WO2008058355A2 - Descriptive report of patent of invention of the medicament 'atorvastatin + metformin' in combined form for cardiovascular diseases - Google Patents
Descriptive report of patent of invention of the medicament 'atorvastatin + metformin' in combined form for cardiovascular diseases Download PDFInfo
- Publication number
- WO2008058355A2 WO2008058355A2 PCT/BR2007/000346 BR2007000346W WO2008058355A2 WO 2008058355 A2 WO2008058355 A2 WO 2008058355A2 BR 2007000346 W BR2007000346 W BR 2007000346W WO 2008058355 A2 WO2008058355 A2 WO 2008058355A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- insulin
- atorvastatin
- metformin
- cardiovascular diseases
- medicament
- Prior art date
Links
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 title claims abstract description 14
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 title claims abstract description 13
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 229960005370 atorvastatin Drugs 0.000 title claims abstract description 13
- 229960003105 metformin Drugs 0.000 title claims abstract description 13
- 239000003814 drug Substances 0.000 title claims abstract description 11
- 208000024172 Cardiovascular disease Diseases 0.000 title claims abstract description 10
- 230000004872 arterial blood pressure Effects 0.000 claims abstract description 5
- 229940079593 drug Drugs 0.000 claims description 2
- 238000011260 co-administration Methods 0.000 claims 1
- 238000009472 formulation Methods 0.000 claims 1
- 230000006680 metabolic alteration Effects 0.000 claims 1
- 230000002503 metabolic effect Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 abstract description 34
- 102000004877 Insulin Human genes 0.000 abstract description 17
- 108090001061 Insulin Proteins 0.000 abstract description 17
- 229940125396 insulin Drugs 0.000 abstract description 17
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 abstract description 9
- 208000008589 Obesity Diseases 0.000 abstract description 9
- 239000008103 glucose Substances 0.000 abstract description 9
- 235000020824 obesity Nutrition 0.000 abstract description 9
- 206010020772 Hypertension Diseases 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 6
- 206010060378 Hyperinsulinaemia Diseases 0.000 abstract description 4
- 230000003451 hyperinsulinaemic effect Effects 0.000 abstract description 4
- 201000008980 hyperinsulinism Diseases 0.000 abstract description 4
- 208000032928 Dyslipidaemia Diseases 0.000 abstract description 3
- 208000017170 Lipid metabolism disease Diseases 0.000 abstract description 3
- 230000002526 effect on cardiovascular system Effects 0.000 abstract description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 abstract description 3
- 206010022489 Insulin Resistance Diseases 0.000 abstract description 2
- 230000007211 cardiovascular event Effects 0.000 abstract description 2
- 150000002632 lipids Chemical class 0.000 abstract description 2
- 230000007246 mechanism Effects 0.000 abstract description 2
- ZXKXJHAOUFHNAS-UHFFFAOYSA-N fenfluramine hydrochloride Chemical compound [Cl-].CC[NH2+]C(C)CC1=CC=CC(C(F)(F)F)=C1 ZXKXJHAOUFHNAS-UHFFFAOYSA-N 0.000 abstract 2
- 230000005856 abnormality Effects 0.000 abstract 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 abstract 1
- 239000003102 growth factor Substances 0.000 abstract 1
- 230000004060 metabolic process Effects 0.000 abstract 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 abstract 1
- 108010007622 LDL Lipoproteins Proteins 0.000 description 11
- 102000007330 LDL Lipoproteins Human genes 0.000 description 11
- 230000002440 hepatic effect Effects 0.000 description 8
- 108010062497 VLDL Lipoproteins Proteins 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 206010012601 diabetes mellitus Diseases 0.000 description 6
- 235000021588 free fatty acids Nutrition 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 5
- 208000004611 Abdominal Obesity Diseases 0.000 description 4
- 206010065941 Central obesity Diseases 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 108010010234 HDL Lipoproteins Proteins 0.000 description 3
- 102000015779 HDL Lipoproteins Human genes 0.000 description 3
- 102000004895 Lipoproteins Human genes 0.000 description 3
- 108090001030 Lipoproteins Proteins 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- 102000003929 Transaminases Human genes 0.000 description 2
- 108090000340 Transaminases Proteins 0.000 description 2
- 208000037849 arterial hypertension Diseases 0.000 description 2
- 230000003190 augmentative effect Effects 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 208000019622 heart disease Diseases 0.000 description 2
- 210000001596 intra-abdominal fat Anatomy 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- -1 3 - hydroxy -3 - methylglutaryl Chemical group 0.000 description 1
- 101710095342 Apolipoprotein B Proteins 0.000 description 1
- 102100040202 Apolipoprotein B-100 Human genes 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000000853 LDL receptors Human genes 0.000 description 1
- 108010001831 LDL receptors Proteins 0.000 description 1
- 208000007177 Left Ventricular Hypertrophy Diseases 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 102000013566 Plasminogen Human genes 0.000 description 1
- 108010051456 Plasminogen Proteins 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 210000000579 abdominal fat Anatomy 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000923 atherogenic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000004283 biguanides Chemical group 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 230000014101 glucose homeostasis Effects 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000006651 lactation Effects 0.000 description 1
- 208000006443 lactic acidosis Diseases 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 125000003473 lipid group Chemical group 0.000 description 1
- 230000000512 lipotoxic effect Effects 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 208000001022 morbid obesity Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 210000004258 portal system Anatomy 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000009862 primary prevention Effects 0.000 description 1
- 230000008060 renal absorption Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 230000009863 secondary prevention Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 210000002820 sympathetic nervous system Anatomy 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- 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
Definitions
- BJORNTORP E COLS who first related the relation between central obesity with augmented risk of diabetes and cardiovascular disease (CHD) in both men and women.
- CHD cardiovascular disease
- the relation between the degree of obesity and the incidence of heart disease was established in 1983 when were published the results of evolution of 5.209 men and women who took part in Framingham study.
- the resistance to insulin can be defined whit a condition in which occurs lesser glucose utilization in reply to the insulin action in the peripheral tissues.
- the visceral abdominal fat shows itself as metabolically very active tissue, presenting high rate of renewal (8). Concerning the lip ⁇ lise, the visceral fat tissue, shows itself more sensitive to the lipolidica action of the catecholamines than to the antilipolitica action of insulin.
- VLDL very low density lipoproteins
- HDL high density lipoproteins
- the free fatty acids and triglycerides in major quantities in the systemic circulation reach the skeleton muscle and reduce the captation of glucose induced by the insulin, favoring the elevation of the glucose serum levels.
- the major quantity of free fatty acids and the more elevated glicemia estimulate the insulin production.
- the pancreas chronic exposure to the free fatty acids by means of a phenomenon known as lipotoxicity, results in the reduction of the insulin pancreatica secretion, being even able to provoke the appearing of type 2 diabetes.
- the hyperinsulinemia acts rising the activity of the sympathetic nervous system, generating a hyperadrenergico state that promotes vasoconstriction in the musculature contributing for the elevation of the arterial pressure levels.
- either the insulin or the rise of the sympathetic activity can estimulate the renal reabsorption of sodium, which, in turn also contributes for the elevation of arterial pressure.
- the metformin (drawing 01 picture 01) is a compound of the biguanides group which augments the sensitivity of insulin in the peripheral tissues, mainly the liver.
- the reduction of glycemia provoked by metformin (drawing 01 figure 01) is due specially to the diminution of the glucose hepatic production. It is not associated to the rise of weight, being able, inclusively to determine the reduction from two to three kilos during the first six months of treatment. It reduces the triglycerides from 10 to 15% and also from the inhibitor a-1 from activator of plasminogen In the UKPDS 1 the metformin ( drawing 01 picture 01) was the only medication that determined significative reduction of incidence of cardiovascular complications in obese patients, inclusively myocardial infarction and death.
- the metformin ( figure 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 illness ( transaminases > 3 times the superior limit of normality) and abusive use of alcohol.
- the medicament must be interrupted during the surgical procedures, radiographics with use of serious medical contrast and serious medical intervention.
- statins-inhibitors of the 3 - hydroxy -3 - methylglutaryl coenzyma (HMG-CoA) redutase atorvastatin (drawing 01 figure 02) is beneficial for treatment of the lipoproteins anormalities and for primary and secondary prevention of DAC in patients DM type , even in subjects with normal plasmatic levels of LDL-c since the plasmatic levels of HDL - care below the normal and are present hypertrigliceridemia.
- the levels of apolipoprotein B diminishe by the treatment with statins because of the reduction in the synthesis in combination with the augment of the depuration of the plasmatic LDL, resulting in subsequent lipoproteic degration.
- the atorvastatin After ingestion by oral via in the active form with peaks of plasmatic levels occurring 5 hours after the administration, it is a selective and potent competitive inhibitor of the HMG-CoA redutase, the atorvastatin (drawing 01 figure 02), carries out its modifier effects of lipids of two ways: it rises the number of hepatic LDL receptors in the cellular surface augment the capitation and the catabolism of the LDL, and inhibiting the VLDL hepatic synthesis, reducing , then, total number of both.
- the atorvastatin (drawing 01 figure 02) demonstrated to reduce the normal and elevated concentrations of LDL - c.
- the LDL that are formed from the very low density lipoprotein (VDL) and its catabolism occurs predominantly by the receptor of high afinity LDL.
- the mechanism of reductor effect of LDL of the atorvastatin can involve the reduction of VLDL - c cholesterol concentration and the reduction of the LDL " receptor, which leads to the reduction of production and the rise of the LDL - c catabolism.
- the counter-indications consist of hypersensitivity to active principles or to any of the excipients, active hepatopatia or persistent and unexplainable elevation of the serum transaminases, pregnancy and lactation.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The patent of invention of the medicament 'atorvastatin + metformina' in combined form for cardiovascular diseases, is abridged to combination of two medicaments used against the cardiovascular diseases which are main causes of death in globalized world. There are neat correlation between the ponderal again and the weight excess with risk of cardiovascular illness. The weight excess predisposes to these ilnesses due to abnormalities in the metabolism of the lipids, glucose and arterial pressure. The resistance to insulin/ hyperinsulinemia seems to be an risk factors independent risk factors associated as the obesity, hyperlipedemia and hypertension, either in men or in women. The insulin and the growth factors similar to insulin estimulate activity of the smooth muscle cells and are involved in the atherogenese and even in the reestenosis that follows to coronary repair by the angiosplasty. Other insulin effects are related to the mechanisms that contribute for the development either of the hypertension or of the dyslipidemia. The patent of invention of the medicament' atorvastatin + metformin' in combined form for cardiovascular diseases, diminishes the insulin resistance, arterial pressure, ponderal again and improves the lipidic profile of these patients, reducing so much the probability of cardiovascular events and consequently the death of this sort.
Description
DESCRIPTIVE REPORT OF PATENT OF INVENTION OF THE MEDICAMENT "ATORVASTATIN + METFORMIN" IN COMBINED FORM FOR CARDIOVASCULAR DISEASES.
The systematic study of central obesity and insulinic resistance in the 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 a higher risk onto developing the diabetes mellitus, hypertension and cardiovascular disease.
The association among hypertrigliceridemia, obesity, hyperinsulinemia, insulin resistance, intolerance to glucose, hypertension and the coronary disease have been the reasons of studies since 1960. The combination of abdominal obesity and heart disease can be partially explained by the commitment in the glucose homeostasis and insulin as well as lipides and lipoproteins related (Bjomtorp)
BJORNTORP E COLS, who first related the relation between central obesity with augmented risk of diabetes and cardiovascular disease (CHD) in both men and women. The relation between the degree of obesity and the incidence of heart disease was established in 1983 when were published the results of evolution of 5.209 men and women who took part in Framingham study.
Although the obesity shows itself as an independent risk factor for DCV1 it is important to lay stress on the existence of strong association among obesity, dysplidemia, arterial hypertension, intolerance to glucose, and left ventricular hypertrophy. Finally, the association between obesity and the occurrence of stroke vascular disease ( SVD) was also demonstrated in Framingham by HURBERT e COLS. Particularly, in women, these investigators have demonstrated that the obesity contributes form in a remarkable for the risk of SVD. Particularly in women, these investigators have demonstrated that the obesity contributes remarkable for the risk of SVD. Although several studies have demonstrated in the last few decades a neat association between severe obesity and lager mortality, till recently, there are still controversies as to the real damages of an overweight of slight or moderate degree and particularly as to the ideal weight that predispose to the longevity.
In more recent studies, the inclusion of a great number of patients and segment for periods superior to five years have permitted to establish a clear a relation between adiposity excess and the rise of mortality that arise principally from lesions in the vascular system. In fact, the obesity associates very often 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 has repeatedly associated independently to hypertension, diabetes and dyslipidemia, even in individuals who do not present weight excess.
The resistance to insulin can be defined whit a condition in which occurs lesser glucose utilization in reply to the insulin action in the peripheral tissues.
In this condition the lesser comsumption of glucose causes its serum levels to elevate, entailing major stimulate for the production of insulin and hyperinsulinemia. The visceral abdominal fat shows itself as metabolically very active tissue, presenting high rate of renewal (8). Concerning the lipόlise, the visceral fat tissue, shows itself more sensitive to the lipolidica action of the catecholamines than to the antilipolitica action of insulin.
The free fatty acids liberated from the visceral fat get to the liver by the portal system. A larger hepatic volum of free fatty acids has, as consequences, reduction in the capitation and degradation of insulin and augment in the hepatic production of very low density lipoproteins ( VLDL) rich in triglycerides. The larger production of VLDL leads to the larger 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 rise neoglucogenese that result in the larger hepatic production of glucose even in the presence of insulin serum levels, normally capable to inhibit it. This characterizes the hepatic resistance to the insulin action.
Parallelly, the free fatty acids and triglycerides in major quantities in the systemic circulation reach the skeleton muscle and reduce the captation of glucose induced by the insulin, favoring the elevation of the glucose serum levels. Initially, the major quantity of free fatty acids and the more elevated glicemia estimulate the insulin production. The pancreas chronic exposure to the free fatty acids, by means of a phenomenon known as lipotoxicity, results in the reduction of the insulin pancreatica secretion, being even 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 for the elevation of the arterial pressure levels. Besides, either the insulin or the rise of the sympathetic activity can estimulate the renal reabsorption of sodium, which, in turn also contributes for the elevation of arterial pressure.
THE PATENT OF INVENTION OF THE MEDICAMENT "ATORVASTATIN + 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 the liver. The reduction of glycemia provoked by metformin (drawing 01 figure 01) is due specially to the diminution of the glucose hepatic production. It is not associated to the rise of weight, being able, inclusively to determine the reduction from two to three kilos during the first six months of treatment. It reduces the triglycerides from 10 to 15% and also from the inhibitor a-1 from activator of plasminogen In the UKPDS1 the metformin ( drawing 01 picture 01) was the only medication that determined significative reduction of incidence of cardiovascular complications in obese patients, inclusively myocardial infarction and death.
The most frequent adverse effects are: abdominal discomfort and diarrhea, that 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), particulary if respected its counter-indications. THE PATENT OF INVENTION OF THE MEDICAMENT "ATORVASTATIN +
METFORMIN" IN COMBINED FORM FOR CARDIOVASCULAR DISEASES, can be utilized as follows:
The metformin ( figure 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 illness ( transaminases > 3 times the superior limit of normality) and abusive use of alcohol. The medicament must be interrupted during the surgical procedures, radiographics with use of serious medical contrast and serious medical intervention.
The use of statins-inhibitors of the 3 - hydroxy -3 - methylglutaryl coenzyma (HMG-CoA) redutase atorvastatin (drawing 01 figure 02) is beneficial for treatment of the lipoproteins anormalities and for primary and secondary prevention of DAC in patients DM type , even in subjects with normal plasmatic levels of LDL-c since the plasmatic levels of HDL - care below the normal and are present hypertrigliceridemia. The levels of apolipoprotein B diminishe by the treatment with statins because of the reduction in the synthesis in combination with the augment of the depuration of the plasmatic LDL, resulting in subsequent lipoproteic degration.
Consequently, the number of particles of LDL diminishes by the augment of the depuration rate, while the synthesis of particles of cholesterol of the lipoproteins of very low density reduces.
After ingestion by oral via in the active form with peaks of plasmatic levels occurring 5 hours after the administration, it is a selective and potent competitive inhibitor of the HMG-CoA redutase, the atorvastatin (drawing 01 figure 02), carries out its modifier effects of lipids of two ways: it rises the number of hepatic LDL receptors in the cellular surface augment the capitation and the catabolism of the LDL, and inhibiting the VLDL hepatic synthesis, reducing , then, total number of both.
The atorvastatin (drawing 01 figure 02) demonstrated to reduce the normal and elevated concentrations of LDL - c. The LDL that are formed from the very low density lipoprotein (VDL) and its catabolism occurs predominantly by the receptor of high afinity LDL. The mechanism of reductor effect of LDL of the atorvastatin (drawing 01 figure 02) can involve the reduction of VLDL - c cholesterol concentration and the reduction of the LDL" receptor, which leads to the reduction of production and the rise of the LDL - c catabolism.
The counter-indications consist of hypersensitivity to active principles or to any of the excipients, active hepatopatia or persistent and unexplainable elevation of the serum transaminases, pregnancy and lactation.
Claims
CLAIMINGS
THE PATENT OF INVENTION OF THE MEDICAMENT u ATORVASTATIN +
METFORMIN" IN COMBINED FORM FOR CARDIOVASCULAR DISEASES, charactirizes by utilizing more precauciously the strategics of intensive treatment, as treatment combined with metformin (drawing 01 + figure 01) and atorvastatin ( drawing 01 + figure 02) in a combined formulation, where the pharmacocinetic proprieties of these of drugs back up the co-administration of salts. The metformin ( drawing 01 figure 01) in addition to proportioning a major control of the inerent metabolic alterations to the obese patients, reduces the levels of arterial pressure performing a synergism with the atorvastatin ( drawing 01 figure 02) in a major global metabolic control.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BR000688 | 2006-11-16 | ||
| BRMU8600688 | 2006-11-16 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2008058355A2 true WO2008058355A2 (en) | 2008-05-22 |
| WO2008058355A3 WO2008058355A3 (en) | 2009-04-02 |
Family
ID=39402023
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/BR2007/000346 WO2008058355A2 (en) | 2006-11-16 | 2007-11-14 | Descriptive report of patent of invention of the medicament 'atorvastatin + metformin' in combined form for cardiovascular diseases |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2008058355A2 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014011926A1 (en) * | 2012-07-11 | 2014-01-16 | Elcelyx Therapeutics, Inc. | Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk |
| US8796338B2 (en) | 2011-01-07 | 2014-08-05 | Elcelyx Therapeutics, Inc | Biguanide compositions and methods of treating metabolic disorders |
| US9050292B2 (en) | 2011-01-07 | 2015-06-09 | Elcelyx Therapeutics, Inc. | Chemosensory receptor ligand-based therapies |
| US9211263B2 (en) | 2012-01-06 | 2015-12-15 | Elcelyx Therapeutics, Inc. | Compositions and methods of treating metabolic disorders |
| US9480663B2 (en) | 2011-01-07 | 2016-11-01 | Elcelyx Therapeutics, Inc. | Biguanide compositions and methods of treating metabolic disorders |
| US9572784B2 (en) | 2011-01-07 | 2017-02-21 | Elcelyx Therapeutics, Inc. | Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk |
| US10154972B2 (en) | 2011-01-07 | 2018-12-18 | Elcelyx Therapeutics, Inc. | Biguanide compositions and methods of treating metabolic disorders |
| US10668031B2 (en) | 2011-01-07 | 2020-06-02 | Anji Pharma (Us) Llc | Biguanide compositions and methods of treating metabolic disorders |
| US11759441B2 (en) | 2011-01-07 | 2023-09-19 | Anji Pharmaceuticals Inc. | Biguanide compositions and methods of treating metabolic disorders |
| US11974971B2 (en) | 2011-01-07 | 2024-05-07 | Anji Pharmaceuticals Inc. | Compositions and methods for treating metabolic disorders |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040265375A1 (en) * | 2003-04-16 | 2004-12-30 | Platteeuw Johannes J. | Orally disintegrating tablets |
-
2007
- 2007-11-14 WO PCT/BR2007/000346 patent/WO2008058355A2/en active Application Filing
Cited By (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9962344B2 (en) | 2011-01-07 | 2018-05-08 | Elcelyx Therapeutics, Inc. | Chemosensory receptor ligand-based therapies |
| US9481642B2 (en) | 2011-01-07 | 2016-11-01 | Elcelyx Therapeutics, Inc. | Biguanide compositions and methods of treating metabolic disorders |
| US9050292B2 (en) | 2011-01-07 | 2015-06-09 | Elcelyx Therapeutics, Inc. | Chemosensory receptor ligand-based therapies |
| US11974971B2 (en) | 2011-01-07 | 2024-05-07 | Anji Pharmaceuticals Inc. | Compositions and methods for treating metabolic disorders |
| US11759441B2 (en) | 2011-01-07 | 2023-09-19 | Anji Pharmaceuticals Inc. | Biguanide compositions and methods of treating metabolic disorders |
| US9463170B2 (en) | 2011-01-07 | 2016-10-11 | Elcelyx Therapeutics, Inc. | Chemosensory receptor ligand-based therapies |
| US9480663B2 (en) | 2011-01-07 | 2016-11-01 | Elcelyx Therapeutics, Inc. | Biguanide compositions and methods of treating metabolic disorders |
| US10610500B2 (en) | 2011-01-07 | 2020-04-07 | Anji Pharma (Us) Llc | Chemosensory receptor ligand-based therapies |
| US9572784B2 (en) | 2011-01-07 | 2017-02-21 | Elcelyx Therapeutics, Inc. | Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk |
| US10028923B2 (en) | 2011-01-07 | 2018-07-24 | Elcelyx Therapeutics, Inc. | Biguanide compositions and methods of treating metabolic disorders |
| US8796338B2 (en) | 2011-01-07 | 2014-08-05 | Elcelyx Therapeutics, Inc | Biguanide compositions and methods of treating metabolic disorders |
| US11065215B2 (en) | 2011-01-07 | 2021-07-20 | Anji Pharma (Us) Llc | Biguanide compositions and methods of treating metabolic disorders |
| US10668031B2 (en) | 2011-01-07 | 2020-06-02 | Anji Pharma (Us) Llc | Biguanide compositions and methods of treating metabolic disorders |
| US10154972B2 (en) | 2011-01-07 | 2018-12-18 | Elcelyx Therapeutics, Inc. | Biguanide compositions and methods of treating metabolic disorders |
| US10159658B2 (en) | 2011-01-07 | 2018-12-25 | Elcelyx Therapeutics, Inc. | Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk |
| US10201511B2 (en) | 2011-01-07 | 2019-02-12 | Elcelyx Therapeutics, Inc. | Compositions and methods for treating metabolic disorders |
| US10603291B2 (en) | 2012-01-06 | 2020-03-31 | Anji Pharma (Us) Llc | Compositions and methods for treating metabolic disorders |
| US9770422B2 (en) | 2012-01-06 | 2017-09-26 | Elcelyx Therapeutics, Inc. | Compositions and methods for treating metabolic disorders |
| US9211263B2 (en) | 2012-01-06 | 2015-12-15 | Elcelyx Therapeutics, Inc. | Compositions and methods of treating metabolic disorders |
| WO2014011926A1 (en) * | 2012-07-11 | 2014-01-16 | Elcelyx Therapeutics, Inc. | Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk |
| JP2018087214A (en) * | 2012-07-11 | 2018-06-07 | エルセリクス セラピューティクス インコーポレイテッド | Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk |
| JP2015522080A (en) * | 2012-07-11 | 2015-08-03 | エルセリクス セラピューティクス インコーポレイテッド | Compositions for reducing cardiovascular metabolic risk comprising statins, biguanides, and additional agents |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008058355A3 (en) | 2009-04-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2008058355A2 (en) | Descriptive report of patent of invention of the medicament 'atorvastatin + metformin' in combined form for cardiovascular diseases | |
| WO2008058358A2 (en) | Descriptive report of the patent of invention of the medicament 'rosuvastatin + metformin' in combined form for cardiovascular diseases. | |
| JP6421961B2 (en) | Methods for the treatment or prevention of diabetes mellitus and other metabolic imbalances | |
| US12178810B2 (en) | Tesofensine and metoprolol for treatment of hypertension | |
| US6881739B1 (en) | Use of cortisol antagonists in the treatment of heart failure | |
| JP5974056B2 (en) | Composition useful for the prevention of type 2 diabetes and its complications in prediabetic patients with insulin resistance | |
| JP7344422B2 (en) | Pharmaceutical compositions for prevention and treatment of diabetes and their uses | |
| US20120053172A1 (en) | Use of a combination of diazoxide and metformin for treating obesity or obesity related disorders | |
| US6426096B1 (en) | Anorexigenic composition | |
| WO2008058354A2 (en) | Descriptive report of the 'patent of invention of the medicament 'ramipril + metformin in combined form for cardiovascular diseases | |
| WO2008058353A2 (en) | Descriptive report of the patent of invention of the medicament 'telmisartana + metformin' in combined form for cardiovascular diseases | |
| CA2687154A1 (en) | Composition useful for the prevention of the adverse effect due to the use of ppar-gamma agonists | |
| WO2008058357A2 (en) | Descriptive report of patent of invention of the medicament candesartana + metformin in combined form for cardiovascular diseases | |
| CN1976696B (en) | Pharmaceutical composition for prevention or treatment of lipid metabolism disorder | |
| JP5697337B2 (en) | Compositions useful for the treatment of type 2 diabetes | |
| RU2729352C1 (en) | Method of patients with obesity and arterial hypertension state correction | |
| KR20070015114A (en) | Administration method of 3,3,14,14 tetramethyl hexadecane 1,16 diacid | |
| EP2361092A1 (en) | Health care | |
| US20060166957A1 (en) | Methods of treating obesity and related disorders using tellurium selenium compounds | |
| KR101346879B1 (en) | Health food and Composition comprising hydroxybiphenyl derivatives for treating and preventing obesity, diabetes, fat liver, or hyperlipidemia | |
| CN102379875A (en) | Compound preparation containing benidipine hydrochloride and metoprolol tartrate and application thereof | |
| Seng | Management of Type 2 | |
| Seng | Management of Type 2 Diabetes Mellitus | |
| ARONNE et al. | ■ MODIFYING OBESITY AND CARDIOMETABOLIC THERAPEUTIC OPTIONS FOR RISK FACTORS | |
| Ray | The impact of weight loss as possible index of the metabolic syndrome in obese people |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 07845472 Country of ref document: EP Kind code of ref document: A2 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 07845472 Country of ref document: EP Kind code of ref document: A2 |