WO1995029676A1 - Controle de la prise de poids chez le fumeur - Google Patents

Controle de la prise de poids chez le fumeur Download PDF

Info

Publication number
WO1995029676A1
WO1995029676A1 PCT/US1994/004795 US9404795W WO9529676A1 WO 1995029676 A1 WO1995029676 A1 WO 1995029676A1 US 9404795 W US9404795 W US 9404795W WO 9529676 A1 WO9529676 A1 WO 9529676A1
Authority
WO
WIPO (PCT)
Prior art keywords
cotinine
nicotine
medicament
article
body weight
Prior art date
Application number
PCT/US1994/004795
Other languages
English (en)
Inventor
Robert M. Keenan
Original Assignee
Pharmaco Behavioral Associates, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmaco Behavioral Associates, Inc. filed Critical Pharmaco Behavioral Associates, Inc.
Priority to AU68230/94A priority Critical patent/AU6823094A/en
Priority to PCT/US1994/004795 priority patent/WO1995029676A1/fr
Priority to EP94916628A priority patent/EP0758236A1/fr
Publication of WO1995029676A1 publication Critical patent/WO1995029676A1/fr

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/465—Nicotine; Derivatives thereof

Definitions

  • the invention relates to therapeutic methods and articles of manufacture to manage human body weight with the use of cotinine or pharmaceutically acceptable salt thereof.
  • the invention includes methods and articles of manufacture using cotinine or pharmaceutically acceptable salt thereof to manage human body weight in nicotine-abstinent, and nicotine-naive humans.
  • Tobacco use in the United States is responsible for more than 400,000 deaths per year due to many types of cancer and cardiovascular disease (See, Office of Smoking and Health, The Health Consequences of Smoking: Nicotine Addiction. A Report to the Surgeon General. U.S. Government Printing Office, Washington, D.C., DHHS Publication Number (CDC) 88-8406 (1988)).
  • CDC DHHS Publication Number
  • nicotine insufflation significantly reduced the perceived taste intensity of dietary "fat,” but not “sweets.” From this, it appears that nicotine acts to decrease body weight through decreased calorie intake (i.e., appetite suppression) and increased metabolism.
  • appetite suppression i.e., appetite suppression
  • the mechanism for the observed appetite suppression is likely related to the increased serotonergic activity within the hypothalamus of the brain.
  • nicotine appears to act as an appetite suppressant through serotonergic mechanism and is partially effective in preventing the weight gain associated with tobacco use cessation in nicotine-experienced individuals and/or is able to increase metabolism and decrease caloric intake in nicotine-naive individuals
  • nicotine delivered through various forms of approved nicotine pharmacotherapies is toxic and not recommended for long- term use due to its adverse health effects and abuse potential due to nicotine's addicting nature.
  • the present invention provides a therapeutic method to (a) suppress appetite and/or prevent weight gain and/or induce weight loss in nicotine- experienced and/or nicotine-abstinent individuals during the post-tobacco use cessation period, or (b) suppress appetite and/or prevent weight gain and/or reduce body weight in nicotine-naive individuals comprising administering to a human in need of such treatment, i.e., a nicotine-experienced tobacco user or overweight person who does not engage in tobacco use, an amount of cotinine or a pharmaceutically acceptable salt thereof, in an amount effective to significantly suppress appetite and/or prevent weight gain and/or induce weight loss.
  • the present method is effective for short-term appetite suppression and/or induction of weight loss and/or to maintain tobacco abstinence by preventing weight gain for extended periods of time.
  • the present invention is exemplified by a research study in which (-)- cotinine base was intravenously administered in a double-blind placebo- controlled manner to cigarette smokers. Trie ⁇ inine administration when compared to placebo caused a decrease in self-reported ratings of "hunger" over a two hour period post-injection.
  • cotinine While it is known that nicotine is able to increase metabolism and/or decrease caloric intake in nicotine-experienced and nicotine-naive individuals, cotinine has a similar spectrum of pharmacologic activity to nicotine with cotinine being less potent than nicotine. Therefore, cotinine should act as an appetite suppressant in the same manner as nicotine. Cotinine has many qualities which can enhance its value as an appetite suppressant in nicotine-experienced and/or nicotine-naive individuals. Cotinine has a long terminal half-life, complete oral bioavailability, minimal cardiovascular effect, low potential for abuse and has not been reported to be harmfiil even at very high doses in many species including man. Due to cotinine's minimal cardiovascular effect, cotinine should be able to be used in the immediate post-tobacco use cessation period in combination with currently existing and/or future nicotine replacement therapies.
  • the present invention also provides an article of manufacture comprising packaging material, such as a box, bottle, tube, sprayer, insufflator, intravenous (i.v.) bag, envelope and the like; and at least one unit dosage form of a pharmaceutical agent contained within said packaging material, wherein said pharmaceutical compound comprises cotinine or a pharmaceutically acceptable salt thereof in an amount effective to induce appetite suppression and/or prevention of weight gain and/or weight loss in nicotine-experienced and/or nicotine-naive individuals, and wherein said packaging material includes instruction means which indicate that said cotuiine or said pharmaceutically acceptable salt thereof can be used for appetite suppression and/or prevention of weight gain and/or weight loss in nicotine-experienced and/or nicotine-naive individuals.
  • Suitable instruction means include printed labels, printed package inserts, tags, cassette tapes, and the like.
  • Cotinine (l-methyl-5-(3-pyridinyl)-2-pyrrolidinone) has the formula shown above;
  • the physiologically active form is the (-)-isomer, so as used herein, the term "cotinine” includes (-)-cotinine s or the racemic form, (-r/-)-cotinine.
  • the free base depicted above, can be employed in the practice of the invention, as can the pharmaceutically acceptable salts thereof.
  • These include the amine- acid addition salts of nontoxic organic acid or inorganic acids, such as the tartarate, fumarate (“scotine”), citrate, maleate, malate, hydrobromide, hydrochloride, sulfate, phosphate and the like.
  • nontoxic organic acid or inorganic acids such as the tartarate, fumarate (“scotine"), citrate, maleate, malate, hydrobromide, hydrochloride, sulfate, phosphate and the like.
  • cotinine In contrast to nicotine, cotinine has a relatively long terminal elimination half-life (two versus sixteen hours, respectively). Due to this pharmacological characteristic, cotinine has become the principally used objective biochemical marker of nicotine exposure in cigarette smoking and/or cessation-related research paradigms.
  • cotinine and/or its pharmaceutically acceptable salts thereof may be administered as the pure chemicals, as by inhalation of a fine powder via an insufflator, it is preferable to present the active ingredient as a pharmaceutical formulation.
  • the invention thus further provides a pharmaceutical formulation comprising cotinine and/or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers therefore and, optionally, other therapeutic and/or prophylactic ingredients.
  • the carrier(s) must be acceptable, in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions include those suitable for oral or parenteral (including intramuscular, subcutaneous and intravenous) administration.
  • forms suitable for parenteral administration also include forms suitable for adn inistration by inhalation or insufflation or for nasal, or topical (including buccal, rectal, vaginal and sublingual) administration.
  • the formulations may, where appropriate, be conveniently presented in discrete unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with liquid carriers, solid matrices, semi-solid carriers, finely divided solid carriers or combinations thereof, and then, if necessary, shaping the product into the desired delivery system.
  • compositions suitable for oral adniinistration may be presented as discrete unit dosage forms such as hard or soft gelatin capsules, cachets or tablets each containing a pi ⁇ etermined amount of the active ingredient, as a power or as granules; as a solution, a suspension or as an emulsion; or in a chewable base such as a synthetic resin or chicle for ingestion of the cotinine from a chewing gum.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives.
  • the compounds according to the invention may also be formulated for parenteral administration (e.g., by injection, for example, bolus injection or continuous infusion) and may be presented in unit dose form in ampules, prefilled syringes, small column infusion containers or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • the cotinine may be formulated as ointments, creams or lotions, or as the active ingredient of a transdermal patch.
  • Suitable transdermal delivery systems are disclosed, for example, in A. Fisher et al. (U.S. Patent No. 4,788,603), or R Bawa et al. (U.S. Patent Nos. 4,931,279; 4,668,506; and 4,713,224).
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • the active ingredient can also be delivered via iontophoresis, e.g., as disclosed in U.S. Patent Nos. 4,140,122; 4,383,529; or 4,051,842.
  • Formulations suitable for topical administration in the mouth include unit dosage forms such as lozenges comprising active ingredient in a flavored base, usually sucrose and acadia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; mucoadherent gels, and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • the above-described formulations can be adapted to give sustained release of the active ingredient employed, e.g., by combination with certain hydrophilic polymer matrices, e.g., comprising natural gels, synthetic polymer gels or mixtures thereof.
  • Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing, in addition to the active ingredient, such carriers as are known to the art to be appropriate.
  • the compounds according to the invention are conveniently delivered from an insufflator, nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dcWorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds according to the invention may take the form of a dry powder composition, for example, a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in a unit dosage form in, for example, capsules or cartridges or, e.g., gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • the compounds of the invention may be administered via a liquid spray, such as via a plastic bottle atomizer.
  • Typical ofmese are me Mstometer a (Wmfro ⁇ ) and me Medihaler a (Riker).
  • the cotinine can be administered as drops, gels (see, S. Chrai et al., U.S. Patent No. 4,255,415), gums (see, S. L. Lin et al., U.S. Patent No. 4,136,177) or via a prolonged-release ocular insert (see, A. S. Michaels, U.S. Patent No. 3,867,519 and H. M Haddad et al., U.S. Patent No. 3,870,791).
  • compositions according to the invention may also contain other adjuvants such as flavorings, colorings, antimicrobial agents, or preservatives.
  • the amount of cotinine, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • a suitable dose will be in the range of from about 1 to about 200 mg kg, e.g., from about 10 to about 150 mg kg of body weight per day, such as 3 to about 75 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 135 mg/kg/day, most preferably in the range of 15 to 90 mg/kg/day, calculated as (-)-cotinine in the free base form.
  • the compound is conveniently administered in unit dosage form; for example, containing 5 to 2000 mg, conveniently 10 to 1500 mg, most conveniently, 50 to 1000 mg of active ingredient per unit dosage form.
  • the active ingredient should be administered to achieve peak plasma concentration of the active compound of from about 0.5 to about 100 pM, preferably, about 1 to 75 pM, most preferably, about 2 to 50 pM This may be achieved, for example, by the intravenous injection of a 0.05 to 10% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1-200 mg of the active ingredient.
  • Desirable blood levels may be maintained by continuous infusion to provide about 0.01-10.0 mg/kg/hr or by intermittent infusions containing about 0.4-30 mg/kg of the active ingredients).
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub- dose itself may be further divided, e.g., into a number of discrete loosely spaced adriiinistrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • the invention will be further described by reference to the following detailed example.
  • Example I Intravenous Administration of (- ⁇ -Gotinine A.
  • Participants included 18 healthy male volunteers between the ages of 18 and 40 years old who had 1) no history of psychiatric, alcohol and drug abuse disorders, 2) smoked at least one pack of cigarettes per day for one year prior to study admission, 3) an expired-air carbon monoxide concentration of greater than 20 ppm, 4) not currently on any medication, and 5) not donated blood in the past 90 days. Potential subjects were carefully screened for physical and mental health problems.
  • (-)-Cotinine base was synthesized from (-)-nicotine using the bromine-zinc oxidation method described by E.R Bowman et al., Biochem. Preparations. 10. 36 (1963).
  • the term "cotinine” will be used to refer to (-)-cotinine.
  • the cotinine base was analyzed for impurities using gas chromatography/mass spectrometry and thin layer chromatography and was found to be pure. Using sterile techniques, cotinine solution was prepared for intravenous administration. Cotinine base was combined with sterile normal saline solution to achieve a concentration of three mg of cotinine base per one ml of solution.
  • This solution was autoclaved and found to be non-pyrogenic using a standard Limulus pyrogenicity testing techniques.
  • the cotinine solution was again tested for molecular structural integrity and concentration accuracy using GC/MS.
  • 10 ml of cotinine solution (30 mg cotinine) were placed into 20 ml injection vials, sealed and stored in a refrigerator until used.
  • the placebo was ten ml of sterile normal saline solution.
  • Placebo and active drug vials were prepared and labeled in a double-blind manner by pharmacy personnel. In addition to pharmacy personnel, one study physician who had no contact with subjects during the experimental sessions had access to the drug code in the event of a medical emergency.
  • subjects received 10 ml (30 mg) of cotinine base solution diluted to 15 ml with sterile normal saline solution or placebo (15 ml of sterile saline solution) infused intravenously through a 20 gauge indwelling intravenous catheter.
  • This infusion rate was chosen so as not to exceed two mg per minute of cotinine delivered to the subject.
  • Infusions were performed using a controlled rate syringe infusion pump. All subjects received cotinine and placebo infusions using a randomly- assigned double-blind counterbalanced order design.
  • the physiological parameters monitored included heart rate, systolic, diastolic and mean arterial blood pressure, and a 12-lead electrocardiogram (ECG) with measurement of PR, QRS and QT intervals.
  • the biochemical parameters included expired-air carbon monoxide level (CO), serum nicotine and cotinine concentrations. Carbon monoxide was measured using standard techniques. The serum nicotine and cotinine concentration assays were performed using gas chromatography and mass spectrometry at the Laboratory of Physiological Hygiene at the University of Minnesota Medical School.
  • VAS forms Two VAS forms were used. One with 11 adjectives including "Pleasant,” “Need for Cigarettes,” “Energy,” “Hungry,” “Down,” “Sedated,” “Anxious,” “Stimulated,” “Fatigue,” “Craving for Cigarettes,” and a separate VAS for “Craving for Tobacco.” Also, an adverse effects questionnaire (AEQ) was used to assess possible problems associated with cotinine administration. These problems were restlessness, headaches, tachycardia/palpitations, tremor, excessive seating, nausea/vomiting, upset stomach, lightheadedness/dizzy, drowsy, irritable, and excessive salivation. The symptoms assessed were those known to be experienced following nicotine administration. D.
  • Sessions 2 and 4 were used for baseline measurement of all variables under conditions of ad libitum cigarette smoking. These sessions occurred between 5 and 7 PM, and lasted about 15 minutes. Vital signs, CO, WSC, VAS, POMS and AEQ were completed. Also, blood was drawn for later measurement of serum nicotine and cotinine concentration. Sessions 2 and 4 were held seven days apart and began at the same time as sessions 3 and 5. After departing the laboratory, the subjects were required to refrain from cigarette smoking and other forms of tobacco use over the 48 hours following sessions 2 and 4 and prior to sessions 3 and 5, at which time they were to report back to the laboratory for their drug infusion during sessions 3 and 5.
  • sessions 3 and 5 subjects received cotinine or placebo infusions in a counterbalanced order. Sessions 3 and 5 were held 48 hours after sessions 2 and 4 during which time the subject was tobacco abstinent. After the subject reported to the laboratory, baseline measurements of CO, vital signs, WSC, VAS, POMS and AEQ were made. Next, the ECG electrodes were attached to the chest wall and limbs. For intravenous drug administration and access in the event of an adverse event, a 20 gauge indwelling catheter was placed in a prominent vein in the non-dominant forearm. This allowed the subject to freely complete subjective effects questionnaires during the remainder of the session. Heart rate and blood pressure were recorded.
  • Intravenous cotinine adniinistration had no effect on specific cardiovascular parameters such as heart rate, blood pressure and the electrocardiographic intervals (e.g., PR, QRS and QT). These findings are consistent with previous reports.
  • the biochemical variables of interest included the serum cotinine and nicotine concentrations.
  • the serumnicotine concentration showed no significant change during the session which rules out the possibility of unanticipated nicotine administration as the factor responsible for the reported effects in this experiment.
  • cotinine may serve to as an appetite suppressant and could be responsible in part for the decreased body weight of tobacco users.
  • the data suggest that cotinine is a psychomotor stimulant and its ability to suppress appetite probably stems from this activity. Acutely, psychomotor stimulants typically make people feel more anxious, irritable, restless and impatient until they become tolerant to these effects. Also, psychomotor stimulants typically are used as appetite suppressants (e.g., phentermine, phenmetrazine, emphetamine, fenfluramine, diethylproprion). Nicotine has been shown to increase resting metabolism and decrease perceived taste intensity of various foods in nicotine-experienced and nicotine-naive individuals suggesting a mechanism by which this drug exerts its effects. If nicotine and cotinine act through the same mechanism, then cotinine should act similarly in nicotine-experienced, nicotine-absent and/or nicotine-naive individuals.
  • cotinine was administered to nicotine-experienced tobacco users.
  • Cotinine is pharmacologically-active and produced subjective changes including decreased self-reported ratings of hunger consistent with psychomotor stimulant activity without significantly affecting cardiovascular activity.
  • cotinine serves to act as an appetite suppressant which can reduce body weight in nicotine-experienced, nicotine- absent and/or nicotine-naive humans.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Procédé et article thérapeutiques servant à contrôler la prise de poids chez le fumeur au moyen de cotinine ou d'un de ses sels acceptables pharmaceutiquement.
PCT/US1994/004795 1994-04-29 1994-04-29 Controle de la prise de poids chez le fumeur WO1995029676A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU68230/94A AU6823094A (en) 1994-04-29 1994-04-29 Human body weight management
PCT/US1994/004795 WO1995029676A1 (fr) 1994-04-29 1994-04-29 Controle de la prise de poids chez le fumeur
EP94916628A EP0758236A1 (fr) 1994-04-29 1994-04-29 Controle de la prise de poids chez le fumeur

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1994/004795 WO1995029676A1 (fr) 1994-04-29 1994-04-29 Controle de la prise de poids chez le fumeur

Publications (1)

Publication Number Publication Date
WO1995029676A1 true WO1995029676A1 (fr) 1995-11-09

Family

ID=22242519

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1994/004795 WO1995029676A1 (fr) 1994-04-29 1994-04-29 Controle de la prise de poids chez le fumeur

Country Status (3)

Country Link
EP (1) EP0758236A1 (fr)
AU (1) AU6823094A (fr)
WO (1) WO1995029676A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2476471A (en) * 2009-12-22 2011-06-29 Norwich Pharma Technologies Ltd Cotinine formulation for the treatment of obesity

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023045A1 (fr) * 1992-05-18 1993-11-25 Pharmaco Behavioral Associates, Inc. Utilisation de la cotinine pour calmer le syndrome de sevrage du tabac

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023045A1 (fr) * 1992-05-18 1993-11-25 Pharmaco Behavioral Associates, Inc. Utilisation de la cotinine pour calmer le syndrome de sevrage du tabac

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
C. POMERLEAU ET AL.: "The female weight-control smoker: A profile", J. SUBST. ABUSE, vol. 5, no. 4, 1993, pages 391 - 400 *
O. POMERLEAU ET AL.: "Effects of fluxetine on weight gain and food intake in smokers who reduce nicotine intake", PSYCHONEUROENDOCRINOLOGY, vol. 16, no. 5, 1991, pages 433 - 440 *
R. NIAURA ET AL.: "Increased salvia cotinine concentrations in smokers during rapid weight loss", J. CONSULT. CLIN. PSYCHOL., vol. 60, no. 6, 1992, pages 985 - 987 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2476471A (en) * 2009-12-22 2011-06-29 Norwich Pharma Technologies Ltd Cotinine formulation for the treatment of obesity

Also Published As

Publication number Publication date
EP0758236A1 (fr) 1997-02-19
AU6823094A (en) 1995-11-29

Similar Documents

Publication Publication Date Title
US5573774A (en) Nicotine metabolites, nicotine dependence and human body weight
US5869505A (en) Nicotine metabolites and nicotine dependence
Williams et al. Bronchodilator effect of delta1-tetrahydrocannabinol administered by aerosol of asthmatic patients.
US5596007A (en) Therapeutic method to alleviate the craving associated with cessation of tobacco with cotinine
Sutherland et al. Naltrexone, smoking behaviour and cigarette withdrawal
Albus et al. Anxiogenic properties of yohimbine: I. Behavioral, physiological and biochemical measures
Nemeth-Coslett et al. Nicotine gum: dose-related effects on cigarette smoking and subjective ratings
Gourlay et al. Antismoking products
JP2008519847A (ja) 運動障害の治療方法
Hughes Risk-benefit assessment of nicotine preparations in smoking cessation
WO2008085567A1 (fr) Procédés d'utilisation de doxépine faiblement dosée pour améliorer le sommeil
Naidoo THE EFFECTS OF RESERPINE (SERPASIL®) ON THE CHRONIC DISTURBED SCHIZOPHRENIC: A COMPARATIVE STUDY OF RAUWOLFIA ALKALOIDS AND ELECTROCONVULSIVE THERAPY
Leischow et al. Effects of nicotine dose and administration method on withdrawal symptoms and side effects during short-term smoking abstinence.
Schroeckenstein et al. Twelve-hour bronchodilation in asthma with a single aerosol dose of the anticholinergic compound glycopyrrolate
US5612357A (en) Use of cotinine to assist in the cessation of tobacco smoking
WO1995007690A1 (fr) Composition et procede destines a traiter le besoin de nicotine chez les personnes qui cessent de fumer
Nemeth-Coslett et al. Nicotine gum: chew rate, subjective effects and plasma nicotine
US5643928A (en) Human body weight management
AU670794B2 (en) Use of cotinine to alleviate tobacco withdrawal syndrome
US5880164A (en) Nicotine-free smoking material
Pomerleau et al. Differences between smokers and never‐smokers in sensitivity to nicotine: a preliminary report
Miller et al. Nicotine dependence: Diagnosis, chemistry, and pharmacologic treatments
EP0758236A1 (fr) Controle de la prise de poids chez le fumeur
Klesges et al. Behavioral and biobehavioral aspects of smoking and smoking cessation: The problem of postcessation weight gain
JPH0149124B2 (fr)

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AT AU BB BG BR BY CA CH CN CZ DE DK ES FI GB GE HU JP KG KP KR KZ LK LU LV MD MG MN MW NL NO NZ PL PT RO RU SD SE SI SK TJ TT UA UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1994916628

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1994916628

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: CA

WWW Wipo information: withdrawn in national office

Ref document number: 1994916628

Country of ref document: EP