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1.
Birth Defects Res ; 115(7): 797-800, 2023 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-36855851

RESUMO

BACKGROUND: The sixth Strategic Planning Session of the Society for Birth Defects Research and Prevention (BDRP) was held on April 24-25, 2022, in Alexandria, VA. METHODS: This effort built upon previous strategic planning sessions, conducted every 5 years. RESULTS: The overall process was designed to identify BDRP's vision, purpose, culture, and potential, as well as to communicate the value that BDRP brings to its members, volunteers, partners, and the greater community. CONCLUSIONS: The BDRP 2022-2027 Strategic Plan provides the BDRP leadership, members, and staff with a clearly articulated framework and direction to support long-term sustainability and growth of the society.


Assuntos
Liderança , Sociedades , Humanos , Projetos de Pesquisa
2.
Reprod Toxicol ; 86: 33-44, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30876927

RESUMO

Predicting embryotoxicity of pharmaceutical compounds or industrial chemicals is crucial for public safety. Conventional studies which monitor embryo-fetal development in rats and rabbits are costly and time consuming. Alternative assays which are simpler and less costly are being pursued. The purpose of this research was to assess the capacity for the zebrafish development assay to predict mammalian plasma levels that are embryotoxic. Previously published data on rat plasma levels associated with embryotoxicity were used to guide concentration ranges for each of 25 chemicals dissolved in the media bathing developing zebrafish embryos. Embryotoxic media concentrations were compared to embryotoxic rat plasma concentrations. Assays were conducted in parallel at multiple sites as a consortium effort through the Health and Environmental Sciences Institute (HESI). Considering results from all sites, the zebrafish embryo development assay predicted (within 1-log) the rat maternal exposure levels associated with embryotoxicity 75% of the time.


Assuntos
Embrião não Mamífero , Desenvolvimento Embrionário , Testes de Toxicidade , Peixe-Zebra , Animais , Animais Geneticamente Modificados , Embrião de Mamíferos , Feminino , Desenvolvimento Fetal , Masculino , Preparações Farmacêuticas/sangue , Ratos
3.
Crit Rev Toxicol ; 47(5): 402-414, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27766926

RESUMO

A database of embryo-fetal developmental toxicity (EFDT) studies of 379 pharmaceutical compounds in rat and rabbit was analyzed for species differences based on toxicokinetic parameters of area under the curve (AUC) and maximum concentration (Cmax) at the developmental lowest adverse effect level (dLOAEL). For the vast majority of cases (83% based on AUC of n = 283), dLOAELs in rats and rabbits were within the same order of magnitude (less than 10-fold different) when compared based on available data on AUC and Cmax exposures. For 13.5% of the compounds the rabbit was more sensitive and for 3.5% of compounds the rat was more sensitive when compared based on AUC exposures. For 12% of the compounds the rabbit was more sensitive and for 1.3% of compounds the rat was more sensitive based on Cmax exposures. When evaluated based on human equivalent dose (HED) conversion using standard factors, the rat and rabbit were equally sensitive. The relative extent of embryo-fetal toxicity in the presence of maternal toxicity was not different between species. Overall effect severity incidences were distributed similarly in rat and rabbit studies. Individual rat and rabbit strains did not show a different general distribution of systemic exposure LOAELs as compared to all strains combined for each species. There were no apparent species differences in the occurrence of embryo-fetal variations. Based on power of detection and given differences in the nature of developmental effects between rat and rabbit study outcomes for individual compounds, EFDT studies in two species have added value over single studies.


Assuntos
Embrião de Mamíferos/fisiologia , Desenvolvimento Embrionário/efeitos dos fármacos , Preparações Farmacêuticas , Animais , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Embrião de Mamíferos/efeitos dos fármacos , Coelhos , Ratos
4.
Crit Rev Toxicol ; 46(10): 900-910, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27848393

RESUMO

Regulatory non-clinical safety testing of human pharmaceuticals typically requires embryo-fetal developmental toxicity (EFDT) testing in two species (one rodent and one non-rodent). The question has been raised whether under some conditions EFDT testing could be limited to one species, or whether the testing in a second species could be decided on a case-by-case basis. As part of a consortium initiative, we built and queried a database of 379 compounds with EFDT studies (in both rat and rabbit animal models) conducted for marketed and non-marketed pharmaceuticals for their potential for adverse developmental and maternal outcomes, including EFDT incidence and the nature and severity of adverse findings. Manifestation of EFDT in either one or both species was demonstrated for 282 compounds (74%). EFDT was detected in only one species (rat or rabbit) in almost a third (31%, 118 compounds), with 58% (68 compounds) of rat studies and 42% (50 compounds) of rabbit studies identifying an EFDT signal. For 24 compounds (6%), fetal malformations were observed in one species (rat or rabbit) in the absence of any EFDT in the second species. In general, growth retardation, fetal variations, and malformations were more prominent in the rat, whereas embryo-fetal death was observed more often in the rabbit. Discordance across species may be attributed to factors such as maternal toxicity, study design differences, pharmacokinetic differences, and pharmacologic relevance of species. The current analysis suggests that in general both species are equally sensitive on the basis of an overall EFDT LOAEL comparison, but selective EFDT toxicity in one species is not uncommon. Also, there appear to be species differences in the prevalence of various EFDT manifestations (i.e. embryo-fetal death, growth retardation, and dysmorphogenesis) between rat and rabbit, suggesting that the use of both species has a higher probability of detecting developmental toxicants than either one alone.


Assuntos
Desenvolvimento Fetal/efeitos dos fármacos , Substâncias Perigosas/toxicidade , Modelos Animais , Testes de Mutagenicidade/métodos , Teratogênicos/toxicidade , Anormalidades Induzidas por Medicamentos , Animais , Coelhos , Ratos
5.
Regul Toxicol Pharmacol ; 77: 100-8, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26930635

RESUMO

During the past two decades the use and refinements of imaging modalities have markedly increased making it possible to image embryos and fetuses used in pivotal nonclinical studies submitted to regulatory agencies. Implementing these technologies into the Good Laboratory Practice environment requires rigorous testing, validation, and documentation to ensure the reproducibility of data. A workshop on current practices and regulatory requirements was held with the goal of defining minimal criteria for the proper implementation of these technologies and subsequent submission to regulatory agencies. Micro-computed tomography (micro-CT) is especially well suited for high-throughput evaluations, and is gaining popularity to evaluate fetal skeletons to assess the potential developmental toxicity of test agents. This workshop was convened to help scientists in the developmental toxicology field understand and apply micro-CT technology to nonclinical toxicology studies and facilitate the regulatory acceptance of imaging data. Presentations and workshop discussions covered: (1) principles of micro-CT fetal imaging; (2) concordance of findings with conventional skeletal evaluations; and (3) regulatory requirements for validating the system. Establishing these requirements for micro-CT examination can provide a path forward for laboratories considering implementing this technology and provide regulatory agencies with a basis to consider the acceptability of data generated via this technology.


Assuntos
Anormalidades Induzidas por Medicamentos/diagnóstico por imagem , Osso e Ossos/diagnóstico por imagem , Biologia do Desenvolvimento/métodos , Feto/diagnóstico por imagem , Testes de Toxicidade/métodos , Microtomografia por Raio-X , Animais , Osso e Ossos/anormalidades , Osso e Ossos/efeitos dos fármacos , Consenso , Biologia do Desenvolvimento/normas , Feto/anormalidades , Feto/efeitos dos fármacos , Guias como Assunto , Humanos , Variações Dependentes do Observador , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Testes de Toxicidade/normas , Microtomografia por Raio-X/normas
6.
Reprod Toxicol ; 59: 22-30, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26854737

RESUMO

Small molecule pharmaceutical products are assumed to reach concentrations in semen similar to those in blood plasma. Exposure modeling for these small-molecule products in humans assumes a daily dose of 5mL of semen and 100% absorption from the vagina with distribution to the conceptus through the maternal systemic circulation. Monoclonal antibody drugs are present in semen at concentrations about 2% or less of those in blood, and the modeling used for small molecules will over-estimate the possibility of conceptus exposure to immunoglobulins. It is not known whether peptide products reach semen, but in general peptide medications are destroyed by vaginal peptidases, and conceptus exposure is predicted to be minimal. Theoretical exposure routes to pharmaceuticals that might result in exposure of the conceptus greater than that of maternal systemic exposures include direct access through the cervical canal, adsorption to sperm for carriage into the oocyte, and direct delivery from the vaginal veins or lymphatics to the uterine artery. There is some evidence for direct access to the uterus for progesterone, terbutaline, and danazol, but the evidence does not involve exposures during pregnancy in most instances. Studies in mice, rats, rabbits, and monkeys do not suggest that exposure to small molecule pharmaceuticals in semen imposes risks to the conceptus beyond those that can be predicted using modeling of systemic maternal exposure. Monoclonal antibody and peptide exposure in semen does not pose a significant risk to the conceptus.


Assuntos
Anticorpos Monoclonais/metabolismo , Embrião de Mamíferos/metabolismo , Feto/metabolismo , Peptídeos/metabolismo , Preparações Farmacêuticas/metabolismo , Sêmen/metabolismo , Vagina/metabolismo , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/química , Anticorpos Monoclonais/toxicidade , Transporte Biológico , Embrião de Mamíferos/efeitos dos fármacos , Feminino , Feto/efeitos dos fármacos , Haplorrinos , Humanos , Masculino , Exposição Materna , Camundongos , Modelos Animais , Modelos Biológicos , Exposição Paterna , Peptídeos/química , Peptídeos/toxicidade , Permeabilidade , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/química , Coelhos , Medição de Risco , Absorção Vaginal
7.
Reprod Toxicol ; 58: 213-21, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26545974

RESUMO

Small molecule pharmaceutical products are assumed to reach concentrations in semen similar to those in blood plasma. Exposure modeling for these small-molecule products in humans assumes a daily dose of 5mL of semen and 100% absorption from the vagina with distribution to the conceptus through the maternal systemic circulation. Monoclonal antibody drugs are present in semen at concentrations about 2% or less of those in blood, and the modeling used for small molecules will over-estimate the possibility of conceptus exposure to immunoglobulins. It is not known whether peptide products reach semen, but in general peptide medications are destroyed by vaginal peptidases, and conceptus exposure is predicted to be minimal. Theoretical exposure routes to pharmaceuticals that might result in exposure of the conceptus greater than that of maternal systemic exposures include direct access through the cervical canal, adsorption to sperm for carriage into the oocyte, and direct delivery from the vaginal veins or lymphatics to the uterine artery. There is some evidence for direct access to the uterus for progesterone, terbutaline, and danazol, but the evidence does not involve exposures during pregnancy in most instances. Studies in mice, rats, rabbits, and monkeys do not suggest that exposure to small molecule pharmaceuticals in semen imposes risks to the conceptus beyond those that can be predicted using modeling of systemic maternal exposure. Monoclonal antibody and peptide exposure in semen does not pose a significant risk to the conceptus.


Assuntos
Anticorpos Monoclonais/metabolismo , Colo do Útero/metabolismo , Embrião de Mamíferos/metabolismo , Preparações Farmacêuticas/metabolismo , Proteínas/metabolismo , Sêmen/metabolismo , Vagina/metabolismo , Animais , Anticorpos Monoclonais/efeitos adversos , Transporte Biológico , Colo do Útero/efeitos dos fármacos , Embrião de Mamíferos/efeitos dos fármacos , Feminino , Humanos , Masculino , Modelos Biológicos , Gravidez , Proteínas/efeitos adversos , Medição de Risco , Fatores de Risco , Especificidade da Espécie , Vagina/efeitos dos fármacos
8.
Birth Defects Res B Dev Reprod Toxicol ; 101(6): 423-8, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25475026

RESUMO

Validation of alternative assays requires comparison of the responses to toxicants in the alternative assay with in vivo responses. Chemicals have been classified as "positive" or "negative" in vivo, despite the fact that developmental toxicity is conditional on magnitude of exposure. We developed a list of positive and negative developmental exposures, with exposure defined by toxicokinetic data, specifically maternal plasma Cmax . We selected a series of 20 chemicals that caused developmental toxicity and for which there were appropriate toxicokinetic data. Where possible, we used the same chemical for both positive and negative exposures, the positive being the Cmax at a dose level that produced significant teratogenicity or embryolethality, the negative being the Cmax at a dose level not causing developmental toxicity. It was not possible to find toxicokinetic data at the no-effect level for all positive compounds, and the negative exposure list contains Cmax values for some compounds that do not have developmental toxicity up to the highest dose level tested. This exposure-based reference list represents a fundamentally different approach to the evaluation of alternative tests and is proposed as a step toward application of alternative tests in quantitative risk assessment.


Assuntos
Desenvolvimento Fetal/efeitos dos fármacos , Teratogênese/efeitos dos fármacos , Teratogênicos/toxicidade , Testes de Toxicidade , Bioensaio , Ensaios de Triagem em Larga Escala , Técnicas In Vitro , Medição de Risco
9.
Reprod Toxicol ; 48: 138-47, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24887033

RESUMO

A ß-actin-luc transgenic mouse model was used to evaluate whether embryo-fetal exposure could occur after intravaginal administration of a compound. A bioluminescent substrate, d-luciferin, was delivered intravaginally to mimic compound exposure to the female reproductive track and the embryo-fetus. Bioluminescence was observed throughout the reproductive tract during diestrus, but not during estrus, 2-5min after intravaginal d-luciferin administration to female ß-actin-luc mice. Intravaginal administration of d-luciferin to wild-type females mated with male ß-actin-luc mice indicated that the substrate reached the developing embryo-fetus, with bioluminescence corresponding to transgene expression in the embryo-fetus. d-Luciferin substrate rapidly reached the embryo-fetus regardless of the administration route (intravaginal, intraperitoneal, subcutaneous, or intravenous). Vaginal ligation appeared to block at least some direct exposure to the embryo-fetus, but did not prevent d-luciferin from eventually reaching the embryo-fetus. Additional work will be necessary to form the basis for a reliable assessment of the human risk for male-mediated teratogenicity.


Assuntos
Benzotiazóis/administração & dosagem , Benzotiazóis/farmacocinética , Embrião de Mamíferos/metabolismo , Feto/metabolismo , Administração Intravaginal , Animais , Ciclo Estral , Feminino , Luciferases/genética , Luminescência , Masculino , Camundongos Transgênicos , Imagem Óptica , Gravidez
11.
ALTEX ; 30(3): 353-77, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23861079

RESUMO

To address the pressing need for better in vitro testicular toxicity models, a workshop sponsored by the International Life Sciences Institute (ILSI), the Health and Environmental Science Institute (HESI), and the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), was held at the Mt. Washington Conference Center in Baltimore, MD, USA on October 26-27, 2011. At this workshop, experts in testis physiology, toxicology, and tissue engineering discussed approaches for creating improved in vitro environments that would be more conducive to maintaining spermatogenesis and steroidogenesis and could provide more predictive models for testicular toxicity testing. This workshop report is intended to provide scientists with a broad overview of relevant testicular toxicity literature and to suggest opportunities where bioengineering principles and techniques could be used to build improved in vitro testicular models for safety evaluation. Tissue engineering techniques could, conceivably, be immediately implemented to improve existing models. However, it is likely that in vitro testis models that use single or multiple cell types will be needed to address such endpoints as accurate prediction of chemically induced testicular toxicity in humans, elucidation of mechanisms of toxicity, and identification of possible biomarkers of testicular toxicity.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Poluentes Ambientais/toxicidade , Testículo/efeitos dos fármacos , Alternativas aos Testes com Animais , Animais , Biomarcadores , Técnicas de Cultura de Células , Células Cultivadas , Humanos , Masculino , Modelos Biológicos , Valor Preditivo dos Testes , Testículo/citologia , Testes de Toxicidade/métodos
12.
Artigo em Inglês | MEDLINE | ID: mdl-21312321

RESUMO

Workshops on maternal toxicity were held at the annual Society of Toxicology, Teratology Society, and European Teratology Society meetings in 2009. Speakers presented background information prior to a general discussion on this topic. The following recommendations/options are based on the outcome of the discussions at the workshops: 1. A comprehensive evaluation of all available data from general toxicity studies, range-finding Developmental and Reproductive Toxicology (DART) studies, class effects, structure-activity relationships, exposure studies, etc. is essential for appropriate dose selection for definitive DART studies. The intent is to avoid marked maternal toxicity leading to mortality or decreased body weight gains of greater than 20% for prolonged periods. (a) Evaluate alternative endpoints for dose selection and data interpretation (e.g., target tissue effects and pharmacology) for biotherapeutics. (B) Evaluate additional maternal parameters based on effects and/or target organs observed in short-term (e.g., 2- or 4-week) general toxicity studies. 2. Evaluate all available data to determine a cause-effect relationship for developmental toxicity. (a) Conduct a pair-feeding/pair-watering study as a follow-up. (b) Evaluate individual data demonstrating maternal toxicity in the mother with adverse embryo-fetal outcomes in the litter associated with the affected mother. (c) Conduct single-dose studies at increasing doses as a complement to conventional embryo-fetal toxicity studies for certain classes of compounds that affect the hERG channel. 3. Support statements that embryo-fetal effects are caused by maternal toxicity and/or exaggerated pharmacology, especially for malformations. (a) Provide mechanistic or other supporting data. (b) Establish the relevance of the DART findings in animals for human exposures. Birth Defects Res (Part B) 92:36-51, 2010. © 2011 Wiley-Liss, Inc.


Assuntos
Exposição Materna , Projetos de Pesquisa , Estatística como Assunto , Testes de Toxicidade/métodos , Animais , Peso Corporal , Desenvolvimento Embrionário , Feminino , Feto/patologia , Humanos , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Coelhos , Ratos
13.
Birth Defects Res B Dev Reprod Toxicol ; 83(4): 446-56, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18702117

RESUMO

A meeting was convened so that users of three models for in vitro developmental toxicity (embryonic stem cells, whole embryo culture, and zebrafish) could share their experiences with each model, and explore the areas for improvement. We present a summary of this meeting and the recommendations of the group.


Assuntos
Técnicas de Cultura Embrionária/métodos , Células-Tronco Embrionárias/citologia , Testes de Toxicidade/métodos , Peixe-Zebra/embriologia , Animais , Embrião de Mamíferos/citologia , Embrião não Mamífero/citologia , Camundongos
14.
J Med Chem ; 46(4): 457-60, 2003 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-12570368

RESUMO

Novel pyrazolopyridopyridazine derivatives have been prepared as potent and selective PDE5 inhibitors. Compound 6 has been identified as a more potent and selective PDE5 inhibitor than sildenafil (1). It is as efficacious as sildenafil in in vitro and in vivo PDE5 inhibition models, and it is orally bioavailable in rats and dogs. The superior isozyme selectivity of 6 is expected to exert less adverse effects in humans when used for erectile dysfunction treatment.


Assuntos
3',5'-GMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Piridazinas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Pressão Sanguínea/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Cães , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Disfunção Erétil/tratamento farmacológico , Feminino , Masculino , Pênis/irrigação sanguínea , Piridazinas/farmacocinética , Piridazinas/farmacologia , Coelhos , Ratos , Relação Estrutura-Atividade
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