Teratogenicity of Artemether–Clindamycin Nanostructured Lipid Carriers in Rats

Abstract

Currently, artemisinin-based combination therapy is considered the best option in the treatment of malaria. However, toxicity of artemisinins limits their use in pregnancy. In the absence of sufficient toxicity data, the World Health Organization recommends that artemisinins are not to be used in the first trimester of pregnancy and can be used only in second and third trimesters, when other treatments are not available. We have recently observed that drugs loaded in nanolipid carriers are selectively taken up in Plasmodium-infected erythrocytes with a concomitant reduction in the dose required to cure animals. Thus, 20% of the therapeutic dose of artemether-clindamycin (ARM-CP) loaded in nanostructured lipid carriers (NLCs; mean particle size 55 ± 10 nm) resulted in complete parasite clearance and 100% survival of infected mice. Here, we investigate the teratogenicity of this formulation in rodents (dosing on alternate days from 6th day to 18th day of gestation; 12-15 animals/group). The teratogenicity of drug-free NLCs and artesunate-clindamycin (ARS-CP) solution was also evaluated. We found that the therapeutic dose of ARS-CP caused fetal resorptions (87.5% resorptions in 8 litters), suggesting its unsuitability for use in pregnancy. Artesunate-clindamycin NLCs at therapeutic doses also resulted in ∼90% fetal resorptions in 10 litters examined. However, postimplantation losses or fetal malformations were not observed at the dose of ARM-CP NLCs that was required for complete parasite clearance in preclinical trials (ie, 20% of the therapeutic dose). Our data suggest that the NLCs loaded with 20% of the therapeutic dose of ARM-CP may have potential in treating malaria during pregnancy.

Teratogen update: Malaria in pregnancy and the use of antimalarial drugs in the first trimester

“…Studies of DHA (Longo, Zanoncelli, Manera, et al, 2006) and other studies of artemisinins in rats (Abolaji et al, 2013; Adebisi, 2008, 2010; Boareto et al, 2008, 2012, 2013; Chung, Yu, Lee, & Lee, 2013; Clark, Brannen, Sanders, & Hoberman, 2011; El‐Dakdoky, 2009; Jain, et al, 2016; Rath, Jena, Samal, & Rath, 2010), rat whole embryo culture (Longo, Zanoncelli, Manera, et al, 2006; Longo, Zanoncelli, Torre, et al, 2006), and rabbits (Schmuck, Klaus, Krotlinger, & Langewische, 2009) have shown a similar pattern of embryo death and/or cardiovascular malformations. Studies conducted since 2007 were recently reviewed by González et al, 2020.…”

The immunosuppressive activity of artemisinin‐type drugs towards inflammatory and autoimmune diseases

“…Nevertheless, should this nanoparticle formulation be further developed as drug, its use in pregnancy must be excluded. 167…”