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WO1990001330A1 - UTILISATION DE NEUROMEDINES U8 et U25 COMME COMPOSES THERAPEUTIQUES - Google Patents

UTILISATION DE NEUROMEDINES U8 et U25 COMME COMPOSES THERAPEUTIQUES Download PDF

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Publication number
WO1990001330A1
WO1990001330A1 PCT/GB1989/000924 GB8900924W WO9001330A1 WO 1990001330 A1 WO1990001330 A1 WO 1990001330A1 GB 8900924 W GB8900924 W GB 8900924W WO 9001330 A1 WO9001330 A1 WO 9001330A1
Authority
WO
WIPO (PCT)
Prior art keywords
neuromedin
gastrointestinal
nmu
blood
blood flow
Prior art date
Application number
PCT/GB1989/000924
Other languages
English (en)
Inventor
Terence Bennett
Sheila Margaret Gardiner
Original Assignee
Terence Bennett
Sheila Margaret Gardiner
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
Priority claimed from GB888819137A external-priority patent/GB8819137D0/en
Priority claimed from GB898907376A external-priority patent/GB8907376D0/en
Application filed by Terence Bennett, Sheila Margaret Gardiner filed Critical Terence Bennett
Publication of WO1990001330A1 publication Critical patent/WO1990001330A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones

Definitions

  • cDNA clone banks may be made from mRNA prepared from mammalian tissue which produces the neuromedin U. A gene encoding a mammalian neuromedin U may then be identified by probing the cDNA banks with labelled DNA probes based on the
  • the invention provides a pharmaceutical composition in unit dosage form, each unit dose comprising an amount of neuromedin U sufficient to
  • the invention provides a process for the production of a pharmaceutical composition according to the sixth aspect of the invention comprising bringing a neuromedin U into association with a pharmaceutically acceptable carrier, excipient or diluent.
  • the invention provides the use of neuromedin U for the manufacture of a medicament for the treatment of
  • compositions for use according to the present invention may be formulated in conventional manner, optionally with one or more physiologically acceptable carriers, excipients or diluents.
  • Neuromedin Us for use according to the present invention may be formulated for oral, buccal, parenteral or rectal
  • compositions may take the form of, for example, tablets or capsules prepared by
  • polyvinylpyrrolidone or hydroxypropyl methylcellulose fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g sodium lauryl sulphate).
  • the tablets may be coated by methods well known in the art.
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents emulsifying agents, non-aqueous vehicles and preservatives.
  • the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • the neuromedin U may be formulated for parenteral administration by injection e.g. by bolus injection or continuous infusion.
  • NMU-8 may be administered to an average 70kg man by IV infusion at doses in the range 0.01 ⁇ g/min to 1.5 ⁇ g/min over a time period of 60 minutes and NMU-25 may be administered to an average 70kg man by IV infusion at dose in the range 0.05ug/min to 5.00 ⁇ g/min over a time period of 60 minutes.
  • the lowest dose is administered for a period of 10 minutes and this dose is then doubled every ten minutes until the desired effect is seen up to a maximum of 1.5 ⁇ g/min.
  • the total of neuromedin administered may be up to 22.25 ⁇ g which may be administered twice a day.
  • Figure 1 shows the cardiovascular responses to bolus injections of
  • Figure 4 shows the cardiovascular changes at the end of a 60 min infusion of NMU-8 (10nmol/h) in a conscious rat.
  • Figure 5 shows the cardiovascular changes at the onset and offset of a Ih infusion of NMU-25 in a conscious rat.
  • Animals were anaesthetised (sodium methohexitone, 60mg/kg i.p.) and had miniaturised, pulsed Doppler probes implanted around the left renal and the superior mesenteric arteries and the distal abdominal aorta, below the level of the ileocaecal artery (this probe is thus positioned to monitor hindquarters flow).
  • the wires from the probes were tunnelled subcutaneously and exited at the back of the neck through a small incision, where they were anchored to the skin with their ends free. Animals were allowed to recover for at least 7 days with access to food and water.
  • rats with acceptable signals from all 3 probes were briefly re-anaesthetised (sodium methohexitone, 40mg/kg i.p.) and had an intravenous and an intra-arterial (abdominal aorta via the caudal artery) catheter implanted. These catheters were tunnelled subcutaneously and exited at the same point as the Doppler probe wires. The latter were soldered into a micro-connector that was clamped into a harness fitted to the rat. This same harness was connected to a flexible spring through which the catheters ran, for protection.
  • Rats (n 8) with pulsed Doppler probes received bolus doses of rat NMU (Conlon et al; J. Neurochem 51 988-991 (1988)) (0.001, 0.01 and 0.1nmol) and a 20 min infusion (at 10 nmol/h) of this peptide.
  • vasoconstrictor effects in conscious rats is vasopressin.
  • administration of exogenous vasopressin, sufficient to cause a pressor effect, (or at lesser doses) does not pick out the superior mesenteric circulation in the way described here for NMU-8 or NMU-25 or rat NMU, since vasopressin also causes a marked reduction in hindquarters blood flow, and, moreover, elicits a substantial bradycardia.
  • mesenteric blood flow without an increase in systemic arterial BP or any adverse cardiac effects, at least as judged by the absence of arrhythmias or bradycardia.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Zoology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Est décrit l'emploi de peptides de la famille de neuromédines U dans la réduction sélective d'écoulement sanguin au tube digestif. L'utilisation de neuromédine U pour parvenir à une réduction sélective de l'écoulement sanguin au tube digestif sert de technique de traitement, par exemple, du saignement gastro-intestinal et de l'hypotension post-prandiale. La neuromédine U est aussi décrite pour une utilisation dans la diagnose du site de saignement gastro-intestinal.
PCT/GB1989/000924 1988-08-11 1989-08-11 UTILISATION DE NEUROMEDINES U8 et U25 COMME COMPOSES THERAPEUTIQUES WO1990001330A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB888819137A GB8819137D0 (en) 1988-08-11 1988-08-11 Therapeutic compounds compositions & uses thereof
GB8819137.4 1988-08-11
GB898907376A GB8907376D0 (en) 1989-03-31 1989-03-31 Therapeutic compounds,compositions and uses thereof
GB8907376.1 1989-03-31

Publications (1)

Publication Number Publication Date
WO1990001330A1 true WO1990001330A1 (fr) 1990-02-22

Family

ID=26294266

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1989/000924 WO1990001330A1 (fr) 1988-08-11 1989-08-11 UTILISATION DE NEUROMEDINES U8 et U25 COMME COMPOSES THERAPEUTIQUES

Country Status (1)

Country Link
WO (1) WO1990001330A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001025269A2 (fr) * 1999-09-24 2001-04-12 Solvay Pharmaceuticals B.V. Nouveau recepteur couple a la proteine g humaine
WO2002032937A2 (fr) * 2000-10-16 2002-04-25 Merck Patent Gmbh Neuromedine u delta
US6998255B1 (en) 1999-09-24 2006-02-14 Solvay Pharmaceuticals B.V. Human G-protein coupled receptor

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Biochemical and Biophysical Research Communication, Volume 140, No. 3, 14 November 1986, Academic Press, Inc., J. DOMIN et al.: "Characterization of Neuromedin U like Immunoreactivity in Rat, Porcine Guinea-Pig and Human Tissue Extracts using a Specific Radioimmuno-Assay", pages 1127-1134 *
Biochemical and Biophysical Research Communications, Volume 130, No. 3, 15 August 1985, Academic Press, Inc., N. MINAMINO et al.: "Neuromedin U-8 and U-25: Novel Uterus Stimulating and Hypertensive Peptides Identified in Porcine Spinal Cord", pages 1078-1085 *
Deutsche Apotheker Zeitung, Volume 128, No. 21, 26 May 1988, (Stuttgart, DE), H.J. ROTH: "Polypeptide als Arzneistoffe", pages 1085-1102 *
Life Science, Volume 41, 1987, Pergamon Journal Ltd, (US), S. SUMI et al.: "Effect of Synthetic Neuromedin U-8 and U-25, Novel Peptides Identified in Procine Spinal Cord, on splanchnic Circulation in Dogs", pages 1585-1590 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001025269A2 (fr) * 1999-09-24 2001-04-12 Solvay Pharmaceuticals B.V. Nouveau recepteur couple a la proteine g humaine
WO2001025269A3 (fr) * 1999-09-24 2001-10-11 Solvay Pharm Bv Nouveau recepteur couple a la proteine g humaine
US6998255B1 (en) 1999-09-24 2006-02-14 Solvay Pharmaceuticals B.V. Human G-protein coupled receptor
US7151165B2 (en) 1999-09-24 2006-12-19 Solvay Pharmaceutical B.V. Antibodies immunospecific for a novel human G-protein coupled receptor family
US7459279B2 (en) 1999-09-24 2008-12-02 Solvay Pharmaceuticals, Inc. Binding assay employing IGS4, a human G-protein coupled neuromedin receptor
US7459292B2 (en) 1999-09-24 2008-12-02 Solvay Pharmaceuticals, Inc. Polynucleotides and expression system of a novel human G-protein coupled receptor
EP2298803A2 (fr) 1999-09-24 2011-03-23 Abbott Healthcare Products B.V. Récepteur couplé à la protéine G et son ligands
EP2298803A3 (fr) * 1999-09-24 2011-06-22 Abbott Healthcare Products B.V. Récepteur couplé à la protéine G et son ligands
WO2002032937A2 (fr) * 2000-10-16 2002-04-25 Merck Patent Gmbh Neuromedine u delta
WO2002032937A3 (fr) * 2000-10-16 2002-08-15 Merck Patent Gmbh Neuromedine u delta

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