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Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the vanilloid receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC). Similar to capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC 50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC 50 value of 6.0 nM), whereas capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by capsazepine. Specificity for VR1 was demonstrated against 63 other receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of ϳ1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than capsazepine for testing the role played by VR1 in rat models of human disease.

ISRCTN Register: ISRCTN45537485 .

Background PRO 140 is a humanized CCR5 monoclonal antibody that has demonstrated potent antiviral activity when administered intravenously to adults infected with CCR5-tropic (R5) human immunodeficiency virus type 1 (HIV-1). This study is the first to evaluate subcutaneous (SC) administration. Methods A randomized, double-blind, placebo-controlled study was conducted in 44 subjects with HIV-1 RNA > 5,000 copies/mL, CD4+ cells > 300/μL, no antiretroviral therapy for ≥12 weeks, and only R5 HIV-1 detectable. Subjects received placebo, 162mg PRO 140, or 324mg PRO 140 weekly for three weeks or 324mg PRO 140 every other week for two doses by SC infusion. Subjects were monitored for 58 days for safety, antiviral effects and PRO 140 serum concentrations. Results SC PRO 140 demonstrated potent and prolonged antiretroviral activity. Mean log10 reductions in HIV-1 RNA were 0.23, 0.99 (p=0.0093), 1.37 (p=0.0001), and 1.65 (p<0.0001) for the placebo, 162mg weekly, 324mg biweekly and 324mg weekly dose groups, respectively. Viral loads remained suppressed between successive doses. Treatment was generally well tolerated. Conclusions This trial is the first to demonstrate proof of concept for a mAb administered subcutaneously in HIV-1 infected subjects. SC PRO 140 offers the potential for significant dose-dependent HIV-1 RNA suppression and infrequent patient self-administration. Trial registration Clinicaltrials.gov register NCT00642707