Sodium Channel Inhibitors in Clinical Development for Pain Management: A Focused Review.

The US Food and Drug Administration (FDA) is a remarkable hybrid. Part regulatory agency, part public health agency, it sits at the intersection of science, law, and public policy. The FDA’s mission can be considered in the context of 2 broad dimensions: the products it regulates and its core functions. Both fall under the rubric of protecting and promoting the public health. The FDA’s remit is both broad and diverse: altogether, the agency has regulatory responsibility for >20% of the US economy. The products it is charged with overseeing through its various centers1 encompass food and cosmetics (regulated by the Center for Food Safety and Applied Nutrition); food and drugs for animals, including companion animals and animals used for food (regulated by the Center for Veterinary Medicine); and medical devices, drugs, and biologics (regulated by the Centers for Devices and Radiological Health, Drug Evaluation and Research, and Biologics Evaluation and Research, respectively). Tobacco products were added to the FDA’s portfolio by the Tobacco Control Act of 2009, and are overseen by the Center for Tobacco Products. Regardless of the specific product regulated, the FDA’s core mission remains the same: to protect the US population by helping to ensure the fundamental safety of the food Americans consume and the medical products prescribed by their clinicians. At the same time, this primary mission is complemented by a mandate to promote the public health by reviewing research and taking appropriate action on the marketing of regulated products in a timely manner. Not only do people need access to advances in nutrition and medical therapies, but also the American spirit is itself characterized by a strong current of scientific and technological innovation. At first glance, differences in these 2 priorities, protecting the public safety and promoting the public health through encouraging innovation, might …

Voltage-gated ion channels are implicated in pain sensation and transmission signaling mechanisms within both peripheral nociceptors and the spinal cord. Genetic knockdown and knockout experiments have shown that specific channel isoforms, including NaV1.7 and NaV1.8 sodium channels and CaV3.2 T-type calcium channels, play distinct pronociceptive roles. We have rationally designed and synthesized a novel small organic compound (Z123212) that modulates both recombinant and native sodium and calcium channel currents by selectively stabilizing channels in their slow-inactivated state. Slow inactivation of voltage-gated channels can function as a brake during periods of neuronal hyperexcitability, and Z123212 was found to reduce the excitability of both peripheral nociceptors and lamina I/II spinal cord neurons in a state-dependent manner. In vivo experiments demonstrate that oral administration of Z123212 is efficacious in reversing thermal hyperalgesia and tactile allodynia in the rat spinal nerve ligation model of neuropathic pain and also produces acute antinociception in the hot-plate test. At therapeutically relevant concentrations, Z123212 did not cause significant motor or cardiovascular adverse effects. Taken together, the state-dependent inhibition of sodium and calcium channels in both the peripheral and central pain signaling pathways may provide a synergistic mechanism toward the development of a novel class of pain therapeutics.A novel organic compound stabilizes slow-inactivated sodium and calcium channels to reduce the excitability of nociceptors and dorsal horn neurons and attenuate neuropathic pain signaling.

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Safety concerns at the FDA

e23021 Background: Restrictive eligibility criteria may limit demographic representation in clinical trials. Beginning in 2020, the US Food and Drug Administration (FDA) published draft guidance on broadening eligibility criteria by aligning them with investigational agents’ safety data. The extent to which this guidance has been adopted in current curative-intent phase III breast cancer trials, as well as its potential to impact demographic representation, is unclear. Methods: Eligibility criteria from US trials registered on ClinicalTrials.gov from 10/2023-10/2024 were catalogued. “FDA” guidance-based eligibility criteria were developed from available safety data using FDA drug labels and study protocols. A cohort of newly diagnosed patients treated with curative-intent therapy from 2006-2024 was identified using a real-world electronic health records database (TriNetX; Cambridge, MA) comprised of 87 US healthcare organizations. The primary endpoint was the median difference in the proportion of patients eligible using FDA versus actual criteria. Secondary endpoints were changes in the number of criteria and in eligibility by race/ethnicity. Endpoints were summarized descriptively and differences tested by univariate analysis. Results: There were 14 trials identified and 2990 patients in the analysis. Median age was 54 years, 10.7% were Hispanic, 2.5% Non-Hispanic (NH) Asian (NHA), 16.9% NH Black (NHB), 59.7% NH White (NHW), and 10.0% Unknown/Other (U/O). The median number of criteria per trial decreased from 13 (actual) to 4 (FDA). Cohort eligibility increased 12.8% (95% CI: 9.9, 18.2; p = 0.002) when moving from actual (86.7%) to FDA (98.2%) criteria. Changes in eligibility proportions when moving from actual to FDA criteria by trial ranged from -0.7-17.6%, with significant increases for 12 trials. Eligibility increased most through broadening the following criteria: creatinine clearance (6.6%), hemoglobin (1.6%), ALT (1.3%). Using actual criteria, median eligibility differences by race and ethnicity, compared to NHW (89.5% eligible), were: Hispanic (-3.1%), NHA (3.4%), NHB (-9.6%), O/U (-6.5%; all pairwise p < 0.002). Median differences using FDA criteria, compared to NHW (98.9% eligible) were: Hispanic (0.1%; p = 0.8), NHA (-2.1%; p = 0.002), NHB (-1.8%; p = 0.003), O/U (-3.4%; p = 0.002). Changes in median eligibility proportions between actual and FDA criteria for race/ethnic groups relative to NHW are shown in the Table. Conclusions: FDA guidance has not been widely adopted in current phase III trials. Utilizing FDA guidance will likely improve trial representation, especially for minoritized racial and ethnic groups. Race/Ethnicity NHB NHA Hispanic O/U Median % change compared to NHW % change* 8.1 -4.9 3.1 3.2 p-value 0.007 0.001 0.001 0.007 *Positive change indicates relatively more eligibility.

Report of the Topical Calcineurin Inhibitor Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology

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*These authors contributed to the devlopment and review of this manuscript but are unable to endorse the request for NIH funding. On Sept. 20, 2011, the American Association for Cancer Research (AACR) released its inaugural AACR Cancer Progress Report to commemorate the

Inhibition of neuronal voltage-gated sodium channels by brilliant blue G.

“Black box” 101: How the Food and Drug Administration evaluates, communicates, and manages drug benefit/risk

Straying from the target

SummaryVolatile anesthetics induce hyperactivity during induction while producing anesthesia at higher concentrations. They also bidirectionally modulate many neuronal functions. However, the neuronal mechanism is unclear. The effects of isoflurane on sodium channel currents were analyzed in acute mouse brain slices, including sodium leak (NALCN) currents and voltage-gated sodium channels (Nav) currents. Isoflurane at sub-anesthetic concentrations increased the spontaneous firing rate of CA3 pyramidal neurons, whereas anesthetic concentrations of isoflurane decreased the firing rate. Isoflurane at sub-anesthetic concentrations enhanced NALCN conductance but minimally inhibited Nav currents. Isoflurane at anesthetic concentrations depressed Nav currents and action potential amplitudes. Isoflurane at sub-anesthetic concentrations depolarized resting membrane potential (RMP) of neurons, whereas hyperpolarized the RMP at anesthetic concentrations. Isoflurane at low concentrations induced hyperactivity in vivo, which was diminished in NALCN knockdown mice. In conclusion, enhancement of NALCN by isoflurane contributes to its bidirectional modulation of neuronal excitability and the hyperactivity during induction.

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The US Food and Drug Administration Centers for Regulatory Science and Innovation: Current Activities and Future Promise to Accelerate Innovations.

Toward Project Optimus for Oncology Precision Medicine: Multi-Dimensional Dose Optimization Enabled by Quantitative Clinical Pharmacology.