Effect of praziquantel on the immature stages of Schistosoma haematobium

Schistosoma mansoni is known to be refractory to praziquantel treatment in the pre-patent period of infection. Since Schistosoma haematobium has a much longer pre-patent period (10-12 weeks vs. 5-6 for the former species), we asked the question whether a correspondingly longer period of insusceptibility exists in urinary schistosomiasis. In hamsters treated at different times after infection, S. haematobium was partially refractory to praziquantel when treatment was given at week 5, but showed practically full sensitivity at 7-8 weeks and later times. Schistosoma haematobium worms obtained at different times after infection and exposed in vitro to praziquantel were refractory to low drug concentrations between 4 and 6 weeks, but were clearly affected at higher concentrations and at later time points. We conclude that S. haematobium does not have a praziquantel-insensitive window longer than in S. manson, in spite of its much longer maturation period. In addition, refractoriness of immature stages can be overcome at higher drug concentrations.     

Therapeutic failure of praziquantel in the treatment of Schistosoma haematobium infection in Brazilians returning from Africa

Several cases of therapeutic failure of praziquantel used for the treatment of urinary schistosomiasis have been reported. Alternative drugs, like niridazol and metrifonate, have shown a lower therapeutic effect and more side effects than praziquantel. Twenty-six Brazilian military men (median age of 29 years) with a positive urine parasitological exam who were part of a United Nation peace mission in Mozambique in 1994 were treated with 40 mg/kg body weight praziquantel, single dose. They swam in Licungo river (Mocuba city, Mozambique) during the weekends. After this, they presented haematuria, dysuria, polakiuria, and lumbar pain. Control cystoscopy examinations carried out between 6 and 24 months after each treatment (including two additional treatments at a minimum interval of 6 months) revealed the presence of viable eggs. Granulomas in the vesical submucosa were observed in 46.2% (12/26) of the individuals. A vesical biopsy confirmed the presence of granulomas in all of these patients and the presence of viable eggs in 34.3% (9/26) of individuals who no longer excreted eggs in urine. The eggs filled with miracidia showed characteristics of viability. Histopathological examination using different strains demonstrated therapeutic failure and the need for repeated treatment. In this study, we demonstrated a low efficacy of praziquantel in the treatment of schistosomiasis haematobia, and the necessity of the urinary bladder biopsy as criterion of cure.     

Schistosoma haematobium treatment in 1-5 year old children: safety and efficacy of the antihelminthic drug praziquantel

Background

Morbidity due to schistosomiasis is currently controlled by treatment of schistosome infected people with the antihelminthic drug praziquantel (PZQ). Children aged up to 5 years are currently excluded from schistosome control programmes largely due to the lack of PZQ safety data in this age group. This study investigated the safety and efficacy of PZQ treatment in such children.

Methods

Zimbabwean children aged 1–5 years (n = 104) were treated with PZQ tablets and side effects were assessed by questionnaire administered to their caregivers within 24 hours of taking PZQ. Treatment efficacy was determined 6 weeks after PZQ administration through schistosome egg counts in urine. The change in infection levels in the children 1–5 years old (n = 100) was compared to that in 6–10 year old children (n = 435).

Principal Findings

Pre-treatment S. haematobium infection intensity in 1–5 year olds was 14.6 eggs/10 ml urine and prevalence was 21%. Of the 104 children, 3.8% reported side effects within 24 hours of taking PZQ treatment. These were stomach ache, loss of appetite, lethargy and inflammation of the face and body. PZQ treatment significantly reduced schistosome infection levels in 1–5 year olds with an egg reduction rate (ERR) of 99% and cure rate (CR) of 92%. This was comparable to the efficacy of praziquantel in 6–10 year olds where ERR was 96% and CR was 67%.

Interpretation/Significance

PZQ treatment is as safe and efficacious in children aged 1–5 years as it is in older children aged 6–10 years in whom PZQ is the drug of choice for control of schistosome infections.     

Susceptibility of Iraqi fresh water snails to infection with Schistosoma haematobium and Schistosoma mansoni Egyptian strains

A great number of Egyptian workers and farmers are seeking settlement in Iraq and some of them proved to have either Schistosoma Haematobium (S.h.) or Schistosoma mansoni (S.m) or even mixed infection. Besides, there is the possibility that some of the Iraqi fresh water snails may prove to be susceptible to infection by one or both of the Schistosoma Egyptian strains. The present study deals with investigations on the susceptibility of Iraqi B. truncatus, Gyranaulus ehrenbergi, Physa c.f. fontinalis, Lymnea lagetis, Melanoides tuberculata and Melanopsis nodes by these parasites. Egyptian S. haematobium but not Egyptian S. mansoni infect Iraqi B. truncatus and both proved to be unable to infect any of the other snails included in the study. Yet, the number of cercariae shedded by B. truncatus snails infected with the Egyptian S. haematobium strain, was much less that the number of cercariae shedded by these snails when infected with the Iraqi S. Haematobium strain.     

The effect of treatment on the age-antibody relationship in children infected with Schistosoma mansoni and Schistosoma haematobium

The effect of praziquantel treatment on the age-antibody relationship was studied in 174 children aged between 6 and 17 years from a schistosome endemic area in Zimbabwe. The children were co-infected with Schistosoma mansoni and S. haematobium with infection prevalences of 74% and 53% respectively. Antibody levels for the isotypes IgA, IgE, IgM, IgG1, IgG2, IgG3 and IgG4, directed against soluble egg antigen were measured using an indirect ELISA assay. Treatment resulted in a significant increase in levels of IgG2 and IgG3 while levels of IgA decreased significantly. In untreated children there were significant decreases in levels of IgG4. Treatment also resulted in significant alteration in the age-antibody profiles for the isotypes IgE, IgM, IgG1 and IgG2 in treated children but not in untreated children. The results are discussed in the context of factors believed to give rise to the age-antibody relationship; i.e. age-related exposure patterns, age-related development of acquired immunity, age-related hormonal changes and age-related changes in innate susceptibility to infection.     

Altered response of strain of Schistosoma mansoni to oxamniquine and praziquantel

The susceptibility of a fourth generation Ouh strain (Paranapanema Valley, S?o Paulo, Brazil) of Schistosoma mansoni to oxamniquine (OXA) and praziquantel (PZQ) was studied. Ten groups of 13 female albino mice each were infected with 70 cercariae per animal. These mice were medicated orally on the 50th day after infection. Five groups were given OXA doses of 0, 100, 200, 300 and 400 mg/kg (single doses) and the rest were treated with PZQ doses of 0, 100, 200, and 250 mg/kg/5 days. Each group was sub-divided: 8 animals underwent perfusion after 15 days treatment, 5 mice followed up for oviposition and their feces were tested every 15 days for miracidia hatching. The efficacy of the OXA doses of 100 and 200 mg/kg was 66% and 91.4%, respectively and for the 100 mg/kg PZQ dose it was 90.1%. The follow-up groups with 100 and 200 mg/kg of OXA and PZQ, 100 and 150 mg/kg, showed that they re-established the oviposition after a period of 60 to 75 days of treatment. The ED50 was 69.6 mg/kg OXA and 39.4 mg/kg PZQ. The results show the tolerance of the Ouh strain to a dose of 100 mg with both drugs and they appoint the need for a dose review during the follow up of the oviposition and in monitoring phenomena in the field.     

The prepatent period and cercarial production of Schistosoma haematobium in Bulinus truncatus (Egyptian field strains) at different constant temperatures

The developmental time of Schistosoma haematobium in Bulinus truncatus snails (field strains) was determined in the laboratory at different constant temperatures between 18 and 32 degrees C. The basic relationship between the length of the minimum prepatent period (y, in days) and the temperature (x, in degree C) is given by the hyperbolic formula y = 295/(x-15.3), 15.3 being the theoretical "developmental null point" and 295 the constant time-temperature product. The shortest prepatency was 17-19 days at 30, 31 and 32 degrees C; at 18 degrees C, cercarial development required at least 106-113 days. The maturation time frequently exceeded the possible minimum by several weeks. No schistosome matured in our experiments at 17 degrees or 33 degrees C. The cercarial release per snail at weekly exposures showed a maximum at 25 degrees C with a geometric mean of 109 cercariae (95% confidence limits 79-149), decreasing to 8 (2-30) at 18 degrees C and 62 (38-100) at 32 degrees C. The absolute maximum of cercariae shed by one snail during 5 h "stimulation" was 2,150 in a 25 degrees C batch, 48 at 18 degrees C and 529 at 32 degrees C. The epidemiological application, the prognosis of the transmission period and the estimation of the transmission potential in relation to climatic conditions are discussed.     

The effect of praziquantel on Schistosoma mansoni.

3 x 10(-6)M praziquantel fails to completely paralyse miracidia and cercariae in a short time but they are not infective when maintained in the solution. 3 x 10(-5)M praziquantel prevents infected snails shedding cercariae but does not kill daughter sporocyts or developing cercariae. As the action of praziquantel on adult worms is not blocked by 10(-2)M mecamylamine, pempidine or carbachol, but is reduced by calcium depletion, it is suggested that praziquantel may act by permitting calcium influx to muscle cells causing them to contract.     

The effect of praziquantel on the ultrastructure of Schistosoma margrebowiei

The effect of various concentrations of praziquantel at different time intervals post-treatment on the ultrastructure of Schistosoma margrebowiei using scanning and transmission electron microscopy has been examined. The major changes involved blebbing of the entire surface tegument of both sexes (although more marked in males) together with vacuolation of the basal membrane accompanied by the development of membraneous whorls. These effects were progressively more marked with increased concentration and time of exposure resulting in severe erosion of the tubercles and collapse of the sensory organelles. Exposure of the underlying tegumental tissue resulted and paralysis and contraction of the suckers and neck region was apparent. Disruption of the subtegumental musculature and the appearance of vacuolation and membraneous whorl formation were seen. The gastrodermis was similarly affected and the S4 cells of the vitelline gland showed protein disruption of the vitelline droplets. Host cells were seen adhering to the surface of the worms following drug treatment and the synergism between PZQ and the action of the hosts immune system has been discussed.     

Schistosoma haematobium: the pathology of experimental infection

The pathologic changes in experimental animals infected with Schistosoma haematobium are reviewed and compared to the pathology in infected humans. The clinically important lesions in persons infected with S. haematobium are generally confined to the urogenital system. In experimental animals, functionally important lesions of the urogenital system are the exception but do occur in a significant proportion of infected primates. The acute lesions of the urinary tract in primates are similar to those in infected persons. Chronic lesions characterized by the extensive submucosal accumulation of calcified eggs are common in infected humans but uncommon in S. haematobium-infected animals.     

Effects of praziquantel and oxamniquine on a Saudi Arabian strain of Schistosoma mansoni in mice

The prophylactic and curative effects of praziquantel and oxamniquine on a Saudi Arabian strain of Schistosoma mansoni in MF-1 mice were assessed. The drugs were administered orally. At 240 mg/kg praziquantel, there was a reduction of 89.1% in adult worm recovery and a marked reduction in tissue deposited eggs. The reduction in adult worm recovery after dosing with 50 mg/kg oxamniquine was 89.2%. At low doses (40 mg/kg praziquantel and 30 mg/kg oxamniquine) administered at 11 days, 5 days and 3 h before and 5, 21 and 49 days after infection, the reduction in adult worm recovery was 0.0%, 65.1%, 58.8%, 33.6%, 0.0% and 76.0% for praziquantel and 0.0%, 66.0%, 60.0%, 41.3%, 10.8% and 79.0% for oxamniquine. Numbers of lung schistosomula and the size of hepatic granulomata were also reduced.     

Schistosoma haematobium: oxidoreductase histochemistry and ultrastructure of niridazole-treated females

Administration of niridazole to Saccostomus campestris produced changes in enzyme activity in Schislosoma haematobium females as indicated histochemically by a decrease in the activity of cytochrome oxidase (EC 1.9.3.1), malate (NAD) dehydrogenase (EC 1.1.1.37), malate (NADP) dehydrogenase (EC 1.1.1.40), succinate dehydrogenase (EC 1.3.99.11), isocitrate (NAD) dehydrogenase (EC 1.1.1.41), isocitrate (NADP) dehydrogenase (EC 1.1.1.42), lactate dehydrogenase (EC 1.1.1.27), glucose-6-phosphate dehydrogenase (EC 1.1.1.49), NADH: tetrazolium oxidoreductase, NADPH: tetrazolium oxidoreductase, and a disappearance of both the activity of phenolase (EC 1.10.3.1) and the reactivity of vitelline phenols. These changes were associated with the following alterations in the ultrastructure of the parasites: a decrease in number of immature vitelline cells of gonial type, a disruption of the tegument surface, a swelling of mitochondria in vitelline cells, a disappearance of the regular structure of the endoplasmic reticulum and a vaeuolization of the cytoplasm in vitelline cells, an appearance of areas of focal cytoplasmic degradation in vitelline cells, and a disruption of shell globules. The degree of changes in enzyme activity and ultrastructure increased both with increase in the dose of niridazole administered to the hosts, and with length of time after treatment.Preincubation of control sectioned material in a buffered niridazole-sucrose solution produced total inhibition of succinate dehydrogenase activity, whereas the activity of other enzymes examined remained unchanged.     

Schistosoma mekongi: the in vitro effect of praziquantel and artesunate on the adult fluke

The efficacy and tolerance of 80 microg/ml praziquantel (PZQ) and 40 microg/ml artesunate (ATS) against adult stage Schistosoma mekongi in vitro were investigated after 3, 6, 12, and 24h incubation by monitoring worm motility and compared tegumental changes using scanning electron microscopy (SEM). Thirty mice were infected with S. mekongi cercaria for 49 days. Adult worms were collected by perfusion method and prepared for in vitro study. Contraction and decreased motor activity were observed after as little as 3h incubation with PZQ and ATS. Some of the worms were immobile 12h after exposure, and died within 24h. The tegument of S. mekongi showed severe swelling, vacuolization and disruption, fusion of the tegumental ridges, collapse and peeling. After 12-24h incubation, PZQ induced similar but they less severe, tegumental changes to those observed after exposure to ATS. The direct observation of the fluke motility and SEM study suggest that ATS is more effective than PZQ in causing tegumental damage in adult S. mekongi, and provides a basis for subsequent clinical trials.     

Schistosoma mansoni: dose-related tegumental surface changes after in vivo treatment with praziquantel

The in vivo effects of a range of concentrations of praziquantel (10, 25, 50, 100, 200 and 500 mg/kg body weight of mouse) on the tegumental surface of adult Schistosoma mansoni were studied using scanning electron microscopy. Worms were recovered from mice at 1 and 4 h post-treatment. In general, irrespective of the dose level, male worms exhibited more pronounced and extensive surface alterations which included surface bleeding, swellings, wrinkling and constrictions and surface lesions, particularly on the spined tubercles. In male worms, in particular, the number of worms exhibiting damage and the amount of tegumental surface damage depended, mainly, on the concentration of praziquantel, although, at any given dose level, the extent of the damage increased with time post-treatment.