PMID- 21312322
OWN - NLM
STAT- MEDLINE
DCOM- 20110727
LR  - 20181201
IS  - 1542-9741 (Electronic)
IS  - 1542-9733 (Linking)
VI  - 92
IP  - 1
DP  - 2011 Feb
TI  - Artesunate and artelinic acid: association of embryotoxicity, reticulocytopenia, 
      and delayed stimulation of hematopoiesis in pregnant rats.
PG  - 52-68
LID - 10.1002/bdrb.20282 [doi]
AB  - The artemisinin antimalarials cause embryo death and malformations in animals by 
      killing embryonic erythroblasts. Groups of pregnant rats (N = 4) were 
      administered 35 and 48 micromol/kg artesunate and 17.2, 28.7, 48, 96, and 191 micromol/kg 
      artelinic acid as a single oral dose on gestational day (GD) 12. Litters were 
      examined on GD21. The ED(50) for embryo death with artelinic acid (23.4 micromol/kg) 
      was just slightly lower than that for decreased reticulocyte count at 24 hr 
      postdose (33.5 micromol/kg) and both had similarly steep dose responses (maximal 
      effects of total litter loss and  approximately 60% decreases in reticulocyte count at 48 
      micromol/kg). Results with artesunate were similar. The correlation coefficient 
      between embryo death and decreased reticulocyte count was 0.82 (p<0.01). The 
      close relationship between embryotoxicity and reticulocytopenia is suggestive of 
      a common mechanism-artemisinin-induced mitochondrial damage leading to cell 
      death. At 9 days postdose, treatment with artesunate and artelinic acid also 
      caused increases in counts of reticulocytes, lymphocytes, basophils, and 
      monocytes (up to 3.7 x, 1.7 x, 4.7 x, and 1.7 x control, respectively). This 
      stimulation of hematopoiesis may have been mediated by the direct oxidative 
      conversion of artesunate or artelinic acid to the artemisininyl hydroperoxide 
      within the bone marrow cells or by an indirect increase in reactive oxygen 
      species. The high correlation between embryotoxicity and reticulocytopenia 
      further supports the assertion that therapeutic dosage regimens of artemisinins 
      that cause decreases in reticulocyte count in pregnant women during the putative 
      critical period (approximately postconception wk 3 to 9) are at risk of also 
      causing adverse effects on the embryo.
CI  - (c) 2011 Wiley-Liss, Inc.
FAU - Clark, Robert L
AU  - Clark RL
AD  - Artemis Pharmaceutical Research, Lansdale, PA 19446, USA. clarkl33@hotmail.com
FAU - Brannen, Kimberly C
AU  - Brannen KC
FAU - Sanders, James E
AU  - Sanders JE
FAU - Hoberman, Alan M
AU  - Hoberman AM
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Birth Defects Res B Dev Reprod Toxicol
JT  - Birth defects research. Part B, Developmental and reproductive toxicology
JID - 101155115
RN  - 0 (Artemisinins)
RN  - 08X93406PG (artelinic acid)
RN  - 60W3249T9M (Artesunate)
SB  - IM
MH  - Animals
MH  - Artemisinins/chemistry/*toxicity
MH  - Artesunate
MH  - Body Weight/drug effects
MH  - Embryo, Mammalian/*drug effects
MH  - Female
MH  - Hematopoiesis/*drug effects
MH  - Leukocyte Count
MH  - Litter Size
MH  - Platelet Count
MH  - Pregnancy
MH  - Rats
MH  - Reticulocyte Count
MH  - Reticulocytes/*drug effects/*pathology
MH  - Spleen/drug effects/pathology
MH  - *Toxicity Tests
EDAT- 2011/02/12 06:00
MHDA- 2011/07/28 06:00
CRDT- 2011/02/12 06:00
PHST- 2011/02/12 06:00 [entrez]
PHST- 2011/02/12 06:00 [pubmed]
PHST- 2011/07/28 06:00 [medline]
AID - 10.1002/bdrb.20282 [doi]
PST - ppublish
SO  - Birth Defects Res B Dev Reprod Toxicol. 2011 Feb;92(1):52-68. doi: 
      10.1002/bdrb.20282.