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Effect of trans(E)‐clopenthixol on Plasmodium berghei in vivo

Previous in vitro studies have shown suppression of the growth of Plasmodium falciparum by the neuroleptic agents chlorpromazine and zuclopenthixol (formerly known as cis(Z)‐clopenthixol) as well as by the neuroleptic inactive steroisomer trans(E)‐clopenthixol. These compounds are chemically related to riboflavin and may act as inhibitors of riboflavin metabolism. As trans(E)‐clopenthixol has been found active against chloroquine‐resistant strains of P. falciparum in vitro and has been approved for human use, though inactive as a neuroleptic, this drug was selected for the present in vivo study. The dosage of trans(E)‐ clopenthixol was optimized through a pharmacokinetic study, and the suppression of the growth of Plasmodium berghei in vivo was tested in mice, with chloroquine acting as the positive and saline as the negative control. Trans(E)‐clopenthixol did not inhibit the growth of P. berghei, whereas chloroquine almost eradicated the infection. The use of in vitro screening for anti‐malarial activity in drugs approved for human use for other indications is discussed in the light of the results. It is concluded that the selection of drugs for further studies in vivo cannot solely be based on positive results in vitro.