Mechanism of action
Experimental evidence indicates praziquantel increases the permeability of the membranes of schistosome cells towards calcium ions. The drug thereby induces contraction of the parasites' muscle, resulting in paralysis in the contracted state. Another early effect of praziquantel on schistosomes is morphological disruption of the tegumental surface of the worm, exposing parasite antigens to the host immune system, and likely rendering the parasite more susceptible to host immune attack.[34] The dying parasites are dislodged from their site of action in the host organism and may enter systemic circulation or may be destroyed by host immune reaction (phagocytosis). Additional mechanisms including focal disintegrations and disturbances of oviposition (laying of eggs) are seen in other types of sensitive parasites.[35]
Praziquantel is administered as a racemate; the (R)-enantiomer has greater antiparasitic activity than the (S)-enantiomer, both in vitro and in vivo; the enantiomers may be separated using a resolution of an amine obtained from praziquantel, as well as by other methods.[36]
Praziquantel is not effective against juvenile (3-4 week post-infection) mammalian-stage schistosomes, a property that has implications for efficacy and timing of drug treatment.[37]
The primary molecular target of the drug appears to be TRPMPZQ, a Ca2+-permeable transient receptor potential (TRP) ion channel that is found in schistosomes and other praziquantel-sensitive platyhelminths.[38] TRPMPZQ is a voltage-independent channel that is a member of the TRPM family of the TRP ion channel superfamily.[39][40] The active (R)-enantiomer of praziquantel activates Schistosoma mansoni TRPMPZQ with an EC50 of 597 nM (154 nM at 37°C); the EC50 for the less biologically active (S)-enantiomer is 27.9 μM. TRPMPZQ is also found in the praziquantel-insensitive liver fluke, Fasciola hepatica, but exhibits a critical amino acid change in the praziquantel binding pocket from asparagine to threonine, resulting in insensitivity to activation of the channel by praziquantel. Schistosomes selected for diminished sensitivity to praziquantel exhibit reduced levels of TRPMPZQ expression.[38] The physiological role of TRPMPZQ in the parasite is currently unknown.[38]
Interestingly, the inactive (S)-enantiomer of praziquantel activates a human TRPM8 channel, and it has been suggested that this interaction may enhance a praziquantel-induced elimination of schistosomes by increasing vascular contraction in host mesenteric vessels, where parasites may reside (the interaction with TRPM8 may as well be responsible for the unpleasant taste of the drug).[41]
Although TRPMPZQ appears to be the primary target of praziquantel, it is clear that praziquantel also interacts with other targets. These include a platyhelminth-specific voltage-gated calcium channel β subunit that, when paired with an α1 subunit, results in activation of the expressed channel by 100 nM praziquantel.[42] Interestingly, praziquantel also disrupts the polarity of regeneration in free-living planarians (eg, Dugesia), an effect dependent on the expression of neuronal voltage-operated calcium channel isoforms.[43]
Praziquantel is also an inhibitor of, and a likely substrate for, a schistosome P-glycoprotein-like multidrug resistance transporter. Increased expression of this or another schistosome multidrug resistance transporter correlates with reduced sensitivity to praziquantel, while inhibition or knockdown of expression of these proteins increases worm responsiveness to praziquantel.[44][45]
Another hypothesis for praziquantel mode of action is that it interferes with adenosine uptake in schistosomes.[46] This effect may have therapeutic relevance given that schistosomes, as well as Taenia and the Echinococcus (other praziquantel-sensitive parasites), are unable to synthesize purines, such as adenosine, de novo.[47]
Bayer's Animal Health Division website states, "Praziquantel is active against cestodes (tapeworms). Praziquantel is absorbed, metabolized in the liver, and excreted in the bile. Upon entering the digestive tract from the bile, cestocidal activity is exhibited. Following exposure to praziquantel, the tapeworm loses its ability to resist digestion by the mammalian host. Because of this, whole tapeworms, including the scolices (plural of "scolex"), are very rarely passed after administration of praziquantel. In many instances, only disintegrated and partially digested pieces of tapeworms will be seen in the stool. The majority of tapeworms are digested and are not found in the feces."[48][49]
