Teratogenicity of Artemether-Clindamycin Nanostructured Lipid Carriers in Rats.
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.
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, Maharashtra, India.
Soniya A
SA
Jain
National Centre for Preclinical Reproductive and Genetic Toxicology, National Institute for Research in Reproductive Health, Mumbai, Maharashtra, India.
Madhavi
M
Awale
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India.
Sulabha
S
Pathak
National Centre for Preclinical Reproductive and Genetic Toxicology, National Institute for Research in Reproductive Health, Mumbai, Maharashtra, India vanageg@nirrh.res.in geetavanage@gmail.com.
Geeta
G
Vanage
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, Maharashtra, India.
Vandana B
VB
Patravale
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India.
Shobhona
S
Sharma
D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D000077549:Artemether; D037621:Artemisinins / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D002981:Clindamycin / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D004075:Diglycerides / Q000737:chemistry; D004337:Drug Carriers / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D005260:Female; D008288:Malaria / Q000188:drug therapy*; D008297:Male; D008431:Maternal-Fetal Exchange; D051379:Mice; D050178:Monoglycerides / Q000737:chemistry; D049329:Nanostructures / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D011247:Pregnancy; D017207:Rats, Sprague-Dawley
D000962:Antimalarials; D037621:Artemisinins; C000608598:Capmul MCM; D004075:Diglycerides; D004337:Drug Carriers; D050178:Monoglycerides; C025405:1,2-didodecanoylglycerol; D002981:Clindamycin; D000077549:Artemether
NLCs; artemether; clindamycin; malaria; pregnancy; teratogenic toxicity