Tolerability profile of topical cannabidiol and palmitoylethanolamide: a compilation of single-centre randomized evaluator-blinded clinical and in vitro studies in normal skin.

BACKGROUND: An increasing number of studies have investigated the adverse effect profile of oral cannabinoids; however, few studies have provided sufficient data on the tolerability of topical cannabinoids in human participants. AIM: To assess the tolerability profile of several commercial topical formulations containing cannabidiol (CBD) and palmitoylethanolamide (PEA) on the skin of healthy human participants. METHODS: Three human clinical trials and one in vitro study were conducted. The potential for skin irritation, sensitization and phototoxicity of several products, were assessed via patch testing on healthy human skin. The products assessed included two formulations containing CBD and PEA, one containing hemp seed oil and four concentrations of CBD alone. Ocular toxicity was tested using a traditional hen's egg chorioallantoic membrane model with three CBD, PEA and hemp seed oil formulations. RESULTS: There was no irritation or sensitization of the products evident via patch testing on healthy participants. Additionally, mild phototoxicity of a hemp seed oil product was found at the 48-h time point compared with the negative control. The in vitro experiment demonstrated comparable effects of cannabinoid products with historically nonirritating products. CONCLUSION: These specific formulations of CBD- and PEA-containing products are nonirritating and nonsensitizing in healthy adults, and further encourage similar research assessing their long-term safety and efficacy in human participants with dermatological diseases. There are some limitations to the study: (i) external validity may be limited as formulations from a single manufacturer were used for this study, while vast heterogeneity exists across unregulated, commercial CBD products on the market; and (ii) products were assessed only on normal, nondiseased human skin, and therefore extrapolation to those with dermatological diseases cannot be assumed.

Necrotic arachnidism.

UNLABELLED: Necrotic arachnidism is the potential cutaneous reaction to spider bite venom. In the United States, members of 7 spider families may be responsible for envenomation sufficiently severe to warrant treatment. Characteristics of several spiders, in particular Loxosceles spiders, whose bite is toxic to humans are described, and diagnostic standards, preventive measures, and treatment options are reviewed. (J Am Acad Dermatol 2001;44:561-73.) LEARNING OBJECTIVE: After the completion of this learning activity, participants should be familiar with the characteristics of several different spider families endemic to the United States. Furthermore, this learning activity should aid in the prevention and diagnosis of spider bites as well as in the classification and treatment of specific bites.

Substance P has a role in neurogenic mediation of human burn wound healing.

Knowledge of biochemical and molecular events during burn wound healing may optimize treatment of patients with thermal injuries. Substance P (SP), a neuropeptide present in C fibers of the skin, has been implicated as a mediator of inflammation and wound healing. This neuropeptide induces vasodilitation and vascular permeability by stimulating endothelial cells to round up, vascular smooth cells to relax, and mast cells to release histamine. SP also induces cytokine release by macrophages and neutrophils. Because many of the functions of SP seemed relevant to wound repair in burns, we used immunocytochemistry to characterize SP+ nerve fibers in healing human burn wounds. Deep partial-thickness burns collected from 20 patients at the time of excision and grafting were formalin fixed, paraffin-embedded, sectioned, and labeled with a monoclonal antibody to SP with use of an immunoperoxidase technique. Our tissue samples included normal skin and 20 specimens from postburn days 2 through 49. In normal adult skin, SP+ nerve fibers surrounded vessels throughout the skin and extended from the papillary dermis into the epidermis. SP+ fibers were absent in early wound beds. SP immunostaining did occur in the advancing epidermis, endothelial cells, and mast cells. SP+ fibers could be identified in the deep dermis and subjacent to the advancing epithelium before the wound beds. Maximum numbers of SP+ fibers were present subjacent to the advancing epithelium at 2 weeks after burn injury. After 4 weeks, the distribution of SP+ fibers in reepithelialized areas was similar to that of normal skin. Our data corroborate published reports of SP+ fiber regeneration in guinea pig burns and correlates with clinical observations of pain and pruritus in patients with thermal injuries. The absence of SP+ fibers in the early wounds with SP immunostaining in the epidermis and extracellular matrix suggests that SP may be released from injured nerves and supports neurogenic mediation of inflammation and vasodilitation in early wound repair. Repopulation of the wound beds with SP+ fibers appeared to follow neovascularization originating in the deep reticular dermis and wound edge.

Mechanism mediating basolateral transport of 2,4-dichlorophenoxyacetic acid in rat kidney.

The organic anions, p-aminohippurate (PAH) and fluorescein, are transported across the basolateral membrane of the renal proximal tubule in exchange for intracellular alpha-ketoglutarate (alpha KG), a mechanism indirectly coupled to sodium via Na+/alpha KG cotransport. To determine whether this mechanism mediates the basolateral transport of other organic anions, transport of the herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D), was examined in rat renal cortical slices and basolateral membrane vesicles. In slices, uptake of 2,4-D increased steadily over time, approaching steady-state tissue/medium ratios of approximately 8 after 60 min. Probenecid, PAH and chlorophenol red inhibited steady-state uptake of 2,4-D. Accumulation of 10 microM 2,4-D was stimulated 2-fold by 60 microM glutarate; other dicarboxylic acids failed to stimulate uptake. In the presence of sodium, the addition of 5 mM LiCl or 2 mM ouabain to the bathing medium abolished glutarate stimulation. Removal of sodium from the bathing medium reversibly inhibited uptake as much as 75%. Furthermore, PAH inhibited 2,4-D uptake by slices in a dose-dependent manner, and increasing the external 2,4-D concentration decreased the inhibitory potency of PAH. In basolateral membrane vesicles, unlabeled 2,4-D inhibited sodium glutarate-coupled uptake of 3H-labeled PAH and 2,4-D in a concentration-dependent manner. Moreover, concentrative uptake of 2,4-D into vesicles could be driven by an outwardly directed gradient of glutarate or alpha KG that was generated by lithium-sensitive Na+/dicarboxylate cotransport or imposed experimentally. An outwardly directed gradient of unlabeled 2,4-D or PAH also stimulated uptake of 2,4-D. Based on these data, basolateral accumulation of 2,4-D by the renal proximal tubule is mediated by 2,4-D/alpha KG exchange, a mechanism energetically coupled to Na+/alpha KG cotransport and shared with PAH.