WO1994018958A1 - Compositions antagonistes des recepteurs 5-ht2 utiles dans le traitement de pathologies veineuses - Google Patents

Compositions antagonistes des recepteurs 5-ht2 utiles dans le traitement de pathologies veineuses Download PDF

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Publication number
WO1994018958A1
WO1994018958A1 PCT/US1993/001485 US9301485W WO9418958A1 WO 1994018958 A1 WO1994018958 A1 WO 1994018958A1 US 9301485 W US9301485 W US 9301485W WO 9418958 A1 WO9418958 A1 WO 9418958A1
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Prior art keywords
receptor antagonist
hydrochloride
receptor
ethyl
piperazinyl
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PCT/US1993/001485
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English (en)
Inventor
M. Samir Amer
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Sam Amer & Co., Inc.
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Filing date
Publication date
Application filed by Sam Amer & Co., Inc. filed Critical Sam Amer & Co., Inc.
Priority to PT93906979T priority Critical patent/PT684816E/pt
Priority to ES93906979T priority patent/ES2215990T3/es
Priority to KR1019950703438A priority patent/KR100278522B1/ko
Priority to DK93906979T priority patent/DK0684816T3/da
Priority to EP93906979A priority patent/EP0684816B1/fr
Priority to CA002156481A priority patent/CA2156481C/fr
Priority to DE69333413T priority patent/DE69333413T2/de
Priority to AT93906979T priority patent/ATE258789T1/de
Priority to AU37748/93A priority patent/AU678149B2/en
Publication of WO1994018958A1 publication Critical patent/WO1994018958A1/fr
Priority to US08/512,235 priority patent/US5605902A/en

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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
    • A61K31/435—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
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • 5-HT 2 RECEPTOR ANTAGONIST COMPOSITIONS USEFUL IN TREATING VENOUS CONDITIONS This invention relates to the treatment of and to compositions containing 5- HT 2 receptor antagonists useful in treating such venous conditions as hemorrhoids, varicose veins, venous insufficiency and wounds.
  • 5-HT 2 receptor antagonists useful in treating such venous conditions as hemorrhoids, varicose veins, venous insufficiency and wounds.
  • 5-HT2 receptor antagonist can also be administered prophylactically.
  • Serotonin or 5-hydrox tryptamine " or 5- HT is a vasoconstrictor and a powerful stimulant of a variety of smooth muscles and nerves.
  • a derivative of the amino acid tryptophan, 5-HT is formed predominantly in enterochromaffin or argentaffin cells of the intestinal tract. It is transported in the blood by platelets and is present in the brain and other tissues. Its pharmacological actions result in a variety of responses involving, inter alia, the cardiovascular, respiratory, and gastrointestinal systems, smooth muscles, exocrine glands, carbohydrate metabolism, sensory nerve endings, autono ic ganglia, the adrenal medulla, and the central nervous system.
  • Cellular reaction is determined by the type and number of receptors on the outer membrane of the cells. Consequently, one hormone can trigger different responses in different cells because it may have different receptors. Thus, the same hormone that can contract one smooth muscle cell, can also relax a skeletal muscle cell having a different receptor to the same hormone. This is true for 5-HT.
  • 5-HT 5-HT
  • the antagonists are classified according to their ability to displace the labeled hormone from the receptor in question. Those that can displace it from a particular receptor are said to be antagonists to that receptor. Some antagonists can displace the hormone from one receptor without affecting' its binding to another, and the degree of selectivity can thus be determined.
  • the ability of antagonists to antagonize some of the effects of the hormone thought to be related to one receptor or another are examined.
  • a suitable example relates to the hormone histamine.
  • Some antagonists can antagonize its acid secretory receptors with little or no effect on its lung receptors and thus inhibit acid secretion by the stomach without causing bronchodilatation.
  • Other antagonists antagonize histamine's lung effects with almost no activity against its acid secretory effects.
  • Biochemical studies are those in which the biochemical effects of the hormone in question can be antagonized selectively by one receptor antagonist or another.
  • Serotonin receptors are divided into several classes, one of which is referred to as the 5-HT2 receptor. A complete discussion of such receptors will be found in "The Peripheral Actions of 5-Hydroxytryptamine" edited by John R. Fozard (Oxford University Press, 1989) . Receptors for 5-HT have been classified based on the responses they produce when stimulated by 5- HT. At present four main classes and several subclasses of 5-HT receptors are generally recognized. The four main classes are:
  • 5-HT- ⁇ receptorst These receptors appear to mediate the relaxation of smooth muscles and increased heart rate.
  • 5-HTn receptors These receptors appear to mediate vasoconstriction and platelet aggregation.
  • 5-HT3 receptors These"receptors ⁇ appear to mediate vomiting by action in the central nervous system.
  • 5-HT receptor antagonists produce different pharmacological responses depending on the type and location of the 5-HT receptor they antagonize of block. They produce a variety of different responses in the central nervous system. Peripherally, such antagonists can sometimes produce antagonistic responses. This is similar in many respects to the Histamine antagonists. Histamine-1 (H-l) antagonists inhibit bronchioconstriction but have no effect on gastric acid secretion while Histamine-2 (H- 2) antagonists inhibit gastric acid secretion with no effects on the lungs.
  • Histamine-1 (H-l) antagonists inhibit bronchioconstriction but have no effect on gastric acid secretion while Histamine-2 (H- 2) antagonists inhibit gastric acid secretion with no effects on the lungs.
  • 5-Hydroxytryptamine (5-HT 2 ) receptor antagonists are different from other 5-HT receptor antagonists in many respects in that 5- HT 2 receptor antagonists: a. Antagonize serotonin stimulation of intra-cellular calcium levels via stimulation of phosphoinostiide hydrolysis in smooth muscle, human and rabbit platelets and astrocytes. b. Antagonize serotonin contraction of the canine and human basilar artery while producing no hypotension. c. Antagonize the increased vascular permeability induced by 5-hydroxytryptamine d.
  • 5-HT can induce both contraction and relaxation in blood vessels.
  • the type of responses produced depends on the type of receptor present. For example, 5-HT 2 receptor stimulation contracted the porcine coronary arteries (Daniel J. Cushing and Marlene L. Cohen, " Comparison of the Serotonin Receptors That Mediate Smooth Muscle Contraction in Canine and Porcine Coronary Artery” J. Pharmacol. Exptl. Therapy. 261, 856 - 862, 1992) but dilated the canine renal artery (Shoji et al.
  • 5-HT can mediate both contraction and relaxation in the same tissue (Zeljko S. Radic et al., "Alterations in Serotonergic Receptor Expression in Experimental Vein Grafts;” J. Vascular Surgery 14, 40 - 47, 1991) .
  • Tissues respond to hormones only if they possess specific receptors capable of recognizing and interacting with the hormone in question.
  • the selective and sometimes opposite responses of different tissues to the same hormone, in this case 5-hydroxytryptamine (5-HT) or serotonin is determined by the type and density of the receptors to the hormone -that exist in the particular tissue. It is not possible to predict the activity of 5-HT receptor antagonists in a particular disease condition unless the tissue involved in that disease is tested. For example, 5-HT will not contract the colon vein of cats or dogs since the colon veins from both animals species have no 5-HT receptors. 5-HT will contract the human colon vein because the human colon vein contains 5-HT2 receptors that mediate contraction, (see example below) .
  • 5-HT 2 receptor antagonists are expected to antagonize the increased contraction of the colonic veins induced by 5-HT (shown in the data) and decrease the vascular permeability that mediate the swelling and discomfort of hemorrhoids.
  • Other 5-HT receptor antagonists (as S-HT- ⁇ 1A 1B lc ID IP and 3 ⁇ w ⁇ not mediate these effects and are expected to have no beneficial effects in treating hemorrhoids, varicose veins, venous insufficiency and the healing of wounds.
  • 5-HT 2 receptor antagonists produce several effects including inhibition of platelet aggregation and decreasing vascular permeability.
  • 5-HT 2 receptor antagonist compounds have traditionally been used as anti- anxiety agents, antidepressants, antipsychotics, anti-migraine agents or as modifers of certain other CNS functions.
  • 5-HT 2 receptor antagonists do not cause vasodilation in the arteries and do not lower blood pressure. This is shown in the example below where the 5-HT 2 receptor antagonist 2' [2- (1-methyl-2-piperidyl) ethyl] cinnamanilide hydrochloride do not lower blood pressure. This is also exemplified by ritanserine and ICI 169, 269 (Gerard J. Blauw et al. , "Antihypertensive Treatment with Ketanserine Shows No Evidence of Vascular
  • Serotonin is not a general endogenous vasoconstrictor. Its effects in the different blood vessels varies depending on the location and size of the vessel in question (P. . van Zwieten et al., "Pharmacological Profile of Antihypertensive" Drugs with Serotonin Receptor and alpha-Adrenoreceptor Activity Drugs 40 (suppl 4) 1 - 8, 1990) .
  • Hemorrhoids is a disease of veins not arteries. Drugs that are expected to have beneficial activity in hemorrhoids must be able to antagonize the contractile effects of 5-HT on the colon vein.
  • Hemorrhoids is a varicose dilation of veins in the superior or inferior hemorrhoidal plexus, resulting from a persistent increase in venous pressure" (Dorland's Illustrated Medical Dictionary, 25th Edition, .B. Saunders, Philadelphia, 1974) . Hemorrhoids refer to a madd of dilated veins in swollen tissue situated near the anal sphincter. They are believed to result from a persistent increase in venous pressure, which may be due, in part, to a constriction of the large downstream colonic veins. Occlusion due to platelet aggregation and thrombus formation may also contribute to the symptoms of hemorrhoids by interrupting blood flow and increasing blood stasis and tissue congestion. Varicose veins are enlarged, twisted superficial veins. Varicose veins partially result from incompetent venous valves that may be acquired or congenital.
  • Venous insufficiency results from increase tone (partial constriction) of the deeper veins (particularly in muscles) which impedes good circulation and results in blood pooling and stasis. This is turn results in pain, tenderness and edema.
  • 5-hydroxytryptamine (5-HT or serotonin) is released from the blood platelets when the blood sits around for a long time and is thought to mediate the contraction of the exit veins.
  • 5-HT is released from blood platelets causing venous constriction and interfering with good drainage and circulation. Good drainage and circulation are needed for proper and fast healing of the wounds.
  • This invention is directed to compositions or medicines useful in treating or preventing such conditions as hemorrhoids, varicose veins, venous insufficiency and wounds.
  • a 5- hydroxytryptamine-2 receptor antagonist (5-HT 2 ) to treat an animal or human, in need of such treatment.
  • the 5-HT receptor antagonist can also be used prophylactically.
  • the 5-HT 2 receptor antagonist is used at an effective therapeutic dose.
  • Preferred 5-HT 2 receptor antagonists include 2 ' [2- (1-methyl-2-piperidyl) ethyl] cinnamanilide hydrochloride; 2- [3- [4- (3- chlorophenyl) -1-piperazinyl]propyl-5-ethyl-2,4- dihydro-4- (2-phenoxyethyl) -3H-l,2,4-triazol-3- one hydrochloride,8- [4- [4- (l,2-benzisotriazol-3- yl) -1-piperazinyl]butyl] -8-azaspiro[4,5] decane- 7,9-dione hydrochloride and any mixture thereof.
  • the 5-HT 2 receptor antagonist 2' - [2- (l-methyl-2- piperidyl) ethyl] cinnamanilide hydrochloride is disclosed and claimed in U.S. Patent Re. 30, 811 (Dysktra et al. Mead Johnson & Company) .
  • the 5- HT 2 receptor antagonist 2- [3- [4- (3- chlorophenyl) -1-piperazinyl]propyl-5-ethyl-2,4- dihydro-4- (2-phenoxyethyl) -3H-l,2,4-triazol-3- one hydrochloride is disclosed in U.S. Patents 4,338,317 and 4,487,773.
  • the 5-HT 2 receptor antagonist 8- [4- [4(l,2-benzisotriazol-3-yl) -1- piperazinyl]butyl] -8-azaspiro [4,5] decane-7,9- dione hydrochloride is disclosed in German Patent DE 3,247,530 and U.S. Patent 4,411,901.
  • representative 5-HT 2 receptor antagonists were found to produce highly surprising results in blocking the contractile effects of 5-HT on the human colon.
  • Human colonic vein rings were isolated from discarded human colon tissue following surgery (colostomy) . The rings were prepared immediately after surgery and were suspended in buffered physiological saline. The contractions produced by the rings in response to the addition of 5-HT in vitro were measured.
  • the effects of three selected 5-HT 2 receptor antagonist compounds on antagonizing 5-HT contractile effects were also determined.
  • Table A also includes the activities of the three compounds on four receptors to determine receptor selectivity.
  • Compound I as used herein has the chemical formula: 2 ' [2- (l-methyl-2- piperidyl)ethyl] cinnamanilide hydrochloride, and has the following structural formula:
  • Compound II as used herein has the chemical formula : 2 - [3 - [4- (3 -chlorophenyl) -1- piperazinyl] propyl-5-ethyl-2 , 4-dihydro-4- (2 - phenoxyethyl) -3H-l, 2 , 4-triazol-3 -one hydrochloride, and has the following structural formula : CI
  • Compound III as used herein has the chemical formula: 8- [4- [4- (l,2-benzisotriazol-3-yl) -1- piperazinyl]butyl] -8-azaspiro[4,5] decane-7,9- dione hydrochloride, and has the following structural formula:
  • the IC-50 is the concentration that inhibits agonist binding to the receptor by 50%.
  • the activity is determined as follows: Rings of human colon veins are prepared and hung in a tissue bath. The contractions of the rings are monitored. Adding 5-HT causes the rings to contract. Pre-addition of increasing concentrations of the antagonist result in lesser contractions. The amount of antagonist causing a 50% inhibition of the contractions is then calculated.
  • the receptor blocking profile is determined as follows: Labeled 5-HT is mixed with a purified preparation containing the receptor. The amount of labeled material that attaches itself to the receptor and cannot be washed off is calculated. In a series of other similar tubes, the same quantity of labeled 5-HT is mixed with increasing concentrations of the antagonist which will antagonize the binding of 5-HT to the receptor. Decreasing quantities of the labeled material will bind to the receptor. The concentration of the antagonist that inhibits the binding of 50% is then calculated. Table B Activity against 5-HT on the human colon in vitro
  • Beagle hounds of either sex weighing 8 - 20 kg were acclimated (18 - 29°C, humidity 30 - 70%) for a minimum of 21 days with automatically controlled illumination (12 hours light/12 hours dark) prior to use.
  • Each animal received approximately 300 grams of Purina Lab Canine Diet #5006 daily which was adjusted as needed for each animal to maintain appropriate body weight.
  • Husbandry practices and veterinary care were in accordance with the Guide for Care and Use of Laboratory Animals (NIH Publication No. 85 - 23)
  • the 5-HT 2 receptor antagonists of this invention may be used topically or systemically, and they may be taken orally, in liquid, powder, table or capsule form; parenterally, by intravenous, subcutaneous, or intramuscular injection; transdermally, topically by direct application in the form of a cream, gel, or ointment; rectally by suppository or enema; or by inhalation therapy.
  • the 5-HT 2 receptor antagonists of this invention may be prepared and used in any suitable solid or liquid form, e.g. powder, cream, paste, table, lozenge, gel, chewing gum, solution, suspension, emulsion, salve, aerosol or the like.
  • pharmacological agents may be administered in admixture with a pharmaceutically acceptable carrier or a dermatologically acceptable carrier for the topical preparations.
  • compositions contain the active ingredient in an amount ranging from less than 1% to over 99%, with the remainder being a pharmaceutically acceptable or dermatologically acceptable solid or liquid carrier, which may contain other conventional excipients.
  • carrier and excipients include fillers, binders, flavors, sweetners, bulking and coloring agents, antioxidants, anionic, nonionic, cationic, zwitterionic, and amphoteric surface active detergents, sudsing, dispersing and emulsifying agents, buffering and pH adjusting agents, water and organic solvents, humectants, thickeners, preservatives, stabilizers, mold release agents, disintegrates, anti-distingegrants, lubricants and the like.
  • the topical compositions typically contain from 0.1 to 20 weight % of a 5-HT 2 receptor antagonist. Preferably, they contain from 0.5 to 10 weight %. More preferably, from 1 - 5 weight %.
  • Transdermal compositions typical contain from 0.1 to 20 weight % of a 5-HT 2 receptor antagonists. Preferably, they contain from 0.5 to 10 weight %. More preferably, from 1- 5 weight %.
  • Suppositories typically contain from 0.1 to 20 weight % of a 5-HT 2 receptor antagonist. Preferably, they contain from 0.5 to 10 weight %. More preferably, from 1- 5 weight %.
  • Wound dressings typically contain from 0.1 to 20 weight % of a 5-HT 2 receptor antagonist. Preferably, they contain from 0.5 to 10 weight %. More preferably, from 1- 5 weight %.
  • compositions of this invention consist of sufficient material to provide a dose of from 0.05 - 10 mg. per kg. of body weight, more suitably 0.2 - 6 mg/kg body weight. These compositions may be taken 1 - 3 times daily or as needed until the pain or symptoms of the conditions have subsided.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Cardiology (AREA)
  • Dermatology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
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Abstract

L'invention concerne des compositions contenant des antagonistes des récepteurs 5-HT2 utiles dans le traitement de pathologies veineuses telles que les hémorroïdes, les veines variqueuses, les insuffisances veineuses et les blessures. Le traitement consiste notamment à utiliser un antagoniste des récepteurs 5-hydroxytryptamine-2 (5-HT2) à une dose thérapeutique appropriée au traitement d'un patient ou d'un animal souffrant d'une telle pathologie. L'antagoniste du récepteur 5-HT2 peut également être administré à titre prophylactique.
PCT/US1993/001485 1992-01-09 1993-02-19 Compositions antagonistes des recepteurs 5-ht2 utiles dans le traitement de pathologies veineuses WO1994018958A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
PT93906979T PT684816E (pt) 1992-01-09 1993-02-19 Composicoes antagonistas do receptor da 5-ht2 uteis no tratamento de doencas venosas
ES93906979T ES2215990T3 (es) 1992-01-09 1993-02-19 Antagonistas del receptor 5-ht2 para tratar enfermedades venosas.
KR1019950703438A KR100278522B1 (ko) 1992-01-09 1993-02-19 정맥성 질환 치료에 유용한 5-ht2 수용체 길항제 조성물
DK93906979T DK0684816T3 (da) 1992-01-09 1993-02-19 5-HT2-receptorantagonister til behandling af venöse tilstande
EP93906979A EP0684816B1 (fr) 1992-01-09 1993-02-19 Antagonistes des recepteurs 5-ht2 pour le traitement de pathologies veineuses
CA002156481A CA2156481C (fr) 1992-01-09 1993-02-19 Compositions antagonistes du recepteur 5-ht2, utiles pour le traitement des troubles veineux
DE69333413T DE69333413T2 (de) 1992-01-09 1993-02-19 5-ht2-antagonisten in der behandlung venöser zustände
AT93906979T ATE258789T1 (de) 1992-01-09 1993-02-19 5-ht2-antagonisten in der behandlung venöser zustände
AU37748/93A AU678149B2 (en) 1992-01-09 1993-02-19 5-HT2 receptor antagonist compositions useful in treating venous conditions
US08/512,235 US5605902A (en) 1992-01-09 1995-08-07 5-HT2 receptor antagonist compositions useful in treating venous conditions

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US07/818,389 US5266571A (en) 1992-01-09 1992-01-09 Treatment of hemorrhoids with 5-HT2 antagonists

Publications (1)

Publication Number Publication Date
WO1994018958A1 true WO1994018958A1 (fr) 1994-09-01

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PCT/US1993/001485 WO1994018958A1 (fr) 1992-01-09 1993-02-19 Compositions antagonistes des recepteurs 5-ht2 utiles dans le traitement de pathologies veineuses

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US (2) US5266571A (fr)
EP (1) EP0684816B1 (fr)
KR (1) KR100278522B1 (fr)
AT (1) ATE258789T1 (fr)
AU (1) AU678149B2 (fr)
CA (1) CA2156481C (fr)
DE (1) DE69333413T2 (fr)
DK (1) DK0684816T3 (fr)
ES (1) ES2215990T3 (fr)
PT (1) PT684816E (fr)
WO (1) WO1994018958A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5605902A (en) * 1992-01-09 1997-02-25 Sam Amer & Co. 5-HT2 receptor antagonist compositions useful in treating venous conditions
WO1998038165A1 (fr) * 1997-02-28 1998-09-03 Moh Samir Amer S-2'-(2-(1-methyl-2-piperidyl)ethyl)cinnamanilide en tant qu'antagoniste du recepteur de 5-ht2
WO2012026914A1 (fr) * 2010-08-23 2012-03-01 Sam Amer & Co., Inc. Procédés et compositions pour traitement d'hémorroïdes internes et externes

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US5869059A (en) * 1996-01-16 1999-02-09 Mon's Tea Partnership Herbal composition for hemorrhoid treatment
GB9720270D0 (en) * 1997-09-25 1997-11-26 Pharmagene Lab Limited Medicaments for the treatment of migraine
DE10025644A1 (de) * 2000-05-24 2001-12-06 Lohmann Therapie Syst Lts Schmales bandförmiges transdermales therapeutisches System zur Applikation von Wirkstoffen direkt über dem arteriellen oder venösen Gefäßsystem
US6365198B1 (en) * 2001-01-28 2002-04-02 Gulf Pharmaceutical Industries Pharmaceutical preparation for the treatment of gastrointestinal ulcers and hemorrhoids
GB0306604D0 (en) * 2003-03-21 2003-04-30 Curidium Ltd Second medical use
US20050107867A1 (en) * 2003-11-17 2005-05-19 Taheri Syde A. Temporary absorbable venous occlusive stent and superficial vein treatment method
US20060052822A1 (en) * 2004-08-31 2006-03-09 Mirizzi Michael S Apparatus and material composition for permanent occlusion of a hollow anatomical structure
WO2006081238A2 (fr) * 2005-01-25 2006-08-03 Vnus Medical Technologies, Inc. Structures pour l'occlusion permanente d'une structure anatomique creuse
US20070082076A1 (en) * 2005-10-12 2007-04-12 Spencer Feldman Glutathione and coffee suppository
US9017361B2 (en) * 2006-04-20 2015-04-28 Covidien Lp Occlusive implant and methods for hollow anatomical structure
CN108440520A (zh) * 2018-03-12 2018-08-24 首都医科大学 苯并异噻唑类化合物及其制备方法和在治疗抑郁症方面的用途

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US5605902A (en) * 1992-01-09 1997-02-25 Sam Amer & Co. 5-HT2 receptor antagonist compositions useful in treating venous conditions
WO1998038165A1 (fr) * 1997-02-28 1998-09-03 Moh Samir Amer S-2'-(2-(1-methyl-2-piperidyl)ethyl)cinnamanilide en tant qu'antagoniste du recepteur de 5-ht2
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WO2012026914A1 (fr) * 2010-08-23 2012-03-01 Sam Amer & Co., Inc. Procédés et compositions pour traitement d'hémorroïdes internes et externes

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US5605902A (en) 1997-02-25
ES2215990T3 (es) 2004-10-16
DK0684816T3 (da) 2004-06-14
EP0684816B1 (fr) 2004-02-04
KR960700696A (ko) 1996-02-24
US5266571A (en) 1993-11-30
PT684816E (pt) 2004-06-30
DE69333413D1 (de) 2004-03-11
CA2156481A1 (fr) 1994-09-01
CA2156481C (fr) 2004-05-11
AU3774893A (en) 1994-09-14
EP0684816A1 (fr) 1995-12-06
DE69333413T2 (de) 2004-12-02
ATE258789T1 (de) 2004-02-15
KR100278522B1 (ko) 2001-01-15
AU678149B2 (en) 1997-05-22

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