WO1993018768A1 - Combinations of parasympathomimetic agents with muscarinic antagonists for treating nicotine craving in smoking cessation - Google Patents
Combinations of parasympathomimetic agents with muscarinic antagonists for treating nicotine craving in smoking cessation Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- component
- nicotine
- craving
- composition
- person
- Prior art date
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Classifications
-
- 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.
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP93908484A EP0630243A1 (en) | 1992-03-16 | 1993-03-11 | Combinations of parasympathomimetic agents with muscarinic antagonists for treating nicotine craving in smoking cessation |
JP5516788A JPH07505367A (en) | 1992-03-16 | 1993-03-11 | Combination of parasympathomimetics and muscarinic antagonists for the treatment of nicotine craving in smoking cessation |
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 (en) | 1993-09-30 |
Family
ID=25312038
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1993/002650 WO1993018768A1 (en) | 1992-03-16 | 1993-03-11 | Combinations of parasympathomimetic agents with muscarinic antagonists for treating nicotine craving in smoking cessation |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0630243A1 (en) |
JP (1) | JPH07505367A (en) |
CA (1) | CA2132209A1 (en) |
WO (1) | WO1993018768A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004069246A1 (en) * | 2003-02-09 | 2004-08-19 | Shandong Luye Natural Drugs Research And Develop Company Ltd. | Drug compositions comprising inhibitors of cholinesterase for treating senile dementia |
WO2012045210A1 (en) * | 2010-10-09 | 2012-04-12 | 中国人民解放军第二军医大学 | Pharmaceutical composition for treating septic shock and its use |
CN103110950A (en) * | 2011-11-16 | 2013-05-22 | 高尔医药科技(上海)有限公司 | Application of medicinal composition |
Citations (3)
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 |
-
1993
- 1993-03-11 CA CA002132209A patent/CA2132209A1/en not_active Abandoned
- 1993-03-11 JP JP5516788A patent/JPH07505367A/en active Pending
- 1993-03-11 WO PCT/US1993/002650 patent/WO1993018768A1/en not_active Application Discontinuation
- 1993-03-11 EP EP93908484A patent/EP0630243A1/en not_active Ceased
Patent Citations (3)
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 (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004069246A1 (en) * | 2003-02-09 | 2004-08-19 | Shandong Luye Natural Drugs Research And Develop Company Ltd. | Drug compositions comprising inhibitors of cholinesterase for treating senile dementia |
WO2012045210A1 (en) * | 2010-10-09 | 2012-04-12 | 中国人民解放军第二军医大学 | Pharmaceutical composition for treating septic shock and its use |
WO2012045285A1 (en) * | 2010-10-09 | 2012-04-12 | 中国人民解放军第二军医大学 | Pharmaceutical composition and application thereof |
CN103110950A (en) * | 2011-11-16 | 2013-05-22 | 高尔医药科技(上海)有限公司 | Application of medicinal composition |
Also Published As
Publication number | Publication date |
---|---|
CA2132209A1 (en) | 1993-09-30 |
JPH07505367A (en) | 1995-06-15 |
EP0630243A1 (en) | 1994-12-28 |
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