WO2008106738A1 - Compositions pour le traitement des dysfonctionnements sexuels - Google Patents

Compositions pour le traitement des dysfonctionnements sexuels Download PDF

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Publication number
WO2008106738A1
WO2008106738A1 PCT/AU2008/000310 AU2008000310W WO2008106738A1 WO 2008106738 A1 WO2008106738 A1 WO 2008106738A1 AU 2008000310 W AU2008000310 W AU 2008000310W WO 2008106738 A1 WO2008106738 A1 WO 2008106738A1
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WO
WIPO (PCT)
Prior art keywords
cholinergic
tricyclic antidepressant
clomipramine
muscarinic agent
agent
Prior art date
Application number
PCT/AU2008/000310
Other languages
English (en)
Inventor
Jakov Vaisman
Original Assignee
Jakov Vaisman
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 AU2007901213A external-priority patent/AU2007901213A0/en
Application filed by Jakov Vaisman filed Critical Jakov Vaisman
Publication of WO2008106738A1 publication Critical patent/WO2008106738A1/fr

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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders

Definitions

  • the invention relates to methods and compositions for the treatment of sexual dysfunction, and particularly to the treatment of premature ejaculation.
  • the invention has been developed primarily for use as a pharmaceutical composition for the treatment of premature ejaculation comprising the administration of a therapeutically effective amount of a tricyclic antidepressant with anticholinergic side effects and a cholinergic (muscarinic) agent and will be described hereinafter with reference to this application. However, it will be appreciated that the invention is not limited to this particular field of use.
  • Antidepressants have been administered orally, in tablet form, to treat premature ejaculation, although there are significant side effects with this approach.
  • antidepressants can lead to nausea, vomiting, dizziness, dry mouth and blurred vision.
  • Premature ejaculation has been treated in the past by the topical application of compositions containing local anaesthetics, such as lidocaine, to the skin of the penis to reduce sensitivity.
  • compositions containing local anaesthetics such as lidocaine
  • One limitation of such a method of treatment is that the composition must be substantially removed from the skin prior to intercourse to avoid transferring the anaesthetic to a female partner, thereby reducing reduced vaginal sensitivity.
  • Clomipramine has been found by the present inventor to be a very satisfactory in treating sexual dysfunction. However, when used for extended periods of time, or in large doses, side effects have been observed. These include drying of the mucosa, particularly the nasal mucosa, especially when delivered directly to the mucus membranes.
  • a pharmaceutically acceptable carrier such as in the recitation of a “pharmaceutically acceptable carrier” is meant a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • Carriers or “vehicles” as used herein refer to conventional pharmaceutically acceptable carrier materials suitable for drug administration, and include any such materials known in the art that are nontoxic and do not interact with other components of a pharmaceutical composition or drug delivery system in a deleterious manner.
  • treating and “treatment” as used herein refer to the ability to effect the time to ejaculation relative to that individual's response in the absence of therapy as - A - provided herein.
  • an individual's time to ejaculation is increased by at least a factor of two, more preferably a factor of four and most preferably a factor of at least ten.
  • an “effective” amount or a “therapeutically effective amount” of a drug or pharmacologically active agent is meant a nontoxic but sufficient amount of the drug or agent to provide the desired effect, i.e., delayed ejaculation as explained above.
  • the amount that is “effective”, however, will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent or agents, and the like. Thus, it is not always possible to specify an exact “effective amount”. However, an appropriate “effective” amount in any individual case may be determined by the administering clinician.
  • the invention is specifically directed to "as-needed” dosing, also referred to as “pro re nata” dosing, “prn” dosing, and “on-demand” dosing or administration, is meant the administration of an active agent at a time just prior to the time at which drug efficacy is wanted, e.g., just prior to anticipated sexual activity, and within a time interval sufficient to provide for the desired effect.
  • "As-needed" administration herein does not involve priming doses or administration at regular time intervals on an ongoing basis.
  • Mucosal drug delivery is meant administration of a drug to the mucosal surface of an individual so that the drug passes through the mucosal tissue and into the individual's blood stream.
  • Mucosal (or transmucosal) drug delivery may be intra-nasally delivery as preferred here but may also be “buccal” or “transbuccal”, referring to delivery of a drug by passage through an individual's buccal mucosa and into the bloodstream.
  • transmucosal drug delivery herein is "sublingual” drug delivery, which refers to delivery of a drug by passage of a drug through an individual's sublingual mucosa and into the bloodstream.
  • transmucosal drug delivery herein is "rectal” or “transrectal” drug delivery, referring to delivery of a drug by passage of a drug through an individual's rectal mucosa and into the bloodstream.
  • the invention provides a method for treating sexual dysfunction to a subject in need thereof comprising administering to the subject an effective amount of a tricyclic antidepressant and a cholinergic/muscarinic agent to a mucus membrane.
  • the tricyclic antidepressant may have anticholinergic side effects and may be chosen from the group consisting of nortriptyline, clomipramine, dothiepin, imipramine, amitriptyline and doxepin. However, a preferred tricyclic antidepressant is clomipramine.
  • the sexual dysfunction is male sexual dysfunction, and most preferably premature ejaculation.
  • the cholinergic/muscarinic agent may be chosen from the group consisting of pilocarpine, methacholine, carbachol, bethanechol. However, the cholinergic/muscarinic agent is preferably pilocarpine. Preferably the clomipramine and cholinergic agent are administered prior to sexual activity.
  • the clomipramine and the cholinergic agent are administered separately, however, it is more preferred if the clomipramine and the cholinergic agent are administered concurrently.
  • the clomipramine and the cholinergic agent are preferably administered to the mucosa, and most preferably the clomipramine and the cholinergic agent are administered to the nasal mucosa.
  • the clomipramine and the cholinergic agent are administered to the pulmonary mucosa (inhalation) or the buccal mucosa (troche).
  • the clomipramine is administered in an amount of between 0.1 and 1000 mg per dose, more preferably in an amount of between 1 and 100 mg per dose and even more preferably in an amount of between 5 and 25 mg per dose.
  • the cholinergic agent is administered in an amount of between 0.01 and 1000 mg per dose, more preferably in an amount of between 0.01 and 10 mg per dose and even more preferably in an amount of between 0.01 and 5.0 mg per dose.
  • the cholinergic/muscarinic agent and the tricyclic antidepressant are each titrated to suit the individual patients requirements.
  • the clomipramine and cholinergic agent are taken together intra-nasally within 30 minutes prior to intercourse.
  • the clomipramine and cholinergic agent are administered intra-nasally by means of one or two metered doses shortly before intercourse.
  • the invention provides a method for prolonging sexual intercourse involving a male, the method including the step of administering to the mucus membrane of the male prior to intercourse an amount of a tricyclic antidepressant effective to delay ejaculation and a cholinergic/muscarinic agent.
  • the invention provides a method for prolonging sexual intercourse involving a male over a prolonged number of episodes, the method including the step of administering to the mucus membrane of the male prior to intercourse an amount of a tricyclic antidepressant effective to delay ejaculation and a cholinergic/muscarinic agent.
  • the invention provides a composition for the treatment of premature ejaculation, said composition comprising a tricyclic antidepressant and a cholinergic/muscarinic agent.
  • the antidepressant is preferably clomipramine which is preferably formulated as the hydrochloride salt.
  • the cholinergic/muscarinic agent is preferably pilocarpine.
  • the composition preferably includes a carrier to facilitate the administration of the antidepressant.
  • the composition is preferably formulated for mucosal administration, and can be a troche for buccal administration, a suppository for rectal administration, or, most preferably, formulated for intra-nasal administration.
  • the intra-nasal spray is in the form of an aqueous or non-aqueous gel, suspension, liposomal dispersion, emulsion or microemulsion or in powdered, microsphere, coated microsphere or liposomal form.
  • composition may also be formulated for administration to the lungs via inhalation and in the form of a dry powder (preferably with a particle size of the dry powder less than 10 microns), a micronized drug suspended in a liquefied propellant (e.g. an aerosol with chlorofluorocarbon or hydrofluoroalkane propellant), or a drug dissolved, either alone or by way of a cosolvent, in a liquefied propellant.
  • a liquefied propellant e.g. an aerosol with chlorofluorocarbon or hydrofluoroalkane propellant
  • surfactants may be included in the formulations of the present invention.
  • Preferred surfactants include oleic acid, sorbitan trioleate, lecithin and their mixtures thereof.
  • the invention provides the use of a tricyclic antidepressant and a cholinergic/muscarinic agent in the manufacture of a medicament for administration to the mucus membrane for the treatment of premature ejaculation.
  • the cholinergic/muscarinic agent is preferably pilocarpine.
  • the medicament is preferably formulated for intra-nasal administration.
  • the mucosal, and particularly the intra-nasal mucosal route of the present invention allows the drugs to bypass the first metabolism of the liver, and cross the blood/brain barrier to act straight away on the brain.
  • This mode of action may serve to explain the small doses used to achieve success, the rapid onset of action and the consistency in dose/response patterns.
  • the antidepressant agent typically used for the treatment of clinical depression
  • a cholinergic/muscarinic agent such as pilocarpine
  • the antidepressant agent and the cholinergic/muscarinic agent are delivered to the same site concurrently or sequentially.
  • Clomipramine can be administered intra-nasally at a fraction of the dose usually used to treat depression, with rapid onset of action and with a high degree of predictability. For example, when clomipramine is delivered directly to the mucus membrane a therapeutic effect will result in about 10 to 15 minutes (compared to oral administration in tablet form which will provide a therapeutic effect in hours or more). However, clomipramine alone can cause the nasal mucosa to dry up. As the nasal mucosa dries up, dryness and cracking of the nasal surfaces can result. This can lead to feelings of discomfort, and can also allow for the onset of bacterial infection.
  • drying of the mucosa means that the absorption of clomipramine is reduced, and consequently a larger dose is required to achieve the primary effect.
  • the only option is to discontinue medication and allow the patients nasal mucosa to recover. However, that can take time and during that period, sexual dysfunction (premature ejaculation) is likely to recur.
  • a cholinergic/muscarinic agent has been found to surprisingly counteract the drying of the mucosa without counteracting the desired effects of clomipramine in countering sexual dysfunction when delivered directly to the mucus membrane.
  • Other antidepressants may be used in combination with the cholinergic/muscarinic agent, and they may be used alone or with one or more carriers for facilitating the application of the antidepressant agent to the skin or to the mucosa.
  • Clomipramine is usually provided as clomipramine hydrochloride, but any pharmaceutically acceptable form is acceptable.
  • the clomipramine is administered in an amount effective to delay premature ejaculation, of between 0.1 and lOOOmg per dose, depending upon the severity of the patients problems, as well as other factors such as patient size. More preferably, the dosage will be between 1 and 1 OOmg antidepressant, even more preferably between 5 and 25 mg antidepressant. Again, the exact dosage will be readily determined by a trained clinician.
  • the cholinergic/muscarinic agent is administered in an amount effective to delay premature ejaculation, of between 0.01 and lOOOmg per dose, depending upon the nature of active ingredient used and the severity of the patients problems, as well as other factors such as patient size. More preferably, if the active agent is pilocarpine, the dosage will be between 0.01 and lOmg, even more preferably between 0.01 and 5 mg. The exact dosage will be readily determined by a trained clinician.
  • compositions for mucosal administration may be in many forms. Most typically, the invention is formulated as a spray for intra-nasal administration, although it may be formulated for buccal administration in the form of a troche or in the form of a suppository for rectal administration.
  • the important consideration is to select the dosages of clomipramine and cholinergic agent in combination to provide a sufficient therapeutic effect to prevent premature ejaculation whilst preventing nasal dryness.
  • Nasal formulations include gels, suspensions, liposomal dispersions, emulsions or microemulsions and may be any combination of aqueous and non-aqueous components.
  • the nasal formulations may be in powdered form, such as microspheres, liposomes, coated microspheres (for example, such as those with a cellulose or polysaccharide coating).
  • the nasal formulations of the present invention may include conventional additives and excipients, such as buffers, thickening agents, soothing agents, sweeteners and membrane conditioners or transport agents, antioxidants, preservatives, penetrating agents and other carriers which will be known by those skilled in the art. It is preferably dispensed via a metered spray vessel. Administering the dose in a metered fashion enables a use of a defined quantity of the active ingredient involved.
  • Nasal formulations may typically include water, polyethylene glycols (various pharmaceutically acceptable PEG's,) glycerine, DMSO, ascorbic acid or ascorbate salts or bisulfites.
  • the dosage is taken intra-nasally just prior to intercourse, between 10 and 30 minutes prior to intercourse, most preferably around 20 minutes prior to intercourse.
  • the nasal composition may be administered by means of one or two metered doses shortly before intercourse.
  • the volume of one actuation of a metered dose is generally 20 to 500 microlitres. by way of a troche or suppository which are administered slightly further ahead of time.
  • a typical intra-nasal spray of the present invention contains clomipramine such that a single dose typically delivers from 2 to 50 mg clomipramine.
  • the amount of pilocarpine is typically such that the single dose delivered is 0.1 mg.
  • kits are contemplated wherein two separate unit dosage forms are combined: for example, a clomipramine pharmaceutical composition and a pilocarpine pharmaceutical composition.
  • the kit will preferably include directions for the administration of the separate components.
  • kits may comprise, in separate containers in a single package, pharmaceutical compositions for use in combination to treat sexual dysfunction which comprises in one container a therapeutically effective amount of clomipramine or a pharmaceutically acceptable salt, solvate, hydrate or crystalline polymorph form thereof in a pharmaceutically acceptable carrier and in a second container a therapeutically effective amount of pilocarpine or a pharmaceutically acceptable salt, solvate or hydrate thereof in a pharmaceutically acceptable carrier.
  • the formulations can be prepared using conventional pharmaceutical excipients and additives using conventional techniques.
  • Such pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavorings, thickeners, coloring agents, emulsifiers and the like.
  • Other ingredients for desired formulation and preparation of dosage forms is described in standard texts and manuals, for example Pharmaceutics - The Science of Dosage Form Design, Ed. Michael E. Aulton, Churchill Livingstone Press (1998); The Pharmaceutical Code, Edition 12, Ed. W. Lund, The Pharmaceutical Press (1994).
  • a subject had been treated successfully for premature ejaculation by administering clomipramine intra-nasally. However, after some time the subject developed a dry nose, which became uncomfortable, and appeared to be exhibiting a reduced response to clomipramine. After a rest period, with no medication, the patients nasal mucosa recovered but premature ejaculation re-emerged as a problem.
  • a formulation in accordance with example 1 was administered to a subject who again exhibited successful treatment of premature ejaculation without the detrimental side effects of nasal dryness. No other side effects were detected as a result of the combination therapy of the present invention.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Reproductive Health (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Emergency Medicine (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention porte sur un procédé destiné au traitement de dysfonctionnements sexuels, et particulièrement de l'éjaculation précoce, ledit procédé consistant à administrer à un patient une quantité efficace d'un antidépresseur tricyclique (clomipramine par exemple) et d'un agent cholinergique/muscarinique (pilocarpine par exemple) par voie muqueuse, et notamment par l'intermédiaire de la muqueuse nasale.
PCT/AU2008/000310 2007-03-08 2008-03-06 Compositions pour le traitement des dysfonctionnements sexuels WO2008106738A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU2007901213A AU2007901213A0 (en) 2007-03-08 Compositions for the treatment of sexual dysfunction
AU2007901213 2007-03-08

Publications (1)

Publication Number Publication Date
WO2008106738A1 true WO2008106738A1 (fr) 2008-09-12

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PCT/AU2008/000310 WO2008106738A1 (fr) 2007-03-08 2008-03-06 Compositions pour le traitement des dysfonctionnements sexuels

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011044105A1 (fr) * 2009-10-05 2011-04-14 Vivus, Inc. Traitement avec des agonistes cholinergiques

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002053104A2 (fr) * 2001-01-02 2002-07-11 Sention, Inc. Utilisation d'inhibiteurs de catecholamine reuptake pour ameliorer la memoire
WO2005115471A2 (fr) * 2004-05-27 2005-12-08 Neurocure Ltd. Procedes et compositions pour le traitement de la dependance a la nicotine et de la demence
WO2006125042A1 (fr) * 2005-05-19 2006-11-23 Boehringer Ingelheim International Gmbh Procede pour le traitement de dysfonctionnements sexuels d’origine medicamenteuse

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002053104A2 (fr) * 2001-01-02 2002-07-11 Sention, Inc. Utilisation d'inhibiteurs de catecholamine reuptake pour ameliorer la memoire
WO2005115471A2 (fr) * 2004-05-27 2005-12-08 Neurocure Ltd. Procedes et compositions pour le traitement de la dependance a la nicotine et de la demence
WO2006125042A1 (fr) * 2005-05-19 2006-11-23 Boehringer Ingelheim International Gmbh Procede pour le traitement de dysfonctionnements sexuels d’origine medicamenteuse

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DRINGENBERG H.C. ET AL.: "Effect of tacrine on EEG slowing in the rat: enhancement by concurrent monoamine therapy", NEUROBIOLOGY OF AGING, vol. 21, no. 1, January 2000 (2000-01-01) - February 2000 (2000-02-01), pages 135 - 143, XP001188233 *
GLENERT U.: "Effects of chronic anethole trithione and amitryptyline treatment on rat parotid gland signalling", EUR. J. PHARMACOLOGY-MOLECULAR PHARMACOLOGY SECTION, vol. 226, 1992, pages 43 - 52, XP003021935 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011044105A1 (fr) * 2009-10-05 2011-04-14 Vivus, Inc. Traitement avec des agonistes cholinergiques

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