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WO1999003491A1 - New use of nociceptin - Google Patents

New use of nociceptin Download PDF

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Publication number
WO1999003491A1
WO1999003491A1 PCT/DK1998/000321 DK9800321W WO9903491A1 WO 1999003491 A1 WO1999003491 A1 WO 1999003491A1 DK 9800321 W DK9800321 W DK 9800321W WO 9903491 A1 WO9903491 A1 WO 9903491A1
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WO
WIPO (PCT)
Prior art keywords
gly
arg
phe
ala
lys
Prior art date
Application number
PCT/DK1998/000321
Other languages
French (fr)
Inventor
Anders Fink Jensen
Uffe Bang Olsen
Original Assignee
Novo Nordisk A/S
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Filing date
Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU83339/98A priority Critical patent/AU8333998A/en
Publication of WO1999003491A1 publication Critical patent/WO1999003491A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/33Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin

Definitions

  • the present invention relates to the use of compounds of the general formula I for the treatment of vasomotor disturbances, in particular the peripheral vasomotor effects known as hot flushes or hot flashes.
  • the present invention also embraces pharmaceutical compositions comprising these compounds and methods of using the com- pounds and their pharmaceutical compositions.
  • a "hot flush” is a sudden transient sensation ranging from warmth to intense heat and typically accompanied by flushing and perspiration. It is the classic sign of the menopause and the predominant complaint of menopausal women. Epidemiological studies report that the majority of menopausal women experience hot flushes, although with large variation in frequency and intensity (Treatment of the Postmenopausal Women, Basic and Clinical Aspects, Raven Press 1994, ed. R.A. Lobo).
  • Nociceptin and analogues thereof have been disclosed in WO 97/07212 and in WO 97/07208. These peptides and inhibitors thereof are said to be useful for antagonising physiologic effects of an opioid in an animal, and for treating/preventing a disease related to: hyperalgesia, neuroendocrine secretion, stress, locomotor activity, anxiety etc.
  • the present invention provides the use of a compound selected from nociceptin or an analogue, a variant or a homologue thereof, wherein 1 to 12 amino acid(s) have been deleted, 1-82 amino acid(s) have been added and/or 1-15 amino acid(s) have been substituted, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances, in particular the peripheral vasomotor effects known as hot flushes or hot flashes, wherein the deletion(s), addition(s) and/or substitution(s) does not substantially reduce the vasomotor disturbing effects of the analogue, variant or homologue of nociceptin.
  • nociceptin and nociceptin analogues, variants or homologues inhibit cordal stimulated vasodilatation in the pithed rat (an in-vivo-model for the hot flushes, hereafter referred to as "the pithed rat") which is known to be mediated by CGRP (Nuki Y. et al. Effects of Dorsal Rhizotomy on Depressor Response to Spinal Cord Stimulation Mediated by Endogenous Calcitonin Gene-related Peptide in the Pithed Rat. J. Neurosurg. 1993; 79:899-904).
  • the present invention relates to the use of a compound selected from nociceptin or an analogue, a variant or a homologue thereof, wherein 1 to 12 amino acid(s) have been deleted, 1-82 amino acid(s) have been added and/or 1- 15 amino acid(s) have been substituted, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances , in particular the peripheral vasomotor effects known as hot flushes or hot flashes or for alleviating symptoms of drug withdrawal in particular abstinence symptoms occuring during withdrawal from abusive drugs, wherein the deletion(s), addition(s) and/or substitution(s) does not substantially reduce the vasomotor disturbing effects of the analogue, variant or homologue of nociceptin.
  • a 1 is Thr, Leu or Met
  • a 2 is Gly, Arg or Thr
  • a 3 is Ala, Arg or Ser
  • a 4 is Arg, lie Glu or Gin
  • a 5 is Lys, Arg or Phe;
  • a 6 is Ser, Pro Lys;
  • the peptide of formula I is disclosed in WO 97/07212, wherein i.a. a procedure for the preparation thereof has been described.
  • composition in a form suitable for oral, nasal, transdermal, pulmonal, or parenteral administration.
  • the compound is administered as a dose in the range from about 0.01 to about 100 g per patient per day, preferably from about 1 to about 1000 mg per patient per day, especially from about 10 to about 100 mg per patient per day, e.g. about 100 mg per patient per day.
  • the amino acids are all in either the D or L stereochemical configuration, preferably the L stereochemical configuration.
  • the compounds of the invention may comprise both L and D amino acids.
  • the invention in a second aspect relates to a method for the treatment or prevention of vasomotor disturbances, in particular the peripheral vasomotor effects known as hot flushes or hot flashes or for alleviating symptoms of drug withdrawal in particular abstinence symptoms occuring during withdrawal from abusive drugs, the method comprising administering to a patient in need thereof an effective amount of nociceptin or an analogue, a variant or a homologue thereof, wherein 1 to 12 amino acid(s) have been deleted, 1-82 amino acid(s) have been added and/or 1-15 amino acid(s) have been substituted, or a pharmaceutically acceptable salt thereof, wherein the deletion(s), addition(s) and/or substitution(s) does not substantially reduce the vasomotor disturbing effects of the analogue, variant or homologue of nociceptin.
  • the effective, such as the therapeutically effective, amount of nociceptin or an analogue, a variant or a homologue thereof will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the nociceptin or an analogue is administered as a dose with an effective amount in the range from about 0.01 to about 100 g per patient per day, preferably from about 1 to about 1000 mg per patient per day, especially from about 10 to about 100 mg per patient per day, e.g. about 100 mg per patient per day .
  • the invention includes the D and/or L stereochemical configuration of all the amino acids which constitutes nociceptin and analogs, variants or homologs hereof.
  • the term "patient” comprises any mammal which may benefit from treatment or prevention of vasomotor disturbances, such as a human, especially if the mammal is a female, such as a woman. However, “patient” is not intended to be limited to a woman.
  • the compounds intended to be embraced by the present invention are such peptides which are disclosed in WO 97/07208 and/or in WO 97/07212, as well as close analogs thereof.
  • said compounds e.g. nociceptin, analogs, variants and homologues of nociceptin as well as compounds of formula I are all together termed "nociceptins", however this term does not in any way limit the scope of the present invention.
  • Methods of preparing these nociceptins are either conventional and known to the man skilled in the art, or described in WO 97/07208 or in WO 97/07212.
  • nociceptin is intended to comprise the peptide Phe-Gly-Gly-Phe-Thr-Gly- Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-GIn, which peptide is disclosed in both WO 97/07208 and WO 97/07212.
  • an analogue, a variant or a homologue thereof, wherein 1-12 amino acid(s) have been deleted, 1-82 amino acid(s) have been added and/or 1-15 amino acid(s) have been substituted is intended to comprise nociceptin wherein 1-12 amino acid(s) have been deleted, 1-82 amino acid(s) have been added and/or 1-15 amino acid(s) have been substituted.
  • treatment is also meant to comprise profylactic treatment.
  • the nociceptins may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids.
  • salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like.
  • Suitable inorganic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like.
  • Further e- xamples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science. 66, 2 (1977) which are known to the skilled artisan.
  • Also intended as pharmaceutically acceptable acid addition salts are the hydrates which the present nociceptins are able to form.
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the nociceptins of this invention may form solvates with standard low molecular weight solvents using methods known to the man skilled in the art.
  • the nociceptins may be administered in pharmaceutically acceptable acid addition salt form or, where appropriate, as a alkali metal or alkaline earth metal or lower alkylammonium salt. Such salt forms are believed to exhibit approximately the same order of activity as the free base forms.
  • the present invention relates to the use of a compound, e.g. selected from the nociceptins disclosed herein, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances, in particular the peripheral vasomotor effects known as hot flushes or hot flashes, the compound being characterized by inhibiting cordal stimulated vasodilatation in "the pitched rat” and/or binding to nociceptin receptors (i.e. ORL-1 receptors as disclosed in WO 97/07212 and in WO 97/07208).
  • the invention relates to the use of a compound, e.g. selected from the nociceptins disclosed herein, for the preparation of a pharmaceutical composition for alleviating symptoms of drug withdrawal in particular abstinence symptoms occuring during withdrawal from abusive drugs.
  • a pharmaceutical composition for use in accordance with the present invention comprises, one or more nociceptins as active ingredient(s), or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
  • compositions containing nociceptins of the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy. 19 th Ed., 1995.
  • the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • compositions include nociceptins or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container.
  • the carrier When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohol's, polyethylene glycol's, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatine, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • compositions can be sterilised and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
  • the route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment.
  • the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • the carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
  • solubilizing agents e.g. propylene glycol
  • surfactants e.g. propylene glycol
  • absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin
  • preservatives such as parabenes.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydro- xylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet which may be prepared by conventional tabletting techniques may contain:
  • Active compound 100 mg Colloidal silicon dioxide (Aerosil) 1.5 mg
  • mice Male Sprague Dawley rats ( 300 ⁇ 25 g) were anaesthetised with pentobarbital sodium (50 mg/kg i.p.) and polyethylene catheters were positioned in both femoral veins for the intravenous administration of drugs, such as nociceptin and analogues, and into the left femoral artery in order to measure arterial blood pressure and heart rate.
  • drugs such as nociceptin and analogues
  • the trachea was cannulated with polyethylene tubing and the rat was pithed, ventilated and drug treated as described by Nuki Y. et al. (Effects of Dorsal Rhizotomy on Depressor Response to Spinal Cord Stimulation Mediated by Endogenous Calcitonin Gene-related Peptide in the Pithed Rat. J. Neurosurg. 1993; 79:899-904).

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Abstract

The present invention relates to the use of compounds of the general formula (I): (Xaa)n-Phe-Gly-Gly-Phe-(A?1)-(A2)-(A3)-(A4)-(A5)-(A6)-(A7)-(A8)-(A9)-(A10)-(A11)-(A12¿)-Gln-(Xaa)¿n? for the treatment of vasomotor disturbances, in particular the peripheral vasomotor effects known as hot flushes or hot flashes. The present invention also embraces pharmaceutical compositions comprising these compounds and methods of using the compounds and their pharmaceutical compositions.

Description

TITLE New Use of Nociceptin
FIELD OF INVENTION
The present invention relates to the use of compounds of the general formula I for the treatment of vasomotor disturbances, in particular the peripheral vasomotor effects known as hot flushes or hot flashes. The present invention also embraces pharmaceutical compositions comprising these compounds and methods of using the com- pounds and their pharmaceutical compositions.
BACKGROUND OF THE INVENTION
A "hot flush" is a sudden transient sensation ranging from warmth to intense heat and typically accompanied by flushing and perspiration. It is the classic sign of the menopause and the predominant complaint of menopausal women. Epidemiological studies report that the majority of menopausal women experience hot flushes, although with large variation in frequency and intensity (Treatment of the Postmenopausal Woman, Basic and Clinical Aspects, Raven Press 1994, ed. R.A. Lobo).
A positive correlation between plasma levels of calcitonin gene-related peptide (CGRP) and frequency of hot flushes in women has recently been reported (Chen et al., 1993, Lancet (342) 49), in accordance with the potent vasodilatory effect of CGRP (Brain et al., 1985, Nature, (313) 54-56).
Recently, a novel heptadeca peptide, nociceptin, was discovered (Meunier et al., 1995, Nature (377) 532-535, Reinscheid et al., 1995, Science (270) 792-794)
Nociceptin and analogues thereof have been disclosed in WO 97/07212 and in WO 97/07208. These peptides and inhibitors thereof are said to be useful for antagonising physiologic effects of an opioid in an animal, and for treating/preventing a disease related to: hyperalgesia, neuroendocrine secretion, stress, locomotor activity, anxiety etc.
SUMMARY OF THE INVENTION
The present invention provides the use of a compound selected from nociceptin or an analogue, a variant or a homologue thereof, wherein 1 to 12 amino acid(s) have been deleted, 1-82 amino acid(s) have been added and/or 1-15 amino acid(s) have been substituted, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances, in particular the peripheral vasomotor effects known as hot flushes or hot flashes, wherein the deletion(s), addition(s) and/or substitution(s) does not substantially reduce the vasomotor disturbing effects of the analogue, variant or homologue of nociceptin.
It is an object of the invention to use a compound selected from nociceptin or an analogue, a variant or a homologue thereof, for the preparation of a pharmaceutical composition for a new use (new medical indication).
Further objects will become apparent from the following description.
DETAILED DESCRIPTION OF THE INVENTION
It has been found that nociceptin and nociceptin analogues, variants or homologues inhibit cordal stimulated vasodilatation in the pithed rat (an in-vivo-model for the hot flushes, hereafter referred to as "the pithed rat") which is known to be mediated by CGRP (Nuki Y. et al. Effects of Dorsal Rhizotomy on Depressor Response to Spinal Cord Stimulation Mediated by Endogenous Calcitonin Gene-related Peptide in the Pithed Rat. J. Neurosurg. 1993; 79:899-904).
Accordingly, in a first aspect, the present invention relates to the use of a compound selected from nociceptin or an analogue, a variant or a homologue thereof, wherein 1 to 12 amino acid(s) have been deleted, 1-82 amino acid(s) have been added and/or 1- 15 amino acid(s) have been substituted, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances , in particular the peripheral vasomotor effects known as hot flushes or hot flashes or for alleviating symptoms of drug withdrawal in particular abstinence symptoms occuring during withdrawal from abusive drugs, wherein the deletion(s), addition(s) and/or substitution(s) does not substantially reduce the vasomotor disturbing effects of the analogue, variant or homologue of nociceptin.
In one embodiment of the first aspect the compound is selected from
Phe-Ser-Glu-Phe-Met-Arg-Gln-Tyr-Leu-Val-Leu-Ser-Met-Gln-Ser-Ser-GIn, Thr-Leu-His-Gln-Asn-Gly-Asn-Val, (both of which are produced as disclosed in WO 97/07208), and from Tyr-Gly-Gly-Phe-Leu-Arg-Arg-lle-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln, Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr, Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr and Tyr-GIy-Gly-Phe-Leu (all of which are produced as disclosed in WO 97/07212).
In a second embodiment of the first aspect the invention relates to the use of a compound of the general formula I
(Xaa)n-Phe-Gly-Gly-Phe-(A1)-(A2)-(A3)-(A4)-(A5)-(A6)-(A7)-(A8)-(A9)-(A10)-(A11)-(A12)- Gln-(Xaa)n (I)
wherein A1 is Thr, Leu or Met;
A2 is Gly, Arg or Thr;
A3 is Ala, Arg or Ser;
A4 is Arg, lie Glu or Gin;
A5 is Lys, Arg or Phe; A6 is Ser, Pro Lys;
A7 is Ala, Lys, Gin or Val; A8 is Arg, Leu, Thr or Val; A9 is lys, Pro or Thr; A10 is Tyr, Leu or Trp; A11 is Ala, Asp or Val; A12 is Asn, or Thr; and (Xaa) is any amino acid; n and m are integers wherein n + m is no more than 82; and wherein the amino acids are each individually in either the D or L stereochemical configuration, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances, in particular the peripheral vasomotor effects known as hot flushes or hot flashes. The peptide of formula I is disclosed in WO 97/07212, wherein i.a. a procedure for the preparation thereof has been described.
In a third embodiment of the first aspect the compound is selected from the group consisting of
Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-GIn, Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-GIn, Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Tyr-Ala-Asn-GIn, Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln and
Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Tyr-Ala-Asn-GIn (all of which are produced as disclosed in WO 97/07212).
In a fourth embodiment of the first aspect the composition is in a form suitable for oral, nasal, transdermal, pulmonal, or parenteral administration.
In a fifth embodiment of the first aspect the compound is administered as a dose in the range from about 0.01 to about 100 g per patient per day, preferably from about 1 to about 1000 mg per patient per day, especially from about 10 to about 100 mg per patient per day, e.g. about 100 mg per patient per day. In a sixth embodiment of the first aspect the amino acids are all in either the D or L stereochemical configuration, preferably the L stereochemical configuration. However, the compounds of the invention may comprise both L and D amino acids.
In a second aspect the invention relates to a method for the treatment or prevention of vasomotor disturbances, in particular the peripheral vasomotor effects known as hot flushes or hot flashes or for alleviating symptoms of drug withdrawal in particular abstinence symptoms occuring during withdrawal from abusive drugs, the method comprising administering to a patient in need thereof an effective amount of nociceptin or an analogue, a variant or a homologue thereof, wherein 1 to 12 amino acid(s) have been deleted, 1-82 amino acid(s) have been added and/or 1-15 amino acid(s) have been substituted, or a pharmaceutically acceptable salt thereof, wherein the deletion(s), addition(s) and/or substitution(s) does not substantially reduce the vasomotor disturbing effects of the analogue, variant or homologue of nociceptin.
The effective, such as the therapeutically effective, amount of nociceptin or an analogue, a variant or a homologue thereof will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
In one embodiment of the second aspect the nociceptin or an analogue, a variant or a homologue thereof is administered as a dose with an effective amount in the range from about 0.01 to about 100 g per patient per day, preferably from about 1 to about 1000 mg per patient per day, especially from about 10 to about 100 mg per patient per day, e.g. about 100 mg per patient per day .
Within its scope the invention includes the D and/or L stereochemical configuration of all the amino acids which constitutes nociceptin and analogs, variants or homologs hereof. As used herein the term "patient" comprises any mammal which may benefit from treatment or prevention of vasomotor disturbances, such as a human, especially if the mammal is a female, such as a woman. However, "patient" is not intended to be limited to a woman.
The compounds intended to be embraced by the present invention are such peptides which are disclosed in WO 97/07208 and/or in WO 97/07212, as well as close analogs thereof. For the purpose of facilitating the reading of the present description said compounds, e.g. nociceptin, analogs, variants and homologues of nociceptin as well as compounds of formula I are all together termed "nociceptins", however this term does not in any way limit the scope of the present invention. Methods of preparing these nociceptins are either conventional and known to the man skilled in the art, or described in WO 97/07208 or in WO 97/07212.
The term "nociceptin" is intended to comprise the peptide Phe-Gly-Gly-Phe-Thr-Gly- Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-GIn, which peptide is disclosed in both WO 97/07208 and WO 97/07212.
The term "an analogue, a variant or a homologue thereof, wherein 1-12 amino acid(s) have been deleted, 1-82 amino acid(s) have been added and/or 1-15 amino acid(s) have been substituted" is intended to comprise nociceptin wherein 1-12 amino acid(s) have been deleted, 1-82 amino acid(s) have been added and/or 1-15 amino acid(s) have been substituted.
As used herein the term "treatment" is also meant to comprise profylactic treatment.
Within the present invention, the nociceptins may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids. Examples of such salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like. Suitable inorganic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like. Further e- xamples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science. 66, 2 (1977) which are known to the skilled artisan.
Also intended as pharmaceutically acceptable acid addition salts are the hydrates which the present nociceptins are able to form.
The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
The nociceptins of this invention may form solvates with standard low molecular weight solvents using methods known to the man skilled in the art.
The nociceptins may be administered in pharmaceutically acceptable acid addition salt form or, where appropriate, as a alkali metal or alkaline earth metal or lower alkylammonium salt. Such salt forms are believed to exhibit approximately the same order of activity as the free base forms.
In a broad aspect the present invention relates to the use of a compound, e.g. selected from the nociceptins disclosed herein, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances, in particular the peripheral vasomotor effects known as hot flushes or hot flashes, the compound being characterized by inhibiting cordal stimulated vasodilatation in "the pitched rat" and/or binding to nociceptin receptors (i.e. ORL-1 receptors as disclosed in WO 97/07212 and in WO 97/07208). In a further aspect the invention relates to the use of a compound, e.g. selected from the nociceptins disclosed herein, for the preparation of a pharmaceutical composition for alleviating symptoms of drug withdrawal in particular abstinence symptoms occuring during withdrawal from abusive drugs.
PHARMACEUTICAL COMPOSITIONS
A pharmaceutical composition for use in accordance with the present invention comprises, one or more nociceptins as active ingredient(s), or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
Pharmaceutical compositions containing nociceptins of the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy. 19th Ed., 1995. The compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
Typical compositions include nociceptins or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container for example in a sachet. Some examples of suitable carriers are water, salt solutions, alcohol's, polyethylene glycol's, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatine, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents. The formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
The pharmaceutical compositions can be sterilised and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
The route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment.
If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
For nasal administration, the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes. For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydro- xylated castor oil.
Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
A typical tablet which may be prepared by conventional tabletting techniques may contain:
Core:
Active compound (as free compound or salt thereof) 100 mg Colloidal silicon dioxide (Aerosil) 1.5 mg
Cellulose, microcryst. (Avicel) 70 mg
Modified cellulose gum (Ac-Di-Sol) 7.5 mg
Magnesium stearate Ad.
Coating:
HPMC approx. 9 mg
*Mywacett 9-40 T approx. 0.9 mg
*Acylated monoglyceride used as plasticizer for film coating.
Any novel feature or combination of features described herein is considered essential to this invention. Pharmacological effects:
Male Sprague Dawley rats ( 300±25 g) were anaesthetised with pentobarbital sodium (50 mg/kg i.p.) and polyethylene catheters were positioned in both femoral veins for the intravenous administration of drugs, such as nociceptin and analogues, and into the left femoral artery in order to measure arterial blood pressure and heart rate. The trachea was cannulated with polyethylene tubing and the rat was pithed, ventilated and drug treated as described by Nuki Y. et al. (Effects of Dorsal Rhizotomy on Depressor Response to Spinal Cord Stimulation Mediated by Endogenous Calcitonin Gene-related Peptide in the Pithed Rat. J. Neurosurg. 1993; 79:899-904).
Results:
Electrical stimulation of the rod at 4 Hz induced a profound decrease in arterial blood pressure which could be completely blocked by nociceptin and the nociceptin analogues.

Claims

CLAIMS:
1. Use of nociceptin or an analogue, a variant or a homologue thereof, wherein 1-12 amino acid(s) have been deleted, 1-82 amino acid(s) have been added and/or 1-15 amino acid(s) have been substituted, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances or for alleviating symptoms of drug withdrawal in particular abstinence symptoms occuring during withdrawal from abusive drugs, wherein said deletion(s), addition(s) and/or substitution(s) does not substantially reduce the vasomotor disturbing effects of said analogue, variant or homologue of nociceptin.
2. Use of nociceptin or an analogue, a variant or a homologue thereof, wherein 1-12 amino acid(s) have been deleted and/or 1-15 amino acid(s) have been substituted, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances or for alleviating symptoms of drug withdrawal in particular abstinence symptoms occuring during withdrawal from abusive drugs, wherein said deletion(s) and/or substitution(s) does not substantially reduce the vasomotor disturbing effects of said analogue, variant or homologue of nociceptin.
3. Use of nociceptin or an analogue, a variant or a homologue thereof, wherein 1-15 amino acid(s) have been substituted, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances or for alleviating symptoms of drug withdrawal in particular abstinence symptoms occuring during withdrawal from abusive drugs, wherein said substitution(s) does not substantially reduce the vasomotor disturbing effects of said analogue, variant or homologue of nociceptin.
4. Use according to claim 1 , 2 or 3 wherein the compound is selected from the group consisting of Phe-Ser-Glu-Phe-Met-Arg-Gln-Tyr-Leu-Val-Leu-Ser-Met-Gln-Ser-Ser-GIn, Thr-Leu-His-Gln-Asn-Giy-Asn-Val,
Tyr-Gly-Gly-Phe-Leu-Arg-Arg-lle-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln, Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr, Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr and Tyr-Gly-Gly-Phe-Leu.
5. Use of a compound of the general formula I
(Xaa)n-Phe-Gly-Gly-Phe-(A1)-(A2)-(A3)-(A4)-(A5)-(A6)-(A7)-(A8)-(A9)-(A10)-(A11)-(A12)- Gln-(Xaa)n
wherein A1 is Thr, Leu or Met; A2 is Gly, Arg or Thr; A3 is Ala, Arg or Ser; A4 is Arg, lie Glu or Gin; A5 is Lys, Arg or Phe; A6 is Ser, Pro Lys; A7 is Ala, Lys, Gin or Val; A8 is Arg, Leu, Thr or Val; A9 is lys, Pro or Thr; A10 is Tyr, Leu or Trp; A11 is Ala, Asp or Val; A12 is Asn, or Thr; and (Xaa) is any amino acid; n and m are integers wherein n + m is no more than 82; and wherein the amino acids are each individually in either the D or L stereochemical configuration, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances or for alleviating symptoms of drug withdrawal in particular abstinence symptoms occuring during withdrawal from abusive drugs.
6. Use according to claim 5 wherein n+m is zero.
7. Use according to any one of the claims 5 or 6 wherein said amino acids are all in the L stereochemical configuration.
8. Use according to any one of the claims 5 or 6 wherein said amino acids are all in the D stereochemical configuration.
9. Use according to any one of the claims 1-3, 5, 6 or 7 wherein the compound is selected from the group consisting of
Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-GIn, Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-GIn, Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Tyr-Ala-Asn-GIn, Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-GIn and Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Tyr-Ala-Asn-Gln.
10. Use according to any one of the claims 1-9 wherein said composition is in a form suitable for oral, nasal, transdermal, pulmonal, or parenteral administration.
11. Use according to any one of the claims 1-10 wherein said compound is administered as a dose in the range from about 0.01 to about 100 g per patient per day.
12. Use according to any one of the claims 1-11 wherein said peripheral vasomotor disturbances are hot flushes or hot flashes.
13. A method for the treatment of vasomotor disturbances or for alleviating symptoms of drug withdrawal in particular abstinence symptoms occuring during withdrawal from abusive drugs, the method comprising administering to a patient in need thereof an effective amount of nociceptin or an analogue, a variant or a homologue thereof, wherein 1-12 amino acid(s) have been deleted, 1-82 amino acid(s) have been added and/or 1-15 amino acid(s) have been substituted, or a pharmaceutically acceptable salt thereof, wherein said deletion(s), addition(s) and/or substitution(s) does not substantially reduce the vasomotor disturbing effects of said analogue, variant or homologue of nociceptin.
14. A method for the treatment of vasomotor disturbances or for alleviating symptoms of drug withdrawal in particular abstinence symptoms occuring during withdrawal from abusive drugs, the method comprising administering to a patient in need thereof an effective amount of nociceptin or an analogue, a variant or a homologue thereof, wherein 1-12 amino acid(s) have been deleted and/or 1-15 amino acid(s) have been substituted, or a pharmaceutically acceptable salt thereof, wherein said deletion(s) and/or substitution(s) does not substantially reduce the vasomotor disturbing effects of said analogue, variant or homologue of nociceptin.
15. A method for the treatment of vasomotor disturbances or for alleviating symptoms of drug withdrawal in particular abstinence symptoms occuring during withdrawal from abusive drugs, the method comprising administering to a patient in need thereof an effective amount of nociceptin or an analogue, a variant or a homologue thereof, wherein 1-15 amino acid(s) have been substituted, or a pharmaceutically acceptable salt thereof, wherein said substitution(s) does not substantially reduce the vasomotor disturbing effects of said analogue, variant or homologue of nociceptin.
16. The method according to claim 13, 14 or 15 wherein the compound is selected from the group consisting of
Phe-Ser-Glu-Phe-Met-Arg-Gln-Tyr-Leu-Val-Leu-Ser-Met-Gln-Ser-Ser-GIn, Thr-Leu-His-Gln-Asn-Gly-Asn-Val,
Tyr-Gly-Gly-Phe-Leu-Arg-Arg-lle-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln, Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr, Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr and Tyr-Gly-Gly-Phe-Leu.
17. A method for the treatment of vasomotor disturbances or for alleviating symptoms of drug withdrawal in particular abstinence symptoms occuring during withdrawal from abusive drugs, the method comprising administering to a patient in need thereof an effective amount of a compound of the general formula I
(Xaa)n-Phe-Gly-Gly-Phe-(A1)-(A )-(A3)-(A4)-(A5)-(A6)-(A7)-(A8)-(A9)-(A10)-(A11)-(A12)- Gln-(Xaa)n
wherein A1 is Thr, Leu or Met; A2 is Gly, Arg or Thr;
A3 is Ala, Arg or Ser; A4 is Arg, lie Glu or Gin; A5 is Lys, Arg or Phe; A6 is Ser, Pro Lys; A7 is Ala, Lys, Gin or Val; A8 is Arg, Leu, Thr or Val; A9 is lys, Pro or Thr; A10 is Tyr, Leu or Trp; A11 is Ala, Asp or Val; A12 is Asn, or Thr; and (Xaa) is any amino acid; n and m are integers wherein n + m is no more than 82; and wherein the amino acids are each individually in either the D or L stereochemical configuration, or a pharmaceutically acceptable salt thereof.
18. The method according to claim 17 wherein n+m is zero.
19. The method according to any one of the claims 17 or 18 wherein said amino acids are in the L stereochemical configuration.
20. The method according to any one of the claims 17 or 18 wherein said amino acids are in the D stereochemical configuration.
21. The method according to any one of the claims 13-15, 17, 18 or 19 wherein the compound is selected from the group consisting of
Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-GIn, Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-GIn, Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Tyr-Ala-Asn-GIn, Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln and Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Tyr-Ala-Asn-Gln.
22. The method according to any one of the claims 13-21 wherein said composition is in a form suitable for oral, nasal, transdermal, pulmonal, or parenteral administration.
23. The method according to any one of the claims 13-22 wherein said compound is administered as a dose in the range from about 0.01 to about 100 g per patient per day.
24. The method according to any one of the claims 13-23 wherein said peripheral vasomotor disturbances are hot flushes or hot flashes.
25. Use of nociceptin or an analogue, a variant or a homologue thereof, wherein 1-12 amino acid(s) have been deleted, 1-82 amino acid(s) have been added and/or 1-15 amino acid(s) have been substituted, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances, wherein said deletion(s), addition(s) and/or substitution(s) does not substantially reduce the vasomotor disturbing effects of said analogue, variant or homologue of nociceptin.
PCT/DK1998/000321 1997-07-15 1998-07-10 New use of nociceptin WO1999003491A1 (en)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009043460A1 (en) * 2007-09-11 2009-04-09 Mondobiotech Laboratories Ag Use of alpha-endorphin as a therapeutic agent
WO2009043459A1 (en) * 2007-09-11 2009-04-09 Mondobiotech Laboratories Ag Use of a platelet fibrinogen receptor hexapeptide antagonist and alpha-endorphin as therapeutic agents
WO2009046868A1 (en) * 2007-09-11 2009-04-16 Mondobiotech Laboratories Ag Use of a peptide as a therapeutic agent
WO2009039983A3 (en) * 2007-09-11 2009-05-28 Mondobiotech Lab Ag Use of a peptide as a therapeutic agent
US8551949B2 (en) 2009-07-27 2013-10-08 Nocicepta Llc Methods for treatment of pain
US11389473B2 (en) 2015-01-07 2022-07-19 Tonix Pharmaceuticals Holding Corp. Magnesium-containing oxytocin formulations and methods of use
US12156897B2 (en) 2016-04-12 2024-12-03 Tonix Pharma Limited Magnesium-containing oxytocin formulations and methods of use

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997007212A1 (en) * 1995-08-11 1997-02-27 Oregon Health Sciences University Opioid antagonists and methods of their use
WO1997007208A1 (en) * 1995-08-15 1997-02-27 Universite Libre De Bruxelles Nucleic acid molecules encoding peptides having pronociceptive properties

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997007212A1 (en) * 1995-08-11 1997-02-27 Oregon Health Sciences University Opioid antagonists and methods of their use
WO1997007208A1 (en) * 1995-08-15 1997-02-27 Universite Libre De Bruxelles Nucleic acid molecules encoding peptides having pronociceptive properties

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LIFE SCIENCES, Volume 60, No. 16, March 1997, HUNTER C. CHAMPION et al., "Nociceptin, an Endogenous Ligand for the Orl, Receptor, Has Novel Hypotensive Activity in the Rat", pages 241-245. *
PEPTIDES, Volume 18, No. 5, 1997, H.C. CHAMPION et al., "Nociceptin, an Endogenous Ligand for the ORL1 Receptor, Decreases Cardiac Output and Total Peripheral Resistance in the Rat", pages 729-732. *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009043460A1 (en) * 2007-09-11 2009-04-09 Mondobiotech Laboratories Ag Use of alpha-endorphin as a therapeutic agent
WO2009043459A1 (en) * 2007-09-11 2009-04-09 Mondobiotech Laboratories Ag Use of a platelet fibrinogen receptor hexapeptide antagonist and alpha-endorphin as therapeutic agents
WO2009046857A1 (en) * 2007-09-11 2009-04-16 Mondobiotech Laboratories Ag Use of a peptide as a therapeutic agent
WO2009046868A1 (en) * 2007-09-11 2009-04-16 Mondobiotech Laboratories Ag Use of a peptide as a therapeutic agent
WO2009039983A3 (en) * 2007-09-11 2009-05-28 Mondobiotech Lab Ag Use of a peptide as a therapeutic agent
US8551949B2 (en) 2009-07-27 2013-10-08 Nocicepta Llc Methods for treatment of pain
US9238053B2 (en) 2009-07-27 2016-01-19 Nocicepta Llc Methods for treatment of pain
US11389473B2 (en) 2015-01-07 2022-07-19 Tonix Pharmaceuticals Holding Corp. Magnesium-containing oxytocin formulations and methods of use
US12156897B2 (en) 2016-04-12 2024-12-03 Tonix Pharma Limited Magnesium-containing oxytocin formulations and methods of use

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