USE OF CALMODULIN BINDING DRUGS IN UTERUS TO PREVENT PREGNANCY

Abstract: Method of preventing pregnancy. The use of calmodulin binding drugs by injecting or introducing such drugs into the uterus is disclosed as a means of preventing pregnancy after intercourse has occurred. Various groups of effective calmodulin binding drugs are disclosed, including psychoactive drugs, naphthalene sulfonic acid derivatives, and phenothiazine sulfoxides.

Description: -1- Description USE OF CALMODULIN BINDING DRUGS IN UTERUS TO PREVENT PREGNANCY Technical Field The present invention relates to a method of preventing pregnancy. More specifically, the present invention relates to the use of calmodu- lin binding drugs as a means to prevent preg¬ nancy after intercourse by injecting such drugs into the uterus. Background Art Presently, there is no effective method or product known for preventing conception or preg¬ nancy after sexual intercourse has occurred, especially after an hour or more has elapsed after intercourse. For the purpose of this application pregnancy is intended to be defined as the implantation of a fertilized egg to the uterus. Currently, in cases of rape or other cases of intercourse where pregnancy is unwanted, other than using douches or other normally inef¬ fective methods to attempt to prevent concep¬ tion, the normal practice is to wait to see whether the signs of pregnancy occur and, if so, have an abortion if the pregnancy is to be ter¬ minated. Drugs that are capable of binding with cal- modulin only in the presence of calcium are known as calmodulin binding drugs. Psychoactive -2- drugs constitute one class of calmodulin binding drugs. Other known calmodulin binding drugs are disclosed in this application. Psychoactive drugs are currently used clin¬ ically to treat certain types of mental dis¬ orders and stress, Chemical classes of psy- choactive drugs and examples of drugs in each class are as follows: Chemical Class Examples Phenothiazines Trifluoperazine Fluphenazine Thioridazine Chlorpromazine Promethazine Thioxanthenes Chlorprothixene Butyrophenones Penfluridol Benperidol Haloperidol Diphenylbutylamines Pimozide Dibenzodiazepines Clozapine Benzodiazepines Medazepam Chlordiazepoxide Dibenzazepines Imipramine Amitriptyline Protriptyline Desipramine The use of psychoactive drugs as medications to affect mental processes has become widespread since the early 1950s. Such use typically entails taking such drugs internally at dosages ranging from 10 to 120 milligrams daily. For a detailed background of such use and description -3- of such drugs see Chapter 12 of The Pharmacolo¬ gical Basis of Therapeutics, 5th Ed., edited by L. S. Goodman and A. Gilman (1975). Disclosure of Invention The present invention comprises the use of calmodulin binding drugs to prevent pregnancy. The introduction of such drugs into the uterus can be accomplished by normal clinical methods, such as injection by way of the vaginal tract, through the cervix and into the uterus. Such treatment is quick and simple; at least as sim¬ ple as the currently used procedure for PAP Smears. -By introduction of an effective amount or concentration of one or a combination of calmodulin binding drugs into the uterus prior to the implantation of a fertilized egg to the wall of the uterus, pregnancy will be pre¬ vented. Calmodulin binding drugs in the uterus will either prevent conception, if it has not yet taken place, or embryonic development of a fertill-zed egg prior to and necessary for implantation. Since implantation normally does not occur for several days after conception, the present invention may be used effectively for a significant period of time after intercourse, perhaps up to three or four days later. The present invention does not involve the killing of the sperm, but instead directly and specifically blocks the physiological process of conception and embryonic development. It has been shown in the past few years that there is a regulatory protein known as calmodulin, found in -4- all cells of higher organisms and which is the key to the control of a wide variety of physio¬ logical processes. We have found that calmodu¬ lin is involved in triggering the activation of mammalian spermatozoa, a prerequisite to the fertilization process, as well as in triggering the early events of ovum development after fer¬ tilization has occurred. Calmodulin is a calci¬ um binding protein, which means that when calci- um is bound to the protein the resulting calcium-protein complex turns on a variety of cellular processes including spermatozoan or ovum activation. We have found that calmodulin binding drugs inhibit the calmodulin function, and, as a result, use of such drugs will prevent the activation of spermatozoa and will prevent embryonic development following fertilization. Calmodulin binding drugs are drugs that will bind tightly to calmodulin only in the presence of calcium. The binding of these drugs to cal¬ modulin results in the inhibition of calmodulin function. The use of an affective calmodulin binding drug in the uterus to prevent pregnancy has a number of advantages. First, it is extremely effective since the specific binding of the drug to calmodulin would turn off spermatozoan or ovum activation and embryonic development and thus prevent pregnancy. Experimental evidence has demonstrated that the phenothiazine drugs penetrate the spermatozoan membranes within sec¬ onds and concentrate in the region of the cell occupied by calmodulin. Second, there will be ■ 5- no expected side effects since the drug would not be used internally and since low concentra¬ tions will be very effective. Third, the effec¬ tiveness of an application may last for hours due to the stability of these drugs. Other known calmodulin binding drugs include the following three classes of compounds. The first class includes, and is exemplified by the following compounds: a) 8-anilino-l-naphthalenesulfonate b) 9-anthroylcholine c) N-phenyl-1-naphthylamine The second class of compounds includes, and is exemplified by the following compounds: a) N-(6 aminohexyl)-5-chloro-l-naρhtha- lenesulfonamide b) N-(6 aminohexyl)-5-chloro-2-naphtha- lenesulfonamide c) N-(6 aminohexyl)-5-bromo-2-naphtha- lenesulfonamide . The third class of compounds is the phenothiazine sulfoxides, which includes and is exemplified by the following compounds: a) chlorpromazine sulfoxide b) 2-Trifluoromethyl-N-10 (3* - propriόamino) phenothiazine sulfoxide c) phenothiazine sulfoxide O PI -6- Best Mode for Carrying Out the Invention The most effective drugs can be predicted based on their effectiveness in binding to cal¬ modulin. Therefore, the most promising specific psychoative drugs, in order of effectiveness, are: penfluridol, pimozide, trifluoperazine, fluphenazine, chlorprothixene, thioridazine, chlorpro azine, benperidol, haloperidol, and clozapine. To accomplish the present invention the cal¬ modulin binding drugs would be combined with an appropriate carrier medium, such as paraffin oil, foam carriers or jelly carriers. A preferred embodiment of the present inven- tion comprises a buffered two percent concentra¬ tion of chlorpromazine sulfoxide in paraffin oil, introduced into the uterus in sufficient quantity and under known methods within six hours after sexual intercourse has occurred and allowed to remain therein. OMPI

Claims: -7- Claims : 1. A method of preventing pregnancy in a female which comprises introducing an effective amount of a calmodulin binding 5 drug into the uterus of the female. 2. The method as described by claim 1, wherein the step of introducing said cal¬ modulin binding drug comprises introducing a mixture of said calmodulin binding drug and 10 a foam carrier into the uterus of the female after sexual intercourse by foam injection means. 3. The method as described by claim 1, wherein the step of introducing said cal- 15 modulin binding drug comprises introducing a mixture of said calmodulin binding drug and a jelly carrier into the uterus of the female after sexual intercourse by jelly insertion means. 20 4. The method as described by claim 1, * --wherein the step of introducing said cal¬ modulin binding drug comprises introducing a mixture of said calmodulin binding drug and paraffin oil into the uterus of the female 25 after sexual intercourse by injection means. 5. The method as described by claim 4, wherein said injection means is accom¬ plished by way of the vaginal tract, through the cervix and into the uterus. 30 6. The method as described by claims 1, 2, 3, 4, or 5, wherein said calmodulin binding drug is a psychoactive drug. OMPI -8- 7. The method as described by claim 6, wherein said psychoactive drug is selected from the group consisting of the phenothiazines, thioxanthenes, butyrophe- 5 nones, diphenylbutylamines, dibenzodiaze- pines, benzodiazepines, and dibenzazepines. 8. The method as described by claim 6, where said psychoactive drug is selected from the group consisting of penfluridol, 10 pimozide, trifluoperazine, fluphenazine, chlorprothixene, thioridazine, chlorproma¬ zine, benperidol, haloperidol, and clozapine. 9. The method as described by claim 8, wherein the amount of the psychoactive 15 drug introduced into the uterus is about 10 milligrams or greater. 10. The method as described by claims 1, 2, 3, 4, or 5, wherein said calmodulin binding drug is 8-anilino-l-naphthalene- 20 sulfonate, 9-anthroylcholine, or N-phen l-1- naphthylamine. - . 11. The method as described by claims I, 2, 3, 4, or 5, wherein said calmodulin binding drug is N-(6 aminohexyl)-5-chloro-l- 25 naphthalenesulfonamide, N-(6 aminohexyl)-5- chloro-2-naphthalenesulfonamide, or N-(6 aminohexyl)-5-bromo-2-naphthalenesulfonamide. 12. The method as described by claim II, wherein the amount of the drug 30 introduced into the uterus is about 10 milligrams or greater. 13. The method as described by claims 1, 2, 3, 4, or 5 wherein said calmodulin binding drug is one of the phenothiazine 35 sulfoxides. /^ MPI -9- 14. The method as described by claim 13, wherein said drug is selected from the group consisting of chlorpromazine sulfoxide, 2-Trifluoromethyl-N-10 (3'-pro- 5 prioamino) phenothiazine sulfoxide, and phenothiazine sulfoxide. 15. The method as described by claim 14, wherein the amount of the drug intro¬ duced into the uterus is about 10 milligrams 10 or greater. 16. A pregnancy prevention composition comprising an effective amount ' of one or more calmodulin binding drugs and a suitable carrier medium selected from the group con- 15 sisting of jelly carriers, foam carriers, and paraffin oil, for introducing said cal¬ modulin binding drugs into the uterus. 17. The composition as described by claim 16, wherein said calmodulin binding 20 drug is a psychoactive drug. 18. The composition as described by claim 17, wherein said psychoactive drug is selected from the group consisting of the phenothiazines, thioxanthenes, butyrophe- 25 nones, diphenylbutylamines, dibenzodiaze- pines, benzodiazepines, and dibenzazepines, and mixtures thereof. 19. The composition as described by claim 17, wherein said psychoactive drug is 30 selected from the group consisting of penfluridol, pimozide, trifluoperazine, fluphenazine, chlorprothixene, tnioridazine, chlorpromazine, benperidol, haloperidol, and clozapine, and mixtures thereof. - JRE OMPI " ° -10 - 20. The composition as described by claim 16, wherein said calmodulin binding drug is selected from the group consisting of 8-anilino-l-naphthalenesulfonate, 9-an- 5 throylcholine, or N-phenyl-1-naphthylamine and mixtures thereof. 21. The composition as described by claim 16, wherein said calmodulin binding drug is N-(6 aminohexyl)-5-chloro-l-naphtha- 10 lenesulfonamide, N-{6 aminohexyl)-5-chloro- 2-naphthalenesulfonamide, or N-(6 amino¬ hexyl)-5-bromo-2-naphthalenesulfonamide, and mixtures thereof. 22. The composition as described by 15 claim 16, wherein said calmodulin binding .drug is one of the phenothiazine sulfoxides. 23. The composition as described by claim 22, wherein said calmodulin binding drug is chlorpromazine sulfoxide, 2-Tri- 20 fluororaethyl-N-10 (3'-proprioamino) pheno¬ thiazine sulfoxide, or phenothiazine sulfoxide, and mixtures thereof. 24. The composition as described by claims 16, 17, 18, 19, 20, 21, 22, or 23, 25 wherein the concentration of said drug is equal to or greater than 5 milligrams per milliliter of said carrier medium. f OMPI

Inventors: CORMIER MILTON J, CORMIER, MILTON, J.
Applicants: UNIV GEORGIA, UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.
Application year: 1982
Main classification: A61K31
IPC codes: A61K31