There is a lack of dosing guidelines for use in obese children. Moreover, the impact of obesity on drug safety and clinical outcomes is poorly defined. The paucity of information needed for the safe and effective use of drugs in obese patients remains a problem, even after drug approval. To assess the current incorporation of obesity as a covariate in pediatric drug development, the pediatric medical and clinical pharmacology reviews under the Food and Drug Administration (FDA) Amendments Act of 2007 and the FDA Safety and Innovation Act (FDASIA) of 2012 were reviewed for obesity studies. FDA labels were also reviewed for statements addressing obesity in pediatric patients. Forty-five drugs studied in pediatric patients under the FDA Amendments Act were found to have statements and key words in the medical and clinical pharmacology reviews and labels related to obesity. Forty-four products were identified similarly with pediatric studies under FDASIA. Of the 89 product labels identified, none provided dosing information related to obesity. The effect of body mass index on drug pharmacokinetics was mentioned in only 4 labels. We conclude that there is little information presently available to provide guidance related to dosing in obese pediatric patients. Moving forward, regulators, clinicians, and the pharmaceutical industry should consider situations in drug development in which the inclusion of obese patients in pediatric trials is necessary to facilitate the safe and effective use of new drug products in the obese pediatric population.
Background Relatively few neonatal drug development studies have been conducted, but an increase is expected with the enactment of the Food and Drug Administration Safety and Innovation Act (FDASIA). Understanding the safety of drugs studied in neonates is complicated by the unique nature of the population and the level of illness. The objective of this study was to examine neonatal safety data submitted to the FDA in studies pursuant to the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) between 1998 and 2015. Methods FDA databases were searched for BPCA and/or PREA studies that enrolled neonates. Studies that enrolled a minimum of 3 neonates were analyzed for the presence and content of neonatal safety data. Results The analysis identified 40 drugs that were studied in 3 or more neonates. Of the 40 drugs, 36 drugs received a pediatric labeling change as a result of studies between 1998 and 2015, that included information from studies including neonates. Fourteen drugs were approved for use in neonates. Clinical trials for 20 of the drugs reported serious adverse events (SAEs) in neonates. The SAEs primarily involved cardiovascular events such as bradycardia and/or hypotension or laboratory abnormalities such as anemia, neutropenia, and electrolyte disturbances. Deaths were reported during studies of 9 drugs. Conclusions Our analysis revealed that SAEs were reported in studies involving 20 of the 40 drugs evaluated in neonates, with deaths identified in 9 of those studies. Patients enrolled in studies were often critically ill, which complicated determination of whether an adverse event was drug-related. We conclude that the traditional means for collecting safety information in drug development trials needs to be adjusted for neonates and will require the collaboration of regulators, industry, and the clinical and research communities to establish appropriate definitions and reporting strategies for the neonatal population.
Aim: Gene delivery to the kidney by adeno-associated virus (AAV) remains a relatively unexplored field. We found that the cells in renal tissue infected by AAV9 vectors were very few but interestingly distributed in some specific regions adjacent to the glomerulus. Therefore we aim to identify the type of the cells infected by the AAV9 vectors, and compare it with other AAVs for the specific targeting by different routes of vector injection.Material and Methods: We injected AAV9-CMV-GFP, AAVH43-CMV-GFP and AAVH48-CMV-GFP (5×1011 vg /mouse) into the adult C57BL/6 mice (n=4 /group) via the tail vein. For the renal parenchyma injection (n=3/group) the vectors (10µl, 1 × 1011vg) were slowly injected into the renal parenchyma by a 33-gauge needle, which was connected to a 50µl Hamilton syringe with PE10 tubing. Two weeks later, kidneys were frozen and sectioned to slices of 10 µm.Results: We found that the AAV9 vector specifically infected juxtaglomerular apparatus in the kidney by intravenous injection. The infection efficiency reached up to 58.2±3.2% of total juxtaglomerular apparatus. On the other hand, The AAVH43 and AAVH48 vectors were negative in the kidney yet achieved GFP expression similarly to AAV9 in the heart and liver. Immunostaining showed the cells infected by AAV9-CMV-GFP vectors were exclusively adjacent to juxtaglomerular (JG) cells. These JG cells synthesize, store and secrete renin, and were identified by anti-renin antibody. Neuronal nitric oxide synthase (nNOS) and prostaglandin E receptor 3 (EP3) immunostaining further indicated that GFP-positive cells were perimacular cells, including the cells opposite the macula densa plaque. These were epithelial cells around the macula densa and one of four contact sites between the distal nephron and vasculature. The peri-macular cells, not including the macula densa, can generate spontaneous [Ca2+ ]i oscillations, and signal to the connected arterioles, regulating renal blood flow and tubular flow. Interestingly, specific infection in the juxtaglomerular apparatus by AAV9 vectors was dependent on the route of vector injection. When injected directly into the renal parenchyma, the peri-macular cells could no longer be infected, whereas the AAVH43 and AAVH48 vectors infected renal tubular epithelial cells. Conclusion:We have identified for the first time that a peri-macular cell type of the kidney is selectively targeted by intravenous AAV9 injection. Considering the importance role of those cells in regulation of renal blood flow and tubular flow, specific targeting by AAV9 may present a novel therapeutic method for renal hypertension and renal dysfunction. On the other hand, the data provide novel proof that the peri-macular cells are a group of functional epithelial cells, which differ from other renal tubular cells and may highly express AAV9 receptors. Additionally, the specificity of AAV9 infection in peri-macular cells was via the blood vessel, suggesting unique communication routes between peri-macular cells and the arterioles.
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