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Drugs which inhibit protein or purine synthesis

A rational therapy of T. cruzi should be based on drugs that inhibit protein or purine synthesis. One of these drugs is allopurinol. T. cruzi is not able to synthesize purines de novo as human do. Allopurinol (4-hydroxypirazol (3,4-d) pyrimidine) HPP (Fig. 31.1) is an analog of hypoxanthine, which decreases uric acid and the conversion of hypoxanthine to xanthine.

For this reason it is used to treat gout, which is characterized by the deposit of uric acid in the joints. HPP inhibits the epimastigote forms in culture. In mice infected with T. cruzi and treated with allopurinol, an important reduction of the

Chemical structure of allopurinol (4-hydroxypirazol (3,4-d) pyrimidine)

Figure 31.1 Chemical structure of allopurinol (4-hydroxypirazol (3,4-d) pyrimidine).

parasitemia is obtained, although some parasite strains are resistant to the drug.8 T. cruzi changes HPP to APP (4-aminopyrazol (3,4-d) pyrimidine), which is 15 times more powerful against epimastigotes than HPP. If APP is administered to infected T. cruzi mice a suppression of the parasitemia is obtained with a dose 400 times lower than allopurinol.9 In patients with acute Chagas disease treated with allopurinol at high doses (20—30 mg/day) for 60 days, no reduction of the parasite burden was obtained. In a multinational study performed in Argentina, Brazil, and Bolivia in patients with chronic Chagas disease treated with 900 mg/day for 60 days, no parasitological cure was obtained. This drug was well tolerated in a number of studies performed in patients with chronic Chagas disease, and in some of these an improvement of the electrocardiographical alterations in Chagas cardiopathy (CCC) was demonstrated.10 It has been used in heart transplantation in Chagas patients with good results.11 In a combined treatment in chronic chagasic patients with 600 mg of allopurinol daily for 3 months followed by 30 days of benznidazole good results have been obtained.12 In exceptional cases it has been necessary to suspend the treatment due to the secondary effects of allopurinol.13

Megazole (CL 641855), 2-amino-5-(methyl-5-nitro-2-inidazole)-1,3,4-thiazole, is a nitroimidazole-thiadiazol derivative that inhibits the protein synthesis of T. cruzi. With this drug a cure of mice inoculated with Y20 strains and Colombian T. cruzi was obtained. The parasitological cure was demonstrated by hemocultures, reinoculations, and an indirect immunofluorescence (IF) test. The drug has not been used in human clinical studies, since the experimental survey in animals demonstrated

that it was mutagenic.14,15

MK-436 is a compound, 3-(methyl-5-nitroimidazole-2-yl)-3a,4,5,6,7,7a-hexahy- dro-1,2-benzisoxazole, that is a substitute for 5-nitroinidazole and its derivative dihydro (L-634, 549). It affects amastigotes in culture tissue, and in acute and chronic infections in mice. With this drug a parasitological cure of the treated animals is obtained. To date it has not been used in human patients with Chagas disease.

 
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