Emetine Hydrochloride

Abstract: Background: Drug repurposing or repositioning refers to the usage of existing drugs in diseases other than those it was originally used for. For diseases like malaria, where there is an urgent need for active drug candidates, the strategy offers a route to significantly shorten the traditional drug development pipelines. Preliminary highthroughput screens on patent expired drug libraries have recently been carried out for Plasmodium falciparum. This study reports the systematic and objective further interrogation of selected compounds reported in these studies, to enable their repositioning as novel stand-alone anti-malarials or as combinatorial partners. Methods: SYBR Green flow cytometry and micro-titre plate assays optimized in the laboratory were used to monitor drug susceptibility of in vitro cultures of P. falciparum K1 parasite strains. Previously described fixed-ratio methods were adopted to investigate drug interactions. Results: Emetine dihydrochloride hydrate, an anti-protozoal drug previously used for intestinal and tissue amoebiasis was shown to have potent inhibitory properties (IC50 doses of ~ 47nM) in the multidrug resistant K1 strain of P. falciparum. The sum 50% fractional inhibitory concentration (∑FIC50, 90) of the interaction of emetine dihydrochloride hydrate and dihydroartemisinin against the K1 strains of P. falciparum ranged from 0.88-1.48. Conclusion: The results warrant further investigation of emetine dihydrochloride hydrate as a potential stand-alone anti-malarial option. The interaction between the drug and the current front line dihydroartemisinin ranged from additive to mildly antagonistic in the fixed drug ratios tested.

Abstract: This report details a Phase I dose‐ranging experiment of the use of emetine in patients with a variety of malignant diseases. The data show that emetine can be given intravenously at 4‐day intervals with minimal toxicity. Severe muscle weakness, the most important dose‐limiting toxic effect, began at approximately a 15 mg/kg cumulative dose level and resulted in discontinuance of therapy in two patients. Of 5 patients who received greater than 10.4 mg/kg, 2 stabilized previously rapidly progressive disease, one had marked reduction in a purulent bloody vaginal discharge, and 2 who had received the highest total dose had 50% or greater reduction in lung tumor size. The present data suggest a reasonable regimen to be 1.5 mg/kg IV weekly for a minimum total dose of 15 mg/kg. Emetine is not myelosuppressive and therefore may be useful in the patient with poor marrow reserve. Alternatively, it can be used in combination with agents of different toxicities in hope of showing additive effects without additive toxicity.

Abstract: • The abuse of ipecac syrup for three years resulted in painless, nonfatigable, chiefly proximal weakness in a 27-year-old woman. Electromyography (EMG) and a muscle biopsy revealed features of a myopathy similar to those previously reported in experimental emetine myopathy. Clinical weakness and EMG abnormalities improved after discontinuation of ipecac administration. A direct toxic action of ipecac (acting through its active alkaloid, emetine hydrochloride) on muscle fibers seemed to be responsible for the weakness in this patient.