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=Meclonazepam=

Meclonazepam is an anxiolytic, benzodiazepine derivative drug. It has been shown that, when administered at high doses, it can act as an effective therapeutic and prophylactic treatment of schistosomiasis. Meclonazepam has been proposed as a new schistosomicidal drug due to its effectiveness against S. mansoni and S. haematobium trematode worms, however it has been proven to have a low level of selectivity, casting doubt on whether it is the best drug to treatment schistosomiasis. Meclonazepam is not FDA approved in the US.

History
Meclonazepam, was discovered by a team at Hoffmann-La Roche in the 1970s. It was developed due to parasite resistance to Preziquantel, the only available drug to treat schistosomiasis at the time. A key factor that led to researchers’ interest in Meclonazepam as a schistomicidal drug treatment was its structural similarity to the drug clonazepam, a benzodiazepine derivative that had already been shown to have both antiepileptic and anxiolytic effects.

Mechanism of Action
There is uncertainty about the exact mechanism of action of meclonazepam, but two benzodiazepine-binding sites have been identified as possible drug targets.

Pharmacological Properties
Various studies of S. mansoni have identified some of the pharmacological properties of meclonazepam. Findings of these studies have shown that meclonazepam has a low affinity binding site and a Kd of 2 µM, as well as a half maximal lethal concentration (LC50) of 3 µM, which suggest that administration of meclonazepam leads to parasite death through calcium dependent paralysis and tegumental dysfunction. The Cmax of meclonazepam has been found to be less than 600 nM. This indicates that when administered in vivo, meclonazepam likely acts at unidentified receptors, as this concentration is less than that which would be effective on schistosomes in culture.

Both meclonazepam and clonazepam show an inversely proportional relationship between the proportion of the drug in blood plasma and the dose of the drug, showing that their structural similarities lead to pharmacological similarities.

Chemical Properties and Adverse Effects
Molecular modeling has been used to determine the structure and chemical properties of meclonazepam. The chemical structure contains a 1,4-diazepine ring in an equatorial position, which minimizes the steric hindrance of amide and imine moieties present on the compound. A key structural aspect that leads to schistosomicidal effect of the drug is the amide moiety of the M conformation of S-(+)-meclonazepam, as it is also found in R-(-)-praquantel, which elicits the same schistosomicidal effect. In addition to its therapeutic effects, meclonazepam shares the same adverse effects as other benzodiazepines such drowsiness, ataxia and muscle weakness. These side effects can be overcome, however, when it is administered in conjunction with the drug Ro 15-1788.

Biological assays
Meclonazepam has been studied, along with praziquantel and clonazepam, in relation to short-term worm motility. The application of each of these drugs paralyzed spastic movements in worms.

Binding assay
When evaluated through a binding assay, meclonazepam showed less of an affinity for both central and peripheral benzodiazepine binding sites relative to other ligands.

Schistosomicidal effect
An in vitro study in parasitic worms showed meclonazepam to have therapeutic effects against schistosomaisis. A 5-day exposure to the drug resulted in the death of all of the worms exposed.

Dosing studies
Central arousal, mood and psychomotor performance were all evaluate after single oral doses of meclonazepam were administered. Doses greater than 1 mg elicited impairments in all three areas. With a dose of 4 mg, these impairments were most prominent in the first three hours, but lasted for up to 6 hours.