Antischistosomal drugs: Past, present … and future?

In mice experimentally infected with Schistosoma mansoni, praziquantel (2-cyclohexylcarbonyl-1,3,4,6,7,11b-hexahydro-2H-pyrazino[2,1-a]isoquinoline-4-one), administered orally at the levels of 100 and 50 mg/kg, for 5 consecutive days, produced oogram changes in all animals and a pronounced hepatic shift of schistosomes (97.1 and 89.1, respectively). At lowest levels (12.5 and 6.3 mg/kg), alterations in the oogram could still be detected, although hepatic shift of schistosomes was no more evident. After a single intramuscular injection, the results obtained paralleled those observed with a single-dose oral treatment. The hepatic shift was only moderate at 200 and 100 mg/kg and the percentages of worms retained in the liver, after perfusion, were particularly low. When nasal route in a 1-day regimen was used, the results obtained were slightly less evident as compared with those observed by oral route (5-day schedule).

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Experimental Chemotherapy of Schistosomiasis mansoni

Synthesis and evaluation of antimicrobial activity of 4H-pyrimido[2,1-b]benzothiazole, pyrazole and benzylidene derivatives of curcumin.

Several major developments have occurred in the chemotherapy of schistoso­ miasis since Archer & Yarinsky reviewed the subject in 1972 (1). Perhaps the outstanding discovery has been the broad-spectrum, well-tolerated drug prazi­ quantel, which is rapidly becoming the drug of choice in the treatment of schistosomiasis. Two other new broad-spectrum, clinically effective drugs that have made their appearance in recent years are oltipraz and amoscanate. We have also made some progress in understanding the mode of action of some of the older antischistosomal drugs such as hycanthone, oxamniquine, niridazole, and metrifonate, but little is known about the mechanism of action of the newer drugs. In order to focus attention on this problem, the Steering Committee of the Scientific Working Group on Schistosomiasis sponsored a symposium in Geneva January 30-February 1, 1984 (2) that was devoted exclusively to the biochemistry and chemotherapy of this disease. Wherever possible, this chap­ ter devotes particular attention to the mode of action of clinically active agents and some of their relevant analogues.

The chemotherapy of schistosomiasis.

In mice experimentally infected with Schistosoma mansoni, praziquantel (2-cyclohexylcarbonyl-1,3,4,6,7,11b-hexahydro-2H-pyrazino[2,1-a]isoquinoline-4-one), administered orally at the levels of 100 and 50 mg/kg, for 5 consecutive days, produced oogram changes in all animals and a pronounced hepatic shift of schistosomes (97.1 and 89.1, respectively). At lowest levels (12.5 and 6.3 mg/kg), alterations in the oogram could still be detected, although hepatic shift of schistosomes was no more evident. After a single intramuscular injection, the results obtained paralleled those observed with a single-dose oral treatment. The hepatic shift was only moderate at 200 and 100 mg/kg and the percentages of worms retained in the liver, after perfusion, were particularly low. When nasal route in a 1-day regimen was used, the results obtained were slightly less evident as compared with those observed by oral route (5-day schedule). Considering the percentage of oogram changes, the degree of hepatic shift of schistosomes and the percentage of worms fixed in the liver, the antischistosomal activity of praziquantel was greater in hamsters than in mice. Actually, a daily dose as low as 12.5 mg/kg, administered for 5 consecutive days, was sufficient to shift 60.4% of the worms towards the liver and to produce alterations of the oogram in 60% of the animals. In Cebus monkeys orally treated with 10 and 20 mg/kg of praziquantel, given 3 times within a single day (total doses of 30 and 60 mg/kg, respectively), a remarkable reduction in worm burden was observed. A single oral or intramuscular dose of 100 mg/kg was found to be curative. One Cebus dosed with 100 mg/kg, by nasal spray, was found to harbor only female worms at autopsy performed 69 days after treatment.

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Experimental chemotherapy of schistosomiasis mansoni. XIII. Activity of praziquantel, an isoquinoline-pyrazino derivative, on mice, hamsters and Cebus monkeys.

5-[nitro-thiazolyl-(2)]-2-oxo-tetrahydroimidazole was found to possess schistosomicidal and amoebicidal properties. In mice this substance exhibited a curative effect in experimental infections withS. mansoni andS. japonicum. Preliminary clinical trials indicated that the compound is effective and well tolerated in the treatment of vesical bilharziasis.

C. R. Lambert

Papers

Eine neue gegen Bilharziose und Amoebiase wirksame Verbindung