US3063900A

US3063900A - Therapeutic composition for the treatment of angina pectoris and method

Info

Publication number: US3063900A
Application number: US498A
Authority: US
Inventors: Winsor Travis
Original assignee: Individual
Current assignee: Individual
Priority date: 1960-01-05
Filing date: 1960-01-05
Publication date: 1962-11-13
Anticipated expiration: 1979-11-13

Description

United States Patent G 3,063,960 THERAPEUTIC COMPOSITION FOR THE TREAT- MENT F ANGINA PECTORIS AND METHOD Travis Winser, 4641 Wiishire Blvd Los Angeles 5, Calif. No Drawing. Filed Jan. 5, 1960, Ser. No. 498 3 Claims. (Cl. 167-65) This invention relates to a new and novel therapeutic composition for use in the treatment of angina pectoris and to a method of treatment.

Angina pectoris is a disease marked by paroxysmal thoracic pain, with suffocation and syncope which is most frequently due to anoxia of the myocardium. Anginal attacks are most often precipitated in patients by effort and excitement. Any form of physical effort is contraindicated in many patients who on occasions can experience up to 50 or even more attacks per day. Classic therapy for this disease has been rest, the administration of nitroglycerine for immediate relief of acute attacks and the use of longer acting nitrates such as pentaerythritol tetranitrate to reduce the frequency and severity of anginal attacks.

There has long been a need for an effective composition and method for treating this disease which will not only reduce the frequency and severity of attacks but will also permit increased physical activity for those patients who, under classic therapy, must remain virtually bed-ridden.

It is, therefore, a particular object of the present invention to provide a new and improved therapeutic composition which is effective in the treatment of angina pectoris.

Other objects and the advantages of this invention will appear hereinafter.

It has now been found that the administration of a combination of a long-acting effective organic nitrate and a nontoxic monoamine oxidase inhibitor to patients suffering from angina pectoris is remarkably effective in mitigating clinical symptoms and in affording relief from the manifestations of this disease.

It has recently been discovered that the enzyme monoamine oxidase has a significant effect on the activity of the central nervous system and in other areas of the body in that this enzyme promotes the destruction of serotonin and catechol amines. It has been observed that the administration of an inhibitor of monoamine oxidase results in a stimulation of the central nervous system brought about by the increase in the concentra tion of serotonin and catechol amines. The present invention is based upon the discovery that a combination of a long-acting effective organic nitrate with anon-toxic monoamine oxidase inhibitor is remarkably effective in the treatment of angina pectoris.

The term a long-acting effective organic nitrate as used throughout the specification and in the claims refers to any of the known long-acting organic nitrate vasodilators which have been used in the treatment of angina pectoris. Such compounds have a relatively slow onset of activity but are effective for several hours after administration. 'Bhey) differ, therefore, from fast-acting organic nitrates such as nitroglycerin. Useful long-acting effective organic nitrates which may be used in combination with a non-toxic effective monoamine oxidase inhibitor are pentaerythritol tetranitrate, 1,4:3,6- dianhydrosorbitol 2,5-dinitrate, triethanolamine trinitrate biphosphate and the like. Pentaerythritol tetranitrate is preferred.

Any non-toxic compound which is an effective inhibitor of monoamine oxidase may be used in the therapeutic compositions of the present invention. It is possible, by means of a well accepted pharmacological test, to determine readily whether a particular compound is effective ICC as an inhibitor of this enzyme. This test is based on the fact that when mice are pre-treated with an effective monoamine oxidase inhibitor and are thereafter challenged with resperpine they exhibit manifestations of ex citation and aggressiveness. Where the compound in question is ineffective as an inhibitor of monoamine oxidase no such manifestations occur following 'resperpine challenge.

The term an effective monoamine oxidase inhibitor, as used throughout the specification and in the claims, refers to a compound which is effective at a dosage of mg./ kg. of body weight or less in mice as determined by the following test procedure. The compound is administered at graded doses intraperitoneally to a series of mice. Three to nine hours after administration each mouse is challenged with reserpine at a' dosage of 1 mg./kg. of body weight, administered intravenously. If the mouse exhibits manifestations of excitation and aggressiveness at a dosage of 100 mg./kg. or less, the compound in question is an effective monoamine oxidase 1nhibitor. Where the compound is administered as a pharmaceutically acceptable acid salt, dosages are calculated based on the free base.

It is also an essential requirement vthat the compound be non-toxic in relation to the effective dose, a property which may be readily evaluated by well-known pharmacological test procedures.

Non-toxic, effective monoamine oxidase inhibitors which may be used in combination with a long-acting effective organic nitrate in accordance with this invention are preferably hydrazine derivatives, for example:

1-isonicotinyl-2-isopropylhydrazine which is reported by E. A. Zeller et al., Proc. Soc. Exptl. Biol. Med 81, 459 (1952), as having in vivo activity in inhibiting monoamine oxidase and which has been used clinically as an antidepressant;

N-benzyl-fi-(isonicotinylhydrazino) propionamide and compounds related thereto as described in US. Patent No. 2,894,972;

1-benzyl-2-(5 methyl-3-isoxazolylcarbonyl) hydrazine which has been tested clinically in depressed patients as reported by H. F, Darling et al., Dis. Nerv. Syst. 20, 269 (1959);

[3-Phenylisopropylhydrazine, a known inhibitor of monoamine oxidase as reported by Horita, J. Pharmacol. Exper. Therap. 122, 176 (1958);

Hydrazine derivatives of the structure Re where X is halogen, hydroxyl, alkoxy, alkyl or amino; A is -CH lower alkyl CH2'-CH2, OI and R1- and R2 are hydrogen, lower alkyl or acyl as disclosed in copending applications Serial' Numbers 766,407, 766,408,- 766,409, 766,410, 766,413, all filed October 10,1958, of which 766,410 and 766,413 are now abandoned, and 773,572, filed November 13, 1958;

Hydrazine derivatives of the structure lower alkyl where X is hydrogen, halogen, hydroxy or lower alkoxy and R is lower alkyl or c H Y where n is 2 or 3 and Y is hydroxyl, chloro, di-lower alkylamino, piperidino, piperazino, morpholino or pyrrolidino, as disclosed in 3 copending application Serial Number 850,988 filed November 5, 1959.

The hydrazine derivatives enumerated above may also be used in the form of their non-toxic salts in formula-ting the compositions of this invention.

It has been found that the administration of ,B-phenethylhydrazine or its non-toxic acid salts in combination with the widely utilized pentaerythritol tetranitrate is a particularly elfective method of treating angina pectoris. The therapeutic compositions of the present invention comprise a combination in each dosage unit of about 3 to about 50 milligrams of the non-toxic effective monoamine 'oxidase inhibitor (about 5 to about 25 milligrams with the preferred B-phenethylhydrazine) and about 2 to about 40 milligrams of the long-acting effective organic nitrate (about to about 40 milligrams with the preferred pentaerythritol tetranitrate). In the treatment of angina pectoris, the daily dosage is about 9 to about 150 milligrams of the inhibitor (about to about 75 milligrams with the preferred fi-phenethylhydrazine) and about 10 to about 120 milligrams of the long-acting effective organic nitrate (about 30 to about 120 milligrams with the preferred pentaerythritol tetranitrate). Vlhere the monoamine oxidase inhibitor is present as a non-toxic salt, the above milligram quantities refer to the amount of the free base resulting from hydrolysis of the salt form. The actual dosage schedule selected for any patient depends on the particular compounds used, the tolerance of the patients to the compounds and the severity of the angina pectoris condition.

In the treatment of angina pectoris the substituted hydrazine and the long-acting eifective organic nitrate may be administered separately, but it is preferable that the two compounds be combined in a single dosage unit form. Any of the various dosage forms commonly employed in therapeutics may be used with core-type tablets being generally preferred to prevent any possible chemical reaction between the active ingredients. In each dosage unit, the active ingredients are combined with suitable pharmaceutical diluents and carriers, depending on the physical form of the dosage unit.

Data on a group of angina pectoris patients who have been studied in the clinic to determine the efiectiveness of administration of pentaerythritol tetranitrate alone, ,B-phenethylhydrazine hydrogen sulfate alone and the simultaneous administration of both compounds has been obtained. In 70 percent of the patients, the best results in terms of reduction of severity and frequency of anginal attacks and the ability of the patients to tolerate greater physical activity were obtained with the simultaneous administration of both compounds.

The following example is given in order further to illustrate the present invention:

EXAMPLE A core-type tablet comprising as active ingredients a combination of phenethylhydrazine sulfate and pentaerythritol tetranitrate is prepared by the following procedure:

A. Tablet Cores A quantity of 12.9 grams phenethylhydrazine sulfate and 174 grams mannitol are milled and passed through a number 1 screen. 6 grams polyvinylpyrrolidone is dissolved in ml. isopropyl alcohol by mild heating and the screened mixture of phenethylhydrazine sulfate and mannitol is granulated with the resulting solution. The

granules are then regranulated with about 30 ml. isopropyl alcohol. The resulting granules are dried and passed through a number 12 screen. The screened granules are then blended with 4 grams magnesium stearate and 4 grams starch, and the resulting mixture is com pressed into 200 milligram tablets.

B. Tablet Coating The tablets prepared as described in A above are coated twice with pharmaceutical glaze (7 pound out) and the coated tablets are dusted with talc. The dusted coated tablets are then coated with a gelatin-syrup solution and dusted again with a duster powder comprising calcium carbonate, kaolin, talc, acacia and powdered sugar. The steps of coating with gelatin-syrup solution and dusting with duster powder are repeated several times. Tablets are then dusted repeatedly with a mixture of 1 part pentaerythritol tetranitrate and 1.8 parts mannitol with the number of applications being sufficient so that upon assay each dusted tablet contains 20 milligrams pentaerythritol tetranitrate. The tablets are finally coated with a gelatin-syrup solution, dusted with additional duster powder and finally coated with a standard polishing solution.

Each tablet contains 12.9 milligrams phenethylhydra- Zine sulfate (corresponding to 7.5 milligrams phen' ethylhydrazine base) and 20 milligrams pentaerythritol tetranitrate.

It is understood that the foregoing detailed description is given merely by way of illustration and that many variations may be made therein without departing from the spirit of my invention.

Having described my invention, what I desire to secure by Letters Patent is:

l. A therapeutic composition in dosage unit form for use in the treatment of angina pectoris which comprises a combination of about 10 to about 40 milligrams of pentaerythritol tetranitrate and about 5 to about 25 milligrams of a member selected from the group consisting of fi-phenethylhydrazine and the non-toxic salts thereof.

2. A therapeutic composition according to claim 1 which comprises about 7.5 milligrams of B-Phenethylhydrazine as the sulfate salt thereof and about 20 milligrams of pentaerythritol tetranitrate.

3. A method of treating angina pectoris which comprises administering daily about 20 to about milligrams of a member selected from the group consisting of B-phenethylhydraziue and the non-toxic salts thereof and about 30 to about milligrams of pentaerythritol tetranitrate.

References Cited in the file of this patent

Claims

1. A THERAPEUTIC COMPOSITION IN DOSAGE UNIT FORM FOR USE IN THE TREATMENT OF ANGINA PECTORIS WHICH COMPRISES A COMBINATION OF ABOUT 10 TO ABOUT 40 MILLIGRAMS OF PENTAERYTHRITOL TETRANITRATE AND ABOUT 5 TO ABOUT 25 MILLIGRAMS OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF B-PHENETHYLHYDRAZINE AND THE NON-TOXIC SALTS THEREOF.