Mem Inst Oswaldo Cruz, Rio de Janeiro, 94(6) Nov/Dez 1999
Efficacy of a New Schistosomicidal Agent 2-[(methylpropyl)amino]-1-octanethiosulfuric Acid against an Oxamniquine Resistant Schistosoma mansoni Isolate
Departamento de Análises Clínicas, Faculdade de Farmácia e Bioquímica, UFJF, Campus Universitário, 36036-330 Juiz de Fora, MG, Brasil
IDepartamento de Parasitologia, Instituto de Ciências Biológicas, UFMG, Av. Antônio Carlos 6.627, 31270-091u00a0Belo Horizonte, MG, Brasil and Santa Casa de Misericórdia, Belo Horizonte, MG, Brasil
IIDepartamento de Alimentos, Faculdade de Farmácia, UFMG, Belo Hozizonte, MG, Brasil
The schistosomicidal activity of one alky-laminoalkanethiosulfuric acid was studied against a recently described oxamniquine resistant strain of Schistosoma mansoni. This drug exhibited an activity against the resistant strain (R1) similar to that shown against non-resistant, standard LE strain.
PMZ Coelho et al. (1997 Rev Inst Med Trop S Paulo 39: 101-106) have recently described a natural strain of S. mansonipartially resistant to oxamniquine (Mansil, Pfizer) one of the drugs of choice in the treatment of schistosomiasis. When given to infected mice, a 250 mg/kg dose of oxamniquine killed all the worms of the LE strain (standard) known to be susceptible to oxamniquine at this treatment schedule, but some worms of the resistant strain, designed as R1, were recovered from mice treated with the same dose. The resistance was more evident when the dose of 200 mg/kg was used, since the recoveries of male and female worms of the LE strain were 1.1% and 20.6% and for the R1 strain, 18.6% and 61.1%, respectively. The dose of 500 mg/kg of praziquantel (Cestox, Merck), also an important drug for the treatment of schistosomiasis, was equally efficient in mice against both these S. mansoni strains when administered orally (R Gönnert & P Andrews 1977 Ztschr f Parasitenk 52: 129-150).
The schistosomicidal activity of alkylamino-alkanethiosulfuric acids was first described by DL Nelson and J Pellegrino (1976 Rev Inst Med Trop S Paulo 18: 365-370). Since then, the efficacy of newly synthesized compounds of this group has been studied in order to determine their utility as a cheaper, alternative schistosomicidal drug (WY Liu 1981 Síntese de Ácidos N-alquilamino-alcano-tiossulfúricos Potencialmentes Ativos contra Schistosoma mansoni, MSc Thesis, Universidade Federal de Minas Gerais, Belo Horizonte xii+179 pp., MG Cardoso 1988 Síntese de ácidos alquilamino-heptanotiossulfúricos e di-(N-alquilamino) propanotiossulfúricos potencial-mente ativos contra Schistosoma mansoni, MSc Thesis, Universidade Federal de Minas Gerais, Belo Horizonte xiv+126 pp., MLO Penido et al. 1990 J Braz Chem Soc 1: 35-39).
One of these compounds, 2-[(methylpro-pyl)amino]-1-octanethiosulfuric acid, obtained by Penido et al. (1990 loc. cit.) (I,Fig.), has proved to be effective against S. mansoni in mice at a dose range of 600 to 800 mg/kg, with a preferential activity against the female worms, that have been eliminated from infected mice at a level of 90 to 95%, whereas the males were reduced to 50-60% (MLO Penido et al. 1994 Mem Inst oswaldo Cruz 89: 595-602). MLO Penido et al. (1995Parasitology 111: 177-185) also showed that this compound is taken up by the worm and metabolized into a hydrophobic substance identified as the disulphide derivative of the parent compound.
As much as the living standards of the susceptible human populations have improved, chemotherapy is still important for the control of schistosomiasis (N Katz 1998 Mem Inst Oswaldo Cruz 93: 33-35). However, the increased use of the two main schistosomicidal drugs by larger populations could result in the appearance of resistant strains of S. mansoni (FF Stelma et al. 1995 Am J Trop Med Hyg 53: 167-170, PG Fallon et al. 1995 Am J Trop Med Hyg 53: 61-62, Coelho et al.loc. cit.). The discovery of new, effective compounds should be encouraged as alternatives for the control of the disease, specially cheaper, effective compounds which could be used in chemotherapy control programs (S Archer et al. 1990 Mol Biochem Parasitol 43: 89-96, Katz loc. cit.).
The present work was designed to study the efficacy of the new schistosomicidal agent 2-[(methylpropyl)amino]-1-octanothiosulfuric acid (I) against the R1 oxamniquine resistant S. mansoni strain described by Coelho et al. (loc. cit.). In a comparative study of the efficacy of (I), the LE oxamniquine-susceptible strain of S. mansoni which has been maintained in the Schistosomiasis Research Unit, UFMG, Brazil for more than 30 years, and is considered as a standard in drug trial experiments, and the R1 strain, isolated from faecal material obtained from a patient (Coelho et al. loc. cit.) and maintained at the same Schistosomiasis Research Unit, were used. Two groups of 30 albino (defined breed) Swiss mice were infected with LE and R1 cercariae. On day 60 of infection, 15 mice of each group were treated per os with 700 mg/kg of (I) as a suspension in 1% cremophor El (an emulsifying agent used as vehicle - Sigma). The two remaining groups were maintained as controls and were treated only with the vehicle. The mice were sacrificed 30 days after treatment for worm recovery as described by J Pellegrino and AF Siqueira (1956 Rev Bras Malariol 3: 589-597). Data obtained were evaluated using the Kruskal-Wallis non parametric method.
The results of worm burden recovery from each group are shown in the Tables I and II. Table III shows the percentage reductions in the mean number of female, male and total worm burdens for both strains, LE and R1.
The reduction observed in the number of female worms of the LE (93%) and R1 (88%) strains, as compared with their respective control groups was similar to those observed in previous experiments (Penido et al. 1994 loc. cit.). Table IIIshows that the percentage reduction of female worms was the same for both strains. A slightly statistical significant difference (P = 0.05) can be noted between the percentage reductions for males, indicating that compound (I) may be more active against oxamniquine resistant R1 strain (25%) than LE oxamniquine sensitive LE strain (15%). The small reduction in the male worm burdens was an unexpected result as compared to the nearly 50% reductions observed previously.
These results together with previous data (Penido et al. 1994 loc. cit.) emphasize the need to test the alkylaminoalkanethiosulfuric acids in other experimental models, such as monkeys, to evaluate its potential as an alternative clinical schistosomicidal drug. The apparently large dose of (I) will certainly be smaller in heavier animals than with mice, since the rate of liver metabolism in the former is lower, as demonstrated for praziquantel (Gönnert & Andrewsloc. cit.). As pointed out by D Ciolli et al. (1993 Parasitol Today 9: 162_166, 1995 Pharmacol Therap 68: 35-85), the emergence of strains of S. mansoni resistant to conventional drugs stimulates and justifies the search of new alternative compounds. Also, acute and chronic toxicities should be studied to evaluate safety of this compound for human use.