WO2006128035A2 - Compositions enantiomeres de cicletanine, combinees a d'autres agents, pour le traitement de l'hypertension - Google Patents

Compositions enantiomeres de cicletanine, combinees a d'autres agents, pour le traitement de l'hypertension Download PDF

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WO2006128035A2
WO2006128035A2 PCT/US2006/020547 US2006020547W WO2006128035A2 WO 2006128035 A2 WO2006128035 A2 WO 2006128035A2 US 2006020547 W US2006020547 W US 2006020547W WO 2006128035 A2 WO2006128035 A2 WO 2006128035A2
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cicletanine
furopyridine
disease
enantiomer
formulation
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PCT/US2006/020547
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WO2006128035A3 (fr
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Glenn Cornett
Jim Page
Karen Page
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Navitas Pharma, Inc.
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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
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline

Definitions

  • the field of this invention relates to the use of racemic and non-racemic cicletanine compositions, alone and in combination with other agents, and the use of these compositions for prophylaxis and/or treatment of a variety of diseases including, by way of example diabetes, cardiac disease, neurodegenerative disease, coronary restenosis, and hypertension.
  • Diabetic nephropathy a complication of diabetes, is a leading cause of end-stage renal disease and a major contributor to the total cost of diabetes care; other significant complications of diabetes include retinopathy, neuropathy and claudication.
  • the etiology of diabetic nephropathy involves an interplay of metabolic factors, such as hyperglycemia, and hemodynamic factors, such as high blood pressure, in the renal microcirculation.
  • the cardinal lesion of diabetic nephropathy, diabetic glomerulosclerosis represents damage to the endothelium and basement membrane of the renal glomeruli.
  • nephropathy An early manifestation of nephropathy is albuminuria, the appearance of plasma albumin in urine; this occurs as a result of impairment in the kidney's ability to selectively filter and retain plasma proteins appropriately.
  • albuminuria the appearance of plasma albumin in urine; this occurs as a result of impairment in the kidney's ability to selectively filter and retain plasma proteins appropriately.
  • several renal functional changes occur, including renal hyperfiltration, hyperperfusion, and increasing capillary permeability to macromolecules.
  • diabetic patients with albuminuria are at greater risk of developing myocardial infarctions, cerebrovascular accidents, severe progressive retinopathy, and peripheral and autonomic neuropathy.
  • PLC protein kinase C
  • LY333531 protein kinase C
  • calcium channel blocking agents such as LY333531
  • adrenergic nerve blocking agents such as beta-adrenergic, alpha/beta blockers, and nonspecific alpha blockers
  • ACE angiotensin-converting enzyme
  • the calcium channel blocking agents also called slow channel blockers or calcium antagonists, inhibit the movement of ionic calcium across the cell membrane, and consequently have the effect of reducing the force of contraction of muscles of the heart and arteries.
  • the calcium channel blockers are treated as a group, there are four different chemical classes, leading to significant variations in the activity of individual drugs.
  • Nifedipine Adalat®, Procardia®
  • verapamil Calan®, Isoptin®
  • diltiazem Cardizem®
  • Second generation, long-acting calcium channel blockers include netrendipine or amlodipine.
  • Peripheral vasodilators such as hydralazine (Apresoline®), isoxuprine (Vasodilan®), and minoxidil (Loniten®) act by relaxing blood vessels.
  • Adrenergic agents act by reducing adrenergic nerve stimulation, the excitatory input from the sympathetic nervous system that causes contraction of the muscles in the arteries, veins, and heart.
  • beta-adrenergic blockers beta-adrenergic blockers
  • alpha/beta adrenergic blockers there are also non-specific adrenergic blocking agents.
  • Beta blockers include propranolol (Inderal®), atenolol (Tenormin®), and pindolol (Visken®).
  • Propranolol acts on the beta-adrenergic receptors anywhere in the body, and has been used as a treatment for emotional anxiety and rapid heart beat.
  • Atenolol and acebutolol (Sectral®) act specifically on the nerves of the heart and circulation.
  • alpha/beta adrenergic blockers such as labetolol (Normodyne®, Trandate®). These work similar to the beta blockers.
  • Angiotensin-converting enzyme (“ACE”) inhibitors act by inhibiting the production of angiotensin II, a substance that both induces constriction of blood vessels and retention of sodium, which leads to water retention and increased blood volume.
  • ACE inhibitors include captopril (Capoten®), benazepril (Lotensin®), enalapril (Vasotec®), and quinapril (Acupril®). The primary differences among these drugs involve their time of onset and duration of action.
  • angiotensin Il receptor agonists directly inhibit the effects of angiotensin Il rather than blocking its production (as do the ACE inhibitors).
  • losartan candesartan
  • Atacand® candesartan
  • irbesartan Avapro®
  • telmisartan Micardis®
  • eprosartan Teveten®
  • Their therapeutic effects are similar to the ACE inhibitors, but they may have a more favorable side effect and safety profile.
  • thiazide diuretics which include hydrochlorothiazide (Hydrodiuril®, Esidrex®), indapamide (Lozol®), polythiazide (Renese®), and hydroflumethiazide (Diucardin®).
  • the drugs in this class lower blood pressure through several mechanisms; by promoting sodium loss, they lower blood volume, and with lower volume, the pressure of the walls of blood vessels is lowered, and the peripheral vascular resistance is lowered.
  • Thiazide diuretics are commonly used as the first choice in an effort to reduce mild hypertension, and are commonly used in combination with other antihypertensive drugs.
  • Aldosterone antagonists are another class of antihypertensive agents.
  • Aldosterone is a mineralocorticosteroid hormone that exerts its actions on the heart, kidney, and vascular system through effects on regulation of sodium levels.
  • Aldosterone antagonists have proven an effective treatment in congestive heart failure, hypertension, and microalbuminuria (Kleyman, et al. (P&T (February 2003) vol. 28 (2) : pages 91-93).
  • combination therapies may replace monotherapeutic approaches with the frontline drugs, for example combinations of ACE inhibitors and calcium antagonists may replace ACE inhibitors as the first-line treatment for diabetic nephropathy (Brezel, Am J Hypertens 1997, 10:208S-217S).
  • ACE inhibitors and certain calcium antagonists have nephroprotective capacity beyond their systemic blood pressure lowering effects, and initial clinical trials with combinations have revealed additive nephroprotective effects as well.
  • ACE inhibitors and calcium antagonists have no adverse effects on glycemic control or lipid levels.
  • combination therapies are useful when the mechanisms of action of the partner drugs are distinct from each other.
  • the combined action is thus broader than that offered by a monotherapy, and additionally allows for the possibility of using doses of the individual drugs that are lower than those used in monotherapeutic mode.
  • Such lower doses tend to decrease the frequency of the appearance of unwanted drug effects that accompany higher doses, and the effects of one drug may, in fact, mitigate unwanted effects of another drug.
  • two combined agents may act synergistically, i.e., offer a combined effect that is greater than that anticipated if the effects of individual agents were simply added together.
  • Embodiments of the invention include oral formulations and drug-eluting stent formulations comprising a furopyridine composition and one or more second agents, the oral formulation being therapeutically sufficient for the treating diseases and associated complications in human subjects.
  • Embodiments of the invention further include methods for treating subjects with embodiments of the oral formulation in a manner sufficient to provide therapeutic benefit to the subject.
  • the diseases that may be amenable to effective treatment may include, for example, diabetes, metabolic syndrome, hypertension, vascular disease, heart failure, angina, and coronary restenosis.
  • Diseases and conditions may further include retinopathy, neuropathy, nephropathy, microalbuminuria, claudication, macular degeneration, and erectile dysfunction.
  • the furopyridine species of embodiments of the invention may vary in terms of their enantiomeric profile.
  • a furopyridine, such as cicletanine may be present as a substantially pure positive (+) enantiomer, a substantially pure negative (-) enantiomer, a racemic mixture of the (+) and (-) enantiomers, or a non-racemic mixture of the (+) and (-) enantiomers, with either enantiomer being the major species.
  • one or more furopyridines may be included in various embodiments of the invention, each furopyridine species, itself, being present independently of the other with respect to the various enantiomeric profiles.
  • Embodiments of the furopyridine composition in terms of cicletanine molecular weight equivalent, include daily dosages that range from between about 12.5 mg and about 1000 mg, more particularly, between about 25 mg and about 600 mg, and still more particularly, between about 50 mg and about 300 mg.
  • the second agents of the embodiments of the furopyridine-based formulation may include, for example, antihypertensive agents, such as beta blockers, aldosterone blockers, calcium antagonists, and metal supplements.
  • antihypertensive agents such as beta blockers, aldosterone blockers, calcium antagonists, and metal supplements.
  • beta blocker is carvediliol.
  • aldosterone blocker is eplerenone.
  • An example of a calcium antagonist is lacidipine.
  • metal supplement is magnesium, in various oxide and salt forms.
  • the second agents of embodiments of the inventive formulation may also be classified in terms of their mechanism of action.
  • a second agent for example, may include a phosphodiesterase inhibitor, an agent that increases prostacyclin activity, or an agent that increases cellular sensitivity to insulin.
  • Combination therapies that include a furopyridine composition and one or more second agent, for treatment of hypertension
  • a combination therapy is disclosed for treating diabetes, metabolic syndrome, hypertension and from complications that ensue during the course of the disease.
  • Embodiments of the presently described invention are primarily focused on treatment of hypertension. However, other complications such as hyperglycemia and hyperlipidemia, are addressed as well, as these other complications are not innocent of contributing to the onset and progression of hypertension.
  • the therapeutic benefit may be one of preventing disease, or slowing its progression.
  • embodiments of the invention are used as therapeutic formulations for human patients or subjects; these formulations may be appropriate for treatment of ongoing disease of any stage of progression or severity, as well as prophylaxis for patients medically considered to be at risk for the development of a disease, such as diabetes, heart disease, or hypertension.
  • embodiments of the invention are also applicable to the veterinary uses.
  • Typical embodiments of the formulation of the invention are for oral use; other embodiments are for administration by any conventional mode of administration, including injection, intravenous administration, and any form of parenteral administration.
  • Embodiments of formulation of the invention may include non-medicinal constituents (i.e., non-furopyridine and non-second therapeutic agent) that help the effectiveness or bioavailability of the biologically active agents.
  • Such additives to the formulation may include absorption enhancers, tissue selectivity enhancers, tissue adhesion enhancers, polymers, and other agents to improve stability and bioavailability, half-life in vivo, duration of effect, and/or effectiveness of drug delivery to appropriate target tissues.
  • Embodiments of the invention include compositions of cicletanine chemical name: +- 3-(4- chlorophenyl)-1 ,3-dihydro-6-methylfuro-[3,4-c]pyridin-7-ol) or other furopyridines that vary in terms of the relative presence of positive (+) and (-) enantiomers (see below). These varied compositions may be used as a monotherapy or in combination therapy, with second agents, to treat subjects with various diseases. In general terms, these compositions varying with respect to their enantiomeric profile, can take the following forms:
  • Non-racemic compositions of cicletanine (NRC) or other furopyridines involving a mixture of (+) cicletanine or other furopyridine and (-) cicletanine or other furopyridine where the ratio of (+) to (-) is greater than 1 :1 ,
  • Racemic cicletanine a mixture of (+) cicletanine or other furopyridine and (-) cicletanine or other furopyridine where the ratio of (+) to (-) is 1:1,
  • Non-racemic cicletanine (NRC) or other furopyridine involving a mixture of (+) cicletanine or other furopyridine and (-) cicletanine or other furopyridine where the ratio of (+) to (-) is less than 1 :1 , and
  • enantiomeric compositions being “pure” is meant “substantially pure”, i.e., pure by standard methods of analysis, including the respective margin of error in the method.
  • a wide range in relative presence is meant, for example, a range in ratios varying from one extreme of between about 1% (+) ::99% (-) to the other extreme of about 99% (+) ::1% (-).
  • the ratio of (-) enantiomer :: (+) enantiomer may, for example, be about 95::5, about 90::10, about 80::20, about 70::30, about 60::40, about 55::45, about 40::60, about 30::70, about 20::80, about 10::90, or about 5::95.
  • Other embodiments may include variations of these ratios, occupying the approximate midpoint range thereof.
  • Embodiments of the invention include treatment with furopyridines other than cicletanine.
  • furopyridines other than cicletanine An example of such is (+/-) 3-(4-fluorophenyl)-1 ,3-dihydro-7-hydroxy-6-methylfurop-[3,4-c] pyridine.
  • This compound can be produced in a racemic mixture and can be used in either purified enantiomer condition or in a weighted, non-racemic enantiomeric mixture.
  • Other furopyridine compounds have been identified, by Garay, et al., for example, ("Stimulation of K+ fluxes by diuretic drugs in human red cells"; Biochemical Pharmacology 33, #13, 2013 - 2020, 1984).
  • Daily dosages of embodiments of the furopyridine-based oral formulation include cicletanine-molecular weight normalized amounts between about 25 mg and 1000 mg. More particularly, daily dosages range between about 75 and 400 mg. Still more particularly, daily dosages range between about 100 mg and 300 mg.
  • compositions that include more than one furopyridine, each present at total dosage levels independent of the other within the constraints of total daily dosing as described herein, and each of which could be present, respectively, as one of the five enantiomeric profiles described above.
  • compositional embodiments of medical treatment provided by the invention further include metabolites of furopyridines that are made within the body following administration of the furopyridines at the dosage levels described herein, even metabolites that are not currently known. And method of treatment embodiments of the invention include receiving the medically beneficial effects of such metabolites.
  • inventive treatment in addition to the administration of furopyridine compositions at dosages described, may further include the generation of metabolites of the administered furopyridines in the body of the patient, where such metabolites, themselves, may be responsible for- or contribute to medically beneficial effects.
  • Formulations and methods of treatment with such formulations are understood to be therapeutically sufficient or effective when the treatment results in a clinically apparent improvement in any clinical sign or symptom associated with any of the aforementioned forms of hypertension, as measured or assessed by a responsible health care professional, working in the bounds of currently accepted standards of practice, or as perceived by a cognizant and reasonable patient being provided the inventive treatment.
  • Cicletanine is a drug that increases endogenous prostacyclin levels, although it may have other actions as well. It was originally developed as an antihypertensive agent that has diuretic properties at high doses. Cicletanine occurs naturally as a racemic (1:1) composition of the two enantiomers [(-) and (+)-cicletanine] which, according to the observations of the inventors, independently contribute to the vasorelaxant and natriuretic mechanisms of this drug.
  • the (-) enantiomer contributes to antihypertensive activity by reducing the vascular reactivity to endogenous pressor substances such as angiotensin Il and vasopressin; (2) the (-) enantiomer reduces the Et-1 (endothelin-1) dependent vasoconstriction more potently than (+)-cicletanine, and (3) both enantiomers have cardioprotective effects.
  • (-) enantiomer has a greater protective effect (anti-ischemic and antiarrythmic), and the antiarrythmic action of (-) cicletanine may be of particular significance in combination therapies involving sulfonylureas, some of which have been associated with an increased incidence of cardiac arrhythmias.
  • cicletanine a furopyridine antihypertensive drug
  • Cicletanine has several mechanisms of action. Its natriuretic activity is attributed to inhibition of apical Na + -dependent CIVHCO 3 " anion exchanger in the distal convoluted tubule.
  • vasorelaxant activity of cicletanine is more complex and involves inhibition of low Km cGMP phosphodiesterases; stimulation of vascular NO synthesis, inhibition of protein kinase C, and antioxidant activity. Combination of the above effects explains the results of numerous clinical and experimental reports regarding the most promising feature of cicletanine, i.e., organ protection, including, merely by way of example, protection of the kidney, vascular structures, and the eye.
  • cicletanine exhibits moderate diuretic and natriuretic effects.
  • cicletanine induces natriuresis without affecting plasma potassium levels, although its effect is milder than that of thiazide diuretics.
  • natriuretic properties of cicletanine in the hypertensives are related to its renoprotective (vs. direct renotubular) effect.
  • cicletanine normalized the blood pressure in 50% of patients from all three groups without major adverse effects. Accordingly, the inventors propose that cicletanine may be effective respect to lowering the blood pressure, particularly in cases of NaCI sensitive hypertension.
  • beta-2 isoform of the PKC is thought to be a promising direction in the treatment of diabetic complications (Meier M. & King G. L. 2000 Vase Med 5:173-85). According to the inventors' understanding of the actions of PKC and cicletanine, the inventors propose the cicletanine may inhibit the activity of PKC.
  • cicletanine may be able to improve insulin sensitivity, in a manner consistent with the ability of cicletanine to inhibit PKC, which is involved in the mechanisms of tissue insulin resistance.
  • cicletanine due to a unique combination of several properties: vasorelaxation, natriuresis, renal protection, improvement of endothelial function, inhibition of PKC, improvement of glucose/insulin metabolism, may be especially effective as a monotherapy and in combination with the other drugs in the hypertensive patients with diabetes mellitus and metabolic syndrome.
  • a combination of cicletanine with a second agent such as an antihypertensive agent (an ACE inhibitor, angiotensin Il receptor antagonist, beta blocker, calcium channel blocker, etc.), or an oral antidiabetic (a sulfonurea, biguanines, an alpha- glucosidase inhibitor, a triazolidinedione or a meglitinide), or a lipid-lowering agent (a resin, an HMG CoA Reductase Inhibitor, a fibric acid derivative (or fibrin), or nicotinic acid, or probucol) be assessed in a study in the hypertensives with and without type 1 or 2 diabetes mellitus or metabolic syndrome.
  • the major endpoints of such a study would be effects of blood pressure, left ventricular function, insulin sensitivity, blood glucose, HDL levels, LDL levels, and renal functions.
  • cicletanine would ameliorate the development of hypertension and protect the cardiovascular and renal systems against the injuries seen in hypertension.
  • Inventors further propose that PKC-induced phosphorylation of cardiac alpha-1 Na/K-ATPase is a likely target for cicletanine action.
  • the inventors propose that cicletanine may have a renal-protective action, which is not related to improvement of diabetes or improvement of high blood pressure in diabetic rats with hypertension.
  • Embodiments of the present invention include combination therapies, wherein a furopyridine composition is combined with a second agent.
  • a furopyridine composition refers to any agent other than the cicletanine compositions;
  • second agent refers to any agent other than the cicletanine compositions;
  • second agent as such is a generic term that may include a plurality of agents that are members of this non-cicletanine class.
  • Such second agents may be, by themselves, effective agents for lowering blood glucose, improving the blood lipid profile, lowering blood pressure, and/or treating any complications associated with these diseases.
  • the combination therapies comprise fixed doses (of each component), in single tablet form.
  • combination therapies unified within a single tablet is to simplify treatment regimens, and thereby support patient compliance.
  • doses of the combined agents relative to each other are fixed, based on supporting an appropriate level of simplicity for treatment regimens. The establishment of doses appropriately fixed relative to each other, still allows for variation in total dosage.
  • Combination therapy in general, supports appropriate level dosing in that it allows the application of doses of individual agents lower than those that elicit the unwanted side effects that may occur at higher dose levels.
  • synergistic therapeutic effects may occur. Synergistic effects, by their nature, are not commonly predictable, based solely on an understanding of the mechanisms of the combined individual agents, respectively.
  • a therapeutic embodiment of the present invention comprises a prostacyclin, or more particularly, an agonist or an inducer thereof such as a composition of cicletanine, in combination with an oral antidiabetic drug selected from sulfonureas, biguanines, alpha- glucosidase inhibitors, triazolidinediones and meglitinides are listed in Table 1. These drugs represent treatments that combat the hyperglycemia of diabetes and metabolic syndrome, and by lowering blood glucose, in turn, they slow the progression of complications of the disease, including hypertension.
  • Existing oral antidiabetic medicaments to be used in such treatment include the classic insulinotropic agents sulphonylureas (Lebovitz H. E. 1997 "The oral hypoglycemic agents”. In: Ellenberg and Rifkin's Diabetes Mellitus. D. J. Porte and R. S. Sherwin, Editors: Appleton and Lange, p. 761-788). They act primarily by stimulating the sulphonylurea-receptor on the insulin producing beta-cells via closure of the K.sup.+ ATP-sensitive channels.
  • Alpha-glucosidase inhibitors such as a carboys, have also been shown to be effective in reducing the postprandial rise in blood glucose (Lefevre, et a/. 1992 Drugs 44:29-38).
  • Another treatment used primarily in obese diabetics is metformin, a biguanide.
  • a combination therapy for treating diabetes and metabolic syndrome comprising combining a prostacyclin, an agonist thereof, or an inducer thereof, most particularly cicletanine, in combination with a blood lipid- lowering agent.
  • lipid profile of patients with diabetes and metabolic syndrome have elevated levels of lipid, for example, total cholesterol, low density lipoprotein (LDL), and triglycerides in blood, and lowering these levels is a therapeutic goal.
  • LDL low density lipoprotein
  • a higher level may be more desirable than a lower level.
  • a low level of HDL may be considered in relative terms, where HDL, regardless of its level in absolute terms, is low relative to the level of LDL.
  • improving the profile of lipids and lipoproteins in blood takes the relative proportions of lipid molecules to each other.
  • Table 2 lists a number of agents that are therapeutically useful in lowering blood lipids, and more generally useful in improving the blood lipid profile. These agents are further detailed in a section below, entitled "Oral Antidiabetics”. Fibrates are known for their lipid lowering activity; in embodiments of the present invention, they may further have the effect of reducing the first-pass hepatic metabolism of cicletanine.
  • the (-) enantiomer undergoes a higher rate of first pass metabolism than does the (+) enantiomer.
  • the (-) enantiomer is the predominant vasodilator, and may be the predominant metabolic agent with regard to the glucose and lipid lowering actions of the two enantiomers.
  • Use of fibrates to inhibit first pass cicletanine metabolism therefore may have the effect of increasing the vasorelaxant and favorable metabolic effects, as well as generally increasing bioavailability. Table 2. Blood Lipid-Lowering Agents
  • a combination therapy for treating hypertension, and more particularly, for treating and/or preventing the clinical consequences of hypertension, such as nephropathies in hypertensive diabetic patients.
  • Table 3 provides an overview of components of such therapeutic combinations, along with ranges of dosages appropriate for clinical application.
  • Cicletanine in Combination with Representative Anti-Hypertensive Agents e.g., carvedilol, lacidipine, eplerenone, and magnesium
  • the second agent a hypertensive agent with which the first agent is therapeutically combined
  • the second agent includes such agents as carvedilol, lacidipine (also known as Caldine, Lacimen, Lacipil, Midotens, Motens), eplerenone, and a metal supplement such as magnesium (e.g. elemental magnesium, magnesium oxide, magnesium citrate, magnesium sulfate, magnesium hydroxide, or other therapeutically-appropriate form of magnesium).
  • Carvedilol is a member of the class of drugs known as betablockers
  • lacidipine is a member of the drug class known as calcium channel blockers, or as calcium antagonists.
  • Eplerenone is an aldosterone blocker
  • magnesium is an agent that will have the therapeutic effect of replacing magnesium that is lost through the diuretic action of other drugs.
  • the second agent is carvedilol (a beta-blocker, also known as Coreq), which has specific advantages over most beta-blockers.
  • carvedilol has neutral effects upon blood glucose as measured in a head-to-head trial against another beta-blocker (metoprolol).
  • metoprolol a beta-blocker
  • Bakris GL, et al. Metalabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial. JAMA (2004) Nov 10;292(18):2227-36. In this study involving over 1200 patients, carvedilol did not raise HbAIc significantly, but metoprolol did.
  • carvedilol is also distinguished from other beta blockers by its dual action.
  • carvedilol is a particularly desireable agent for combination use with cicletanine in the target population of hypertension patients, particularly those with metabolic disease, e.g. patients that have hypertension coincident with elevated total cholesterol, elevated LDL cholesterol, impaired glucose tolerance, impaired fasting glucose, and/or elevated triglycerides.
  • the second agent is lacidipine (also known as Caldine, Lacimen, Lacipil, Midotens, Motens), an orally-administered, lipophilic dihydropyridine calcium antagonist .
  • Lacidipine has a long duration of action, a high degree of vascular selectivity, and an intrinsically slow onset of activity, resulting in a lack of reflex tachycardia. Lacidipine has similar efficacy but a better safety profile (particularly regarding edema) in head- to-head comparison with amlodipine. See Zanchetti A. (2003) "Emerging data on calcium- channel blockers: the COHORT study," Clin Cardiol.
  • Lacidipine has better activity than other CCBs (including amlodipine and lercanidipine) against oxidative stress [Sobal G, Menzel EJ, Sinzinger H. (2001) "Calcium antagonists as inhibitors of in vitro low density lipoprotein oxidation and glycation,” Biochem Pharmacol. Feb 1 ;61(3):373-9], which is getting increasing attention as a major factor metabolic-disease pathology. See Vincent AM, Brownlee M, Russell JW. (2002) "Oxidative stress and programmed cell death in diabetic neuropathy," Ann N Y Acad Sci. Apr;959:368-83. See also Giardino, I.
  • lacidipine 2 - 6mg orally once daily had anti-hypertensive efficacy similar to that of other long-acting dihydropyridine calcium antagonists, thiazide diuretics, atenolol (a ⁇ -blocker) and enalapril (an ACE inhibitor).
  • Lacidipine was effective in elderly patients (including those with isolated systolic hypertension), Nigerian patients and patients with concurrent type 2 diabetes mellitus.
  • the incidence of cardiovascular events and mortality with lacidipine was similar to that with chlorthalidone or atenolol.
  • lacidipine is a particularly desireable agent for combination use with cicletanine in the target population of hypertension patients, particularly those with metabolic disease, e.g. patients that have hypertension coincident with elevated total cholesterol, elevated LDL cholesterol, impaired glucose tolerance, impaired fasting glucose, and/or elevated trigycerides.
  • the second agent is magnesium (e.g. magnesium oxide, magnesium citrate, magnesium sulfate, magnesium hydroxide, or other therapeutically- appropriate form of magnesium).
  • Embodiments of the inventive oral formulation thus may include magnesium at dosage levels between 100 and 600 mg elemental magnesium equivalent.
  • Cicletanine particularly at doses of 100 mg or above, results in a reduction of potassium levels. While these tend to normalize over the course of a few weeks for the 100 mg dose, such problems can be persistent at 150 mg or higher. Also, cicletanine results in moderately-increased diuresis of magnesium, which again tends to resolve over time, particularly at the lower doses.
  • the approach should decrease or eliminate loss of potassium and magnesium associated with cicletanine use. Given the decreased loss of potassium and magnesium, this should allow for use of higher doses of cicletanine (e.g. greater than 150 mg and as high as 300 mg). Because of the positive correlation between dosage level of cicletanine and metabolic control (i.e. higher doses of cicletanine translate to more dramatic reduction of glucose, triglycerides and total cholesterol), the combination with magnesium should allow for better control of metabolic parameters (particularly glucose) in the context of higher doses of cicletanine.
  • the second agent is eplerenone, a member of a class of agents known as "aldosterone blockers", which includes a larger class of compounds related to spironolactone. These compounds bind to the cellular receptor for aldosterone, thereby inhibiting or blocking its action.
  • Aldosterone is a member of the family of steroid compounds secreted by the adrenal glands, known as mineralocorticoids.
  • Eplerenone by virtue of blocking access of aldosterone to its receptor, is a member of a larger class of therapeutic agents known as "RAAS" drugs, which engage the rennin-angtiotensin-aldosterone system at some level.
  • Some embodiments of the present invention comprise a composition of cicletanine, in combination with one or more other antihypertensive agents, selected from the group consisting of diuretics, potassium-sparing diuretics, beta blockers, ACE inhibitors or angiotensin Il receptor antagonists, calcium antagonists (more particularly second generation, long-acting calcium channel blockers, such as amlodipine), a nitrate, a nitrate donor, nitric oxide (NO) inducers, an enhancer of eNOS coupling (e.g., tetrahydrobiopterin), a phosphodiesterase inhibitor, an inhibitor of iNOS inducible nitric oxide synthase, and aldosterone antagonists.
  • the therapeutic utility of combinations of anti-hypertensive agents with separate mechanism of action is known (see Table 4).
  • the present invention represents an improvement on such existing combinations, by the further inventive inclusion of a cicletanine composition.
  • the combination therapy includes in addition to the furopyridine, acting as an prostacyclin inducer, a phosphodiesterase (PDE) inhibitor, which stabilizes cAMP (second messenger for prostacyclins), and may amplify the vasodilatory and/or nephroprotective actions of the prostacyclin agonist or inducer.
  • PDE phosphodiesterase
  • the combination therapy comprises cicletanine and amlodipine.
  • the combination therapy comprises cicletanine and an ACE inhibitor or angiotensin Il receptor antagonist.
  • the combination therapy comprises cicletanine and a thiazolidinedione (e.g., rosiglitazone, pioglitazone), which is known to be a ligand of the peroxisome proliferator-activated receptor gamma (PPARgamma).
  • PPARgamma peroxisome proliferator-activated receptor gamma
  • the combination therapy comprises cicletanine and a peroxisome proliferator-activated receptor (PPAR) agonist, including but not limited to agonists of one or more of the following types: alpha, gamma and delta).
  • the combination therapy comprises cicletanine and a sulfonurea (e.g., glibenclamide, tolbutamide, melizide, glipiziede, gliclazide).
  • the combination therapy comprises cicletanine and a meglitinide (e.g., repaglinide, nateglinide).
  • the combination therapy comprises cicletanine and a biguanide (e.g., metformin, diaformin).
  • the combination therapy comprises cicletanine and a lipid-lowering agent.
  • the combination therapy comprises a fixed dose (of each component) in an oral dosage formulation (e.g., single tablet, capsule, etc.) that provides a systemic action (e.g., blood pressure-lowering, organ-protective, glucose-lowering, lipid- lowering, etc.) with minimal side effects.
  • a systemic action e.g., blood pressure-lowering, organ-protective, glucose-lowering, lipid- lowering, etc.
  • the rationale for using a fixed- dose combination therapy in accordance with a preferred embodiment of the present invention is to obtain sufficient blood pressure control by employing an antihypertensive agent, e.g., cicletanine, which also lowers blood glucose and LDLs, while enhancing compliance by using a single tablet that is taken once or twice daily.
  • Using low doses of different agents can also minimize the clinical and metabolic effects that occur with maximal dosages of the individual components of the combined tablet.
  • the combination may be formulated to generate an enhanced clinical benefit which is related to the diminished side-effect(s) of one or both of the drugs.
  • one significant side-effect of calcium antagonists such as amlodipine (Norvasc R®), the most commonly prescribed calcium channel blocker, is edema in the legs and ankles.
  • cicletanine has been shown to cause significant and major improvement in edema of the lower limbs (Tarrade et al. 1989 Arch MaI Couer Vaiss 82 Spec No. 4:91-7).
  • the combination of cicletanine and amlodipine may be particularly beneficial as a result of diminished edema in the lower limbs.
  • aldosterone antagonists may cause hyperkalemia, while cicletanine in high doses causes potassium excretion.
  • the combination of cicletanine and an aldosterone antagonist may relieve hyperkalemia, a potential side effect of the aldosterone inhibitor alone.
  • thiazolidinediones also known as glitazones
  • Rosiglitazone Rosiglitazone (Avandia®) and Pioglitazone (Actos®)
  • Actos® tends to reduce LDL
  • Avandia® tends to increase LDL
  • Thiazolidinediones also known to cause weight gain and fluid retention.
  • composition of the present invention will allow a lowering of the thiazolidinediones dose necessary to achieve a comparable level of insulin sensitization and glucose control, thereby reducing the risk of hepatotoxicity.
  • the prostacyclin species induced by cicletanine compositions of embodiments of the invention include any eicosanoid that exhibits vasodilatory effects.
  • Some eicosanoids, however, such as the thromboxanes have opposing vasoconstrictive effects, and would therefore not be particularly for use in the inventive formulations.
  • the eicosanoids are defined herein as a class of oxygenated, endogenous, unsaturated fatty acids derived from arachidonic acid.
  • the eicosanoids include prostanoids (which refers collectively to a group of compounds including the prostaglandins, prostacyclins and thromboxanes), leukotrienes and hydroxyeicosatetraenoic acid compounds. They are hormone-like substances that act locally, near the site of synthesis without having such effects at distant sites within the body.
  • the prostanoids are any of a group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase (COX) pathway, that are potent mediators of a diverse group of physiologic processes.
  • the prostaglandins (PGs) are designated by adding one of the letters A through I to indicate the type of substituents found on the hydrocarbon skeleton and a subscript (1 , 2, or 3) to indicate the number of double bonds in the hydrocarbon skeleton for example, PGE 2 .
  • the predominant naturally occurring prostaglandins all have two double bonds and are synthesized from arachidonic acid (5, 8, 11 , 14 eicosatetraenoic acid).
  • the 1 series and 3 series are produced by the same pathway with fatty acids having one fewer double bond (8, 11 , 14 eicosatrienoic acid or one more double bond (5, 8, 11 , 14, 17 eicosapentaenoic acid) than arachidonic acid.
  • the prostaglandins act by binding to specific cell surface receptors causing an increase in the level of the intracellular second messenger cyclic AMP (and in some cases cyclic GMP). The effect produced by the cyclic AMP increase depends on the specific cell type. In some cases there is also a positive feedback effect, whereby increased cyclic AMP increases prostaglandin synthesis, leading to further increases in cyclic AMP.
  • Prostaglandins have a variety of roles in regulating cellular activities, for example, in the inflammatory response where they may act as vasodilators in the vascular system. In a more homeostatic role, they cause vasoconstriction or vasodilatation together with bronchodilation in the lung and act as hyperalgesics. Prostaglandins are rapidly degraded in the lungs and therefore do not persist in the circulation.
  • Prostacyclin also known as PGI 2 , is an unstable vinyl ether formed from the prostaglandin endoperoxide, PGH 2 . The conversion of PGH 2 to prostacyclin is catalyzed by prostacyclin synthetase.
  • Prostacyclin is primarily produced in vascular endothelium and plays an important inhibitory role in the local control of vascular tone and platelet aggregation.
  • Prostacyclin has biological properties opposing the effect of thromboxane ⁇
  • Prostacyclin is a vasodilator and a potent inhibitor of platelet aggregation whereas thromboxane A 2 is a vasoconstrictor and a promoter of platelet aggregation.
  • a physiological balance between the activities of these two effectors is probably important in maintaining a healthy blood supply.
  • the relative dosages and administration frequency of the prostacyclin agent and the second therapeutic agent may be optimized by monitoring the thromboxane/PGI 2 ratio. Indeed, it has been observed that this ratio is significantly increased in diabetics compared to normal individuals, and even higher in diabetics with retinopathy (Hishinuma et a/. 2001 Prostaglandins, Leukotrienes and Essential Fatty Acids 65(4): 191-196).
  • the thromboxane/PGI 2 ratio may be determined as detailed by Hishinuma et a/., (2001) by measuring the levels (pg/mg) in urine of 11-dehydro-thromboxane B 2 and 2,3-dinor-6-keto-prostaglandin F ⁇ lpha., the urinary metabolites of thromboxane A 2 and prostacyclin, respectively. Hishinuma et al. found that the thromboxane/PGI 2 ratio in healthy individuals was 18.4.+-.14.3. In contrast, the thromboxane/PGI 2 ratio in diabetics was 52.2.+- .44.7.
  • thromboxane/PGI 2 ratio was even higher in diabetics exhibiting microvascular complications, such as retinopathy (75.0. +-.67.8). Accordingly, optimization of relative dosages and administration frequencies would target thromboxane/PG 2 ratios of less than about 50, and more particularly between about 20 and 50, and most particularly, about 20.
  • the treating physician may also monitor a variety of indices, including blood glucose, blood pressure, lipid profiles, impaired clotting and/or excess bleeding, as well known by those of skill in the art.
  • Prostacyclin Agonists-Prostacyclin is unstable and undergoes a spontaneous hydrolysis to 6-keto-prostaglandin F1.alpha. (6-keto-PGF1.alpha.). Study of this reaction in vitro established that prostacyclin has a half-life of about 3 min. Because of its low stability, several prostacyclin analogues have been synthesized and studied as potential therapeutic compounds.
  • One of the most potent prostacyclin agonists is iloprost, a structurally related synthetic analogue of PGI. sub.2. Cicaprost is closely related to iloprost and possess a higher degree of tissue selectivity.
  • prostacyclin analogs include beraprost, epoprostenol (Flolan®) and treprostinil (Remodulin®).
  • Prostacyclin plays an important role in inflammatory glomerular disorders by regulating the metabolism of glomerular extracellular matrix (Kitahara M. et a/. 2001 Kidney Blood Press Res 24:18-26). Cicaprost attenuated the progression of diabetic renal injury, as estimated by lower urinary albumin excretion, renal and glomerular hypertrophies, and a better renal architectural preservation. Cicaprost also induced a significant elevation in renal plasma flow and a significant decrease in filtration fraction. These findings suggest that oral stable prostacyclin analogs could have a protective renal effect, at least in this experimental model (Villa E. et a/. 1993 Am J Hypertens 6:253-7).
  • the three therapies attenuated equivalently the progression of diabetic renal injury, as estimated by lower urinary albumin excretion, renal and glomerular hypertrophies, and a better renal architectural preservation.
  • No synergistic action was observed with the combined therapy.
  • renal preservation achieved with cicaprost was not linked to reductions in systemic blood pressure, whereas in the groups treated with fosinopril the hypotensive effect of this drug could have contributed to the positive outcome of the therapy.
  • the authors speculated that impaired prostacyclin synthesis or bioavailability may have been involved in the pathogenesis of the diabetic nephropathy in this model.
  • endothelial dysfunction in both type 1 and type 2 diabetics. This dysfunction is manifest as blunting of the biologic effect of a potent endothelium-derived vasodilator, nitric oxide (NO), and increased production of vasoconstrictors such as angiotensin II, ET-1 , and cyclooxygenase and lipoxygenase products of arachidonic acid metabolism.
  • NO potent endothelium-derived vasodilator
  • vasoconstrictors such as angiotensin II, ET-1 , and cyclooxygenase and lipoxygenase products of arachidonic acid metabolism.
  • Reactive oxygen species overproduced in diabetics, may serve as signaling molecules that mediate many of the cellular biochemical reactions that result in these deleterious effects.
  • Adverse vascular consequences associated with endothelial dysfunction in diabetes mellitus include: decreased NO formation, release, and action; increased formation of reactive oxygen species; decreased prostacyclin formation and release; increased formation of vasoconstrictor prostanoids; increased formation and release of ET-1 ; increased lipid oxidation; increased cytokine and growth factor production; increased adhesion molecule expression; hypertension; changes in heart and vessel wall structure; and acceleration of the atherosclerotic process. It is proposed that treatment with antioxidants and ACE inhibitors may reverse some of the pathologic vascular changes associated with endothelial dysfunction. Further, since prostacyclins enhance NO release and exert direct vasodilatory effects, treatment with prostacyclin agonists or inducers should be effective in protecting against and possibly reversing vascular changes associated with diabetic glomerulosclerosis.
  • cicletanine plus an ACE inhibitor could provide an effective combination therapy in treating diabetes patients with hypertension. It is anticipated that cicletanine would produce positive results in diabetic animal models, both alone and in combination with the ACE inhibitor, fosinopril, and to reduce microalbuminuria in diabetic humans. Cicletanine is also suggested as a drug of choice in diabetics because it inhibits the beta isoform of PKC, and such inhibition has been demonstrated effective against diabetic complications in animal models, and increasingly, in human clinical trials. Another reason for using cicletanine in combination with an ACE inhibitor is the predicted balance between cicletanine's enhancement of potassium excretion and the mild retention of potassium typically seen with ACE inhibitors.
  • Cicletanine is particularly interesting in this regard because of evidence that it has, at least in some populations, a three-fold action of glycemic control, blood-pressure reduction and PKC inhibition.
  • the combination of cicletanine with a commonly-used antihypertensive medication is therefore a promising approach to treating hypertension, particularly in patients with diabetes or metabolic syndrome.
  • PPH primary pulmonary hypertension
  • Prostacyclin agonists such as epoprostenol (Flolan®)
  • Flolan® epoprostenol
  • Flolan® epoprostenol
  • These agonists have been shown to exert direct effects the blood vessels of the lung, relaxing them enabling the patient to breathe easier.
  • This treatment regimen is used for primary pulmonary hypertension, and may also slow the PPH scarring process.
  • the intravenous prostacyclin agonist, epoprostenol has been shown to improve survival, exercise capacity, and hemodynamics in patients with severe PPH.
  • Aerosolization of prostacyclin and its stable analogues caused selective pulmonary vasodilation, increased cardiac output and improved venous and arterial oxygenation in patients with severe pulmonary hypertension.
  • the severe vasodilator action of prostacyclin and its analogs also produced severe headache and blood pressure depression.
  • Inhaled prostacyclin therapy for pulmonary hypertension may offer selectivity of hemodynamic effects for the lung vasculature, thus avoiding systemic side effects.
  • Phospodiesterases potentiate prostacyclin activity. Although aerosolized prostacyclin (PGI 2 ) has been suggested for selective pulmonary vasodilation, its effect rapidly levels off after termination of nebulization. Stabilization of the second-messenger cAMP by phosphodiesterase (PDE) inhibition has been suggested as a strategy for amplification of the vasodilative response to nebulized PGI 2 .
  • PDE phosphodiesterase
  • Lung PDE3/4 inhibition achieved by intravascular or transbronchial administration of subthreshold doses of specific PDE inhibitors, synergistically amplified the pulmonary vasodilatory response to inhaled PGI 2 , concomitant with an improvement in ventilation-perfusion matching and a reduction in lung edema formation.
  • the combination of nebulized PGI 2 and PDE3/4 inhibition may thus offer a new concept for selective pulmonary vasodilation, with maintenance of gas exchange in respiratory failure and pulmonary hypertension (Schermuly R. T. et al. 2000 J Pharmacol Exp Ther 292:512-20).
  • a phosphodiesterase (PDE) inhibitor is any drug used in the treatment of congestive cardiac failure (CCF) that works by blocking the inactivation of cyclic AMP and acts like sympathetic simulation, increasing cardiac output.
  • CCF congestive cardiac failure
  • PDE phosphodiesterase
  • Other phosphodiesterase inhibitors include sildenafil (Viagra®); a PDE V inhibitor used to treat neonatal pulmonary hypertension) and Amrinone (Inocor®) used to improve myocardial function, pulmonary and systemic vasodilation.
  • Isozymes of cyclic-3',5'-nucleotide phosphodiesterase are important component of the cyclic-3',5'-adenosine monophosphate (cAMP) protein kinase A (PKA) signaling pathway.
  • PDE protein kinase A
  • the superfamily of PDE isozymes consists of at least nine gene families (types): PDE1 to PDE9. Some PDE families are very diverse and consist of several subtypes and numerous PDE isoform-splice variants.
  • PDE isozymes differ in molecular structure, catalytic properties, intracellular regulation and location, and sensitivity to selective inhibitors, as well as differential expression in various cell types. Type 3 phosphodiesterases are responsible for cardiac function.
  • PDE isozymes play a role in several pathobiologic processes in kidney cells.
  • Administration of selective PDE isozyme inhibitors in vivo suppresses proteinuria and pathologic changes in experimental anti-Thy-1.1 mesangial proliferative glomerulonephritis in rats.
  • Increased activity of PDE5 (and perhaps also PDE9) in glomeruli and in cells of collecting ducts in sodium-retaining states, such as nephrotic syndrome accounts for renal resistance to atriopeptin; diminished ability to excrete sodium can be corrected by administration of the selective PDE5 inhibitor zaprinast.
  • PDE4 activity in collecting ducts is a basis of unresponsiveness to vasopressin in mice with hereditary nephrogenic diabetes insipidus.
  • PDE isozymes are a target for action of numerous novel selective PDE inhibitors, which are key components in the design of novel "signal transduction" pharmacotherapies of kidney diseases (Dousa T. P. 1999 Kidney lnt 55:29-62).
  • Nitric oxide (NO) donors/inducers Nitric oxide (NO) donors/inducers
  • NO is an important signaling molecule that acts in many tissues to regulate a diverse range of physiological processes.
  • One role is in blood vessel relaxation and regulating vascular tone.
  • Nitric oxide is a short-lived molecule (with a half-life of a few seconds) produced from enzymes known as nitric oxide synthetases (NOS). Since it is such a small molecule, NO is able to diffuse rapidly across cell membranes and, depending on the conditions, is able to diffuse distances of more than several hundred microns.
  • NOS nitric oxide synthetases
  • NOS The earliest medical applications of NO relate to the function of NOS in the cardiovascular system. Nitroglycerin was first synthesized by Alfred Nobel in the 1860s, and this compound was eventually used medicinally to treat chest pain. The mechanism by which nitrovasodilators relax blood vessels was not well defined but is now known to involve the NO signaling pathway.
  • Cells that express NOS include vascular endothelial cells, cardiomyocytes and others. In blood vessels, NO produced by the NOS of endothelial cells functions as a vasodilator thereby regulating blood flow and pressure. Mutant NOS knockout mice have blood pressure that is 30% higher than wild-type littermates. Within cardiomyocytes, NOS affects Ca.sup.2+ currents and contractility.
  • NOS NOS
  • the unique N-terminal sequence of NOS is about 70 residues long and functions to localize the enzyme to membranes. Upon myristoylation at one site and palmitoylation at two other sites within this segment, the enzyme is exclusively membrane-bound. Palmitoylation is a reversible process that is influenced by some agonists and is essential for membrane localization.
  • NOS is targeted to the caveolae, small invaginations characterized by the presence of proteins called caveolins. These regions serve as sites for the sequestration of signaling molecules such as receptors, G proteins and protein kinases.
  • the oxygenase domain of NOS contains a motif that binds to caveolin-1 , and calmodulin is believed to competitively displace caveolin resulting in NOS activation. Bound calmodulin is required for activity of NOS, and this binding occurs in response to transient increases in intracellular Ca 2+ .
  • NOS occurs at sites of signal transduction and produces short pulses of NO in response to agonists that elicit Ca 2+ + transients.
  • Physiological concentrations of NOS-derived NO are in the picomolar range.
  • NOS Within the cardiovascular system, NOS generally has protective effects. Studies with NOS knockout mice clearly indicate that NOS plays a protective role in cerebral ischemia by preserving cerebral blood flow. During inflammation and atherosclerosis, low concentrations of NO prevent apoptotic death of endothelial cells and preserve the integrity of the endothelial cell monolayer. Likewise, NO also acts as an inhibitor of platelet aggregation, adhesion molecule expression, and vascular smooth muscle cell proliferation. Therefore, NOS-related pathologies usually result from impaired NO production or signaling. Altered NO production and/or bioavailability have been linked to such diverse disorders as hypertension, hypercholesterolemia, diabetes, and heart failure.
  • Cicletanine's vasorelaxant and vasoprotective properties may be mediated by its effects on nitric oxide and superoxide. It was been shown in situ that cicletanine stimulates NO release in endothelial cells at therapeutic concentrations. (Kalinowski, et a/. 2001 J Vascular Pharmacol 37:713-724). NO release was observed at concentrations similar to the plasma concentrations obtained following dosing with 75-200 mg of cicletanine. While cicletanine stimulates both NO release and release of O 2 ' , cicletanine scavenges superoxide at nanomolar levels. Thus, cicletanine is able to increase the net production of diffusible NO. These effects may contribute to the potent vasorelaxation properties of cicletanine.
  • Inorganic NO donors -SNP sodium nitroprusside, sodium pentacyanonitrosyl ferrate
  • other commonly used anti-ischemic drugs like glyceryl trinitrate, amyl nitrite and isosorbide dinitrate
  • SNP is an inorganic complex, in which Fe 2+ atom is surrounded by 4 cyanides, has a covalent binding to NO, and forms an ion bond to one Na.sup. ⁇ . When the compound becomes decomposed, cyanides are released and this may induce toxicity in long term clinical use.
  • S-nitrosothiols thionitrates, RSNO)--S-nitroso-N-acetylpenicillamine (SNAP) is one of the most commonly used NO donors in experimental research since the mid-1990's.
  • RSNO thionitrates
  • SNAP S-nitroso-N-acetylpenicillamine
  • Sydnonimines -SIN-1 is the active metabolite of the antianginal prodrug molsidomine (N-ethoxycarbonyl-3-morpholinosydnonimine), these two compounds are sydnonimines that are also mesoionic heterocycles. Liver metabolism needs to convert molsidomine it into its active form.
  • SIN-1 is a potent vasorelaxant and an antiplatelet agent causing spontaneous, extracellular release of NO. SIN-1 can activate sGC independently of thiol groups.
  • SIN-1 can rapidly and non-enzymatically hydrolyze into SIN-1 A when there are traces of oxygen present, it donates NO and spontaneously turns into NO-deficient SIN-1 C.
  • SIN-1 C prevents human neutrophil degranulation in a concentration-dependent manner and can reduce Ca 2+ increase, a property which is common to SIN-1.
  • SIN-1 has been shown to release NO, ONOO- and O.sup.2-.
  • NO inducers various drugs and compositions have been shown to up-regulate endogenous NO release by inducing NOS expression.
  • endotoxin lipopolysaccharide, LPS
  • endotoxin-induced hypotension is, in part, mediated via induction of NOS, release of nitric oxide, and suppression of vascular reactivity (vasoplegia).
  • Calcium channel blockers act by blocking the entry of calcium into muscle cells of heart and arteries so that the contraction of the heart decreases and the arteries dilate. With the dilation of the arteries, arterial pressure is reduced so that it is easier for the heart to pump blood. This also reduces the heart's oxygen requirement. Calcium channel blockers are useful for treating angina. Due to blood pressure lowering effects, calcium channel blockers are also useful to treat high blood pressure. Because they slow the heart rate, calcium channel blockers may be used to treat rapid heart rhythms such as atrial fibrillation. Calcium channel blockers are also administered to patients after a heart attack and may be helpful in treatment of arteriosclerosis.
  • Examples of calcium channel blockers include, but are not limited to diltiazem malate, amlodipine bensylate, verapamil hydrochloride, diltiazem hydrochloride, efonidipine, nifedipine, felodipine, lacidipine, nisoldipine, isradipine, nimodipine, nicardipine hydrochloride, bepridil hydrochloride, and mibefradil di-hydrochloride.
  • Preferred calcium channel blockers comprise amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, and verapamil, or, e.g. dependent on the specific calcium channel blockers, a pharmaceutically acceptable salt thereof.
  • the scope of the present invention includes all those calcium channel blockers now known and all those calcium channel blockers to be discovered in the future.
  • the compounds to be combined can be present as pharmaceutically acceptable salts. If these compounds have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The compounds having at least one acid group (for example COOH) can also form salts with bases. Corresponding internal salts may furthermore be formed, if a compound of formula comprises e.g., both a carboxy and an amino group.
  • Suitable salts of corresponding calcium channel blockers include, but are not limited to amlodipine besylate, diltiazem hydrochloride, fendiline hydrochloride, flunarizine di-hydrochloride, gallopamil hydrochloride, mibefradil di-hydrochloride, nicardipine hydrochloride, lercanidipine and verapamil hydrochloride.
  • cicletanine is administered together with the second generation calcium antagonist, amlodipine.
  • the combination may administered in a sustained release dosage form. Because amlodipine is a long acting compound it may not warrant sustained release; however, where cicletanine is dosed two or more times daily, then in accordance with one embodiment, the cicletanine may be administered in sustained release form, along with immediate release amlodipine.
  • the combination dosage and release form is optimized for the treatment of hypertensive patients, more particularly, the oral combination is administered once daily.
  • Angiotensin converting enzyme (ACE) inhibitors are compounds that inhibit the action of angiotensin converting enzyme, which converts angiotensin I to angiotensin II.
  • ACE inhibitors have individually been shown to be somewhat effective in the treatment of cardiac disease, such as congestive heart failure, hypertension, asymptomatic left ventricular dysfunction, or acute myocardial infarction.
  • ACE inhibitors are known and available. These compounds include inter alia lisinopril (Zestril®; Prinivil®), enalapril maleate (Innovace®; Vasotec®), quinapril (Accupril®), ramipril (Tritace®; Altace®), benazepril (Lotensin®), captopril (Capoten®), cilazapril (Vascace®), fosinopril (Staril®; Monopril®), imidapril hydrochloride (Tanatril®), moexipril hydrochloride (Perdix®; Univasc®), trandolapril (Gopten®; Odrik®; Mavik®), and perindopril (Coversyl®; Aceon®).
  • the scope of the present invention includes all those ACE inhibitors now known and all those ACE inhibitors to be discovered in the future.
  • cicletanine is administered together with an ACE inhibitor.
  • the combination may be administered in a once-daily oral dosage form. More particularly, the combination is optimized for treatment of hypertension in patients with and without type 2 diabetes mellitus. Some of the major endpoints of such a study would be effects on blood pressure, left ventricular function, insulin sensitivity, and renal functions.
  • Angiotensin Il receptor antagonists lower both systolic and diastolic blood pressure by blocking one of four receptors with which angiotensin Il can interact to effect cellular change.
  • angiotensin Il receptor antagonists include losartan potassium, valsartan, irbesartan, candesartan cliexetil, telmisartan, eprosartan mesylate, and olmesartan medoxomil.
  • Angiotensin Il receptor antagonists in combination with a diuretic are also available and include losartan potassium/hydrochlorothiazide, valsartan/-hydrochlorothiazide, irbesartan/- hydrochlorothiazide, candesartan cilexetilA-hydrochlorothiazide- , and telmisartan/- hydrochlorothiazide.
  • the scope of the present invention includes all those angiotensin receptor antagonists now known and all those angiotensin receptor antagonists to be discovered in the future.
  • Individual diuretics increase urine volume.
  • One mechanism is by inhibiting reabsorption of liquids in a specific segment of nephrons, e.g., proximal tubule, loop of Henle, or distal tubule.
  • a loop diuretic inhibits reabsorption in the loop of Henle.
  • diuretics commonly used for treating hypertension include hydrochlorothiazide, chlorthalidone, bendroflumethazide, benazepril, enalapril, and trandolapril.
  • the scope of the present invention includes all those diuretics now known and all those diuretics to be discovered in the future.
  • Beta blockers prevent the binding of adrenaline to the body's beta receptors which blocks the "fight or flight” response. Beta receptors are found throughout the body, including the heart, lung, arteries and brain. Beta blockers slow down the nerve impulses that travel through the heart. Consequently, the heart needs less blood and oxygen. Heart rate and force of heart contractions are decreased.
  • Beta 1 receptors are associated with heart rate and strength of heart beat and some beta blockers selectively block beta 1 more than beta 2.
  • Beta blockers are used to treat a wide variety of conditions including high blood pressure, congestive heart failure, tachycardia, heart arrhythmias, angina, migraines, prevention of a second heart attack, tremor, alcohol withdrawal, anxiety, and glaucoma.
  • Suitable beta blockers include, but are not limited to, atenolol, metoprolol succinate, metoprolol tartrate, propranolol hydrochloride, nadolol, acebutolol hydrochloride, bisoprolol fumarate, pindolol, betaxolol hydrochloride, penbutolol sulfate, timolol maleate, carteolol hydrochloride, esmolol hydrochloride.
  • Beta blockers generally, are compounds that block beta receptors found throughout the body. The scope of the present invention includes all those beta blockers now known and all those beta blockers to be discovered in the future.
  • Aldosterone a mineralocorticoid steroid hormone, acts on the kidney to promote the reabsorption of sodium ions (Na.sup. ⁇ ) into the blood. Water follows the salt, helping maintain normal blood pressure. Aldosterone has the potential to cause edema through sodium and water retention. Aldosterone antagonists inhibit the action of aldosterone and have shown significant benefits for patients suffering from congestive heart failure, hypertension, and microalbuminuria.
  • aldosterone antagonists are known including sprironolactone and eplerenone (Inspra®).
  • Aldosterone antagonists generally, are compounds that block the action of aldosterone throughout the body.
  • the scope of the present invention includes all those aldosterone antagonists now known and those aldosterone antagonists to be discovered in the future.
  • Suitable classes of antihypertensive agents that are envisioned in combination with cicletanine include endothelin antagonists, urotensin antagonists, vasopeptidase inhibitors, neutral endopeptidase inhibitors, hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, vasopressin antagonists, and T-type calcium channel antagonists.
  • Endothelin-1 (ET-1) is a potent vasoconstrictor, and thus its role in the development and/or maintenance of hypertension has been studied.
  • ET-1 the predominant isoform of the endothelin peptide family, regulates vasoconstriction and cell proliferation in tissues both within and outside the cardiovascular system through activation of protein-coupled ETA or ETB receptors.
  • the endothelin system has been implicated in the pathogenesis of arterial hypertension and renal disorders.
  • Plasma endothelin also appears to be greater in obese individuals, particularly obese hypertensives. Blood vessel endothelin expression and cardiac levels of ET-1-like immunoreactivity have been shown to be increased in various animal models of hypertension.
  • Renal prepro-ET-1 mRNA levels are also increased in DOCA-salt hypertensive animals and endothelin production from cultured endothelial cells is upregulated in hypertensive rats. Both ETA and ETB receptors have been shown to be reduced in mesenteric vessels of spontaneously hypertensive rats. Administration of the endothelin-converting enzyme inhibitor, phosphoramidon, or ET-receptor antagonists (e.g., bosentan) have been shown to reduce blood pressure in a number of different hypertensive rat models.
  • ET-receptor antagonists e.g., bosentan
  • angiotensin 11 is an established target of pharmacologic interventions, there is an increasing interest in the biological effects and metabolism of other vasoactive peptides, such as atrial natriuretic peptide (ANP) and ET.
  • ANP atrial natriuretic peptide
  • ET atrial natriuretic peptide
  • Exogenous administration of the vasodilatory and natriuretic ANP and of its analogues improved hemodynamics and renal function in cardiovascular disease, including congestive heart failure.
  • Promising results have been obtained in animal experiments and initial human clinical studies concerning hemodynamics and kidney function with inhibition of ANP metabolism by inhibitors of neutral endopeptidase (NEP).
  • NEP neutral endopeptidase
  • moderately relevant effects of acute intravenous or oral NEP inhibition were observed, but these effects were blunted with acute drug administration.
  • NEP inhibitors such as candoxatril and ecadotril
  • candoxatril and ecadotril expected to exhibit vasodilatory activity at least at certain doses in certain clinical situations, even induce vasoconstriction.
  • An explanation for the ineffectiveness of NEPs in reducing blood pressure when used alone may lie in the effect of the role of NEP in the metabolism of other peptides besides ANP.
  • NEP also metabolizes the vasoactive peptides ET-1 , angiotensin II, and bradykinin.
  • Vasopeptidase inhibition is a novel efficacious strategy for treating cardiovascular disorders, including hypertension and heart failure, that may offer advantages over currently available therapies.
  • Vasopeptidase inhibitors are single molecules that simultaneously inhibit two key enzymes involved in the regulation of cardiovascular function, NEP and ACE. Simultaneous inhibition of NEP and ACE increases natriuretic and vasodilatory peptides (including ANP), brain natriuretic peptide of myocardial cell origin, and C-type natriuretic peptide of endothelial origin. This inhibition also increases the half-life of other vasodilator peptides, including bradykinin and adrenomedullin.
  • vasopeptidase inhibitors By simultaneously inhibiting the renin-angiotensin- aldosterone system, with, for example a renin inhibitor, and potentiating the natriuretic peptide system, vasopeptidase inhibitors reduce vasoconstriction and enhance vasodilation, thereby decreasing vascular tone and lowering blood pressure.
  • a renin inhibitor a renin inhibitor
  • vasopeptidase inhibitors By simultaneously inhibiting the renin-angiotensin- aldosterone system, with, for example a renin inhibitor, and potentiating the natriuretic peptide system, vasopeptidase inhibitors reduce vasoconstriction and enhance vasodilation, thereby decreasing vascular tone and lowering blood pressure.
  • Omapatrilat a heterocyclic dipeptide mimetic, is the first vasopeptidase inhibitor to reach advanced clinical trials in the United States. Unlike ACE inhibitors
  • omapatrilat provides a potent and sustained antihypertensive effect in spontaneously hypertensive rats, a model of human essential hypertension.
  • omapatrilat is more effective than ACE inhibition in improving cardiac performance and ventricular remodeling and prolonging survival.
  • Omapatrilat effectively reduces blood pressure, provides target organ protection, and reduces morbidity and mortality from cardiovascular events in animal models.
  • Human studies with omapatrilat (Vanlev, Bristol-Myers Squibb), administered orally once daily, have demonstrated a dose-dependent reduction of systolic and diastolic blood pressure, regardless of age, race, or gender.
  • systolic blood pressure Its ability to decrease systolic blood pressure is especially notable, since evidence suggests that systolic blood pressure is a better predictor than diastolic blood pressure of stroke, heart attack, and death.
  • Omapatrilat appears to be a safe, well-tolerated, effective hypertensive agent in humans, and it has the potential to be an effective, broad-spectrum antihypertensive agent. Adverse effects are comparable to those of currently available antihypertensive agents.
  • Another vasopeptidase inhibitor that is currently under clinical development is the agent sampatrilat (Chiron).
  • vasopressin plays a particular role in peripheral vasoconstriction, hypertension, and in several disease conditions with dilutional hyponatremia in edematous disorders, such as congestive heart failure, liver cirrhosis, syndrome of inappropriate secretion of antidiuretic hormone, and nephrotic syndrome. These effects of vasopressin are mediated through vascular (Via) and renal (V2) receptors.
  • Via vascular
  • V2 renal receptors.
  • a series of orally active nonpeptide antagonists against the vasopressin receptor subtypes have recently been synthesized and are now under intensive examination.
  • Nonpeptide V1a-receptor antagonists OPC21268 and SR49059, nonpeptide V2-receptor-specific antagonists, SR121463A and VPA985, and combined V1 a/V2-receptor antagonists, OPC31260 and YM087, are currently available.
  • T-Type Calcium Ion Channel Antagonists OPC21268 and SR49059, nonpeptide V2-receptor-specific antagonists, SR121463A and VPA985, and combined V1 a/V2-receptor antagonists, OPC31260 and YM087, are currently available.
  • Mibefradil has antiischemic properties resulting from dilation of coronary and peripheral vascular smooth muscle, and a slight reduction in heart rate.
  • Mibefradil (Posicor®) was approved by the FDA in June 1997 for the treatment of hypertension and angina, but was withdrawn from the market in 1998 because of severe drug interactions. Since the effects of this type of calcium channel blocker were so profound on hypertension, studies with other selective T-type calcium channel antagonists have continued.
  • Urotensin-ll (U-Il) is an important regulator of the cardiovascular system, working to constrict arteries and possibly to increase blood pressure in response to exercise and stress. It was found that U-Il constricts arteries more mildly and for a longer period than other chemicals known for similar effects on blood pressure. The potency of vasoconstriction of U-Il is an order of magnitude greater than that of ET-1 , making human U-Il the most potent mammalian vasoconstrictor identified to date. In vivo, human U-Il markedly increases total peripheral resistance in anesthetized nonhuman primates, a response associated with profound cardiac contractile dysfunction. These effects are mediated by U-Il binding to receptors in the brainstem, heart, and in major blood vessels, including the pulmonary artery, which supplies blood to the lungs, and the aorta, the major vessel leading from the heart.
  • HMG-CoA reductase inhibitors e.g., statins
  • statins Hydroxymethylglutaryl Coenzyme A reductase inhibitors
  • Certain HMG-CoA reductase inhibitors may cause vasodilation by restoring endothelial dysfunction, which frequently accompanies hypertension and hypercholesterolemia.
  • statins Several studies have found that a blood pressure reduction is associated with the use of statins, but conclusive evidence from controlled trials is lacking.
  • HMG-CoA reductase inhibitor pravastatin (20 to 40 mg/day, 16 weeks) decreased total (6.29 to 5.28 mmol/L) and low-density lipoprotein (4.31 to 3.22 mmol/L) cholesterol, systolic and diastolic blood pressure (149/97 to 131/91), and pulse pressure.
  • circulating ET-1 levels were decreased by pretreatment with pravastatin.
  • clinical studies have demonstrated that a specific statin, pravastatin, decreases systolic, diastolic, and pulse pressures in persons with moderate hypercholesterolemia and hypertension.
  • PPARs Peroxisome proliferator-activated receptors
  • PPAR alpha a family of ligand-activated nuclear hormone receptors belonging to the steroid receptor super-family that regulate lipid and carbohydrate metabolism in response to extracellular fatty acids and their metabolites. They are involved in the regulation of fat storage, besides having a potential role in insulin resistance syndrome. They also may have relevance in understanding the cause of common clinical conditions such as type 2 diabetes mellitus, cellular growth and neoplasia, and in the development of drugs for treating such conditions. Three types of receptors were identified: PPAR alpha, gamma and delta.
  • PPAR alpha is a regulator of fatty acid catabolism in the liver
  • PPAR gamma plays a key role in adipogenesis.
  • the use of synthetic PPAR ligands has demonstrated the involvement of these receptors in the regulation of lipid and glucose homeostasis and today PPARs are established molecular targets for the treatment of type 2 diabetes and cardiovascular disease.
  • the fibrate family of lipid lowering agents binds to the alpha isoform and the glitazone family of insulin sensitizers binds to the gamma isoform of PPARs.
  • the sulfonylureas primarily increase insulin secretion; their action is initiated by binding to and closing a specific sulfonylurea receptor (an ATP-sensitive K + channel) on pancreatic beta cells. This closure decreases K + influx, leading to depolarization of the membrane and activation of a voltage-dependent Ca 2+ channel. The resulting increased Ca 2+ flux into the beta cell, activates a cytoskeletal system that causes translocation of insulin to the cell surface and its extrusion by exocytosis.
  • a specific sulfonylurea receptor an ATP-sensitive K + channel
  • the proximal step in this sulfonylurea signal transduction is the binding to high- affinity protein receptors in the beta-cell membrane.
  • high and low-affinity sulfonylurea receptor populations Sulfonylurea binding to the high-affinity sites affects primarily K + (ATP) channel activity, while interaction with the low-affinity sites inhibits both NaVK + - ATPase and K(ATP) channel activities.
  • the potent second-generation sulfonylureas, glyburide and glipizide, are able to saturate receptors in low nanomolar concentration ranges, whereas older, first-generation drugs bind to and saturate receptors in micromolar ranges.
  • sulfonylureas are better effectors of insulin secretion in the presence of glucose. For that reason, the higher the level of plasma glucose at the time of initiation of sulfonylurea treatment, the greater the reduction of hyperglycemia.
  • Insulin is released by the pancreas into the portal vein, where the resultant hyperinsulinemia suppresses hepatic glucose production and the elevated level of arterial insulin enhances muscle glucose uptake, leading to a reduction in postprandial plasma glucose levels.
  • the initial hypoglycemic effect of sulfonylureas results from increased circulating insulin levels secondary to the stimulation of insulin release from pancreatic .beta.-cells and, perhaps to a lesser extent, from a reduction in its hepatic clearance.
  • these initial increases in plasma insulin levels and beta-cell responses to oral glucose are not sustained during chronic sulfonylurea therapy. After a few months, plasma insulin levels decline to those that existed before treatment, even though reduced glucose levels are maintained. Because of downregulation of .beta.-cell membrane receptors for sulfonylurea, its chronic use results in a reduction in the insulin stimulation usually recorded following acute administration of these drugs.
  • insulin which is readily glycated within pancreatic .beta.-cells and under these conditions, when it is secreted it presumably is now ineffective as a ligand.
  • Sulfonylureas may have a direct effect in reducing insulin resistance on peripheral tissues. However, most investigators believe that whatever small improvement in insulin action is observed during sulfonylurea treatment is indirect, possibly explained (as above) by the lessening of glucose toxicity and/or by decreasing the amount of ineffective, glycated insulin.
  • Type 2 diabetes mellitus is part of a complicated metabolic-cardiovascular pathophysiologic cluster alternately referred to as the insulin resistance syndrome, Reaven's syndrome, the metabolic syndrome or syndrome X. Since the macrovascular coronary artery disease associated with insulin resistance and type 2 diabetes is the major cause of death in the latter, it is desirable that any hypoglycemic agent favorably influences known cardiovascular risk factors. But the results in this area have been only mildly encouraging. This invention will add a cardiovascular risk reduction dimension to sulfonylurea therapy.
  • Sulfonylureas may have a neutral or just slightly beneficial effect on plasma lipid levels: plasma triglyceride levels decrease modestly in some studies. This hypolipidemic effect probably results from both a direct effect of sulfonylurea on the metabolism of very-low-density lipoprotein (VLDL) and an indirect effect of sulfonylurea secondary to its reduction of plasma glucose levels.
  • VLDL very-low-density lipoprotein
  • the formulations of this invention provide appropriate therapeutic levels of a sulfonylurea and will enhance and/or extend the beneficial effect of the sulfonylureas upon plasma lipids, coagulopathy and microvascular permeability by additionally lowering the blood pressure.
  • Sulfonylureas under some conditions, have various unwanted side effect; a frequent adverse effect is weight gain, which is also implicated as a cause of secondary drug failure.
  • the side effects of the various sulfonylureas may vary among the members of the family. Sulfonylureas frequently: (1) stimulate renal renin release; (2) inhibit renal carnitine resorption; (3) increase PAI-1 ; and (4) increase insulin resistance. Renal effects from treatment with the sulfonylureas can be detrimental. Because the sulfonylureas are K.sub.ATP blockers they are diuretics although, inevitably, they do not produce kaliuresis.
  • the therapeutic combination of the present invention will be beneficial to controlling the renal side effects of sulfonureas.
  • a particularly adverse effect of chronic sulfonylureas use is long lasting, significant hypoglycemia.
  • the latter may lead to permanent neurological damage or even death, and is most commonly seen in elderly subjects who are exposed to some intercurrent event (e.g., acute energy deprivation) or to drug interactions (e.g., aspirin, alcohol).
  • Some intercurrent event e.g., acute energy deprivation
  • drug interactions e.g., aspirin, alcohol.
  • Long-lasting hypoglycemia is more common with the longer-acting sulfonylureas glyburide and chlorpropamide. For this reason sulfonylurea therapy should be maintained at the lowest possible dose.
  • the formulations of this invention permit the use of minimal doses of sulfonylureas, thereby lowering the risks of sulfonylurea therapy, including hypoglycemia.
  • hypoglycemia As the population ages and as the prevalence of a sedentary life style increases, the danger of sulfonylurea- induced hypoglycemia also increases; and thus increases as well the desirability of therapeutic approaches that allow reductions in sulfonylurea dose levels.
  • Sulfonylureas are divided into first-generation and second-generation drugs.
  • First- generation sulfonylureas have a lower binding affinity to the sulfonylurea receptor and require higher doses than second-generation sulfonylureas.
  • therapy is initiated at the lowest effective dose and titrated upward every 1 to 4 weeks until a fasting plasma glucose level of 110 to 140 mg/dL is achieved.
  • Most (75%) of the hypoglycemic action of the sulfonylurea occurs with a daily dose that is half of the maximally effective dose. If no hypoglycemic effect is observed with half of the maximally effective dose, it is unlikely that further dose increases will have a clinically significant effect on blood glucose level.
  • sulfonylureas are effective glucose-lowering drugs that work by stimulating insulin secretion. They have a beneficial effect on diabetic microangiopathy, but no appreciable beneficial effect on diabetic macroangiopathy. Weight gain is common with their use. Sulfonylureas may cause hypoglycemia, which can be severe, even fatal. They may reduce platelet aggregation and slightly increase fibrinolysis, perhaps indirectly. They have no direct effect on plasma lipids. They inhibit renal resorption of carnitine and may stimulate renal renin secretion. The sulfonylureas, especially generics, are inexpensive. Sulfonylurea dosage can be minimized, therapeutic effect maximized, safety improved and the scope of beneficial effects broadened in progressive insulin resistance, insulin resistance syndrome and type 2 diabetes when delivered in the formulations of this invention.
  • Metformin (Glucophage®) is a representative biguanide, one that has a mechanism of action and that controls hyperglycemia in both obese and normal-weight, type 2 diabetes patients without inducing hypoglycemia, insulin stimulation or hyperinsulinemia. It prevents the desensitization of human pancreatic islets usually induced by hyperglycemia and has no significant effect on the secretion of glucagon or somatostatin. As a result, it lowers both fasting and postprandial glucose and HbAIc levels. Glucose levels are reduced during metformin therapy secondary to reduced hepatic glucose output from inhibition of gluconeogenesis and glycogenosis. Metformin also improves the blood lipid profile, and to a lesser degree it increases insulin action in peripheral tissues.
  • Metformin enhances the sensitivity of both hepatic and peripheral tissues (primarily muscle) to insulin as well as inhibiting hepatic gluconeogenesis and hepatic glycogenosis. This decline in basal hepatic glucose production is correlated with a reduction in fasting plasma glucose levels. Its enhancement of muscle insulin sensitivity is both direct and indirect. Improved insulin sensitivity in muscle from metformin is derived from multiple events, including increased insulin receptor tyrosine kinase activity, augmented numbers and activity of GLUT4 transporters, and enhanced glycogen synthesis. However, the primary receptor through which metformin exerts its effects in muscle and in the liver is as yet unknown. In metform in-treated patients both fasting and postprandial insulin levels consistently decrease, reflecting a normal response of the pancreas to enhanced insulin sensitivity.
  • Metformin has a mean bioavailability of 50-60%. It is eliminated primarily by renal filtration and secretion and has a half-life of approximately 6 hours in patients with type 2 diabetes; its half-life is prolonged in patients with renal impairment. It has no effect in the absence of insulin. Metformin is as effective as the sulfonylureas in treating patients with type 2 diabetes, but has a more prominent postprandial effect than either the sulfonylureas or insulin. It is therefore most useful in managing patients with poorly controlled postprandial hyperglycemia and in obese or dyslipidemic patients; in contrast, the sulfonylureas or insulin are more effective in managing patients with poorly controlled fasting hyperglycemia.
  • Metformin is absorbed mainly from the small intestine. It is stable, does not bind to plasma proteins, and is excreted unchanged in the urine. It has a half-life of 1.3 to 4.5 hours. The maximum recommended daily dose of metformin is 3 g, taken in three doses with meals.
  • metformin When used as monotherapy, metformin clinically decreases plasma triglyceride and low-density lipoprotein (LDL) cholesterol levels by 10% to 15%, reduces postprandial hyperlipidemia, decreases plasma free fatty acid levels, and free fatty acid oxidation. Metformin reduces triglyceride levels in non-diabetic patients with hypertriglyceridemia. HDL cholesterol levels either do not change or increase slightly after metformin therapy. By reducing hyperinsulinemia, metformin improves levels of plasminogen activator inhibitor (PAI-1) and thus improves fibrinolysis in insulin resistance patients with or without diabetes.
  • PAI-1 plasminogen activator inhibitor
  • Weight gain does not occur in patients with type 2 diabetes who receive metformin; in fact, most studies show modest weight loss (2 to 3 kg) during the first 6 months of treatment. In one 1-year randomized, double blind trial, 457 non-diabetic patients with android (abdominal) obesity, metformin caused significant weight loss.
  • Metformin reduces blood pressure, improves blood flow rheology and inhibits platelet aggregation. The latter is also an effect of prostacyclins, and cicletanine which increases endogenous prostacyclin. See e.g., Arch MaI Coeur Vaiss. 1989 November;82 Spec No 4:11-4.
  • metformin beneficial effects of metformin on various elements of the insulin resistance syndrome help define its usefulness in the treatment of insulin resistance and type 2 diabetes. These useful effects are enhanced when metformin is combined with components of this invention (e.g. cicletanine).
  • the latter is envisioned to increase its effectiveness and efficiency, improve its safety and expand the arena of its medical benefit.
  • metformin in combination with cicletanine is envisioned to allow reduction in the dose of the latter to achieve the same antihypertensive effect.
  • Metformin also reduces measurable levels of plasma triglycerides and LDL cholesterol and is the only oral, monotherapy, antidiabetic agent that has the potential to reduce macrovascular complications, although this favorable effect is attenuated by its tendency to increase homocysteine levels. Likewise, it is the only oral hypoglycemic drug wherein most patients treated lose weight or fail to gain weight.
  • This invention introduces a strategy to increase the safety and efficiency of metformin in suppressing recognized risk factors, thus slowing the progression of disease by extending both the duration and the breadth of metformin's therapeutic value.
  • the strategy of this invention will increase the number of patients by whom metformin can be used at reduced dose levels, thereby avoiding, delaying and lessening metformin's adverse effects.
  • Gastrointestinal side effects are the most common adverse events, occurring in 20% to 30% of patients. These side effects usually are mild and transient and can be minimized by slow titration. If side effects occur during titration, they can be eliminated by reducing the dose by administering metformin in the combination of the present invention.
  • Meglitinides such as repaglinide, are derived from the non-sulfonylurea part of the glyburide molecule and nateglinide is derived from D-phenylalanine. Both repaglinide and nateglinide bind competitively to the sulfonylurea receptor of the pancreatic beta cell and stimulate insulin release by inhibiting K A TP channels in the beta cells. The relative potency of inhibition of K A TP channels is repaglinide>glyburide>nateglinide. Nateglinide exhibits rapid inhibition and reversal of inhibition of the KAT P channel.
  • Repaglinide and nateglinide are absorbed rapidly, stimulate insulin release within a few minutes, and are quickly metabolized. Repaglinide is excreted by the liver and nateglinide is excreted by the kidneys.
  • Insulin secretion is more rapid in response to nateglinide than in response to repaglinide. If nateglinide is taken before a meal, insulin becomes available during and after the meal, significantly reducing postprandial hyperglycemia without the danger of hypoglycemia between meals. Nateglinide, therefore, may potentially replace the absent Phase 1 insulin secretion in patients with type 2 diabetes.
  • the meglitinides and D-phenylalanine derivatives must be taken before each meal.
  • the dosage can be adjusted according to the amount of carbohydrate consumed.
  • These drugs are especially useful when metformin is contraindicated (e.g., in patients with creatinine clearance ⁇ 50 ml/min).
  • Treatment can be combined with other OADs as well as with cicletanine.
  • repaglinide and nateglinide may be more effective in reducing postprandial hyperglycemia and pose a lower hypoglycemia risk than sulfonylureas such as glyburide.
  • the .alpha.-glucosidase inhibitors reduce the small intestinal absorption of starch, dextrin, and disaccharides by competitively inhibiting the action of the intestinal brush border enzyme, .alpha.-glucosidase. .alpha.-Glucosidase is responsible for the generation of monosaccharides, so that inhibition of .alpha.-glucosidase, which is the final step in carbohydrate transfer across the small intestinal mucosa, slows down the absorption of carbohydrates.
  • acarbose e.g., miglitol, and voglibose
  • HbAIc glycosylated hemoglobin
  • Miglitol which must be taken with each meal, has little effect on fasting blood glucose concentrations but blunts postprandial glucose increases at lower postprandial insulin concentrations than those observed with sulfonylureas. Unlike glyburide, miglitol is not associated with hypoglycemia, hyperinsulinism, or weight gain. [00138] The combination of acarbose or miglitol with, for example, cicletanine is envisioned to achieve the therapeutic effects of the individual agents in the composition of the present invention at lower doses that when administered individually, therefore reducing the incidence of side effects.
  • Cicletanine due to its multiple therapeutic effects, may also be used in accordance with preferred embodiments of the present invention as a treatment for metabolic syndrome (sometimes also known as “pre-diabetes” or “syndrome X”).
  • the National Cholesterol Education Program (NCEP) at the NIH lists the following as "factors that are generally accepted as being characteristic of [metabolic] syndrome” (Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III; also known as ATP III). Nov. 19, 2002.
  • the metabolic syndrome is identified by the presence of three or more of the components listed in Table 5 below:
  • Cicletanine as a combination therapy with another drug holds promise addressing these five factors.
  • Cicletanine is an effective treatment for hypertension (high blood pressure), as cited in numerous articles (see above) and is approved for the treatment of hypertension in several European countries. Cicletanine has been demonstrated as effective both as a monotherapy (Tarrade T. & Guinot P. 1988 Drugs Exp Clin Res 14:205-14) and in combination with other antihypertensive drugs (Tarrade T. et a/. 1989 Arch MaI Coeur Vaiss 82 Spec No 4:103-8).
  • cicletanine are in contrast to other antihypertensives, particularly diuretics and beta blockers, which tend to have a deleterious effects upon glucose tolerance and plasma lipids (Brook R. D. 2000 Curr Hypertens Rep 2:370-377).
  • a wide variety of pulmonary illnesses involve the activity of prostacyclin, prostaglandins, isoprostanes, nitric oxide, superoxide and peroxynitrite. Cicletanine's effect upon these vasoactive substances allow it to be of therapeutic benefit in all pulmonary diseases wherein dysregulation of these vasoactive substances produces pathologic vasoconstriction or vasodilation, bronchoconstriction, tissue remodeling, or enzymatic inactivation.
  • Specific disease states amenable to cicletanine therapy include adult respiratory distress syndrome, cystic fibrosis, pulmonary embolism, asthma, chronic bronchitis, chronic obstructive pulmonary disease, bronchopulmonary dysplasia, reduction of supplemental oxygen induced pulmonary damage, sarcoidosis, usual interstitial pneumona, idiopathic interstitial pneumonias, pulmonary fibrosis, pulmonary hypertension, desquamative interstitial pneumonia allergic alveolitis, occupational lung disease, pulmonary carcinogenesis, primary pulmonary hypertension, lung transplantation, ischemia reperfusion injury, toxicity of chemotherapeutic agents, such as bleomycin, carmustine, anthracyclines, antimetabolites, and antibiotics (e.g. nitrofurantoin).
  • chemotherapeutic agents such as bleomycin, carmustine, anthracyclines, antimetabolites, and antibiotics (e.g. nitrofurantoin).
  • vascular restonisis vascular restonisis
  • nitrate tolerance vascular restonisis
  • nitrate tachyphylaxis vascular restonisis
  • heart failure and angina vascular restonisis
  • polycystic ovarian syndrome preeclampsia and eclampsia
  • glitazone-related edema vascular restonisis, nitrate tolerance, nitrate tachyphylaxis, heart failure and angina
  • glitazone-related edema glitazone-related edema.
  • Cicletanine has high affinity for lipids and as an analogue of naturally occurring pyridines crosses the blood brain barrier and acts in the central nervous system, as well as in the peripheral nervous system. By modulating free radical production Cicletanine reduces tissue damage due to excessive free radical production and restores nitric oxide signaling.
  • Cicletanine therapy include Alzheimer's dementia, premature dementia associated with Trisomy 21 , Huntington's disease, ALS, Parkinson's disease, CNS Lupus, Multiple sclerosis, vascular dementia, Shydragger syndrome, Pick's disease, Lewy body dementia, psychosis, schizophrenia, epilepsy, Tourette's syndrome, diabetic peripheral neuropathy, idiopathic peripheral neuropathy, diabetic retinopathy, spinal cord injury, radiation induced neuropathy, and chemotherapeutically induced neuropathy, tardive dyskinesia, Wilson's disease, Lesch-Nyan disease, hemochromatosis, ischemic stroke and reperfusion injury.
  • Second agents included in embodiments of the present invention, thus include drugs that are indicated for any of these disease states, as for example an antipsychotic drug.
  • embodiments of the invention may include a pharmaceutical composition in the form of solutions, suspensions, tablets, pills, capsules, powders, and the like.
  • Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are employed along with various disintegrants such as starch and particularly potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, stearic acid and talc are often very useful for tabletting purposes.
  • compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the compounds of this invention can be combined with various sweetening agents, flavoring agents coloring agents, emulsifying agents and/or suspending agents, as well as such diluents such as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts.
  • aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes.
  • the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art.
  • aqueous or partially aqueous solutions are prepared.
  • a therapeutically effective amount of each component may be administered simultaneously or sequentially and in any order.
  • the corresponding active ingredient or a pharmaceutically acceptable salt thereof may also be used in form of a hydrate or include other solvents used for crystallization.
  • the pharmaceutical compositions according to the invention can be prepared in a manner known per se and are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals (warm-blooded animals), including man, comprising a therapeutically effective amount of the pharmacologically active compound, alone or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteral or parenteral application.
  • novel pharmaceutical preparations contain, for example, from about 10% to about 80%, more particularly from about 20% to about 60%, of the active ingredient.
  • pharmaceutical preparations according to the invention for enteral administration are, for example, those in unit dose forms, such as film-coated tablets, tablets, or capsules. These are prepared in a manner known per se, for example by means of conventional mixing, granulating, or film-coating.
  • pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, if desired granulating a mixture obtained, and processing the mixture or granules, if desired or necessary, after addition of suitable excipients to give tablets or film-coated tablet cores.
  • novel pharmaceutical preparations for parenteral administration contain, for example, from about 10% to about 80%, more particularly from about 20% to about 60%, of the active ingredient.
  • novel pharmaceutical preparations include liquid formulations for injection, suppositories or ampoules. These are prepared in manners known in the art, for example by means of conventional mixing, dissolving, or lyophilizing processes.
  • OLETF The characteristic features of OLETF rats are 1) late onset of hyperglycemia (after 18 wk of age); 2) a chronic course of disease; 3) mild obesity; 4) inheritance by males; 5) hyperplastic foci of pancreatic islets; and 6) renal complication (Kawano et al. 1992 Diabetes 41 :1422-1428)
  • a radiotelemetric device (Data Sciences International, Inc., St. Paul, Minn.) is implanted into the lower abdominal aorta of all test animals. Test animals are allowed to recover from the surgical implantation procedure for at least 2 weeks prior to the initiation of the experiments. The radiotransmitter is fastened ventrally to the musculature of the inner abdominal wall with a silk suture to prevent movement. Cardiovascular parameters are continuously monitored via the radiotransmitter and transmitted to a receiver where the digitized signal is then collected and stored using a computerized data acquisition system. Blood pressure (mean arterial, systolic and diastolic pressure) and heart rate are monitored in conscious, freely moving and undisturbed animals in their home cages.
  • the arterial blood pressure and heart rate are measured every 10 minutes for 10 seconds and recorded. Data reported for each rat represent the mean values averaged over a 24-hour period and are made up of the 144 - 10 minute samples collected each day. The baseline values for blood pressure and heart rate consist of the average of three consecutive 24-hour readings taken prior to initiating the drug treatments. All rats are individually housed in a temperature and humidity controlled room and are maintained on a 12 hour light/dark cycle.
  • rats are anesthetized and the heart and kidneys are rapidly removed. After separation and removal of the atrial appendages, left ventricle and left plus right ventricle (total) are weighed and recorded. Left ventricular and total ventricular mass are then normalized to body weight and reported. All values reported for blood pressure and cardiac mass represent the group mean. +-. SEM. The kidneys are dissected for morphological investigation of glomerulosclerosis, renal tubular damage and intrarenal arterial injury.
  • Cicletanine and the second agent are administered via the drinking water either alone or in combination to rats from beginning at 18 weeks of age and continued for 6 weeks. Based on a factorial design, seven (7) treatment groups are used to evaluate the effects of combination therapy on the above-mentioned indices of hypertension, diabetes and nephropathies, as listed below in Table 7.
  • the second agent e.g., calcium channel blockers, ACE inhibitors, angiotensin Il receptor antagonists, oral anti-diabetics, oral lipid-lowering agents, etc.
  • Diabetic renal disease is the leading cause of end-stage renal diseases. Hypertension is a major determinant of the rate of progression of diabetic diseases, especially diabetic nephropathy. It is known that a reduction of blood pressure may slow the reduction of diabetic nephropathy and proteinuria in diabetic patients, however dependent on the kind of antihypertensive administered.
  • NIDDM non-insulin dependent diabetes mellitus
  • Diabetes is induced in hypertensive rats aged about 6 to 8 weeks weighing about 250 to 300 g by treatment e.g. with streptozotocin.
  • the drugs are administered by twice daily average.
  • Untreated diabetic hypertensive rats are used as control group (group 1).
  • Other groups of diabetic hypertensive rats are treated with 40 mg/kg of cicletanine (group 2), with high dose of the second agent (group 3) and with a combination of 25 mg/kg of cicletanine and low dose of the second agent (group 4).
  • group 2 On a regular basis, besides other parameters the survival rate after 21 weeks of treatment is monitored. In week 21 of the study, survival rates are determined.
  • the dosages can be modified by the skilled practitioner without departing from the scope of the above studies.
  • the particularly beneficial effect on glycemic control provided by the treatment of the invention is indicated to be a synergistic effect relative to the control expected for the sum of the effects of the individual active agents.
  • Glycemic control may be characterized using conventional methods, for example by measurement of a typically used index of glycemic control such as fasting plasma glucose or glycosylated hemoglobin (Hb A1c).
  • a typically used index of glycemic control such as fasting plasma glucose or glycosylated hemoglobin (Hb A1c).
  • Hb A1c glycosylated hemoglobin
  • Such indices are determined using standard methodology, for example those described in: Tuescher A, Richterich, P., Sau. Med. Wschr. 101 (1971), 345 and 390 and Frank P., "Monitoring the Diabetic Patent with Glycosolated Hemoglobin Measurements', Clinical Products 1988.
  • the dosage level of each of the active agents when used in accordance with the treatment of the invention will be less than would have been required from a purely additive effect upon glycemic control.
  • the treatment of the invention will effect an improvement, relative to the individual agents, in the levels of advanced glycosylation end products (AGEs), leptin and serum lipids including total cholesterol, HDL-cholesterol, LDL-cholesterol including improvements in the ratios thereof, in particular an improvement in serum lipids including total cholesterol, HDL-cholesterol, LDL-cholesterol including improvements in the ratios thereof, as well as an improvement in blood pressure.
  • AGEs advanced glycosylation end products
  • rats are administered a combination of cicletanine with an oral antidiabetic, after being experimentally induced with type I diabetes, and their urine and blood glucose and insulin levels are determined.
  • One experimental group of rats also receives daily doses of cicletanine.
  • a second experimental group receives daily sub-therapeutic doses of an oral antidiabetic or lipid-lowering agent.
  • a third experimental group receives both daily doses of cicletanine and a daily subtherapeutic dose of an oral antidiabetic or lipid-lowering agent. All animals are fed rat chow and water ad libitum. Plasma glucose levels are done using the Infinity Glucose Reagent® (Sigma Diagnostics, St. Louis, Mo.).
  • the experimental group of rats that receive daily doses of both daily doses of cicletanine and a daily dose of an oral antidiabetic or lipid-lowering agent show reduced levels of glucose and insulin in blood and urine samples when compared with the group of rats that receive daily sub-therapeutic doses of the oral antidiabetic or lipid-lowering agent without receiving daily doses of cicletanine.
  • a composition suitable for use in methods of the invention on glucose and insulin levels, as well as increases in systolic blood pressure
  • rats having type Il diabetes are administered cicletanine, either alone or in combination with sucrose and/or an oral antidiabetic agent, and their systolic blood pressure, urine and blood glucose and insulin levels are determined.
  • Acarbose is known to reduce blood pressure in sucrose induced hypertension in rats (Madar Z, et al., lsr J Med Sci 33:153-159).
  • Total duration of the study is 16 weeks. Plasma insulin levels are measured using Rat Insulin RIA Kit (Linco Research Inc., St. Charles, Mo.). Plasma glucose levels are done using the Infinity Glucose Reagent® ((Sigma Diagnostics, St. Louis, Mo.). Blood pressure is measured using the tail cuff method (see, Madar et al. lsr J Med Sci 33:153-159). The results of this study show that when rats are treated with a combination of cicletanine and a therapeutic dose of an OAD a decrease in systolic pressure is significantly greater when compared to rats treated with cicletanine or an OAD alone.
  • the present invention to provides a pharmaceutical combination composition, e.g. for the treatment or prevention of a condition or disease selected from the group consisting of hypertension, (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation or atrial flutter, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), heart failure, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hyperaldosteronism, primary and pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, Rayn
  • components (i) and (ii) can be obtained and administered together, one after the other or separately in one combined unit dose form or in two separate unit dose forms.
  • the unit dose form may also be a fixed combination.
  • the determination of the dose of the active ingredients necessary to achieve the desired therapeutic effect is within the skill of those who practice in the art.
  • the dose depends on the warm-blooded animal species, the age and the individual condition and on the manner of administration.
  • an approximate daily dosage of cicletanine in the case of oral administration is about 10 - 500 mg/kg/day and more particularly about 30 - 100 mg/kg/day.
  • an oral formulation of one embodiment of the combination invention described above is as follows. Tablets are formed by roller compaction (no breakline), 200 mg cicletanine + 5 mg second agent, with pharmacologically acceptable excipients selected from the group consisting of Avicel PH 102 (filler), PVPP-XL (disintegrant), Aerosil 200 (glidant), and magnesium-stearate (lubricant).
  • an oral tablet containing cicletanine and a second agent may be prepared by wet- granulation followed by compression in a high-speed rotary tablet press, followed by film- coating.
  • Certain aspects of the present invention are embodied and illustrated in the following examples. While each of the combinations depicted below involve total dosages of 100 mg, therapeutic dosages may range from 2 mg to 2000 mg. Additionally, the medication combinations set forth below may be combined into single-dosage forms with other agents, including medications for hypertension such as but not limited to the following classes of agents: angiotensin receptor blockers, angiotensin converting enzyme (ACE) inhibitors, beta blockers, calcium-channel blockers, and diuretics. Additionally, the (+) or (-) enantiomers of Cicletanine may be individually combined into single-dosage forms with other agents useful in treating diabetes, lipid and blood-glucose disorders, and metabolic syndrome.
  • ACE angiotensin converting enzyme

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Abstract

Des modes de réalisation de cette invention concernent des préparations et des méthodes d'utilisation de compositions à base de furopyridine seules ou combinées avec un ou plusieurs seconds agents thérapeutiques en vue de traiter une maladie chez des sujets humains. La composition de furopyridine peut renfermer au moins une espèce de furopyridine, comme par exemple, la ciclétanine. Les furopyridines peuvent prendre diverses formes énantiomères. La ciclétanine, par exemple, peut être présente comme (1) un énantiomère pur (+), (2) un mélange non racémique, dans lequel l'énantiomère (+) constitue la forme majeure et l'énantiomère (-) constitue la forme mineure, (3) un mélange racémique dans lequel les énantiomères (+) et (-) sont présents à nombre égal, (4) un mélange non racémique, dans lequel l'énantiomère (-) constitue la forme majeure et l'énantiomère (+) constitue la forme mineure et, (5) l'énantiomère pur (-). Des seconds agents présentés dans des modes de réalisation de cette invention peuvent être un quelconque médicament utilisé en combinaison avec une composition de furopyridine dans le traitement de maladies. Ces maladies peuvent comprendre, par exemple, une maladie cardiaque, une maladie vasculaire, une hypertension, des diabètes, un syndrome du métabolisme, un syndrome ovarien polykystique, et des troubles autoimmuns. Certaines de ces maladies sont, généralement, associées à un dysfonctionnement endothélial et à des déséquilibres de prostacycline ou d'espèces d'oxygène réactives ou d'espèces d'azote réactives. Les seconds agents peuvent englober, par exemple, des agents antihypertenseurs, tels que des bêta-bloquants, des bloquants d'aldostérone, des antagonistes du calcium et des suppléments métalliques. En terme de mécanisme d'action, ces seconds agents peuvent, de manière avantageuse, renfermer des agents qui augmentent l'activité de la prostacycline, inhibent la phosphodiestérase, les protéines kinases ou accroissent la sensibilité à l'insuline.
PCT/US2006/020547 2005-05-26 2006-05-26 Compositions enantiomeres de cicletanine, combinees a d'autres agents, pour le traitement de l'hypertension WO2006128035A2 (fr)

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EP1951264A2 (fr) * 2005-11-09 2008-08-06 Navitas Pharma, Inc. Utilisation de cicletanine et d'autres furopyridines dans le traitement de l'hypertension
WO2009012223A1 (fr) * 2007-07-13 2009-01-22 Gilead Sciences, Inc. Compositions pour le traitement de troubles métaboliques
CN102370653A (zh) * 2010-08-18 2012-03-14 天津金耀集团有限公司 依普利酮在制备治疗肺部纤维化药物中的应用
CN104000790A (zh) * 2014-04-28 2014-08-27 万特制药(海南)有限公司 拉西地平分散片及其制备方法
WO2015103445A1 (fr) * 2013-12-31 2015-07-09 Rockey Don C Systèmes, procédés, techniques et composés pour la recherche et un traitement de l'hypertension portale et d'autres affections

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EP1951264A2 (fr) * 2005-11-09 2008-08-06 Navitas Pharma, Inc. Utilisation de cicletanine et d'autres furopyridines dans le traitement de l'hypertension
EP1951264A4 (fr) * 2005-11-09 2009-03-25 Navitas Pharma Inc Utilisation de cicletanine et d'autres furopyridines dans le traitement de l'hypertension
WO2009012223A1 (fr) * 2007-07-13 2009-01-22 Gilead Sciences, Inc. Compositions pour le traitement de troubles métaboliques
CN102370653A (zh) * 2010-08-18 2012-03-14 天津金耀集团有限公司 依普利酮在制备治疗肺部纤维化药物中的应用
CN102370653B (zh) * 2010-08-18 2013-07-03 天津金耀集团有限公司 依普利酮在制备治疗肺部纤维化药物中的应用
WO2015103445A1 (fr) * 2013-12-31 2015-07-09 Rockey Don C Systèmes, procédés, techniques et composés pour la recherche et un traitement de l'hypertension portale et d'autres affections
CN104000790A (zh) * 2014-04-28 2014-08-27 万特制药(海南)有限公司 拉西地平分散片及其制备方法

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