EP0808171A2 - Association comprenant un inhibiteur de l'enzyme de conversion de l'angiotensine, une dose a effets secondaires reduits d'un antagoniste d'aldosterone, et un diuretique - Google Patents

Association comprenant un inhibiteur de l'enzyme de conversion de l'angiotensine, une dose a effets secondaires reduits d'un antagoniste d'aldosterone, et un diuretique

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Publication number
EP0808171A2
EP0808171A2 EP96904600A EP96904600A EP0808171A2 EP 0808171 A2 EP0808171 A2 EP 0808171A2 EP 96904600 A EP96904600 A EP 96904600A EP 96904600 A EP96904600 A EP 96904600A EP 0808171 A2 EP0808171 A2 EP 0808171A2
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Prior art keywords
triple therapy
converting enzyme
enzyme inhibitor
receptor antagonist
angiotensin converting
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EP96904600A
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German (de)
English (en)
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Todd E. Maclaughlan
Alfonso T. Perez
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GD Searle LLC
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GD Searle LLC
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Priority to EP01128866A priority Critical patent/EP1201248A3/fr
Publication of EP0808171A2 publication Critical patent/EP0808171A2/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • 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
    • 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

  • Combinations of an angiotensin converting enzyme 10 inhibitor, an aldosterone receptor antagonist and a diuretic are described for use in treatment of circulatory disorders, including cardiovascular diseases such as heart failure, hypertension and congestive heart failure.
  • cardiovascular diseases such as heart failure, hypertension and congestive heart failure.
  • therapies using a spirolactone-type 15 aldosterone receptor antagonist compound in combination with an angiotensin converting enzyme inhibitor with a diuretic using a side-effect-reduced amount of the aldosterone receptor antagonist.
  • Myocardial (or cardiac) failure that is, heart failure ("HF"), whether a consequence of previous myocardial infarction(s) , heart disease associated with 25 hypertension, or primary cardiomyopathy, is a major health problem of worldwide proportions .
  • HF heart failure
  • the incidence of symptomatic heart failure has risen steadily over the past several decades.
  • decompensated cardiac failure consists of a constellation of signs and symptoms that arise from congested organs and hypoperfused tissues to form congestive heart failure (CHF) syndrome.
  • Congestion is caused largely by increased venous pressure and by
  • ALDO is the body's most potent mineralocorticoid hormone. As connoted by the term mineralocorticoid, this steroid hormone has mineral-regulating activity. It promotes Na * reabsorption not only in the kidney, but also from the lower gastrointestinal tract and salivary and sweat glands, each of which represents classic ALDO- responsive tissues. ALDO regulates Na * and water resorption at the expense of potassium (K * ) and magnesium (Mg 2* ) excretion.
  • K * potassium
  • Mg 2* magnesium
  • ALDO can also provoke responses in non-epithelial cells. Elicited by a chronic elevation in plasma ALDO level that is inappropriate relative to dietary Na * intake, these responses can have adverse consequences on the structure of the cardiovascular system. Hence, ALDO can contribute to the progressive nature of myocardial failure for multiple reasons.
  • renin As well as non- renin-dependent factors (such as K * , ACTH) that promote ALDO synthesis.
  • Hepatic blood flow by regulating the clearance of circulating ALDO, helps determine ALDO plasma concentration, an important factor in heart failure characterized by reduction in cardiac output and hepatic blood flow.
  • renin-angiotensin-aldosterone system is one of the hormonal mechanisms involved in regulating pressure/volume homeostasis and also in the development of hypertension, a precursor conditon implicated in the progression of more serious cardiovascular diseases such as congestive heart failure.
  • Activation of the renin- angiotensin-aldosterone system begins with secretion of the enzyme renin from the juxtaglomerular cells in the kidney.
  • the enzyme renin acts on a naturally-occurring substrate, angiotensinogen, to release a decapeptide, Angiotensin I.
  • This decapeptide is cleaved by angiotensin converting enzyme ("ACE") to provide an octapeptide, Angiotensin II, the primary active species of this system.
  • ACE angiotensin converting enzyme
  • This octapeptide, angiotensin II is a potent vasoconstrictor and also produces other physiological effects such as stimulating aldosterone secretion, promoting sodium and fluid retention, inhibiting renin secretion, increasing sympathetic nervous system activity, stimulating vasopressin secretion, causing positive cardiac inotropic effect and modulating other hormonal systems.
  • spironolactone is a drug which acts at the mineralocorticoid receptor level by competitively inhibiting aldosterone binding.
  • This steroidal compound has been used for blocking aldosterone-dependent sodium transport in the distal tubule of the kidney in order to reduce edema and to treat essential hypertension and primary hyperaldosteronism [F. Mantero et al, Clin. Sci. Mol. Med.. 45. (Suppl 1), 219s-224s (1973)].
  • Spironolactone is also used commonly in the treatment of other hyperaldosterone-related diseases such as liver cirrhosis and congestive heart failure [F.J. Saunders et al, Aldactone; Spironolactone: A Comprehensive Review. Searle,
  • Spironolactone at a dosage ranging from 25 mg to 100 mg daily is used to treat diuretic-induced hypokalemia, when orally-administered potassium supplements or other potassium-sparing regimens are considered inappropriate [Physicians' Desk Reference, 46th Edn., p. 2153, Medical Economics Company Inc., Montvale, N.J. (1992)].
  • Combinations of an aldosterone antagonist and an ACE inhibitor have been investigated for treatment of heart failure. It is known that mortality is higher in patients with elevated levels of plasma aldosterone and that aldosterone levels increase as CHF progresses from RAAS activation. Routine use of a diuretic may further elevate aldosterone levels. ACE inhibitors consistently inhibit angiotensin II production but exert only a mild and transient antialdosterone effect.
  • ACE inhibitor Combining an ACE inhibitor and spironolactone has been suggested to provide substantial inhibition of the entire RAAS.
  • a combination of enalapril and a 25 mg daily dose of spironolactone has been administered to ambulatory patients with monitoring of blood pressure [P. Poncelet et al, Am. J. Cardiol.. £ ⁇ (2), 33K-35K (1990)].
  • a combination of spironolactone in a range from 50 mg/day to 100 mg/day (average 73 mg/day) and captopril was administered and found effective to control refractory CHF without serious incidents of hyperkalemia [U. Dahlstrom et al, Am. J. Cardiol..
  • Spironolactone dosage at 100 mg/day coadministered with an ACE inhibitor was reported to be highly effective in 13 of 16 patients afflicted with congestive heart failure, with a 25 mg/day to 50 mg/day spironolactone maintenance dosage given at trial completion to compensated patients being treated with an ACE inhibitor and loop diuretic [A.A. van Vliet et al, Am. J. Cardiol.. 71. 21A- 28A (21 Jan 1993)].
  • Fig. 1 shows urinary aldosterone levels at different rates of spironolactone administration (12.5 mg,25 mg,50mg,75mg) , as compared to placebo, co-administered with stable doses of ACE inhibitor and loop diuretic.
  • Fig. 2 shows plasma renin activity at different rates of spironolactone administration (12.5 mg,25 mg,50mg,75mg) , as compared to placebo, co-administered with stable doses of ACE inhibitor and loop diuretic.
  • Fig. 3 shows N-Terminal ANF levels at different rates of spironolactone administration (12.5 mg,25 mg,50mg,75mg) , as compared to placebo, co-administered with stable doses of ACE inhibitor and loop diuretic.
  • Fig. 4 shows changes in supine blood pressure at different rates of spironolactone administration (12.5 mg,25 mg,50mg,75mg) , as compared to placebo, co-administered with stable doses of ACE inhibitor and loop diuretic.
  • Fig. 5 shows changes in supine heart rate at different rates of spironolactone administratio (12.5 mg.25 mg,50mg,75mg) , as compared to placebo, co-administered with stable doses of ACE inhibitor and loop diuretic.
  • a combination therapy comprising a therapeutically-effective amount of an angiotensin converting enzyme ("ACE") inhibitor along with a therapeutically-effective amount of a spirolactone-type aldosterone receptor antagonist and a diuretic.
  • ACE angiotensin converting enzyme
  • the spirolactone-type aldosterone receptor antagonist is administered in the combination therapy at a low dose, that is, at a dose lower than has been conventionally used in clinical situations.
  • angiotensin converting enzyme inhibitor (“ACE inhibitor”) is intended to embrace an agent or compound, or a combination of two or more agents or compounds, having the ability to block, partially or completely, the rapid enzymatic conversion of the physiologically inactive decapeptide form of angiotensin ("Angiotensin I”) to the vasoconstrictive octapeptide form of angiotensin (“Angiotensin II”) .
  • Blocking the formation of Angiotensin II can quickly affect the regulation of fluid and electrolyte balance, blood pressure and blood volume, by removing the primary actions of Angiotensin II. Included in these primary actions of Angiotensin II are stimulation of the synthesis and secretion of aldosterone by the adrenal cortex and raising blood pressure by direct constriction of the smooth muscle of the arterioles.
  • aldosterone receptor antagonist embraces an agent or compound, or a combination of two or more of such agents or compounds, which agent or compound binds to the aldosterone receptor as a competitive inhibitor of the action of aldosterone itself at an aldosterone receptor site, such as typically found in the renal tubules, so as to modulate the receptor-mediated activity of aldosterone.
  • Typical of such aldosterone receptor antagonists are spirolactone-type compounds.
  • the term “spirolactone-type” is intended to characterize a steroidal structure comprising a lactone moiety attached to a steroid nucleus, typically at the steroid "D" ring, through a spiro bond configuration.
  • phrase "combination therapy” in defining use of an ACE inhibitor agent, an aldosterone receptor antagonist agent and a diuretic, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent.
  • terapéuticaally-effective is intended to qualify the amount of each agent for use in the combination therapy which will achieve the goal of improvement in cardiac sufficiency by reducing or preventing, for example, the progression of congestive heart failure, while avoiding adverse side effects typically associated with each agent.
  • low-dose amount in characterizing a therapeutically-effective amount of the aldosterone receptor antagonist agent in the combination therapy, is intended to define a quantity of such agent, or a range of quantity of such agent, that is capable of improving cardiac sufficiency while reducing or avoiding one or more aldosterone-antagonist-induced side effects, such as hyperkalemia.
  • a dosage of spironolactone which would accomplish the therapic goal of favorably enhancing cardiac sufficiency, while reducing or avoiding side effects, would be a dosage that substantially avoids inducing diuresis, that is, a substantially non-diuresis-effective dosage.
  • a preferred combination therapy would consist essentially of three active agents, namely, an ACE inhibitor agent, aldosterone receptor antagonist agent and a diuretic.
  • an ACE inhibitor agent for the ACE inhibitor and an ALDO antagonist combination the agents would be used in combination in a weight ratio range from about 0.5-to-one to about twenty- to-one of the angiotensin converting enzyme agent to the aldosterone receptor antagonist agent.
  • a preferred range of these two agents (ACE inhibitor-to-ALDO antagonist) would be from about one-to-one to about fifteen-to-one, while a more preferred range would be from about one-to-one to about five-to-one, depending ultimately on the selection of the ACE inhibitor and ALDO antagonist.
  • the diuretic agent may be present in a ratio range of 0.1-to-one to about ten to one (ACE Inhibitor to diuretic) .
  • ACE inhibitors which may be used in the combination therapy are shown in the following four categories.
  • a first group of ACE inhibitors consists of the following compounds: AB-103, ancovenin, benazeprilat, BRL- 36378, BW-A575C, CGS-13928C, CL-242817, CV-5975, Equaten, EU-4865, EU-4867, EU-5476, foroxy ithine, FPL 66564, FR- 900456, Hoe-065, I5B2, indolapril, ketomethylureas, KRI- 1177, KRI-1230, L-681176, libenzapril, MCD, MDL-27088, MDL- 27467A, moveltipril, MS-41, nicotianamine, pentopril, phenacein, pivopril, rentiapril, RG-5975, RG-6134, RG-6207, RGH-0399, ROO-911, RS-10085-197, RS-2039, RS 5139, RS 86127,
  • a second group of ACE inhibitors of interest consists of the following compounds: Asahi Brewery AB-47, alatriopril, BMS 182657, Asahi Chemical C-lll, Asahi Chemical C-112, Dainippon DU-1777, mixanpril, Prentyl, zofenoprilat and 1-(-(l-carboxy-6-(4-piperidinyl)hexyl) a ino)-1-oxopropyl octahydro-lH-indole-2-carboxylic acid.
  • a third group of ACE inhibitors of greater interest consists of the following compounds: Bioproject BP1.137, Chiesi CHF 1514, Fisons FPL-66564, idrapril, Marion Merrell Dow MDL-100240, perindoprilat and Servier S-5590.
  • a fourth group of ACE inhibitors of highest interest consists of the following compounds: alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, i idapril, lisinopril, perindopril, quinapril, ramipril, saralasin acetate, temocapril, trandolapril, ceranapril, moexipril, quinaprilat and spirapril.
  • ACE inhibitors are commercially available, expecially those listed in the fourth group, above.
  • a highy preferred ACE inhibitor, captopril is sold by E.R. Squibb & Sons, Inc., Princeton, N.J., now part of Bristol-Myers-Squibb, under the trademark "CAPOTEN", in tablet dosage form at doses of 12.5 mg, 50 mg and 100 mg per tablet.
  • Enalapril, or Enalapril Maleate, and Lisinopril are two more highly preferred ACE inhibitors sold by Merck & Co, West Point, Pa.
  • Enalapril is sold under the trademark "VASOTEC” in tablet dosage form at doses of 2.5 mg, 5 mg, 10 mg and 20 mg per tablet.
  • Lisinopril is sold under the trademark "PRINIVIL” in tablet dosage form at doses of 5 mg, 10 g, 20 mg and 40 mg per tablet.
  • a family of spirolactone-type compounds of interest is defined by Formula I
  • R is lower alkyl of up to 5 carbon atoms
  • Lower alkyl residues include branched and un- branched groups, preferably methyl, ethyl and n-propyl.
  • a second family of spirolactone-type compounds of interest is defined by Formula II:
  • R 1 is C._ 3 -alkyl or C ⁇ _ 3 acyl and R 2 is H or C ⁇ -alkyl.
  • Specific coirpounds of interest within Formula II are the following: l ⁇ -Acetylthio-15 ⁇ ,16 ⁇ -methylene-7 ⁇ -methylthio-3-oxo- 17 ⁇ -pregn-4-ene-21,17-carbolactone; and
  • a third family of spirolactone-type compounds of interest is defined by a structure of Formula III:
  • R is lower alkyl, with preferred lower alkyl groups being methyl, ethyl, propyl and butyl.
  • Specific compounds of interest include:
  • a fourth family of compounds of interest is represented by Formula IV:
  • E' is selected from the group consisting of ethylene, vinylene and (lower alkanoyl) thioethylene radicals
  • E" is selected from the group consisting of ethylene, vinylene, (lower alkanoyl) thioethylene and (lower alkanoyl) thiopropylene radicals
  • R is a methyl radical except when E' and E" are ethylene and (lower alkanoyl) thioethylene radicals, respectively, in which case R is selected from the group consisting of hydrogen and methyl radicals
  • the selection of E' and E" is such that at least one (lower alkanoyl)thio radical is present.
  • a preferred family of compounds within Formula IV is represented by Formula V:
  • a more preferred compound of Formula V is l-acetylthio-17 ⁇ - (2-carboxyethyl ) -17 ⁇ -hydroxy-androst-4-en- 3 -one lactone .
  • More preferred compounds within Formula VI include the following:
  • alkyl is intended to embrace linear and branched alkyl radicals containing one to about eight carbons.
  • (lower alkanoyl)thio" o II embraces radicals of the formula lower alkyl c s .
  • spironolactone having the following structure and formal name:
  • the diuretic agent which is used with the combination of ACE inhibitor and aldosterone receptor antagonist may be selected from several known classes, such as thiazides and related sulfonamides, potassium-sparing diuretics, loop diuretics and organic mercurial diuretics.
  • thiazides are bendroflumethiazide, benzthiazide, chlorothiazide, cyclothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide and trichlormethiazide.
  • sulfonamides related to thiazides are chlorthalidone, quinethazone and metolazone.
  • potassium-sparing diuretics examples are triameterene and amiloride.
  • loop diuretics i.e., diuretics acting in the ascending limb of the loop of Henle of the kidney, are furosemide and ethynacrylic acid.
  • organic mercurial diuretics examples include mercaptomerin sodium, merethoxylline, procaine and mersalyl with theophylline.
  • a triple therapy of ACE inhibitor, spironolactone and loop diuretic was evaluated in humans as described in the following clinical trials.
  • Patients Two-hundred fourteen (214) patients with symptomatic heart failure had an ejection fraction ⁇ 35%, a history of New York Heart Association (NYHA) functional classification III-IV six months prior to enrollment, and current classification II-IV were randomized among five treatment groups. Patients were assigned to receive either spironolactone 12.5 mg (41 patients), 25 mg (45 patients), 50 mg (47 patients), 75 mg (41 patients), or placebo (40 patients) once a day for 12 weeks. Two patients that were randomized failed to take the study medication and were excluded from the analysis. All patients were taking a stable dose of ACE inhibitor, loop diuretic, and optional digitalis for 30 days prior to the first dose of study medication.
  • NYHA New York Heart Association
  • Potassium supplement therapy that was stable for 14 days prior to the first dose of study medication was also allowed. Informed consent was obtained from all patients, and the protocol was approved by each ethical committee. At enrollment all patients had normal serum potassium values ( ⁇ 5.5 mmol/L) and creatinine values of 2.0 mg/dL or ⁇ 180 mmol/L.
  • Patients were excluded from enrollment if they: (1) were diagnosed with either an acute life-threatening disease (included patients with automatic implantable cardioverter/ defibrillator) , valvular disease, unstable angina, insulin-dependent diabetes, cancer (without a reoccurrence within the last five years), or primary hepatic failure; (2) were on a waiting list for a heart transplant or experienced a myocardial infarction 30 days prior to the first dose of study medication; (3) had laboratory values for hematology or biochemistry considered abnormal and clinically significant prior to the first dose of study medication; (4) received a potassium spacing diuretic within 30 days prior to the first dose of study medication.; (5) were receiving, on a regular basis, either non-steroidal anti- inflammatory drugs or aspirin >325 mg/day, steroids, dopa ine agonists or antagonists, insulin or heparin; (6) were on any investigational medication within 30 days of the first dose of medication.
  • Cardiac assessments that included blood pressure, pulse, sodium retention score (general assessment of a patient's edematous state was derived from the summation of scores obtained from Table I), NYHA classification, and
  • Hematology White blood cell count (WBC) hematocrit, hemoglobin, platelet count.
  • Biochemistry Creatinine, potassium, AST, SGOT, urinary sodium/ potassium ratio, bicarbonate, calcium, chloride, creatinine, creatinine clearance, magnesium, glucose, urea, uric acid.
  • Neurohormones Plasma renin activity, pro-atrial natriuretic factor, urinary aldosterone.
  • Patient Characteristics Patient demographic, vital signs, and cardiac status at baseline are summarized in Table II.
  • the treatment groups did not differ significantly with respect to changes in dose of ACE inhibitor, digitalis or potassium supplements at any visit (p . ⁇ O.ll).
  • Table IV contains details of the different clinical laboratory values that showed statistically significant treatment differences with respect to mean changes at Week 12 visit compared with their respective baseline value. TABLE IV Week 12 Mean Change
  • Urinary aldosterone (nmol/D) 4 4..2211 4.27 8.11 11.13 0.76 0.00
  • N-Terminal ANF pmol/L
  • PRA NgAngl/L/s 9.90 9.33 13.18 10.23 0.50 0.00
  • Hematocrit (%) 0.00 -0.02 -0.02 -0.03 0.00 0.00 0.00 0.00 0.00 Hemoglobin (mmol/L/Fe) 0.12 -0.20 -0.31 -0.46 0.00 0.00 0.00 Potassium (mmol/L) 0.18 0.37 0.51 0.58 -0.10 0.00 Creatinine (umol/L) 6.83 9.30 14.06 21.90 -1.96 0.00 Sodium (mmol/L) -1.61 -1.85 -2.52 -3.37 -0.03 0.00
  • Plasma Renin Activity (PRA) (See Fi ⁇ . 2): A statistically significant dose-response with respect to change from baseline in PRA was seen at Day 9, Week 4 and Week 12 (P O.OOl) with higher doses of spironolactone associated with greater increases in PRA. PRA was not measured at Week 8.
  • Predictors of Hvperkalemia Seven possible predictors of hyperkalemia (potassium >5.5 mmol/L) were included in a step-wise Cox regression analysis: randomized treatment (treated as a categorical variable) , age, baseline NYHA class, baseline serum potassium, baseline PRA, baseline creatinine, baseline urinary aldosterone, and type and dose of ACE-I. Besides the dose of spironolactone, the following predictors of hyperkalemia were statistically significant in the step-wise regression analysis: type of ACE-I (captopril versus other) , baseline serum creatinine, and baseline serum potassium. Results are summarized as follows:
  • the risk ratio can be thought of as the probability that the patient with the risk factor will develop hyperkalemia, relative to the probability that a patient without the risk factor will develop it. (For example, patients on captopril are about one-third as likely to develop hyperkalemia as a patient on another ACE-I.)
  • Risk ratios relative to placebo for the various doses of spironolactone are: D__£__. - alU? Risk Ra in
  • Serum Magnesium Change from baseline in serum magnesium showed a statistically significant dose-response at Day 9 and Week 4 (p 0.048), with more patients in the placebo group showing decreases in serum magnesium. However, this effect was not seen at later visits (p >0.083) .
  • Tr ⁇ fltffient P lftg gbp 12 S mo 25 m ⁇ 50 m ⁇ 75 m ⁇ £. Patients ( % ) 5 ( 12 .5% ) 3 ( 7 .3% ) 3 ( 6 . 6% ) 13 (27 . 6% ) 6 ( 14 . 6% ) N . S .
  • Administration of the angiotensin converting enzyme inhibitor, the aldosterone receptor antagonist and diuretic may take place sequentially in separate formulations, or may be accomplished by simultaneous administration in a single formulation or separate formulations. Administration may be accomplished by oral route, or by intravenous, intramuscular or subcutaneous injections.
  • the formulation may be in the form of a bolus, or in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions.
  • solution and suspensions may be prepared from sterile powders or granules having one or more pharmaceutically-acceptable carriers or diluents, or a binder such as gelatin or hydroxypropyl-methyl cellulose, together with one or more of a lubricant, preservative, surface-active or dispersing agent.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules.
  • the ACE inhibitor may be present in an amount from about 1 to 200 mg, preferably from about 2 to 150 mg, depending upon the specific ACE inhibitor selected. A suitable daily dose for a mammal may vary widely depending on the condition of the patient and other factors.
  • the ALDO antagonist may be present in an amount of from about 1 to 400 mg, preferably from about 2 to 150 mg, depending upon the specific ALDO antagonist compound selected and the specific disease state being targetted for the combination therapy.
  • the ALDO antagonist component typically spironolactone
  • the combination therapy will be present in an amount in a range from about 1 mg to about 25 mg per dose.
  • a preferred range for spirolactone would be from about 5 mg to 15 mg per dose. More preferably, the spironolactone dosage would be in a range from about 10 mg to 15 mg per dose per day.
  • the diuretic agent may be present in a range from about 1 mg to about 200 mg, prefeably from 5 mg to 150 mg, depending upon the diuretic selected and the disease state targetted.
  • the active ingredients may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.
  • the dosage regimen for treating a disease condition with the combination therapy of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex and medical condition of the patient, the severity of the disease, the route of administration, and the particular compound employed, and thus may vary widely.
  • the active components of this combination therapy invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os. the components may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
  • Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
  • Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration.
  • the components may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
  • Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
  • compositions for use in the treatment methods of the invention may be administered in oral form or by intravenous adminstration.
  • Oral administration of the combination therapy is preferred.
  • Dosing for oral administration may be with a regimen calling for single daily dose, or for a single dose every other day, or for multiple, spaced doses throughout the day.
  • the active agents which make up the combination therapy may be administered simultaneously, either in a combined dosage form or in separate dosage forms intended for substantially simultaneous oral administration.
  • the active agents which make up the combinatin therapy may also be administered sequentially, with either active component being administered by a regimen calling for multi-step ingestion.
  • a regimen may call for sequential administration of the active agents with spaced-apart ingestion of the separate, active agents.
  • the time period between the multiple ingestion steps may range from a few minutes to several hours, depending upon the properties of each active agent such a potency, solubility, bioavailability, plasma half-life and kinetic profile of the agent, as well as depending upon the age and condition of the patient.
  • the active agents of the combined therapy may involve a regimen calling for administration of one active agent by oral route and the other active agent by intravenous route. Whether the active agents of the combined therapy are adminstered by oral or intravenous route, separately or together, each such active agent will be contained in a suitable pharmaceutical formulation of pharmaceutically- acceptable excipients, diluents or other formulations components. Examples of suitable pharmaceutically- acceptable formulations containing the active components for oral administration are given below. Even though such formulations list both active agents together in the same recipe, it is appropriate for such recipe to be utilized for a formulation containing one of the active components.
  • An oral dosage may be prepared by screening and then mixing together the following list of ingredients in the amounts indicated. The dosage may then be placed in a hard gelatin capsule.
  • captopril 62.0 mg spironolactone 12.5 mg furosemide 73.9 mg magnesium stearate 10 mg lactose 100 mg
  • An oral dosage may be prepared by mixing together granulating with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with starch, talc and stearic acid, screened and compressed into a tablet.
  • An oral dosage may be prepared by screening and then mixing together the following list of ingredients in the amounts indicated. The dosage may then be placed in a hard gelatin capsule.
  • An oral dosage may be prepared by mixing together granulating with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with starch, talc and stearic acid, screened and compressed into a tablet.

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  • General Chemical & Material Sciences (AREA)
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  • Diabetes (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des associations d'un inhibiteur de l'enzyme de conversion de l'angiotensine (ACE), d'un antagoniste du récepteur d'aldostérone et d'un diurétique, en d'autres termes, des associations thérapeutiques triples, destinées au traitement des troubles du système circulatoire. L'invention concerne plus particulièrement des associations thérapeutiques triples comprenant le captopril ou l'énalapril, administrés conjointement avec une faible dose de spironolactone et de furosémide. Cette association thérapeutique triple pourrait s'avérer particulièrement utile pour le traitement d'une insuffisance cardiaque congestive, ou pour prévenir son évolution, tout en permettant d'éviter ou de réduire les effets secondaires induits par les antagonistes d'aldostérone, tels que l'hyperkalémie.
EP96904600A 1995-02-10 1996-02-09 Association comprenant un inhibiteur de l'enzyme de conversion de l'angiotensine, une dose a effets secondaires reduits d'un antagoniste d'aldosterone, et un diuretique Withdrawn EP0808171A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP01128866A EP1201248A3 (fr) 1995-02-10 1996-02-09 Combinaison thérapeutique d'un inhibiteur d'A.C.E., une quantité d'antagoniste d'aldostérone qui réduit ses effets secondaires et un diurétique, pour le traitement des maladies cardiovasculaires

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US38685895A 1995-02-10 1995-02-10
US386858 1995-02-10
PCT/US1996/001764 WO1996024372A2 (fr) 1995-02-10 1996-02-09 Association comprenant un inhibiteur de l'enzyme de conversion de l'angiotensine, une dose a effets secondaires reduits d'un antagoniste d'aldosterone, et un diuretique

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP01128866A Division EP1201248A3 (fr) 1995-02-10 1996-02-09 Combinaison thérapeutique d'un inhibiteur d'A.C.E., une quantité d'antagoniste d'aldostérone qui réduit ses effets secondaires et un diurétique, pour le traitement des maladies cardiovasculaires

Publications (1)

Publication Number Publication Date
EP0808171A2 true EP0808171A2 (fr) 1997-11-26

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Family Applications (2)

Application Number Title Priority Date Filing Date
EP96904600A Withdrawn EP0808171A2 (fr) 1995-02-10 1996-02-09 Association comprenant un inhibiteur de l'enzyme de conversion de l'angiotensine, une dose a effets secondaires reduits d'un antagoniste d'aldosterone, et un diuretique
EP01128866A Withdrawn EP1201248A3 (fr) 1995-02-10 1996-02-09 Combinaison thérapeutique d'un inhibiteur d'A.C.E., une quantité d'antagoniste d'aldostérone qui réduit ses effets secondaires et un diurétique, pour le traitement des maladies cardiovasculaires

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP01128866A Withdrawn EP1201248A3 (fr) 1995-02-10 1996-02-09 Combinaison thérapeutique d'un inhibiteur d'A.C.E., une quantité d'antagoniste d'aldostérone qui réduit ses effets secondaires et un diurétique, pour le traitement des maladies cardiovasculaires

Country Status (8)

Country Link
EP (2) EP0808171A2 (fr)
JP (1) JPH10513472A (fr)
KR (1) KR19980702100A (fr)
AU (1) AU4866196A (fr)
BR (1) BR9607612A (fr)
CA (1) CA2212712A1 (fr)
NZ (2) NZ510572A (fr)
WO (1) WO1996024372A2 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000027380A2 (fr) 1998-11-06 2000-05-18 G.D. Searle & Co. Combinaisons therapeutiques d'inhibiteur d'enzyme de conversion de l'angiotensine et d'antagoniste vis-a-vis de l'aldosterone permettant de reduire la morbidite et la mortalite liees aux maladies cardio-vasculaires
AU2001255730A1 (en) * 2000-04-26 2001-11-07 First Horizon Pharmaceutical Corporation Methods and compositions for the treatment of cardiac indications

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9624372A2 *

Also Published As

Publication number Publication date
BR9607612A (pt) 1998-06-09
NZ302578A (en) 2001-05-25
EP1201248A2 (fr) 2002-05-02
AU4866196A (en) 1996-08-27
NZ510572A (en) 2002-11-26
JPH10513472A (ja) 1998-12-22
WO1996024372A3 (fr) 1996-09-26
EP1201248A3 (fr) 2002-05-08
CA2212712A1 (fr) 1996-08-15
KR19980702100A (ko) 1998-07-15
WO1996024372A2 (fr) 1996-08-15

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