RT Journal Article
SR Electronic
T1 Topical Application of ASN008, a Permanently Charged Sodium Channel Blocker, Shows Robust Efficacy, a Rapid Onset, and Long Duration of Action in a Mouse Model of Pruritus
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 521
OP 528
DO 10.1124/jpet.120.265074
VO 374
IS 3
A1 Roshni Ramachandran
A1 Scott K. Thompson
A1 Shelle Malkmus
A1 Tsutomu Mieda
A1 Jun-Hsiang Lin
A1 Sandeep Gupta
A1 Tony L. Yaksh
YR 2020
UL http://jpet.aspetjournals.org/content/374/3/521.abstract
AB The sensation of pruritus, or itch, is associated with a variety of skin and medical disorders. Itch is transmitted through afferent C-fibers, and sodium channels play a key role in the transmission process. Local anesthetics, which block sodium channels, are used topically to treat itch but generally have a short duration of action and are not selective for afferent nerves underlying the itch sensation. Accordingly, there is a substantial unmet need for safe, efficacious, long-acting treatments for chronic pruritus, including nonhistaminergic itch. We investigated the dose-response, time to onset, and duration of action of ASN008 topical gel, which targets small afferent sodium channels, in a murine model of pruritus in which scratching behavior is induced by intradermal injection of chloroquine into the nape of the neck of C57BL/6 mice. Topical application of ASN008 gel resulted in a concentration-dependent reduction of scratching behavior. Onset of action was ≤1 hour, and duration of scratching inhibition was 15–24 hours. In a further study involving once-daily application for 5 days with chloroquine challenge on day 5, treatment with ASN008 gel again resulted in a concentration-dependent reduction of chloroquine-induced scratching, even when the gel was removed 3 hours after each daily application. In conclusion, topical ASN008 gel produces a dose-dependent reduction of scratching in a mouse model of pruritus, with a rapid onset and long duration of action, and may prove to be an effective, once-daily treatment of a variety of pruritic conditions in humans, including nonhistaminergic itch.SIGNIFICANCE STATEMENT ASN008 gel produces a dose-dependent reduction of scratching in a mouse model of pruritus, with a rapid onset and long duration of action, and may prove to be an effective, once- or twice-daily treatment for a variety of pruritic conditions in humans. ASN008 gel has demonstrated good safety and tolerability in healthy volunteers and is currently under investigation in a phase 1b clinical study to evaluate safety, tolerability, pharmacokinetics, and preliminary antipruritic efficacy in atopic dermatitis patients (ClinicalTrials.gov ID: NCT03798561).