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WO1997036586A1 - Traitement ou prophylaxie de la diarrhee - Google Patents

Traitement ou prophylaxie de la diarrhee Download PDF

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Publication number
WO1997036586A1
WO1997036586A1 PCT/EP1997/001463 EP9701463W WO9736586A1 WO 1997036586 A1 WO1997036586 A1 WO 1997036586A1 EP 9701463 W EP9701463 W EP 9701463W WO 9736586 A1 WO9736586 A1 WO 9736586A1
Authority
WO
WIPO (PCT)
Prior art keywords
diarrhoea
granisetron
treatment
prophylaxis
composition according
Prior art date
Application number
PCT/EP1997/001463
Other languages
English (en)
Inventor
Peter Robin Blower
Original Assignee
Smithkline Beecham P.L.C.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham P.L.C. filed Critical Smithkline Beecham P.L.C.
Priority to AU22905/97A priority Critical patent/AU2290597A/en
Publication of WO1997036586A1 publication Critical patent/WO1997036586A1/fr

Links

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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to prevention and treatment of diarrhoea, and pharmaceutical compositions therefor.
  • EP-A- 189002 (Sandoz-Patent-Gmbh) relates to the use of certain compounds for the treatment of serotonin induced gastrointestinal disturbances incuding diarrhoea e.g. secretory diarrhoea, bacterial induced diarrhoea, choleic diarrhoea, traveller's diarrhoea and psychogenic diarrhoea.
  • diarrhoea e.g. secretory diarrhoea, bacterial induced diarrhoea, choleic diarrhoea, traveller's diarrhoea and psychogenic diarrhoea.
  • Tropisetron [(3 ⁇ -tropanyl)-lH-indole-3-carboxylic acid ester] and benzo[b]thiophen-3-yl carboxylic acid endo-9- methyl-aza-bicyclo[3,3,l]non-3-yl ester were reported to inhibit cholera toxin-induced secretory diarrhoea in mice at a dose of 100 to 500 ⁇ g/kg.
  • Example 6 of EP-A-2004 4 (Beecham Group p.l.c.) describes the preparation of the compound, granisetron (or BRL 43694 monohydrochloride) which is available in the United Kingdom as KYTRIL* a medicament for the treatment of cytotoxic agent induced nausea and vomiting in cancer patients.
  • Diarrhoea is often associated with HIV positive and ALDS conditions and other immunodeficiency diseases especially those involving gastrointestinal mucosal integrity and/or local mucosal inflammatory conditions, carcinoid syndrome and other gastro-intestinal tumours and also treatment regimens for cancer. Diarrhoea is also associated with cholera.
  • the present invention provides the use of granisetron in the manufacture of a medicament for the treatment or prophylaxis of diarrhoea.
  • the present invention also provides a method of treatment of or prophylaxis of diarrhoea in mammals, including man, by administration of granisetron to the mammal in need thereof.
  • the administration of granisetron may be by way of known methods, such as oral, or parenteral administration.
  • An amount effective to treat the disorder hereinbefore described depends on the usual factors such as the nature and severity thereof and the weight of the mammal. However, a unit dose will normally contain 0.5 to 10 mg, for example 1 to 3 mg of granisetron.
  • granisetron is administered in the form of a unit-dose composition, such as a unit dose oral or parenteral composition.
  • a unit dose composition such as a unit dose oral or parenteral composition.
  • Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletung agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycoUate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the ⁇ active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, 5 methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl c-hydroxybenzoate or 10 sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, 5 methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan mono
  • Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
  • fluid unit dose forms are prepared containing granisetron and a sterile vehicle.
  • the compound depending on the vehicle and the 15 concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compou ⁇ d in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water 20 removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution 2.5 of the compound of the invention.
  • compositions will usually be accompanied by written or printed directions for use in the treatment concerned.
  • the present invention further provides a pharmaceutical composition for use in the treatment and/or prophylaxis of diarrhoea, which comprises granisetron and a 30 pharmaceutically acceptable carrier.
  • a pharmaceutical composition for use in the treatment and/or prophylaxis of diarrhoea which comprises granisetron and a 30 pharmaceutically acceptable carrier.
  • Such compositions may be prepared in the manner as hereinbefore described.
  • a modified triple-lumen intestinal perfusion technique is used in which very small amounts of pure cholera toxin (15-20 ⁇ g) are introduced into an isolated segment of human proximal small intestine. This results in the production of a subclinical secretory state in which the rate of water and electrolyte secretion is identical to that in human cholera.
  • This model thus, presents a unique situation for studying the mechanism of cholera-toxin CT-induced secretion in man, and enables the study of potentially useful antisecretory compounds.
  • 5-HT is released into the intestinal lumen in this model and secretion can be reversed with glucose-electrolyte solutions, which are currently the standard therapy for replacing water and electrolytes in acute diarrhoeal states.
  • the effect of granisetron on basal and CT-induced secretory states is studied using triple-lumen perfusion to measure changes in water and electrolyte transport.
  • the triple-lumen assembly is passed through the mouth into the proximal small intestine where a segment of jejunum is isolated between two occluding balloons. 15-20 ⁇ g of highly purified CT is then introduced into the occluded segment and allowed to remain there for 2h. Granisetron is administered at the same time that the CT is introduced into the intestinal segment. At the end of the 2h period, the segment is drained, gently lavaged to remove "unbound" CT and the balloons then deflated. Perfusion of the segment with an isotonic plasma elecrolyte solution is then commenced and the effect of granisetron or placebo is assessed on water and electrolyte transport.

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  • 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)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention a pour objet l'utilisation de granisétron dans la fabrication d'un médicament pour le traitement ou la prophylaxie de la diarrhée.
PCT/EP1997/001463 1996-03-29 1997-03-20 Traitement ou prophylaxie de la diarrhee WO1997036586A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU22905/97A AU2290597A (en) 1996-03-29 1997-03-20 Treatment or prophylaxis of diarrhoea

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9606745.9A GB9606745D0 (en) 1996-03-29 1996-03-29 Pharmaceuticals
GB9606745.9 1996-03-29

Publications (1)

Publication Number Publication Date
WO1997036586A1 true WO1997036586A1 (fr) 1997-10-09

Family

ID=10791339

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/001463 WO1997036586A1 (fr) 1996-03-29 1997-03-20 Traitement ou prophylaxie de la diarrhee

Country Status (6)

Country Link
AR (1) AR006437A1 (fr)
AU (1) AU2290597A (fr)
CO (1) CO4790092A1 (fr)
GB (1) GB9606745D0 (fr)
WO (1) WO1997036586A1 (fr)
ZA (1) ZA972684B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000048597A1 (fr) * 1999-02-18 2000-08-24 Novartis Ag Utilisation systemique d'antagonistes du recepteur 5-ht3 contre des processus inflammatoires rhumatismaux

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
A. SJÖQVIST ET AL.: "Actions of serotonin antagonists on cholera-toxin-induced intestinal fluid secretion", ACTA PHYSIOL.SCAND., vol. 145, no. 3, July 1992 (1992-07-01), pages 229 - 237, XP000674376 *
E.BEUBLER ET AL.: "Inhibition of 5-hydroxytryptamine- and enterotoxin-induced fluid secretion by 5-HT receptor antagonists in the rat jejunum", EUR. J .PHARMACOL., vol. 248, no. 2, 2 August 1993 (1993-08-02), pages 157 - 162, XP000674373 *
E.BEUBLER ET AL.: "Serotonin Antagonists Inhibit Sennoside-Induced Fluid Secretion and Diarrhea", PHARMACOLOGY, vol. 47, no. Suppl. 1, 23 April 1993 (1993-04-23), pages 64 - 69, XP000674379 *
F H MOURAD ET AL.: "Role of 5-hydroxytryptamine type 3 receptors in rat intestinal fluid and electrolyte secretion induced by cholera and Escherichia coli enterotoxins", GUT, vol. 37, no. 3, September 1995 (1995-09-01), pages 340 - 345, XP000674378 *
J.L. TURVILL ET AL.: "SELECTIVE 5-HYDROXYTRYPTAMINE TYPE 4 (5-HT4) ANTAGONIST INHIBITS CHOLERA TOXIN (CT)- BUT NOT E. COLI HEAT LABILE TOXIN (LT)-INDUCED SECRETION", GASTROENTEROLOGY, vol. 110, no. 4 Suppl., April 1996 (1996-04-01), pages A368, XP000674435 *
M.B.HANSEN ET AL.: "Ketanserin and Granisetron Reduce Cholera Toxin-Induced Hypersecretion in Pig Jejunum", SCAND. J. GASTROENTEROL., vol. 29, no. 10, October 1994 (1994-10-01), pages 908 - 915, XP000674375 *
M.BOURIN ET AL.: "5-HTP induced diarrhea as a carcinoid syndrome model in mice?", FUNDAM. CLIN. PHARMACOL., vol. 10, no. 5, 1996, pages 450 - 457, XP000674377 *
M.KADOWAKI ET AL.: "Effect of FK1052, a Potent 5-Hydroxytryptamine3 and 5-Hydroxytryptamine4 Receptor Dual Antagonist, on Colonic Function in Vivo", J.PHARMACOL.EXP.THER., vol. 266, no. 1, July 1993 (1993-07-01), pages 74 - 80, XP000674371 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000048597A1 (fr) * 1999-02-18 2000-08-24 Novartis Ag Utilisation systemique d'antagonistes du recepteur 5-ht3 contre des processus inflammatoires rhumatismaux
US6384042B2 (en) 1999-02-18 2002-05-07 Faerber Lothar Systemic use of 5-HT3 receptor antagonists against rheumatic inflammatory processes

Also Published As

Publication number Publication date
AU2290597A (en) 1997-10-22
ZA972684B (en) 1998-09-28
AR006437A1 (es) 1999-08-25
CO4790092A1 (es) 1999-05-31
GB9606745D0 (en) 1996-06-05

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