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WO1993018768A1 - Combinaisons d'agents parasympathomimetiques et d'antagonistes muscariniques servant a traiter le manque en nicotine dans l'arret du tabac - Google Patents

Combinaisons d'agents parasympathomimetiques et d'antagonistes muscariniques servant a traiter le manque en nicotine dans l'arret du tabac Download PDF

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Publication number
WO1993018768A1
WO1993018768A1 PCT/US1993/002650 US9302650W WO9318768A1 WO 1993018768 A1 WO1993018768 A1 WO 1993018768A1 US 9302650 W US9302650 W US 9302650W WO 9318768 A1 WO9318768 A1 WO 9318768A1
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WO
WIPO (PCT)
Prior art keywords
component
nicotine
craving
composition
person
Prior art date
Application number
PCT/US1993/002650
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English (en)
Inventor
Enoch Callaway
Original Assignee
The Regents Of The University Of California
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 The Regents Of The University Of California filed Critical The Regents Of The University Of California
Priority to JP5516788A priority Critical patent/JPH07505367A/ja
Priority to EP93908484A priority patent/EP0630243A1/fr
Publication of WO1993018768A1 publication Critical patent/WO1993018768A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention generally relates to treating smoking withdrawal symptoms, and more particularly. to a composition useful in relieving craving in a nicotine- habituated patient abstaining from or reducing nicotine intake.
  • Smoking cessation programs often address both the physiological (biochemical) factor and the psychological factor.
  • nicotine-releasing patches have been highly advertised, and are presumably useful by maintaining a nicotine-habituated patient on nicotine while addressing the psychological factor. Methods that maintain a patient on nicotine do not provide a- long term solution to the problem. For example, there are now a number of -patients addicted to nicotine containing gum, some of whom are seeking treatment for their new or substitute addiction.
  • Atropine and scopolamine are alkoids that block the action of acetylcholine at muscarinic receptors to produce antispasmodic, antisecretory, and antiparkinsonism actions.
  • Scopolamine (sometimes also called "hyoscine”) -is a powerful suppressant of salivation (as is atropine), and. is effective in the prevention and control of motion sickness.
  • Physostigmine (sometimes called "eserine") is an inhibitor of acetylcholine metabolism (by inhibiting the enzyme acetylcholinesterase) and is an antagonist of scopolamine. Since the action of acetylcholine . is terminated by its rapid hydrolysis into choline and acetic acid, acetylcholinesterase inhibitors prolong or mimic the action of the neurotransmitter, acetylcholine.
  • Acetylcholine is released into synapses where it behaves as a neurotransmitter that associates with macromolecular receptors.
  • the association of acetylcholine with its receptors initiates a physiological response, probably by opening membrane calcium channels.
  • the acetylcholine receptors appear to be of two general subtypes.
  • One subtype appears to have nicotine as an agonist (that is, the nicotine molecule appears to fit into the one subtype of acetylcholine receptor) .
  • the nicotinic effect of acetylcholine can be revealed when its degradation by acetylcholinerase is inhibited, as is discussed by Vidal and Changeux, Neuroscience, 29 (2) , pp. 261-270 (1989) .
  • the other general subtype of acetylcholine receptors is muscarinic. Muscarine is an alkaloid that mimics the action of acetylcholine.
  • cholinergic receptors Activation of cholinergic receptors results in bradycardia, increased secretion (e.g. salivary and sweat) , gastrointestinal contractions, and other symptoms.
  • Hypotensive, cardiac inhibitory effects caused by low doses of acetylcholine are similar to those produced by muscarine and appear to be mediated via muscarinic acetylcholinase receptors at postganglionic parasympathetic terminals, whereas effects at autonomic ganglion and skeletal neuromuscular junctions result from nicotinic acetylcholine receptors.
  • a method for relieving craving in a nicotine-habituated person who is abstaining from or reducing nicotine ' intake is provided by administering an admixture of first and second components.
  • the first component is a non-specific acetylcholine agonist, preferably having at least one determinable muscarinic effect
  • the second component is a muscarinic antagonist having a determinable antimuscarinic effect.
  • Aparticularlypreferred composition for relieving craving takes the form of a tablet suitable for oral administration wherein the first component is a water soluble physostigmine and the second component is a water soluble scopolamine.
  • the combination of the first and second components is surprising because the two classes of drugs (non-specific acetylcholine agonist and muscarinic antagonist, respectively) have been viewed as mutual antagonists, with antimuscarinics being conventional antidotes for antichounerase poisoning.
  • the inventive method comprises administrating an admixture that must include two essential components.
  • the first component is a non-specific acetylcholine agonist.
  • the first component preferably has at least one determinable muscarinic effect and one determinable nicotinic effect were it administered by itself.
  • non-specific is meant that the actions of the first component are not limited to one class or type of acetylcholine receptors, but rather that the first component acts on both the muscarinic receptors and the nicotinic receptors.
  • a "determinable muscarinic effect” is meant that pharmacologically effective dosages- will produce one or more of the typical muscarinic effects* (e.g.
  • a- “determinable nicotinic effect” is meant typical activation of nicotinic receptors when a physiologically effective dose is administered, such as one or more of increased skeletal and/or muscle excitability, adrenaline release (such as tachycardia) and so forth.
  • the second component is a muscarinic antagonist that preferably has at least one determinable " antimuscarinic effect were it administered by itself.
  • a “determinable antimuscarinic effect” is meant dry mouth, dry skin, impaired attention or alertness, and decreased gastrointestinal motility.
  • Inventive admixtures of the first and second components are in a balanced weight ratio of first and second components sufficient substantially to eliminate the determinable muscarinic and antimuscarinic effects (with the exception of some typical increased alertness) , yet to be in an amount effective substantially to relieve nicotine craving for a duration of time.
  • the duration in which craving is relieved depends upon several factors, such as the duration of action for the particular first and second components chosen, the particular patient (degree of habituation, weight, etc.), but preferably is on an order of several hours.
  • first and second components for the admixture will normally be readily determined empirically by the physician or health care professional treating the nicotine-habituated patient. Treatment normally begins with established, pharmaceutically effective doses of each component by itself, then by establishing through observation and discussion with the patient whether the balance has been established that is sufficient substantially to eliminate the determinable muscarinic and antimuscarinic effects yet while being in an amount effective substantially to relieve nicotine craving for some measurable period of time.
  • first and second components must- be able to pass the blood-brain barrier (usually due to a lipophilic nature) so as to have central nervous system effects.
  • a particularly preferred first component is a water soluble physostigmine and a particularly preferred second component is a water soluble scopolamine, with the inventive admixture being an amount of each component (per each oral dose) of between about 0.3 mg to about 0.9 mg, with the first and second components being in about a 1:1 weight ratio such an admixture relieves craving for about four hours.
  • non-specific acetylcholine agonists suitable as the first component are physostigmine, methacholine, edrophonium, quaternary tetraalkylammonium salts, 9-amino-l,2,3,4-tetrahydracridine (also known as "tacrine”) , diisopropyl fluorophosphate, paraoxon, and soman.
  • tacrine 9-amino-l,2,3,4-tetrahydracridine
  • diisopropyl fluorophosphate paraoxon
  • soman diisopropyl fluorophosphate
  • These non-specific acetylcholine agonists include both reversible and irreversible inhibitors of acetylcholinesterase and also direct agonists such as arecoline.
  • Suitable first and second components are preferably in a water soluble form, such as being present as pharmaceutically acceptable salts, which is meant to include both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, .maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, 5 calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and 0 tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • Physostigmine is generally ' regarded as an irreversible acetylcholinesterase inhibitor because it forms a covalent bond with the catalytic site of the enzyme.
  • Physostigmine is preferred as the first component due to a duration of activity that is equivalent to -the 0 preferred second component, and due to its orally active forms.
  • Particularly preferred forms of physostigmine are water soluble derivatives, and include physostigmine salicylate and physostigmine sulfate.
  • Physostigmine crosses the blood-brain barrier and can be administered 5 subcutaneously, intramuscularly, by slow intravenous injection, and orally (when in the water soluble salicylate or sulfate forms) .
  • Muscarinic antagonists suitable as the second component include scopolamine, atropine, benactyzine, 0 oxybutynin, quinuclidinyl benzilate, 3-quinuclidinyl- xanthene-9-carboxylate, and quinuclidinyl atrolactate.
  • muscarinic antagonists that have limited or no central antimuscarinic effects, such as methoctramine.
  • the water soluble scopolamine derivatives 5 are particularly preferred, such as scopolamine butylbromide, scopolamine hydrobromide, and scopolamine methobromide.
  • the quaternary derivatives (butylbromide, methobromide, and methonitrate) do not readily cross the blood-brain barrier.
  • Scopolamine ' hydrobromide is a particularly preferred water soluble scopolamine for use as the second component.
  • compositions for use in the inventive method for relieving craving preferably are formed as tablets or capsules suitable for oral administration and have the first and second components admixed therein.
  • the quantities of first and second components so admixed are wherein a dose of one or more tablets, preferably several, is effective substantially to relieve nicotine craving for a duration of time, preferably several hours, most preferably about three hours or more.
  • each tablet preferably has the components in about a 1:1 weight ratio and each tablet delivers a dose of about 0.3 mg.
  • Tablets of the invention optionally include one or more pharmacologically suitable component or. components such as buffering agent, preservative (e.g. antioxidants) , excipients and/or tabletting agents, flavoring agents, and the like. Suitable such components are well-known to the tabletting art.
  • composition embodiments of the ' invention were formulated and administered to patients by a treating physician as will now be described for purposes of illustrating the invention.
  • Patients were chosen who were unable to stop smoking and were able to verbally report their feelings of craving. Once every four or more days the patient met with a treating physician at an agreed-upon time when the patient expected to experience craving for nicotine to a degree that would ordinarily cause the patient to smoke a cigarette. For example, the subject will have refrained from using nicotine just before his or her appointment so that the subject was expected to be experiencing strong, but tolerable, craving within an hour after coming to the laboratory. The patient's heart rate,* blood pressure, and temperature were recorded and a questionnaire about the patient's moods was filled out and the degree of craving was rated on a simple scale. .
  • a composition of the invention was then administered and over the following two hours the patient rated his or her craving on the scale at fifteen minute intervals and, with the help of the treating physician, made a record of various reactions (happy, anxious, tense, and so forth) .
  • balanced amounts of physostigmine and scopolamine were established for each patient (where substantially no sweating, increased GI activity, and bowel cramping, one hand, and no dry mouth, trouble concentrating, and a "spacey" feeling, on the other hand, were experienced) , but where craving for nicotine was diminished.
  • a recommended dose for self- medication is likely a maximum of about six capsules per day (each preferably with 0.3 mg of water soluble scopolamine and water soluble physostigmine for one preferred embodiment) at the rate of about one capsule per hour to one per three hours.
  • Smokers (some of whom were nicorette-users) attempting to abstain from nicotine intake were initially administered small, equal doses of scopolamine (HBr, 0.3 mg) and physostigmine (S0 4 , 0.3 mg) tabletted with 0.5 g ascorbic acid as a stabilizing (antioxidant) agent. Pulse, blood pressure (systolic/diastolic) and orally taken temperature were recorded.
  • Table 1 summarizes data from six persons participating in the study.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

L'invention décrit un procédé servant à soulager la manque chez un individu dépendant de la nicotine, ainsi qu'une composition de traitement. Ladite composition comprend un agoniste d'acétylcholine non spécifique et un agoniste muscarinique. Une composition particulièrement préférée de soulagement du manque se présente sous forme d'un comprimé dans lequel le premier constituant est une physostigmine soluble dans l'eau et le deuxieme constituant est une scopolamine soluble dans l'eau. Le traitement a demontré une légère augmentation de la vigilance chez le patient, ainsi qu'une diminution du besoin de nicotine.
PCT/US1993/002650 1992-03-16 1993-03-11 Combinaisons d'agents parasympathomimetiques et d'antagonistes muscariniques servant a traiter le manque en nicotine dans l'arret du tabac WO1993018768A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP5516788A JPH07505367A (ja) 1992-03-16 1993-03-11 喫煙停止におけるニコチン渇望の処置のための副交感神経作用剤とムスカリン性拮抗剤との配合
EP93908484A EP0630243A1 (fr) 1992-03-16 1993-03-11 Combinaisons d'agents parasympathomimetiques et d'antagonistes muscariniques servant a traiter le manque en nicotine dans l'arret du tabac

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US85191492A 1992-03-16 1992-03-16
US07/851,914 1992-03-16

Publications (1)

Publication Number Publication Date
WO1993018768A1 true WO1993018768A1 (fr) 1993-09-30

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PCT/US1993/002650 WO1993018768A1 (fr) 1992-03-16 1993-03-11 Combinaisons d'agents parasympathomimetiques et d'antagonistes muscariniques servant a traiter le manque en nicotine dans l'arret du tabac

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EP (1) EP0630243A1 (fr)
JP (1) JPH07505367A (fr)
CA (1) CA2132209A1 (fr)
WO (1) WO1993018768A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004069246A1 (fr) * 2003-02-09 2004-08-19 Shandong Luye Natural Drugs Research And Develop Company Ltd. Compositions pour medicament renfermant des inhibiteurs de cholinesterase en vue du traitement de la demence senile
WO2012045285A1 (fr) * 2010-10-09 2012-04-12 中国人民解放军第二军医大学 Composition pharmaceutique et son application
CN103110950A (zh) * 2011-11-16 2013-05-22 高尔医药科技(上海)有限公司 一种药物组合物的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4555397A (en) * 1983-08-12 1985-11-26 Nicholas Bachynsky Method for anti-cholinergic blockage of withdrawal symptoms in smoking cessation
US4835162A (en) * 1987-02-12 1989-05-30 Abood Leo G Agonists and antagonists to nicotine as smoking deterents
US4952586A (en) * 1982-08-27 1990-08-28 The Regents Of The University Of California Edrophonium-atropine composition and therapeutic uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4952586A (en) * 1982-08-27 1990-08-28 The Regents Of The University Of California Edrophonium-atropine composition and therapeutic uses thereof
US4555397A (en) * 1983-08-12 1985-11-26 Nicholas Bachynsky Method for anti-cholinergic blockage of withdrawal symptoms in smoking cessation
US4835162A (en) * 1987-02-12 1989-05-30 Abood Leo G Agonists and antagonists to nicotine as smoking deterents

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
DRUG CHEM, TOXICOL. vol. 1, no. 4, 1978, pages 355 - 362 D.L. STITCHER 'Effects of pyridostigmine and cholinolytics on cholinesterase and acetylcholine in soman poisoned rats.' *
NAUNYN-SCHMIEDEBERG'S ARCH. PHARMACOL. vol. 327, no. 1, 1984, pages 64 - 69 L. HARRIS 'Protection against diisopropylfluorophosphate intoxication by pyridostigmine and physostigmine in combination with atropine and mecamylamine.' *
PROG. NEURO-PSYCHOPHARMACOL. BIOL. PSYCHIATR. vol. 14, no. 1, 1990, pages 83 - 90 M.C. CASSONE 'Effects of combinations of arecoline and atropine on mouse motor activity.' *
REYNOLDS, J.E.F. (ED.), 'MARTINDALE THE EXTRA PHARMACOPOEIA'. 29TH EDITION, 1989, THE PHARMACEUTICAL PRESS, LONDON. *
STN INTERNATIONAL, KARLSRUHE. FILE CA, CHEMICAL ABSTRACTS. AN=CA112(19):173741b. R.P. SOLANA. 'Comparing the efficacy of physostigmine pretreatment in combination with scopolamine versus artane against soman challenge' *
STN INTERNATIONAL, KARLSRUHE. FILE CA, CHEMICAL ABSTRACTS. AN=CA89(23):191258k. S. ERIKSEN, 'Effects on muscarinic receptors of various agents in reversal of neuro-muscular blockade. A study evaluating atropine, glycopyrron, ...' *
STN INTERNATIONAL, KARLSRUHE. FILE CA, CHEMICAL ABSTRACTS. AN=CA92(9):69703y. J. HRBEK. 'On the acute effects of scopolamine (0.6 mg), physostigmine (1.0 mg), and a complex combination of both the drugs on the higher nervous ...' *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004069246A1 (fr) * 2003-02-09 2004-08-19 Shandong Luye Natural Drugs Research And Develop Company Ltd. Compositions pour medicament renfermant des inhibiteurs de cholinesterase en vue du traitement de la demence senile
WO2012045285A1 (fr) * 2010-10-09 2012-04-12 中国人民解放军第二军医大学 Composition pharmaceutique et son application
WO2012045210A1 (fr) * 2010-10-09 2012-04-12 中国人民解放军第二军医大学 Composition pharmaceutique destinée au traitement d'un choc septique et son utilisation
CN103110950A (zh) * 2011-11-16 2013-05-22 高尔医药科技(上海)有限公司 一种药物组合物的应用

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Publication number Publication date
JPH07505367A (ja) 1995-06-15
CA2132209A1 (fr) 1993-09-30
EP0630243A1 (fr) 1994-12-28

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