Concentrations Of Praziquantel Research Articles

Rifampin markedly decreases plasma concentrations of praziquantel in healthy volunteers

Praziquantel is extensively metabolized by the hepatic cytochrome P450 (CYP) enzymes. The CYP3A isoforms are likely to be major enzymes responsible for praziquantel metabolism. Rifampin (INN, rifampicin), a potent enzyme inducer of CYP-mediated metabolism (especially CYP2C9, CYP2C19, and CYP3A4), is known to markedly decrease plasma concentrations and effects of a number coadministered drugs. The aim of this investigation was to study the possible pharmacokinetic interaction between rifampin and praziquantel. An open, randomized, 2-phase crossover design was used in each study of single or multiple doses. In the single-dose study, 10 healthy Thai male volunteers ingested single doses of 40 mg/kg praziquantel alone (phase 1) or after pretreatment with 600 mg of oral rifampin once daily for 5 days (phase 2). In the multiple-dose study, all participants received multiple doses of 25 mg/kg praziquantel alone (phase 1) or after 5-day pretreatment with 600 mg of oral rifampin once daily (phase 2). Plasma concentrations of praziquantel in each phase were determined by the HPLC method. In the single-dose study, rifampin decreased plasma praziquantel concentrations to undetectable levels in 7 of 10 subjects, whereas praziquantel concentrations were reduced by rifampin to undetectable levels in 5 of 10 subjects in the multiple-dose study. In 3 subjects with measurable concentrations in the single-dose study, rifampin significantly decreased the mean maximum plasma concentration (C(max)) and area under the plasma concentration-time curve from 0 to 24 hours [AUC(0-24)] of praziquantel by 81% (P <.05) and 85% (P <.01), respectively, whereas rifampin significantly decreased the mean C(max) and AUC(0-24) of praziquantel by 74% (P <.05) and 80% (P <.01), respectively, in 5 subjects with measurable concentrations in the multiple-dose study. The mean C(max) and AUC(0-24) of praziquantel in subjects whose praziquantel concentrations could not be detected in the single-dose study (7 subjects) after rifampin pretreatment were reduced by approximately 99% (P <.001) and 94% (P <.001), respectively, and in the multiple-dose study (5 subjects), they were reduced by 98% (P <.05) and 89% (P <.01), respectively. Rifampin greatly decreased plasma concentrations of single and multiple oral doses of praziquantel to levels lower than that of the minimum therapeutic concentration. Because praziquantel and rifampin are widely used in the treatment of liver flukes (Opisthorchis viverrini) and Mycobacterium tuberculosis, respectively, in Thailand and in some other countries in southeast Asia, the possibility of one drug influencing the pharmacokinetics of the other must be considered. Therefore simultaneous use of rifampin and praziquantel must be avoided in medical practice to optimize the therapeutic efficacy of praziquantel.

Cimetidine enhances the plasma praziquantel concentration and treatment efficacy against Microcotyle sebastis in cultured rockfish Sebastes schlegeli.

The effect of cimetidine on the praziquantel concentration in the blood of the rockfish Sebastes schlegeli and the consequent effect on the treatment efficacy against Microcotyle sebastis were investigated. Fish were divided into 7 groups and orally administered praziquantel alone (200 and 100 mg kg(-1) body weight [BW]) or in combination with cimetidine (in doses of 200, 100 or 50 mg kg(-1) BW cimetidine with a praziquantel dose of 100 mg kg(-1) BW). The fish in the sixth group were coadministered 50 mg praziquantel and 200 mg cimetidine kg(-1) BW. The fish in the control group were administered only saline. At 24 h post-treatment, the plasma was analyzed for praziquantel by reversed-phase high-performance liquid chromatography (RP-HPLC) using diazepam as the internal standard, and the gills were examined to confirm the effectiveness of each treatment. The praziquantel concentration in plasma of fish administered 100 mg praziquantel + 200 mg cimetidine kg(-1) BW was not significantly different from that of fish treated with 200 mg praziquantel kg(-1) BW and was significantly (p < 0.05) higher (about 2 times) than that of fish administered 100 mg praziquantel kg(-1) BW. The group of fish administered 50 mg praziquantel + 200 mg cimetidine kg(-1) BW showed a similar plasma praziquantel concentration to that in the fish treated with 100 mg praziquantel kg(-1) BW. The treatment efficacies of the groups of fish coadministered 100 mg praziquantel kg(-1) BW and various concentrations of cimetidine (200, 100 and 50 mg kg(-1) BW) were not significantly different from that of the group of fish administered 200 mg praziquantel kg(-1) BW, but were significantly higher than those of the groups of fish fed 100 mg praziquantel kg(-1) BW alone or coadministered 50 mg praziquantel + 200 mg cimetidine kg(-1) BW.

Effect of bilirubin on toxicity induced by trifluoperazine, dibucaine and praziquantel to erythrocytes

Unconjugated bilirubin (UCB), like trifluoperazine (TFP), dibucaine (DBC) and praziquantel (PZQ), induces erythrocyte morphological changes, lysis and lipid exfoliation. In the present study we determined whether TFP, DBC and PZQ toxicity to erythrocytes was potentiated or reverted by UCB. Human erythrocytes were either treated or non-treated with 34.2 μmol/L UCB for 10 min prior to the incubation with toxic concentrations of TFP (0.12 mmol/L), DBC (1.5 mmol/L) or PZQ (3.0 mmol/L), for 1 h (37°C). Studies of toxic effects included morphological analysis of erythrocytes, evaluation of hemoglobin release and loss of membrane lipids. Although UCB has an echinocytogenic effect, its co-incubation with TFP or PZQ did not alter the stomatocytogenic effect of the drug but enhanced DBC-induced stomatocytosis. Cell fusion was a common feature in experiments with DBC. Injurious effect of DBC to erythrocytes was potentiated by UCB as manifested by a marked increase in hemolysis (171%, p<0.05), and in elution of membrane cholesterol (73%, p<0.01) and phospholipids (123%, p<0.01). In opposite, toxic events produced by TFP and PZQ to erythrocytes were not aggravated by UCB. Interestingly, UCB prevented the loss of membrane cholesterol by PZQ (−36%, p<0.01), as well as that of phospholipids by TFP (−28%, p<0.05). These findings indicate that UCB potentiates DBC injury to erythrocytes, while protects membrane lipid elution by PZQ and TFP. Therefore, the relation of the benefits and risks of the administration of DBC to jaundiced patients should be carefully considered.

Depletion of praziquantel in plasma and muscle tissue of cultured rockfish Sebastes schlegeli after oral and bath treatment.

Depletion of praziquantel in plasma and muscle tissue after oral and bath treatments was studied in cultured rockfish Sebastes schlegeli. In the oral treatment, a single dose of 400 mg praziquantel kg(-1) body weight was administered by intubation of the stomach. A bath treatment at 100 ppm of praziquantel for 4 min was also carried out. Plasma and muscle tissue samples were collected at 3, 6, 12, 24, 48, 72, 96, 120, 144 and 168 h post-treatment, and analyzed for praziquantel by reversed-phase HPLC using diazepam as the internal standard. Following oral treatment, praziquantel was detected in plasma and muscle tissue until 96 h after treatment. In plasma the praziquantel concentration was highest at the 9 h sampling time and declined sharply at the 48 h sampling point. The concentrations of praziquantel in the muscle tissue were lower than those in the plasma, and the highest value was found at the 9 h sampling time. Following bath treatment, praziquantel was found in plasma and muscle tissue until 72 and 24 h after treatment, respectively. In plasma the praziquantel concentration was highest at the 12 h sampling time and declined sharply thereafter. The concentrations of praziquantel in the muscle tissue were significantly lower than those in the plasma, and the concentrations declined consistently with time.

A direct competitive enzyme-linked immunosorbent assay (ELISA) for determination of praziquantel concentration in serum

A simple and reproducible enzyme-linked immunosorbent assay (ELISA) for the determination of the concentration of praziquantel in the serum was developed. Since praziquantel has no functional group to conjugate with carrier protein, praziquantel was first converted to a compound with an amino group similar to praziquantel. This compound was then conjugated to bovine serum albumin for use as an immunogen, and to horseradish peroxidase, as enzyme-labeled praziquantel, respectively. The conjugate of praziquantel-bovine serum albumin conjugate was used to raise anti-praziquantel antiserum in mice. The direct competitive ELISA was conducted by simultaneously incubating praziquantel and horseradish peroxidase-labeled praziquantel conjugate with anti-praziquantel antiserum over a second antibody and the enzyme activity of the remaining horseradish peroxidase-labeled praziquantel conjugate was measured. The intra- and inter-assay coefficient of variation was <10% in the range of 1.0 to 30 ng ml −1, and the limit of the detection was 0.3 ng ml −1. The cross reactivities of anti-praziquantel antibody with compounds related to praziquantel were negligible. Using this ELISA, serum levels of praziquantel were easily determined in male Wistar rats up to 8 h following a single intraperitoneal injection at 2 mg kg −1 of body weight.

Membrane effects of trifluoperazine, dibucaine and praziquantel on human erythrocytes

Trifluoperazine (TFP) is a potent antipsychotic agent, dibucaine (DBC) is a local anaesthetic and praziquantel (PZQ) is a highly effective agent against schistosomiasis. The present work was conducted to (i) investigate the cytotoxic effects of TFP, DBC and PZQ on human erythrocyte membranes; and (ii) compare the alterations induced by the cationic drugs (TFP and DBC) with those induced by the uncharged compound (PZQ), in an attempt to have a better insight on the pathways of each drug–membrane interaction. The erythrocyte morphological alterations induced by sublytic concentrations of TFP, DBC and PZQ were evaluated by scanning electron microscopy and expressed quantitatively by the morphological index. Haemolysis and release of membrane lipids (phospholipids and cholesterol) produced by selected concentrations of TFP, DBC and PZQ, were compared with those resulting from the corresponding triple concentrations of each drug. Our results showed that the uncharged molecule of PZQ induces the same morphological alterations (stomatocytosis) as the cationic drugs TFP and DBC. Haemolysis was shown to vary with the drug used and to be concentration-dependent, with values ∼10-fold more elevated for TFP and DBC than for PZQ, which revealed a maximum of 6% haemolysis for the highest concentration tested. Different concentration–response curves were obtained for lipid elution, although the profiles of cholesterol and phospholipids released were similar for all drugs. Nevertheless, at a fixed rate of 50% haemolysis, TFP induced a ∼2-fold increment in the elution of cholesterol when compared with that produced by DBC ( P<0.05). The different effects induced by TFP, DBC and PZQ on erythrocyte morphology, haemolysis and lipid exfoliation are related to the physical and chemical characteristics of each compound. These results suggest that distinct cell membrane interaction pathways lead to drug-specific mechanisms of cytotoxicity.

Detection of praziquantel resistance in schistosomes.

The tolerance of Schistosoma mansoni to praziquantel has been reported in some endemic regions ( Fallon et al. 1995 ; Stelma et al. 1995 ; Ismail et al. 1996 ; Guisse et al. 1997 ). To establish the reasons for clinical failures of praziquantel, a simple, quick and economic assay is required to detect resistance. Ideally this will involve the use of eggs or miracidia since these are the stages of the parasite life cycle which can easily be obtained from the faecal material of infected humans. As praziquantel causes changes in the shape of miracidia ( Coles 1979), this was used as the basis for designing a test for resistance. In 24-well flat bottom microplates we observed the effect of praziquantel on miracidia hatched from eggs obtained from the faeces of mice infected with six isolates of S. mansoni. Two isolates were praziquantel-susceptible (one from Puerto Rico and one a mixture of isolates from Puerto Rico, Brazil, Egypt and Kenya), and four isolates were praziquantel-insusceptible, including a laboratory-selected praziquantel-resistant population ( Fallon & Doenhoff 1994) and three Senegalese isolates. The cessation of swimming of miracidia was observed in different concentrations of praziquantel at various times and then the morphological changes were checked by adding a drop of Lugol's iodine. When the miracidia of both the susceptible and insusceptible isolates were exposed to 10−3 and 10−4 M praziquantel, they immediately contracted in the middle part of their bodies, giving the shapes of an unequal dumbbell or calabash, with the greater mass at the anterior end. In 5 × 10−6 M praziquantel 100% of miracidia from the susceptible isolates immediately changed shape, whereas only 11–15% of those from the insusceptible isolates did. Thus by addition of Lugol's iodine immediately after administering praziquantel, an objective measure of susceptibility could be obtained. After 1 minute in 10−6 M praziquantel 52% to 100% of susceptible miracidia had changed shape, and after 5 min 100% had done so compared with 3% to 15% and 9% to 18% of the insusceptible miracidia. Susceptibility could also be detected by determining whether miracidia had stopped swimming but this was less easy to read as a test than change in shape. By exposing freshly hatched miracidia to 10−6 M praziquantel and observing change in shape over one minute it should be possible to determine whether failed therapy is due to the presence of praziquantel-tolerant worms. It is planned to investigate this in field trials in China. The work was supported by the UNDP/World Bank/WHO Special Programmme for Research and Training in Tropical Diseases.

Pharmacokinetic optimisation of the treatment of neurocysticercosis.

Neurocysticercosis is the most important parasitic infection of the nervous system. It is common in communities living in conditions with poor hygiene. Until the last 2 decades, there was no specific pharmacological treatment: surgery and corticosteroids were the only medical alternatives. The recent introduction of anticysticercal drugs, an isoquinoline (praziquantel) and a benzimidazole (albendazole), has dramatically changed the medical management of neurocysticercosis. Praziquantel is taken orally and undergoes extensive first pass hepatic biotransformation. Peak concentration in serum is reached after 1 to 2 hours and the elimination half-life is between 1 and 3 hours. Praziquantel permeates the blood-brain barrier, thus explaining its effectiveness on parenchymal brain cysticercosis. Plasma concentrations of the drug are increased when a high carbohydrate diet is administered. Cimetidine also increases the plasma concentration of praziquantel by inhibition of cytochrome P450. Bioavailability of the drug is markedly reduced when given jointly with antiepileptics or corticosteroids, specially carbamazepine, phenytoin or dexamethasone. The current schedule for neurocysticercosis treatment lasts 2 weeks at daily doses of 50 mg/kg. Recently, a new therapeutic scheme has been proposed that considers the pharmacokinetics of the drug. This regime lasts only 1 day and includes 3 dosages of 25 mg/kg at 2-hour intervals. This increases the time that the parasite is exposed to high drug concentrations. This therapeutic scheme has produced similar results to longer schemes, with the additional advantages of cost, length of usual treatments and reduction in total dose received (being one-tenth of the total dosage). Albendazole is considered by many as the drug of choice for treatment of neurocysticercosis. It is given orally and is rapidly and extensively metabolised to albendazole sulfoxide (ALBSO), which is considered to be the metabolite directly or indirectly responsible for both toxicity and efficacy outside the gastrointestinal tract. Concentrations of ALBSO are highly variable between individuals and it has a half-life of between 6 and 15 hours. It also crosses the blood-brain barrier. In patients with extrahepatic obstruction, the elimination process is prolonged and plasma concentration is increased. Fatty meals improve absorption. Concomitant administration of albendazole with dexamethasone or with praziquantel increases plasma concentration of ALBSO. Albendazole is administered in an 8 day course of 15 mg/kg per day in 2 divided doses 12 hours apart. This scheme, based on drug pharmacokinetics, has proven to be highly effective. Inflammation is a common accompaniment of neurocysticercosis; in many cases it is the aetiopathogen responsible for histological damage. Corticosteroid therapy is useful for preventing further tissue injury. Long term corticosteroid therapy can be accomplished with 50 mg of oral prednisone 3 times a week. Acute corticosteroid therapy includes brief courses with high dosages of intramuscular dexamethasone or intravenous methylprednisolone. Clinical decisions on cysticidal and anti-inflammatory treatments must be made with the information gathered by neuroimaging studies, either computed tomography or magnetic resonance, and by the analysis of cerebrospinal fluid.

Schistosoma japonicumGSHS-TransferaseSj26 Is Not the Molecular Target of Praziquantel Action

It has been suggested thatSj26, aSchistosoma japonicumGSHS-transferase, is the molecular target of the antischistosomal drug praziquantel (McTigueet al.,1995,J. Mol. Biol.246,21–27). We tested this hypothesis by asking two questions: (1) does praziquantel inhibitSj26 activity with a variety of model substrates; and (2) does praziquantel prevent the binding toSj26 of physiologically relevant nonsubstrate ligands? High concentrations of praziquantel (up to 500 μM) did not inhibitSj26 activity using the model substrates 1-chloro-2,4-dinitrobenzene, 3,4-dichloronitrobenzene, or ethacrynic acid.Sj26 had no measurable activity with two higher molecular weight GSHS-transferase substrates: 5-androsten-3,17-dione and sulfobromophthalein. We also assessed the ability of praziquantel to prevent the inhibition ofSj26 by a series ofS-alkyl-GSH conjugates. The half-maximal inhibitory concentrations ofS-hexyl-GSH,S-octyl-GSH, andS-decyl-GSH (10, 10, and 5 μM,respectively) forSj26 were not affected by up to 500 μMpraziquantel. This suggests that praziquantel does not compete with GSH forSj26 binding. In order to determine if praziquantel disrupts binding of nonsubstrate ligands toSj26, we tested praziquantel for its ability to prevent the inhibition ofSj26 by both bilirubin and hematin. Praziquantel (100 or 500 μM) did not alter inhibition ofSj26 by 3 μMbilirubin, but partially protectedSj26 against inhibition by hematin (0.1 to 2.0 μM). Interestingly, in a similar reaction, 100 μMS-methyl-GSH protectedSj26 from inhibition equally as well as praziquantel. Bovine serum albumin (5 μM) completely protected against inhibition by 1 μMhematin. These results indicate that although praziquantel partially protectsSj26 from hematin inhibition, this protection is neither specific to praziquantel nor physiologically relevant. Our results do not support the hypothesis that the mechanism of praziquantel action involves competitive inhibition ofSj26 catalytic activity or blocking binding of nonsubstrate ligands. We can, therefore, find no evidence thatSj26 is the molecular target of the antischistosomal activity of praziquantel.

Praziquantel has no direct effect on (Na ++K +)-ATPases and (Ca 2+-Mg 2+)ATPases of Schistosoma mansoni

Therapeutic concentrations of praziquantel produce a rapid and intense contraction of the human flatworm Schistosoma mansoni. As an action on ATPases responsible for calcium homeostasis arises as a possible explanation for the molecular mechanism of this effect, we tested here the effect of praziquantel on different preparations from male adult worms that were previously characterized for their content in (Na ++K +)-ATPase and (Ca 2+-Mg 2+)ATPase activities from different origins. Concentrations as high as 100 μM praziquantel did not inhibit (Na ++K +)-ATPase from tegument and carcass nor (Ca 2+-Mg 2+)ATPase from heterogeneous (P 1) and microsomal (P 4) fractions. As 100 μM praziquantel was also without effect on calcium permeability of microsomal vesicles actively loaded with 45Ca 2+, the present results discard three hypotheses recently raised for the mechanism of praziquantel-induced contraction of S. mansoni.

Characterization of isolates of Schistosoma mansoni from Egyptian villagers that tolerate high doses of praziquantel.

To determine if resistance/tolerance to the antischistosomal drug praziquantel (PZQ) is appearing in Egyptian villages within the Nile delta region, where it has been used extensively, we treated 1,607 infected villagers and observed that 321 required one additional treatment while 89 villagers required two additional treatments; 24 of the 89 were still not cured after a third dose of this drug. Eggs were isolated from fecal samples and serum was isolated from blood taken from seven villagers successfully treated after a single dose and from 14 villagers not successfully treated after two or three doses of PZQ. The eggs were used to establish infections in mice (isolates), which were then treated six weeks after infection with three different doses of PZQ. Serum was used to determine the concentration of PZQ in the infected humans. Three of the egg isolates from the 14 villagers that could not be treated with three doses of PZQ produced infections in mice that were statistically less responsive to PZQ when compared with isolates obtained from patients that were cured after a single dose of this drug. Pharmacokinetic parameters were the same in patients treated successfully after a single dose versus those not treated successfully following two or three doses, thus eliminating the possibility that poor cure rates among infected villagers was due to a decrease in PZQ bioavailability. From our data, approximately 1-2.4% of the villagers treated with PZQ could not be completely cured of their infection and three of every 1,000 treated villagers may harbor parasites that can tolerate high doses of PZQ. These results indicate that the extensive use of PZQ in the Nile delta region of Egypt has not resulted in a dramatic change in the efficacy of this drug. The isolation of schistosomes that are less susceptible to PZQ may be a warning signal that will require establishment of a monitoring system, similar to the one we have developed, to determine if the percentage of patients that cannot be cured by PZQ is increasing. Furthermore, if that percentage begins to increase over time, it will be critical to determine, by pharmacologic methods reported in this study, whether isolates obtained from uncured patients are becoming increasingly resistant to PZQ.

Cimetidine-induced rise in praziquantel levels in a patient with neurocysticercosis being treated with anticonvulsants.

A patient had neurocysticercosis complicated by a seizure disorder requiring anticonvulsants; previous praziquantel therapy (50 mg/kg/day) had failed to eradicate the disease. In an attempt to inhibit cytochrome P-450 metabolism of praziquantel, cimetidine (1600 mg/day) was coadministered. Before addition of cimetidine, the maximum concentration of praziquantel was 350 ng/mL; concurrent cimetidine administration increased the maximum concentration to 826 ng/mL. The elimination half-life increased from 1.7 h without cimetidine to 3.3 h with cimetidine and the area under the curve for the 12-h sampling period rose from 754 ng.h/mL to 3050 ng.h/mL. Coadministration of cimetidine raises serum praziquantel levels and may be helpful in patients treated concomitantly with praziquantel and anticonvulsants.

Plasma Pharmacokinetics and Therapeutic Efficacy of Praziquantel and 4-Hydroxypraziquantel in Schistosoma japonicum-Infected Rabbits after Oral, Rectal, and Intramuscular Administration

The relationship between plasma level and therapeutic efficacy of praziquantel (PZQ) and its major human oxidative metabolite, 4-hydroxypraziquantel (4-OHPZQ), has been investigated in Schistosoma japonicum-infected rabbits using three different routes of PZQ administration. After intramuscular administration (20 mg/kg), the maximum level of PZQ in rabbit cardiac plasma was 1.6 +/- 1.0 micrograms/ml (mean +/- SD) 30 min after administration. After oral or rectal administration (40 mg/kg), maximum plasma levels were 0.1 +/- 0.2 microgram/ml (oral) and 0.5 +/- 0.4 micrograms/ml (rectal). The corresponding maximum 4-OHPZQ concentrations in cardiac plasma were 4.6 +/- 1.8 micrograms/ml (intramuscular), 1.7 +/- 0.5 micrograms/ml (oral), and 4.1 +/- 1.6 micrograms/ml (rectal) 2 hr after administration of PZQ. After administration of similar doses, maximum levels of PZQ in plasma from the femoral vein were 29.3 +/- 27.5 micrograms/ml (intramuscular), 0.6 +/- 1.0 microgram/ml (oral), and 0.7 +/- 0.6 microgram/ml (rectal). However, 60 min after intramuscular administration, the maximum PZQ concentration in portal venous blood was only 1.0 +/- 0.6 microgram/ml, which is substantially less than corresponding maximum portal vein levels after oral (6.8 +/- 6.5 micrograms/ml) or rectal (3.7 +/- 4.6 micrograms/ml) administration. Therapeutically, in spite of the 4-6-fold lower levels of PZQ in portal venous plasma after intramuscular administration, adult worm reduction rates in infected rabbits using the above doses were 92.2% (intramuscular), 90.1% (rectal), and 72.5% (oral), respectively, four weeks after treatment. Thus, no direct correlation between levels of PZQ in peripheral or portal venous blood and therapeutic efficacy was observed in rabbits infected with S. japonicum.

Phenytoin and carbamazepine decreased oral bioavailability of praziquantel.

Antiepileptic drugs, especially carbamazepine and phenytoin, are potent liver enzyme inducers. Since praziquantel, the drug used to treat neurocysticercosis, undergoes extensive liver first-pass metabolism, we carried out a prospective study to verify whether there was a decrease in oral bioavailability induced by carbamazepine and phenytoin. Carbamazepine and phenytoin significantly decreased concentrations of praziquantel, due to increased clearance secondary to induction of first pass-liver metabolism. The magnitude of the decrease is surprisingly high and may be responsible for failures of treatment.

The effect of praziquantel on the ultrastructure ofSchistosoma 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.

Uptake and Effect of Praziquantel and the Major Human Oxidative Metabolite, 4-Hydroxypraziquantel, by Schistosoma japonicum

After exposure to praziquantel in vitro at a concentration of 1 microgram/ml for 0.5-2 hr, amounts of praziquantel in Schistosoma japonicum varied from 2.1 +/- 1.2 to 3.7 +/- 1.6 ng/male worm and 1.3 +/- 1.2 to 2.2 +/- 1.5 ng/female worm during the time studied. At 30 micrograms/ml, praziquantel amounts were 11-33-fold higher. However, within 2 hr after removal from a medium containing 30 micrograms/ml praziquantel, 95% of the drug was released from the parasites. When S. japonicum worm pairs were incubated in vitro with 1, 10, and 30 micrograms/ml of 4-hydroxypraziquantel, the major human oxidative metabolite of praziquantel, 0.2 +/- 0.2, 3.8 +/- 1.3, and 7.4 +/- 1.3 ng/worm pair, respectively, were found after a 2-hr incubation. 15-30-fold lower than corresponding worm pair amounts of praziquantel. In vivo, when 4- or 5-wk S. japonicum-infected mice were treated orally with praziquantel (300 mg/kg), peak concentrations of praziquantel in plasma determined by high pressure liquid chromatography were 14.7 +/- 1.5 micrograms/ml (4-wk infection) and 16.7 +/- 2.8 micrograms/ml (5-wk infection) 15 min after treatment. Corresponding in vivo worm praziquantel amounts were 1.8 +/- 0.4 ng/male worm and 2.4 +/- 1.1 ng/female worm, respectively, in the 4-wk infection and 4.6 +/- 1.6 ng/male worm and 5.6 +/- 1.2 ng/female worm in the 5-wk infection. Peak plasma concentrations of 4-hydroxypraziquantel were similar but corresponding in vivo worm amounts were 1-20-fold lower, depending on the time after drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Praziquantel treatment of muscleTaenia solium cysticercosis

The in vitro effect of Praziquantel (PZQ) on Taenia solium cysticerci was analyzed. The oxygen consumption rate of the parasites was inhibited and the release of proteins was enhanced, but no statistically significant differences were found between the control group and the experimental groups. The drug had a significant, dose-dependent negative effect on the evagination ability of the larvae; 50% effect was seen at concentrations of between 10(-9) and 10(-8) M PZQ. The drug also induced morphological disturbances in the tegument of the worm and of the bladder wall. Finally, a very drastic effect was the induction of spastic paralysis in evaginated cysticerci at high drug doses and of flaccid paralysis at lower PZQ concentrations. The dose inducing these effects was various orders of magnitude lower than that inhibiting the evagination ability of intact cysts. Moreover, the latter effect was reversible after had been washed out the drug and the parasites had been cultured. We suggest that PZQ alters the Ca2+ flux in T. solium as it does in other helminths. Furthermore, we corroborated the protective role of the bladder for the invaginated worm. Finally, we think that in vivo the drug must act synergistically with the immune system components so as to eliminate the parasite.

Effect of experimentally-induced hepatic cirrhosis on the pharmacokinetics of orally administered praziquantel in the rat

The effects of pretreatment with the hepatotoxin, thioacetamide, on the pharmacokinetics of praziquantel, a broad spectrum schistosomicidal agent with a high hepatic clearance, were studied in male Wistar rats. Animals were pretreated with either thioacetamide (25 mg in 100 ml of drinking water, n = 5) for 24 weeks or received plain drinking water (n = 5) over the same period. After the treatment period, praziquantel was administered orally (25 mg/kg as a 20 mg/ml solution in PEG 200) as a single dose. Blood samples (0.3 ml) were collected from the clipped tail at various times up to 4 h post administration. Plasma was analysed for praziquantel using an HPLC method. Mean peak plasma praziquantel concentrations were approximately 1.0 mg/l for both groups. The time to reach peak concentrations, and post-peak elimination half-life, were approximately 0.7 h and 1.0 h, respectively, for both groups. Similarly, mean AUC was approximately 2.0 mg.h/l for both groups. Statistical comparisons indicated that there were no significant differences in the pharmacokinetic parameters estimated in the two groups of animals. It was concluded that thioacetamide-induced hepatic cirrhosis has no effect on the pharmacokinetics of orally administered praziquantel in the rat, at the dose level studied.

Praziquantel-Induced Secretion of Proteolytic Enzyme from Schistosoma mansoni Cercariae

The effect of praziquantel (PZQ) on secretion of proteolytic enzyme by Schistosoma mansoni cercariae was examined using an azocoll assay. The cercariae secreted proteolytic enzyme in various concentrations of PZQ (0.1, 1, and 10 micrograms/ml), but secretion of enzyme was highest at the lowest concentration. PZQ-induced secretion of proteolytic enzyme was partially inhibited by treatment with verapamil and ethylene glycol-bis(beta-aminoethyl ether)N,N,N',N'-tetra-acetic acid but not by calmodulin antagonist W-7 and protein kinase C inhibitor H-7.

Echinococcus granulosus: the effects of praziquantel, in vivo and in vitro, on the ultrastructure of equine strain murine cysts.

Praziquantel (500 mg/kg) administered orally to BALB/c mice with secondary equine E. granulosus daily for 21, 30 or 30 + 30 days without the drug resulted in the majority of cysts, using bench criteria of turgidity and eosin exclusion, being assessed as 'alive'. Ultrastructural examination of 54 of these 'alive' cysts did not support this conclusion. They all showed increased vesiculation of the germinal layer leading, in many, to the loss of its integrity. Increased mitochondrial numbers occurred frequently. The longer drug treatments appeared to have greater effects on the germinal layer of 'alive' cysts and there was no detectable reestablishment of structural organization within 30 days after drug withdrawal. Subjectively, there was no substantial difference between cysts from 4-month and 9-month infections or between affected peritoneal and hepatic cysts. Tissue from collapsed cysts was necrotic. Peak serum levels of praziquantel (6430-6136 micrograms/l) occurred 5-10 min after drug administration (500 mg/kg) and dropped rapidly to less than 10 micrograms/l at 3 h. In an in vitro study at praziquantel concentrations of 1000 and 5000 micrograms/l over a 10-day period, most cysts were judged 'alive' by bench criteria but showed ultrastructurally a time- and concentration-dependent loss of integrity identical to that seen in vivo. Turgidity and eosin exclusion therefore underestimate the effect of praziquantel and the results indicate that in vitro experiments can fulfil a legitimate preliminary role in a hydatid chemotherapy programme.