Birth Defects Research Part B: Developmental and Reproductive Toxicology
Wiley InterScience : Birth Defects Research Part B: Developmental and Reproductive Toxicology

Juvenile animal studies for the development of paediatric medicines: a descri...
by Beatriz Silva-Lima, Mette Due Theilade-Thomsen, Jacqueline Carleer, Jean-Marc Vidal, Paolo Tomasi, Agnes Saint-Raymond
14 Jul 2010 at 8:55am
A workshop organised by the European Medicines Agency involved assessors and experts present in a Nonclinical Working Group evaluating juvenile animal studies for Paediatric Investigation Plans in collaboration with the Paediatric Committee and the Safety Working Party of the Committee for Human Medicinal Products. The objective of the workshop was to analyse which juvenile animal studies proposals were received and agreed by the Paediatric Committee, to check consistency and how to apply the existing European guideline on juvenile animal studies. A comparison of main organ system development in man vs. animal species was presented to guide the review and to support species selection and protocol design. An analysis of juvenile animal studies included in finalised PIP's was also presented. Out of 109 paediatric investigation plans finalised between November 2008 and March 2009, 43 included one or more juvenile animal studies. In most cases the preferred species was the rat; one species only was requested to be studied (20/22), but in a minority two species were required (2/22). When deciding on the characteristics of the juvenile animal studies, such as age of animals at study start, the age of the children targeted by the medicine was considered. It is expected that the increasing experience gained by Applicants and Regulators will allow further refining the criteria for these juvenile animal studies. Further research on this topic is highly encouraged in the European Regulatory framework. Birth Defects Res (Part B) XX:1-7, 2010. © 2010 Wiley-Liss, Inc.
The etiology of cleft palate: a 50-year search for mechanistic and molecular ...
by Barbara D. Abbott
2 Jul 2010 at 4:50am
Dates of special, historical significance, such as the 50th anniversary of the founding of the Teratology Society, prompt a desire to pause and look back and contemplate where we began, how far we have come, and consider the future for our scientific endeavors. The study of the etiology of cleft palate extends many years into the past and was a subject of interest to many of the founding members of the Teratology Society. This research area was intensively pursued and spawned a vast portfolio of published research. This article will look back at the state of the science around the time of the founding of the Teratology Society, in the 1950s and 1960s, and track the emergence and pursuit of an interest in an etiology for cleft palate involving failure of palatal fusion. Studies of medial epithelial cell fate and induction of cleft palate by interference with adhesion or fusion span the period from the 1960s to the present time. Teratology Society members have been and continue to be key players in cleft palate research. In this retrospective article, seminal research published by Teratology Society members will serve as a platform to launch the discussion of the emergence of our current understanding of medial epithelial cell differentiation and fate and the potential for these processes to be targets of teratogenic action. Birth Defects Res (Part B) XX:1-9, 2010. Published 2010 Wiley-Liss, Inc.
Hypoxia and the Edema Syndrome: elucidation of a mechanism of teratogenesis
by Neil Chernoff, John M. Rogers
30 Jun 2010 at 9:08am
The elucidation of mechanisms and pathogenesis of birth defects is exceedingly complex. Consequently, there are few examples where the etiology of birth defects caused by a specific agent has been well described. One such example is the "Edema Syndrome" first described by Casimer Grabowski in the 1960s as a mechanism of hypoxia-induced malformations in the chick embryo. The Edema Syndrome comprised a series of events in the embryo starting with osmotic imbalances followed by edema, distention, blisters, hematomas, and hemorrhage in or near developing structures. Malformation or deformation of structures resulted from mechanical disruption or loss of blood supply. A similar etiology has since been described by others in a variety of laboratory mammals following treatment with drugs including epinephrine, hydroxyurea, cocaine, phenytoin, and potassium channel-blocking drugs. Free radical excess following transient hypoxia may be a common factor in all of these insults. Vascular disruption is also associated with a number of birth defects in humans, including limb and digit reduction defects and urogenital defects. Birth Defects Res (Part B) XX:1-4, 2010. Published 2010 Wiley-Liss, Inc.
Development in the cynomolgus macaque following administration of ustekinumab...
by Pauline L. Martin, Clifford Sachs, Noritaka Imai, Hideshi Tsusaki, Satoru Oneda, Qun Jiao, George Treacy
10 Jun 2010 at 5:13am
BACKGROUND: Ustekinumab is a human monoclonal antibody that binds to the p40 subunit of interleukin (IL) 12 and IL-23 and inhibits their pharmacological activity. To evaluate potential effects of ustekinumab treatment during pregnancy, developmental studies were conducted in cynomolgus macaques. METHODS: Ustekinumab was tested in two embryo/fetal development (EFD) studies and in a combined EFD/pre and postnatal development (PPND) study. In the EFD studies, pregnant macaques (12/group) were dosed with saline or ustekinumab (9 mg/kg IV, 22.5 mg/kg SC, or 45 mg/kg IV or SC during the period of major organogenesis, gestation day [GD] 20-50). Fetuses were harvested on GD100-102 and examined for any effects on development. In the EFD/PPND study, pregnant macaques were injected with saline or ustekinumab (22.5 or 45 mg/kg SC) from GD20 through lactation day 33. Infants were examined from birth through 6 months of age for morphological and functional development. Potential effects on the immune system were evaluated by immunophenotyping of peripheral blood lymphocytes and immunohistopathology of lymphoid tissues in fetuses and infants and by T-dependent antibody response (TDAR) to KLH and TTX and by DTH response in infants. Ustekinumab concentrations were measured in serum from dams, fetus, and infants and in breast milk. RESULTS: Ustekinumab treatment produced no maternal toxicity and no toxicity in the fetuses or infants, including no effects on the TDAR or DTH responses. Ustekinumab was present in serum from GD100 fetuses and was present in infant serum through day 120 post-birth. Low levels of ustekinumab were present in breast milk. CONCLUSIONS: Exposure of macaque fetuses and infants to ustekinumab had no adverse effects on pre- and postnatal development. Birth Defects Res (Part B) XX:1-13, 2010.© 2010 Wiley-Liss, Inc.
Maternal-placental insulin-like growth factor (IGF) signaling and its importa...
by Christopher J. Bowman, Randal D. Streck, Robert E. Chapin
10 Jun 2010 at 5:13am
As background for an antibody-based therapeutic program against the IGF receptor, we undertook a review of available information on the early pregnancy-specific regulation and localization of IGFs, IGF-binding proteins (BPs), IGFBP-specific proteases, and the type 1 IGF receptor relative to placental maintenance, function of placental nutrient transporters, placental cellular differentiation/turnover/apoptosis, and critical hormone signaling needed to maintain pregnancy. Possible adverse outcomes of altered IGF signaling include prenatal loss, fetal growth retardation, and maldevelopment are also discussed. It appears that the IGF axes in both the conceptus and mother are important for normal embryo-fetal growth. Thus, all molecules (i.e., both small and large) that disrupt the IGF axis could be expected to have some degree of fetal consequences. Birth Defects Res (Part B) xx:1-11, 2010. © 2010 Wiley-Liss, Inc.
Embryo-fetal developmental toxicity of figitumumab, an anti-insulin-like grow...
by Christopher J. Bowman, Gary Chmielewski, Satoru Oneda, Deborah Finco, Mary A. Boucher, Marque Todd
10 Jun 2010 at 5:13am
BACKGROUND: Insulin-like growth factor (IGF) signaling has been linked to tumor cell survival and tumorigenesis. The anti-IGF-1 receptor monoclonal antibody, figitumumab, has been developed as an anti-cancer therapeutic. As part of the safety evaluation, an embryo-fetal developmental toxicity study was conducted in the cynomolgus monkey. METHODS: Figitumumab was administered once weekly intravenously at a dose of 5, 15, or 100 mg/kg during the period of major organogenesis (gestation days [GD] 20-48) with scheduled cesarean section around GD100. Maternal endpoints included clinical observations, food consumption, body weights, hematology, placental weights, toxicokinetics, and immunogenicity. Fetal evaluations included viability; body weights; external, visceral, and skeletal examination (and measurements); drug exposure; and immunogenicity. RESULTS: There was a dose-dependent increase in embryo-fetal loss in the presence of decreased maternal food consumption and slight reduction in body weight. Figitumumab-related embryo-fetal developmental toxicity was observed as growth retardation exhibited by reduced fetal body weights at all doses with corresponding developmental delays in morphology. Treatment-related fetal structural malformations were also observed in the mid- and high-dose groups. CONCLUSIONS: Maternal figitumumab dosing only during the period of organogenesis was associated with pregnancy loss and fetal growth deficits; both considered consistent with inhibition of IGF signaling. Fetal malformations were also observed, and were considered secondary to altered placental function and/or reduced fetal growth; however, direct inhibition of IGF signaling in the conceptus cannot be ruled out. This appears to be the first report of treatment-related fetal anomalies with a monoclonal antibody when administered only during the period of major organogenesis. Birth Defects Res (Part B) xx:1-13, 2010.© 2010 Wiley-Liss, Inc.
Computational models of ethanol-induced neurodevelopmental toxicity across sp...
by Julia M. Gohlke, William C. Griffith, Elaine M. Faustman
18 Dec 2007 at 7:46am
Computational, systems-based approaches can provide a quantitative construct for evaluating risk in the context of mechanistic data. Previously, we developed computational models for the rat, mouse, rhesus monkey, and human, describing the acquisition of adult neuron number in the neocortex during the key neurodevelopmental processes of neurogenesis and synaptogenesis. Here we apply mechanistic data from the rat describing ethanol-induced toxicity in the developing neocortex to evaluate the utility of these models for analyzing neurodevelopmental toxicity across species. Our model can explain long-term neocortical neuronal loss in the rodent model after in utero exposure to ethanol based on inhibition of proliferation during neurogenesis. Our human model predicts a significant neuronal deficit after daily peak BECs reaching 10-20 mg/dl, which is the approximate BEC reached after drinking one standard drink within one hour. In contrast, peak daily BECs of 100 mg/dl are necessary to predict similar deficits in the rat. Our model prediction of increased sensitivity of primate species to ethanol-induced inhibition of proliferation is based on application of in vivo experimental data from primates showing a prolonged rapid growth period in the primate versus rodent neuronal progenitor population. To place our predictions into a broader context, we evaluate the evidence for functional low-dose effects across rats, monkeys, and humans. Results from this critical evaluation suggest subtle effects are evident at doses causing peak BECs of approximately 20 mg/dl daily, corroborating our model predictions. Our example highlights the utility of a systems-based modeling approach in risk assessment. Birth Defects Res (Part B) © 2007 Wiley-Liss, Inc.

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