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WO2003030903A1 - Utilisation de la tizanidine pour traiter des troubles metaboliques associes a une secretion anormale d'insuline - Google Patents

Utilisation de la tizanidine pour traiter des troubles metaboliques associes a une secretion anormale d'insuline Download PDF

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Publication number
WO2003030903A1
WO2003030903A1 PCT/GB2002/004501 GB0204501W WO03030903A1 WO 2003030903 A1 WO2003030903 A1 WO 2003030903A1 GB 0204501 W GB0204501 W GB 0204501W WO 03030903 A1 WO03030903 A1 WO 03030903A1
Authority
WO
WIPO (PCT)
Prior art keywords
disorder
use according
insulin secretion
tizanidine
metabolic disorders
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/GB2002/004501
Other languages
English (en)
Inventor
Hazel Judith Bardsley
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Arachnova Therapeutics Ltd
Original Assignee
Arachnova Therapeutics Ltd
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 Arachnova Therapeutics Ltd filed Critical Arachnova Therapeutics Ltd
Publication of WO2003030903A1 publication Critical patent/WO2003030903A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles

Definitions

  • This invention relates to new therapeutic uses for tizanidine, a known compound.
  • Type 2 diabetes mellitus (formerly known as non-insulin-dependent diabetes) features early onset of insulin resistance. This leads to greater than normal levels of insulin or hyperinsulinemia, with resultant elevation of blood glucose when the pancreas can no longer keep up with increased insulin requirements. Often, patients with hyperinsulinemia and diabetes also have hypertension, obesity and dyslipidemia, all occurring in a disorder constellation often referred to as "syndrome X" or "metabolic syndrome".
  • pancreas exhibits defective insulin secretion. This is often characterised by decreased first phase insulin response, abnormal pulsatile insulin release, an increased ratio of proinsulin to insulin and reduced orderliness of insulin secretory pattern.
  • Imidazoline drugs potentiate glucose-induced insulin secretion from isolated islets incubated in vitro and are also effective when administered to experimental animals in vivo.
  • the compound tizanidine i.e.5-chloro-N-(4,5-dihydro-1 H-imidazolyl-2-yl)- 2,1 ,3-benzothiadiazol-4-amine; see US-A-3843668 and US-A-4053617), has alpha 2 agonist properties and is used as a skeletal muscle relaxant.
  • Tizanidine has been found to bind to kidney imidazoline receptors with approximately 20 times more affinity than the alpha 2 adrenoceptors; see Muramatsu etal, Japan
  • tizanidine is able to cause a dose- dependent decrease in insulin secretion.
  • tizanidine can be used for the treatment or prevention of a metabolic disorder characterised by defective or abnormal insulin secretion where inhibition of that insulin secretion is beneficial.
  • Figures 1 to 3 are each graphs of insulin secretion (i.e. "IS”, ng/islet/h) against concentration of tizanidine ("IT]", ⁇ M).
  • a number of diseases characterised by abnormal insulin secretion can be treated. These include type 2 diabetes, obesity, metabolic syndrome or syndrome X, polycystic ovary syndrome, hyperinsulinemia, dyslipidemia, drug-induced weight gain, congestive heart disease, glucose intolerance, renal disease, type 1 diabetes and persistent hyperinsulinemic hypoglycemia of infancy.
  • the active compound can be formulated in any suitable manner together with a conventional diluent or carrier.
  • the active compound is preferably administered by the oral route; other suitable routes of administration include sublingual/buccal, transdermal, intramuscular, intranasal, rectal, parenteral, subcutaneous, pulmonary and topical.
  • An effective dose of the active agent will depend on the nature and degree of the complaint, the age and condition of the patient and other factors known to those skilled in the art.
  • a typical daily dosage is 0.01 to 1000 mg.
  • a pharmaceutical composition containing the active ingredient may be in the form of a sublingual tablet or patch.
  • suitable compositions for oral use include tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups and elixirs.
  • Suitable additives include sweetening agents, flavouring agents, colouring agents and preserving agents.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, e.g. inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated, to form osmotic therapeutic tablets for controlled release.
  • Hard gelatin capsules may include an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin; soft gelatin capsules may include water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • the active compound may be tizanidine itself or a derivative, such as a salt or metabolite thereof.
  • a prodrug form may also be used.
  • Islets of Langerhans were isolated from male Wistar rats (180-200 g body weight) by collagenase digestion of the excised pancreas. Islets were hand- picked under a binocular dissecting microscope to minimise their contamination with exocrine tissue. Islets were used within 2 hours of the death of the animal and were incubated in groups of 3 in bicarbonate-buffered saline solution (pH 7.4) supplemented with 2 mM Ca and 1 mg/ml bovine serum albumin. Islets were incubated for 1 hour at 37°C, after which samples of the medium were removed for measurement of insulin secretion by radioimmunoassay.

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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)

Abstract

La tizanidine est utile pour le traitement ou la prévention d'un trouble métabolique caractérisé par une sécrétion d'insuline anormale ou imparfaite, pour lequel l'inhibition de ladite sécrétion d'insuline présente un effet bénéfique.
PCT/GB2002/004501 2001-10-05 2002-10-04 Utilisation de la tizanidine pour traiter des troubles metaboliques associes a une secretion anormale d'insuline Ceased WO2003030903A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0123991.2 2001-10-05
GBGB0123991.2A GB0123991D0 (en) 2001-10-05 2001-10-05 New therapeutic use

Publications (1)

Publication Number Publication Date
WO2003030903A1 true WO2003030903A1 (fr) 2003-04-17

Family

ID=9923329

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2002/004501 Ceased WO2003030903A1 (fr) 2001-10-05 2002-10-04 Utilisation de la tizanidine pour traiter des troubles metaboliques associes a une secretion anormale d'insuline

Country Status (2)

Country Link
GB (1) GB0123991D0 (fr)
WO (1) WO2003030903A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006079021A3 (fr) * 2005-01-20 2007-03-22 Sirtris Pharmaceuticals Inc Methodes et compositions destinees au traitement des bouffees vasomotrices et de la prise de poids d'origine medicamenteuse
WO2008014299A3 (fr) * 2006-07-27 2008-04-24 Allergan Inc Méthodes et compositions utiles pour le traitement de l'hyperlipidémie

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
KEULEN L. ET AL.: "Antihypertensive treatment and cardiovascular risk management in patients with the metabolic syndrome - focus on SNS and insulin resistance", J. CLIN. BASIC CARDIOL., vol. 4, 2001, pages 193 - 195, XP001121531 *
KRENTZ A J ET AL: "Selective imidazoline receptor agonists for metabolic syndrome.", LANCET. ENGLAND 17 JAN 1998, vol. 351, no. 9097, 17 January 1998 (1998-01-17), pages 152 - 153, XP002225611, ISSN: 0140-6736 *
MURAMATSU I ET AL: "Tizanidine may discriminate between imidazoline-receptors and alpha 2-adrenoceptors.", JAPANESE JOURNAL OF PHARMACOLOGY. JAPAN AUG 1992, vol. 59, no. 4, August 1992 (1992-08-01), pages 457 - 459, XP009002924, ISSN: 0021-5198 *
REID J L: "Update on rilmenidine: clinical benefits.", AMERICAN JOURNAL OF HYPERTENSION: JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION. UNITED STATES NOV 2001, vol. 14, no. 11 Pt 2, November 2001 (2001-11-01), pages 322S - 324S, XP001121530, ISSN: 0895-7061 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006079021A3 (fr) * 2005-01-20 2007-03-22 Sirtris Pharmaceuticals Inc Methodes et compositions destinees au traitement des bouffees vasomotrices et de la prise de poids d'origine medicamenteuse
WO2008014299A3 (fr) * 2006-07-27 2008-04-24 Allergan Inc Méthodes et compositions utiles pour le traitement de l'hyperlipidémie

Also Published As

Publication number Publication date
GB0123991D0 (en) 2001-11-28

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