Classifications

• • 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
  • A61K31/66—Phosphorus compounds
  • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• • 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
• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
  • A61K31/355—Tocopherols, e.g. vitamin E
• • 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
  • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
• • 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
  • A61K31/60—Salicylic acid; Derivatives thereof
  • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
  • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
• • 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
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • 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
  • 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
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • 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
  • A61P9/08—Vasodilators for multiple indications
• • 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
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • 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 present invention relates to the use of an inhibitor of the renin-angiotensin system or a pharmaceutically acceptable derivative thereof, optionally together with an other antihypertensive, a cholesterol lowering agent, a diuretic or aspirin, in the manufacture of a medicament for the prevention of cardiovascular events; to a method of preventing cardiovascular events comprising administering to a patient in need of such prevention an effective amount of an inhibitor of the renin angiotensin system or a pharmaceutically acceptable derivative thereof, optionally together with an other antihypertensive, a cholesterol lowering agent, a diuretic or aspirin; or to a combination product containing an an inhibitor of the renin-angiotensin system or a pharmaceutically acceptable derivative thereof and a cholesterol lowering agent.
• the renin-angiotensin system can be intefered with by inhibition of the enzymes synthesizing angiotensins or by blocking the corresponding receptors at the effector sites.
• RAS renin-angiotensin system
• ACE angiotensin-converting enzyme
• antagonists at angiotensin receptors more specifically, currently, the AT 1 receptor
• Angiotensin II Antagonists whose approved names generally end in “-sartan”.
• NEP neutral endopeptidase
• ACE inhibitors are well known in the art for their activity in inhibiting angiotensin converting enzyme, thereby blocking conversion of the decapeptide angiotensin I to angiotensin II.
• the principal pharmacological and clinical effects of ACE inhibitors arise from suppression of synthesis of angiotensin II.
• Angiotensin II is a potent pressor substance and, therefore, blood pressure lowering can result from inhibition of its biosynthesis, especially in animals and humans whose hypertension is angiotensin II related.
• ACE inhibitors are effective antihypertensive agents in a variety of animal models and are clinically useful for the treatment of hypertension in humans.
• ACE inhibitors are also employed for the treatment of heart conditions such as hypertension and heart failure. It is known that at least some ACE inhibitors can improve (i.e., decrease) morbidity and mortality in patient populations with heart conditions, ie. patients with low ejection fraction (EF) or heart failure (HF), but their role in a broader population of high risk patients without ventricular dysfunction or HF is unknown.
• EF ejection fraction
• HF heart failure
• the present invention generally relates to the use of an inhibitor of the renin-angiotensin system or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the prevention of cardiovascular events.
• the present inventios further relates to the use of an inhibitor of the renin-angiotensin system or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the prevention of myocardial infarction (MI), worsening of angina and cardiac arrest.
• MI myocardial infarction
• the present invention relates the use of an inhibitor of the renin-angiotensin system or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the prevention of cardiovascular events such as for example myocardial infarction (MI), worsening of angina or cardiac arrest in a patient with an increased cardiovascular risk, for example due to a manifest coronory heart disease, a history of transient ischaemic attacks or stroke, or a history of peripheral vascular disease.
• MI myocardial infarction
• the present invention relates the use of an inhibitor of the renin-angiotensin system or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the prevention of cardiovascular events in patients with no evidence of left ventricular dysfunction or heart failure.
• the present invention further relates the use of an inhibitor of the renin-angiotensin system or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the prevention of myocardial infarction (MI), stroke, cardiovascular death or overt nephropathie in a diabetic patient.
• MI myocardial infarction
• stroke cardiovascular death
• overt nephropathie myocardial infarction
• Another embodiment of the present invention is, the use of an inhibitor of the renin-angiotensin system or a pharmaceutically acceptable derivative thereof together with an other antihypertensive, a cholesterol lowering agent, a diuretic or aspirin in the manufacture of a medicament for the prevention of cardiovascular events, for example stroke, congestive heart failure, cardiovascular death, myocardial infarction, worsening of angina, cardiac arrest, or revascularisation procedures.
• cardiovascular events for example stroke, congestive heart failure, cardiovascular death, myocardial infarction, worsening of angina, cardiac arrest, or revascularisation procedures.
• Yet another embodiment of the present invention is the use of an inhibitor of the renin-angiotensin system or a pharmaceutically acceptable derivative thereof together with an other antihypertensive, a cholesterol lowering agent, a diuretic or aspirin in the manufacture of a medicament for the prevention of diabetes or diabetic complications.
• a further embodiment of the present invention is the use of an inhibitor of the renin-angiotensin system or a pharmaceutically acceptable derivative thereof together with an other antihypertensive, a cholesterol lowering agent, a diuretic or aspirin in the manufacture of a medicament for the prevention of congestive heart failure (CHF) in a patient not previously having congestive heart failure.
• CHF congestive heart failure
• Another embodiment of the present invention is a combination product containing an inhibitor of the renin-angiotensin system or a pharmaceutically acceptable derivative thereof and an other antihypertensive, a cholesterol lowering agent, a diuretic or aspirin for the use in the prevention of cardiovascular events.
• Yet another embodiment of the present invention is a combination product containing an inhibitor of the renin-angiotensin system or a pharmaceutically acceptable derivative thereof and a cholesterol lowering agent.
• a further embodiment of the present invention is a method of preventing cardiovascular events, for example myocardial infarction, worsening of angina and cardiac arrest, comprising administering to a patient in need of such prevention an effective amount of an inhibitor of the renin-angiotensin system or a pharmaceutically acceptable derivative thereof, and particular in patients having an increased cardioavascular risk.
• An other embodiment of the present invention is a method of preventing myocardial infarction, stroke, cardiovascular death or overt nephropathie in a diabetic patient, comprising administering to said patient an effective amount of an inhibitor of the renin-angiotensin system or a pharmaceutically acceptable derivative thereof.
• a further embodiment of the present invention is a method of preventing cardiovascular events, for example stroke, congestive heart failure, cardiovascular death, myocardial infarction, worsening of angina, cardiac arrest, or revascularisation procedures, or diabetes or diabetic complications comprising administering to a patient in need of such prevention an effective amount of an inhibitor of the renin-angiotensin system or a pharmaceutically acceptable derivative thereof together with an effective amount of an other antihypertensive, a cholesterol lowering agent, a diuretic or aspirin (combination therapy).
• cardiovascular events for example stroke, congestive heart failure, cardiovascular death, myocardial infarction, worsening of angina, cardiac arrest, or revascularisation procedures, or diabetes or diabetic complications
• administering to a patient in need of such prevention an effective amount of an inhibitor of the renin-angiotensin system or a pharmaceutically acceptable derivative thereof together with an effective amount of an other antihypertensive, a cholesterol lowering agent, a diuretic or aspir
• Yet another embodiment of the present invention is a method of preventing congestive heart failure in a patient not previously having congestive heart failure, comprising administering to said patient an effective amount of an inhibitor of the renin-angiotensin system or a pharmaceutically acceptable derivative thereof together with an effective amount of an other antihypertensive, a cholesterol lowering agent, a diuretic or aspirin (combination therapy).
• cardiovascular events such as stroke, congestive heart failure, cardiovascular death, myocardial infarction, worsening of angina, cardiac arrest, or revascularisation procedures such as coronary atery bypass graft surgery (CABG), PTCA, Peripheral Angioplasty Surgery, Amputation, Cariotid Endarterectomy) and metabolic disorders such as diabetis or diabetic complications such as overt nephropathy, renal dialysis or laser therapy, or new microalbuminuria can be prevented in a broad population of high risk patients with no evidence of left venticular dysfunction or heart failure, by use of an inhibitor of the RAS system.
• CABG coronary atery bypass graft surgery
• PTCA Peripheral Angioplasty Surgery
• Amputation Cariotid Endarterectomy
• metabolic disorders such as diabetis or diabetic complications
• overt nephropathy renal dialysis or laser therapy
• new microalbuminuria can be prevented in a broad population of high risk patients with no evidence of left venticular dysfunction or heart failure, by use
• cardiovascular events are also observed in a very broad range of high risk patients in addition to other effective therapies with for example antihypertensives (other than inhibitors of the RAS system), diuretics, cholesterol lowering agents or aspirin.
• antihypertensives other than inhibitors of the RAS system
• diuretics other than inhibitors of the RAS system
• cholesterol lowering agents or aspirin.
• the present invention describes a new method to prevent cardiovascular events, comprising administering to a patient in need of such prevention an effective amount of an inhibitor of the renin angiotensin system or a pharmaceutically acceptable derivative thereof, optionally together with an other antihypertensive, a cholesterol lowering agent, a diuretic or aspirin.
• High risk patients are for instance those patients which are at risk having a cardiovascular event due to a manifest coronary heart disease, a history of transient ischaemic attacks or stroke, or a history of peripheral vascular disease.
• Another group of high risk patients include those patients with diabetis.
• diabetes includes both type I diabetis, also known as insulin-dependent, diabetis mellitus (IDMM), and type II diabetis, also known as non-insulin-dependent diabetis mellitus (NIDDM).
• IDMM insulin-dependent, diabetis mellitus
• NIDDM non-insulin-dependent diabetis mellitus
• diabetic complications includes overt nephropathy, need for laser therapy or dialysis).
• inhibitor of the renin-angiotensin system includes any compound which by itself or upon administration blocks the negative effects of angiotensin II on the vasculature either by reducing the synthesis of angiotensin II or blocking its effect at the receptor.
• Inhibitors of the RAS include ACE inhibitors, Angiotensin II antagonist and renin inhibitors and the pharmaceutically accetable derivatives thereof including prodrugs and metabolites.
• ACE inhibitor 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”).
• ACE inhibitor also embraces so-called NEP/ACE inhibitors (also referred to as selective or dual acting neutral endopeptidase inhibitors) which possess neutral endopeptidase (NEP) inhibitory activity and angiotensin converting enzyme (ACE) inhibitory activity.
• Example of ACE inhibitors suitable for use herein are for instance the following compounds: AB-103, ancovenin, benazeprilat, BRL-36378, BW-A575C, CGS-13928C, CL242817, CV-5975, Equaten, EU4865, EU4867, EU-5476, foroxymithine, FPL 66564, FR-900456, Hoe-065, I5B2, indolapril, ketomethylureas, KRI-1177, KRI-1230, L681176, libenzapril, MCD, MDL-27088, MDL-27467A, moveltipril, MS-41, nicotianamine, pentopril, phenacein, pivopril, rentiapril, RG-5975, RG-6134, RG-6207, RGH0399, ROO-911, RS-10085-197, 'RS-2039, RS 5139, RS 86127, RU
• a group of ACE inhibitors of high interest are alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, ramiprilat, saralasin acetate, temocapril, trandolapril, trandolaprilat, ceranapril, moexipril, quinaprilat and spirapril.
• ACE inhibitors are commercially available, especially those listed in the above group.
• a highly preferred ACE inhibitor ramipril (known from EP 79022) is sold by Aventis, e.g. under the trademark Delix® or Altace®.
• Enalapril or Enalapril Maleate and Lisinopril are two more highly preferred ACE inhibitors sold by Merck & Co.
• Enalapril is sold under the trademark Vasotec®.
• Lisinopril is sold under the trademark Prinivil®.
• NEP/ACE inhibitors suitable for use herein inclose those disclosed in U.S. Pat. Nos. 5,508,272, 5,362,727, 5,366,973, 5,225,401, 4,722,810, 5,223,516, 5,552,397, 4,749,688, 5,504,080, 5,612,359, 5,525,723, 5,430,145, and 5,679,671, and European Patent Applications 0481522, 0534263, 0534396, 0534492 and 0671172.
• NEP/ACE inhibitors which are designated as preferred in the above U.S. patents and European Patent Applications and are incorporarted herein by reference.
• NEP/ACE inhibitor omapatrilat (disclosed in U.S. Pat. No. 5,508,272, or MDL100240 (disclosed in U.S. Pat. No. 5,430,145).
• angiotensin II antagonist 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 binding of angiotensin II at angiotensin receptors, specifically at the AT 1 receptor.
• Angiotensin II Antagonists suitable for use herein are for instance the following compounds:
• a group of Angiotensin II Antagonists of high interest are saralasin acetate, candesartan cilexetil, valsartan, candesartan, losartan potassium, eprosartan, irbesartan, tasosartan, or telmisartan.
• renin inhibitors suitable for use herein are for instance the following compounds: enalkrein; RO 42-5892; A 65317; CP 80794; ES 1005; ES 8891; SQ 34017; CGP 29287; CGP 38560; SR 43845; U-71038; A 62198; A 64662, A-69729, FK 906 and FK 744.
• compositions of RAS inhibitors are understood to include physiologically tolerable salts of RAS inhibitors, such physiologically tolerable salts are understood as meaning both their organic and inorganic salts, such as are described in Remington's Pharmaceutical Sciences (17th Edition, page 1418 (1985)).
• acidic groups inter alia, sodium, potassium, calcium and ammonium salts are preferred; for basic groups, inter alia, salts of hydrochloric acid, sulfuric acid, phosphoric acid or of carboxylic acids or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid are preferred.
• basic groups inter alia, salts of hydrochloric acid, sulfuric acid, phosphoric acid or of carboxylic acids or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid are preferred.
• RAS inhibitors suitable for use herein or their pharmaceutically acceptable derivatives can be used in animals, preferably in mammals, and in particular in human, as pharmaceuticals per se, in mixtures with one another or in the form of pharmaceutical preparations.
• the present invention also relates to pharmaceutical formulations comprising as active ingredient at least one RAS inhibitor and/or an pharmaceutically acceptable derivative thereof in addition to customary pharmaceutically innocuous excipients and auxiliaries and their use in the prevention of cardiac events and the production of medicaments therefor.
• the pharmaceutical preparations normally contain 0.1 to 99 percent by weight, preferably 0.5 to 95 percent by weight, of the RAS inhibitor and/or an pharmaceutically acceptable derivative thereof.
• the pharmaceutical preparations can be prepared in a manner known per se.
• the RAS inhibitor and/or an pharmaceutically acceptable derivative thereof are brought, together with one or more solid or liquid pharmaceutical excipients and/or auxiliaries and, if desired, in combination with other pharmaceutical active compounds into a suitable administration form or dose form, which can then be used as a pharmaceutical in human medicine or veterinary medicine.
• RAS inhibitors and/or an pharmaceutically acceptable derivative thereof can be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred administration being dependent on the particular symptoms of the disorder.
• the RAS inhibitors and/or an pharmaceutically acceptable derivative thereof can be used here on their own or together with pharmaceutical auxiliaries, namely both in veterinary and in human medicine.
• auxiliaries which are suitable for the desired pharmaceutical formulation.
• auxiliaries which are suitable for the desired pharmaceutical formulation.
• solvents for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers or colorants.
• the active compounds are mixed with the additives suitable therefor, such as excipients, stabilizers or inert diluents and are brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic or oily solutions.
• suitable administration forms such as tablets, coated tablets, hard capsules, aqueous, alcoholic or oily solutions.
• Inert excipients which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. Preparation can take place here both as dry and as moist granules.
• Possible oily excipients or solvents are, for example, vegetable or animal oils, such as sunflower oil or codliver oil.
• the active compounds are brought into solution, suspension or emulsion, if desired with the substances customary therefor such as solubilizers, emulsifiers or other auxiliaries.
• Suitable solvents are: water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, and additionally also sugar solutions such as glucose or mannitol solutions, or alternatively a mixture of the various solvents mentioned.
• compositions suitable for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compound of the formula I in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water, or a mixture of such solvents.
• a pharmaceutically acceptable solvent such as, in particular, ethanol or water, or a mixture of such solvents.
• the formulation can also contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers, and also a propellant.
• auxiliaries such as surfactants, emulsifiers and stabilizers, and also a propellant.
• Such a preparation customarily contains the active compound in a concentration from approximately 0.1 to 10, in particular from approximately 0.3 to 3% by weight.
• the dose of the active compound to be administered and the frequency of administration will depend on the potency and duration of action of the compounds used; additionally also on the nature of the indication and on the sex, age, weight and individual responsiveness of the mammal to be treated.
• the daily dose in a patient weighing approximately 75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg, to about 20 mg/kg, preferably 1 mg/kg, of body weight.
• RAS inhibitors and/or an pharmaceutically acceptable derivative thereof can also be used to achieve an advantageous theraupeutic action together with other pharmacologically active compounds for the prevention of the abovementioned syndromes.
• the present invention furthermore relates to a combination product containing an inhibitor of the renin-angiotensin system or a pharmaceutically acceptable derivative thereof and an other antihypertensive, a cholesterol lowering agent, a diuretic or aspirin for the use in the prevention of cardiovascular events.
• the invention additionally relates very generally to the combination of a RAS inhibitor and/or an pharmaceutically acceptable derivative thereof with a cholosterol lowering agent.
• the invention also relates to the simultaneous, separate or sequential administration of an RAS inhibitor and/or an pharmaceutically acceptable derivative thereof with an other antihypertensive, a cholesterol lowering agent, a diuretic or aspirin.
• the invention additionally relates to a pharmaceutical preparation comprising an RAS inhibitor and/or an pharmaceutically acceptable derivative thereof and a cholesterol lowering agent (combination product).
• the pharmaceutical preparations of the combination product according to the invention can be prepared, for example, by either intensively mixing the individual components as a powder, or by dissolving the individual components in the suitable solvent such as, for example, a lower alcohol and then removing the solvent.
• suitable solvent such as, for example, a lower alcohol
• the weight ratio of the RAS inhibitor and/or an pharmaceutically acceptable derivative thereof and the cholesterol lowering agent in the novel combinations and preparations lies in the range from 1:0.01 to 1:100, preferably 1:0.1 to 1:10.
• novel combinations and preparations in total may contain 0.5-99.5% by weight, in particular 4-99% by weight, of these active compounds.
• the doses of the various active compound components vary in the range from 0.001 to 100 mg/kg/day.
• the individual daily dosages for these combinations can range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly.
• the effect of one combination component can be potentiated by the other respective component, i.e. the action and/or duration of action of a novel combination or preparation is stronger or longer lasting than the action and/or duration of action of the respective individual components (synergistic effect).
• the novel combinations and preparations accordingly have the advantage that the amounts of active compound to be administered can be significantly reduced and undesired side effects can be eliminated or greatly reduced.
• a preferred combination product would contain for instance as a RAS inhibitors alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, ramiprilat, saralasin acetate, temocapril, trandolapril, trandolaprilat, ceranapril, moexipril, quinaprilat or spirapril, most preferably ramipril and as a cholosterol lowering agent lovastatin, pravastatin, simvastatin or fluvastatin.
• phrase “combination therapy”, in defining use of an inhibitor of the RAS system together with an other antihypertensive, a cholosterol lowering agent, a diuretic or aspirin 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 by oral ingestion of a single capsule having a fixed ratio of these active agents or ingestion of multiple, separate capsules for each agent.
• Combination therapy will also include simultaneous or sequential administration by intravenous, intramuscular or other parenteral routes into the body, including direct absorption through mucuous membrane tissues, as found in the sinus passages. Sequential administration also includes drug combination where the individual elements may be administered at different times and/or by different routes but which act in combination to provide a beneficial effect.
• Examples of classes of other antihypertensives for use in the combination product or useful in the combination therapy are for example calcium channel blockers (or calcium antagonists) and beta-blockers.
• Useful beta-blockers include timolol, atenolol, metoprolol, propanolol, nadolol and pindololpropanolol.
• Useful calicum channel blockers include diltiazem, felodipine, nifedipine, amlodipine, nimodipine, isradipine, nitrendipine and verapamil.
• Useful diuretics include methyclothiazide, hydrochlorothiazide, torsemide, metolazone, furosemide, chlorthalidone, N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide, triamterene, chlorothiazide, indapamide, bumetanide, amiloride, spironolactone, bendroflumethiazide, benzthiazide, cyclothiazide, quinethazone, hydroflumethiazide, polythiazide, trichlormethiazide, and ethacrynic acid.
• statins An example for useful cholesterol lowering agents are statins.
• HMGCoA 3-hydroxy-Omethylglutaryl-coenzyme A
• mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMGCoA reductase.
• Statins inhibit HMGCoA reductase from catalyzing this conversion. As such, statins are collectively potent cholesterol lowering agents.
• Statins include such compounds as simvastatin, disclosed in U.S. Pat. No. 4,444,784, pravastatin, disclosed in U.S. Pat. No. 4,346,227, cerivastatin, disclosed in U.S. Pat. No. 5,502,199 mevastatin, disclosed in U.S. Pat. No. 3,983,140, velostatin, disclosed in U.S. Pat. No. 4,448,784 and U.S. Pat. No. 4,450,171; fluvastatin, disclosed in U.S. Pat. No. 4,739,073, compactin, disclosed in U.S. Pat. No. 4,804,770; lovastatin, disclosed in U.S. Pat. No.
• Preferred statins include lovastatin, pravastatin, simvastatin and fluvastatin.
• Aspirin irreversibly inactivates platelet cyclooxygenase by acetylating this enzyme at the active site. In addition to reducing mortality, aspirin also reduces strokes and myocardial infarction. The exact mechanisms of the benefit of aspirin is not known.
• HOPE Heart Outcomes Prevention Evaluation
• Ramipril significantly reduces mortality, myocardial infarction, stroke, revascularization procedures, and heart failure and prevents diabetic complications in a broad range of high risk patients without low EF or heart failure.
• Patents who had HF, were known to have low EF, those on ACE-I or vitamin E, those with uncontrolled hypertension or, overt nephropathy, or recent MI ( ⁇ 4 weeks) were excluded. In this large, simple trial it was impractical to measure left ventricular function in all patients (none of whom had heart failure or were considered to need an ACE-I). Instead, echocardiograms were done in all patients (n 496) from 3 centres who entered a substudy.
• Subground analyses were conducted utilizing tests for interaction in the Cox regression model. This model was also used for treatment effect estimates adjusted for any imbalances in key prognostic factors. The adjusted and unadjusted analyses provided virtually identical results, so only the unadjusted estimates are provided.
• the proportion taking study or open label ACE-I was 87.4% at 1 year, 85.2% at 2 years, 82.2% at 3 years, 75.5% at 4 years and 78.3% at the final visit. 82.9% were receiving 10 mg of Ramipril at 1 year, 74.8% at 2 years, 71.0% at 3 years, 62.8% at 4 years and 64.6% at last visit.
• the proportion on open label ACE-I was 3.4%, 6.0%, 8.1%, 10.7% and 12.7% respectively.
• 1.6% of Ramipril patients and 1.9% of placebo patients were receiving an angiotensin-2 receptor antagonist.
• the BP at entry was 139/79 in both groups. This decreased to 133/76 in the active group and 137/78 in the control group at 1 month, 135/76 and 138178 at 2 years and 136/76 and 139/77 at the end of the study.
• ACE-I cardiovascular disease
• betablockers Yamaf S et al., Prog Cardiovasc Dis 1985; 27(5): 335-371
• aspirin BMJ 1994; 308(6921): 81-106
• lipid lowering Law M. Lipids and cardiovascular disease. Chpt 13 In: Yusuf S, Cairns J A, Camm A J, Fallen E L, Gersh B J. (Eds), Evidence Based Cardiology. London: BMJ Books, 1998. Pg. 191-205
• the ACE-inhibitor Ramipril was generally well tolerated in the trial. Apart from an increase in the number of patients stopping Ramipril for cough (excess of 5%), no other side effect was significantly more frequent. There was a small nonsignificant increase in the number of patients stopping medication for dizziness/hypotension (0.3%). The majority of patients (approximately 80%) remained on an ACE-I over the 4.2 year duration of the trial.

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