Praziquantel

Toxicity

The acute toxicity of praziquantel is relatively low, as demonstrated by oral LD50 values ranging between 200 - 2976 mg/kg in various species.

Description

Praziquantel (PZQ) is an isoquinoline derivative with most of the biological activity found in the levo enantiomer. The compound has no activity against nematodes, but it is highly effective against cestodes and trematodes.

Chemical properties

White Solid

Originator

Cesol ,Merck ,W. Germany ,1980

The Uses of Praziquantel

Praziquantel is a highly effective anthelmintic used against schistosome and many cestode infestations. It is used to study voltage-gated Ca2+ channels and is a potential small molecule neurogenic.

The Uses of Praziquantel

Anthelmintic, effective against flatworms.

The Uses of Praziquantel

anthelmintic; EMBAY-8440

Background

An anthelmintic used in most schistosome and many cestode infestations.

Indications

For the treatment of infections due to all species of schistosoma.

Indications

The neuromuscular effects of praziquantel (Biltricide) appear to increase parasite motility leading to spastic paralysis. The drug increases calcium permeability through parasite-specific ion channels, so that the tegmental and muscle cells of the parasite accumulate calcium.This action is followed by vacuolization and the exposure of hitherto masked tegmental antigens, lipidanchored protein, and actin. Insertion of the drug into the fluke’s lipid bilayer causes conformational changes, rendering the fluke susceptible to antibody- and complement-mediated assault.

Definition

ChEBI: 2-[cyclohexyl(oxo)methyl]-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one is a member of isoquinolines.

Manufacturing Process

15 g of a nickel-aluminum alloy (1:1) is introduced in incremental portions and under agitation into 200 ml of 20% sodium hydroxide solution within 5 minutes; the mixture is maintained at 80°C for 45 minutes, then allowed to settle, decanted off, washed with water, and 1,000 ml of 1% (-)-tartaric acid solution is added thereto, adjusted to pH 5 with 1 N sodium hydroxide solution. The mixture is heated under agitation for 90 minutes to 80°C, decanted, and washed with water and methanol. The thus-obtained (-)tartaric acid-Raney nickel catalyst is added to a solution of 2cyclohexylcarbonyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino[2,1-a]isoquinoline. The reaction mixture is hydrogenated under normal pressure and at room temperature. After the catalyst has been filtered off and the solvent evaporated, 2-cyclohexylcarbonyl-4-oxo-1,2,3,6,7,11b-hexahydro-4Hpyrazino[2,1-a]isoquinoline, melting point 136°C to 138°C, is produced.

brand name

Biltricide (Bayer).

Therapeutic Function

Anthelmintic

Acquired resistance

There is evidence that resistance to praziquantel is emerging in schistosomes, although there is debate as to whether treatment failures are due to resistance or innate tolerance.

Pharmaceutical Applications

A synthetic pyrazinoquinoline formulated for oral administration. It is stable in the dry state, but hygroscopic.

Mechanism of action

Praziquantel is readily absorbed (80% in 24 hours) after oral administration, with serum concentrations being maximal in 1 to 3 hours; the drug has a half-life of 0.8 to 1.5 hours. Its bioavailability is reduced by phenytoin or carbamazepine and increased by cimetidine. Dexamethasone decreases plasma praziquantel levels by 50%. Praziquantel is excreted by the kidneys.

Pharmacokinetics

Praziquantel is an anthelmintic used in most schistosome and many cestode infestations. Praziquantel effects the permeability of the cell membrane resulting in the contraction of schistosomes. The drug further causes vacuolization and disintegration of the schistosome tegument. The effect is more marked on adult worms compared to young worms. An increased calcium influx may play an important role. Secondary effects are inhibition of glucose uptake, lowering of glycogen levels and stimulation of lactate release. The action of praziquantel is limited very specifically to trematodes and cestodes; nematodes (including filariae) are not affected.

Pharmacokinetics

Oral absorption: >80%
C_max 50 mg/kg oral: 1 mg/L after 1–2 h
Plasma half-life: parent drug: 1–1.5 h
metabolites: 4–6h
Plasma protein binding: 80%
Praziquantel is rapidly absorbed when given orally, but it undergoes extensive first-pass biotransformation and the concentration of unchanged drug in plasma is low. The major metabolite, a 4-hydroxy derivative, retains little to no antiparasitic activity. About 80% of the oral dose, as parent drug and its metabolites, is excreted in the urine by the fourth day post-treatment, 90% of this in 24 h. A higher peak plasma concentration is achieved in infected people, but other pharmacokinetic values are unchanged.

Clinical Use

Schistosomiasis
Other trematode infections (except F. hepatica)
Tapeworm infection, including cerebral cysticercosis
Treatment may need to be prolonged in cerebral cysticercosis.

Clinical Use

2-(Cyclohexylcarbonyl)-1,2,3,6,7, 11b-hexahydro-4Hpyrazino[2,1-a]isoquinolin-4-one (Biltricide) is a broadspectrumagent that is effective against various trematodes (flukes). It has become the agent of choice for the treatmentof infections caused by schistosomes (blood flukes).
The drug also provides effective treatment for fasciolopsiasis(intestinal fluke), clonorchiasis (Chinese liver fluke),fascioliasis (sheep liver fluke), opisthorchosis (liver fluke),and paragonimiasis (lung fluke). Praziquantel increases cellmembrane permeability of susceptible worms, resulting inthe loss of extracellular calcium. Massive contractions andultimate paralysis of the fluke musculature occurs, followedby phagocytosis of the parasite.
Following oral administration, about 80% of the doseis absorbed. Maximal plasma concentrations are achievedin 1 to 3 hours. The drug is rapidly metabolized in theliver in the first-pass. It is likely that some of the metabolitesare also active. Praziquantel occurs as a white crystallinesolid that is insoluble in water. It is available as600-mg film-coated tablets. The drug is generally welltolerated.

Clinical Use

Praziquantel is an extremely active broad-spectrum anthelmintic that is well tolerated. It is the most effective of the drugs used in the treatment of schistosomiasis, possessing activity against male and female adults and immature stages. Unlike other agents, it is active against all three major species (S. haematobium, S. mansoni, and S. japonicum). In addition, it has activity against other flukes, such as C. sinensis, Paragonimus westermani, O. viverrini, and the tapeworms (D. latum, H. nana, T. saginata, and T. solium). It is not as effective against F. hepatica. It is used effectively in the treatment of clonorchiasis and paragonimiasis and is an effective alternative agent to niclosamide in the treatment of tapeworm infestations.

Side Effects

Very few side effects have been reported. In the treatment of cerebral cysticercosis the death of cysts in the brain may cause local inflammation and edema, but this usually subsides quickly. Ocular cysticercosis should not be treated with this drug, because parasite destruction in the eye can lead to irreparable lesions. Adverse events seen in the treatment of schistosomiasis, including abdominal pain, nausea, anorexia, diarrhea and mild neurological effects, are almost certainly due to the death and disintegration of the large adult worms.

Side Effects

Adverse reactions tend to occur within a few hours of administration. They include gastrointestinal intolerance with nausea, vomiting, and abdominal discomfort. This may be due to the liberation of helminth proteins from dead worms rather than any direct effect of the drug.

Safety Profile

Poison by intraperitoneal route.Moderately toxic by ingestion and other routes. Humanmutation data reported. When heated to decomposition itemits toxic fumes of NOx.

Synthesis

Praziquantel, 2-(cyclcohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino [2,1a]isoquinolin-4-one (38.1.15), is a derivative of pyrazinoquinoline that is made in two ways. According to one of them, 1-aminomethyl-1,2,3,4-tetrahydroisoquinoline is alkylated with chloroacetic acid, and then the resulting amine is acylated with cyclohexanecarbonyl chloride to make 1-(N-carboxymethyl-N-cyclohexylcarbonylaminomethyl)-1,2,3,4-tetra-hydroisoquinoline (38.1.14), which is heated at 150°C to give the desired praziquantel.

Another way of synthesizing this drug begins with isoquinoline, which is reacted with a mixture of cyclohexanecarbonyl chloride / potassium cyanide to make a dihydro derivative of isoquinoline (38.1.16). This is reduced by hydrogen over Raney nickel to give the reduction–reamidation product—the amide 1-(N-cyclohexylcarbonylaminomethyl)- 1,2,3,4-tetrahydroisoquinoline (38.1.17). Acylating this with chloracetic acid chloride gives a chlroacetyl derivative (38.1.18), which when heated in the presence of diethylamine results in an intramolecular alkylation, giving the desired product—prazi quantel.

Veterinary Drugs and Treatments

Praziquantel is indicated for (approved labeling) for the treatment of Dipylidium caninum, Taenia pisiformis, and Echinococcus granulosis in dogs, and Dipylidium caninum and Taenia taeniaeformis in cats. Fasting is not required nor recommended before dosing. A single dose is usually effective, but measures should be taken to prevent reinfection, particularly against D. caninum. Praziquantel can also be used for treating Alaria spp. in dogs and cats and Spirometra mansonoides infections in cats.
Praziquantel has been used in birds and other animals, but it is usually not economically feasible to use in large animals. In humans, praziquantel is used for schistosomiasis, other trematodes (lung, liver, intestinal flukes) and tapeworms. It is not routinely effective in treating F. hepatica infections in humans.
Combination products can give a wide spectrum of internal parasite control in a variety of species.

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: concentration reduced by rifampicin - avoid.
Antiepileptics: concentration reduced by carbamazepine, fosphenytoin, phenobarbital, phenytoin and primidone.
Antimalarials: concentration reduced by chloroquine.
Ulcer-healing drugs: concentration reduced by cimetidine.

Metabolism

Praziquantel is rapidly absorbed and undergoes hepatic first-pass metabolism. The metabolites are either less active or inactive and consist of hydroxylated compounds. In the serum, the major metabolite appears to be the monohydroxylated 4-hydroxycyclohexylcarboxylate, whereas in the urine, 50 to 60% of the initial PZQ exists as dihydroxylated products.These hydroxylation reactions are catalyzed by CYP2B6 and CYP3A4. The metabolites would be expected to exist in the conjugated form in the urine.