ABSTRACT
Carisbamate is an antiepileptic drug and it also has broad neuroprotective activity and anticonvulsant reaction. In this study, a liquid chromatography-quadrupole time-of-flight mass spectrometric (LC-qTOF-MS) method was developed and applied for the determination of carisbamate in rat plasma to support in vitro and in vivo studies. A quadratic regression (weighted 1/concentration2), with an equation y = ax2 + bx + c, was used to fit calibration curves over the concentration range from 9.05 to 6,600 ng/mL for carisbamate in rat plasma. Preclinical in vitro and in vivo studies of carisbamate have been studied through the developed bioanalytical method. Based on these study results, human pharmacokinetic (PK) profile has been predicted using physiologically based pharmacokinetic (PBPK) modeling. The PBPK model was optimized and validated by using the in vitro and in vivo data. The human PK of carisbamate after oral dosing of 750 mg was simulated by using this validated PBPK model. The human PK parameters and profiles predicted from the validated PBPK model were similar to the clinical data. This PBPK model developed from the preclinical data for carisbamate would be useful for predicting the PK of carisbamate in various clinical settings.
ABSTRACT
Carisbamate is an antiepileptic drug and it also has broad neuroprotective activity and anticonvulsant reaction. In this study, a liquid chromatography-quadrupole time-of-flight mass spectrometric (LC-qTOF-MS) method was developed and applied for the determination of carisbamate in rat plasma to support in vitro and in vivo studies. A quadratic regression (weighted 1/concentration2), with an equation y = ax2 + bx + c, was used to fit calibration curves over the concentration range from 9.05 to 6,600 ng/mL for carisbamate in rat plasma. Preclinical in vitro and in vivo studies of carisbamate have been studied through the developed bioanalytical method. Based on these study results, human pharmacokinetic (PK) profile has been predicted using physiologically based pharmacokinetic (PBPK) modeling. The PBPK model was optimized and validated by using the in vitro and in vivo data. The human PK of carisbamate after oral dosing of 750 mg was simulated by using this validated PBPK model. The human PK parameters and profiles predicted from the validated PBPK model were similar to the clinical data. This PBPK model developed from the preclinical data for carisbamate would be useful for predicting the PK of carisbamate in various clinical settings.
ABSTRACT
This study was conducted to investigate the potential effects of alpha-chlorohydrin (ACH) on epididymal function and antioxidant system in male rats. The test chemical was administered to male rats by gavage at doses of 0, 3, 10, and 30 mg/kg/day for 7 days. Twenty-four male rats were randomly assigned to four experimental groups, with six rats in each group. Spermatotoxicity was assessed by measurement of reproductive organ weight, testicular sperm head count, epididymal sperm motility and morphology, histopathologic examination, and oxidative damage analysis in rats. At 30 mg/kg/day, an increase in the incidence of clinical signs, epididymis weight, and gross necropsy findings of the epididymis, a decrease in the sperm motility, and an increased incidence of histopathological changes of the epididymis were observed in a dose-dependent manner. At 10 mg/kg/day, an increased incidence of clinical signs and histopathological changes and decreased sperm motility were observed. In the oxidative damage analysis, an increase in the malondialdehyde concentration and a decrease in the glutathione content and glutathione peroxidase and catalase activities in the epididymal tissue were detected at > or =3 mg/kg/day. The results show that graded doses of ACH elicit depletion of the antioxidant defense system and that the spermatotoxicity of ACH may be due to the induction of oxidative stress.
Subject(s)
Animals , Humans , Male , Rats , alpha-Chlorohydrin , Catalase , Epididymis , Glutathione , Glutathione Peroxidase , Incidence , Malondialdehyde , Organ Size , Oxidative Stress , Sperm Head , Sperm Motility , SpermatozoaABSTRACT
OBJECTIVES: The present study investigated the potential adverse effects of multi-wall carbon nanotubes (MWCNTs) on pregnant dams and embryonic development following maternal exposure in rats. METHODS: MWCNTs were orally administered to pregnant rats from gestational day (GD) 6 through 19 at dose levels of 0, 8, 40, 200, and 1000 mg/kg/day. During the test period, clinical signs, mortality, body weights, food consumption, serum biochemistry, oxidant-antioxidant status, gross findings, organ weights, and Caesarean section findings were examined. RESULTS: All animals survived to the end of the study. A decrease in thymus weight was observed in the highest dose group. However, maternal body weight, food consumption, serum biochemical parameters, and oxidant-antioxidant balance in the kidneys were not affected by treatment with MWCNTs. No treatment-related differences in gestational index, embryo-fetal mortality, or fetal and placental weights were observed between treated and control groups. CONCLUSIONS: The results show that 14-day repeated oral dosing of MWCNTs during pregnancy induces minimal maternal toxicity at 1000 mg/kg/day in rats. Under these experimental conditions, the no-observed-adverse-effect level of MWCNTs is considered to be 200 mg/kg/day for dams and 1000 mg/kg/day for embryonic development.
Subject(s)
Animals , Female , Pregnancy , Rats , Biochemistry , Body Weight , Carbon , Cesarean Section , Embryonic Development , Kidney , Maternal Exposure , Nanotubes, Carbon , No-Observed-Adverse-Effect Level , Organ Size , Oxidative Stress , Thymus Gland , Weights and MeasuresABSTRACT
Bone remodeling in response to force requires coordinated actions of osteoblasts, osteoclasts, osteocytes, and periodontal ligament cells. Coordination among these cells may be mediated, in part, by cell-to-cell communication via gap junctions. This study was designed to evaluate the expression of gap junction, connection 43 in periodontal tissue during the experimental movement of rat's incisors, by LSAB(labelled streptavidine biotin) immunohistochemical staining for connexin 43. Twenty seven Sprague-Dawley rats were divided into a control group(3 rats), and 6 experimental groups(24 rats) where 75g of force was applied from helical springs across the maxillary incisors. Rats of experimental groups were sacrificed at 12 hours, 1, 4, 7, 14 and 28 days after force application, respectively. And the tissues of a control group and experimental groups were studied immunohistochemically. The results were as follows : 1. In control group, the expression of connexin 43 was rare in gingiva, dentin, cementum, periodontal ligament, and bone cells. 2. In experimental group, the expression of connexin 43 was increased in pulp, periodontal ligament, osteoblasts, and osteoclasts, comparing to that in control. And it was rare in gingiva, dentin, and odontoblasts regardless of the duration of force application, which was not different from that of control group. 3. The expression of connexin 43 in pulp of experimental group began to increase in 4-day after force application and got to the highest degree at 7-day. And it decreased after 14-day to be similar to that of control group at 28-day. 4. The expression of connexin 43 in periodontal ligament was noted in small capillaries adjacent to alveolar bone, showing higher intensity of immunolabelling after 4-day. And it was stronger in the pressure side than in tension side of periodontal ligament. After 7-day, decrease in connexin 43 expression was observed. 5. The expression of connexin 43 in alveolar bone began to increase 1-day, reached to the highest degree at 4-day, and decreased at 7-day. And the expression in osteoclasts was more than that in osteoblasts or osteocyte at 7-day.
Subject(s)
Animals , Rats , Bone Remodeling , Capillaries , Connexin 43 , Dental Cementum , Dentin , Gap Junctions , Gingiva , Incisor , Odontoblasts , Osteoblasts , Osteoclasts , Osteocytes , Periodontal Ligament , Rats, Sprague-Dawley , Streptavidin , Tooth Movement Techniques , ToothABSTRACT
The purpose of this study was to evaluate the torque effect of orthodontic wires. Ten types of orthodontic wires (five types of materials, two types of cross-sectional dimensions) were selected. Each group of wire type was constituted with five specimens. These specimens were tested on the universal testing machine(Instron) with specially-designed jig. The torque-twist curve of each wire was obtained and the results were analyzed statistically. The results were as follows: 1. 0.017" X 0.025" wire showed more torque effect than 0.016" X 0.022" wire at the same twist. 2. Torque effect was the greatest in stainless steel and the least in Nitinol. 3. The maximum amount of torque was the greatest in heat-treated Blue Elgiloy and the least in Nitinol.