PT  - JOURNAL ARTICLE
AU  - Roshni Ramachandran
AU  - Scott K. Thompson
AU  - Shelle Malkmus
AU  - Sandeep Gupta
AU  - Tsutomu Mieda
AU  - Jun-Hsiang Lin
AU  - Tony L Yaksh
TI  - 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
AID  - 10.1124/jpet.120.265074
DP  - 2020 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.120.265074
4099  - http://jpet.aspetjournals.org/content/early/2020/07/02/jpet.120.265074.short
4100  - http://jpet.aspetjournals.org/content/early/2020/07/02/jpet.120.265074.full
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 non-histaminergic 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 for a variety of pruritic conditions in humans, including non-histaminergic 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, including non-histaminergic itch. ASN008 topical gel is currently under investigation in Phase 1 clinical studies to evaluate safety, tolerability, pharmacokinetics and preliminary anti-pruritic efficacy in atopic dermatitis patients (ClinicalTrials.gov ID: NCT03798561).