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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
• • 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
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
• • 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
  • A61P1/12—Antidiarrhoeals
• • 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
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention provides a method for preventing and treating gastrointestinal diseases such as dyspepsia, irritable bowel disease and chemotherapy-associated nausea by administering an antagonist or partial agonist of 5HTla receptors.
• Dyspepsia is a common symptom ranging in prevalence from 26% in the United States to 41% in England (1). Whilst only 1 in 4 patients seek medical help (2) the condition results in significant health care costs (3) and an organic cause is found in only 40% of patients.
• Serotonin (5HT) is a neurotransmitter both in the enteric nervous system (8) and in the brain (9). It plays a key role in regulating gut physiology, including peristalsis and intestinal tone (10). Animal studies have shown that intracerebro ventricular injection of fenfluramine (a serotonin releasing agent) inhibits gastric emptying (11). Selective serotonin reuptake inhibitors, such as fluoxetine and sertraline, are widely used in the treatment of depression and produce a transient syndrome similar to NUD in up to 30% of patients treated (12).
• cannula inserted in a forearm vein.
• Buspirone (30mg) or matching placebo was administered orally at 0900h (Time 0). Blood was taken at 0, 30, 60, 90, 120 and ISOmin.
• Prolactin levels
• the present invention provides a means for prevention and treatment of gastrointestinal disease by administration of a substance that reduces the sensitivity of 5HTla receptors.
• a preferred means is the administration of RS pindolol or a salt thereof.
• An especially preferred means is the administration of S (-) pindolol or a salt thereof.
• this invention can use any substance that is an antagonist or a partial agonist of 5HTla receptors such that the sensitivity of 5HTla receptors described above is reduced.
• Pindolol is a beta adrenergic antagonist, used in the treatment of hypertension and angina. It also has affinity for 5HTla receptors of a similar magnitude as its affinity for beta adrenergic receptors. Until now, no therapeutic applications of this phenomenon have been discovered. Pindolol is used therapeutically in hypertension and angina as the racemic substance, RS pindolol. Most or all of the pharmacological effects of pindolol are possessed by the isomer S (- ) pindolol.
• the present invention utilizes pindolol to reduce the sensitivity of 5HTla receptors and as a result to provide the means for prevention and treatment certain gastrointestinal diseases, including non-ulcerative dyspepsia.
• a preferred embodiment of the invention is the isomer S (-) pindolol or salts thereof.
• Another method utilizes the administration of cyproheptadine, described in U.S. Patents 5,324,738 and 5,403,848. The latter also describes a method for diagnosis of non-ulcerative dyspepsia by measuring the responsiveness of 5HTla receptors.
• RS pindolol has an advantage over cyproheptadine of greater selectivity for the 5HTla receptor and S (-) pindolol has further advantages of greater potency and specificity.
• the invention is likely to be effective in various presentations of gastrointestinal disease in which there is altered sensitivity of 5HTla receptors. We have specific demonstration of the role of 5HTla receptors in non-ulcerative dyspepsia, but there is likely to be also benefit in certain cases of irritable bowel syndrome, especially that occurring in the upper intestinal region and in certain cases of motility disorders (including nausea) caused by cancer chemotherapy.
• compositions for oral use including (but not limited to) tablets, capsules, oral solutions and suspensions and parenteral solutions. Included are also pharmaceutical formulations for oral use in which the active substance is released in a controlled and slower fashion such that the treatment may be administered less frequently.
• RS pindolol and S (-) pindolol will be in the range of 2.5mg to 50mg daily in single or divided doses, depending upon the therapeutic response and the pharmaceutical form.
• S (-) pindolol will be lesser than those of RS pindolol since the former will be more potent because it is responsible for most or all of the pharmacological effects.
• the invention is intended for the treatment of mammals, including humans.
• An example of an immediate-release formulation of S (-) pindolol is as follows. Quantities for 100,000 tablets
• Compress tablets at lOOmg on a rotary compression machine Compress tablets at lOOmg on a rotary compression machine.
• Talley NJ Colin- Jones D, Koch Kl, Koch M, Nyren O, Stranghellini V. Functional dyspepsia: a classification with guidelines of diagnosis and management. Gastroenterol Int 1991;4:145-60. 5.
• Talley NJ Zinsmeister AR, Schleck CD, Melton LJ. Dyspepsia and dyspepsia subgroupings: a population-based study. Gastroenterology 1992;102:1259-68.

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• Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Hospice & Palliative Care (AREA)
• Otolaryngology (AREA)
• Nutrition Science (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Indole Compounds (AREA)

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• 2001
  • 2001-10-11 EP EP01986602A patent/EP1408937A2/de not_active Withdrawn
  • 2001-10-11 JP JP2002533849A patent/JP2004510814A/ja active Pending
  • 2001-10-11 CA CA002425910A patent/CA2425910A1/en not_active Abandoned
  • 2001-10-11 WO PCT/IB2001/002759 patent/WO2002030406A2/en active Application Filing

Non-Patent Citations (1)

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