FDA Perspectives on the Regulation of Neuromodulation Devices.

The United States Food and Drug Administration (FDA) ensures that patients in the United States have access to safe and effective medical devices. The division of neurological and physical medicine devices reviews medical technologies that interface with the nervous system, including many neuromodulation devices. This article focuses on neuromodulation devices and addresses how to navigate the FDA's regulatory landscape to successfully bring devices to patients.

Skin sensitization testing needs and data uses by US regulatory and research agencies.

United States regulatory and research agencies may rely upon skin sensitization test data to assess the sensitization hazards associated with dermal exposure to chemicals and products. These data are evaluated to ensure that such substances will not cause unreasonable adverse effects to human health when used appropriately. The US Consumer Product Safety Commission, the US Environmental Protection Agency, the US Food and Drug Administration, the Occupational Safety and Health Administration, the National Institute for Occupational Safety and Health, and the US Department of Defense are member agencies of the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM). ICCVAM seeks to identify opportunities for the use of non-animal replacements to satisfy these testing needs and requirements. This review identifies the standards, test guidelines, or guidance documents that are applicable to satisfy each of these agency's needs; the current use of animal testing and flexibility for using alternative methodologies; information needed from alternative tests to fulfill the needs for skin sensitization data; and whether data from non-animal alternative approaches are accepted by these US federal agencies.

FDA Regulation of Neurological and Physical Medicine Devices: Access to Safe and Effective Neurotechnologies for All Americans.

The United States Food and Drug Administration (FDA) ensures that patients in the U.S. have access to safe and effective medical devices. The Division of Neurological and Physical Medicine Devices reviews medical technologies that interface with the nervous system. This article addresses how to navigate the FDA's regulatory landscape to successfully bring medical devices to patients.

Mechanism of promoter activity of the beta-amyloid precursor protein gene in different cell lines: identification of a specific 30 bp fragment in the proximal promoter region.

The amyloid beta-protein (Abeta) deposited in brains of Alzheimer's disease (AD) patients is proteolytically derived from a large Abeta precursor protein (APP). APP gene expression patterns in the AD brain region indicate that abnormalities of gene regulation may be important in AD pathology. To understand the contribution of different cell types to APP gene expression, we studied it at four levels: promoter activity (by reporter gene assay of transfected cells), DNA-nuclear protein interaction (by electrophoretic mobility shift assay), RNA message and protein (by northern and western blotting, respectively). APP mRNA and protein expression levels were greater in neuroblastoma and PC12 cells than in glial or cervix epithelial cells. Relative activity among 12 different promoter regions and within single regions varied according to cell type/cell line. An upstream regulatory region containing a GATA-1 site is necessary for activity in PC12 and glial cells but not in neuroblastoma cells. DNA-protein interactions were examined in three distal and one proximal promoter elements in nuclear extracts belonging to neuronal and non-neuronal cells. The proximal promoter region is important for cell line-specific APP gene expression. Characterization of the APP regulatory region's interaction with cell type-specific nuclear factor(s) is important to understand tissue-specific expression of APP seen in AD subjects.

Phosphorodiamidate morpholino antisense oligomers inhibit expression of human cytochrome P450 3A4 and alter selected drug metabolism.

Antisense phosphorodiamidate morpholino oligomers (PMO) inhibit targeted gene expression by preventing ribosomal assembly, thus preventing translation. Inhibition of cytochrome P450 (P450) 3A4 expression was examined in primary human hepatocytes from 11 donors and in Caco-2 cells (stably transfected with CYP3A4 cDNA on an extrachromosomal vector) by evaluating the metabolism of substrate 7-benzyloxy-4-[trifluoromethyl]-coumarin and Western immunoblot analysis. Cellular uptake of PMO was confirmed in both cell systems using fluorescein-labeled PMOs. Three antisense PMO sequences and two control PMO sequences were tested. AVI-4557, a 20-mer PMO with the sequence 5'-CTGGGATGAGAGCCATCACT-3' was selected as the optimal agent. AVI-4557 inhibited expression of CYP3A4 in Caco-2/h3A4 cells by 64% at 24 h following administration of 2.8 microM by an assisted delivery protocol. Inhibition of CYP3A activity was observed in primary human hepatocytes after 24 h exposure to AVI-4557 by an average of 32 +/- 11%. Furthermore, AVI-4557 exposure resulted in a sequence-dependent inhibition of cyclophosphamide-related cytocidal activity and a sequence-dependent induction of paclitaxel-related cytocidal activity in both cell types. Finally, the cytocidal activity of cisplatin was not affected with AVI-4557 treatment in either cell type. These studies indicate AVI-4557 is an effective and specific inhibitor of CYP3A4 expression.