Association of oxamniquine praziquantel and clonazepam in experimental Schistosomiasis mansoni.

The antischistosomal activity of clonazepam, when administered alone or in association with oxamniquine and praziquantel, was experimentally evaluated in mice infected with Schistosoma mansoni. The animals were treated 45 days post-infection with a single dose, by oral route, according to three treatment schedules: clonazepam 25 mg/kg and sacrificed 15 min, 1h or 4 h after treatment; clonazepam 1.0, 2.5 or 10.0 mg/kg and sacrificed 15 days post-treatment or with the dose of 10 mg/kg in association with oxamniquine 50 mg/kg or praziquantel 200 mg/kg, single dose, orally, every schedule with a control group. The efficacy of the drugs in vivo was assessed by means of worm counts and their distribution in mesentery and liver, mortality and oogram changes. In the chemotherapeutic schedules used, clonazepam did not present antischistosomal activity and the result of the association of this drug with oxamniquine or praziquantel was not significantly different from the one obtained when these two last drugs were administered alone. In the in vitro experiments, the worms exposed to 0.6 mg/mL clonazepam remained motionless throughout the 8-day-period of observation, without egg-laying, whereas the worms of the control group showed normal movements, egg-laying and hatching of miracidia on the last day of observation. The results obtained in the present study confirm the action of clonazepam on S. mansoni adult worm, in vitro, causing total paralysis of males and females. However, no additive or synergistic effects were observed when clonazepam were used in association with oxamniquine or praziquantel.

Field trials with oxamniquine in a Schistosomiasis mansoni-endemic area.

In Peri-Peri (Minas Gerais), an area endemic for Schistosoma mansoni, 591 inhabitants were examined. A coprological survey showed a prevalence of infection of 43.7%. After clinical examination 220 patients were distributed into three groups for treatment with oxamniquine; in Group 1, 19 children (2 to 15 years) were treated with a single oral dose of drug suspension around 20 mg/kg body weight; in Group 2, 47 children were treated orally with two 10 mg/kg doses with a 6- to 8-hour interval between them; in Group 3, 154 adults were treated with a single dose of about 15 mg/kg (capsules). The most frequent side effects were dizziness, drowsiness, and headache. No statistical difference in frequency of side effects was observed between Groups 1 and 2. Nevertheless, after treatment 32% of the patients in Group 1 complained of dizziness and 13% of headache, whereas in Group 2 the frequencies of these symptoms were 2% and 0%, respectively. Adults (Group 3) had a higher frequency of side effects, their chief complaints being dizziness and drowsiness. In Groups 1, 2, and 3, respectively, 73.7%, 62.2%, and 82.4% of the patients were cured. Statistical analysis did not show any difference in cure rates between children in Groups 1 and 2; however a significance was found when compared with the cure rate observed in adults, showing the drug to be more active in the latter group. In 61.8% of the 40 patients not cured a decrease of over 90% in the number of S. mansoni eggs/g feces was observed. From the data above oxamniquine seems to be an effective schistosomicidal drug suitable for use in endemic areas, although further studies are still needed.

Efficacy of alternating therapy with oxamniquine and praziquantel to treat Schistosoma mansoni in children following failure of first treatment.

Two hundred children infected with Schistosoma mansoni were treated with either 20 mg/kg oxamniquine or 60 mg/kg praziquantel. Cure rates (about 85%) were similar as was the percentage reduction (80%) in egg counts in uncured children. Treatment with the alternative drug of children not cured with the first treatment resulted in negative stools in 11 of 12 cases examined one month after the second round of therapy. In order to minimize the risk of the development of drug resistance, our data suggest that infected patients be treated with one drug, and therapeutic failures with another. Evidence from experiments in mice with isolates obtained after failures of one treatment in children suggests that therapeutic failure does not necessarily indicate the presence of drug-resistant schistosomes. The value of using mice to assess drug resistance in schistosomes is questioned.

Effect of combined low dose praziquantel and oxamniquine on different stages of schistosome maturity.

Combined low doses of praziquantel and oxamniquine were tested against different stages of Schistosoma mansoni in infected Swiss albino mice. The effect of combination therapy (1/3 the curative dose of praziquantel plus 1/3 the curative dose of oxamniquine) was compared with the effect of each drug alone, in reduced or full dose. Comparison with infected untreated controls was also made. Drug effects were evaluated on different growth stages of schistosomes by administering the drugs 24 h before infection and 4 h, 1, 2, 3, 4 and 5 weeks after infection. Animals were killed 8 weeks after infection. Worm burden, distribution, tissue egg load and oogram pattern were used in assessing drug efficacy. A potentiating effect was observed in animals receiving combination therapy. The combination regimen was most effective 4 h after infection, producing 96% worm reduction; eggs were not detected in the liver or intestine. Five weeks after infection the same regimen resulted in 98% reduction in the tissue egg load.

Tolerance of Kenyan Schistosoma mansoni to oxamniquine.

Although 30 mg/kg oxamniquine produced high levels (85.5 to 99.5%) of egg reduction in Kenyan children infected with Schistosoma mansoni after a single oral treatment, cure rates from children at Mwea in Kirinyaga district were lower than those from Machakos (58% v. 74%). Redosing uncured children confirmed this lower cure rate (36% v. 83%). Isolates from infected children were passaged into mice and dosed with oxamniquine. Lower than expected reductions in worm numbers were obtained, suggesting that oxaminiquine tolerant S. mansoni are present in the normal worm population in Kenya. It is concluded that mass use of oxamniquine at 30 mg/kg may produce problems of drug resistance.

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.

Effects of certain antibilharzial and contraceptive drugs on liver functions in rats.

Effects of single and combined administration of contraceptive drug (microvlar-30) and anti-urinary bilharzial drug (metriphonate) as well as anti-intestinal bilharzial drug (oxamniquine) on the liver functions of female albino rats were studied. Metriphonate increased serum globulin content and caused no change in the hepatic cells. Oxamniquine significantly increased the activities of serum transaminases and alkaline phosphatase and caused necrosis in some liver cells. Microvlar-30 exhibited no change on the serum enzymes, while marked increase was found in serum triglyceride and protein levels. The combined administration of metriphonate or oxamniquine with microvlar-30 prevented the increase in the levels of serum triglycerides and proteins. Histopathological examination confirmed the results obtained by chemical analysis.

ELISA detection of specific circulating antibodies against Schistosoma mansoni in mice after treatment with oxamniquine.

1. Mice infected with 80 cercariae of Schistosoma mansoni were treated with a single oral dose of oxamniquine (400 mg/kg) 65 days after infection. 2. Groups of 8-12 animals were sacrificed approximately 2 weeks after treatment and then at monthly intervals. The sera obtained were evaluated for S. mansoni antibodies by enzyme-linked immunosorbent assay (ELISA) at 1:200 dilution. 3. Worms could not be recovered on days 14, 28, 58, 90, 119, 154 and 180 after treatment, indicating the efficacy of the chemotherapy. 4. When performed with different antigens obtained from several stages in the life cycle of S. mansoni, i.e., soluble egg antigen, adult worm tegument, cercaria antigen, schistosomule tegument and adult worm (10 micrograms antigen/ml), the ELISA showed a decrease in specific antibody levels as a function of time after treatment starting on day 58, reaching levels close to control (noninfected untreated) in most animals 120 days after treatment. 5. Purified antigens from the adult worm and the schistosomule tegument appear to be promising for use in clinical studies evaluating schistosomiasis after drug treatment.

[Cardiac arrhythmia with oral oxamniquine use in the schistosomiasis mansoni treatment]. / Arritmia cardíaca com uso de oxamniquine oral no tratamento de esquistossomose mansônica.

The authors report a case of a patient with schistosomiasis (S. mansoni) treated with one single dose (15 mg/kg/BWT) of oral oxamniquine who presented Mobitz type I second-degree AV block and sinus arrest with ventricular escape as a side-effect. They conclude that in spite of the safety and good activity of oxamniquine it may be a determinant of cardiotoxicity.

Evaluation of the schistosomicidal efficacy of liposome-entrapped oxamniquine.

Oxamniquine (OXA) was successfully encapsulated in small unilamellar vesicles using a pH gradient method. This procedure led to a high drug encapsulation efficiency (> 85%) at a drug to lipid molar ratio of 1/10. Moreover, these liposomes were found to retain encapsulated OXA efficiently under dialysis conditions at 37 degrees C. Liposome-entrapped OXA (LOXA), OXA, and empty liposomes were tested against Schistosoma mansoni in a murine model. LOXA produced a significant reduction of the worm burden compared to the other preparations, when inoculated by subcutaneous route (s.c.) with 10 mg OXA/kg animal one day before the infection, and 3, 7, and 14 days after. However, LOXA was not effective when given 7 days before, or 35 days after infections. OXA, in the free form, was effective in relation to the untreated group, only when administered 3 days after the infection. Maximum effect of LOXA, with 97% reduction of the parasite number, was observed when the preparation was given s.c. one day before the infection. On the other hand, LOXA inoculated intraperitoneally one day before the infection didn't show any reduction of the parasite count. It can be concluded that LOXA is more effective than OXA for the treatment of experimental schistosomiasis, particularly when administered subcutaneously at a time close to the infection.

Acute schistosomiasis: clinical, diagnostic and therapeutic features.

Three distinct syndromes caused by schistosomiasis have been described: cercarial dermatitis or swimmer's itch, acute schistosomiasis or Katayama fever, and chronic schistosomiasis. Complications of acute schistosomiasis have also been reported. The absence of a serological marker for the acute stage has hindered early diagnosis and treatment. Recently, an ELISA test using KLH (keyhole limpet haemocyanin) as antigen, has proved useful in differentiating acute from chronic schistosomiasis mansoni. Clinical and experimental evidence indicate that steroids act synergistically with schistosomicides in the treatment of Katayama syndrome. In this paper, clinical, diagnostic and therapeutic features of acute schistosomiasis are updated.

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.

Stool examination and rectal biopsy in the diagnosis and evaluation of therapy of schistosomiasis mansoni.

From each of a group of 217 adult males selected through enzyme-immunoassay or skin-test (Group A), six stool samples were examined by both the Lutz/Hoffman, Pons & Janer (Lutz/HPJ) and Kato/Katz methods. In addition, one oogram of the rectal mucosa was performed. By these methods, schistosomiasis was detected in 44.7%, 47.5% and 40.1% of the individuals respectively. To evaluate the methods in the assessment of cure, the last 40 patients from group A, treated with a single oral dose of oxamniquine at 15 mg/kg were followed up for six months (Group B). The criteria for parasitological cure included three stool examinations by Kato/Katz and Lutz/HPJ methods, one, three and six months post-treatment and a rectal biopsy between the fourth and sixth months post-treatment. The examinations were negative in 87.5%, 90% and 95% of the patients, respectively. The efficacy of oxamniquine was 82.5% when the three methods were considered together and there was no statistically significant difference between the sensitivity of the individual methods.

Schistosoma mansoni: acquired immunity in mice after the use of oxamniquine at the evolutive skin and pulmonary phases.

Mice infected with 350 cercariae of Schistosoma mansoni (LE strain) were treated with oxamniquine, at the dose of 400 mg/kg, 24, 48, 72, and 96 h after infection. Forty days after the treatment, the animals were submitted to a challenge infection with 80 cercariae, through the abdominal and ear skins. The number of immature worms in the animal groups treated 24 and 96 h after the first infection was found to be lower than that in the control group, thus showing that the death of schistosomes by chemotherapy, at the skin and pulmonary phases, causes an acquired resistance state.

Oxamniquine pharmacokinetics in healthy Kenyan African volunteers.

Oxamniquine pharmacokinetics were studied following oral administration of 750, 1000 mg or 1250 mg (equivalent to approximately 15 mg/kg) to five healthy Kenyan African volunteers. Peak plasma concentrations ranging between 1 and 4.3 mg/1 were achieved 1 to 4 h after dosing. The estimated mean elimination half-life (t1/2) was 2.2 h. Despite the limited number of subjects in the study, it is concluded that the pharmacokinetics of oxamniquine in healthy Kenyan Africans do not markedly differ from those in Africans from other regions of the continent where previous studies have been reported.

Efficacy of oxamniquine and praziquantel in school children from two Schistosoma mansoni endemic areas.

OBJECTIVE: To determine the relative susceptibility of Schistosoma mansoni infections to treatment with the oxamniquine (OXA) and praziquantel (PZQ). DESIGN AND SETTING: Three separate cross sectional studies were performed in six primary schools located in two Schistosoma mansoni endemic areas in Eastern Kenya: Kangundo (low morbidity) and Kibwezi (high morbidity). SUBJECTS: One thousand two hundred and fourteen infected children aged 6-20 years were involved. INTERVENTION: Each child received either 15-mg OXA/kg body weight twice within an interval of six hours or a single dose of 40 or 60 mg PZQ/kg body weight. Three duplicate Kato stool examinations were done before and four or five weeks after treatment to assess treatment efficacy. RESULTS: The cure rates in different schools with OXA were 71.7-79.7% in Kangundo and 56.7-61.9% in Kibwezi. In children treated with PZQ, the 40-mg/kg-dose regimen achieved cure rates of 77.6-87.2% in Kangundo and 67.1-81.1% in Kibwezi, whereas the 60-mg/kg dose regimen attained cure rates of 93.2% in Kangundo and 76.3% in Kibwezi. Both OXA and PZQ efficacy declined significantly with age in Kangundo, whereas the age effect was not seen in Kibwezi. CONCLUSION: The poorer cure rates in Kibwezi than in the Kangundo children were not due to known previous drug exposure to either OXA or PZQ. The varying efficacy may be attributed to innate low drug susceptibility, possibly related to schistosome strain differences between the two areas.