RESUMEN
Preterm birth is the major challenge in obstetrics, affecting â¼10% of pregnancies. Pan-prostaglandin synthesis inhibitors [nonsteroidal anti-inflammatory drugs (NSAIDs)] prevent preterm labor and prolong pregnancy but raise concerns about fetal renal and cardiovascular safety. We conducted preclinical studies examining the tocolytic effect and fetal safety of the oral prodrug candidate OBE022 [(S)-2-amino-3-methyl-butyric acid (S)-3-{[(S)-3-(biphenyl-4-sulfonyl)-thiazolidine-2-carbonyl]-amino}-3-(4-fluoro-phenyl)-propyl ester] and its parent OBE002 [(S)-3-(biphenyl-4-sulfonyl)-thiazolidine-2-carboxylic acid [(S)-1-(4-fluoro-phenyl)-3-hydroxy-propyl]-amide], both potent and highly selective antagonist of the contractile prostaglandin F2α (PGF2α ) receptor (FP). Efficacy of OBE022 and OBE002, alone and in combination with other tocolytics, was assessed in human tissues and pregnant animal models for inhibition of uterine contraction and delay of parturition. Selective safety of OBE022 and/or OBE002, compared with NSAID indomethacin, was assessed on renal function, closure of the ductus arteriosus, and inhibition of platelet aggregation. In in vitro studies, OBE002 inhibited spontaneous, oxytocin- and PGF2α -induced human myometrial contractions alone and was more effective in combination with atosiban or nifedipine. In in vivo studies, OBE022 and OBE002 reduced spontaneous contractions in near-term pregnant rats. In pregnant mice, OBE022 delayed RU486 [(8S,11R,13S,14S,17S)-11-[4-(dimethylamino)phenyl]-17-hydroxy-13-methyl-17-prop-1-ynyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one] -induced parturition and exerted synergistic effects in combination with nifedipine. OBE022 and/or OBE002 did not show the fetal side effects of ductus arteriosus constriction, impairment of kidney function, or inhibition of platelet aggregation observed with indomethacin. Orally active OBE022 and OBE002 exhibits potent tocolytic effects on human tissues ex vivo and animal models in vivo without causing the adverse fetal side effects seen with indomethacin. Selectively targeting the FP receptor in combination with existing tocolytics may be an effective strategy for preventing or delaying preterm delivery.
Asunto(s)
Ésteres/uso terapéutico , Trabajo de Parto Prematuro/tratamiento farmacológico , Receptores de Prostaglandina/antagonistas & inhibidores , Seguridad , Sulfonas/uso terapéutico , Tiazolidinas/efectos adversos , Tiazolidinas/farmacología , Administración Oral , Animales , Conducto Arterial/efectos de los fármacos , Conducto Arterial/fisiopatología , Ésteres/química , Ésteres/farmacología , Femenino , Humanos , Miometrio/efectos de los fármacos , Miometrio/fisiopatología , Trabajo de Parto Prematuro/fisiopatología , Agregación Plaquetaria/efectos de los fármacos , Embarazo , Ratas , Ratas Sprague-Dawley , Sulfonas/química , Sulfonas/farmacología , Tiazolidinas/administración & dosificación , Tiazolidinas/química , Tiazolidinas/uso terapéutico , Contracción Uterina/efectos de los fármacosRESUMEN
Propaquizafop is an herbicide with demonstrated hepatocarcinogenic activity in rodents. A rodent-specific mode of action (MOA) in the liver via activation of peroxisome proliferator-activated receptor α (PPARα) has been postulated based on existing data. Experience with PPARα-inducing pharmaceuticals indicates a lack of human relevance of this MOA. The objective of the present investigation was to evaluate the dependency of early key events leading to liver tumors on PPARα activation in wildtype (WT) compared to PPARα-knockout (KO) rats following 2 weeks exposure to 75, 500 and 1000â¯ppm propaquizafop in the diet. In WT rats, both WY-14643 (50â¯mg/kgâ¯bw/day) and propaquizafop (dose-dependently) induced marked increases in liver weights, correlating with liver enlargement and hepatocellular hypertrophy, along with increased CYP4A and acyl-CoA oxidase mRNA expression and enzyme activities versus controls, while in KO rats liver weight was mildly increased only at the high dose with minimal microscopic correlates and without any changes in liver peroxisomal or CYP4A activities. In addition, BrdU labeling resulted in higher numbers and density of positive hepatocytes versus controls in WT but not in KO rats, indicating increased mitotic activity and cell proliferation only in WT rats, thus confirming the PPARα-dependency of the biochemical and histological changes in the liver. Based on an assessment of the results of this investigation, together with existing propaquizafop data according to the MOA-Human Relevance Framework, we conclude that liver tumors observed in rodents after dietary administration of propaquizafop do not pose a relevant health risk to humans.
Asunto(s)
Herbicidas/toxicidad , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/metabolismo , PPAR alfa/metabolismo , Propionatos/toxicidad , Acil-CoA Oxidasa/genética , Acil-CoA Oxidasa/metabolismo , Animales , Sistema Enzimático del Citocromo P-450/metabolismo , Dieta , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Tamaño de los Órganos/efectos de los fármacos , PPAR alfa/genética , Ratas Sprague-Dawley , Ratas Transgénicas , Medición de RiesgoRESUMEN
L-Ergothioneine is a naturally occurring histidine-derived betaine (CAS No: 497-30-3) synthesized by bacteria and fungi, and found ubiquitously in plants and animals. It is present in many human foodstuffs. We evaluated the potential reproductive toxicity of L-Ergothioneine in Sprague-Dawley rats. L-Ergothioneine was administered at concentrations of 0.1, 0.3 or 0.9% in diet to F0 males (for 10 weeks before pairing and 3 weeks during pairing) and F0 females (for 13 weeks before pairing, during pairing and gestation, and until day 5 of lactation). Systemic exposure increased with dose-level, but not dose proportionally, suggesting saturation of uptake mechanisms. No clinical signs of toxicity were observed and there were no effects of L-Ergothioneine treatment on mating and reproductive performance or parameters of fertility. All animals mated within a similar number of days and pregnancy rates were uniformly high in control and treated groups. There were no effects of treatment with L-Ergothioneine on the duration of gestation, pre- and post-implantation losses, number of pups delivered and viability index, or on litter parameters (litter size, clinical signs, body weight or sex ratio) and the repartition of found dead/cannibalized pups. In conclusion, L-Ergothioneine was well tolerated and without adverse effects on the reproductive parameters evaluated.
Asunto(s)
Ergotioneína/efectos adversos , Reproducción/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Ergotioneína/química , Femenino , Humanos , Masculino , Estructura Molecular , Ratas , Ratas Sprague-DawleyRESUMEN
TM0601p is a whey protein isolate derived from cow milk, containing a concentrated amount of transforming growth factor ß2 (TGF-ß2), and is intended for nutritional use in infants and adults. In vivo and in vitro studies have been performed to evaluate the safety of this product. In a 13-week toxicity study, treatment of adult Sprague-Dawley rats by gavage at up to 2000mg/kg/day did not result in any significant findings other than minor non-adverse changes in urinary parameters in females. The no-observed-adverse-effect level (NOAEL) was established as 2000mg/kg/day. In a juvenile toxicity study, rat pups received 600mg/kg/day by gavage from postnatal day (PND) 7 to PND 49. Transient lower bodyweight gain in the pre-weaning period was attributed to gastrointestinal effects of the viscous test material; following weaning, bodyweight gain was comparable to the vehicle controls. Reduced eosinophil counts and changes in urinary parameters (females) were recorded in treated pups at PND 49, and higher thymus weights were recorded in males only at the end of the recovery period (Day 77). None of the findings were considered adverse. There were no other significant findings and the NOAEL was established as 600mg/kg/day. No evidence of genotoxicity was seen in the bacterial reverse mutation test or the in vitro micronucleus test. Overall the results obtained present a reassuring safety profile for TM0601p.
Asunto(s)
Proteínas de la Leche/efectos adversos , Factor de Crecimiento Transformador beta2/efectos adversos , Animales , Femenino , Tracto Gastrointestinal/efectos de los fármacos , Masculino , Pruebas de Micronúcleos/métodos , Pruebas de Mutagenicidad , Nivel sin Efectos Adversos Observados , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Seguridad , Aumento de Peso/efectos de los fármacos , Proteína de Suero de LecheRESUMEN
The developmental and reproductive toxicity testing (including teratogenicity) of new foods and food additives is performed worldwide according to the guidelines given in the FDA Redbook. These studies are not required for substances that are generally recognized as safe, according to the FDA inventory. The anticipated cumulated human exposure level above which developmental or reproduction studies are required depends on the structure-alert category. For food additives of concern, both developmental (prenatal) and reproduction (multigeneration) studies are required. The developmental studies are performed in two species, usually the rat and the rabbit. The reproduction study is generally performed in the rat. The two rat studies are preferably combined into a single experimental design, if possible. The test methods described in the FDA Redbook are similar to those specified by the OECD for the reproductive toxicity testing of chemicals.
Asunto(s)
Aditivos Alimentarios/toxicidad , Teratología/métodos , Pruebas de Toxicidad/métodos , Animales , Química Farmacéutica , Relación Dosis-Respuesta a Droga , Vías de Administración de Medicamentos , Determinación de Punto Final , Femenino , Desarrollo Fetal/efectos de los fármacos , Aditivos Alimentarios/administración & dosificación , Aditivos Alimentarios/química , Regulación Gubernamental , Humanos , Masculino , Madres , Embarazo , Conejos , Ratas , Reproducción/efectos de los fármacos , Especificidad de la Especie , Teratología/legislación & jurisprudencia , Estados Unidos , United States Food and Drug Administration/legislación & jurisprudenciaRESUMEN
In Europe, the developmental toxicity testing (including teratogenicity) of new cosmetic ingredients is performed according to the Cosmetics Directive 76/768/EEC: only alternatives leading to full replacement of animal experiments should be used. This chapter presents the three scientifically validated animal alternative methods for the assessment of embryotoxicity: the embryonic stem cell test (EST), the micromass (MM) assay, and the whole embryo culture (WEC) assay.
Asunto(s)
Cosméticos/toxicidad , Teratología/métodos , Pruebas de Toxicidad/métodos , Animales , Línea Celular , Técnicas de Cultivo de Embriones , Células Madre Embrionarias/efectos de los fármacos , Regulación Gubernamental , Guías como Asunto , Células Madre Mesenquimatosas/efectos de los fármacos , Ratones , Ratas , Teratógenos/toxicidad , Teratología/legislación & jurisprudencia , Pruebas de Toxicidad/normasRESUMEN
This article is a report on the Fourth Berlin Workshop on Terminology in Developmental Toxicology, which was held in April 2002. The workshop is part of an international project in the field of harmonization of terminology in developmental toxicology supported by IPCS. The goal of the Harmonization Project is to ensure better chemical risk assessment. The aim of this Fourth Workshop was to discuss the results of a previously conducted survey on classification of external and visceral anomalies, which are listed in the international glossary, developed under the auspices of IFTS (1997 glossary). The discussions among experts from research institutions, regulatory agencies, and industries were mainly focussed on terms for which there was disagreement and/or uncertainties and the possible reasons. For the illustration of "gray-zone" anomalies, pictures were provided by the participants, which constituted the basis for detailed discussions. There was high agreement that most of the external anomalies (>66%) should be classified as malformations. The few external anomalies for which there was low agreement to classify as a malformation were discussed in detail. None of the external findings, which had in the survey a high agreement, were categorized as a variation.A high agreement regarding the classification of approximately one-third of visceral anomalies was achieved with 34 and 2% being described as malformation and variation, respectively. Most of the visceral findings had low agreement indices and there appeared to be several reasons for this. Thus, the response, 'Not known/not used in the laboratory' (N) was often given. A couple of reasons for difficulties in the classification of an anomaly were that it is only rarely seen upon fetal examination or tends to be species specific. Furthermore, the classification of some anomalies as malformation or variation will remain vague as the decision must be made on a case-by-case basis. Factors affecting the decision include: the availability of appropriate historical control data, description of the grading and severity, whether the anomaly occurs in isolation or whether there is a relationship with an abnormal process, and finally, if the change represents an irreversible one, affecting human and/or animal health. It was concluded that a severity grading, supported by pictures of the anomaly, would be especially helpful to classify certain changes as malformation or as variation. Several of the soft tissue changes were considered likely to be the consequence of functional disorders and thus not strictly developmental anomalies. The possibility to describe a finding as 'Not Malformation' (Unclassified) was agreed upon. As a general conclusion it was emphasized that the observation of a permanent structural change should be considered to be a warning of possible consequences to humans, even when there is no apparent adverse effect on health and survival in adult animals of the species under investigation. Therefore, research is needed to further investigate postnatal consequences. Future collaboration in the field of reproductive and developmental toxicology should aim to further develop and implement a harmonized approach to the interpretation of study data. Therefore, this terminology work will continue in close cooperation with the IPCS Harmonization Project. A Steering Group should be established to facilitate the implementation of harmonized terminology into daily scientific work and its regulatory application.