RESUMEN
PURPOSE: This study was conducted with 2 purposes. The first was to determine the effect of a single dose of zoledronic acid (ZA) on the healing of a tooth extraction socket in dogs. The second was to determine if placement of recombinant human bone morphogenetic protein-2 (rhBMP-2)/absorbable collagen sponge (ACS) - INFUSE, (Medtronic, Memphis, TN) into these extraction sockets would inhibit the inhibition on bone healing and remodeling by ZA. MATERIALS AND METHODS: Nine adult female beagle dogs (2 to 3 yr old) were placed into 3 groups of 3 dogs each. Group I received 15 mL of sterile saline intravenously; group II received 2.5 mg of ZA intravenously; and group III received 5 mg of ZA intravenously. Forty-five days after treatment, all dogs underwent extraction of noncontiguous right and left mandibular first molars and second premolars. In group I, the right mandibular extraction sockets had nothing placed in them, whereas the left mandibular sockets had only ACS placed in them. In groups II and III, the right mandibular sockets had rhBMP-2/ACS placed in them, whereas the left mandibular sockets had only ACS placed. All extraction sockets were surgically closed. Tetracycline was given intravenously 5 and 12 days later, and all animals were euthanized 15 days after tooth extraction. The extraction sockets and rib and femur samples were harvested immediately after euthanasia, processed, and studied microscopically. RESULTS: A single dose of ZA significantly inhibited healing and bone remodeling in the area of the tooth extractions. The combination of rhBMP-2/ACS appeared to over-ride some of the bone remodeling inhibition of the ZA and increased bone fill in the extraction sites, and remodeling activity in the area was noted. The effects of rhBMP-2/ACS were confined to the area of the extraction sockets because bone activity at distant sites was not influenced. CONCLUSIONS: A single dose of ZA administered intravenously inhibits early healing of tooth extraction sockets and bone remodeling in this animal model. The combination of rhBMP-2/ACS significantly increased bone fill and bone remodeling in these areas, negating much of the effect of the ZA.
Asunto(s)
Conservadores de la Densidad Ósea/farmacología , Proteína Morfogenética Ósea 2/farmacología , Difosfonatos/farmacología , Imidazoles/farmacología , Alveolo Dental/efectos de los fármacos , Factor de Crecimiento Transformador beta/farmacología , Animales , Antraquinonas , Diente Premolar/cirugía , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/antagonistas & inhibidores , Remodelación Ósea/efectos de los fármacos , Colágeno , Colorantes , Difosfonatos/administración & dosificación , Difosfonatos/antagonistas & inhibidores , Perros , Portadores de Fármacos , Femenino , Fémur/efectos de los fármacos , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Imidazoles/administración & dosificación , Imidazoles/antagonistas & inhibidores , Inyecciones Intravenosas , Diente Molar/cirugía , Osteogénesis/efectos de los fármacos , Proteínas Recombinantes/farmacología , Costillas/efectos de los fármacos , Cloruro de Tolonio , Extracción Dental , Cicatrización de Heridas/efectos de los fármacos , Ácido ZoledrónicoRESUMEN
OBJECTIVES: Burned bone coloration has been used for decades to help in the bioanthropological analysis of burned human bones. However, there is a variety of factors that can interfere with the coloration manifested by bones exposed to heat, resulting in colors that differ from the usual black to white gradient. In this study, we evaluated possible causes of unusual coloration changes and hues in burned bone. MATERIALS AND METHODS: For that purpose, defleshed fresh pig (Sus scrofa) ribs as well as fresh and dry human clavicles were burned at four different temperatures (500, 700, 900 and 1100°C) in contact with different materials (CaO, Zn, Fe, Cu, Mn, and polyester cloth). Observable color changes were assessed through naked eye observation and description, Munsell color charts, and reflectance spectrophotometry. Additionally, chemical changes in bone were assessed using Fourier-transform infrared spectroscopy in attenuated total reflectance (FTIR-ATR) and x-ray fluorescence (XRF). RESULTS: Our results showed that some materials did affect usual burned bone coloration (Fe, Mn, Cu, Zn) and correspondent FTIR-ATR and XRF spectra. As for other materials, although no effect on visual bone coloration was observed, they still affected FTIR-ATR and XRF spectra (CaO and cloth). DISCUSSION: This study can contribute to the anthropological analysis of burned human remains, providing some answers to what can cause unusual types of heat-induced colorations.
Asunto(s)
Color , Calor , Animales , Humanos , Calor/efectos adversos , Espectroscopía Infrarroja por Transformada de Fourier , Porcinos , Espectrometría por Rayos X , Huesos/efectos de los fármacos , Costillas/efectos de los fármacosRESUMEN
Phenylethyl alcohol (PEA) was tested for developmental toxicity. Pregnant rats were fed 0, 83, 266, or 799 mg/kg/d PEA on gestation days (GDs) 6 to 15; only minimal, nonsignificant effects were observed. In dermal studies, PEA (neat) was applied to the skin on GDs 6 to 15 at dosages of 0, 140, 430, or 1400 mg/kg/d and at 0, 70, 140, 280, 430, or 700 mg/kg/d in a corroborative study. Observations included maternal and embryo-fetal toxicity/abnormalities at 1400 mg/kg/d, increased incidences of rudimentary cervical ribs at ≥430 mg/kg/d, and reduced fetal body weights at ≥140 mg/kg/d. Dermal maternal and developmental no-observed-adverse-effect levels are 70 mg/kg/d, based on dermal irritation and reductions (nonsignificant) in fetal body weights. Human exposure from fragrances is 0.02 mg/kg/d, resulting in a margin of safety >2600, when marked differences in dermal absorption between rats and humans are considered. Under normal fragrance use conditions, PEA is not a developmental toxicity hazard for humans.
Asunto(s)
Desarrollo Embrionario/efectos de los fármacos , Desarrollo Fetal/efectos de los fármacos , Exposición Materna , Alcohol Feniletílico/toxicidad , Administración Cutánea , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Femenino , Peso Fetal/efectos de los fármacos , Edad Gestacional , Anomalías Musculoesqueléticas/inducido químicamente , Nivel sin Efectos Adversos Observados , Embarazo , Ratas , Ratas Endogámicas , Costillas/anomalías , Costillas/efectos de los fármacos , Pruebas de ToxicidadRESUMEN
Effects of etidronate on the calcification of scales and ribs were investigated in goldfish. Daily intraperitoneal injections of etidronate at doses of 1 and 10 mgP/kg body weight for 2 weeks inhibited calcification of ontogenic scales and ribs without affecting the accretion of organic matrices. Removal of some scales induced their regeneration within the two-week period. Their newly formed organic matrix was fully uncalcified in fish treated with 10 mgP/kg, whereas in those treated with 1 mgP/kg, the regenerating scales were only partially calcified. Daily administration of etidronate 10 mgP/kg resulted in an increase of body weight. These results suggested that the inhibitory effect of etidronate on the calcification of osseous tissues in mammals can be expected also on comparable tissues in fishes. An appropriate dose of etidronate that inhibits hard tissue calcification but not affects the body growth in fish seemed to exist between 1 and 10 mgP/kg.
Asunto(s)
Calcificación Fisiológica/efectos de los fármacos , Ácido Etidrónico/farmacología , Animales , Peso Corporal , Calcio/sangre , Carpa Dorada , Regeneración , Costillas/efectos de los fármacos , Costillas/crecimiento & desarrolloRESUMEN
PURPOSE: It is unknown whether zoledronic acid (ZA) interferes with initial bone healing at extraction and implant sites. The goal of this study was to examine the effect of short-duration ZA on bone remodeling and healing after surgical insult in an aged dog model. MATERIALS AND METHODS: Four 2- to 3-year-old male dogs were administered ZA (0.1 mg/kg per month for 4 months), and 3 age-matched untreated dogs received no drug. In both groups, after the ZA-treated group had completed receiving the drug, the third premolar was extracted unilaterally and 2 orthodontic mini-implants per jaw per dog were placed on the ipsilateral side. After a 6-week healing period, a pair of calcein bone labels were administered. Bone sections from the mandible, maxilla, rib, and femur were obtained. The percent necrosis in the alveolar and basal regions of tooth-supporting bone was assayed by lactate dehydrogenase, and dynamic histomorphometric parameters were quantified and analyzed by use of mixed models. RESULTS: All extraction sites healed uneventfully, and no lesions resembling osteonecrosis were detected. The total percent necrosis was limited to less than 1% for all the bone sites examined. The ZA reduced bone remodeling at both surgical sites (extraction sites and mini-implant site) and nonsurgical sites. Although there was a significant (P < .05) increase in bone formation rate at the surgical sites in the untreated group, this increase was not significant (P = .3) in the ZA-treated group. CONCLUSIONS: Bone remodeling occurs in ZA-treated animals at surgical sites. ZA dramatically reduced bone turnover, but no exposed lesions resembling osteonecrosis developed at extraction and mini-implant sites after the 4-month drug duration.
Asunto(s)
Conservadores de la Densidad Ósea/farmacología , Remodelación Ósea/efectos de los fármacos , Difosfonatos/farmacología , Imidazoles/farmacología , Mandíbula/cirugía , Maxilar/cirugía , Factores de Edad , Proceso Alveolar/efectos de los fármacos , Animales , Diente Premolar/cirugía , Implantación Dental Endoósea , Perros , Fémur/efectos de los fármacos , Fluoresceínas , Colorantes Fluorescentes , L-Lactato Deshidrogenasa/análisis , Masculino , Mandíbula/efectos de los fármacos , Enfermedades Mandibulares/etiología , Maxilar/efectos de los fármacos , Enfermedades Maxilares/etiología , Modelos Animales , Métodos de Anclaje en Ortodoncia/instrumentación , Osteogénesis/efectos de los fármacos , Osteonecrosis/etiología , Distribución Aleatoria , Costillas/efectos de los fármacos , Extracción Dental , Cicatrización de Heridas/efectos de los fármacos , Ácido ZoledrónicoRESUMEN
BACKGROUND: This study was conducted to evaluate the occurrence and fate of fetal lumbar rib induced by Scutellariae radix (SR) in rats. METHODS: Water extracts of SR were orally administered to pregnant rats from day 7 to day 17 of gestation at a dose of 186 mg/kg/day, equivalent to 25 g/kg of starting material, representing a 100-fold increase over typical human intake level. RESULTS: The incidence of fetal lumbar rib in the SR-treated group was increased on gestational day 20 and then decreased on postnatal day 50. The weight of fetuses in the SR-treated group tended to be less than that in the control group. Alkaline phosphatase in SR-treated dams was increased on gestational day 20, but was decreased on postnatal day 50. There were no significant differences between the vehicle control and SR-treated groups in maternal body weight, embryological, histopathological, hematological, and serum biochemical changes. CONCLUSIONS: The present data suggest that the appearance of lumbar rib induced by SR is a transient fetal variation rather than teratogenicity or maternal toxicity.
Asunto(s)
Feto/efectos de los fármacos , Vértebras Lumbares/embriología , Morfogénesis/efectos de los fármacos , Extractos Vegetales/toxicidad , Costillas/embriología , Scutellaria baicalensis/química , Animales , Femenino , Vértebras Lumbares/efectos de los fármacos , Exposición Materna , Embarazo , Ratas , Ratas Sprague-Dawley , Costillas/efectos de los fármacosRESUMEN
OBJECTIVES - To test the effect of bisphosphonate (BP) treatment for up to 3 years on bone necrosis and osteocyte death in the mandible using a canine model. MATERIALS AND METHODS - Dogs were treated with clinical doses of oral alendronate (ALN, 0.2 or 1.0 mg/kg/day) for 1 or 3 years. In a separate study, dogs were treated with i.v. zoledronate (ZOL) at 0.06 mg/kg/day for 6 months. En bloc staining was used to identify necrotic areas in the mandible; viable osteocytes were identified using lactate dehydrogenase. RESULTS - None of the treatments was associated with exposed bone, but 17-25% of dogs treated for 1 year and 25-33% of dogs treated for 3 years with ALN showed pockets of dead bone. Necrotic areas had no viable osteocytes and were void of patent canaliculi. No control animals demonstrated necrotic bone. ZOL treatment for 6 months was associated with osteocyte death greater than that seen in animals treated with ALN or saline. It is not clear whether osteocyte death occurs because of direct toxic effects of BPs, or because suppressed remodelling fails to renew areas that naturally undergo cell death. Necrotic areas are also associated with bone other than the mandible, e.g. the rib, which normally undergo high rates of remodelling. CONCLUSIONS - Reduced remodelling rate using BPs may contribute to the pathogenesis of bone matrix necrosis. The development of an animal model that mimics important aspects of BP-related osteonecrosis of the jaw is important to understanding the pathogenesis of osteonecrosis.
Asunto(s)
Conservadores de la Densidad Ósea/efectos adversos , Difosfonatos/efectos adversos , Enfermedades Mandibulares/inducido químicamente , Osteonecrosis/inducido químicamente , Alendronato/administración & dosificación , Alendronato/efectos adversos , Proceso Alveolar/efectos de los fármacos , Proceso Alveolar/patología , Animales , Matriz Ósea/efectos de los fármacos , Matriz Ósea/patología , Remodelación Ósea/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Colorantes , Difosfonatos/administración & dosificación , Modelos Animales de Enfermedad , Perros , Femenino , Osteón/efectos de los fármacos , Osteón/patología , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , L-Lactato Deshidrogenasa/análisis , Enfermedades Mandibulares/patología , Osteocitos/efectos de los fármacos , Osteonecrosis/patología , Costillas/efectos de los fármacos , Colorantes de Rosanilina , Factores de Tiempo , Ácido ZoledrónicoRESUMEN
Thallium (Tl) is a highly toxic metal for human beings; higher amounts found in diverse fluids of pregnant women are associated with low birth weight and preterm birth. However, experimental data concerning their effects on the embryonic development of mammalian organisms are limited. Hence, in the present work, TI(I) acetate of 0, 4.6, 9.2, or 18.5â¯mg/kg body weight were administered by intraperitoneal injection to groups of 10 pregnant CD-1 mice on the 7th gestational day, and animals were sacrificed on day 18 of gestation. The fetuses obtained showed some variations, such as trunk bent over (18.5â¯mg/kg), tail variations (all doses), forelimbs malrotation and hind limbs (all doses). Skeletal examination of the fetuses showed a delay in the ossification of skull bones, ribs, and limbs (all doses). In conclusion, the Intraperitoneal injection of Tl(I) acetate to pregnant mice induced morphological variations and a delay of the fetus ossification.
Asunto(s)
Anomalías Inducidas por Medicamentos/etiología , Talio/toxicidad , Animales , Desarrollo Embrionario , Femenino , Feto/efectos de los fármacos , Miembro Anterior/anomalías , Miembro Anterior/efectos de los fármacos , Miembro Anterior/crecimiento & desarrollo , Miembro Posterior/anomalías , Miembro Posterior/efectos de los fármacos , Miembro Posterior/crecimiento & desarrollo , Masculino , Intercambio Materno-Fetal , Ratones , Osteogénesis/efectos de los fármacos , Embarazo , Costillas/efectos de los fármacos , Costillas/crecimiento & desarrollo , Cráneo/efectos de los fármacos , Cráneo/crecimiento & desarrollo , Cola (estructura animal)/anomalías , Cola (estructura animal)/efectos de los fármacosRESUMEN
To investigate the abnormalities that are specific to administration of flucytosine at one time point during embryonic organogenesis, flucytosine was administered orally to pregnant Sprague Dawley (SD) rats in a single dose on day 11 of pregnancy at 25 or 35 mg/kg. Fetuses on day 20 of pregnancy were externally, viscerally, and skeletally examined. Maternal body weight gain and food consumption were suppressed the day after administration of a 35 mg/kg. Fetal examinations revealed various alterations in both dose groups: externally preaxial polydactyly in the hind limb; skeletally fused lumbar centrum, absent sacral centrum, supernumerary sacral vertebra, and absent ribs. Our findings indicated that specific types of external and skeletal anomalies were induced following flucytosine administration on day 11 of pregnancy.
Asunto(s)
Anomalías Inducidas por Medicamentos/patología , Ectromelia/patología , Desarrollo Fetal/efectos de los fármacos , Flucitosina/toxicidad , Polidactilia/patología , Teratógenos/toxicidad , Anomalías Inducidas por Medicamentos/etiología , Administración Oral , Animales , Esquema de Medicación , Ingestión de Alimentos/efectos de los fármacos , Ectromelia/inducido químicamente , Femenino , Feto , Miembro Posterior/anomalías , Miembro Posterior/efectos de los fármacos , Región Lumbosacra/anomalías , Masculino , Exposición Materna/efectos adversos , Organogénesis/efectos de los fármacos , Polidactilia/inducido químicamente , Embarazo , Ratas , Ratas Sprague-Dawley , Costillas/anomalías , Costillas/efectos de los fármacos , Aumento de Peso/efectos de los fármacosRESUMEN
UNLABELLED: Collagen cross-linking is a determinant of bone quality. A three-year treatment of bisphosphonate-incadronate disodium-in beagles increased degree of mineralization, collagen maturity, and pentosidine, a compound with advanced glycation end products. The treatment had no effect on the total amount of enzymatic cross-link formation. INTRODUCTION: Collagen cross-linking is a determinant of bone quality. Recently, we reported that long-term treatment with bisphosphonate increased microdamage accumulation. The aim of this study was to clarify the effect of a three-year treatment with bisphosphonate on degree of mineralization and immature and mature enzymatic cross-links and non-enzymatic collagen cross-link, pentosidine, in cortical bone in the same dogs. METHODS: Twenty-nine 1-year-old beagles (15 males, 14 females) were divided into three groups that daily were given vehicle or incadronate at doses of 0.3 or 0.6 mg/kg/day orally for three years. A cortex of a rib was fractionated into low- and high-density portions. The contents of calcium, phosphorus, enzymatic immature and mature cross-links, and the non-enzymatic glycation product pentosidine were determined in each fraction. RESULTS: Calcium, phosphorus, and pentosidine contents and the ratio of mature to immature cross-links increased significantly with incadronate in a dose-dependent manner, but the total amount of enzymatic cross-links was unchanged. The pentosidine content correlated inversely with cortical activation frequency (p < 0.01). CONCLUSION: Long-term suppression of bone remodeling by bisphosphonate increases degree of mineralization, collagen maturity, and non-enzymatic cross-linking.
Asunto(s)
Arginina/análogos & derivados , Conservadores de la Densidad Ósea/farmacología , Calcificación Fisiológica/efectos de los fármacos , Colágeno/metabolismo , Difosfonatos/farmacología , Lisina/análogos & derivados , Animales , Arginina/metabolismo , Fenómenos Biomecánicos , Conservadores de la Densidad Ósea/administración & dosificación , Resorción Ósea/fisiopatología , Resorción Ósea/prevención & control , Calcificación Fisiológica/fisiología , Calcio/metabolismo , Difosfonatos/administración & dosificación , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Femenino , Productos Finales de Glicación Avanzada/metabolismo , Lisina/metabolismo , Masculino , Fósforo/metabolismo , Costillas/efectos de los fármacos , Costillas/metabolismo , Costillas/fisiologíaRESUMEN
The present study aimed at examining postnatal repairability of sodium valproate-induced skeletal alterations in rats. Sodium valproate (400 mg/kg) or the vehicle (distilled water) was orally administrated to pregnant Sprague-Dawley rats from gestation days 9 to 11. Fetuses and pups were obtained on gestation day 21 and postnatal day 11, respectively, and their skeletons were stained with Alizarin red S and Alcian blue and examined. Sodium valproate-induced costal and vertebral alterations in the fetuses included discontinued rib cartilage, fused rib, full or short supernumerary rib, bipart ossification of thoracic centrum, supernumerary lumbar vertebrae, and lumbarization. In pups, however, discontinued rib cartilage was not observed, and the incidence of a short supernumerary rib was significantly lower than that in the fetuses, suggesting that these alterations are postnatally repairable.
Asunto(s)
Anomalías Inducidas por Medicamentos/rehabilitación , Anticonvulsivantes/efectos adversos , Regeneración Ósea/fisiología , Anomalías Musculoesqueléticas/rehabilitación , Ácido Valproico/efectos adversos , Anomalías Inducidas por Medicamentos/patología , Administración Oral , Azul Alcián , Animales , Animales Recién Nacidos , Antraquinonas , Cartílago/efectos de los fármacos , Cartílago/patología , Femenino , Feto , Edad Gestacional , Vértebras Lumbares/efectos de los fármacos , Vértebras Lumbares/patología , Exposición Materna , Anomalías Musculoesqueléticas/inducido químicamente , Anomalías Musculoesqueléticas/patología , Embarazo , Ratas , Ratas Sprague-Dawley , Costillas/efectos de los fármacos , Costillas/patología , Vértebras Torácicas/efectos de los fármacos , Vértebras Torácicas/patologíaRESUMEN
Some histone deacetylase inhibitors (HDACi) have recently been related to teratogenic effects in rodents. Skeletal defects have been directly associated with embryonic hyperacetylation of somitic nuclei after valproic acid or trichostatin A exposure in vivo. Albeit the antitumoral activity of HDACi has been classically related to chromatin condensation due to histonic lysine hyperacetylation, nonhistonic proteins have also been suggested as an HDACi target. The aim of this work was the study of the effects of three HDACi (apicidin, API; MS-275; sodium butyrate, BUT) on mouse development and their activity on embryonic histonic and nonhistonic proteins. Pregnant mice were ip treated with 10 mg/kg body weight API, 25 mg/kg MS-275, 2000 mg/kg BUT or with the vehicle alone on day 8 post coitum. Embryos were extracted 1, 2, or 3 h after treatment and Western blotting (using antibodies antihyperacetylated histone H4, antiacetylated lysine, or antitubulin) and immunohistochemistry (using the antibody antihyperacetylated histone H4) were performed. Fetuses, explanted at term of gestation, were double stained for bone and cartilage to detect skeletal abnormalities. The studied HDACi were teratogenic. The specific axial skeletal malformations were fusions or homeotic respecifications. These molecules induced hyperacetylation restricted to somitic histones. The hyperacetylation index of histone H4 as well as immunohistochemical and skeletal analyses indicated BUT as the less active molecule. These new data on effects of API, MS-275, and BUT on development suggest histonic hyperacetylation as the mechanism for the induction of the observed skeletal abnormalities.
Asunto(s)
Benzamidas/toxicidad , Butiratos/toxicidad , Inhibidores de Histona Desacetilasas , Péptidos Cíclicos/toxicidad , Piridinas/toxicidad , Costillas/efectos de los fármacos , Columna Vertebral/efectos de los fármacos , Acetilación , Animales , Desarrollo Embrionario/efectos de los fármacos , Femenino , Histonas/metabolismo , Masculino , Ratones , Ratones Endogámicos , Embarazo , Costillas/anomalías , Columna Vertebral/anomalías , Teratógenos/toxicidadRESUMEN
The axial skeleton is routinely examined in standard developmental toxicity bioassays and has proven to be sensitive to a wide variety of chemical agents. Dysmorphogenesis in the skull, vertebral column and ribs has been described in both human populations and in laboratory animals used to assess potential adverse developmental effects. This article emphasizes vertebrae and rib anomalies both spontaneous and agent induced. Topics discussed include the morphology of the more common effects; incidences in both human and experimental animal populations; the types of anomalies induced in the axial skeleton by methanol, boric acid, valproic acid and others; the postnatal persistence of common skeletal anomalies; and the genetic control of the development of the axial skeleton. Tables of the spontaneous incidence of axial anomalies in both humans and animals are provided.
Asunto(s)
Anomalías Inducidas por Medicamentos/etiología , Costillas/efectos de los fármacos , Columna Vertebral/efectos de los fármacos , Teratógenos/toxicidad , Pruebas de Toxicidad/métodos , Xenobióticos/toxicidad , Anomalías Inducidas por Medicamentos/patología , Animales , Humanos , Ratones , Conejos , Ratas , Costillas/anomalías , Columna Vertebral/anomalíasRESUMEN
Delayed (or incomplete) ossification of developing fetal bones and wavy ribs are some of the most common skeletal variations encountered in regulatory guideline developmental toxicity studies. Although they tend to be regarded as minor effects, they can be quite sensitive and consequently may influence the study lowest-observed-adverse-effect levels (LOAELs), and thus, impact classification, labeling, and risk assessment. In this study, we review the underlying mechanisms of these skeletal variations, evaluate different scenarios in which they have been observed, offer guidance for their interpretation, and comment on their use for risk assessment. Both minor delays in ossification and wavy ribs seem to be readily repairable via postnatal skeletal remodeling, are not mechanistically linked to malformation, and often are seen in the presence of maternal or fetal toxicity. As such, these minor variations would not generally be considered adverse in and of themselves but should be interpreted in the context of other maternal and fetal findings, information available on normal skeletogenesis patterns, mode of action of the test agent, and historical control incidence using a weight of evidence approach.
Asunto(s)
Anomalías Inducidas por Medicamentos , Osteogénesis/efectos de los fármacos , Costillas/efectos de los fármacos , Cráneo/efectos de los fármacos , Teratógenos/toxicidad , Xenobióticos/toxicidad , Animales , Humanos , Ratas , Costillas/anomalías , Medición de Riesgo/métodos , Cráneo/anomalías , Teratógenos/clasificación , Factores de Tiempo , Pruebas de Toxicidad/métodos , Xenobióticos/clasificaciónRESUMEN
Standard evaluations for characterizing selective developmental toxicity are traditionally undertaken in vivo. These studies incur significant cost in animal use, labor and compound, ultimately limiting the selection of compounds that can be evaluated in vivo. Such limitations hinder the ability to address questions regarding whether teratogenic outcome was caused by intended pharmacology or attributed to off-target effects associated with the structure of the small molecule. Ascertaining a better understanding of the published literature can enhance interpretation of existing in vivo datasets and hypotheses regarding critical windows of sensitivity and underlying mechanisms of teratogenicity. Thoughtful execution of investigative in vivo and in vitro studies can test and further define the underlying mechanism of teratogenicity. Skeletal variations and malformations are frequently encountered in in vivo studies and can be difficult to interpret in context of defining hazard assessment and mechanisms of abnormal development. This commentary reviews how investigative approaches can be integrated to better understand teratogenic mechanism as it pertains compounds that produce skeletal abnormalities. Approaches are discussed in context of how they could be used to study a compound that has been found to produce fused and wavy ribs in rat fetuses. An investigative approach is described that utilizes three strategies: 1) maximizing the data available from in vivo studies; 2) performing critical window studies in vivo; and 3) performing mechanism of action evaluations using gene expression studies and developmental model systems.
Asunto(s)
Anomalías Inducidas por Medicamentos/etiología , Alternativas a las Pruebas en Animales/métodos , Huesos/efectos de los fármacos , Teratógenos/toxicidad , Pruebas de Toxicidad/métodos , Xenobióticos/toxicidad , Anomalías Inducidas por Medicamentos/genética , Anomalías Inducidas por Medicamentos/patología , Animales , Huesos/anomalías , Desarrollo Embrionario/efectos de los fármacos , Desarrollo Embrionario/genética , Desarrollo Fetal/efectos de los fármacos , Desarrollo Fetal/genética , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/genética , Ratas , Costillas/anomalías , Costillas/efectos de los fármacos , Medición de Riesgo/métodos , Teratógenos/clasificación , Xenobióticos/clasificaciónRESUMEN
A new method to repair rib defects with biomaterials containing recombinant human bone morphogenetic protein-2 (rhBMP-2) is presented in this report. We had reported previously the successful regeneration of bony rib defects by placing a short chain of small beta-tricalcium phosphate (beta-TCP) cylinders on the intact periosteum. The multi-cylinder implants were ineffective in promoting rib repair when the periosteum was absent. By adding rhBMP-2 to the beta-TCP cylinders, we were able to promote rib bone regeneration in the presence or absence of the periosteum. The osteogenic capacity of the rhBMP-2/beta-TCP composite implant and the time required to complete regeneration were evaluated in a canine model. An 8cm long section of rib bone, including the periosteum, was removed and replaced with a chain of the rhBMP-2/beta-TCP cylinders. At 6 weeks after implantation, the ribs were restored to their original configuration and mechanical strength. The multi-cylinder beta-TCP implants were degraded and replaced by new bone in 12 weeks. This new degradable bone-inducing implant material has significant clinical potential for rib repair.
Asunto(s)
Proteínas Morfogenéticas Óseas/farmacología , Regeneración Ósea/efectos de los fármacos , Fosfatos de Calcio/química , Costillas/efectos de los fármacos , Factor de Crecimiento Transformador beta/farmacología , Implantes Absorbibles , Animales , Proteína Morfogenética Ósea 2 , Proteínas Morfogenéticas Óseas/genética , Perros , Humanos , Masculino , Osteogénesis/efectos de los fármacos , Proteínas Recombinantes/farmacología , Costillas/lesiones , Costillas/fisiopatología , Factores de Tiempo , Factor de Crecimiento Transformador beta/genéticaRESUMEN
Chronic exposure to high doses of iodine induces thyroid dysfunction, but effects of chronic exposure to high amounts of iodine on pregnancy and fetal outcome are uncertain. In the present study, Balb/C mice were given different doses of iodine at the levels of 0 (sterile water), 1,500, 3,000, 6,000, 12,000 and 24,000 micro g/L in drinking water for 4 months, then were mated and the developmental toxicity and teratogenicity were evaluated. An obvious colloid goiter was observed, and serum total thyroxine (TT4) levels increased and serum total triiodothyronine (TT3) levels decreased significantly in dams when iodine dose reached 3,000 micro g/L. Maternal effect was evident by the reduction of average daily food consumption in higher doses of iodine groups. Embryotoxicity and teratogenicity were mainly indicated by the reduced body weight in female fetuses, the decreased number of live fetuses, and the increased incidence of resorptions, and especially skeletal variations. These results suggest that exposure to maternally toxic doses of iodine may have a potential developmental toxic effect.
Asunto(s)
Yodo/toxicidad , Glándula Tiroides/efectos de los fármacos , Animales , Coloides/química , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Femenino , Muerte Fetal/inducido químicamente , Desarrollo Fetal/efectos de los fármacos , Reabsorción del Feto/inducido químicamente , Peso Fetal/efectos de los fármacos , Feto/efectos de los fármacos , Feto/fisiología , Bocio Nodular/inducido químicamente , Yodo/administración & dosificación , Yodo/orina , Masculino , Ratones , Ratones Endogámicos BALB C , Embarazo , Resultado del Embarazo , Costillas/anomalías , Costillas/efectos de los fármacos , Factores Sexuales , Esternón/anomalías , Esternón/efectos de los fármacos , Glándula Tiroides/patología , Tiroxina/sangre , Factores de Tiempo , Triyodotironina/sangreRESUMEN
The present study was undertaken to determine histopathologic differences in the ribs of Wistar-albino rat fetuses prenatally exposed to valproic acid (VPA), folic acid (FA) and vitamin E (Vit E), and to compare their differential developmental susceptibility and morphological association with skeletal anomalies. VPA (300 mg/ kg), FA (300mg/kg) and Vit E (250mg/kg) were administered to rats on each of gestation days (GD) 7-9. Fetuses were collected on GD 21 and their ribs were examined for malformations. The fetuses were divided into four groups: blind-trial group, VPA group (vpa), VPA and Vit E group (vpa+vit e), valproic and FA group (vpa+fa). In each group; drug procedure, surgical procedure and histological methods were performed. Later, weights and lengths of fetuses in each group were compared and analyzed by one-way Anova test. As a result, maLformations in fetuses were determined and photographed by Nikon SMZ-2 steromicroscopy, using 2 x objective. Administration of single doses of VPA (300 mg/kg) resulted in weight and length loss between blind-trial and vpa group. However, length and weight differences between the other groups were not significant. The objective of the present study is to analyze morphological and histopathologic changes which may occur in a high-risk experimental model after the administration of VPA. In addition, protective roles of the administration of FA and Vit E are assessed.
Asunto(s)
Ácido Fólico/farmacología , Costillas/embriología , Ácido Valproico/farmacología , Vitamina E/farmacología , Animales , Huesos/efectos de los fármacos , Huesos/embriología , Femenino , Desarrollo Fetal/efectos de los fármacos , Modelos Animales , Embarazo , Ratas , Ratas Wistar , Costillas/efectos de los fármacos , TeratógenosAsunto(s)
Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Encía/patología , Infecciones por VIH/tratamiento farmacológico , Mandíbula/patología , Linfoma Plasmablástico/tratamiento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Antirretroviral Altamente Activa/métodos , Biopsia , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Infecciones por Virus de Epstein-Barr/diagnóstico por imagen , Infecciones por Virus de Epstein-Barr/patología , Infecciones por Virus de Epstein-Barr/virología , Rayos gamma , Encía/diagnóstico por imagen , Encía/efectos de los fármacos , Encía/virología , VIH/efectos de los fármacos , VIH/crecimiento & desarrollo , Infecciones por VIH/diagnóstico por imagen , Infecciones por VIH/patología , Infecciones por VIH/virología , Herpesvirus Humano 4/efectos de los fármacos , Herpesvirus Humano 4/crecimiento & desarrollo , Humanos , Masculino , Mandíbula/diagnóstico por imagen , Mandíbula/efectos de los fármacos , Mandíbula/virología , Linfoma Plasmablástico/diagnóstico por imagen , Linfoma Plasmablástico/patología , Linfoma Plasmablástico/virología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Prednisona/uso terapéutico , Costillas/diagnóstico por imagen , Costillas/efectos de los fármacos , Costillas/patología , Costillas/virología , Escápula/diagnóstico por imagen , Escápula/efectos de los fármacos , Escápula/patología , Escápula/virología , Vincristina/uso terapéuticoRESUMEN
BACKGROUND: The aim of this study is to determine the influence of field of view (FOV) and number of acquisition projection images (frames) on the detection of chemically simulated peri-implant defects by cone-beam computed tomography (CBCT) using an in vitro bovine rib bone model. METHODS: Eighty implants were placed in bovine ribs in which small and large bone defects were created using 70% perchloric acid. CBCT images were acquired at three acquisition protocols: protocol 1 (FOV 4 × 4 cm, 0.08-mm voxel size, 1,009 frames [high fidelity]; protocol 2 (same as protocol 1 except 512 frames [standard]); and protocol 3 (FOV 14 × 5 cm, 0.25-mm voxel size; high fidelity). Two oral and maxillofacial radiologists (OMRs) and two oral and maxillofacial surgeons (OMSs) rated the presence or absence of bone defects on a five-point scale. κ and area under the curve (AUC) were calculated and compared using analysis of variance with post hoc Tukey test at P ≤ 0.05. RESULTS: Intra- and interobserver agreement for OMRs ranged from moderate to good and from slight to moderate for OMSs. For the detection of small lesions, protocol 1 (AUC 0.813 ± 0.045) provided higher detection rates than protocol 2 (AUC 0.703 ± 0.02) and protocol 3 (AUC 0.773 ± 0.55) [F(2,9) = 1.6377]. For larger defects, the trends were similar, with protocol 1 (AUC 0.852 ± 0.108) providing higher detection rates than protocol 2 (AUC 0.730 ± 0.045) and protocol 3 (AUC 0.783 ± 0.058) [F(2,9) = 1.9576]. CONCLUSION: Within the limits of this study, optimal detection of chemically simulated pericircumferential implant crestal bone defects is achieved at the least radiation detriment using the smallest FOV, the highest number of acquisition frames, and the smallest voxel.