MXPA98008184A - Use of derivatives 2,5-dihidroxibencenosulfonicos for the manufacture of medicines intended for the standardization of the endothelial function, for the treatment of sexual dysfunction and the vascular complications of diabetes, as well as the endotel vascular problems of origin - Google Patents
Use of derivatives 2,5-dihidroxibencenosulfonicos for the manufacture of medicines intended for the standardization of the endothelial function, for the treatment of sexual dysfunction and the vascular complications of diabetes, as well as the endotel vascular problems of originInfo
- Publication number
- MXPA98008184A MXPA98008184A MXPA/A/1998/008184A MX9808184A MXPA98008184A MX PA98008184 A MXPA98008184 A MX PA98008184A MX 9808184 A MX9808184 A MX 9808184A MX PA98008184 A MXPA98008184 A MX PA98008184A
- Authority
- MX
- Mexico
- Prior art keywords
- vascular
- diabetes
- derivatives
- treatment
- manufacture
- Prior art date
Links
- 230000003511 endothelial Effects 0.000 title claims abstract description 15
- 230000002792 vascular Effects 0.000 title claims abstract description 15
- 206010012601 Diabetes mellitus Diseases 0.000 title claims abstract description 8
- 239000003814 drug Substances 0.000 title claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 6
- 201000001880 sexual dysfunction Diseases 0.000 title claims abstract description 6
- 231100000872 sexual dysfunction Toxicity 0.000 title claims abstract description 6
- 229940079593 drugs Drugs 0.000 title claims abstract 3
- 239000011575 calcium Substances 0.000 claims description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 7
- 229910052791 calcium Inorganic materials 0.000 claims description 7
- 238000010606 normalization Methods 0.000 claims description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N Diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- 101700080604 INVE Proteins 0.000 claims 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L Sulphite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 claims 1
- 229940077388 benzenesulfonate Drugs 0.000 claims 1
- QGNBTYAQAPLTMX-UHFFFAOYSA-L Calcium dobesilate Chemical compound [Ca+2].OC1=CC=C(O)C(S([O-])(=O)=O)=C1.OC1=CC=C(O)C(S([O-])(=O)=O)=C1 QGNBTYAQAPLTMX-UHFFFAOYSA-L 0.000 description 12
- 229960005438 calcium dobesilate Drugs 0.000 description 12
- 210000003038 Endothelium Anatomy 0.000 description 11
- 210000000709 Aorta Anatomy 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 6
- 210000001367 Arteries Anatomy 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- XYUSESXYUHHDPC-UHFFFAOYSA-N diethylazanium;2,5-dihydroxybenzene-1,4-disulfonate Chemical compound CC[NH2+]CC.CC[NH2+]CC.OC1=CC(S([O-])(=O)=O)=C(O)C=C1S([O-])(=O)=O XYUSESXYUHHDPC-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 4
- HBGOLJKPSFNJSD-UHFFFAOYSA-N 2,5-dihydroxybenzenesulfonic acid;N-ethylethanamine Chemical compound CC[NH2+]CC.OC1=CC=C(O)C(S([O-])(=O)=O)=C1 HBGOLJKPSFNJSD-UHFFFAOYSA-N 0.000 description 3
- 206010020914 Hypervitaminosis Diseases 0.000 description 3
- 206010020915 Hypervitaminosis Diseases 0.000 description 3
- 230000001225 therapeutic Effects 0.000 description 3
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 2
- 210000003989 Endothelium, Vascular Anatomy 0.000 description 2
- 229960002748 Norepinephrine Drugs 0.000 description 2
- 235000015450 Tilia cordata Nutrition 0.000 description 2
- 235000011941 Tilia x europaea Nutrition 0.000 description 2
- 229940046008 Vitamin D Drugs 0.000 description 2
- 229930003316 Vitamin D Natural products 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000001419 dependent Effects 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 230000003184 effect on constriction Effects 0.000 description 2
- 229960004817 etamsylate Drugs 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000004571 lime Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 235000019166 vitamin D Nutrition 0.000 description 2
- 239000011710 vitamin D Substances 0.000 description 2
- 150000003710 vitamin D derivatives Chemical class 0.000 description 2
- IKQCSJBQLWJEPU-UHFFFAOYSA-M 2,5-dihydroxybenzenesulfonate Chemical compound OC1=CC=C(O)C(S([O-])(=O)=O)=C1 IKQCSJBQLWJEPU-UHFFFAOYSA-M 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- 229940011899 Ethamsylate Drugs 0.000 description 1
- 206010062060 Hyperlipidaemia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- 241001490312 Lithops pseudotruncatella Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 210000003899 Penis Anatomy 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- 206010036596 Premature ejaculation Diseases 0.000 description 1
- 229940100996 SODIUM BISULFATE Drugs 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M Sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 206010047163 Vasospasm Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001800 adrenalinergic Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N benzohydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 229960002303 citric acid monohydrate Drugs 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000003247 decreasing Effects 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000001856 erectile Effects 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 244000144993 groups of animals Species 0.000 description 1
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 230000000051 modifying Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Abstract
Use of 2,5-dihydroxybenzenesulfonic derivatives of general formula I, in which R represents HSO-3; B represents Ca ++ or H 2 N + (C 2 H 5) 2; n represents 1 and 2 and m represents 1 or 2, for the manufacture of drugs intended for standardization of endothelial function, treatment of sexual dysfunction, vascular complications of diabetes and vascular problems of endothelial origin
Description
USE OF DERIVATIVES 2.5-DIHIDR0XIBENCEN0SULF0NICOS FOR THE
MANUFACTURE OF MEDICINES INTENDED FOR THE STANDARDIZATION OF THE
ENDOTHELIAL FUNCTION, FOR THE TREATMENT OF SEXUAL DYSFUNCTION
AND THE VASCULAR COMPLICATIONS OF THE DIABETES. AS WELL AS THE VASCULAR PROBLEMS OF PE PHIfiEN ENPTHELIA »
The present invention relates to the use of derivatives of dihydroenzymesulonic acids as well as of their physiologically acceptable salts for the manufacture of medicaments for the normalization of endothelial function and the treatment of sexual dysfunction of the vascular complications of diabetes and vascular problems of endothelial origin. Recent studies have shown that calcium dobesilate, etamrylate and persilate have effects at the endothelium level to facilitate vascular relaxation that depends on the endothelium. This effect is observed both in normal animals and in those that have been experimentally produced vascular aging by administering high doses of vitamin D. This activity of the calcium Dobeysilate »of the Etamsylate and the Persilate can be translated into man into therapeutic effects. In particular, it has been shown that the erection of the penis is modulated by the nitric oxide produced at the endothelial level (AL Burnett et al., 1992, 257: 401-403, J. Rajfer et al., IM Engl. J. Med. 1992 »326: 90-94, Editorial, Lancet» 1992 »340:
882-B83) and that in the circumstances where the endothelial function is altered, as in hyperlipidemia (K. Kugiyama et al., Nature, 1990. 344: 1G0-162), correction of the alteration normalizes erectile function, Accurately measured during nighttime sleep (J.-B. Kostis et al. »J. Clin. Pharmacol.» 1994. 34: 989-996; RC Rosen. "The Pharmacology of Sexual Function and Dysfunction." J. Bancroft ed. Elsevier Sc. »1995» pages 277-287). The normalization of the endothelial function obtained with the calcium dobesilate, the ethamsylate and the persilate may represent a totally new therapeutic approach to the problem of impotence (I. Saenz de Tejada et al., N. Engl. J. Med., 1989. 320: 1025-1030) both in patients with vascular problems of various causes (diabetes, arteriosclerosis, etc.) and in patients in whom only a functional problem can be detected. On the other hand, the normal lifting effect of the endothelial function can also offer therapeutic opportunities in processes of vascular spasms, in the complications of diabetes. (Durante et al., Br. J. Pharmacol .. 1988. 94: 463: 468) and in all the problems. including premature ejaculation (E.M. Hull et al., Neuropharmacology, 1994, 33: 1499-1504), where a deficit in the formation of nitric oxide for the vascular endothelium is evident. The compounds recommended in the context of the present invention correspond to the general formula i:
wherein: R represents a hydrogen atom (H) or a sulfonic group (S0-.:f); B represents a calcium atom (Ca **) or a diethyl group Z »XH * i CxHm)" ,,! ', n represents 1 or 2' and represents 1 or 2.
The compounds of the examples given below are prepared according to the procedures described above.
EXAMPLE 1
2,5-Di hydroxy benzene sulfonate calcium (Calcium Dobeysilate). "The Merck Index". 11th Edition »MercK & Co., Rahway, N.J .. E.U.A .. 1989.
2,5-Dihydroxy benzene sulfonate of diethylamine (Etamsylate). "The Merck Index", 11th edition, Merck & Co., R Rahway, N.J .. E.U.A. 1989
E ^ E? PUP a
2,5-Dihydroxybenzene-1,4-bis-disulfonate bis (die lamellar) (bis (diethylamine)) persilate. French patent FR 73/17709 (publication number 2.201.88). To study the normal lifting effect of the endothelial function of the products object of the present invention, different "in vitro" and "in vivo" studies have been carried out. The results obtained are described below, by way of non-limiting example, with one of the products of the present invention, the calcium dobesilate »demonstrating that it possesses an endothelium-dependent relaxing activity. The studies were carried out using the aortas isolated from male rabbits "according to the techniques described by A. Quintana et al. (Europ. J. Pharmacol» 1978"53: 113-116) and by the group from the University of Edinburgh (Pharmacological Experiment on Isolated Preparations, Edi burg, Livingstone, 1970). The aortas isolated without the endothelium or were prepared according to the technique described by R. Furchgott et al., (J. Cardiol Pharmacol, 1984, 6: S336: S343).
A.- "IN VITRO" STUDIES 1) Effect on contraction of the aorta, maintained by 10 ~ * M of noradrenal na Calcium dobesilate relaxes the noradrenaline contraction in a concentration-dependent manner (between 10- * M I0_ii M) The maximum relaxation was 70%.
2) Effect on tension based! in the aortas arteries with and without endothelium (basal tension = 2 g) The calcium dobesilate at concentrations between 10_ß M and 10- * M relaxes the aortas subjected to a basal tension of 2 grams in a dose-dependent manner. The maximum relaxation was 44% for arteries with endothelium and 4% for arteries without endothelium.
3) Effect on the concentration-effect curve of noradrenaline In arteries with intact endothelium, calcium dobesilate at a concentration of 10-ßM inhibits a
44% contraction obtained with 10- * M of noradrenal ina. On the contrary »with arteries without endothelium» there is no change in the curve.
B.- "IN VIVO" STUDIES The protective effect of endothelium has been studied
the calcium dobesilate in the rabbit. This is why the arterial endothelium in rabbits is damaged by daily treatment with an overdose of vitamin D., and three groups of animals are treated:
0 -. 0 - Control 1 - Hypervi taminosis D-. II - Hypervitaminosis Da + calcium dobesilate 50 mg / kg / day.
Studies are carried out with the arteries from treated rabbits measuring the effect on contraction of the aorta maintained by 10-M noradrenal ina. The calcium dobesilate (between 10- "M and 10-" M) relaxes in a dose-dependent manner the contraction due to noradrenal ina. The minimum relaxation corresponds to the group of hyperviruses s D-. (group I) while maximum relaxation is obtained with the aortas of the group treated with calcium dobesilate (group II). The maximum relaxation obtained by each group was the following:
Group 0 (control): 69%
Group I (hyper i am nos s D ^): 52% Group II (hypervitaminosis D2 + calcium dobesilate): 100%
The results obtained show that the calcium dobesilate acts potential by raising the synthesis and / or the release or by decreasing the destruction of a relaxant factor that depends on the vascular endothelium and that is probably released by the noradrenal ina through its action on the receptors to,. adrenergic In human therapy, the dose of administration is undoubtedly according to the severity of the condition to be treated. Generally »it will be between approximately 0.5 and approximately 2 g / day. The derivatives of the invention will be administered, for example, in the form of a capsule or tablet. Next »two particular galenical forms will be shown» as an example ».
EXAMPLE OF FORMULA FOR CAPSULE
Dobes calcium lime 0.500 g Cellulose 0.023 g Magnesium stearate 0.007 g Colloidal silica dioxide 0.005 g
0. 535 g
Dobes calcium lime 0.2500 g Corn starch 0.0650 g Lactose 0.0520 g Povidone K-30 0.0175 g Citric acid monohydrate 0.0125 g Magnesium stearate 0.0020 g Sodium bisulfate 0.0010 g
0. 4000 g
Taking into account the interesting pharmacological properties related to the compounds of general formula I, the present invention extends to the application of these compounds as medicaments to the pharmaceutical compositions containing them and to their use for the manufacture of medicaments intended for normalization of endothelial function »to the treatment of sexual dysfunction» of vascular complications of diabetes and vascular problems of endothelial origin.
Claims (4)
1. - Use of 2,5-dihydroxy-benzenesulfonic derivatives of general formula i: in which: R represents H or SO--., »B represents Ca ** or n represents 1 or 2 »and m represents 1 or
2. for the manufacture of drugs intended for the normalization of endothelial function» to the treatment of SEXUAL dysfunction »of vascular complications of diabetes and vascular problems of endothelial origin. 2. Use according to claim 1, characterized in that the derivative of the general formula I is calcium 2'-5-dihydroxy benzene sulfonate calcium CDobesylate].
3. Use according to claim 1, characterized in that the derivative of the general formula I is diethylamine-2-dihydroxybenzenesulfonate. CEta si lato3.
4. Use according to the rei indication 1, characterized in that the derivative of the general formula I is the 2 »5-dihydrox encene -?» 4-d sulfonate of bis (diethylamine) CPersi latoJJ.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR96/04182 | 1996-04-03 | ||
| FR9604182 | 1996-04-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA98008184A true MXPA98008184A (en) | 1999-04-06 |
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