Toxicity associated with repeated administration of artemether–lumefantrine in rats

Abstract

Chemotherapy remains an important approach in the fight against malaria. Artemether-lumefantrine combination is widely in use due to its effectiveness against Plasmodium falciparum. Misuse in the form of multiple repeated doses of this anti-malaria drug is rampant in Nigeria. This study was designed to assess the hepatotoxic and clastogenic potential of extreme misuse of artemether-lumefantrine in rats. Graded doses of artemether-lumefantrine (1-5 mg/kg body weight) were administered by oral gavage for 6 weeks, twice daily, for 3 consecutive days per week. Artemether-lumefantrine, at all doses, did not have significant effects on the body and relative liver weight of treated group compared to the negative control group. The mean γ-glutamyltransferase, alanine, and aspartate aminotransaminase activity in groups of artemether-lumefantrine treated rats were significantly higher (p < 0.05) than that of the negative control group indicating that repeated administration of artemether-lumefantrine may be hepatotoxic. Findings from histological analyses of liver cross-section support the enzyme pattern of hepatoxicity. In addition, the drug, at all experimental doses, significantly induced (p < 0.05) formation of micronucleated polychromatic erythrocytes in the bone marrow cells of the treated rats compared with the negative control indicating clastogenic potential of the drug when misused.

A Phase II pilot trial to evaluate safety and efficacy of ferroquine against early Plasmodium falciparum in an induced blood-stage malaria infection study

“…These changes normalized post confinement for ferroquine treatment, but increased again after end of study treatment with A/L, peaking at levels of AST 208 U/L and ALT 347 U/L on day 28 (day 20 post ferroquine). The relationship of these derangements with the administration of ferroquine could not be determined with certainty, as the ALT peak occurred after the subject had received A/L treatment, which can lead to transient elevation of transaminases [ 41 ]. These changes had returned to baseline by day 42.…”

Unsweetened Natural Cocoa Powder: A Potent Nutraceutical in Perspective

“…Increased therapeutic efficacy was reported to be associated with the use of the combination. Treatment failure to these therapies is suspected, and in recent years, some countries have considered increasing the dose of the A/L in treatment in order to arrest the issue of resistance [31], but increase in dose implies that there will be increased side effects, adverse reactions, and hepatotoxic effects [32]. In fact, there are already concerns about frequent usage of A/L on some organ systems [28].…”

Haematological Changes and Nitric Oxide Levels Accompanying Artemether-Lumefantrine Administration in Male Guinea Pigs: Effect of Unsweetened Natural Cocoa Powder.

“…A-L administration has been found to reduce NO levels. On the contrary, other studies have also shown that A-L increases NO levels as a compensatory mechanism in cases of reduced NO levels [ 16 , 26 ].…”

“…Though the WHO-recommended artemisinin-based combination therapy (ACT) [ 22 , 23 ] has impressive parasiticidal properties both in vivo and in vitro , there have been issues of treatment failures, resistance, and increasing cases of toxic effects [ 24 , 25 ]. Some countries have, therefore, considered increasing the dose of A-L used in the management of malaria to arrest the issue of resistance [ 26 ]. However, increase in dose implies that there will be increased side effects, adverse reactions, and other toxic effects [ 27 ].…”