Sensitive periods for developmental toxicity of orally administered artesunate in the rat

White, Tacey E.K.; Clark, Robert L.

doi:10.1002/bdrb.20157

Cited by 52 publications

(85 citation statements)

References 36 publications

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“…During the embryotoxicity of AS, the replacement of these erythroblasts may fail because the embryonic liver has also been shown to be a target for AS in rats. Abnormalities in liver shape and lobation were caused by all four ARTs tested (AS, DHA, artemether and arteether) when administered as a single dose on GD 10 (White et al, 2008;Clark et al, 2008b). Fetal liver necrosis was observed in this study, which could be the basis for the unusual liver shape variation that we observed in this study of the narrow window of AS embryotoxicity.…”

Section: As/dha Therapy Causes Erythrocyte Depletion and Resulting Emsupporting

confidence: 52%

“…A summary of the research findings and possible mechanisms of artemisinin drugs in the embryotoxicity studies in vitro and in vivo (Clark et al, 2009;Efferth & Kaina 2010;Finaurini et al, 2010;Longo et al, 2006aLongo et al, , 2006bLongo et al, , 2008Wartenberg et al, 2003;White et al, 2008) 2.2.1 Inhibitory effects of AS/DHA on hematopoiesis AS is embryolethal and teratogenic in rats, with a very narrow window of sensitivity between days 10-14 of gestation (Clark et al, 2004;Li et al, 2009;White et al, 2006). Further studies with a single oral dose of 17 mg/kg AS on gestational day (GD) 10-11 demonstrated that a paling of the visceral yolk sacs was observed within 3-6 hr after treatment.…”

Section: As/dha Therapy Causes Erythrocyte Depletion and Resulting Emmentioning

confidence: 99%

“…Further evidence has been presented that the mechanism by which embryotoxicity of AS/DHA occurs seems to be limited to fetal erythropoiesis and vasculogenesis/angiogenesis in the very earliest developing red blood cells. The effect of www.intechopen.com AS/DHA on red cell precursors has been shown to cause severe anemia in embryos with higher drug peak concentrations (Clark et al, 2004;White et al, 2008).…”

Section: Embryotoxicity Of As/dha Caused By Defective Vasculogenesis/mentioning

confidence: 99%

“…This hypothesis is supported by the fact that vasculogenesis and hematopoiesis are part of the same process, in which formation of a blood vessel is accompanied by the simultaneous in situ production of blood cells within that vessel (Baron, 2001;Baumann & Dragon, 2005;Sequeira Lopez et al, 2003). In addition, oral and injectable AS treatment has been shown to induce marked embryolethality and a low incidence of teratogenic effects, including cardiovascular defects (ventricular septal and great vessels defects), which significantly affected novel vessel formation (Clark et al, 2004, White et al, 2008Ratajska et al, 2006aRatajska et al, , 2006b). …”

Section: Relevance Of Vasculogenesis and Hematopoiesis To Embryo Devementioning

confidence: 99%

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Therapeutic and Toxicological Inhibition of Vasculogenesis and Angiogenesis Mediated by Artesunate, a Compound with Both Antimalarial and Anticancer Efficacy

Li¹,

Hickman²,

Weina³

2011

Vasculogenesis and Angiogenesis - From Embryonic Development to Regenerative Medicine

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Section: As/dha Therapy Causes Erythrocyte Depletion and Resulting Emsupporting

confidence: 52%

Section: As/dha Therapy Causes Erythrocyte Depletion and Resulting Emmentioning

confidence: 99%

Section: Embryotoxicity Of As/dha Caused By Defective Vasculogenesis/mentioning

confidence: 99%

Section: Relevance Of Vasculogenesis and Hematopoiesis To Embryo Devementioning

confidence: 99%

See 2 more Smart Citations

Therapeutic and Toxicological Inhibition of Vasculogenesis and Angiogenesis Mediated by Artesunate, a Compound with Both Antimalarial and Anticancer Efficacy

Li¹,

Hickman²,

Weina³

2011

Vasculogenesis and Angiogenesis - From Embryonic Development to Regenerative Medicine

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“…Studies in which the response level was <10% were included if long bone and/or scapular defects or skeletal defects in general were noted. A search of the literature since 2006 revealed a few additional studies, particularly studies published on the artemisinins by Clark et al (2004Clark et al ( , 2008 and White and Clark (2008). In addition, spontaneous and chemically induced effects in the Han Wistar rat (Mitchard and Stewart, 2014) and changes as a result of a corticotrophin-releasing hormone (CRF-1) antagonist (De Schaepdrijver et al, 2014) were included.…”

Section: Methodsmentioning

confidence: 99%

Relationship Between Bent Long Bones, Bent Scapulae, and Wavy Ribs: Malformations or Variations?

Kimmel

Garry

DeSesso

2014

Birth Defects Research Pt B

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BACKGROUND: Shortened and bent long bones and bent scapulae are sometimes reported in fetuses with wavy ribs (Carney and Kimmel, 2007). Wavy ribs are typically seen in the presence of maternal and developmental toxicity, are transient and reversible postnatally, and are considered to be variations rather than malformations. METHODS: We further assessed the literature cited in Kimmel and Carney (2007) as well as papers published since then to determine under what conditions bent long bones in the absence of gross limb defects and bent scapulae were reported and whether information was available on the transient or permanent nature of these effects. RESULTS: Long bone and/or scapular changes almost always occurred at a lower incidence than wavy ribs. In every case, maternal and fetal toxicity occurred at the same dose levels. In a few studies, pups were followed sequentially after birth and bent long bones and scapulae were transient in nature and appeared normal by the time of weaning. Rabbits were much less likely to show wavy ribs or long bone and scapular changes at birth, even in the presence of severe maternal and fetal toxicity. This species difference may be due in part to the great increase in bone mass and remodeling that occurs during the first few postnatal weeks in rodents, but which takes place during the longer fetal period in rabbits. CONCLUSION: Our conclusion from this review is that bent long bones and scapulae, like wavy ribs, appear to be secondary to maternal and developmental toxicity, are transient, and like wavy ribs should be considered variations rather than malformations.

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Animal Embryotoxicity Studies of Key Non‐Artemisinin Antimalarials and Use in Women in the First Trimester

Clark

2017

Birth Defects Research

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The World Health Organization currently recommends quinine1clindamycin for use against malaria in the first trimester. This may soon change to recommending artemisinin-based combination therapies (standard duration of dosing 5 3 days). The non-artemisinin partner drugs include amodiaquine, lumefantrine, mefloquine, piperaquine, sulfadoxine1pyrimethamine, and pyronaridine. For quinine, clindamycin, and mefloquine and the combinations of sulfadoxine1pyrimethamine and artemether1lumefantrine, there are reports (including studies without internal comparison groups) that combined describe 304 to >1100 exposures of women in the first trimester for each drug with no conclusive evidence of adverse effects on pregnancy at therapeutic doses. This is despite the fact that all of these drugs or drug combinations caused embryo deaths and/or malformations in at least one animal species and all except lumefantrine had at least one exposure ratio <1. It now seems that these animal studies overestimated the risk of developmental toxicity in women with malaria. Three other non-artemisinins (amodiaquine, piperaquine, and pyronaridine) have few or no reported exposures in women in the first trimester and have exposure ratios 2 based on studies in pregnant rats and rabbits with dosing throughout organogenesis. However, none of these drugs caused embryo deaths or malformations in pregnant rats and rabbits with the exception of pyronaridine, which caused embryo deaths only at a dose that was excessively toxic to the mothers. Thus, for amodiaquine, piperaquine, and pyronaridine, the testing in animals did not reveal findings of concern and the exposure ratios were in the range of the other non-artemisinin antimalarials described above.

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Sensitive periods for developmental toxicity of orally administered artesunate in the rat

Cited by 52 publications

References 36 publications

Therapeutic and Toxicological Inhibition of Vasculogenesis and Angiogenesis Mediated by Artesunate, a Compound with Both Antimalarial and Anticancer Efficacy

Therapeutic and Toxicological Inhibition of Vasculogenesis and Angiogenesis Mediated by Artesunate, a Compound with Both Antimalarial and Anticancer Efficacy

Relationship Between Bent Long Bones, Bent Scapulae, and Wavy Ribs: Malformations or Variations?

Animal Embryotoxicity Studies of Key Non‐Artemisinin Antimalarials and Use in Women in the First Trimester

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