CA2114267A1

CA2114267A1 - Use of oxidase inhibitor with dextromethorphan to treat intractable coughing and dermatitis

Info

Publication number: CA2114267A1
Application number: CA 2114267
Authority: CA
Inventors: Richard A. Smith
Original assignee: Individual
Current assignee: Individual
Priority date: 1993-09-02
Filing date: 1994-01-26
Publication date: 1995-03-03
Anticipated expiration: 2014-01-26
Also published as: CA2712821A1; CA2114267C; CA2712821C

Abstract

USE OF OXIDASE INHIBITOR WITH DEXTROMETHORPHAN
TO TREAT INTRACTABLE COUGHING AND DERMATITIS

ABSTRACT

This invention discloses a method for increasing the effectiveness of dextromethorphan (DM) in treating either severe coughing or dermatitis which do not respond to other drug treatments. This method involves the administration, to a patient who is an extensive metabolizer of dextromethorphan and who is suffering from severe coughing or dermatitis, of dextromethorphan along with a second agent that inhibits the enzymatic activity of debrisoquin hydroxylase (also called sparteine monooxygenase, cytochrome P450DB' and cytochrome P450-2D6). Quinidine is an especially potent inhibitor of enzymatic DM oxidation, but it is not well tolerated by everyone. Other antioxidants which are less potent and better tolerated by some patients include quinine, yohimbine, fluoxetine, haloperidol, ajmaline, lobeline, and pipamperone.
Since people have major variations in their oxidative enzyme activities, screening tests should be undertaken under the supervision of a physician to select a preferred antioxidant for each particular patient. In tests described herein, patients suffering from intractable coughing or dermatitis which did not respond adequately to any other safe and non-addictive drugs reported excellent results and virtually complete elimination of their coughing or dermatitis. In addition, the treated patients did not report any adverse side effects such as drowsiness, fatigue, or nausea.

Claims

1. Use of a combination of dextromethorphan and a second compound at a therapeutically effective dosage which, in the body of a person, is pharmaceutically acceptable and causes a significant inhibition of enzymatic oxidation of dextromethorphan by debrisoquin hydroxylase, for suppression of coughing by such a person who is an extensive metabolizer of dextromethorphan and who is in need of cough suppression.

2. A use according to claim 1 wherein the second compound is selected from the group consisting of quinidine, quinine, and pharmaceutically acceptable salts and analogs thereof which inhibit the enzymatic degradation of dextromethorphan by debrisoquin hydroxylase.

3. A use according to claim 2 wherein said second compound is quinidine and said effective dosage does not exceed about 150 milligrams per day.

4. A use according to claim 1 wherein said second compound is selected from the group consisting of yohimbine, fluoxetine, haloperidol, ajmaline, lobeline, pipamperone, and pharmaceutically acceptable salts and analogs thereof which inhibit the enzymatic degradation of dextromethorphan by debrisoquin hydroxylase.

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5. Use of a combination of dextromethorphan and a second compound at a therapeutically effective dosage which, in the body of a person, is pharmaceutically acceptable and causes a significant inhibition of enzymatic oxidation of dextromethorphan by debrisoquin hydroxylase, for suppression of severe coughing by such a person who is an extensive metabolizer of dextromethorphan where that person's coughing cannot be suppressed adequately by dextromethorphan alone.

6. A use according to claim 5 wherein said second compound is selected from the group consisting of quinidine, quinine, and pharmaceutically acceptable salts and analogs thereof which inhibit the enzymatic degradation of dextromethorphan by debrisoquin hydroxylase.

7. A use according to claim 6 wherein said second compound is quinidine and said effective dosage does not exceed about 150 milligrams per day.

8. A use according to claim 5 wherein said second compound is selected from the group consisting of yohimbine, fluoxetine, haloperidol, ajmaline, lobeline, pipamperone, and pharmaceutically acceptable salts and analogs thereof which inhibit the enzymatic degradation of dextromethorphan by debrisoquin hydroxylase.

9. Use of a therapeutically effective quantity of a compound selected from the group consisting of:

- Page 2 of Claims -(a) dextromethorphan, and (b) pharmaceutically acceptable salts and analogs of dextromethorphan which are effective in treating dermatitis, for treating dermatitis in a person which does not respond adequately to non-prescription drugs.

10. A use according to claim 9 for treating dermatitis in a person who is classified as a "poor metabolizer" and whose enzymes cannot rapidly convert dextromethorphan into dextrorphan.

11. Use of a combination of:
(1) dextromethorphan or a pharmaceutically acceptable salt or analog thereof; and, (2) an antioxidant drug which significantly inhibits enzymatic oxidation of dextromethorphan in a person and which is pharmaceutically acceptable to such a person at therapeutically effective dosages for each compound which allow the antioxidant drug to significantly inhibit enzymatic oxidation of the dextromethorphan or the salt or analog thereof in the body of such person, for treating dermatitis in such person who is an extensive metabolizer of dextromethorphan and who is suffering from dermatitis which does not respond adequately to non-prescription drugs.

12. A use according to claim 11 wherein the antioxidant drug is selected from the group consisting of quinidine, quinine, and fluoxetine, and pharmaceutically acceptable salts and analogs - Page 3 of Claims -thereof which inhibit the enzymatic degradation of dextromethorphan by debrisoquin hydroxylase.

13. A use according to claim 12 wherein said antioxidant drug is quinidine and said effective dosage does not exceed about 150 milligrams per day.

14. A use according to claim 11 wherein the antioxidant drug is selected from the group consisting of yohimbine, fluoxetine, haloperidol, ajmaline, lobeline, and pipamperone, and pharmaceutically acceptable salts and analogs thereof which inhibit the enzymatic degradation of dextromethorphan by debrisoquin hydroxylase.

15. Use of an anti-cholinergic agent which is capable of penetrating the blood-brain barrier and which exerts a pharmaceutically antagonistic effect on cholinergic receptors of the muscarinic type on the surfaces of neurons in the central nervous system in the preparation of a medicament for use in reducing the neurotoxic effects of a NMDA antagonist.

16. A pharmaceutical agent suitable for use in reducing deleterious neurological effects in mammals, comprising a mixture of a NMDA antagonist and an anti-cholinergic agent, wherein the NMDA antagonist is present in a first concentration that can reduce excitotoxic damage in the brain, and wherein the anti-cholinergic agent is present in a second concentration that can reduce one or more neurotoxic effects which otherwise would be - Page 4 of Claims -caused by the NMDA antagonist if administered to the mammal without an accompanying anti-cholinergic agent.

17. An article of manufacture comprising packaging material and an anti-cholinergic agent contained within the packaging material, wherein the anti-cholinergic agent is therapeutically effective for reducing one or more neurotoxic effects of NMDA
antagonists, and wherein the packaging material comprises a label which indicates that the anti-cholinergic agent can be used for reducing one or more neurotoxic effects of NMDA antagonists.

18. Products containing a NMDA antagonist and an anticholinergic agent which is capable of penetrating the blood-brain barrier and which exerts a pharmaceutically antagonistic effect on cholinergic receptors of the muscarinic type on the surfaces of neurons in the central nervous system as a combined preparation for simultaneous, separate or sequential use in neuroligical therapy to protect neurons inside the central nervous system.

- Page 5 of Claims -