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
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
  • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• • 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
  • A61P9/04—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
  • A61P9/06—Antiarrhythmics
• • 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 a combination of dronedarone or a pharmaceutically acceptable salt with at least one diuretic, its therapeutic application.
• Dronedarone blocks potassium, sodium and calcium channels and also has anti-adrenergic properties.
• Dronedarone is an antiarrhythmic agent effective in maintaining sinus rhythm in patients with atrial fibrillation or atrial flutter.
• Potassium is the main intracellular ion and plays a vital role in physiology.
• this ion is the main osmotically active intracellular ion and plays an important role in the regulation of intracellular volume.
• a constant and stable potassium concentration is essential for the functioning of enzymatic systems as well as for good growth and cell division.
• Potassium contributes to the establishment of the resting potential of the cell membrane, therefore changes in potassium concentration, particularly in the extracellular compartment, have effects on cellular excitability in the nervous, muscular and cardiac systems.
• the decrease in potassium concentration is known to increase cardiac hyperexcitability at the ventricular level which can lead to serious, potentially fatal rhythm disturbances.
• sotalol sotalol
• torsade de pointe a severe and potentially fatal ventricular tachycardia.
• Torsades de pointes are facilitated by the decrease in potassium concentration.
• the decrease in potassium concentration following diuretic therapy may be complicated by sudden death, particularly in patients with impaired contractile function of the heart or left ventricular dysfunction or after myocardial infarction.
• Diuretics are widely prescribed for their effectiveness in treating a variety of conditions such as high blood pressure, congestive heart failure, kidney failure, nephrotic syndrome, cirrhosis, glaucoma.
• hypokalemia is known to increase cardiac excitability leading, in some patients, to ventricular arrhythmias and sudden deaths (Cooper et al., Circulation, 1999, 100, pages 1311-1315).
• the subject of the present invention is therefore also the use of a combination of dronedarone and its pharmaceutically acceptable salts with at least one diuretic, in particular a non-potassium sparing diuretic for the preparation of a medicinal product intended to regulate the level of potassium. in the blood, especially for the prevention of hypokalemia.
• the subject of the present invention is also the use of a combination of dronedarone and its pharmaceutically acceptable salts with at least one diuretic, in particular a potassium-sparing diuretic, for the preparation of a medicinal product intended for the prevention of cardiovascular hospitalizations and / or mortality including cardiovascular mortality and more particularly sudden death in patients with a history of atrial fibrillation or flutter auricular especially by regulating the level of potassium in the blood and more particularly by preventing hypokalemia.
• the subject of the present invention is therefore also a combination of dronedarone or a pharmaceutically acceptable salt with at least one diuretic, excluding furosemide, hydrochlorothiazide, metolazone, amiloride and spironolactone. and in particular a non-potassium sparing diuretic excluding furosemide, hydrochlorothiazide and metolazone.
• Said diuretic is administered at therapeutically active doses chosen between 1 mg / day and 2 g / day.
• Said association may be simultaneous, separate or sequential.
• non-potassium sparing diuretic is meant a diuretic increasing the excretion of potassium.
• cardiovascular hospitalization is meant a hospitalization resulting from at least one of the following pathologies (Hohnloser et al., Journal of Cardiovascular Electrophysiology, Jan. 2008, 19, No. 1, pages 69-73): relating to atherosclerosis - myocardial infarction or unstable angina,
• cardiac transplantation except cardiac transplantation, cardiac transplantation, - implantation of a pacemaker, implantable defibrillator (ICD) or other cardiac device, percutaneous coronary intervention, cerebrovascular or peripheral, changes in blood pressure (hypotension, hypertension, except syncope), cardiovascular infection, bleeding / major bleeding (requiring two or more red blood cells or any intracranial hemorrhage),
• ICD implantable defibrillator
• cardiovascular mortality covers, in the context of the invention, mortality due to all cardiovascular causes (all deaths except those due to a non-cardiovascular cause) including death of arrhythmic origin also known as arrhythmic death, and more particularly, sudden death of cardiovascular origin, also called sudden death.
• den death generally refers to death occurring within one hour or less of an hour after the onset of new symptoms or unexpected death without witnesses.
• the expression "having a history of atrial fibrillation or atrial flutter”, “having atrial fibrillation or paroxysmal or persistent atrial flutter”, “having a history / history of atrial fibrillation or atrial flutter or atrial fibrillation or atrial flutter” means a patient who has had in the past one or more episodes of atrial fibrillation or flutter and / or atrial fibrillation or atrial flutter at the time of use of the dronedarone or a pharmaceutically acceptable salt thereof.
• a patient who has had one or more episodes of atrial fibrillation or flutter in the past may have had these episodes at least three months or more before random assignment, for example, between three and six months.
• Patients with a history of atrial fibrillation or atrial flutter may also include patients with at least one of the following risk factors:
• - age equal to or greater than 70 years, more particularly equal to or greater than 75 years, - hypertension
• Patients with a history of atrial fibrillation or atrial flutter may also include patients with additional risk factors, namely at least one of the following conditions: hypertension, underlying structural heart disease, tachycardia, coronary artery disease, - non-rheumatic valve heart disease, dilated cardiomyopathy of ischemic origin, atrial fibrillation or flutter removal, eg by catheter or endomyocardial ablation, supraventricular tachycardia other than atrial fibrillation or flutter, - history of cardiac valve surgery,
• ventricular fibrillation and / or at least one cardiac device chosen from: a pacemaker, an implantable defibrillator ("ICD").
• ICD implantable defibrillator
• regulating the level of potassium in the blood is meant the prevention of the decrease or a possible increase of the said rate.
• non-potassium sparing diuretics are: thiazides, loop diuretics, proximal diuretics (osmotic, carbonic anhydrase inhibitors).
• dronedarone and its pharmaceutically acceptable salts are generally introduced into pharmaceutical compositions.
• These pharmaceutical compositions contain an effective dose of dronedarone or a pharmaceutically acceptable salt thereof, as well as at least one pharmaceutically acceptable excipient.
• Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
• compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration dronedarone, or its salt, may be administered in unit dosage form. , in admixture with conventional pharmaceutical excipients, to animals and to humans in the cases mentioned above.
• Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration , by inhalation, forms of topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal administration forms and implants.
• oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration , by inhalation, forms of topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal administration forms and implants.
• dronedarone and its pharmaceutically acceptable salts can be used in creams, gels, ointments or lotions.
• a unit dosage form of dronedarone or a pharmaceutically acceptable salt thereof in tablet form may correspond to one of the following examples:
• the dose of dronedarone administered per day can be as high as 800 mg in one or more doses.
• the dose of dronedarone administered may be taken with food.
• the dose of dronedarone administered per day, orally can be as high as 800 mg taken twice with a meal.
• the dose of dronedarone administered daily, orally may be taken at a frequency of twice a day with a meal for example with breakfast and dinner.
• both plugs can include the same amount.
• the appropriate dosage for each patient is determined by the physician according to the mode of administration, the weight, the pathology, the body surface, the cardiac output and the response of said patient.
• the present invention also relates to a method of treatment of the pathologies indicated above which comprises administering to a patient an effective dose of dronedarone, or a pharmaceutically acceptable salt thereof.
• Figure 1 represents a Kaplan Meier curve with the cumulative rate of hospitalization or all-cause death over a 24-month period
• Figure 2 shows a Kaplan Meier curve with the cumulative rate of hospitalization or cardiovascular death over a 30-month period;
• Figure 3 represents a Kaplan Meier curve with the cumulative rate of hospitalization or sudden death over a 30-month period
• Figure 4 shows a Kaplan Meier curve with the cumulative rate of hospitalization over a 30-month period
• Figure 5 shows a Kaplan Meier curve with the cumulative rate of all-cause death over a 30-month period
• Figure 6 shows a Kaplan Meier curve with the cumulative rate of cardiovascular death over a 30-month period
• Figure 7 shows a Kaplan Meier curve with the cumulative rate of sudden death over a 30-month period
• Figure 8 shows the average changes in potassium between the first and the last administration over a period of 30 months.
• dronedarone hydrochloride The efficacy of dronedarone and its pharmaceutically acceptable salts compared to placebo for the prevention of cardiovascular hospitalization or mortality was demonstrated by dronedarone hydrochloride in a prospective clinical study. , multinational, multi-centric and double-blind with random assignment into two treatment groups (dronedarone hydrochloride treated group and placebo treated group) of patients with a history of atrial fibrillation or atrial flutter.
• risk factors should be present: age at or above age 70, or even above age 75, with or without at least one of the following risk factors: o hypertension (taking antihypertensive drugs at at least two different classes), o diabetes, history of stroke (transient ischemic attack or cerebrovascular accident) or systemic embolism, o left atrial diameter greater than or equal to 50 mm measured by echocardiography, o fraction of left ventricular ejection less than 40% measured by two-dimensional ultrasound,
• the treatment was initiated from tablets containing either the placebo or a quantity of dronedarone hydrochloride corresponding to 400 mg of dronedarone one tablet in the morning during or shortly after breakfast and one tablet in the evening during or shortly after dinner.
• the duration of the planned treatment was variable depending on the time of inclusion of each patient in the study and could range from 12 months minimum for the last patient included up to a maximum corresponding to the entire duration of the study (12 months + duration of inclusion) is about 30 months for the first patients included.
• RR Relative risk
• Figure 4 which reproduces the results obtained, shows a clear separation of the two cumulative curves, very early after the start of the treatment, this separation persisting in time throughout the duration of the study.
• Potassium variations (in mmol / L) between the first and last administration of study drug are included in Figure 8 wherein B means basal level, J means day and M, month.
• the dronedarone thus makes it possible to regulate the level of potassium in the blood.
• the risk reduction was greater in diuretic-sensitive patient groups such as hypertensives where the risk reduction was approximately 62% compared to a reduction of approximately 45.5% in non-hypertensive patients. hypertensive.

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