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Praziquantel is used to treat schistosomiasis, also known as snail fever or bilharzia, an infection of the urinary tract or bowels, caused by schistosoma (blood fluke), a flatworm parasite. It is also used to treat clonorchiasis infection caused by the Chinese or Oriental liver fluke (Clonorchis sinensis) or opisthorchiasis infection caused by the Southeast Asian liver fluke (Opisthorchis viverrini).
Blood flukes live in freshwater snails and are spread into the surrounding waters (eg, pond). You may get infected when you swim or get in these waters. They enter the body through the skin and travel until they reach your bowels where they grow and lay eggs. Sometimes, the eggs get in the liver, which causes chronic inflammation. Infections with a liver fluke usually occur after eating contaminated raw or undercooked freshwater fish, crabs, or crayfish. They travel from your bowels to the bile ducts in the liver where they live and grow. Most patients infected with liver flukes do not show any symptoms, which may cause the infection to last a long time.
Praziquantel belongs to the family of medicines called anthelmintics. Anthelmintics are used in the treatment of worm infections. Praziquantel works by causing severe spasms and paralysis of the worms' muscles. Some kinds of worms are then passed in the stool. However, you may not notice them since they are sometimes completely destroyed in the bowels.
This medicine is available only with your doctor's prescription.
This product is available in the following dosage forms:
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The anthelmintic drug praziquantel (PZQ) is used to treat schistosomiasis, a neglected tropical disease that affects over 200 million people worldwide. PZQ causes Ca 2+ influx and spastic paralysis of adult worms and rapid vacuolization of the worm surface. However, the mechanism of action of PZQ remains unknown even after 40 years of clinical use. Here, we demonstrate that PZQ activates a schistosome transient receptor potential (TRP) channel, christened Sm.TRPM PZQ , present in parasitic schistosomes and other PZQ-sensitive parasites. Several properties of Sm.TRPM PZQ were consistent with known effects of PZQ on schistosomes, including (i) nanomolar sensitivity to PZQ; (ii) stereoselectivity toward (R)-PZQ; (iii) mediation of sustained Ca 2+ signals in response to PZQ; and (iv) a pharmacological profile that mirrors the well-known effects of PZQ on muscle contraction and tegumental disruption. We anticipate that these findings will spur development of novel therapeutic interventions to manage schistosome infections and broader interest in PZQ, which is finally unmasked as a potent flatworm TRP channel activator.
In , &#;100 million people (&#;80 million school-aged children) received free preventive treatment for schistosomiasis. This treatment depends on a drug called praziquantel (PZQ), 2 as no effective vaccine currently exists ( 4 ). The clinical formulation of PZQ is a racemate (±PZQ) composed of the enantiomers (R)-PZQ and (S)-PZQ. (R)-PZQ is the antischistosomal eutomer, known to cause Ca 2+ influx and spastic paralysis of adult worms and rapid vacuolization of the worm tegumental surface ( 5 ). (S)-PZQ is regarded as the less active distomer ( 6 ). From a therapeutic perspective, it is problematic that despite decades of clinical usage, as well as demonstration of strains with lower sensitivity to PZQ in both laboratory and field, the flatworm target(s) of PZQ remains unknown ( 7 , 8 ). This lack of knowledge is a longstanding roadblock for this field.
Schistosomiasis (bilharzia) is a parasitic worm infection that infects millions of people worldwide ( 1 , 2 ). Mature blood flukes living in the vasculature lay eggs, which become deposited in host tissues, where they trigger local inflammatory responses. Chronic infections become associated with fibrosis and obstructive disease in gastrointestinal tissues and liver (Schistosoma mansoni, Schistosoma japonicum), genitourinary disease (Schistosoma haematobium), anemia, undernutrition, and a heightened risk for other comorbidities ( 3 ). The annual disease burden has been estimated as a loss of up to 70 million disability-adjusted life years ( 1 , 2 ).
The addition of (R)-PZQ (100 nm) to adult schistosome worms ex vivo caused a rapid, spastic paralysis ( A). The addition of the same concentration of (S)-PZQ was ineffective at causing contraction ( A). This demonstrates the differential potency of the two PZQ enantiomers against adult schistosome worms (EC50 for (R)-PZQ = 68 ± 7 nm, EC50 for (S)-PZQ = 1.1 ± 0.4 μm; B) observed both ex vivo and in vivo (6).
Although no binding site(s) for these enantiomers has been identified in parasitic flatworms, there has been considerable recent progress in identifying targets for (R)-PZQ and (S)-PZQ in the human host (9). (R)-PZQ is a partial agonist of the human 5-hydroxytryptamine 2B receptor (5HT2BR (10)), and (S)-PZQ is a partial agonist of the human transient receptor potential melastatin-8 channel (hTRPM8 (11)). Whereas regulation of these host targets occurs over the micromolar range (10,&#;12), molecular divergence between human and flatworm ligand-binding pockets (13, 14) makes it reasonable to anticipate different binding poises and affinities at a homologous schistosome target(s).
Following this logic, we searched for flatworm TRP channels exhibiting sequence homology to hTRPM8. One candidate, christened Sm.TRPMPZQ, mediated robust Ca2+ signals in response to ±PZQ and (R)-PZQ in transfected HEK293 cells that were not observed in either untransfected or vehicle-treated cells expressing Sm.TRPMPZQ ( A). (S)-PZQ also evoked a response in Sm.TRPMPZQ-expressing cells, but with slower kinetics suggestive of a stereoselectivity toward the PZQ enantiomers that would be poorly discriminated at the high concentration of the primary screening (50 μm; A). Established mammalian TRP ligands (menthol, allyl isothiocyanate (AITC), icilin, and capsaicin) did not activate Sm.TRPMPZQ ( A). The PZQ-evoked Ca2+ signal depended on Ca2+ entry across the plasma membrane, as removal of extracellular Ca2+ abolished the sustained cytoplasmic Ca2+ elevation ( B).
Full concentration&#;response curves were performed with (R)-PZQ ( , C and D), (S)-PZQ, and ±PZQ ( D). Sm.TRPMPZQ was activated by ±PZQ (EC50 = 1.08 ± 0.14 μm; D), and activation was stereoselective, with (R)-PZQ evoking Ca2+ signals over a considerably lower concentration range (EC50 = 597 ± 10 nm) than (S)-PZQ (EC50 = 27.9 ± 3.1 μm; D). When the incubation temperature was increased to 37 °C, (R)-PZQ activated Sm.TRPMPZQ over an even lower concentration range (EC50 = 154 ± 33 nm; D).
Early work on schistosomes established key pharmacological characteristics of PZQ action on parasite muscle contraction and/or 45Ca2+ uptake. These include (i) conversion of contraction from sustained to phasic in the presence of elevated Mg2+, (ii) inhibition by La3+, and (iii) insensitivity to several voltage-operated Ca2+ channel (Cav) blockers at specific doses. We therefore examined the impact of these same manipulations on Sm.TRPMPZQ activity. First, increasing the Mg2+/Ca2+ ratio to a level (75:1) that resulted in transient muscle contraction (15, 16) also resulted in a transient PZQ-evoked Ca2+ signal via Sm.TRPMPZQ ( E). Second, preincubation of worms with La3+ (10 mm) inhibited both PZQ-evoked 45Ca2+ accumulation and PZQ-evoked contraction (17). La3+ (10 mm) also inhibited Sm.TRPMPZQ activity ( F). Third, three Cav blockers (methoxyverapamil, nifedipine, and nicardipine) that failed to block PZQ action on worms (17, 18) also failed to inhibit PZQ-evoked Sm.TRPMPZQ activity at the same doses ( F). Therefore, the pharmacological properties of Sm.TRPMPZQ mirror the characteristics of PZQ action on schistosome muscle.
Consistent with the homology-based search strategy, Sm.TRPMPZQ is a member of the TRP melastatin (TRPM) subfamily. Sequence analysis revealed an architecture characteristic of TRPM channels ( G), a well-represented family within flatworm genomes (19). Features include a long N-terminal TRPM homology region (MHR) domain, followed by six predicted transmembrane (TM) domains with a pore-forming re-entry loop between TM5 and TM6, a conserved TRP helix juxtaposed to coiled-coil regions, and a cytoplasmic C-terminal enzymatic domain ( G). This enzyme domain displayed homology with the human ADP-ribose (ADPR) pyrophosphatase NUDT9, a feature characteristic of TRPM2 channels (20,&#;23). TRPM2 and TRPM8 are closely related &#;long&#; TRPM channels, and Sm.TRPMPZQ displays the highest sequence identity with these human TRPM variants (29.5 and 28.5% sequence identity with hTRPM2 and hTRPM8, respectively).
Analysis of flatworm genomic and transcriptomic data sets revealed the presence of Sm.TRPMPZQ homologs in other parasitic flatworms, including cestodes and flukes, known to exhibit PZQ sensitivity (Fig. S1A). To assess the broader PZQ sensitivity of schistosome TRP channels, we screened three other TRPs. First, we examined the previously characterized Sm.TRPA, which has been shown to activated by the ligands AITC and capsaicin (14). Sm.TRPA did not respond to PZQ but, as expected, did respond to the other two compounds (Fig. S1B). Next, we focused on the schistosome TRPM subfamily, which is predicted to contain seven members (Fig. S1A). The two members most closely related to Sm.TRPMPZQ (Smp_ and Smp_) did not respond to PZQ (Fig. S1, C and D). With the caveat that there is no control for functional expression, as endogenous agonists of these TRPM channels are unknown, these data suggest that schistosome TRP (and TRPM) channels are not broadly sensitive to PZQ.
Next, to resolve the single-cell kinetics of Sm.TRPMPZQ activity, we performed confocal Ca2+ imaging. In HEK cells transfected with empty vector, the addition of ±PZQ (10 μm) failed to evoke a cytoplasmic Ca2+ signal ( , A and B), although cells responded to ATP (100 μm), which activated endogenous purinoceptors. In contrast, in HEK cells transiently transfected with Sm.TRPMPZQ, the addition of ±PZQ (1 μm) evoked a rapid and protracted rise in cytoplasmic Ca2+ ( , A and B). Responses were evoked by (R)-PZQ, with (S)-PZQ being ineffective at the same concentration (1 μm; , A and B). The large and persistent increase in fluorescence evidenced little Sm.TRPMPZQ desensitization in the presence of ±PZQ and contrasted with the smaller, transient nature of Ca2+ signals evoked by ATP. This signal was triggered by Ca2+ influx, as this response was seen only when Ca2+-containing medium was re-added to HEK cells initially exposed to ±PZQ in Ca2+-free medium (Fig. S2A). Activation of Sm.TRPMPZQ by ±PZQ was also reversible, as ±PZQ washout resulted in a decrease of signal to baseline (Fig. S2B).
Electrophysiological analysis of Sm.TRPMPZQ was performed by measuring whole-cell currents in HEK cells expressing GFP alone or expressing GFP and Sm.TRPMPZQ. In cells expressing GFP alone, the addition of ±PZQ (2 μm) did not evoke currents (0 of 18 cells examined). In contrast, in HEK cells co-transfected with cDNA encoding both Sm.TRPMPZQ and GFP, the addition of ±PZQ evoked rapidly activating inward currents in all GFP-positive cells (22 of 22 cells, holding potential of &#;40 mV). Characterization of current magnitude after various voltage steps, in the absence and presence of PZQ (2 μm), revealed PZQ-activated Sm.TRPMPZQ-conducted large inward and outward currents with a linear I-V relationship ( C), resembling the linear I-V relationship displayed by hTRPM2 channels (24). Based on sequence homology with another invertebrate TRPM2 channel (Nematostella vectensis TRPM2, Nv.TRPM2) that has been structurally and functionally characterized (25), we speculated that the substantial Ca2+ permeability of Sm.TRPMPZQ ( , B and C) is supported by the presence of a negatively charged residue in the predicted pore filter of Sm.TRPMPZQ (FGD in D). This closely resembles the pore filter sequence of Nv.TRPM2 (YGE in D), which displays substantial Ca2+ permeability (25). Consistent with this idea, PZQ-evoked Ca2+ signals were strongly attenuated in HEK cells expressing the mutant Sm.TRPMPZQ[DA] ( E). Sm.TRPMPZQ therefore displays several characteristics consistent with the properties of TRPM2 channels.
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