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.

A case of Schistosoma mansoni infection treated during the prepatent period.

BACKGROUND: A 40-year-old female laboratory technician accidentally came into contact with water that contained snails shedding Schistosoma mansoni cercariae while she was maintaining an aquarium. Several minutes after exposure to the contaminated water, she experienced severe itching in the area of exposure, and several papules were observed. INVESTIGATIONS: Taking of medical history to provide evidence of accidental contact with water contaminated with S. mansoni cercariae; physical examination; and stool examinations by the Kato-Katz, formol-ether concentration and sedimentation methods carried out four times weekly, starting 45 days after infection and continuing until 10 weeks after infection. DIAGNOSIS: S. mansoni infection. MANAGEMENT: A single oral dose of 50 mg/kg oxamniquine on the day of the incident.

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.

The efficacy of human schistosomicide treatment may depend on the rate of transmission.

The efficacy of different treatment protocols in humans infected with Schistosoma mansoni at sites with different transmission conditions was evaluated by the disappearance of anti-worm intestine IgM antibodies in an indirect fluorescence antibody test (IgM-IFT) and anti-egg antibodies in the circumoval precipitin test (COPT). Patient sera coming from sites of active low transmission (ALT), active high transmission (AHT) and low interrupted transmission (LIT) from Venezuela were studied. Chemotherapy protocols were (1) ALT, 60 mg/kg praziquantel (Pzq60); (2) AHT, one dose of 40 mg/kg Pzq followed by one dose of 20 mg/kg oxamniquine for one group and one dose of 40 mg/kg Pzq alone for the other group; (3) LIT, one dose of 40 mg/kg Pzq repeated every 3 months up to three doses. Cure rates occurred mostly between 3 and 12 months with the exception of Pzq60-ALT where it was evident before 3 months. Higher cure rates were evident in both places of low transmission (ALT and LIT) and the lowest in the AHT regardless of the treatment protocol. Cure was more evident with COPT compared to IgM-IFT. The rate of serological cure appears then to depend on the previous state of transmission. The differential cure rate evaluated by both techniques is probably due to the persistence of antibodies against antigens in different stages of the parasite.

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.

Detection of IgM antibodies to Schistosoma mansoni gut-associated antigens for the study of the dynamics of schistosomiasis transmission in an endemic area with low worm burden

Dados de prevalencia e incidencia da esquistossomose foram estimados, acompanhando-se um grupo de escolares residentes em area rural do municipio de Itariri (Sao Paulo, Brasil), por um periodo de 2 anos, com cinco inqueritos, um a cada semestre, realizados no primeiro semestre de cada ano entre marco e abril e no segundo, entre setembro e outubro. O hospedeiro intermediario do Schistosoma mansoni na area e a Biomphalaria tenagophila. A infeccao pelo S. mansoni foi determinada pelo metodo parasitologico de Kato-Katz, atraves do exame de tres laminas, e os resultados analisados comparativamente aos da reacao de imunofluorescencia para deteccao de anticorpos IgM (RIF-IgM). Foram encontrados nos cinco inqueritos indices de prevalencia de 8,6 por cento, 6,8 por cento, 9,9 por cento, 5,8 por cento e 17,2 por cento pelo metodo parasitologico...

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.

Schistosomiasis control based on repeated chemotherapy in a rural village of the sugar-cane zone in northeast Brazil.

A schedule of repeated chemotherapy with oxamniquine, consisting of biannual treatment of school-aged (7-13 years) children and annual treatment of all other age groups, was used in a representative rural village from a highly endemic area of schistosomiasis in Pernambuco. Significant reductions in infection were obtained only after two cycles of treatment, as the overall prevalence decreased from 72.6% to 41.7% and the geometric mean egg counts per gram of faeces among positives fell from 188.4 to 76. In a school-aged cohort (n = 29) three treatments at six-month intervals were necessary to significantly reduce the proportion of positives (from 75.9% to 51.7%). In a cohort of children under 7 years of age (n = 20) the proportion of positives actually increased (from 30% to 45%) despite two annual treatments. Water contact was intense and host snail density was relatively high. As there is no short-term perspective of improved sanitation, auxiliary measures such as focal mollusciciding are needed for an adequate control of schistosomiasis in this and alike areas.

Effect of praziquantel and oxamniquine treatment on human isotype responses to Schistosoma mansoni: elevated IgE to adult worm.

Pre- and post-treatment antibody isotype responses to Schistosoma mansoni adult worm and soluble egg antigens were compared in a study population previously used to show that IgE against adult worm correlates negatively with intensity of reinfection following chemotherapeutic cure. IgG subclass responses to adult worm were lower after treatment whereas IgM and IgE were higher. The increase in IgE to adult worm was observed with different preparations of adult worm, including the worm tegument, and with both praziquantel and oxamniquine therapy. No significant difference was observed between pre- and post-treatment isotype responses to egg antigens following either praziquantel or oxamniquine therapy.

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.

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.

Evoluçäo histológica em quatro casos de esquistossomose mansônica cutânea ectópica / Histological evolution in four cases of ectopic cutaneous mansonic schistosomiasis

Apresentaçäo de quatro casos de esquistossomose mansônica cutânea ectópica, observados em Pernambuco, onde a doença é freqüente. Na discussäo, os autores analisam a evoluçäo do quadro histológico, considerando semelhanças e diferenças, bem como reaçöes ao tratamento, comuns aos quatro pacientes

Oxamniquine: a labeling procedure with technetium-99m and a biodistribution study in mice.

Oxamniquine (OXY), a tetrahydroquinoline derivative, is used as an antischistosomal drug and generally has been labeled with carbon-14 and tritium. We decided instead to label it with technetium-99 (99mTc). In order to determine the optimal conditions, different concentrations of this drug were incubated with various stannous chloride solutions. We then added 99mTc, and chromatography was performed using 0.9% NaCl solution, acetone and 1.2N HCl as the mobile phase. Using a solution of 1.0 mg/mL stannous chloride and 0.5 mg/mL oxamniquine, over 94% of the radioactivity bound to oxamniquine (99mTc-OXY). In the biodistribution study, 99mTc-OXY was administered in mice intramuscularly, orally and intravenously. When the intramuscular route was used, the main uptake (after 30 minutes) of the labeled drug was in the kidneys, liver and intestines; after 240 minutes the labeled drug was still found in the liver and kidneys, but at increased levels in the intestines. It was also present in the faeces. When the oral route was employed, labeled OXY was mainly found in the stomach after 30 minutes, but there was a decrease after 240 minutes. During this period radioactivity increased in the intestines. When the intravenous route was employed the labeled OXY was found in the liver and spleen. The radioactivity decreased with time in these organs. Using infected animals, radioactivity was found in isolated worms.

[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.

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.

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

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.

Effect of praziquantel and oxamniquine on prostacyclin synthesis by the rat arterial and myometrial tissues.

1. The influence of the two antischistosomal drugs (+/-) praziquantel and (+/-) oxamniquine on PGI2 synthesis by the male rat thoracic aorta and day-20 pregnant rat myometrium in vitro was investigated using a rat platelet antiaggregatory bioassay method. 2. Pretreatment of the tissues with praziquantel (64-512 microM) or oxamniquine (36-288 microM) for 30 min at 37 degrees C significantly inhibited basal PGI2 synthesis in a concentration-dependent manner (P less than 0.005, n = 5-6). 3. Both drugs failed to inhibit PGI2 synthesis in presence of exogenous arachidonic acid (AA) (16.6 microM). 4. Furthermore, they did not antagonize AA (4 nmol kg-1)-induced hypotension in urethane-anaesthetized rats. Thus, the drugs seemed to act via inhibition of phospholipase A2 enzyme (PLA2). 5. The highly lipophilic drugs may interact with membrane phospholipids resulting in prevention of interaction between the substrates and the enzyme's active site.

Comparison of different chemotherapy strategies against Schistosoma mansoni in Machakos District, Kenya: effects on human infection and morbidity.

A comparison was made of the long-term impact of different methods of administration of chemotherapy (oxamniquine, 30 mg/kg in divided doses; or praziquantel, 40 mg/kg) on prevalence and intensity of Schistosoma mansoni infection in four areas in Kangundo Location, Machakos District, Kenya. In Area A, treatment was offered in October 1983 and again in April 1985 to all infected individuals. In Area H, treatment was offered in April 1985 to individuals excreting greater than or equal to 100 eggs per gram (epg) of faeces. In Area S, treatment was offered in April 1985 to all infected school children, within the framework of the primary schools. In the witness area, Area W, treatment was given in April 1985, for ethical reasons, to a small number of individuals excreting greater than or equal to 800 epg. Prevalence and intensities of infection were subsequently monitored at yearly intervals for three complete post-treatment years. In the Area S schools, clinical examination was also carried out at yearly intervals. Treatment of all infected individuals on two occasions (Area A) was the most effective and long-lasting way of reducing prevalence and intensity of infection. In this area, however, some earlier interventions had been carried out and pre-treatment intensities were lower than in the other areas. Treatment only of infected schoolchildren (Area S) also had a marked and prolonged effect, comparable to or better than treatment of individuals with heavy infections (Area H). Treatment of infected schoolchildren also caused a persistent reduction in the prevalence of hepatomegaly, and there was suggestive evidence from intensities of infection in community stool surveys (but not from incidence rates) of an effect on transmission. In all study areas, reinfection was most rapid and most intense among children. These findings are discussed in the light of theoretical considerations and of results from other studies, both on schistosomiasis and on intestinal helminths. We conclude that, in areas of low morbidity such as Kangundo, chemotherapy of schoolchildren only, at intervals of up to 3 years, is a satisfactory way of producing a long-term reduction in both intensity of infection and morbidity.