US3636208A - Method for treating malaria - Google Patents

Abstract

6-SULFANILAMIDO-4-METHOXYPRYIMIDINE (SULFAMONONMETHOXINE) IS CLINICALLY USEFUL FOR TREATING MALARIA, AND WAS FOUND TO BE EFFECTIVE AGAINST BOTH THE ERYTHROCYTIC FORM (BLOOD FORM) AND THE EXOERYTHROCYTIC FORM (TISSUE FORM) OF MALARIA PARASITES.

Description

United States Patent O 3,636,208 METHOD FOR TREATING MALARIA Yuiclli Yamamura and Tetsuo Yoshinaga, Osaka, and

Kiyosh Tsunotla, Yoshiatsu Tsutsumi. and Kazuhiko I-Ioji, Tokyo, Japan, assignors to Daiichi Seiyaku Company Limited, Tokyo, Japan No Drawing. Filed Jan. 2, 1970, Ser. No. 378 Claims priority, application Japan, Oct. 28, 1969,

44/ 85,7 07 Int. Cl. A61k 27/00 US. Cl. 424-229 3 Claims ABSTRACT OF THE DISCLOSURE 6 sulfanilamido-4-methoxypyrimidine (Sulfamonomethoxine) is clinically useful for treating malaria, and was found to be effective against both the erythrocytic form (blood form) and the exoerythrocytic form (tissue form) of malaria parasites.

BACKGROUND OF THE INVENTION (1) Field of the invention This invention relates to antimalarial compositions comprising 6-sulfanilamido-4-methoxypyrimidine and to a method for treating malaria with such compositions.

(2) Description of the prior art It has previously been known that some sulfonamides are experimentally effective against malaria parasites but only in a definite stage of their life cycle. However, since the antimalarial effect of these sulfonamides is very uncertain, these drugs have not been employed clinically. Further, high doses or frequent administration of these sulfonamides is necessary in the treatment of malaria. Furthermore, there is a probability of recidivation of the disease when employing such drugs.

Malaria parasites undergo a specific and complicated life cycle. This life cycle is roughly classified into two forms, the exoerythocytic form (tissue form) and erythrocytic form (blood form). These two forms generally have different sensitivities to chemotherapeutic drugs.

Therefore, no sulfonamides have been known which are perfectly effective against both blood and exoerythro cytic forms. In view of the above, it has not been believed that sulfonamides are worthy of clinical use in the treatment of malaria.

SUMMARY OF THE INVENTION From extensive investigations, however, applicants have found that 6-sulfanilamido-4-methoxypyrimidine, which was already known as an antibacterial agent (generally called sulfamonomethoxine), surprisingly brought about complete cures of malarial infections both in experimental and clinical use.

DETAILED DESCRIPTION OF THE INVENTION According to one feature of the invention, said sulfamonomethoxine shows sufiicient effectiveness, at relatively low doses, against malaria parasites resistant to antimalarial agents as chloroquine or pamaquine, which have heretofore usually been employed for clinical use.

For example, it has been confirmed by experiments using infected domestic fowls and mice that Sulfamonomethoxine is definitely effective against malaria parasites both in the blood and exoerythrocytic stages. Therefore, malaria can be completely cured by several administrations of sulfamonomethoxine.

Sulfamonomethoxine has shown excellent effects with patients suffering from malaria upon oral or intravenous administration of 10-80 mg./kg./day for one to several days, as shown in Example 4. This data was obtained from clinical experiments in the region near the Victoria Lake,

which had been famous for multi-occurrences of malaria. Further, prevention of malaria is also effected by administration of said sulfamonomethoxine at dosages of 1-2 g., once a week.

In addition to the above merits, sulfamonomethoxine has previously been clinically employed as a long acting sulfa-drug, as blood levels remain high for quite some time. In this respect, sulfamonomethoxine is an ideal drug for antimalaria treatment.

Sulfamonomethoxine, further, possesses very low toxicity and very stable physical properties. The compound may therefore be easily made into various pharmaceutical formulations, such as injetcables, syrups, capsules, tablets or powders by well-known pharmaceutical techniques, employing any pharmaceutically acceptable carrier.

EXAMPLE 1.PART l Plas rnodium berghei, which had been collected from infected mice, was inoculated into mice (D.D. strain; 16- 19 g. of body weight) intraperitoneally (2.556.92 10 mg./kg. per mouse). To these mice, various drugs were then orally administered for 7 days, and the infected mice were observed mainly to fall ill and to die. The blood, the liver and the spleen of the mice which survived until the 55th day after the infection were homogenized and inoculated into healthy mice. The existence of parasites diatermined by whether or not the inoculated mice also e l The results are summarized in the following Table 1.

A comparative examination was made on the antimalarial activity of sulfamonomethoxine with several drugs which are known to be somewhat effective against the parasites. The results are shown in the following Table 2. From the results, it is obvious that the sulfainonomethoxine is the most excellent among all sulfa-drugs with regard to the dosage administered compared with the effectiveness of treatment.

TABLE 2 Average N0. of Existdaily dose animals Percent ence of Drugs (mg/kg.) tested protected parasites Sulfamonomethoxine 2. 5 5 :1: 5 5 10 5 100 Sulfamerazine 2. 5 5 0 10 5 0 100 5 80 Sulfaisoxazole 2. 5 5 0 50 5 0 100 5 80 Sulfisomidine 2. 5 5 0 50 5 0 100 5 100 Sulfa-thlazole 100 5 0 200 5 80 Sulforthodirnethoxine 2. 5 5 20 5 5 80 10 5 100 Infected control 5 0 3 EXAMPLE 2 When chicks are infected with Plasmodium: juxtanucleare, the number of the parasites reaches a maximum at 10 days in erythrocytic stages and at 3-4 Weeks in exoerythrocytic stages. Based on the above, the examinations of the activity of sulfamonomethoxine against the parasites both in exoerythrocytic and erythrocytic stages were performed.

Materials and method 4 EXAMPLE 3 A blood infected with Plasmodium ga-llimaceum was injected into eleven-day-old chicks (1.4)(10 nag/kg. per chick) intramuscularly. Each drug, mixed with diet, was administered for 7 days after the infection. Determinations on the effect of the treatment were made by the presence or absence of erythrocyte with parasites after inoculation and by the survival ratio of the chicks at the 40th day after the inoculation.

10 Twenty one-day-old chicks were used as one group. The results are summarized in the following Table 5.

TABLE Survival ratio at 40 Daily After the inoculation days after dose inoculation, Drug (mg./kg.) 8 days 11 days 14 days 30 days percent Suliamonomethoxine 2 100 5 100 10o Pyrimethamine 1 55 15 85 Plasmochin 1 95 5 95 Infected eontroL 0 EXAMPLE 4 Blood infected with Plasmodium juxtanucleare was inoculated into the chicks by intracardiac injection. The drug administration was started from the 8th day after inoculation for the examination in the erythrocytic stage, and from the 17th day after inoculation in the exoerythrocytio stage, for 5 days respectively.

Determinations of the effect of treatment were made by calculation of the rate of erythrocytes within which To 145 patients sufiering from tertian fever, quartan fever, or tropical subtertian malaria who were residing in Embu in Kenya, only sulfamonornethoxine (SMM) was administered intravenously or orally for 1 to 4 days. The treatment effect was determined by the number of days required to achieve clearness of the parasitemia and clinical clearness.

The results are shown in the following Table 6.

TABLE 6 Number Average Average of days to clear days to clear Percent Number Drugs and dosages patients parasitcmia clinically cured 1 SMM 2 g. (i.v.) plus 23 2.2 4. l 100 SMM 1 g. {p.o.) in single dose. 2 SMM 2g. (l.v.) then 29 2.4 3.7 100 0.5 g. daily for 3 days. 3 SMM 2 g. {p.o.) then 46 2. 5 4. 3 100 0.5 g. daily for 2 days. 4 SMM 2g. (p.o.) in 47 2.7 4. 2 100 single dose.

parasites lived to the total erythrocytes and by mortality EXAMPLE 5 of the chicks.

The results are summarized in the following Tables 3 and 4.

TABLE 3.-RESULTS IN ERYTHROCYTIC STAGE Preparation of 500 mg. tablets One thousand tablets for oral use, each containing 500 Erythrocytes with parasites percent Total erythrocytes observed Average Before After administration daily dose adminis- Mortality, Drug (mg.lkg.) tratlon 5 days 15 days 30 days percent Suliamonomethoxine 50 0. 6 (0) (O) (0) 0 10 0. e (0) (0) (0) 0 Infected control 0. 6

TABLE 4.RESULTS IN EXOE RYTH ROCYTIC STAGE Erythrocytes with parasites percent Total erythrocytes observed Average Before After administration daily dose adminis- Mortality, Drug (mg/kg.) tration 5 days 15 days 30 days percent Sulfarnonomethoxine- 1. 4 (0) (0) (0) 0 10 1. 3 (0) 0 Infected control 1. 1

mg. of sulfamonomethoxine, were prepared from the following materials:

Sulfamonomethoxine 500 Corn starch 40 Magnesium stearate 9.4

Sulfamonomethoxine300 g. Sodium hydroxide42 g. Distilled water for injection3 liters The solution containing the above ingredients were filtered and filled into ampoules, then sterilized.

What is claimed is:

1. A method for treating malaria which comprises orally or parenterally administering to a patient infected with malaria, 6-sulfanilamido-4-methoxy pyrimidine in an antimalarially effective dose.

2. The method of claim 1, wherein the antimalarially efiective dose is a range of from 10 mg. to 80 mg. per kg. of body weight per day.

3. The method of claim 1, further comprising in combination with said 6-sulfanilamido-4-methoxy pyrimidine, a pharmaceutically acceptable carrier.

References Cited UNITED STATES PATENTS 3,275,508 9 1966 Tsunoda et al 424-229 FOREIGN PATENTS 588,170 9/ 1960 Belgium 424229 JEROME D. GOLDBERG, Primary Examiner