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1.
Reprod Toxicol ; 34(4): 584-97, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23000234

ABSTRACT

In embryofetal studies in rat and rabbit Piperaquine phosphate (PQP) was not teratogenic at the maximal tolerated dose, even in presence of fetal exposure. In peri- post-natal study in rat, PQP did not interfere with the course of delivery at the dose of 5 mg/kg/day (treatment Gestation Day(GD)6-Lactation Day(LD)21) as well as up to the dose of 20 mg/kg/day (treatment GD6-17 and LD1-21). PQP at the dose of 80 mg/kg, induced prolonged gestation, dystocic delivery and increase perinatal mortality both with interruption of treatment (GD6 to GD17 and LD1-21) and with continuous dosing (GD19-LD21). PQP did not interfere with lactation and pup growth and development, in presence of clear exposure during suckling period, irrespective of the dose and treatment schedules. It was not possible to identify the mechanism leading to the delivery delay. In a comparative study using other antimalarials, only Mefloquine gave similar findings to PQP.


Subject(s)
Antimalarials/toxicity , Quinolines/toxicity , Animals , Female , Gestational Age , Lactation , Maternal-Fetal Exchange , No-Observed-Adverse-Effect Level , Parturition/drug effects , Pregnancy , Rabbits , Rats , Rats, Sprague-Dawley , Ribs/abnormalities
2.
Reprod Toxicol ; 30(4): 583-90, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20708075

ABSTRACT

Three groups of compounds: (i) active peroxides (artemisinin and arterolene), (ii) inactive non-peroxidic derivatives (deoxyartemisinin and carbaOZ277) and (iii) inactive peroxide (OZ381) were tested by WEC system to provide insights into the relationship between chemical structure and embryotoxic potential, and to assess the relationship between embryotoxicity and antimalarial activity. Deoxyartemisinin, OZ381 and carbaOZ277 did not affect rat embryonic development. Artemisinin and arterolane affected primarily nucleated red blood cells (RBCs), inducing anemia and subsequent tissue damage in rat embryos, with NOELs for RBC damage at 0.1 and 0.175µg/mL, respectively. These data support the idea that only active antimalarial peroxides are able to interfere with normal embryonic development. In an attempt to establish whether and to what extent activity as antimalarials and embryotoxicity can be divorced, IC(50)s for activity in Plasmodium falciparum strains and the NOELs for RBCs were compared. From this comparison, arterolane showed a better safety margin than artemisinin.


Subject(s)
Antimalarials/toxicity , Embryo, Mammalian/drug effects , Peroxides/toxicity , Teratogens/toxicity , Adamantane/analogs & derivatives , Adamantane/toxicity , Animals , Antimalarials/chemistry , Artemisinins/toxicity , Branchial Region/drug effects , Branchial Region/pathology , Drug Evaluation, Preclinical/methods , Embryo Culture Techniques , Embryo, Mammalian/blood supply , Embryo, Mammalian/pathology , Embryonic Development/drug effects , Erythrocytes/drug effects , Erythrocytes/pathology , Heterocyclic Compounds, 1-Ring/chemistry , Heterocyclic Compounds, 1-Ring/toxicity , Inhibitory Concentration 50 , No-Observed-Adverse-Effect Level , Peroxides/chemistry , Plasmodium falciparum/drug effects , Rats , Spiro Compounds/chemistry , Spiro Compounds/toxicity , Structure-Activity Relationship , Teratogens/chemistry , Yolk Sac/blood supply , Yolk Sac/drug effects , Yolk Sac/pathology
3.
Reprod Toxicol ; 25(4): 433-41, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18394862

ABSTRACT

Artemisinin derivatives are effective and safe drugs for treating malaria, but they are not recommended during the first trimester of pregnancy because of resorptions and abnormalities observed in animal reproduction studies. Previous studies in rats showed that artemisinin embryotoxicity derives from the depletion of primitive red blood cells (RBCs) over a narrow critical time window (gestation Days 9-14). In order to further investigate the susceptibility of primitive RBCs to artemisinins and to establish whether this susceptibility is species-specific or inherent to the compound, we studied dihydroartemisinin (DHA), both a drug in its own right and the main metabolite of current artemisinin derivatives in use, in the Frog Embryo Teratogenesis Assay-Xenopus (FETAX). This model readily allows investigation and monitoring of primitive and definitive RBCs. Effects on frog larvae exposed to DHA for 48 h during early embryonic development, starting from 24 h post fertilization, were similar to those on rat embryos in terms of reduction in the number of primitive RBCs (clonally produced within the ventral blood island). In contrast, RBCs of older larvae (stage 47, produced at the definitive sites of hematopoiesis) were affected minimally and subsequently recovered. Compared to rat embryos, the frog larvae had no areas of necrosis but they shared similar heart defects. The mitochondrion appeared to be the main subcellular target, similar to observations in Plasmodium. These results implicate artemisinin-induced embryotoxicity through perturbation of metabolically active RBCs; whereas this mode of action does not appear to be species-specific, the stages of susceptibility varied between different species. The window of susceptibility and duration of exposure must be considered to evaluate the clinical relevance of these findings.


Subject(s)
Antimalarials/toxicity , Artemisinins/toxicity , Erythrocytes/drug effects , Animals , Erythrocyte Count , Erythrocytes/cytology , Erythrocytes/ultrastructure , Female , Microscopy, Electron, Transmission , Xenopus laevis
4.
Curr Opin Drug Discov Devel ; 10(1): 53-7, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17265742

ABSTRACT

Currently, several protein kinase-modulating compounds have received market approval across a range of diverse therapeutic indications. Furthermore, a large number of chemical and biological protein kinase-modulating compounds are undergoing testing at the preclinical and clinical level. Protein kinases are both major pharmacological targets and diagnostically useful. Progression of kinase modulators toward clinically viable therapies is aided by a reversible mechanism of action, short treatment durations and patient-compliant administration routes. However, the physiological role and essential functional activity of protein kinases in many organs and tissues complicates, to different extents, the development of useful, highly potent protein kinase modulators. In this review, we will highlight common problems in the development of these compounds and lessons learned from the extensive preclinical and clinical characterization of some key protein kinase modulators, some of which have either entered and successfully completed clinical trials or have been abandoned as a consequence of unacceptable toxicity issues. We will ultimately explore how molecular profiling tools combined with histopathological endpoints can be adopted to address and further understand these toxicities in humans and understand their relevance and characterization when identified during early animal experiments.


Subject(s)
Drug-Related Side Effects and Adverse Reactions/diagnosis , Drug-Related Side Effects and Adverse Reactions/prevention & control , Protein Kinase Inhibitors/adverse effects , Animals , Clinical Trials as Topic , Drug-Related Side Effects and Adverse Reactions/chemically induced , Humans , Molecular Structure , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use
5.
Reprod Toxicol ; 22(4): 797-810, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16959470

ABSTRACT

Artemisinin derivatives are clinically effective and safe antimalarials, but are not recommended during the first trimester of pregnancy because of the resorptions and abnormalities seen in animal reproduction studies. Understanding how, when and what toxicity occurs is crucial to any assessment of clinical relevance. Previously, DHA has been shown in the rat whole embryo culture (WEC) to primarily affect primitive red blood cells (RBCs) causing subsequent tissue damage and dysmorphogenesis. To verify the primary target of DHA in vivo and to detect consequences induced by early damage on embryo development, pregnant female rats were orally treated on gestation days (GD) 9.5 and 10.5 with 7.5 or 15 mg/kg/day DHA and caesarean sectioned on GD11.5, 12.5, 13.5, 15 and 20. A parallel in vitro WEC study evaluated the role of oxidative damage and examined blood islands and primitive RBCs. In accordance with the WEC results, primitive RBCs from yolk sac hematopoiesis were the target of DHA in vivo. The resulting anemia led to cell damage, which depending on its degree, was either diffuse or focal. Embryonic response to acute anemia varied from complete recovery to malformation and death, depending on the extent of cell death. Malformations occurred only in litters with embryonic deaths. DHA induced low glutathione levels in RBCs, indicating that oxidative stress may be involved in artemisinin toxicity; effects were extremely rapid, with altered RBCs seen as early as GD10. In establishing the relevance of these findings to humans, one should consider differences in the development of rodents and humans. While yolk sac hematopoiesis occurs similarly in the two species, early placentation and extent of exposure differ. In particular, early hematopoiesis takes only 7 days in rats (during which RBCs expand in a clonal fashion) compared with 6 weeks in humans; thus the susceptible period in relation to the duration of exposure to an artemisinin-based treatment may be substantially different.


Subject(s)
Antimalarials/toxicity , Artemisinins/toxicity , Embryo, Mammalian/drug effects , Sesquiterpenes/toxicity , Abnormalities, Multiple/chemically induced , Administration, Oral , Animals , Antimalarials/administration & dosage , Antimalarials/blood , Artemisinins/administration & dosage , Artemisinins/blood , Cell Death/drug effects , Cesarean Section/methods , Dose-Response Relationship, Drug , Embryo Culture Techniques , Embryo Loss/chemically induced , Embryo Loss/pathology , Embryo, Mammalian/abnormalities , Erythrocytes, Abnormal/drug effects , Erythroid Precursor Cells/drug effects , Erythroid Precursor Cells/metabolism , Erythropoiesis/drug effects , Female , Fetal Death/chemically induced , Fetal Development/drug effects , Gestational Age , Glutathione/metabolism , Male , Rats , Rats, Sprague-Dawley , Sesquiterpenes/administration & dosage , Sesquiterpenes/blood
6.
Reprod Toxicol ; 21(1): 83-93, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16026965

ABSTRACT

Artemisinin derivatives are not currently recommended for use during the first trimester of pregnancy because they cause embryo death and some abnormalities in early pregnancy in animals. We studied the effects of dihydroartemisinin (DHA) in rat whole embryo cultures (WEC). DHA was added to the culture medium for the entire 48-h culture, 1.5 h at the beginning or at the end of the culture at 0.01-2 microg/mL. DHA affected primarily red blood cells during yolk sac hematopoiesis. Higher concentrations and longer exposure inhibited angiogenesis. Tissue damage (cell deaths) and effects on embryo morphology (neural tube, branchial arches, somites and caudal region defects) were attributed to these events. The viability of severely affected embryos beyond the 48-h assay is uncertain. These results help explain findings from animal data and provide evidence that the yolk sac is highly susceptible to artemisinin compounds. Extrapolating results to pregnant women exposed in the first trimester remains difficult. Pharmacovigilance and further studies of the mechanism of damage are needed.


Subject(s)
Antimalarials/toxicity , Artemisinins/toxicity , Embryonic Development/drug effects , Sesquiterpenes/toxicity , Animals , Erythrocytes/drug effects , Erythrocytes/pathology , In Vitro Techniques , Rats
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