Efficacy and toxicity of praziquantel in helminth-infected barbel (Barbus barbus L.).

This study evaluated efficacy and toxicity of the pyrazinoisoquinoline anthelmintic praziquantel (PZQ) in barbel infected with metacercariae of Diplostomum spathaceum and adult Pomphorhynchus laevis, and assessed antioxidant biomarkers and the lipid peroxidation response in juvenile barbel post-treatment. The estimated 96-hr LC50 of PZQ was 28.6 mg/L. For evaluation of efficacy, barbel naturally infected with D. spathaceum were exposed to a 10 and 20 mg/L PZQ 4-day bath treatment. Both concentrations were 100% effective against D. spathaceum and significantly (p < .01) affected the activity of catalase, superoxide dismutase, glutathione reductase and glutathione-S-transferase as well as levels of reduced glutathione in liver and muscle. The efficacy of orally administered PZQ was assessed in adult barbel naturally infected with P. laevis. Fish were administered 10, 30 and 50 mg/kg of body weight and examined via gut dissection after 6 days. The 50 mg/kg dose significantly decreased the intensity of infection. Praziquantel is a feasible bath treatment for barbel infected with D. spathaceum and has potential for oral treatment of broodfish infected with P. laevis.

The anthelminthic drug praziquantel is a selective agonist of the sensory transient receptor potential melastatin type 8 channel.

Praziquantel is the most effective anthelminthic drug for the treatment of schistosomiasis, an infectious disease caused by the platyhelminth Schistosoma mansoni. While praziquantel is known to trigger calcium influx into schisostomes, followed by spastic paralysis of the worms and tegumental disruption, the mechanism of action of the drug is not completely understood. Although relatively well tolerated, praziquantel has been reported to cause mild adverse effects, including nausea, abdominal pain and headaches. As a number of putative Transient Receptor Potential (TRP) channel genes have recently been predicted in S. mansoni, we sought to investigate the effect of praziquantel on three mammalian TRP channels, TRP melastatin type 8 (TRPM8), TRP vanilloid type 1 (TRPV1) and TRP ankyrin type 1 (TRPA1). Using calcium microfluorimetry and the patch clamp technique, we recorded the effect of praziquantel on HEK293T cells expressing recombinant TRPM8, TRPV1 or TRPA1, as well as on cultured dorsal root ganglion (DRG) neurons from wild type and TRPM8 null mutant mice. We discovered that praziquantel is a relatively potent and selective partial agonist of the mammalian and avian cold and menthol receptor TRPM8. The activation of cultured DRG neurons by clinically relevant concentrations of praziquantel is predominantly mediated by TRPM8. Our results may provide clues to a better understanding of praziquantel's mechanism of action and its adverse effects.

The cytotoxicity study of praziquantel enantiomers.

Praziquantel (PZQ) is prescribed as a racemic mixture (racemic-PZQ, rac-PZQ), which is composed of (R)-PZQ and (S)-PZQ. In this work, the cytotoxicity of rac-PZQ and its two enantiomers (R)-PZQ and (S)-PZQ on eight cell lines (L-02, HepG2, prf-plc-5, SH-SY5Y, HUVEC, A549, HCT-15, Raw264.7) was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphe-nyltetrazolium bromide and lactate dehydrogenase assays. The morphology of apoptotic cells was studied by fluorescence microscope using Hoechst 33342 staining, and the cytotoxicity of the compounds was also tested by lactate dehydrogenase assay. Results revealed that (R)-PZQ had negligible cytotoxicity against L-02, SH-SY5Y, HUVEC, A549, HCT-15, and Raw264.7 cells but selectively inhibited tumor cell lines (prf-plc-5 and HepG2). However, in contrast to (R)-PZQ, the (S)-isomer showed higher cytotoxicity against L-02 cells and lower inhibition on prf-plc-5 and HepG2 cells. Besides, (R)-PZQ showed lower cytotoxicity on SH-SY5Y cells than (S)-PZQ. Meanwhile, (R)-PZQ at <80 µM concentration could promote proliferation of macrophage cells (Raw264.7). Our research revealed that (R)-PZQ has lower cytotoxicity than (S)-PZQ and has similar cytotoxicity with rac-PZQ. (S)-PZQ is the principal enantiomer to cause side effects on human definitive hosts. These findings gave the reasonable reasons for World Health Organization to produce (R)-PZQ as a replacement for rac-PZQ for the treatment of schistosomiasis.

Mutagenic and physiological responses in the juveniles of African catfish, Clarias gariepinus (Burchell 1822) following short term exposure to praziquantel.

Praziquantel (PZQ) is an acylated quinoline-pyrazine originally developed for veterinary application but now one of the most used anti-helminthic drugs for treatment of certain trematodes and cestodes in both human and other animals. The present study investigated the mutagenic and physiological responses in the juveniles of African catfish, Clarias gariepinus following short term exposure to praziquantel. Based on the 53.52 mg/l 96 h LC50 of PZQ obtained, two sublethal concentrations of 5.35 and 10.70 mg/l of the drug were selected and fish were exposed to these concentrations and control for 15 days. Micronuclei induction in the peripheral blood of PZQ-exposed fish was highest on day 10 but the fish morphological parameters were not affected. The packed cell volume (PCV) was significantly reduced (p<0.05) from day 5 while red blood cells (RBC) and hemoglobin (Hb) significantly declined (p<0.05) on day 15. Macrocytic anemia was observed on day 1 of study and thereafter microcytic anemia developed on day 5 of study. The white blood cell (WBC) was significantly (p<0.05) elevated from day 10 of exposure while values of mean cellular volume (MCV), mean cellular hemoglobin (MCH) and mean cellular hemoglobin concentration (MCHC) were not significantly different (p>0.05) from the control. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glucose levels significantly increased while protein reduced (p<0.05) throughout the exposure period but a mixed trend was observed in the leukocyte differentials. PZQ should be used with caution as sublethal exposure elicited micronucleus induction and alterations of hematological and biochemical parameters in the fish.

Antischistosomal action of thioxo-imidazolidine compounds: an ultrastructural and cytotoxicity study.

Schistosomiasis is a disease caused by helminthes of the genus Schistosoma, which threatens approximately 207 million people worldwide. Recently, strains of Schistosoma mansoni appear to be developing tolerance and resistance against Praziquantel, the most commonly available drug on the market used in the treatment of disease. This worrisome development justifies studies that seek alternatives for the prevention, treatment and cure of this disease. This study aimed to evaluate the in vitro activity of new imidazolidine compounds 1-benzyl-4-[(4-chloro-phenyl)-hydrazono]-5-thioxo-imidazolidin-2-one (LPSF/PT-5) and 1-(4-chloro-benzyl)-4-[(4-fluoro-phenyl)-hydrazono]-5-thioxo-imidazolidin-2-one (LPSF/PT-11) against adult worms of S. mansoni. LPSF/PT-5 and LPSF/PT-11 imidazolidine derivatives showed relevant schistosomicidal activity in vitro and induced significant ultrastructural alterations in worms and cell death: results similar to praziquantel. Thus, it is possible that these imidazolidine derivatives can be future candidates as schistosomotic drugs, but further studies are needed to elucidate the induced mechanisms behind this response.

The effect of praziquantel applied per os on selected haematological and biochemical indices in common carp (Cyprinus carpio L.).

The aim of the study was to assess the effects of the anthelminthic, praziquantel, on the haematological and biochemical indices of the blood of common carp (Cyprinus carpio L.). Fish were divided into six groups: two groups received 30 mg kg(-1) body weight (bw) of praziquantel, and two groups were given 50 mg kg(-1) bw of praziquantel mixed into the heat-treated amyloid vehicle. Fish in the remaining two groups were given only the amyloid vehicle and were used as controls. Fish were examined either 24 or 96 h after administration. Praziquantel treatment was characterised by a significantly lower erythrocyte count, haemoglobin level, packed cell volume and total protein at both dose levels after 24 h compared with the controls, but these parameters were similar to the control values at 96 h. The activity of alanine aminotransferase (ALT) was significantly higher after 96 h in the treated groups, which could be attributed to slight hepatocyte damage caused by praziquantel. However, the differences between the treated and the control groups were not great, and we presumed that they were reversible.

A short review of some pharmacological, therapeutic and toxicological properties of praziquantel in man and animals.

Praziquantel is the current drug of choice against many trematodes and cestodes in both man and animals. This article summarizes the main pharmacological, therapeutic and toxicological properties of the drug, especially that have been reported during the last 10 years. In most cases, the effectiveness and safety of the drug have been confirmed, although there are currently concerns about the resistance/decreased effectiveness of the drug to certain Schistosome isolates, and also about the mutagenicity of the drug.

Comparative study of the hepatotoxic, genotoxic and carcinogenic effects of praziquantel distocide & the natural myrrh extract Mirazid on adult male albino rats.

Praziquantel (PZQ) is widely and effectively used in the control of bilharziasis which constitutes a major endemic health problem in Egypt. However, recent studies recommended that the drug must be re-evaluated because of its potential carcinogenicity and genotoxicity. Mirazid is a new natural anti-schistosomal drug formed of myrrh extract and considered to be a safe drug. This work was conducted to evaluate and compare hepatotoxic, genotoxic and carcinogenic effects of PZQ and Mirazid on adult male albino rats by assessment of serum levels of ALT, AST and bilirubin, histopathological study of the liver and cytogenetic study of bone marrow cells. 100 adult male albino rats were equally divided into 4 groups: (I): negative control, (II): control rats received distilled water, (III): received weekly single oral dose of PZQ (1500 mg/kg) for 6 weeks, (IV): received daily oral dose of Mirazid (500 mg/kg) for 6 weeks. At the end of the study 10 rats of each group were investigated by assessment of the levels of AST, ALT, & Bilirubin. After scarification, liver sections were examined by light microscopy. Another 10 rats of each group were submitted to cytogenetic examination. It was found that praziquantel induced a significant increase in the mean values of AST, ALT and bilirubin with areas of hyaline degeneration, fatty changes, dysplasia and necrosis in the liver sections. It also induced a significant increase in the incidence of chromosomal aberrations as polyploidy, fragment, deletion and ring chromosome as compared with control group. Mirazid induced a non significant increase in the mean values of AST, ALT and bilirubin, with a normal hepatic tissue, and a non significant increase in the incidence of chromosomal aberrations, as compared with the control group. On comparing both drugs, praziquantel induced a significant hepatotoxic, genotoxic and carcinogenic effects. It was concluded that, Praziquantel is considered to be a hepatotoxic, genotoxic and carcinogenic drug. On the other hand, Mirazid seemed to be a safe and promising antiparasitic drug, free from hepatotoxic, genotoxic and carcinogenic effects.

Investigation of induced biochemical and histopathological parameters of acetonitril extract of Jatropha carcus in albino rats.

Toxicological and histopathological investigations were carried on the acetonitril extract from J. carcus in comparison to praziquantel, the known antischistosomal drug. On a constant weight dose bases (single dose of 50 mg/Kg body weight injected orally to albino rats), the acetonitril extract from J. carcus showed mild toxicological parameters (AST p < 0.001, ALT & creatinine, non-significant), biochemical parameters (total lipids, cholesterol, triglycerides, HDL, LDL, proteins, albumins globulins, ascorbic acid and bilirubin, non-significant) and histo-pathological profile (slight alterations in liver, kidney and spleen), in comparison to control. However, these side-effects were very little as compared to the severe side-effects caused by Praziquantel.

Albendazole, mebendazole and praziquantel. Review of non-clinical toxicity and pharmacokinetics.

The pharmacokinetics and toxicity of albendazole, mebendazole and praziquantel are extensively reviewed, drawing on original published work and reviews in the open scientific literature and on assessments by international agencies and official regulatory bodies in Europe and the USA. Information about human and veterinary medical uses and adverse reactions is evaluated. The totality of the non-clinical information available about these long-established drugs may not comply with current official guidelines for new medicines but reasons are given why the "deficiencies" are only apparent and the data gaps can be replaced by other results, largely obtained from the target species and the many years of clinical experience of safe use of these drugs in humans and animals.

The toxicity of praziquantel against Mesocestoides vogae (syn. corti) tetrathyridia can be assessed using a novel in vitro system.

We recently standardised Mesocestoides vogae (syn. corti) tetrathyridia cultures in the presence of sodium taurocholate. Parasite clustering and segmentation were observed as taurocholate-dependent effects in biphasic and monophasic media, respectively, and both were inhibited by a specific minimum inhibitory concentration (m.i.c.) of the cestocidal drugs albendazol and praziquantel. In the present study, we analysed the relationship between clustering inhibition and drug toxicity using praziquantel and a mouse experimental infection. In an "in vitro-in vivo" trial, a significant (ANOVA, P<0.05) reduction was observed in the infectivity of tetrathyridia previously cultured with praziquantel m.i.c. (0.06 micro g/ml) for 10 days. In an "in vivo-in vitro" trial, the clustering of tetrathyridia recovered from mice treated with praziquantel was found to be markedly reduced: 22%, compared with 83% cluster-containing wells of parasites from control mice. These results show that the outcome of infection and the suppression of taurocholate-induced clustering provide consistent indications of praziquantel toxicity against M. vogae, an observation confirmed by histological studies. The easily recorded clustering inhibition of M. vogae tetrathyridia in biphasic medium is a potentially useful system for the assessment of drug toxicity against cestode larvae.

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 micromol/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 degrees 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.

[The technology for manufacturing antiparasitic preparations. 9. The new preparation tizanox and an evaluation of its anti-Hymenolepis activity]. / Tekhnologiia proizvodstva protivoparazitarnykh preparatov. 9. Novyi preparat tizanoks i otsenka ego protivogimenolepidoznoi aktivnosti.

The paper describes a procedure for manufacturing the new anthelminthic Tizanox. It shows it necessary to administer a larger dose of the drug than that of azinox (praziquantel) to treat experimental hymenolepiasis. However, the lower toxicity of Tizanox enhances its chemotherapeutical index.

[The technology for manufacturing antiparasitic preparations. 6. The development of a technology for producing the anthelmintic Azinox (praziquantel) and the evaluation of its toxic and anthelmintic properties]. / Tekhnologiia proizvodstva protivoparazitarnykh preparatov. 6. Razrabotka tekhnologii polucheniia antigel'mintika Azinoksa (prazikvantelia) i otsenka ego toksicheskikh i protivogel'mintnykh svoistv.

The paper outlines a procedure for manufacturing the anthelminthic Azinox (biltricide) using the new interfacial transfer catalyst benzyl-di-propyl (beta-hydroxyethyl)ammonium chloride. Azinox has been shown to be identical to biltricide (praziquantel) in its properties. Azinox tests on models of Opisthorchis felineus in golden hamsters and of Hymenolepis nana in albino outbred mice have indicated that the agent is not inferior to biltricide in its antitrematodal and anticestodal activities. Azinox displayed a high activity at the preimaginal stages of O. felineus and H. nana and at the larval stage of H.nana.

Experimental Schistosoma bovis infection in goats: pathological consequences of praziquantel treatment.

Schistosoma bovis-infected goats were treated with praziquantel (60 mg/kg) and killed for examination 1, 7 or 28 days later. Infected non-treated goats and parasite-free, treated or non-treated goats were included for comparison. The gross pathological changes seen in the infected non-treated groups were mild to moderate. The liver appeared discoloured and moderately enlarged. The intestinal lesions were most prominent in the small intestines, which showed catarrhal inflammation with numerous tiny corpuscles beneath the luminal surface. The mesenteric lymph nodes were slightly to moderately enlarged. In contrast, on macroscopical examination, the infected treated groups invariably showed pronounced liver changes and marked enlargement of the lymph nodes, whereas the lesions in the intestines were comparatively slight. Histological lesions related to dead worms were seen in the livers of all treated animals. These lesions included pronounced inflammatory cellular infiltrates, thrombophlebitis, necrosis and periportal fibrosis, still severe 4 weeks after treatment. In the intestines, the deposition of new eggs with little cellular reaction had almost completely ceased 1 week after treatment. Four weeks after treatment, only a very few egg-associated lesions were noted in the intestines. The presence of severe lesions attributable to dead worms in the liver indicates the need for caution when treating animals with high worm loads or concomitant liver disease.

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

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

Risk identification using structural concepts: the potential carcinogenicity of praziquantel.

The potential of praziquantel (PZ) to induce cancers in rodents was evaluated using a structure-activity relational expert system (CASE/MULTICASE). The analyses indicated that based upon structural features PZ had the potential for being a "nongenotoxic" carcinogen. The potential risk to humans of nongenotoxic carcinogens is considered to be much less than that posed by "genotoxic" ones. Moreover, PZ has demonstrated therapeutic effectiveness against parasitic diseases that affect millions of individuals. Additionally, PZ was developed to replace antiparasitic agents which were genotoxic rodent carcinogens. Thus, on balance, the beneficial effects of PZ appear to outweigh its potential for causing harm to humans.

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

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

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

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