Reproductive toxicity testing is characterized by high animal use. For registration of pharmaceutical compounds, developmental toxicity studies are usually conducted in both rat and rabbits. Efforts have been underway for a long time to design alternatives to animal use. Implementation has lagged, partly because of uncertainties about the applicability domain of the alternatives. 相似文献
One of the top priorities of the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) is the identification and evaluation of non‐animal alternatives for skin sensitization testing. Although skin sensitization is a complex process, the key biological events of the process have been well characterized in an adverse outcome pathway (AOP) proposed by the Organisation for Economic Co‐operation and Development (OECD). Accordingly, ICCVAM is working to develop integrated decision strategies based on the AOP using in vitro, in chemico and in silico information. Data were compiled for 120 substances tested in the murine local lymph node assay (LLNA), direct peptide reactivity assay (DPRA), human cell line activation test (h‐CLAT) and KeratinoSens assay. Data for six physicochemical properties, which may affect skin penetration, were also collected, and skin sensitization read‐across predictions were performed using OECD QSAR Toolbox. All data were combined into a variety of potential integrated decision strategies to predict LLNA outcomes using a training set of 94 substances and an external test set of 26 substances. Fifty‐four models were built using multiple combinations of machine learning approaches and predictor variables. The seven models with the highest accuracy (89–96% for the test set and 96–99% for the training set) for predicting LLNA outcomes used a support vector machine (SVM) approach with different combinations of predictor variables. The performance statistics of the SVM models were higher than any of the non‐animal tests alone and higher than simple test battery approaches using these methods. These data suggest that computational approaches are promising tools to effectively integrate data sources to identify potential skin sensitizers without animal testing. Published 2016. This article has been contributed to by US Government employees and their work is in the public domain in the USA. 相似文献
Introduction: The inhalation of substances, both medicinally and recreationally, is a commonly used method of drug administration but has been underutilized in the treatment of neurologic disorders such as migraine. Three drugs have been studied as potential inhalable treatments for acute migraine: dihydroergotamine (MAP0004), prochlorperazine (Staccato prochlorperazine), and loxapine (Staccato loxapine).Areas covered: This review discusses the available literature describing the pharmacokinetics, tolerability and efficacy of MAP0004, Staccato prochlorperazine and Staccato loxapine, including data from Phase II and Phase III clinical trials.Expert opinion: Inhaled DHE offers rapid absorption with a pharmacokinetic profile similar to IV administration. Improved side effect profile results from more selective binding at antimigraine serotonergic receptors 5-HT1B and 5-HT1D. Inhaled prochlorperazine is rapidly absorbed and resulted in statistically significant migraine pain relief at 2 hours compared to placebo but is not currently being pursued by the manufacturer as a potential migraine abortive. Inhaled loxapine is also rapidly absorbed into systemic circulation but Phase IIb trials did not show statistically improved pain relief or pain freedom compared to placebo. MAP0004 will likely provide a good alternative to patients seeking rapid relief without the need for injection or other invasive routes. 相似文献
Regional anesthesia for pain at delivery in the presence of maternal thrombocytopenia is a clinical dilemma. We reviewed 10,369 obstetric cases (12 months) from our tertiary center. Generally, hemodilution of pregnancy does not result in thrombocyte counts of <150,000/mm(3) at delivery. A total of 166 births (1.6%) were recorded in women with thrombocytes <150,000/mm(3) at delivery. Parturients with >150,000/mm(3) at week 36 were separated post hoc (n=35; 21%) and the remaining parturients were divided as having <100,000/mm(3) (n=30; 18%) or 101,000-150,000/mm(3) (n=101; 60.5%). Epidural or spinal anesthesia was administered to 30% women with <100,000/mm(3) whereas 56% women with >101,000/mm(3) received these options (P=0.003). A total of 13.9% of parturients with trimester-long thrombocytopenia required blood products; 10/23 (43.5%) parturients undergoing cesarean section also required blood products (P=0.000). Four of six babies with Apgar scores of 相似文献
Objective Correct prenatal determination of the fetal right/left axis is essential for the diagnosis of fetal malformations, in particular
congenital heart anomalies. A reliable method of transabdominal echocardiographic assessment of the fetal situs in the late
second trimester was established. We aimed to determine the validity of the transvaginal approach to assess fetal axis.
Method The study group consisted of 108 consecutive women in the second trimester of a singleton pregnancy, undergoing elective transvaginal
anatomy scans. All had undergone previous transabdominal echocardiography to establish fetal axis. The same technique was
used to assess the fetal axis during the transvaginal study, and the findings were compared.
Results There was total agreement in fetal axis determination between transabdominal and transvaginal scans in all cases. The accuracy
of the transvaginal study was not affected by maternal obesity, fetal position or the presence of cardiac malformation (in
one case).
Conclusion Transvaginal ultrasonography is the reliable and accurate means of determining the fetal axis.
Both affiliations are affiliated with Sackler Faculty of Medicine, Tel Aviv
University. 相似文献
Context/Objective: Provisions of the Affordable Care Act (ACA) potentially increase insurance options for Veterans with disabilities. We examined Veterans with spinal cord injuries and disorders (SCI/D) to assess whether the ACA was associated with changes in healthcare utilization from Department of Veterans Affairs (VA) healthcare facilities.Design: Using national VA data, we investigated impacts on VA healthcare utilization pre- (2012/13) and post-ACA (2014/15) implementation with negative binomial regression models.Setting: VA healthcare facilities.Participants: 8,591 VA users with SCI/D. Veterans with acute myelitis, Guillain-Barré syndrome, multiple sclerosis, or amyotrophic lateral sclerosis were excluded as were patients who died during the study period.Interventions: We assessed VA healthcare utilization before and after ACA implementation.Outcome Measures: Total numbers of VA visits for SCI/D care, diagnostic care, primary care, specialty care, and mental health care, and VA admissions.Results: The number of VA admissions was 7% higher in the post than pre-ACA implementation period (P < 0.01). The number of VA visits post-implementation increased for SCI/D care (8%; P < 0.01) and specialty care (12%; P < 0.001). Conversely, the number of mental health visits was 17% lower in the post-ACA period (P < 0.001). Veterans with SCI/D who live <5 miles from their nearest VA facility received VA care more frequently than those ≥40 miles from VA (P < 0.001).Conclusion: Counter to expectations, results suggest that Veterans with SCI/D sought more frequent VA care after ACA implementation, indicating Veterans with SCI/D continue to utilize the lifelong, comprehensive care provided at VA. 相似文献
Purpose: Parents/caregivers of children with autism spectrum disorder (ASD) have varying types of initial concerns regarding their child’s development, which may be culturally bound to parents’ perceptions of their child’s development. This study investigated differences in the types of initial developmental concerns reported by parents or caregivers of different racial/ethnic groups with children in an early intervention program.
Method: This study examined the frequency of endorsement of different types of concerns in African American, Caucasian, and Hispanic families.
Results: No significant differences between racial/ethnic groups were found in the endorsement of concerns related to communication, language/speech, motor, problem behavior, sensory, feeding, prematurity, attention, adaptive functioning, and medical conditions. Racial/ethnic groups differed significantly in their endorsement for social concerns.
Conclusion: Racial/ethnic group differences were confirmed regarding initial developmental concerns related to social behavior, which may be due to cultural beliefs. The implications of these findings on early identification are discussed. 相似文献