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WO2006034510A2 - Compositions enantiomeres de cicletanine, seules ou combinees a d'autres agents, utilisees a des fins therapeutiques - Google Patents

Compositions enantiomeres de cicletanine, seules ou combinees a d'autres agents, utilisees a des fins therapeutiques Download PDF

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WO2006034510A2
WO2006034510A2 PCT/US2005/034763 US2005034763W WO2006034510A2 WO 2006034510 A2 WO2006034510 A2 WO 2006034510A2 US 2005034763 W US2005034763 W US 2005034763W WO 2006034510 A2 WO2006034510 A2 WO 2006034510A2
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cicletanine
hypertension
diabetes
blood
glucose
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WO2006034510A3 (fr
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Glenn Cornett
Jim Page
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Priority claimed from US11/035,308 external-priority patent/US20060153934A1/en
Priority claimed from US11/035,328 external-priority patent/US20060154959A1/en
Priority claimed from US11/035,231 external-priority patent/US20060154971A1/en
Priority claimed from US11/232,724 external-priority patent/US20060089374A1/en
Application filed by Individual filed Critical Individual
Priority to EP05800096A priority Critical patent/EP1804795A4/fr
Priority to CA002581337A priority patent/CA2581337A1/fr
Publication of WO2006034510A2 publication Critical patent/WO2006034510A2/fr
Publication of WO2006034510A3 publication Critical patent/WO2006034510A3/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • 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.
  • LDL low density lipoprotein
  • HDL low density lipoprotein
  • 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.
  • 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.
  • Such embodiments comprise a prostacyclin, or an agonist or an inducer thereof, particularly a composition of cicletanine, in combination with a second antihypertensive agent, 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), nitric oxide (NO) inducers, and aldosterone antagonists (see Table 3).
  • a second antihypertensive agent 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 am
  • 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 of cicletanine and amlodipine may be particularly beneficial as a result of diminished edema in the lower limbs.
  • aldosterone antagonists may cause hyperkalemia and 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.
  • 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 near the site of synthesis without altering functions throughout the body.
  • the prostanoids are any of a group of components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase (COX) pathway that are extremely 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.sub.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. Increased cyclic AMP increases prostaglandin synthesis leading to further increases in cyclic AMP.
  • Prostaglandins have a variety of roles in regulating cellular activities, especially in the inflammatory response where they may act as vasodilators in the vascular system, cause vasoconstriction or vasodilatation together with bronchodilation in the lung and act as hyperalgesics. Prostaglandins are rapidly degraded in the lungs and will not therefore persist in the circulation.
  • Prostacyclin is a vasodilator and a potent inhibitor of platelet aggregation whereas thromboxane A.sub.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.sub.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 al. 2001 Prostaglandins, Leukotrienes and Essential Fatty Acids 65(4): 191-196).
  • the thromboxane/PGI.sub.2 ratio may be determined as detailed by Hishinuma et al., (2001) by measuring the levels (pg/mg) in urine of 11-dehydro-thromboxane B.
  • thromboxane/PGI.sub.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 al. 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 al. 1993 Am J Hypertens 6:253-7).
  • the three therapies attenuated equivalents 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.
  • 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, exhibits three major effects, vasorelaxation, natriuretic and diuretic, and organ protection, and they further observe that it has an excellent record of safety and absence of serious side effects.
  • Cicletanine has several mechanisms of action. Its natriuretic activity is attributed to inhibition of apical Na.sup.+-dependent Cl. sup. - /HCO. sub.3. sup.- anion exchanger in the distal convoluted tubule.
  • vasorelaxant activity of cicletanine is more complex and involves inhibition of low K.sub.m 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 50 and 100 mg per day
  • the addition of 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.
  • 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 100 mg per day
  • 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
  • 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.
  • Applicants propose that cicletanine plus an ACE inhibitor could provide a preferred combination therapy in treating diabetes patients with hypertension. It is anticipated that cicletanine would produce positive results in diabetic animal models 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.
  • PDE's Potentiate Prostacyclin Activity-Although aerosolized prostacyclin (PGI. sub.2) has been suggested for selective pulmonary vasodilation as discussed above, 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.sub.2.
  • 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.sub.2, concomitant with an improvement in ventilation-perfusion matching and a reduction in lung edema formation.
  • the combination of nebulized PGI.sub.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 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. Within the membrane, 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.sup.2+.
  • NOS occurs at sites of signal transduction and produces short pulses of NO in response to agonists that elicit Ca. sup.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.
  • 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.sup.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, RSNOJ-S-nitroso-N-acetylpenicillamine (SNAP) is one of the most commonly used NO donors in experimental research since the mid- 1990's.
  • SNAP thionitrates
  • nitrosothiols rapidly decompose to yield NO.
  • the disadvantage of nitrosothiols is that their half-life can vary from seconds to hours even at a pH of 7.4, and this is dependent on the buffer used.
  • physiological buffers many of the RSNOs become decomposed rapidly to yield disulfide and NO.
  • 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-1A 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. sup.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. For example, Hauser et a/. 1996 Am J Physiol 271 :H2529-35), reported that endotoxin (lipopolysaccharide, LPS)-induced hypotension is, in part, mediated via induction of NOS, release of nitric oxide, and suppression of vascular reactivity (vasoplegia).
  • LPS lipopolysaccharide
  • 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 1 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 Iisinopril (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.
  • 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 is a mineralocorticoid steroid hormone which acts on the kidney promoting 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 extensively.
  • 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. There are a number of experimental studies demonstrating that direct and indirect endothelin-antagonists can have beneficial effects in hypertension.
  • 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 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 demonstrates antihypertensive efficacy in low-, normal-, and high-renin animal models.
  • 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.
  • Insulin on the other hand, 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.
  • 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. Biguanides
  • Biguanides (Metformin)-Metformin (Glucophage®) has a unique mechanism of action and controls glycemia 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. It also improves the lipid profile. Glucose levels are reduced during metformin therapy secondary to reduced hepatic glucose output from inhibition of gluconeogenesis and glycogenosis. 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 metformin-treated patients both fasting and postprandial insulin levels consistently decrease, reflecting a normal response of the pancreas to enhanced insulin sensitivity.
  • 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.
  • 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. On the other hand, metformin in combination with cicletanine is envisioned to allow reduction in the dose of the latter to achieve the same antihypertensive effect.
  • components of this invention e.g. cicletanine
  • metformin in combination with cicletanine is envisioned to allow reduction in the dose of the latter to achieve the same antihypertensive effect.
  • 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.
  • -Meglitinides such as repaglinide
  • 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.sub.ATP channels in the .beta. -cells.
  • the relative potency of inhibition of K.sub.ATP channels is repaglinide>glyburide>nateglinide. Nateglinide exhibits rapid inhibition and reversal of inhibition of the K.sub.ATP channel.
  • 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 e.g., acarbose, miglitol, and voglibose
  • 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. [00137] 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.
  • a pharmaceutical composition can take 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.
  • Table 4 provides guidance regarding daily dosage levels of cicletanine compositions as well as exemplary second agents that are included in various combination-therapy embodiments of the present invention.
  • Table 4 Daily Dosage Ranges for Cicletanine Compositions and Second Agents included in the embodiments of combination therapies
  • Ezetimibe 2.5 to 50 mg particularly: 5 to 40 mg more particularly: 10 mg to 30 mg
  • 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 has also been shown to enhance natriuresis, thereby countering at least one of the hypertensive effects of obesity cited above (Garay R. P. et al. 1995 Eur J Pharmacol 274:175-180).
  • 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 al. 1989 Arch MaI Coeur Vaiss 82 Spec No 4:103-8).
  • 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.
  • 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.
  • 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.
  • 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). 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.
  • a typically used index of glycemic control such as fasting plasma glucose or glycosylated hemoglobin (Hb A1c).
  • Hb A1c glycosylated hemoglobin
  • 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-choIesterol 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 sub-therapeutic 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.
  • 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.
  • 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.
  • 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
  • a non-racemic combination drug is formulated into a pill of mixed composition comprising approximately 90 mg of the (+) enantiomer of Cicletanine and is combined with 10 mg of the (-) enantiomer of Cicletanine and is administered orally, once a day, to subjects suffering from uncomplicated hypertension (that is hypertension without complications such as diabetes, kidney disease, or metabolic syndrome).
  • the nonracemic formulated drug is administered, alone or in combination with drugs from other classes, either as a first-line drug or as a drug given in addition to or as a replacement for a previous/current drug given for hypertension.
  • a non-racemic combination drug is formulated into a pill of mixed composition of approximately 80 mg of the (+) enantiomer of Cicletanine and is combined with 20 mg of the (-) enantiomer of Cicletanine and is administered orally, once a day, to subjects suffering symptoms from one or more of the following descriptions: uncomplicated hypertension, either alone or combined with drugs from other classes, or with hypertension in the presence of mildly-elevated triglycerides, cholesterol, or blood glucose; but not in the presence of actual metabolic syndrome.
  • the formulated drug is administered either as a first-line drug or as a drug given in addition to, or as a replacement for a previous/current drug given for hypertension.
  • a non-racemic combination drug is formulated into a pill of mixed composition of approximately 70 mg of the (+) enantiomer of Cicletanine combined with 30 mg of the (-) enantiomer of Cicletanine and is administered orally once a day to subjects suffering symptoms from one or more of the following descriptions: uncomplicated hypertension, either alone or combined with drugs from other classes or hypertension in the presence of mildly or moderately-elevated triglycerides, cholesterol or blood glucose, but not in the presence of actual metabolic syndrome.
  • the drug is administered either as a first- line drug or as a drug given in addition to or as a replacement for a previous/current drug given for hypertension.
  • a non-racemic combination drug is formulated into a pill of mixed composition of approximately 60 mg of the (+) enantiomer of Cicletanine combined with 40 mg of the (-) enantiomer of Cicletanine and is administered orally, once a day, to subjects suffering symptoms from one or more of the following descriptions: hypertension in the presence of mildly or moderately-elevated triglycerides, cholesterol, or blood glucose both in and out of the presence of actual metabolic syndrome.
  • the drug is administered either as a first-line drug or as a drug given in addition to, or as a replacement for a previous/current drug given for hypertension.
  • a non-racemic combination drug is formulated into a pill of mixed composition of approximately 20 mg of the (+) enantiomer of Cicletanine combined with 80 mg of the (-) enantiomer of Cicletanine and is administered orally, once a day, to subjects suffering symptoms from one or more of the following descriptions: uncomplicated hypertension, either alone or combined with drugs from other classes; hypertension in the presence of mildly or moderately-elevated triglycerides, cholesterol or blood glucose; hypertension in the presence of diabetes or metabolic syndrome; diabetes or metabolic syndrome in the presence of prehypertension (at least 120/80) or borderline hypertension; and with disorders of lipid (triglycerides, cholesterol, etc.) metabolism; impaired glucose tolerance, or with complications of diabetes.
  • the drug is administered either as a first-line drug or as a drug given in addition to, or as a replacement for a previous/current drug given for hypertension, diabetes, blood-lipid disorders, or metabolic syndrome (or a component thereof).
  • the non-racemic drug formulation above has a diuretic effect, as well as vasorelaxant and organ-protective effects.
  • the vasorelaxant and organ protective effects are more pronounced than the diuretic effect.
  • the potassium-lowering effect and the effect of this drug upon lipids and cholesterol are healthier and less pronounced than that of the thiazide-type diuretics.
  • a non-racemic combination drug is formulated into a pill of mixed composition of approximately 10 mg of the (+) enantiomer of Cicletanine combined with 90 mg of the (-) enantiomer of Cicletanine and is administered orally, once a day, to subjects suffering symptoms from one or more of the following descriptions: uncomplicated hypertension, either alone or combined with drugs from other classes; hypertension in the presence of mildly or moderately-elevated triglycerides, cholesterol or blood glucose; hypertension in the presence of diabetes or metabolic syndrome; diabetes or metabolic syndrome in the presence of prehypertension (at least 120/80) or borderline hypertension; and with disorders of lipid (triglycerides, cholesterol, etc.) metabolism; impaired glucose tolerance, or with complications of diabetes.
  • the non-racemic drug formulation above has a diuretic effect, as well as vasorelaxant and organ-protective effects.
  • the vasorelaxant and organ protective effects are more pronounced than the diuretic effect.
  • the potassium-lowering effect and the effect of this drug upon lipids and cholesterol are healthier and less pronounced than that of the thiazide-type diuretics.

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Abstract

Dans des modes de réalisation préférés, la présente invention concerne des médicaments thérapeutiques et des combinaisons de médicaments ainsi que des méthodes connexes pour le traitement et/ou la prévention de complications pouvant survenir chez des patients souffrant de diabète, d'un syndrome du métabolisme et/ou d'hypertension. Plus particulièrement, certains aspects de l'invention concernent l'utilisation de la ciclétanine comme monothérapie ou en combinaison avec d'autres agents pour le traitement de la maladie. Qu'elle soit utilisée en monothérapie ou en combinaison avec d'autres médicaments, la ciclétanine peut se présenter sous la forme d'un mélange non racémique d'énantiomères négatifs (-) et positifs (+) de ciclétanine, ou bien sous la forme de l'énantiomère (-) ou (+) seul.
PCT/US2005/034763 2004-09-22 2005-09-22 Compositions enantiomeres de cicletanine, seules ou combinees a d'autres agents, utilisees a des fins therapeutiques Ceased WO2006034510A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP05800096A EP1804795A4 (fr) 2004-09-22 2005-09-22 Compositions enantiomeres de cicletanine, seules ou combinees a d'autres agents, utilisees a des fins therapeutiques
CA002581337A CA2581337A1 (fr) 2004-09-22 2005-09-22 Compositions enantiomeres de cicletanine, seules ou combinees a d'autres agents, utilisees a des fins therapeutiques

Applications Claiming Priority (14)

Application Number Priority Date Filing Date Title
US61232304P 2004-09-22 2004-09-22
US61236904P 2004-09-22 2004-09-22
US60/612,369 2004-09-22
US60/612,323 2004-09-22
US11/035,308 2005-01-13
US11/035,308 US20060153934A1 (en) 2005-01-13 2005-01-13 Combination therapies of cicletanine and magnesium
US11/035,328 US20060154959A1 (en) 2005-01-13 2005-01-13 Combination therapies of cicletanine and carvedilol
US11/035,328 2005-01-13
US11/035,231 US20060154971A1 (en) 2005-01-13 2005-01-13 Combination therapies of cicletanine and lacidipine
US11/035,231 2005-01-13
US68468405P 2005-05-26 2005-05-26
US60/684,684 2005-05-26
US11/232,724 2005-09-21
US11/232,724 US20060089374A1 (en) 2003-07-17 2005-09-21 Enantiomeric compositions of cicletanine, alone and in combination with other agents, for the treatment of disease

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WO2006034510A3 WO2006034510A3 (fr) 2006-06-01

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WO2009012223A1 (fr) * 2007-07-13 2009-01-22 Gilead Sciences, Inc. Compositions pour le traitement de troubles métaboliques
WO2011059053A1 (fr) 2009-11-13 2011-05-19 東レ株式会社 Agent de traitement ou de prévention du diabète

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HUP0300990A2 (hu) * 2003-04-15 2005-05-30 SynoSens Kutató és Fejlesztő Kft. Szinergista gyógyszer-kombináció a diabetesz megelőzésére vagy kezelésére
WO2005009446A1 (fr) * 2003-07-17 2005-02-03 Cotherix, Inc. Polytherapies destinees au traitement de l'hypertension et de complications chez des patients souffrant de diabetes ou du syndrome metabolique
US20050113314A1 (en) * 2003-08-29 2005-05-26 Fong Benson M. Cicletanine in combination with oral antidiabetic and/or blood lipid-lowering agents as a combination therapy for diabetes and metabolic syndrome

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009012223A1 (fr) * 2007-07-13 2009-01-22 Gilead Sciences, Inc. Compositions pour le traitement de troubles métaboliques
WO2011059053A1 (fr) 2009-11-13 2011-05-19 東レ株式会社 Agent de traitement ou de prévention du diabète
KR20120087987A (ko) 2009-11-13 2012-08-07 고쿠리츠다이가쿠호우진 도쿄다이가쿠 당뇨병의 치료 또는 예방약
EP2500020A4 (fr) * 2009-11-13 2013-02-06 Toray Industries Agent de traitement ou de prévention du diabète
TWI513462B (zh) * 2009-11-13 2015-12-21 Toray Industries 糖尿病之治療或預防藥
US9492422B2 (en) 2009-11-13 2016-11-15 Toray Industries, Inc. Therapeutic or prophylactic agent for diabetes
KR101701943B1 (ko) 2009-11-13 2017-02-02 도레이 카부시키가이샤 당뇨병의 치료 또는 예방약

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EP1804795A2 (fr) 2007-07-11
CA2581337A1 (fr) 2006-03-30
WO2006034510A3 (fr) 2006-06-01
EP1804795A4 (fr) 2007-11-07

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