METHOD AND COMPOSITION FOR BLOCKING ANTIGEN-INDUCED ALLERGIC RESPONSES

Abstract: Antigen-induced allergic responses are inhibited by administration of opioid antagonists. A preferred antagonist is 6-methylene-6-desoxy-n-cyclopropylmethyl-14-hydroxydihydronormorphine. Oral administration is preferred.

Description: METHOD AND COMPOSITION FOR BLOCKING ANTIGEN-INDUCED ALLERGIC RESPONSES FIELD OF THE INVENTION The present invention is directed to a method and composition for blocking antigen-induced allergic responses. More particularly, the invention is concerned with blocking such responses through adminis¬ tration of a pure opioid antagonist. BACKGROUND OF THE INVENTION A large segment of the population suffers from antigen-induced allergies. Typical allergic responses include rhinitis, urticaria, eczema, skin flushing, pruritis, angioedema and bronchoconstriction (asthma) . A host of preparations are available to persons suffering from allergies. Desirable qualities for relief of allergic symptoms include effectiveness of relief, length of effective action and safety of active ingredient. It is known that opioids can precipitate asthma attacks in anesthetized patients, and that morphine and related opioids are to be avoided during asthma attacks. It also is known that morphine causes itching, which may be related to degranulation of mast cells. Degranula- tion of mast cells is believed to play a central role in causing allergic responses. Bernstein and Swift (Arch. Dermatol. 115: 1366, Nov. 1979) showed that subcutaneous administration of naloxone blocked pruritis caused by primary bilary cirrhosis. Leslie, Bellamy and Pike (Br. Med. J. 280: 16-18, Jan. 5, 1980) showed that intravenous naloxone blocked, asthma precipitated by chloropropamide and alcohol. It is believed ' that chloropropamide and alco¬ hol cause release of endogenous opioids. The same article showed that administering an enkephalin analog with opioid-like activity precipitated asthma in one patient. Bernstein U.S. Patent 4,181,726 discloses treatment of itching associated with Hodgkin's disease. mycosis funsoides, intractable pruritis and the like by injection of naloxone. Parenteral administration of naloxone for treating antigen-induced itch, asthma, urticaria and angioedema- is disclosed by S itz et al, Am. Intern. Med., 97(5), 788-9 (1982). SUMMARY OF THE INVENTION A first aspect of this invention is directed to a metirαd for blocking an antigen-induced allergic response iir. a subject comprising administering to said subject an amount, of the compound 6- methylene-6-desoxy-n-cyclo- propylmethyl-14-hydroxydihydronormorphine in an amount sufficient to inhibit the antigen-induced allergic response. In a second embodiment, this invention provides a method for blocking an antigen-induced allergic response of the group consisting of bronchoconstriction, rhinitis, urticaria, eczema, skin flushing, angioedema and pruritis in a subjeσt, comprising administering to the subject an amount of the compound 6-methylene-6- desoxy-n-cycloproρylmeth l-14-hydroxydihydronormorphine sufficient to inhibit the antigen-induced allergic response. A further embodiment includes a composition for blocking an antigen-induced allergic reponse in a subject, comprising: an amount of 6-methylene-6-desoxy-n-cyclopropyl- methyl-14-hydroxydihydronormorphine sufficient to inhibit the antigen-induced allergic response in the subject; and a pharmaceutically acceptable carrier therefor. Yet another aspect of the invention provides a method for blocking an antigen-induced allergic response in a subject, comprising orally administering to the subject a pure opioid antagonist in an amount sufficient to inhibit the antigen-induced allergic response. A still further embodiment is directed to an oral composition for blocking an antigen-induced allergic response in a subject comprising: an amount of pure opioid antagonist sufficient to block the antigen-induced allergic response in the subject; and a pharmaceutically acceptable oral carrier therefor. DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to blocking antigen-induced allergic responses with an opioid antagonist. The antagonist may be administered prophyl- actically or remedially. Oral administration is preferred for its convenience, especially for prophylac¬ tic uses. It is preferred that a pure opioid antagonist be used, so that any opioid-like side effects are avoided. A preferred group of pure opioid antagonists is disclosed in U.S. Patents 3,814,768 and 3,896,226, the disclosures of which are incorporated herein by refer- ence. Particularly preferred is 6-methylene-6-desoxy- n-cyclopropylmethyl-14-hydroxydihydronormorphine (USAN- nalmefene) , which has been found to be quite safe and highly effective, and exhibits a longer period of activity than other antagonists. Other antagonists also are useful, such as naltrexone. The opioid antagonists are useful in blocking a wide variety of antigen-induced allergic responses. Such responses include bronchoconstriction, rhinitis, urticaria, eczema, skin flushing, angioedema and pruritis. Of these, bronchoconstriction is believed to be the most pervasive antigen-induced allergic response. The present invention is useful in both preventing and alleviating such responses. Oral administration is preferred for its conven- ience. However, faster action could be obtained through parenteral or pulmonary administration. Pulmonary administration preferably is accomplished through use of a metered dose inhaler and an inhalation device as disclosed in Sackner et. al. U.S. Patent 4,484,577, the disclosure of which is incorporated herein by reference. Oral administration may be through tablets or capsules formed from conventional formulating ingredients. The amount of active ingredient administered is about 1-60 mg per day, preferably about 2-20 mg per day, more- preferably about 10 mg per day. Oral dosage unit forms,. e..g. , tablets or capsules, can contain suitable amounts of active ingredient to meet these dosages, preferably about 2-20 mg per dosage unit, more prefer¬ ably about 10 mg per dosage unit. The safety and efficacy of the active ingredient, particularly when it is 6-methylene-6-desoxy-n-cyclopropylmethyl-14-hydroxy- dihydronormorphine, make the present invention useful in treating or preventing both mild and severe allergic responses. EXAMPLE Experiments are conducted on five adult sheep which are allergic to ascaris suum extract. The experimental method is from Abraham et al. (Am. Rev. Resp. Pis. 128:839-844). Allergic response to the antigen was confirmed by cutaneous reaction to the antigen injected dermally into each sheep. The antigen challenge to the lungs is delivered by aerosol. An aerosol containing ascaris suum extract (1:20) is generated with a disposable nebulizer. The output from the nebulizer is connected to an endo- tracheal tube located in the sheep's trachea. Specific resistance to airflow in the lung is determined before and after aerosol delivery of the antigen. Airflow resistance in the lung is measured as follows. The sheep remain unsedated with their heads restrained. The nasal passages treated with a two percent lidocaine local anesthetic. A balloon catheter is then threaded through one nostril and into the lower esophogus. Intubation is done with a cuffed endotra- cheal tube through the other nostril. The cuff of the tube is inflated only during measurements of airway mechanics. An esophageal balloon catheter provides for measurement of pleural pressure. Pressure in the trachea is measured from a side hole catheter at the distal tip of the nasal tracheal tube. A differential pressure transducer measures the transpulmonary pressure and the difference between tracheal pressure and pleural pressure. Airflow resistance is measured by connecting the nasal tracheal tube to a pneumotachograph. Trans¬ pulmonary pressure and flow are registered on an oscilloscope recorder. Five to ten breathes are used for each determination of airflow resistance, with resistance equalling pressure difference/flow. Baseline measurements of airflow resistance are made before and after intravenous injection of 6- methylene-6-desoxy-n-cyclopropylmeth l-14-hydroxydi- hydronormorphine. In two sheep, a dose of 0.05 mg/kg is used while in three other sheep the doses are 0.1, 0.2 and 0.5 mg/kg, respectively. Intravenous administration is used since the active ingredient does not show good bioavailability in sheep upon oral administration, despite the good oral bioavailability in humans. The results of the tests are shown in the table below. Table 1 PERCENT INCREASE IN AIR FLOW RESISTANCE IN RESPONSE TO ANTIGEN Before Treatment Dose After Treatment Sheep #1 144% 0.05 mg/kg 39% Sheep #2 674% 0.05 mg/kg 0% Sheep #3 726% 0.1 mg/kg 233% Sheep #4 699% 0.2 mg/kg 6% S Shheeeepp ##55 4 49977%% 0 0..55 mmgg//kkgg 5% It can be seen that the opioid antagonist was effective in blocking antigen-induced bronchoconstric- tion. Near total block was provided in four of the five sheep. In the remaining sheep, the response in airway resistance was decreased by about 70%, from 726% to 233%. Although a detailed description of the present invention has been provided above, the invention is not limited thereto, but rather is defined by the following claims.

Claims: WHAT IS CLAIMED IS: 1. A method for blocking an antigen-induced allergic response in a subject, comprising administering to said subject the compound 6-methylene-6-desoxy-n- cyclopropylmethyl-14-hydroxydihydronormorphine sufficient to inhibit said antigen-induced allergic response. 2. The method of claim 1, wherein said 6- methylene-6-desoxy-n-cyclopropylmeth l-14-hydroxydi- hydronormorphine is administered orally. 3. The method of claim 1, wherein the amount administered is from about 1 to about 60 mg per day. 4. The method of claim 1, wherein the 6-methylene- 6-desoxy-n-cyclopropylmethyl-14-hydroxydihydronormor- phine is administered to the subject prophylactically. 5. The method of claim 1, wherein the 6-methylene- 6-desoxy-n-cyclopropylmethyl-14-hydroxydihydronormor- phine is administered to provide relief to a subject suffering from the antigen-induced allergic reponse. 6. A method for blocking an antigen-induced allergic response of the group consisting of broncho¬ constriction, rhinitis, urticaria, eczema, skin flushing, angioedema and pruritis in a subject, comprising administering to said subject an amount of the compound 6-methylene-6-desoxy-n-cyclopropylmethyl- 14-hydroxy-dihydronormorphine sufficient to inhibit the antigen-induced allergic response. 7. The method of claim 6, wherein said 6- methylene-6-desoxy-n-cyclopropylmethyl-14-hydroxydi- hydronormorphine is administered orally. 8. The method of claim 6, wherein the amount administered is from about 1 to about 60 mg per day. 9. The method of claim 8, wherein the amount is about 2 to about 20 mg per day. 10. The method of claim 9, wherein the amount is about 10 mg per day. 11. The method of claim 6, wherein the 6-methylene- 6-desoxγ-n-cyclopropylmethyl-14-hydroxydihydronormor- phine is administered prophylactically. 12. The method of claim 6, wherein the 6-methylene- 6-desoxy-n-cyclopropylmethyl-14-hydroxydihydronormor- phine is administered to provide relief to a subject suffering from the antigen-induced allergic reponse. 13. The method of claim 6, wherein the antigen- induced allergic response is bronchoconstriction. 14. A composition for blocking an antigen-induced " allergic reponse in a subject, comprising: an. amount of 6-methylene-6-desoxy-n-cyclopropyl- methyl-14-hydroxydihydronormorphine sufficient to inhibit the antigen-induced allergic response in the subject; and a pharmaceutically acceptable carrier therefor. 15. The composition of claim* 14, wherein said carrier is suitable for oral administration. 16. The composition of claim 15, wherein said composition is in a single dosage unit form. 17. The composition of claim 16, wherein the amount of 6-methylene-6-desoxy-n-cyclopropylmethyl-14-hydroxy- dihydronormorphine in the dosage unit is about 2-20 mg. 18. A method for blocking an antigen-induced allergic response in a subject, comprising orally administering to the subject a pure opioid antagonist in an amount sufficient to inhibit said antigen-induced allergic response. 19. The method of claim 18, wherein said antagonist is administered orally in the amount of about 1-60 mg per day. 20. The method of claim 18, wherein the antigen- induced allergic response is of the group consisting of bronchoconstriction, rhinitis, urticaria, eczema, skin flushing, and pruritis. 21. An oral composition for blocking an antigen- induced allergic response in a subject comprising: an amount of pure opioid antagonist sufficient to block the antigen-induced allergic response in the subject; and a pharmaceutically acceptable oral carrier therefor. 22. The composition of claim 21, wherein the amount of antagonist is about 2-20 mg. 23. The composition of claim 19, wherein the antigen—induced allergic response is of the group consisting: of bronchoconstric¬ tion, rhinitis, urticaria, eczema, skin flushing, angioedema and pruritis.

Inventors: TUTTLE RONALD R, TUTTLE, RONALD, R.
Applicants: KEY PHARMA, KEY PHARMACEUTICALS, INC.
Application year: 1986
Main classification: A61K31
IPC codes: A61K31, C07D489