Classifications

• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• • 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
  • A61K31/365—Lactones
  • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
• • 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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • 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
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • 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
  • A61P3/04—Anorexiants; Antiobesity agents
• • 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
  • A61P3/06—Antihyperlipidemics
• • 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
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
  • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
• • 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
  • 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

• the subject of the present invention is the use of a cannabinoid CB receptor antagonist compound, derived from pyrazole, for the preparation of medicaments useful in the prevention and treatment of dyslipidemias and of diseases associated with dyslipidemias and / or obesity such as, in particular, metabolic syndrome, as well as cardiovascular risks and hepatic risks.
• Dyslipidemia is defined by an increase in triglycerides, LDL-c (from English Low Density Lipoprotein Cholesterol), by a low concentration of HDL-c (from English High Density Lipoprotein Cholesterol), by the increase in the ratio total cholesterol / HDL-c, by the presence of small LDL particles.
• This dyslipidemia often present in the obese subject, is also recognized as having an atherogenic profile, that is to say which increases the risk of atheromatous disease.
• Obesity is now recognized as one of the major public health problems. Correlated with a large number of cardiovascular diseases, in particular arteriosclerosis, diabetes, hepatic diseases, in particular non-alcoholic steatohepatitis, cancers, respiratory disorders, it is associated with an increase in the mortality rate.
• the annual costs generated by the somatic complications of obesity are estimated by the World Health Organization (WHO) at one third of the world health budget.
• WHO World Health Organization
• Metabolic syndrome refers to a set of risk factors including dyslipidemia (low HDL-c level, high triglyceride level), increased abdominal girth / obesity, but also insulin resistance (hyperglycemia to fasting), and high blood pressure.
• This syndrome affects several million people worldwide, putting them at greater risk of developing diabetes with its complications of renal failure and retinopathy, or of causing cardiovascular disease such as coronary artery disease, coronary insufficiency, myocardial infarction, angina , atherosclerosis, arteriosclerosis, stroke, thrombosis, atherothrombosis or glaucoma, or a liver disease such as steatosis, non-alcoholic steatohepatitis, or non-alcoholic fatty degeneration of the liver.
• cardiovascular disease such as coronary artery disease, coronary insufficiency, myocardial infarction, angina , atherosclerosis, arteriosclerosis, stroke, thrombosis, atherothrombo
• metabolic syndrome By improving each parameter of the metabolic syndrome, particularly by preventing and treating the elements components of dyslipidemia and obesity, the prevention and treatment of metabolic syndrome in patients at risk can help reduce the onset of cardiovascular disease and type 2 diabetes or liver disease.
• the definition of metabolic syndrome is not globally unified, that given by the National Cholesterol Education Program (NCEP, USA), within the framework of a group of experts ATP III (from the English Adult Treatment Panel III) retains the criteria listed in the following table. Patients have a metabolic syndrome when they meet at least 3 of the 5 criteria indicated: increase in abdominal circumference / obesity, dyslipidemia, hypertension, hyperglycemia.
• the term “cannabinoid receptor antagonist derived from pyrazole” means a compound chosen from N-piperidino-5- (4-chlorophenyl) - 1 - (2,4-dichlorophenyl) -4-methylpyrazole-3- carboxamide, the international common name of which is rimonabant, described in European patent 656354 and N-piperidino-5- (4-bromophenyl) -l- (2,4-dichlorophenyl) -4-ethylpyrazole-3-carboxamide, described in European patent 1150961. Clinical studies carried out with rimonabant have shown that it acts on food intake quantitatively and qualitatively and reduces the body weight of obese patients (G. Le Fur, 2003, 35, First European Workshop on Cannabinoid Research,
• a cannabinoid CB receptor antagonist derived from pyrazole, is chosen among rimonabant and N-piperidino-5- (4-bromophenyl) - l- (2,4-dichlorophenyl) -4-ethylpyrazole-3-carboxamide, has lipid-lowering properties (in dyslipidemic subjects) which can thus contribute to decrease metabolic syndrome in patients with this syndrome, and decrease the risk of cardiovascular disease and liver disease associated with obesity and / or dyslipidemia.
• a compound cannabinoid CB receptor antagonist derived from pyrazole, chosen from rimonabant and N-piperidino-5- (4-bromophenyl) -l- (2,4-dichlorophenyl) -4- ethylpyrazole-3-carboxamide, can be used for the preparation of drugs useful to prevent and treat dyslipidemia and metabolic syndrome, more particularly such a compound antagonist of the CB ⁇ cannabinoid receptor can be used to treat and prevent the risks of cardiovascular diseases and liver disease associated with obesity and or dyslipidemia.
• Cardiovascular risks associated with dyslipidemia and / or obesity are understood to mean cardiovascular diseases such as: coronary artery disease, coronary insufficiency, atherosclerosis, arteriosclerosis, stroke, myocardial infarction, angina, thrombosis, atherothrombosis or glaucoma.
• cardiovascular diseases such as: coronary artery disease, coronary insufficiency, atherosclerosis, arteriosclerosis, stroke, myocardial infarction, angina, thrombosis, atherothrombosis or glaucoma.
• hepatic diseases associated with dyslipidaemia and or obesity, one understands: hepatic steatosis, non-alcoholic steatohepatitis, non-alcoholic fatty degeneration of the liver (in English: Non Alcoholic Fatty Liver Disease).
• compositions according to the present invention contain an effective dose of a cannabinoid CBj receptor antagonist compound, derived from pyrazole, chosen from rimonabant and N-piperidino-5- (4-bromophenyl) -l- (2,4 - dichlorophenyl) -4-ethylpyrazole-3-carboxamide, as well as at least one pharmaceutically acceptable excipient.
• a cannabinoid CBj receptor antagonist compound derived from pyrazole, chosen from rimonabant and N-piperidino-5- (4-bromophenyl) -l- (2,4 - dichlorophenyl) -4-ethylpyrazole-3-carboxamide, 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.
• the active principle can be administered in unit administration form, in mixture with conventional pharmaceutical excipients, to animals and humans for the prevention or treatment of disorders or diseases above.
• suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular, intranasal administration forms , by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
• the compounds according to the invention can be used in creams, gels, ointments or lotions.
• Forms for oral administration such as capsules or tablets are preferred. More particularly, capsules or tablets containing rimonabant are preferred at a dose of between 5 and 50 mg, more particularly doses of 5 and 20 mg.
• a cannabinoid receptor antagonist derived from pyrazole, chosen from rimonabant and N-piperidino-5- (4-bromophenyl) -l- (2,4-dichlorophenyl) -4- ethylpyrazole-3-carboxamide
• another active ingredient chosen from one of the following therapeutic classes: - an angiotensin II receptor antagonist AT], alone or combined with a diuretic; - a converting enzyme inhibitor, alone or combined with a diuretic or a calcium antagonist; - a calcium antagonist; - a beta-blocker alone or combined with a diuretic or a calcium antagonist; - an antihyperlipaptant or an antihypercholestérolaptant; - an anti-diabetic; - another anti-obesity agent.
• the present invention also relates to pharmaceutical compositions containing in association a cannabinoid CBj receptor antagonist, derived from pyrazole, chosen from rimonabant and N-piperidino-5- (4-bromophenyl) -l- (2, 4-dichlorophenyl) -4-ethylpyrazole-3-carboxamide, and another active ingredient chosen from one of the following therapeutic classes: - an angiotensin II AT ⁇ receptor antagonist, alone or in combination with a diuretic or a calcium antagonist; - an ACE inhibitor, alone or in combination with a diuretic; - a calcium antagonist; - a beta-blocker alone or combined with a diuretic or a calcium antagonist; - an antihyperlipaptant or an antihypercholestérolaptant; - an anti-diabetic; - another anti-obesity agent.
• a cannabinoid CBj receptor antagonist derived from pyrazole, chosen from rimona
• angiotensin II ATi receptor antagonist is meant a compound such as candesartan cilexitil, eprosartan, irbesartan, losartan potassium, olmesartan medoxomil, telmisartan, valsartan, each of these compounds being able to be itself associated with a diuretic such as l hydrochlorothiazide.
• converting enzyme inhibitor is meant a compound such as alacépril, benazepril, captopril, cilazapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril, spirapril, temocapril, trofenopril of these compounds which can itself be combined with a diuretic such as hydrochlorothiazide or indapamide or with a calcium antagonist such as amlodipine, diltiazem, felodipine or verapamil.
• a diuretic such as hydrochlorothiazide or indapamide
• a calcium antagonist such as amlodipine, diltiazem, felodipine or verapamil.
• calcium antagonist means a compound such as amlodipine, aranidipine, benidipine, bepridil, cilnidipine, diltiazem, efonidipine hydrochloride ethanol, fasudil, feludipipine, lacidipine, lercanidipine hydrochloride, manidipine nipidipine nidipine, nidipine hydrochloride nisoldipine, nitrendipine, terodiline, verapamil.
• beta-blocker is meant a compound such as acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol, bunitrolol, butofilolol, carololololololololololololololol , indenolol, labetalol, levobunolol, levomoprolol, mepindolol, metipranolol, metoprolol, nadolol, nebivolol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolo
• the present invention has for subject a pharmaceutical composition containing in combination rimonabant, atorvastatin or pravastatin, or preferably rimonabant and simvastatin.
• antidiabetic means a compound belonging to one of the following classes: sulfonylureas, biguanidines, alpha glucosidase inhibitors, thiazolidinedione, metiglinides, such as acarbose, acetohexamide, carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide , glimepiride, glipizide, gliquidone, glisoxepide, glybuzole, glymidine, metahexamide, metformin, miglitol, nateglinide, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide, troglitazone,
• anti-obesity agent a compound such as amfepramone, benfluorex, benzphetamine, indanorex, mazindole, mefenorex, methamphetamine, D-norpseudoephedrine or another antagonist of CB ⁇ cannabinoid receptors.
• the subject of the present invention is a pharmaceutical composition containing in combination rimonabant and an angiotensin II AT1 receptor antagonist, in particular irbesartan, losartan or valsartan.
• the present invention relates to a pharmaceutical composition containing in association rimonabant and irbesartan or N-piperidino-5- (4-bromophenyl) -l- (2,4-dichlorophenyl) -4-ethyl ⁇ yrazole-3 -carboxamide and irbesartan, as well as a pharmaceutical composition containing in combination rimonabant, irbesartan and hydrochlorothiazide or N-piperidino-5- (4-bromophenyl) -l- (2,4-dichlorophenyl) - 4-ethylpyrazole-3-carboxamide, irbesartan and hydrochlorothiazide.
• the present invention relates to a pharmaceutical composition containing in combination rimonabant and simvastatin.
• the cannabinoid receptor antagonist derived from pyrazole, chosen from rimonabant and N-piperidino-5- (4-bromophenyl) - 1 - (2,4-dichlorophenyl) -4 -ethylpyrazole-3 -carboxamide, and the other associated active ingredient can be administered simultaneously, separately or spread over time.
• “separate use” is meant the administration, at the same time, of the two compounds of the composition according to the invention, each included in a separate pharmaceutical form.
• use spread over time means the successive administration of the first compound of the composition according to the invention, included in a pharmaceutical form, then of the second compound of the composition according to the invention, included in a form separate pharmaceutical.
• the period of time between the administration of the first compound of the composition according to the invention and the administration of the second compound of the same composition according to the invention does not exceed generally not 24 hours, it may be higher if one or the other of the compounds is presented in a pharmaceutical formulation allowing, for example, weekly administration.
• the pharmaceutical forms comprising either only one of the constituent compounds of the composition according to the invention or the combination of the two compounds, or if necessary of three compounds, which can be used in the different types of uses described below.
• the invention therefore also relates to a kit containing a cannabinoid CB i receptor antagonist, derived from pyrazole, chosen from rimonabant and N-piperidino-5- (4-bromophenyl) -l- (2,4-dichlorophenyl) - 4-ethylpyrazole-3-carboxamide, and another active principle or, where appropriate, two associated active principles in which said cannabinoid CB receptor antagonist, derivative of pyrazole, and said active principle or, where appropriate, two active principles associated are in separate compartments and in similar or different packaging, and are intended to be administered simultaneously, separately or spread over time.
• a cannabinoid CB i receptor antagonist derived from pyrazole, chosen from rimonabant and N-piperidino-5- (4-bromophenyl) -l- (2,4-dichlorophenyl) - 4-ethylpyrazole-3-carboxamide
• mice with established obesity The effect of long-term (2 months) treatment with rimonabant was studied in mice with established obesity.
• the study was carried out in mice receiving either a normal diet or a fatty diet. Obesity developed in mice receiving a fatty diet and stabilized after 5 months.
• the mice were then divided into 3 groups:, group 1: maintenance of the fatty diet and oral treatment for 2 months with rimonabant at 10 mg / kg / day, in water with 0.1% Tween 80 (vehicle); group 2: maintenance of the fatty diet and administration of the vehicle (water + 0.1% of Tween 80); group 3: return to a normal diet and administration of the vehicle (water + 0.1% Tween 80); group 4 consists of mice receiving from the start a normal diet and the vehicle.
• group 1 maintenance of the fatty diet and oral treatment for 2 months with rimonabant at 10 mg / kg / day, in water with 0.1% Tween 80 (vehicle);
• group 2 maintenance of the fatty
• mice After 5 months of a fatty diet, the mice showed a 46% weight gain and a marked increase in serum leptin, insulin, glucose and total cholesterol levels.
• the levels of HDLc (from English: high density lipoprotein cholesterol) and LDLc (from English: low density lipid cholesterol) were measured for these obese mice and an increase in these levels was observed, accompanied by a decrease in HDLc / LDLc ratio.
• the weight of group 1 mice decreased by 34.5 + 0.8 g, that is to say in the same proportions as that of group 3 mice brought back to a normal diet. (33.7 + 0.6 g).
• mice showed a reduction in serum leptin, insulin and glucose levels; in the same way, these levels were reduced for the mice of group 3.
• the data measured during the assays of the triglycerides and the lipoproteins of cholesterol are reported in the tables below:
• n number of animals. From Tables 2 and 3, it can be seen that treatment with rimonabant, as administered to animals in group 1, corrects the hypertriglyceridemia observed in animals fed a fatty diet (group 2). According to Tables 2 and 3, it can be seen that treatment with rimonabant makes it possible to lower the total cholesterol level, but not to normalize it; this same treatment normalizes the LDLc level with the consequence of increasing the HDLc / LDLc ratio.
• a clinical trial was carried out for 4 weeks on 287 obese patients whose body mass index (in English BMI: body mass index) was between 30 and 40. After receiving placebo for 2 weeks, the patients were randomized to receive doses of 5, 10 or 20 mg / day of rimonabant or the placebo. A follow-up visit was made 4 weeks after the end of treatment. During the study period, patients were asked to follow a low-calorie diet (deficit of 500 kcal / day). The results observed at the end of the treatment are reported in the following table:
• Adiponectin reflects the state of insulin resistance: the change in its rate is inversely proportional to that of insulin resistance.
• the increase in the rate of adiponectin indicates the decrease in the rate of insulin resistance.
• 60.2% of patients cease to display the characteristics of the metabolic syndrome, while the proportion is 40.4% in the placebo group (p ⁇ 0.001).
• the placebo group being subjected to the same low-calorie diet as the treated group, it appears that rimonabant has a specific effect on the reduction of the metabolic syndrome.
• EXAMPLE 4 Effect of rimonabant on steatosis and steatohepatitis in obese rats.
• the effect of rimonabant on steatosis and steatohepatitis has been studied in obese Zucker fa / fa rats.
• Obese Zucker fa / fa rats, whose functionally defective leptin receptors, show obesity associated with hyperleptinemia, hyperinsulinemia, dyslipidemia and exhibit steatohepatitis.
• 3 groups are made up: - Group of thin rats / vehicle: thin Zucker rats treated with the vehicle (water and 0.1% Tween 80). - Obese rats / vehicle group: Zucker obese fa / fa rats treated by the vehicle (water and 0.1% Tween 80). - Obese rats / rimonabant group: Zucker obese fa / fa rats treated orally for 2 months with rimonabant at 30 mg / kg / day, in the vehicle (water and 0.1% Tween 80). After 2 months of treatment, the body weight and the weight of the liver are measured for each rat and a histopathological analysis of the fatty load of the livers is carried out.
• liver / body weight ratio is 41% higher in the group of obese / vehicle rats compared to the group of thin rats / vehicle.
• the treatment of obese fa / fa rats with rimonabant reduces by 80% the increase in the liver / body weight ratio observed in the rats of the obese / vehicle group, to reach a ratio of a value comparable to that observed in the group of thin rats / vehicle (Table 5).
• EXAMPLE 5 Action of rimonabant and irbesartan on plasma lipid levels in obese rats.
• the effect of rimonabant alone or in combination with irbesartan was studied in the obese Zucker fa / fa rat.
• group 1 thin Zucker rats treated with the vehicle
• group 2 obese Zucker rats fa / fa treated with the vehicle
• group 3 obese Zucker rats fa / fa treated with the rimonabant at 1 mg / kg / day
• group 4 obese Zucker fa / fa rats treated with rimonabant 3 mg / kg / day per os
• group 5 obese Zucker fa / fa rats treated with irbesartan 3 mg / kg / day per os
• group 6 obese Zucker fa / fa rats treated with rimonabant at 1 mg / kg / day per os and irbesartan 3 mg / kg / day per os
• group 7 obese Zucker fa / fa rats treated with rimonabant rimonabant at 3 mg / kg / day orally and irbesartan 3 mg / kg / day or
• rimonabant + irbesartan significantly reduces the plasma cholesterol and triglyceride levels in obese Zucker fa / fa rats.
• the administration of the 2 associated compounds improves the HDLc / LDLc ratio for the treated animals.
• EXAMPLE 6 Pharmaceutical composition.
• rimonabant is formulated in compositions which are harmless and which are re-arried by wet ranulation.
• Povidone is defined in the European Pharmacopoeia as follows: poly (1- (2-oxo-1-pyrrolidinyl) ethylene) and is made up of linear polymers of 1-vinylpyrrolidin-2-one. The tablets are preferably coated using an appropriate excipient.

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