Gaps and challenges in nonclinical assessments of pharmaceuticals: An FDA/CDER perspective on considerations for development of new approach methodologies.

Previously, we provided an FDA/CDER perspective on nonclinical testing strategies and briefly discussed the opportunities and challenges of using new approach methodologies (NAMs) in drug development, especially for regulatory purposes. To facilitate the integration of NAMs into nonclinical regulatory testing, we surveyed the CDER Pharmacology/Toxicology community to identify the nonclinical challenges faced by CDER review staff, including gaps and areas of concern underserved by current nonclinical testing approaches, and to understand how development of NAMs with specific contexts of use (COUs) could potentially alleviate them. Survey outcomes were coalesced into CDER-identified needs for which NAMs with specific COUs could potentially be developed to address gaps and challenges in nonclinical safety assessments.

The US Food and Drug Administration's Perspective on the New Antipsychotic Pimavanserin.

Objective: To summarize the US Food and Drug Administration's (FDA's) review of the safety and effectiveness for pimavanserin, an atypical antipsychotic, for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis. We describe the regulatory and clinical issues important to the FDA's approval of this New Drug Application, with special focus on the risk-benefit balance. We also describe a new labeling feature that presents additional efficacy data to clinicians.

Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy.

The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by mutation of the telomeric survival motor neuron 1 (SMN1) gene with retention of the centromeric SMN2 gene. We sought to establish whether the potent and specific hydroxamic acid class of histone deacetylase (HDAC) inhibitors activates SMN2 gene expression in vivo and modulates the SMA disease phenotype when delivered after disease onset. Single intraperitoneal doses of 10 mg/kg trichostatin A (TSA) in nontransgenic and SMA model mice resulted in increased levels of acetylated H3 and H4 histones and modest increases in SMN gene expression.

The role of histone acetylation in SMN gene expression.

Increasing survival motor neuron 2 (SMN2) gene expression may be an effective strategy for the treatment of spinal muscular atrophy (SMA). Histone deacetylase (HDAC) inhibitors have been shown to increase SMN transcript and protein levels, but the specific role of histone acetylation in regulating SMN gene expression has not been explored. Using chromatin immunopreciptation, we investigated the levels of acetylated H3 and H4 histones and HDACs associated with different regions of the human and mouse SMN genes in both cultured cells and tissues.

Gene dose-dependent alterations in extraneuronal serotonin but not dopamine in mice with reduced serotonin transporter expression.

Serotonin (5-HT) plays an integral regulatory role in mood, anxiety, cognition, appetite and aggressive behavior. Many therapeutic and illicit drugs that modulate these functions act at the serotonin transporter (SERT), thus a mouse model with reduced transporter expression was created to further investigate the effects of differential serotonin reuptake. In the present study, in vivo microdialysis was used to determine homeostatic alterations in extracellular 5-HT levels in unanesthetized SERT knockout mice.

Differential regulation of nicotinic acetylcholine receptors in PC12 cells by nicotine and nerve growth factor.

Neuronal nicotinic receptors in PC12 cells were measured by binding with [3H]epibatidine and in functional studies with agonist-stimulated 86Rb+ efflux and [3H]norepinephrine release assays. Two subtypes of receptors labeled by [3H]epibatidine were found: one that was increased about 4-fold in cells grown for 2 to 4 days in the presence of nicotine and one that was increased 5-fold in cells grown for 2 to 4 days in the presence of nerve growth factor (NGF). The actions of the two treatments were superadditive, resulting in approximately a 13-fold increase in binding sites in cells grown in the combination of the two treatments.