EP0892639A1 - PROCEDE DE TRAITEMENT DES CONTRACTIONS UTERINES INDESIRABLES PAR UTILISATION D'ISOMERES R OU RR OPTIQUEMENT PURS D'AGONISTES $g(b)-2 ADRENERGIQUES - Google Patents

PROCEDE DE TRAITEMENT DES CONTRACTIONS UTERINES INDESIRABLES PAR UTILISATION D'ISOMERES R OU RR OPTIQUEMENT PURS D'AGONISTES $g(b)-2 ADRENERGIQUES

Info

Publication number
EP0892639A1
EP0892639A1 EP97905640A EP97905640A EP0892639A1 EP 0892639 A1 EP0892639 A1 EP 0892639A1 EP 97905640 A EP97905640 A EP 97905640A EP 97905640 A EP97905640 A EP 97905640A EP 0892639 A1 EP0892639 A1 EP 0892639A1
Authority
EP
European Patent Office
Prior art keywords
isomer
approximately
agonist
individual
uterine contractions
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
EP97905640A
Other languages
German (de)
English (en)
Other versions
EP0892639A4 (fr
Inventor
E.Charles Pesterfield, Jr.
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.)
Savor Evelyn
Original Assignee
Savor Evelyn
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 US08/592,988 external-priority patent/US5708036A/en
Application filed by Savor Evelyn filed Critical Savor Evelyn
Publication of EP0892639A1 publication Critical patent/EP0892639A1/fr
Publication of EP0892639A4 publication Critical patent/EP0892639A4/fr
Ceased legal-status Critical Current

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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine

Definitions

  • enantiomers Many biologically active molecules exist as enantiomers. Although structurally identical, enantiomers can have different effects in biological systems: one enantiomer may have specific therapeutic activity while the other enantiomer may have no therapeutic activity or may have entirely different forms of biological activity.
  • the form in which adrenergic beta-2 agonists presently are used are as racemic mixtures of two isomers (R- and S-albuterol; R- and S-terbutaline; R- and S-salmeterol; RR- and SS-fenoterol; and RR- and SS-formoterol) .
  • R-isomer of a racemic compound is structurally identical to the S-isomer and structurally the isomers differ only in that one isomer is a mirror image of the other.
  • a molecule has two chiral centers, there are four isomers, called RR-, SS, RS, and SR.
  • the marketed racemic beta-agonists formoterol and fenoterol each consists of a mixture of an RR-isomer (50%) and an SS-isomer (50%) .
  • eutomer(s) refers to the R-isomers of albuterol, terbutaline or salmeterol and/or the RR-isomers of fenoterol or formoterol
  • distomer(s) refers to the S-isomer(s) of albuterol, terbutaline or salmeterol and/or the SS-isomer(s) of fenoterol or formoterol.
  • beta-2 adrenergic drugs The therapeutic action of beta-2 adrenergic drugs is to activate adrenergic (82-receptors and thereby initiate cellular responses, the most well-known is the relaxation of bronchial smooth muscles.
  • Beta-2 agonists are most commonly used to treat bronchial spasms associated with asthma. These drugs can also be used to inhibit undesired contractions of the uterus, but there are potentially hazardous side effects of the drug when used for this indication.
  • the potentially hazardous side effects have now been found to include induction of uterine hyperreactivity (stimulation of uterine contractions) and teratogenic and unwanted effects of the drug to the fetus.
  • the present invention relates to a method of inhibiting undesired uterine contractions in a female individual, by administering a pure eutomer which relaxes uterine smooth muscle, while eliminating side effects caused by the distomer.
  • the method is particularly useful in treating subjects that have demonstrated a propensity for irregular uterine contractions, induced by known or unknown causes.
  • it is important to have an effective spasmolytic medication that does not further facilitate uterine contractions.
  • the medication should not cause harm to the fetus and should not exhibit other adverse side effects.
  • a composition containing the pure eutomer is particularly useful for this application because the eutomers exhibits these desired characteristics.
  • the present method provides a safe, effective method for treating irregular uterine contractions while reducing undesirable side effects, both in non-pregnant females and in pregnant females and their fetuses, for example bronchial hyperreactivity, tremor, nervousness, shakiness, dizziness, increased appetite, cardiac tachycardia, and particularly uterine hyperreactivity, associated with adrenergic beta-2 agonists.
  • racemic mixtures of beta- 2-agonists may also cause teratogenic effects, which are believed to be associated with the distomer(s) .
  • Administration of a pure eutomer eliminates any side effect that is associated with the distomer.
  • administration of a pure eutomer also eliminates irregular contractions of the uterine smooth muscle while avoiding the uterine hyperreactivity that has now been found to be induced by the S- or SS-isomers of beta-2 agonists.
  • the present invention relies on the utero-spasmolytic activity of the R-isomer (resp. the RR-isomer) of a beta-agonist to provide relief from undesired uterine contrac ⁇ tions, both in the non-pregnant female ("dysmenorrhea”) and in the pregnant female (“tocolysis”) , while simultaneously eliminating uterine hyperreactivity and other side effects, that have now been found to be caused by the distomer.
  • undesired uterine contractions is intended herein to include irregular contractions of the non-pregnant uterus in female individuals as well as premature uterine contractions of the pregnant uterus in female individuals.
  • side effects that reside in both isomers will be reduced by using the pure R- or RR-isomer.
  • the optically pure R- or RR-isomer of a beta-agonist is administered alone, or in combination with one or more other drugs in adjunctive treatment, to an individual in whom relief from uterine contractions is desired.
  • the R-isomer of albuterol as used herein refers to the optically pure isomer of cc' [ (tert-butylamino) methyl] -4-hydroxy-m-xylene- ⁇ ,cc' -diol, and to any biologically acceptable salt or ester thereof.
  • the RR-isomer of fenoterol as used herein refers to the optically pure RR-isomer of 1- (3, 5-dihydroxy phenyl) -l-hydroxy-2- [ (4-hydroxyphenyl) isopropylamino] ethane, and to any biologically acceptable salt or ester thereof.
  • the RR-isomer of formoterol refers to the optically pure isomer of 2' - hydroxy-5' - [ (RS) -l-hydroxy-2- [ [ (RS) -p-methoxy- ⁇ - methylphenethyl] amino] ethyl] formanilide, and to any biologically acceptable salt or ester thereof.
  • the R-isomer of terbutaline as used herein refers to the optically pure isomer of 1- (3 , 5-dihydroxyphenyl) -2 - (tert-butylamino) ethanol, and to any biologically acceptable salt or ester thereof.
  • the R-isomer of salmeterol as used herein refers to the optically pure isomer of 4-hydroxy-cc' - [ [ [6- (4- phenylbutoxy) -hexyl] amino]methyl] - m-xylene cc,cc' -diol, and to any biologically acceptable salt or ester thereof.
  • the term "optically pure” or “substantially free of the S- or SS-enantiomer” as used herein means that the composition contains at least 85% by weight of the R- or RR-isomer of a beta-agonist and 15% by weight or less of the S- or SS-isomer.
  • Optically pure adrenergic betaagonists are readily obtainable by methods known to those skilled in the art, for example, by synthesis from an optically pure intermediate or resolution of the racemic compound into its isomers.
  • the eutomer of a beta-agonist is administered to an individual, who suffers from undesired uterine contractions of uterine smooth muscle.
  • R-albuterol or RR-formoterol is administered to an individual after the onset of undesired uterine smooth muscle contractions to reduce or eliminate said contractions.
  • an optically pure eutomer of a beta-agonist is administered prophylactically to an individual predisposed to undesired uterine contractions, that is, administration of the drug before the uterine contractions begin, to prevent their occurrence or to reduce the extent to which they occur.
  • the optically active R- or RR-isomer of a beta-agonist can be administered by inhalation, parenterally, subcutaneously, intravenously, intramuscularly or other injection or infusion, orally, sublingually, topically, transdermally, vaginally, rectally or via an implanted reservoir containing the drug.
  • the form in which the drug will be administered e.g. inhalant, powder, tablet, capsule, solution, emulsion etc.
  • the route by which it is administered will depend on the route by which it is administered.
  • the quantity of the drug to be administered will be determined on an individual basis, and will be based on the pharmacological potency of the drug, the route of administration, and at least in part on consideration of the individual's size, the severity of the symptoms to be treated and the results sought. In general, quantities of optically pure R- or RR-isomer sufficient to eliminate undesired uterine contractions will be administered.
  • the actual dosage (quantity administered at a time) and the number of administrations per day will depend on the pharmacokinetic property of the drug and the mode of drug administrations, for example, by inhaler, nebulizer or oral administration.
  • R(-) -isomer of albuterol may be given by various forms of inhalation devices (etered dose inhalers, dry powder inhalers, nebulizers etc.) , 1 to 50 mg may be given by the oral route (tablets, caplets, controlled release formulations including enteric coated oral preparations, etc.) or the sublingual routes once or more times per day may be adequate in most individuals to produce the desired effect.
  • inhalation devices etered dose inhalers, dry powder inhalers, nebulizers etc.
  • 1 to 50 mg may be given by the oral route (tablets, caplets, controlled release formulations including enteric coated oral preparations, etc.) or the sublingual routes once or more times per day may be adequate in most individuals to produce the desired effect.
  • R-albuterol e.g. tablet or syrup
  • a dose of about 1 mg to about 15 mg one to four times daily is administered to produce the desired effect.
  • Controlled - release, sustained-released or delayed-released formulations of R-albuterol containing 1 mg to 50 mg may be used to obtain controlled, sustained, or delayed therapeutic effects.
  • Controlled or delayed release formulations e.g. enteric coated formulations or other formulations that avoid exposing the drug substance to the acid environment of the stomach, other types of slow-release formulations or of sustained release formulations
  • the dose and the dosing frequency will be decreased.
  • the dose of RR-formoterol may be half or less than half the dose of R-- albuterol and the dosing may also be less frequent .
  • the optically pure R- or RR-isomer of a beta-agonist can be administered together with one or more other compound(s) .
  • various utero-spasmolytic drugs such as anticholinergic drugs, leucotriene antagonists, lipoxygenase inhibitors, cyclooxygenase inhibitors, thromboxane antagonists, thromboxane synthetase inhibitors, PAF-antagonists, antihistaminergic drugs, antiserotonergic drugs or other adrenergic beta-2 stimulators can be given with or between the doses of the selected R-or RR-isomer.
  • Compounds that improve or prolong the therapeutic effect of the selected R- or RR-isomer may also be co-administered to patients given the selected isomer.
  • the two (or more) drugs can be administered in one composition or as separate entities. For example they can be administered in a single formulation, such as a capsule, tablet, powder, or liquid, mist, aerosol, injec- tion, etc. or as separate formulations.
  • a composition to be administered in inhalant form can include, in addition to the drug(s), a liquid carrier and/or propellant.
  • a composition to be administered in tablet form for oral or sublingual use can include in addition to the drug a filler (e.g., lactose) , a binder (e.g., carboxymethyl cellulose, gum arable, gelatin) , an adjuvant, a flavoring agent, a coloring agent and a coating material (e.g., wax or a plasticizer) .
  • a composition to be administered in liquid form can include the combination of drugs and, optionally, an emulsifying agent, a flavoring agent and/or a coloring agent.
  • a composition to be administered vaginally or rectally may include the combination of drugs consisting of the selected R- or RR-isomer and for example at least one additional drug selected from the group consisting of smooth muscle relaxants, antihistamines, antiserotonergics, anticholinergics, antiprostaglandins, and metabolic sulfation inhibitors.
  • the optically pure R- or RR-isomer of albuterol, terbutaline, fenoterol, salmeterol or formoterol, alone or in combination with another drug(s) is administered to an individual periodically as necessary to reduce undesired uterine contractions.
  • the present composition and method provide effective treatment to inhibit or reduce uterine contractions while minimizing the undesired effects associated with the use of the racemic drug.
  • side effect include central nervous system effects, tremor, shakiness, dizziness and increased appetite, and cardiac effects and uterine contractions, induced by the S- or SS-isomer of the selected drug.
  • teratogenic effects associated with racemic beta-2 agonists are believed to reside in the S- or SS-enantiomer.
  • the pure R- or RR-isomer of a beta-2 agonist the teratogenic effects and the unwanted uterine contractile or contraction-promoting effects of the corresponding S- or SS-isomer will be avoided.
  • Administration of the pure eutomer instead of the racemate may also result in a prolonged duration of therapeutic activity, for example by the distomer counteracting the therapeutic effects (e.g. causing smooth muscle hyperreactivity) of the eutomer.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de prévention ou d'inhibition des contractions utérines indésirables chez la femme. Ce procédé consiste en l'administration d'un eutomère pur d'un agoniste β-2 adrénergique provoquant le relâchement du muscle lisse utérin, tout en éliminant les effets secondaires imputables au distomère. Le procédé convient particulièrement au traitement des patientes enceintes ou non enceintes qui ont fait preuve d'une propension aux contractions utérines indésirables, tout en réduisant chez ces patientes et/ou leur foetus les effets secondaires tels que l'hyperréactivité bronchique, le tremblement, la nervosité, les pertes d'équilibre, les vertiges, la boulimie et la tachycardie cardiaque. Il est à remarquer que l'administration d'un eutomère pur élimine également les contractions indésirables du muscle lisse de l'utérus, tout en évitant l'hyperréactivité utérine qui s'est avérée être induite par les isomères S ou SS des agonistes β-2.
EP97905640A 1996-01-29 1997-01-28 PROCEDE DE TRAITEMENT DES CONTRACTIONS UTERINES INDESIRABLES PAR UTILISATION D'ISOMERES R OU RR OPTIQUEMENT PURS D'AGONISTES -g(b)-2 ADRENERGIQUES Ceased EP0892639A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US592988 1996-01-29
US08/592,988 US5708036A (en) 1996-01-29 1996-01-29 Method of treating premature uterine contractions using the optically active R(-)-isomer of albuterol
US2299596P 1996-08-02 1996-08-02
US22995P 1996-08-02
PCT/US1997/001342 WO1997026871A1 (fr) 1996-01-29 1997-01-28 PROCEDE DE TRAITEMENT DES CONTRACTIONS UTERINES INDESIRABLES PAR UTILISATION D'ISOMERES R OU RR OPTIQUEMENT PURS D'AGONISTES β-2 ADRENERGIQUES

Publications (2)

Publication Number Publication Date
EP0892639A1 true EP0892639A1 (fr) 1999-01-27
EP0892639A4 EP0892639A4 (fr) 1999-06-09

Family

ID=26696599

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97905640A Ceased EP0892639A4 (fr) 1996-01-29 1997-01-28 PROCEDE DE TRAITEMENT DES CONTRACTIONS UTERINES INDESIRABLES PAR UTILISATION D'ISOMERES R OU RR OPTIQUEMENT PURS D'AGONISTES -g(b)-2 ADRENERGIQUES

Country Status (4)

Country Link
EP (1) EP0892639A4 (fr)
AU (1) AU2247997A (fr)
CA (1) CA2247953A1 (fr)
WO (1) WO1997026871A1 (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2286913C (fr) * 1997-04-30 2008-12-09 Bridge Pharma, Inc. Composition et procedes employant un eutomere
ZA994264B (en) 1998-07-01 2000-01-25 Warner Lambert Co Stereoisomers with high affinity for adrenergic receptors.
US7232837B2 (en) 1999-06-29 2007-06-19 Mcneil-Ppc, Inc. Stereoisomers with high affinity for adrenergic receptors
WO2002039998A2 (fr) * 2000-11-01 2002-05-23 Sention, Inc. Procedes et compositions permettant de reguler la consolidation de la memoire
US7619005B2 (en) 2000-11-01 2009-11-17 Cognition Pharmaceuticals Llc Methods for treating cognitive impairment in humans with Multiple Sclerosis
US20030232890A1 (en) 2000-11-01 2003-12-18 Sention, Inc. Methods for treating an impairment in memory consolidation
WO2010104986A1 (fr) * 2009-03-13 2010-09-16 Loma Linda University Procédé permettant d'intervenir sur la période de maturation cervicale et de parturition

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3163871D1 (en) * 1980-07-09 1984-07-05 Draco Ab 1-(dihydroxyphenyl)-2-amino-ethanol derivatives; preparation, compositions and intermediates
DK0431519T3 (da) * 1989-12-04 1994-07-04 Searle & Co System til transdermal indgivelse af albuterol
US5362755A (en) * 1990-01-05 1994-11-08 Sepracor, Inc. Method for treating asthma using optically pure (R)-albuterol
DE4014252A1 (de) * 1990-05-04 1991-11-07 Boehringer Ingelheim Vetmed Enantiomerentrennung von cimaterol, (-)-cimaterol und dessen verwendung als arzneimittel oder als leistungsfoerderer
WO1992016173A1 (fr) * 1991-03-19 1992-10-01 Sepracor, Inc. Procedes et compositions de traitement de troubles pulmonaires utilisant de la terbutaline optiquement pure
US5370135A (en) * 1993-10-13 1994-12-06 Biex, Inc. Use of estriol measurement to monitor tocolytic therapy

Also Published As

Publication number Publication date
CA2247953A1 (fr) 1997-07-31
EP0892639A4 (fr) 1999-06-09
WO1997026871A1 (fr) 1997-07-31
AU2247997A (en) 1997-08-20

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