceeds a normal limit. This upper limit is generally defined as the ninety-fifth percentile of a random population. Elevated levels of these substances have also been positively correlated with atherosclerosis and the often resulting cardiac infarction, or "heart attack", which accounts for approximately half of all deaths in the United States. Strong clinical evidence has been presented which correlates a reduction in plasma lipoprotein concentration with a reduced risk of atherosclerosis (Noma, A. , et al.
  • HDL serve to remove free cholesterol from the plasma.
  • a high HDL concentration, as a percentage of total plasma cholesterol, has been associated with a reduced risk of atherosclerosis and heart disease.
  • HDL are known in the lay press as "good" cholesterol. Therefore, therapeutic strategies involve attempts both to reduce plasma LDL and VLDL content (that is, reduce total plasma cholesterol), and to increase the HDL fraction of total plasma cholesterol.
  • Several lines of research indicate that simply increasing HDL is of benefit even in the absence of LDL or VLDL reduction: Bell, G.P. et al. , Atherosclerosis 36:47-54, 1980; Fears, R., Biochem. Pharmacol. 33_:219-228, 1984; Thompson, G., Br. Heart J. 5.1:585-588, 1989; Blackburn, H. N.E.J.M. 202:426-428, 1983.
  • Hyperlipoproteinemias include a low fat diet and elimination of aggravating factors such as sedentary lifestyle. If the hyperlipoproteinemia is secondary (i.e. , incident to e.g. , a deficiency of lipoprotein lipase or LDL receptor, various endocrine pathologies, alcoholism, renal disorders, or hepatic disorders) then control of the underlying disease is also central to treatment. Hyperlipoproteinemias are also treated with drugs, which usually alter the levels of particular components of the total plasma cholesterol, as well as reduce the total plasma lipid component.
  • HMG- CoA 3-hydroxy-3-methylglutaryl coenzyme A reductase
  • This drug specifically reduces total cholesterol and can cause a modest (5-10%) increase in HDL concentrations.
  • benefits from these therapies vary from subject to subject.
  • use of the HMG-CoA enzyme inhibitor is sometimes accompanied by side effects such as liver toxicity, renal myoglobinuria, renal shutdown, and lenticular opacity. The risk of such side effects necessitates close monitoring of the patients (e.g. , liver function is tested monthly).
  • clofibrate Another drug prescribed against hyperlipoproteinemia is clofibrate.
  • the effectiveness of clofibrate also varies from subject to subject and its use is often accompanied by such side effects as nephrotic syndromes, myalgia, nausea, and abdominal pain.
  • NIDDM Type ⁇ Diabetes
  • Type II diabetes also known as non-insulin dependent diabetes mellitus (NIDDM)
  • NIDDM non-insulin dependent diabetes mellitus
  • NIDDM can strike suddenly or lie undiagnosed for years while attacking the blood vessels and nerves.
  • Individuals suffering from NIDDM, as a group, are far more often afflicted with blindness, heart disease, stroke, kidney disease, hearing loss, gangrene, and impotence.
  • One third of all visits to physicians are occasioned by this disease and its complications, and diabetes and its complications are a leading cause of untimely death in the United States and in the Western world.
  • NIDDM adversely affects the way the body uses sugars and starches which, during digestion, are converted into glucose.
  • Insulin a hormone produced by the pancreas, makes the glucose available to the body's cells for energy.
  • adipose (fat), and connective tissues insulin facilitates the entry of glucose into the cells by an action on the cell membranes.
  • the ingested glucose is normally converted in the liver to CO 2 and H 2 O (50%); to glycogen (5 %); and to fat (30-40%), the latter being stored in fat deposits.
  • Fatty acids from the adipose tissues are circulated by the bloodstream, returned to the liver for re-synthesis of triacylglycerol, and metabolized to ketone bodies for utilization by the tissues.
  • the fatty acids are also metabolized by other organs. Fat formation is a major pathway for carbohydrate utilization.
  • insulin-dependent diabetes IDDM or Type I diabetes
  • the pancreas In insulin-dependent diabetes (IDDM or Type I diabetes) the pancreas produces little or no insulin, and insulin must be injected daily for the survival of the diabetic.
  • IDM insulin-dependent diabetes
  • noninsulin-dependent diabetes the pancreas retains the ability to produce insulin and, in fact, may produce higher than normal amounts of insulin, but the amount of insulin is relatively insufficient, or less than fully effective, due to cellular resistance to insulin, i.e. cells do not respond to normal levels of insulin by taking up glucose, amino acids, and fat.
  • Hyperinsulinemia is a higher- than-normal level of insulin in the blood.
  • Insulin resistance can be defined as a state in which a normal amount of insulin produces a subnormal biologic response by cells. In insulin-treated patients with diabetes, insulin resistance is considered to be present whenever the therapeutic dose of insulin exceeds the secretory rate of insulin in normal persons. Insulin resistance is also associated with higher-than-normal levels of insulin i.e. hyperinsulinemia — when normal or elevated levels of blood glucose are present.
  • bromocriptine a sympatholytic dopamine D 2 receptor agonist ("D 2 agonist”) with 2 adrenergic receptor agonist (" ⁇ 2 agonist”) and ⁇ , adrenergic receptor antagonist (“c ⁇ antagonist”) activities, as well as serotonin (“5-hydroxytryptamine” or “5HT”) inhibiting activities, has been demonstrated to reduce body fat stores in a variety of animals including humans without a concomitant reduction in food consumption.
  • Timed administration of bromocriptine has also been found to reduce hyperinsulinemia, hyperlipidemia, and glucose intolerance.
  • timed administration i.e., administration at a time of day when the body, because of circadian neurooscillations, is most responsive to a bioactive agent
  • D 2 certain prolactin reducing dopamine
  • prolactin-increasing substances such as (a) dopamine antagonists, such as metoclopramide and
  • serotonin agonists and precursors including by way of non- limiting example 5-hydroxytryptophan reduce body fat stores, obesity, plasma triglycerides, and cholesterol as well as hyperglycemia, hyperinsulinemia, and insulin resistance.
  • This work is disclosed in U.S. Patent Nos. 4,659,715; 4,749,709; 4,783,469; 5,006,526.
  • prolactin reducing substances at a first predetermined time of day to effect a decrease in the circulating prolactin levels of the subject to be treated during an interval within the subject's daily prolactin cycle or rhythm when circulating (blood) prolactin levels are low in young, healthy subjects of the same species, thereby causing the prolactin rhythm of the treated subject to approach or to conform to the standard or healthy subjects' prolactin rhythm.
  • prolactin-increasing substances at a second predetermined time of day to effect an increase in the circulating prolactin levels of the subject to be treated during an interval within the subject's daily prolactin cycle or rhythm when circulating (blood) prolactin levels are high in young healthy subjects of the same species, thereby causing the prolactin rhythm of the treated subject to approach, or conform to, the standard or healthy subjects' prolactin rhythm.
  • Such methods are disclosed in U.S. Patent Nos. 5,468,755; 5,496,803; 5,344,832; 5,585,347, USSN 08/456,952, and PCT applications US93/12701 and US95/09061.
  • the present inventors have now unexpectedly discovered that administration of a D, or D 2 agonist (or both) in the morning (e.g. , between the hours of 5:00 and 13:00), combined with administration of a 5HT 1B receptor subtype agonist ("5HT, B agonist") at night (e.g. , between the hours of 17:00 and 0:00) results in a surprising and unexpected reduction in food consumption and body weight. Such administration also results in a decrease in one or more metabolic indices related to lipid and glucose metabolism, such as serum glucose levels, total body fat, and body weight.
  • the present invention which utilizes specific 5HT 1B receptor subtype agonists, provides significant advantages over the administration of 5-HTP to patients. Since the 5HT, B agonists act specifically at the 5HT 1B receptor subtype, side effects associated with a nonspecific increase in serotonin associated with non-specific 5-HTP administration can be avoided.
  • Another object of this invention is to provide methods for reducing at least one of insulin resistance (impaired glucose tolerance), hyperinsulinemia and hyperglycemia, and glycosylated hemoglobin (including A1C), and abating Type U diabetes or Syndrome X.
  • a further object is to provide methods for reducing or retarding or arresting atherosclerosis by reducing at least one of hyperlipoproteinemia and elevated blood triglycerides and/or cholesterol.
  • a dopamine D 2 agonist (ii) a dopamine D 2 agonist; (iii) at least one of an adrenergic ⁇ , antagonist, an adrenergic ⁇ 2 agonist, and a serotonergic inhibitor;
  • a dopamine D 2 agonist further conjoined with at least one of an adrenergic ⁇ , antagonist, an adrenergic ⁇ 2 agonist, and a serotonergic inhibitor; and also (B) administering to the subject a 5HT, B agonist.
  • the foregoing agents in (i), (ii), (iii) or (iv) above are admimstered at a predetermined time of day, i.e., within a restricted portion of a 24-hour period, preferably in the morning (i.e. close to the time of light onset). Since the dopamine D, agonist amplifies the effect of the other agent or agents, the Dj agonist is also preferably administered at about the same time. The 5HT 1B agonist should be administered at night.
  • a dopamine D] or D 2 agonist in the morning and the administration of a 5HT, B agonist at night results in substantially augmented, and in fact often synergistic, effects in improvement of one or more metabolic indices related to glucose or lipid metabolism, and thus an improved modification or regulation of at least one of glucose metabolism, lipid metabolism, food consumption, body fat or weight gain.
  • D 2 agonist is employed, it is preferably an ergot alkaloid, most preferably bromocriptine.
  • the present invention is directed to administering to a subject in the morning a D 2 agonist and a 5HT, B agonist at night, preferably at or shortly before a subject's bedtime.
  • Figure 1 depicts body weight gain or loss in leptin-deficient mice as a result of treatment with various D,, D 2 , and 5HT agonists, and combinations thereof.
  • Figure 2 depicts fat body mass in leptin-deficient mice as a result of treatment with various D,, D 2 , and 5HT agonists and combinations thereof.
  • Figure 3 shows lean body mass in leptin-deficient mice as a result of treatment with various D,, D 2 , and 5HT agonists and combinations thereof.
  • Figure 4 shows the effect on food consumption over the test period in leptin-deficient mice as a result of treatment with various D,, D 2 , and 5HT agonists and combinations thereof.
  • Figure 5 is a depiction of blood glucose at the end of treatment in leptin- deficient mice as a result of treatment with various D,, D 2 , and 5HT agonists, and combinations thereof.
  • Figure 6 depicts serum free fatty acids at the end of the treatment period in leptin-deficient mice as a result of treatment with various D,, D 2 , and 5HT agonists, and combinations thereof.
  • Figure 7 is a plot of body weight in rats on the first and last day of treatment with a vehicle control, a D 2 agonist with a D ! agonist, a D 2 agonist with a 5HT 1B agonist, and a D, agonist with a 5HT 1B agonist.
  • Figure 8 is a plot of food consumption, in grams, of the rats treated as described in Figure 7 over the treatment period.
  • a D, dopamine agonist is administered, preferably in the morning, and a 5HT, B agonist is administered at night, to a subject in need of treatment.
  • a D 2 dopamine agonist is administered, preferably in the morning, and a 5HT, B agonist is administered at night, to a subject in need of treatment.
  • a Dl dopamine agonist is admimstered in conjunction with a D 2 dopamine agonist, preferably both are administered in the morning, and a 5HT 1B agonist is administered at night, to a subject in need of treatment.
  • a D, dopamine agonist is administered in conjunction with a second agent, consisting of at least one of a D 2 agonist, an 2 agonist, an « ⁇ antagonist, and a serotonergic inhibitor (or a D 2 agonist and at least one of the remaining agents) preferably in the morning, and a 5HT, B agonist is administered at night, to a subject in need of treatment.
  • the terms “conjoined” or “in conjunction” mean that the subject being thus treated receives a first active agent and also at least one other active agent, but not necessarily within the same formulation or dosage form and not necessarily at the same administration time.
  • the Dj agonist and D 2 agonist or the other agent(s) can be admimstered at the same time (in the same dosage form or in two or more divided dosage forms) or sequentially at different times and in different dosage forms.
  • Two subtypes of dopamine receptors, Dj like and D 2 like were identified on the basis of pharmacological and biochemical criteria (see, e.g., Kebabian and Cave, Nature, 277:93 (1979)).
  • D, dopamine agonist or “D] agonist” is a compound which is capable of activating or potentiating D, dopamine receptors (e.g. D,-like receptors such as D, and D 5 dopamine receptors).
  • D, dopamine receptors e.g. D,-like receptors such as D, and D 5 dopamine receptors.
  • Suitable assays for testing compounds for D, or D 2 agonist activity are well known in the art, see. e.g., Javitch, et al., Proc. Natl. Acad. Sci. USA 91:10355 (1994); Piercey, et al., Eur. J. Pharm. 317:29 (1996); Paveney, et al., Eur. J. Pharm. , 317: 175 (1996); Lovenberg, et al., Eur. J. Pharm. , 166:111 (1989); Wahs, et al.
  • the D, agonist is a selective agonist for the D, receptor over the D 2 receptor (e.g., the compound has a lower K ; or EC 50 for the D] receptor than the D 2 receptor).
  • the D, agonist is a weak agonist (e.g. , Kj or EC J of greater than 1 ⁇ M or lmM) or is not a D 2 agonist (e.g. , K, or EC 50 of greater than 10 mM).
  • the Dj dopamine agonist may be any one or more of those substances known to those skilled in the art that are capable of activating or potentiating D, dopamine receptors.
  • the D, agonists that are suitable for use in the present invention include SKF38393, dihydrexidine, SKF 75670, SKF 82957, A77636, A68930, SKF 82526 (fenoldopam), and racemic trans-10, 11-dihydroxy 5, 6, 6a, 7, 8, 12b- hexahydro, and those Dj agonists disclosed in the references cited herein.
  • the preferred D, dopamine agonist is SKF 38393.
  • D 2 dopamine agonist or a “D 2 agonist” is a compound which is capable of activating or potentiating D 2 dopamine receptors (e.g., D 2 , D 2 short and D 2 long receptors, D 3 , and D 4 dopamine receptors).
  • D 2 dopamine receptors e.g., D 2 , D 2 short and D 2 long receptors, D 3 , and D 4 dopamine receptors.
  • the D 2 agonist is a selective agonist for the D 2 receptor over the D, receptor.
  • the D 2 agonist is a weak D, agonist or is not a D, agonist.
  • the D 2 agonists for use in the present invention can be any one or more of those compounds known to those skilled in the art that are capable of activating or potentiating D 2 dopamine receptors.
  • D 2 agonists suitable for use in the present invention include benzamides (e.g., sulphide or raclopride), butyrophenones (e.g.
  • D 2 agonists include ergot alkaloids such as
  • bromocriptine 2-bromo-alpha-ergocriptine
  • dihydroergotamine 6-methyl 8- beta-carbobenzyloxyaminoethyl-10-alpha-ergoline
  • 8-acylaminoergoline 6-methyl-8- alpha-(N-acyl)amino-9-ergoline
  • pergolide lisuride
  • 6-methyl-8-alpha-(N-phenyl- acetyl)amino-9-ergoline ergocornine, 9,10-d ydroergocornine, any D-2-halo-6-alkyl- 8-substituted ergoline, and D-2-bromo-6-methyl-8-cyanomethylergoline.
  • bromocriptine is most preferred.
  • Effective amounts of ergot alkaloid for humans and vertebrates when administered alone are typically within the range of 5.0 ug/kg/day to 0.2 mg/kg/day.
  • the amount of the D, agonist, or the D 2 agonist, ⁇ agonist, ⁇ 2 agonist, serotonin inhibitor, or 5HT, B agonist depends on the condition being treated, the route of administration chosen, and the specific activity of the compound used and ultimately wil e decided by the attending physician or veterinarian.
  • effective amounts of D 2 agonist for humans and vertebrates are within the range of 5 ug/kg/day to 3.5 mg/kg/day.
  • adrenergic a ⁇ antagonist or an " ⁇ , antagonist” is a compound which is capable of blocking activation or down regulating ⁇ , adrenergic receptors, e.g., binding to but not activating or down regulating (see, e.g. , Hieble, et al., J. Med. Chem. , 38:3416 (1995);).
  • Suitable assays for testing compounds for ⁇ , or ⁇ , antagonist activity are well known in the art. See, e.g., Marshall, et al., Br. J. Pharmacol , 119:407 (1996); Galligan, J., J. Pharm. Exp. Ther. , 264:375 (1993); Silva, et al., J. Pharm. Exp. Ther. , 277:872 (1996); Paris, et al., Mol. Pharm. , 35:345 (1989); Morrow, et al. , Mol. Pharm. , 29:321 (1986); Andoin, et al., Life Sciences, 43: 1805 (1988); Chein, et al. , J. Med. Chem. , 36:2196 (1993); Piercey, et al., Eur. J. Pharm. , 317:29 (1996).
  • the a antagonist is a selective antagonist for the ] adrenergic receptor over the ⁇ 2 adrenergic receptor (e.g., the compound has as lower K; for the ⁇ , receptor than for the 2 receptor).
  • the ⁇ , antagonist is a weak ⁇ 2 antagonist or is not a ⁇ antagonist.
  • the a x antagonists for use in the present invention can be any one or more of those compounds known to those skilled in the art that directly or indirectly block activation of ⁇ , adrenoceptors.
  • the a ⁇ antagonists suitable for use in the present invention include bromocriptine, benoxathin HCl, naftopidil 2HC1, ( ⁇ )-niguldi ⁇ ine HCl, S(-(-)-niguldipine HCl, prazosin HCl, doxazosin HCl, spiperone HCl, urapidil HCl, 5-methyl urapidil, WB-4101 HCl, or those ⁇ , antagonists disclosed in the references cited herein.
  • Effective amounts of ⁇ antagonist for humans and vertebrates are generally within the range of 0.02 to 0.3 mg/kg/day.
  • an "adrenergic 2 agonist” or a “ ⁇ 2 agonist” is a compound capable of activating or potentiating 2 adrenergic receptors.
  • the ⁇ 2 agonist is a selective agonist for the 2 adrenergic receptor over the « ⁇ adrenergic receptor.
  • the ⁇ 2 agonist is a weak ⁇ , agonist or is not an ⁇ , agonist.
  • the a 2 agonists for use in the present invention can be any one or more of those compounds known to those skilled in the art that are capable of activating 2 adrenoceptors.
  • the 2 agonists suitable for use in the present invention include bromocriptine, epinephrine, norepinephrine, agmatine sulfate, p-aminoclonidine HCl, B-HT 920 diHCl, B-HT 933 diHCl, clonidine HCl, guanabenz acetate, p-iodoclonidine HCl, oxymetazoline HCl, UK 14,304, and xylazine HCl or those ⁇ 2 agonists disclosed in the references cited herein.
  • Effective amounts of a 2 agonist for humans and vertebrates are generally within the range of 1 ug/kg/day to 0.3 mg/kg/day, and preferably between about 100 ug/kg/day and 0.25 mg/kg/day.
  • the serotonergic inhibitors suitable for use in the present invention include bromocriptine.
  • Effective amounts of serotonergic inhibitors for humans and vertebrates are generally within the range of 5 ug/kg/day to 0.2 mg/kg/day.
  • a “5HT, B agonist” is a compound which is capable of activating or potentiating 5HT ⁇ B receptors.
  • Suitable assays for testing compound for 5HT 1B activity are well known in the art. See, e.g. , Schoeffer, et al., Naunyn- Schmiedeberg's Arch. Pharmacol , 339:675 (1989); Pauwels, et al., Eur. J. Pharmacol , 290:95 (1995); Pauwels, et al. , Neuropharmacology, 33:67 (1994); Parker, et al., J. Neurochemistry, 60:380 (1993).
  • the 5HT, B agonist is a selective agonist for the 5HT !B receptor over the 5HT 1A receptor. In another embodiment, the 5HT, B agonist is a selective for the 5HT 1B receptor over the 5HT 2 receptor.
  • the 5HT IB agonist may be any one or more of those substances known to those skilled in the art that are capable of activating or potentiating 5HT, B receptors.
  • Specific 5HT, B agonists that are suitable for use in the present invention include RU24969 and CP93,129.
  • effective amounts of 5HT, B agonists for humans and vertebrates are from about 0.01 to about 5.0 mg/kg of body weight.
  • the dopamine D, agonist and the dopamine D 2 agonist and/or other agent conjoined with the D t agonist (or with the D 2 agonist) as well as the 5HT, B agonist may be administered to a subject preferably orally, or parenterally, e.g. , by subcutaneous, intravenous or intramuscular injection.
  • Dermal delivery systems e.g., skin patches, such as ionophoretic patches, as well as suppositories and other well- known systems for administering pharmaceutical agents can also be employed.
  • Sublingual, nasal and other transmucosal modes of administration are also contemplated. Accelerated release compositions, such as those disclosed in U.S. Patent Application Ser. No. 08/459,021, are preferred.
  • Each of the D 2 agomst, ⁇ antagonist, ⁇ 2 agonist, serotonergic inhibitor, and 5HT 1B agonist are preferably administered at a predetermined time of day.
  • the reason is that the effect of each of these agents on lipid and/or glucose metabolism is time-sensitive, as is explained in more detail for D 2 agonists in U.S. Patent 5,585,347 and USSN 08/456,952, but is also applicable to the ⁇ , antagonists, 2 agonists, serotonergic inhibitors, and 5HT 1B agonists.
  • the preferred time of administration of D, agonists, ⁇ , antagonists, ⁇ 2 agonists, and serotonergic inhibitors is within an interval that results in effective blood levels of the agent(s) at a time during which the standard prolactin levels in healthy subjects of the species to be treated are low.
  • the predetermined time of admmistration of one or more of the foregoing agents is between the hours of 5:00 and 13:00, preferably between about 7:00 and about 12:00 or between 07:00 and 09:00.
  • Divided doses can be administered and the schedule of administration can be varied to take into account pharmacokinetic properties of each active agent. Details of administration are given in U.S.
  • Patent 5,585,347 and USSN 08/456,952 for bromocriptine but also apply to the ⁇ , antagonists, 2 agonists, and serotonergic inhibitors employed in the present invention.
  • the preferred time of administration of the first active agent is within 1 hour after light onset. It is further preferred that the administration take place when the subject is neither active nor feeding.
  • the preferred time of administration for the second active agent, a 5HT, B agonist, to mice is 11 hours after light onset.
  • the preferred time of administration of D,, D 2 , ⁇ ,, 2 , and serotonergic inhibitors can be ascertained by reference to the standard prolactin rhythm for the species of the animal to be treated.
  • the standard prolactin curve can be generated by measuring prolactin in young, healthy members of the species over a 24 hour period.
  • the D thread D 2 , or,, ⁇ 2 , and serotonergic inhibitors should be administered at a time when prolactin levels are low in young, healthy, lean animals of the same species and sex. See U.S. Patent 5,585,347 and USSN 08/456,952.
  • the administration of the D, agonist is also preferably timed, i.e. the D, agomst is also administered at a predetermined time. Because the D, agonist amplifies the effect of the conjoined agent, it is advantageous to administer the D, agonist at or about the time of administration of the conjoined agent(s), such that the activity period of the D, agonist in the bloodstream of the treated subject overlaps (in fact preferably overlaps as much as possible) with the activity period of the conjoined agent. For convenience of administration and in order to promote subject compliance, the D, agonist can be administered at the same time as the conjoined agent(s).
  • the D, agonist may but need not be in the same formulation or dosage form (or form part of the same composition) as the conjoined agent(s). If more than one conjoined agent is administered, the conjoined agents may but need not be in the same formulation or dosage form or form part of the same composition.
  • the 5HT 1B agonist is preferably administered at night, most preferably at or shortly before a subject's bedtime. In other vertebrate animals, the 5HT 1B agomst should be administered at or shortly before the time interval during which young, healthy, lean animals of the same species and sex have the highest daily levels of prolactin.
  • dosages of the Dj and D 2 agonists and conjoined agent(s) are typically administered over a period ranging from about 10 days to about 180 days, or longer.
  • Some patients e.g., patients in particularly poor physical condition, or those of advanced age
  • a treatment duration exceeding six months or even continuous treatment may be desirable even when not required.
  • the 5HTj B agonist admmistration will typically continue for as long as the Dj or D 2 agonist administration continues.
  • At least one of body fat deposits, body weight, plasma or blood glucose, circulating insulin, plasma triglycerides (TG), plasma free fatty acids (FFA), and food consumption of the subject will be reduced as the result of the treatment.
  • Disorders of lipid and glucose metabolism are thereby treated and subjects suffering from such pathologies as hyperphagia, obesity, insulin resistance (impaired glucose tolerance), hyperlipidemia, hyperinsulinemia, and hyperglycemia will exhibit improvement in corresponding metabolic indices.
  • the present invention permits but does not require each agent to be administered in an amount over the threshold amount (in the absence of a conjoined agent) to improve one or more metabolic indices precisely because of the augmented effect on these indices achieved by conjoined administration according to the present invention.
  • Buspirone (“Busp”; a 5HT, A agonist) (3 mg/kg) at 11 HALO;
  • RU24969 (5HT, B agomst) (3 mg/kg) at 11 HALO; 5) bromocriptine (“BC”) (12mg/kg BW) at 1 HALO;
  • SKF38393 (D, agonist) (20mg/kg BW) at 1 HALO; and 10) SKF(20 mg/kg) at 1 HALO plus RU (3 mg/kg) at 11 HALO for two weeks.
  • Animals were held on 12-hour daily photoperiods and allowed to feed ad libitum. Food consumption was monitored daily for 3 days before the initiation of treatment throughout the 14-day treatment period. Animals were sacrificed between 1 and 3 HALO on the day following the final treatment and plasma was collected for the analyses of insulin, glucose, and Iipids while the carcasses were solubilized in ethanolic KOH and analyzed for protein and lipid content.
  • Blood glucose was measured with an Accu-Chek Advantage glucose meter (Boehringer). Serum insulin was measured with a radioimmunoassay kit (Linco Research) using rat insulin standards. Total triglycerides and free fatty acids were measured with kits from Sigma Diagnostics and Wako Chemicals, respectively.
  • Body weight gain or loss as a result of treatment is depicted in Figure 1. Fat body mass is depicted in Figure 2. Lean body mass is shown in Figure 3. Food consumption over the test period is shown in Figure 4. Blood glucose at the end of treatment is shown in Figure 5. Serum free fatty acids at the end of the treatment period is shown in Figure 6.
  • Bromocriptine, Buspirone, and DOI individually, were ineffective in reducing body weight gain, body fat stores, or food intake.
  • mice with SKF and RU showed the most dramatic results.
  • Food consumption was decreased by 52% and body weight showed a 4g loss vs. a 6.4 g gain in controls.
  • Body fat stores were decreased 32 % compared to controls.
  • Serum glucose was reduced by 42%, and serum free fatty acids were reduced 47%.
  • the BC and SKF were admimstered at 1 hour after light onset (HALO) and the RU and SKF77434 were admimstered at 11 HALO.
  • Animals were held on 12-hour daily photoperiods and allowed to feed ad libitum. Food consumption was monitored daily for 3 days before the initiation of treatment throughout the 8-day treatment period.
  • the body weight of the rats at the beginning of the treatment period was from about 385 to 390 grams.

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Abstract

L'invention concerne de nouvelles méthodes améliorées qui permettent la régulation chez un mammifère d'au moins une des caractéristiques suivantes: poids du corps, teneur en graisses du corps, consommation d'aliments, métabolisme des lipides et métabolisme du glucose. L'administration d'un agoniste D1 ou D2 ou de ces deux agonistes, le matin, en combinaison avec l'administration d'un agoniste du sous-type du récepteur 5HT1B la nuit, se traduit par la réduction de la consommation de nourriture, du poids du corps, des taux de glucose sérique et de la teneur totale en graisses du corps.
PCT/US1997/010838 1996-06-06 1997-06-06 Traitement des troubles du metabolisme des lipides et du metabolisme du glucose a l'aide d'antagonistes de la dopamine et de la seratonine WO1997046239A1 (fr)

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JP10500941A JP2000513337A (ja) 1996-06-06 1997-06-06 ドーパミン及びセロトニンアゴニストによる脂質及びグルコース代謝障害の治療
AU34080/97A AU3408097A (en) 1996-06-06 1997-06-06 Treatment of lipid and glucose metabolism disorders with dopamine and seroto nin agonists
CA002257084A CA2257084A1 (fr) 1996-06-06 1997-06-06 Traitement des troubles du metabolisme des lipides et du metabolisme du glucose a l'aide d'antagonistes de la dopamine et de la seratonine

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Cited By (11)

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WO1999021540A2 (fr) * 1997-10-28 1999-05-06 Schering Corporation Procede de reduction de l'appetence chez les mammiferes
US6262049B1 (en) 1997-10-28 2001-07-17 Schering Corporation Method of reducing nicotine and tobacco craving in mammals
WO2002074321A1 (fr) * 2001-03-21 2002-09-26 N.V. Nutricia Composition comportant du cacao et un agoniste du recepteur d2 de la dopamine
WO2008014299A2 (fr) * 2006-07-27 2008-01-31 Allergan, Inc. Méthodes et compositions utiles pour le traitement de l'hyperlipidémie
US20130158064A1 (en) * 2011-12-19 2013-06-20 Map Pharmaceuticals, Inc. Novel iso-ergoline derivatives
US8841448B2 (en) 2011-06-23 2014-09-23 Map Pharmaceuticals, Inc. Fluoroergoline analogs
US8946420B2 (en) 2011-12-21 2015-02-03 Map Pharmaceuticals, Inc. Neuromodulatory compounds
US9012640B2 (en) 2012-06-22 2015-04-21 Map Pharmaceuticals, Inc. Cabergoline derivatives
US9777016B2 (en) 2015-01-20 2017-10-03 Xoc Pharmaceuticals, Inc. Isoergoline compounds and uses thereof
US9938277B2 (en) 2015-01-20 2018-04-10 Xoc Pharmaceuticals, Inc. Ergoline compounds and uses thereof
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US20050058696A1 (en) * 2003-09-12 2005-03-17 Allergan, Inc. Methods and compositions for the treatment of pain and other alpha 2 adrenergic-mediated conditions

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US4971969A (en) * 1988-11-24 1990-11-20 Akzo N.V. Pharmaceutical composition containing 1-(mono- or bis(trifluoromethyl)-2-pyridinyl)piperazines
US5344832A (en) * 1990-01-10 1994-09-06 The Board Of Supervisors Of Louisiana University And Agricultural And Mechanical College Method for the long term reduction of body fat stores, insulin resistance, hyperinsulinemia and hyperglycemia in vertebrates

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999021540A2 (fr) * 1997-10-28 1999-05-06 Schering Corporation Procede de reduction de l'appetence chez les mammiferes
WO1999021540A3 (fr) * 1997-10-28 1999-09-02 Schering Corp Procede de reduction de l'appetence chez les mammiferes
US6262049B1 (en) 1997-10-28 2001-07-17 Schering Corporation Method of reducing nicotine and tobacco craving in mammals
WO2002074321A1 (fr) * 2001-03-21 2002-09-26 N.V. Nutricia Composition comportant du cacao et un agoniste du recepteur d2 de la dopamine
WO2008014299A2 (fr) * 2006-07-27 2008-01-31 Allergan, Inc. Méthodes et compositions utiles pour le traitement de l'hyperlipidémie
WO2008014299A3 (fr) * 2006-07-27 2008-04-24 Allergan Inc Méthodes et compositions utiles pour le traitement de l'hyperlipidémie
US9365591B2 (en) 2011-06-23 2016-06-14 Map Pharmaceuticals, Inc. Fluoroergoline analogs
US9150593B2 (en) 2011-06-23 2015-10-06 Map Pharmaceuticals, Inc. Fluoroergoline analogs
US8841448B2 (en) 2011-06-23 2014-09-23 Map Pharmaceuticals, Inc. Fluoroergoline analogs
US8927567B2 (en) 2011-06-23 2015-01-06 Map Pharceuticals, Inc. Fluoroergoline analogs
US8933093B2 (en) 2011-06-23 2015-01-13 Map Pharmaceuticals, Inc. Fluoroergoline analogs
US8969374B2 (en) 2011-12-19 2015-03-03 Map Pharmaceuticals, Inc. Iso-ergoline derivatives
US8592445B2 (en) * 2011-12-19 2013-11-26 Map Pharmaceuticals, Inc. Iso-ergoline derivatives
US20130158064A1 (en) * 2011-12-19 2013-06-20 Map Pharmaceuticals, Inc. Novel iso-ergoline derivatives
US8946420B2 (en) 2011-12-21 2015-02-03 Map Pharmaceuticals, Inc. Neuromodulatory compounds
US9012640B2 (en) 2012-06-22 2015-04-21 Map Pharmaceuticals, Inc. Cabergoline derivatives
US9938277B2 (en) 2015-01-20 2018-04-10 Xoc Pharmaceuticals, Inc. Ergoline compounds and uses thereof
US9815830B2 (en) 2015-01-20 2017-11-14 Xoc Pharmaceuticals, Inc. Isoergoline compounds and uses thereof
US9777016B2 (en) 2015-01-20 2017-10-03 Xoc Pharmaceuticals, Inc. Isoergoline compounds and uses thereof
US9951070B2 (en) 2015-01-20 2018-04-24 Xoc Pharmaceuticals, Inc. Ergoline compounds and uses thereof
US10246458B2 (en) 2015-01-20 2019-04-02 Xoc Pharmaceuticals, Inc. Ergoline compounds and uses thereof
US10308651B2 (en) 2015-01-20 2019-06-04 Xoc Pharmaceuticals, Inc. Ergoline compounds and uses thereof
US10464936B2 (en) 2015-01-20 2019-11-05 Xoc Pharmaceuticals, Inc. Ergoline compounds and uses thereof
US10703753B2 (en) 2015-01-20 2020-07-07 Xoc Pharmaceuticals, Inc. Ergoline compounds and uses thereof
US10301311B2 (en) 2017-06-01 2019-05-28 Xoc Pharmaceuticals, Inc. Polycyclic compounds and uses thereof
US10815235B2 (en) 2017-06-01 2020-10-27 Xoc Pharmaceuticals Polycyclic compounds and uses thereof

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