Parul S. Pall

Humanized NaV1.8 rats overcome cross-species potency shifts in developing novel NaV1.8 inhibitors

Dillon S. McDevitt, Joshua D. Vardigan, Xiaoping Zhou, Thomas W. Rosahl et autres

• MSD199 is a potent and selective Nav1.8 inhibitor. • Humanized rats can overcome species potency shifts in developing NaV1.8 inhibitors. • MSD199 demonstrates preclinical efficacy in SNL and CFA. Voltage-gated sodium channel isoform 1.8 (Na V 1.8) has emerged as a …

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Analgesia and peripheral c-fiber modulation by selective Nav1.8 inhibition in rhesus

Joshua D. Vardigan, Parul S. Pall, Dillon S. McDevitt, Chien-Jung Huang et autres

ABSTRACT: Voltage-gated sodium (Na v ) channels present untapped therapeutic value for better and safer pain medications. The Na v 1.8 channel isoform is of particular interest because of its location on peripheral pain fibers and demonstrated role in rodent preclinical pain …

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Translational Pharmacokinetic–Pharmacodynamic Modeling of NaV1.7 Inhibitor MK-2075 to Inform Human Efficacious Dose

Jeanine Ballard, Parul S. Pall, Joshua D. Vardigan, Fuqiang Zhao et autres

MK-2075 is a small-molecule selective inhibitor of the NaV1.7 channel investigated for the treatment of postoperative pain. A translational strategy was developed for MK-2075 to quantitatively interrelate drug exposure, target modulation, and the desired pharmacological response in preclinical animal models for the …

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Development of ProTx-II Analogues as Highly Selective Peptide Blockers of Nav1.7 for the Treatment of Pain

Gregory L. Adams, Parul S. Pall, Steven M. Grauer, Xiaoping Zhou et autres

Inhibitor cystine knot peptides, derived from venom, have evolved to block ion channel function but are often toxic when dosed at pharmacologically relevant levels in vivo . The article describes the design of analogues of ProTx-II that safely display systemic in vivo …

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Na v 1.7 target modulation and efficacy can be measured in nonhuman primate assays

Richard L. Kraus, Fuqiang Zhao, Parul S. Pall, Dan Zhou et autres

1.7 target modulation in rhesus macaques and determine the plasma concentration required to produce a predetermined level of inhibition. The calculated plasma concentration for preclinical efficacy could be used to guide human efficacious exposure estimates. Given the translatable nature of the assays …

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Application of Pharmacokinetic-Pharmacodynamic Modeling to Inform Translation of In Vitro NaV1.7 Inhibition to In Vivo Pharmacological Response in Non-human Primate

Jeanine Ballard, Parul S. Pall, Joshua D. Vardigan, Fuqiang Zhao et autres

PURPOSE: This work describes a staged approach to the application of pharmacokinetic-pharmacodynamic (PK-PD) modeling in the voltage-gated sodium ion channel (NaV1.7) inhibitor drug discovery effort to address strategic questions regarding in vitro to in vivo translation of target modulation. METHODS: PK-PD analysis …

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Pharmacological validation of a novel nonhuman primate measure of thermal responsivity with utility for predicting analgesic effects

Joshua D. Vardigan, Andrea K. Houghton, Henry S. Lange, Emily D. Adarayan et autres

INTRODUCTION: The development of novel analgesics to treat acute or chronic pain has been a challenge due to a lack of translatable measurements. Preclinical end points with improved translatability are necessary to more accurately inform clinical testing paradigms, which may help guide …

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Ablation of IB4 non-peptidergic afferents in the rat facet joint prevents injury-induced pain and thalamic hyperexcitability via supraspinal glutamate transporters

Christine L. Weisshaar, Jeffrey V. Kras, Parul S. Pall, Sonia Kartha et autres

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Pain from intra-articular NGF or joint injury in the rat requires contributions from peptidergic joint afferents

Jeffrey V. Kras, Christine L. Weisshaar, Parul S. Pall, Beth A. Winkelstein

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Psychophysical Measurements of Itch and Nociceptive Sensations in an Experimental Model of Allergic Contact Dermatitis

Parul S. Pall, Olivia Hurwitz, Brett King, Robert H. LaMotte

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