WO2008058354A2

WO2008058354A2 - Descriptive report of the 'patent of invention of the medicament 'ramipril + metformin in combined form for cardiovascular diseases

Info

Publication number: WO2008058354A2
Application number: PCT/BR2007/000345
Authority: WO
Inventors: Walter Santos Junior
Original assignee: Walter Santos Junior
Priority date: 2006-11-16
Filing date: 2007-11-14
Publication date: 2008-05-22
Also published as: BRMU8602968U; WO2008058354A3

Abstract

The patent of invention of the medicament 'ramipril + metformin' in combined form for cardiovascular diseases, is comprised in the to combination of two medicaments used against the cardiovascular diseases, are the main causes of death in globalized world. There's neat correlation between the ponderal again and the weight excess with risk of cardiovascular diseases. The excess of weight predisposes to these diseases due to abnormalities in the metabolism of the lipids, glucose and arterial pressure. The insulin resistance / hyperinsulinemia seems to be an independent risk factor of other associated risk factors such as obesity, hyperlipedemia and hypertension, either in men or in women. The insulin and the growth factors similar to insulin estimulate activity of the smooth muscles cells and are involved in the atherogenese and even in the reestenose which follows to the coronary repair by the angiosplaty. Other insulin effects are related linked to the mechanisms that contribute for the development either of the hypertension or of the dyslipidemia. The patent of invention of the medicament ' ramipril + metformin' in combined form for cardiovascular diseases, diminishing the insulin resistance, arterial pressure, the ponderal gain and improving the lipidic profile of these patients would reduces so much the probability of cardiovascular events and consequently this kind of death in our population.

Description

DESCRIPTIVE REPORT OF THE "PATENT OF INVENTION OF THE MEDICAMENT "RAMIPRIL + METFORMIN IN COMBINED FORM FOR CARDIOVASCULAR DISEASES.

The systematic study of central obesity and insulinic resistance in the 5 population will show us in near future a constellation of highly harmful clinical events to our cardiovascular system, brain - vascular, not to mention on the augmented risk and of the inexorable evolution onto diabetes. The individuals with superior distribution fat (neck, shoulder and abdomen) present higher risk for the development of mellitus diabetes, hypertension and cardiovascular show

10 a higher risk onto developing the mellitus diabetes, hypertension and heart disease.

The association among hypertrigliceridemia, obesity, hyperinsulinemia, insulin resistance, intolerance to glucose, hypertension and coronary disease have been the reasons of studies since 1960. The combination of abdominal

15 obesity and cardiovascular disease can be partially explained by the commitment in the glucose homeostasis of glucose and insulin as well as lipides and lipoproteins related (Bjorntorp)

BJORNTORP E COLS, who first related the relation between central obesity with augmented risk of diabetes and cardiovascular disease (DCD) in

20. both men and women. The relation between the degree of obesity and the incidence of heart disease whit established in 1983 when were published the results of evolution of 5.209 men and women who took part in Framingham's study.

Although the obesity shows itself as an independent risk factor for DCD, it is important to emphasize the existence of strong association among obesity, dysplidemia, arterial hypertension, intolerance to glucose, and left ventricular hypertrophy . Finally, the association between the obesity and the occurrence of stroke vascular disease ( SVD ) was also demonstrated in Framingham's study by HURBERT e COLS. Particularly, in women, these investigators have demonstrated that the obesity contributes notably for the risk of SVD.

Although several studies have demonstrated in the last few decades a neat association between severe obesity and lager mortality, untill recently, there have been controversies as for the real damages of overweight of slight or moderate degree and particularly, as for the ideal weight that predisposes to the longevity.

In more recent studies, the inclusion of a great number of patients and the segment for periods superior to five years have permitted to establish a clear a relation between excess of adiposity and augment of mortality which occurs mainly from lesions in the vascular system. In fact, the obesity associates very frequently with conditions such as dyslipidemia, diabetes and arterial hypertension which favor the occurrence of cardiovascular events, particularly the coronary ones. Since it was described by JEAN VAGUE, in 1974, the abdominal obesity have been repeatedly associated independently to hypertension, to diabetes and to dyslipidemia, even in individuals who do not present weight excess. The insulin resistance can be defined with a condition in which occurs lesser utilization of glucose in reply to the insulin action in the peripheral tissues. Under such condition, the lesser consumption of glucose causes its serum levels to elevate, entailing lager stimulus for the production of insulin and hyperinsulinemia. The visceral abdominal fat shows itself as metabolically very active tissue, presenting high rate of renewal. Concerning the lipόlise, the visceral fatty tissue, shows itself more sensitive to the lipolidica action of the catecholamines than to the antilipolitica action of the insulin. The free fatty acids liberated from the visceral fat get to the liver by the portal system. A major hepatic volume of free fatty acids have as consequences reduction in the captation and degradation of insulin and augment in the hepatic production of very low density lipoproteins ( VLDL) rich in triglycerides. The major production of VLDL leads to the major conversion of low density lipoproteins (LDL), with elevated atherogenic potency and to the reduction in the serum levels of high density lipoproteins (HDL). In addition, the accumulation of free fatty acids in the liver entails augment in the neoglicogenese that result in the major hepatic production of glucose, albeit in the presence of insulin serum levels normally able to inhibit it. This characterizes a hepatic resistance to the insulin action. Parallelly, the free fatty acids and triglycerides in larger quantities in the systemic circulation reach the skeleton muscle and reduce the captation of glucose induced by the insulin, favoring the elevation of the serum levels of glucose. Initially, the major quantity of free fatty levels and the more elevated glicemia estimulate the insulin production. The chronic exposure of the free fatty acids by means of a phenomenon known as lipotoxicity results in the reduction of the pancreatic secretion of insulin, being then able to provoke the appearing of type 2 diabetes.

It is well known that, acting in the central nervous system, the hyperinsulinemia acts rising the activity of the sympathetic nervous system , generating a hyperadrenergico state that promotes vasoconstriction in the musculature contributing to the elevation of the arterial pressure levels. In addition , either the insulin or the augment of the sympathetic activity can estimulate the sodium renal reabsorption which in turn also contributes for the elevation of arterial pressure.

THE PATENT OF INVENTION OF THE MEDICAMENT "RAMIPRIL + METFORMIN" IN COMBINED FORM FOR CARDIOVASCULAR DISEASES, interacts as follows:

The metformin (drawing 01 picture 01) is a compound of the biguanides group which augments the sensitivity of insulin in the peripheral tissues, mainly in the liver. The reduction of glicemia provoked by metformin (drawing 01 figure 01) is especially due to the diminution of the hepatic production of glucose. It is, not linked to the augment of weight being inclusively able to determine a diminution from two to three kilos during the first six months of treatment. It reduces the triglycerides levels from 10 to 15% and also from the inhibitor a-1 of the activator of the plasminogen. In the UKPDS the metformin ( drawing 01 picture 01) was the only medication that determined a significant diminution of the incidence of cardiovascular complications in obese patients, even myocardial infarction and death.

The most frequent adverse effects are: abdominal discomfort and diarrhea, wich are usually slight and transitory. Less than 5% of the patients do not tolerate metformin (drawing 01 picture 01). Lactic acidosis is rare (about three cases per 100.000 patients/year), particularly if respected its counter- indications.

The metformin (drawing 01 picture 01) is counter-indicated in patients with renal insufficiency ( creatinine > 1 ,5 mg/dl in men and >1 ,4 mg/dl in women), congestive cardiac insufficiency, chronic hepatic ilness ( transaminases > 3 times the superior limit of the normality) and abusive use of alcohol. The medicament must be interrupted during the surgical procedures, radiographics with use of contraste and serious medical intervention.

In the heart, the inhibitors of the conversion enzyme have demonstrated evidences of its benefits by the confirmed reduction of left ventricular hypertrophy. It has positive actuation in the augment of the coronary reserve and in the attenuation of the vasoconstriction of the coronary arteries, for they do not estimulate the sympathetic nervous system in its peripheral vasodilatation action.

The RAMIPRIL ( drawing 01 figure 02) augments the sensitiveness to insulin, what constitutes a especial advantage of its use in diabetics, especially the obese ones. The consequent reduction of the plasmatic insulin levels confers to this drug a positive action against the deposition of placas of aterona in the vascular wall.

Though what has been exposed, we can affirm that the iECAS have its preferential indication in the situations in which the hypertension is associated to obesity, to mellitus diabetes and current clinical evidence, also when associated to myocardial infarction and coronary disease.

In renal disfunction, it is needful caution, especially in the sense of pushing away, previously, the possibility of estenosis from the bilateral renal arteries or the existence of estenosis from the renal artery in one only kidney, in view of which, by the fact of diminishing the intraglomerular pressure, reducing a filtration rate can, then unchain IRA situations.

To improve the patient's treatment, acting doubly in the metabolic alteration and in the pressure control, of the obese people and intolerant to glucose, hypertensives, preventing more completely the appearing of cardiovascular evens in this population, therefore, that association of ramipril ( drawing 01 figure 02) + metformina ( drawing 01 figure 02) in fixed and combined doses, is ideal for the prevention of cardiovascular events.

Claims

THE PATENT OF INVENTION OF THE MEDICAMENT " RAMIPRIL + METFORMIN" IN COMBINED FORM FOR CARDIOVASCULAR DISEASES, characterizes by utilizing more precautiously the strategies of intensive treatment, as treatment combined with metformin (drawing 01 + figure 01) and ramipril ( drawing 01 + figure 02), where the pharmacocineticas proprieties of these drugs back up the co-administration of salts. The metformin ( drawing 01 figure 01) in addition to proportioning a major control of the inherent metabolic alterations to the obese patients, reduces the levels of arterial pressure making a synergism whit the ECA inhibitors.