O6-methylguanine and O6-methylguanine-DNA [corrected] methyltransferase activity in tissues of BDF-1 mice treated with antiparasitic drugs.

Levels of the DNA promutagenic methylation damage, O6-methylguanine (O6-MeG) and the activity of the O6-methylguanine-DNA methyltransferase (MGMT), the enzyme responsible for repairing O6-MeG, were measured at various time intervals in tissues of BDF-I mice administered a single therapeutic dose of the antischistosomal agents hycanthone, oxaminiquine and metrifonate. Hycanthone increased O6-MeG in the liver-DNA after 6 h, then decreased by 3-fold after 48 h. Lower levels of the adduct and a slower rate of formation were found in the intestine and bladder. MGMT activities were significantly lower in the liver (74%) and bladder (25%) compared to control animals after 6 h, then restored by 48 h. Oxaminiquine increased O6-MeG in all tissues, but spleen, after 6 h and persisted only in the bladder after 48 h. Liver and bladder tissues of these animals exhibited a pattern of alteration in the MGMT activity similar to that observed for hycanthone. Metrifonate induced a profile of O6-MeG comparable to that of oxaminiquine but the levels of the adduct were about 2-fold lower. Hepatic MGMT in these animals was significantly lower (approximately 38%) than the control values after 6 h, then restored by 48 h. A significant negative correlation was obtained between O6-MeG and MGMT activity in the liver (r=- 0.85), intestine (r=- 0.62) and bladder (r=- 0.59). These results demonstrate that treatment with antischistosomal agents may lead to the formation of promutagenic alkylation damage in the tissue DNA and alterations in the DNA repair capacity.

Effect of schistosomal infection and its treatment on some key enzymes of glucose metabolism in mice livers.

Three antischistosomal drugs, praziquantel (CAS 55268-74-1, EMBAY 8440, Prz), oxamniquine (CAS 21738-42-1, Oxa) and oltipraz (CAS 64224-21-1, Olt) were examined for their ability to reverse the disturbances in carbohydrate metabolism induced by Schistosoma mansoni (S. mansoni) infection. The infected mice were screened every 2 weeks for 16 weeks for their body and liver weights in addition to assessment of the activities of liver pyruvate kinase (PK), phosphofructokinase (PFK) (glycolysis), citrate synthase (CS) (Krebs' cycle) glycogen phosphorylase (GP) (glycogenolysis), glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) (hexose monophosphate shunt). Results of the study showed that infection with S. mansoni caused the following changes in mice livers: 1. significant increase in liver weights from the 6th week of infection, which coincided with schistosomal egg deposition, whereas body weights were reduced, 2. remarkable increase in the activities of PK and PFK from the 4th week of infection, 3. marked reduction in CS, GP, G6PDH and 6PGDH. These results lead to the conclusion that glycolysis is largely stimulated in the livers of infected mice on the expense of other metabolic pathways of glucose utilization. Administration of Prz to infected mice caused normalization of all measured enzyme activities almost from the 2nd week of infection, whereas liver and body weights were improved from the 10th week. Oxa was less effective in these regards while Olt was the least. These data support the selection of Prz as a drug of choice for S. mansoni infection.

Lethal effect of oxamniquine and praziquantel on mice experimentally infected with Schistosoma mansoni

Pesquisou-se a letalidade causada por administracao de drogas (oxamniquina e praziquantel) em camundongos infectados por Schistosoma mansoni e seus respectivos controles nao infectados. Os resultados indicam que os animais infectados apresentam claramente taxas de mortalidade mais altas, quando foi utilizado o praziquantel...

Lethal effect of oxamniquine and praziquantel on mice experimentally infected with Schistosoma mansoni.

Lethality caused by administration of oxamniquine and praziquantel to mice infected with Schistosoma mansoni, and their respective controls (uninfected), has been studied. As the results indicate, the infected animals clearly showed higher mortality rates when praziquantel was used. Surprisingly, it may be noted that exactly the contrary occurs in relation to the use of oxamniquine, inasmuch as marked higher mortality rates were seen in the control animals (uninfected). These observations lead to the conclusion that further toxicological studies of antischistosomal drugs using. S. mansoni infected animals are needed.

Preliminary investigations of some derivatives of oxamniquine.

Oxamniquine is a potent schistosomicide used clinically in the treatment of infections due to Schistosoma mansoni. Although relatively well tolerated, some central nervous system (CNS) effects characterised by convulsions have been reported in a small proportion of the population receiving this drug. Oxamniquine, the major metabolite and the secondary alcohol have been screened for convulsant activity by assessing their ability to potentiate catechol induced seizures in urethane anaesthetised mice. Significant (p < 0.05) potentiation was observed with subconvulsive doses (1.5 mg/kg) of strychnine. In contrast, oxamniquine and the secondary alcohol, each at 200 mg/kg ip, both produced significant (p < 0.05) depressions of seizures in this model whereas no effect was seen following 140 mg/kg ip of the acid derivative. These results indicate anticonvulsant rather than convulsant activity in oxamniquine and the alcohol derivative. The failure to observe any effect with the acid derivative may have been due to poorer CNS penetration.

The acute toxicity of oxamniquine in rats; a sex-dependent hepatotoxicity.

Toxicity studies with oxamniquine in several laboratory animal species revealed an idiosyncratic sensitivity of rats, females being much more sensitive than males. After single p.o. doses of oxamniquine, rats died up to 14 days after the dose from hepatic failure. At doses near the LD-50, serum transaminases were high and proteins low from 24 h after the dose in females and from 48 h in males; serum and liver triglycerides showed no clear changes. Histologically the livers were characterised by cytoplasmic inclusion bodies, parenchymal necrosis, and bile duct proliferation. Metabolism and pharmacokinetic data were inadequate to explain the sex-dependency of this toxicity, but tissue distribution studies with carbon-14 labelled oxamniquine showed that 72 h after a given dose livers of female rats retained more label than males, and that little of this was due to unchanged drug.