Praziquantel

Praziquantel

File:Praziquantel.svg
File:Praziquantel.gif
Systematic (IUPAC) name
(RS)-2-(Cyclohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one
Clinical data
Trade names	Biltricide
AHFS/Drugs.com	monograph
MedlinePlus	a608048
Pregnancy category	Only when clearly needed (lack of sufficient data in humans)
Legal status	U.S.: Rx-only (human use), over-the-counter (veterinary use)[1]
Routes of administration	oral
Pharmacokinetic data
Bioavailability	relatively small
Metabolism	hepatic
Biological half-life	0.8 to 1.5 hours (Main Metabolites 4 to 5 hours)
Excretion	mainly in urine
Identifiers
CAS Number	55268-74-1 Y
ATC code	P02BA01 (WHO) QP52AA01 (WHO)
PubChem	CID: 4891
DrugBank	DB01058 Y
ChemSpider	4722 Y
UNII	6490C9U457 Y
KEGG	D00471 Y
ChEMBL	CHEMBL976 Y
Chemical data
Formula	C19H24N2O2
Molecular mass	312.411
SMILES O=C4N2C(c1c(cccc1)CC2)CN(C(=O)C3CCCCC3)C4
InChI InChI=1S/C19H24N2O2/c22-18-13-20(19(23)15-7-2-1-3-8-15)12-17-16-9-5-4-6-14(16)10-11-21(17)18/h4-6,9,15,17H,1-3,7-8,10-13H2 Y Key:FSVJFNAIGNNGKK-UHFFFAOYSA-N Y
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Praziquantel, marketed as Biltricide, is an anthelmintic used in humans and animals for the treatment of tapeworms and flukes. Specifically, it is effective against schistosoma, Clonorchis sinensis the fish tapeworm Diphyllobothrium latum.

It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.

Medical uses

Praziquantel is used to treat diseases in humans, mammals, and fish that are caused by infection with several types of internal/gastrointestinal, and external parasites, including:

• Salmon poisoning disease
• Hydatid disease caused by infection of various organs with larval stages of tapeworms of the genus Echinococcus
• Cysticercosis caused by infection of the brain and/or muscles with the eggs and larvae of the pork tapeworm Taenia solium (though it has been judged less effective than albendazole in treatment of neurocysticercosis)
• In cats and dogs whose gastrointestinal tract is infected with the tapeworms Dipylidium caninum or Taenia taeniaeformis, respectively; praziquantel is also often used in fixed combination with pyrantel embonate against the roundworms (ascarids): Toxocara cati and Toxascaris leonina. Praziquantel is also effective against Echinococcus multilocularis.
• Schistosomiasis caused by trematodes of the genus Schistosoma. As of 2005, praziquantel is the primary treatment for human schistosomiasis, for which it is usually effective in a single dose.
• Clonorchiasis brought on by the Chinese liver fluke Clonorchis sinensis
• Paragonimiasis caused by infection with lung flukes, mostly of the species Paragonimus westermani
• Fasciolopsiasis caused by intestinal fluke Fasciolopsis buski
• Diplozoon paradoxum and other Trematoda infections of many fish species

Side effects

The majority of side effects develop due to the release of the contents of the parasites as they are killed and the consequent host immune reaction. The heavier the parasite burden, the heavier and more frequent the side effects normally are.

• Central nervous system: Frequently occurring side effects are dizziness, headache, and malaise. Drowsiness, somnolence, fatigue, and vertigo have also been seen. Almost all patients with cerebral cysticercosis experience CNS side effects related to the cell-death of the parasites (headache, worsening of pre-existing neurological problems, seizures, arachnoiditis, and meningism). These side effects may be life-threatening and can be reduced by coadministration of corticosteroids. It is strongly recommended that all patients with cerebral cysticercosis are hospitalized during treatment.
• GI Tract: Approximately 90% of all patients have abdominal pain or cramps with or without nausea and vomiting. Diarrhea may develop and may be severe with colic. Sweating, fever, and sometimes bloody stools may occur together with diarrhea.
• Liver: Asymptomatic and transient increases of liver enzymes (AST and ALT) are noted frequently (up to 27%). No case of symptomatic liver damage has ever been seen so far.
• Sensitivity reactions: Urticaria, rash, pruritus and eosinophilia in white blood cell counts
• Other locations/body as a whole: Lower back pain, myalgia, arthralgia, fever, sweating, various cardiac arrhythmias, and hypotension

Drug interactions

The antibiotic rifampicin decreases plasma concentrations of praziquantel.

Carbamazepine and phenytoin are reported to reduce the bioavailability of praziquantel.

Chloroquine reduces the bioavailability of praziquantel.

The drug cimetidine heightens praziquantel bioavailability.

Mechanism of action

The mode of action is not exactly known at present, but experimental evidence indicates praziquantel increases the permeability of the membranes of schistosome cells towards calcium ions. The drug thereby induces contraction of the parasites, resulting in paralysis in the contracted state. 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.

Another hypothesis concerning the mechanism of action of praziquantel has been recently reported. The drug seems to interfere with adenosine uptake in cultured worms. This effect may have therapeutical relevance given that the schistosome, as the Taenia and the Echinococcus (other praziquantel-sensitive parasites), is unable to synthesize purines such as adenosine de novo.

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."

Praziquantel is administered as a racemate, but only the (R)-enantiomer is biologically active; the enantiomers may be separated using a resolution of an amine obtained from praziquantel.

Pharmacokinetics

Praziquantel is well absorbed (about 80%) from the gastrointestinal tract. However, due to extensive first-pass metabolism, only a relatively small amount enters systemic circulation. Praziquantel has a serum half-life of 0.8 to 1.5 hours in adults with normal renal and liver function. Metabolites have a half-life of 4 to 5 hours. In patients with significantly impaired liver function (Child Pugh classes B ll///d C), the serum half-life is increased to 3 to 8 hours. Praziquantel and its metabolites are mainly excreted renally; within 24 hours after a single oral dose, 70 to 80% is found in urine, but less than 0.1% as the unchanged drug. Praziquantel is metabolized through the cytochrome P450 pathway via CYP3A4. Agents that induce or inhibit CYP3A4 such as phenytoin, rifampin, and azole antifungals will affect the metabolism of praziquantel.

Praziquantel has a particularly dramatic effect on patients with schistosomiasis. Studies of those treated have shown that within six months of receiving a dose of praziquantel, up to 90% of the damage done to internal organs due to schistosomiasis infection can be reversed.

History

Praziquantel was developed in the laboratories for parasitological research of Bayer AG and Merck KGaA in Germany (Elberfeld and Darmstadt) in the mid 1970s.

Society and culture

Brand names

• Biltricide (Bayer) Tablets (for human use)
• Cesol (Merck) Tablets
• Cestoved (Vedco) both tablets and injectable for veterinary use
• Cysticide (Merck) Tablets
• Distoside (Chandra Bhagat Pharma Pvt Ltd) tablet (for human use)
• Droncit (Bayer) for veterinary use
• Drontal (combination with pyrantel pamoate) (Bayer) for veterinary use
• D-Worm (Farnum) for veterinary use; note that D-Worm also makes roundworm medicine containing piperidine which is not effective against tapeworms.
• Fish Tapes (Thomas Labs) for aquarium use
• Kaicide (Taiwan)
• Milbemax (combination with milbemycin oxime) (Novartis) for veterinary use
• Popantel (Jurox)
• PraziPro (Hikari) for aquarium use
• Praz-Tastic (NFP/National Fish Pharmaceuticals) for aquarium use
• Pure Prazi (COTS Koi/Children of the Sun Koi) for aquarium use
• PraziPure (J.K.O., Inc. d/b/a Kodama Koi Farm & Kodama Koi Garden; licensed by COTS Koi) for aquarium use
• Profender (combination with emodepside) (Bayer) for veterinary use
• Tape Worm Tabs (Trade Winds) for veterinary use
• Zentozide (Berich (Thailand) Co)

Regulatory approval

Praziquantel is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.

Praziquantel is not licensed for use in humans in the UK but it can be imported when necessary on a named patient basis. It is available in the UK as a veterinary anthelmintic.

Praziquantel is FDA approved in the US for the treatment of schistosomiasis and liver fluke, although it is effective in other infections.