ABSTRACT:On the basis of the ability of capsaicin to activate the transient receptor potential vanilloid 1 receptor (TRPV1) expressed in nociceptive sensory neurons, topical and injectable high-concentration formulations are being developed as potential treatments for various pain syndromes. As much of the published literature on capsaicin is based on pepper extracts, which are typically a mixture of capsaicin and other capsaicinoids (including norhydrocapsaicin, dihydrocapsaicin, homocapsaicin and homodihydrocapsaicin), the purpose of this investigation was to study the in vitro metabolism of pure capsaicin. The metabolism of capsaicin was similar in human, rat, and dog microsomes and S9 fractions.In these assays, three major metabolites were detected and identified as 16-hydroxycapsaicin, 17-hydroxycapsaicin, and 16,17-dehydrocapsaicin. In addition to these three metabolites, rat microsomes and S9 fractions also produced vanillylamine and vanillin. Biotransformation of capsaicin was slow in human skin in vitro, with the majority of the applied capsaicin remaining unchanged and a small fraction being metabolized to vanillylamine and vanillic acid. These data suggest that the metabolism of capsaicin by cytochrome P450 enzymes in skin is minimal, relative to hepatic metabolism.Capsaicin is the most abundant pungent molecule produced by pepper plants and thereby represents an important ingredient in spicy foods consumed throughout the world. The capsaicin content of peppers ranges from 0.1 to 2.5 mg/g (Parrish, 1996), and the resulting average human capsaicin consumption is on the order of 0.5 to 4 mg/kg/day (EC Scientific Committee on Food, 2002, http://ec.europa.eu/food/fs/sc/scf/out120_en.pdf). In addition to its extensive role as a food additive, there is also substantial human exposure to capsaicin in the form of nonprescription (in the United States) or prescription (in the European Union) topical analgesics, self-defense products (e.g., pepper spray), and oral herbal supplements.Capsaicin is a highly selective agonist for the TRPV1 [formerly known as the vanilloid receptor 1 (VR1)]. TRPV1 is a ligand-gated, nonselective cation channel preferentially expressed on small-diameter sensory neurons, especially those nociceptors that specialize in the detection of painful or noxious sensations (C-fibers and to a lesser extent A␦-fibers) (Caterina et al., 1997;Szallasi and Blumberg, 1999). The initial effect of capsaicin is the activation of TRPV1-expressing nociceptors, resulting in a burning sensation, hyperalgesia, allodynia, and erythema (Szallasi and Blumberg, 1999); these events are followed by a reversible defunctionalization of nociceptive sensory axons (Bley, 2004). Defunctionalization of hyperactive nociceptors is thought to underlie the pain relief that follows topical application or intra-articular injections of capsaicin (Bley, 2004).Much of the published literature on capsaicin relates to extracts of capsaicin derived from peppers; these extracts are typically a mixture of capsaicin, norhydrocapsaicin...

Capsaicin, a pungent compound in chili peppers, is a highly selective agonist for the transient receptor potential vanilloid 1 receptor expressed in nociceptive sensory nerves. A high-concentration (640 microg/cm2) capsaicin patch, designated NGX-4010, is in clinical evaluation for the management of peripheral neuropathic pain. To determine systemic capsaicin exposure after single 60- or 90-minute NGX-4010 applications, plasma samples were collected from 173 patients with postherpetic neuralgia (PHN), painful human immunodeficiency virus-associated neuropathy (HIV-AN), and painful diabetic neuropathy (PDN). The percentages of patients with quantifiable levels of capsaicin at any time point were 31% for PHN (30 of 96), 7% for HIV-AN (3 of 44), and 3% for PDN (1 of 33). The maximum plasma concentration observed in any patient was 17.8 ng/mL. Due to the limited number of quantifiable levels, a population analysis was performed to characterize the pharmacokinetics (PK) of capsaicin. Plasma concentrations were fitted adequately using a 1-compartment model with first-order absorption and linear elimination. Capsaicin levels declined very rapidly, with a mean population elimination half-life of 1.64 hours. Mean area under the curve and C max values after a 60-minute application were 7.42 ng x h/mL and 1.86 ng/mL, respectively. Only a few correlations between calculated PK parameters and patient characteristics were observed. Duration and area of application of the patch were detected as significant covariates explaining the PK of capsaicin. Ninety-minute applications of NGX-4010 resulted in capsaicin area under the curve and Cmax values approximately 1.78- and 2.15-fold higher than those observed in patients treated for 60 minutes. Treatment on the feet (patients with HIV-AN and PDN) produced far lower systemic exposure than treatment on the trunk (patients with PHN). Finally, larger treatment areas were associated with statistically higher Vc/F values. The low systemic exposure and very rapid elimination half-life of capsaicin after NGX-4010 administration are unlikely to result in systemic effects and support the overall safety profile of this investigational cutaneous patch.

Estradiol (E(2)) applied topically twice weekly to mouse skin at doses as low as 1 nmol inhibited hair growth by blocking the transition of the hair follicle from the resting phase (telogen) to the growth phase (anagen). In contrast, application of

BackgroundPhosphodiesterase‐4 (PDE4) is a promising target in atopic dermatitis (AD) treatment. The pharmacokinetics (PK), safety, and efficacy of crisaborole topical ointment, 2% (formerly AN2728) (Anacor Pharmaceuticals, Palo Alto, CA), a boron‐based benzoxaborole PDE4 inhibitor, were evaluated in children with mild to moderate AD.MethodsThis phase 1b, open‐label, maximal‐use study of crisaborole topical ointment, 2% applied twice daily (dose 3 mg/cm2) for 28 days enrolled patients ages 2 to 17 years with extensive AD involving 25% or more or 35% or more treatable body surface area, depending on age. Primary PK and safety assessments included systemic exposure to crisaborole and its metabolites after 7 days of treatment and the incidence of treatment‐emergent adverse events (TEAEs). Secondary efficacy assessments included change from baseline in Investigator Static Global Assessment (ISGA), treatment success (ISGA score ≤1 with a two‐grade or greater improvement from baseline), and improvement in five AD signs and symptoms.ResultsOf 34 patients enrolled, 31 completed the study. Crisaborole was rapidly absorbed, with limited systemic exposure between days 1 and 8. Twenty‐three of 34 patients reported one or more TEAEs; 95% were mild or moderate and one patient discontinued because of a TEAE. Mean ISGA scores declined from 2.65 at baseline to 1.15 at day 29, 47.1% of patients achieved treatment success, and 64.7% of patients achieved ISGA scores of clear (0) or almost clear 1. Mean severity scores for AD signs and symptoms declined throughout the study.ConclusionsThis open‐label study provides evidence that crisaborole topical ointment, 2% was well tolerated, with limited systemic exposure under maximal‐use conditions in patients ages 2 years and older.

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug that causes massive centrilobular hepatic necrosis at high doses, leading to death. The objectives of this study were to test our working hypothesis that preplaced cell division and hepatic tissue repair by prior thioacetamide (TA) administration provides protection against APAP-induced lethality and to investigate the underlying mechanism. Male Sprague-Dawley rats were treated with a low dose of TA (50 mg/kg, intraperitoneally [i.p.]) before challenge with a 90% lethal dose (1,800 mg/kg, i.p.) of APAP. This protocol resulted in a 100% protection against the lethal effect of APAP. Because TA caused a 23% decrease of hepatic microsomal cytochromes P-450, the possibility that TA protection may be caused by decreased bioactivation of APAP was examined. A 30% decrease in cytochromes P-450 induced by cobalt chloride failed to provide protection against APAP lethality. Time course of serum enzyme elevations (alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase) indicated that actual infliction of liver injury by APAP peaked between 12 to 24 hours after the administration of APAP, whereas the ultimate outcome of that injury depended on the biological events thereafter. Although liver injury progressed in rats receiving only APAP, it regressed in rats pretreated with TA. Acetaminophen t1/2 was not altered in TA-treated rats, indicating that significant changes in APAP disposition and bioactivation are unlikely. Moreover, hepatic glutathione was decreased to a similar extent regardless of TA pretreatment, suggesting that decreased bioactivation of APAP is unlikely to be the mechanism underlying TA protection. [3H]Thymidine incorporation studies confirmed the expected stimulation of S-phase synthesis, and proliferating cell nuclear antigen studies showed a corresponding stimulation of cell division through accelerated cell cycle progression. Intervention with TA-induced cell division by colchicine antimitosis ended the TA protection in the absence of significant changes in the time course of serum enzyme elevations during the inflictive phase of APAP hepatotoxicity. These studies suggest that hepatocyte division and tissue repair induced by TA facilitate sustained hepatic tissue repair after subsequent APAP-induced liver injury, producing recovery from liver injury and protection against APAP lethality.

No abstract

These results provide preliminary evidence for the limited systemic exposure, safety, and effectiveness of crisaborole topical ointment, 2% in adolescents with mild to moderate AD.

No abstract