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Level IV: Case series.

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BACKGROUND AND PURPOSEOestrogens can interact directly with membrane receptors and channels and can activate vascular BKCa channels. We hypothesized that novel oestrogen derivatives could relax smooth muscle by an extracllular effect on the α and β1 subunits of the BKCa channel, rather than at an intracellular site. EXPERIMENTAL APPROACHWe studied the effects of novel oestrogens on the tension of pre-contracted isolated rat aortic rings, and on the electrophysiological properties of HEK 293 cells expressing the hSloα or hSloα+β1 subunits. Two of the derivatives incorporated a quaternary ammonium side-chain making them membrane impermeable. KEY RESULTSOestrone, oestrone oxime and Quat DME-oestradiol relaxed pre-contracted rat aorta, but only Quat DME-oestradiol-induced relaxation was iberiotoxin sensitive. However, only potassium currents recorded in HEK 293 cells over-expressing both hSloα and hSloβ1 were activated by oestrone, oestrone oxime and Quat DME-oestradiol. CONCLUSION AND IMPLICATIONSThe novel oestrogens were able to relax smooth muscle, but through different mechanisms. In particular, oestrone oxime required the presence of the endothelium to exert much of its effect, whilst Quat DME-oestradiol depended both on NO and BKCa channel activation. The activation of BKCa currents in HEK 293 cells expressing hSloα+β1 by Quat DME-oestradiol is consistent with an extracellular binding site between the two subunits. The binding site resides between the extracellular N terminal of the α subunit and the extracellular loop between TM1 and 2 of the β1 subunit. Membrane-impermeant Quat DME-oestradiol lacks an exchangeable hydrogen on the A ring obviating antioxidant activity. AbbreviationsBKCa, large conductance calcium-activated potassium channel; DMAEC HCl, 2-dimethylamine ethyl chloride; DMF, dimethylformamide; hSloα, the alpha subunit of the human BKCa channel; hSloβ1, the beta1 subunit of the human

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There are a number of methods of investigating the function of recombinant proteins such as ion channels. However, after channel purification there are few methods to guarantee that the protein still functions. For ion channels, reconstituting back into planar lipid bilayers and demonstrating preserved function is a convenient and trusted method. It is cell free and even inaccessible, intracellular ion channels can be studied. We have used this method to study the function of recombinant channels of known subunit composition and have found it convenient for investigating the mode of action of ion channel modulators.

Small molecule medications like apremilast are emerging as promising options for patients with psoriasis and other inflammatory conditions. Apremilast was approved by the Food and Drug Administration in 2014 for the management of both psoriasis and psoriatic arthritis. Apremilast inhibits phosphodiesterase-4, which increases the intracellular levels of cyclic AMP, thereby reducing inflammatory cytokine production. This review aims to discuss the published evidence and evaluate the differential use of apremilast in plaque psoriasis of the body and scalp, nail psoriasis, and palmoplantar psoriasis. In clinical trials, apremilast effectively reduced the severity of different dermatological manifestations of psoriasis and improved patients’ quality of life. It has an acceptable safety profile and is generally well-tolerated. Oral medications like apremilast offer an alternative route of administration which can be more convenient and appropriate for some patients. Additionally, pharmacoeconomic analyses of available anti-psoriatic systemic agents favor apremilast as a cost-effective therapeutic option.

Since vismodegib’s approval for advanced or metastatic basal cell carcinoma, there has been concern over vismodegib’s potential to induce secondary neoplasms of the skin, such as cutaneous squamous cell carcinoma (cSCC). In this article, we provide a comprehensive review of the literature on vismodegib’s relationship to cSCC. A systematic search of PubMed and Ovid MEDLINE was performed with terms “vismodegib” AND “squamous cell carcinoma.” Studies ranged from May 2013 to January 2022 and 25 articles were ultimately included. In total, of the 2576 patients included in the review, there were 197 cSCCs reported. Numerous reports have published conflicting findings. While one retrospective cohort study did find an increased risk, additional studies have found that the rates of cSCC are comparable between those exposed and those not exposed. Because a causal relationship between vismodegib and cSCC has not been proven, its use should not be avoided due to concerns of causing cSCC. However, patients treated with vismodegib should be closely monitored by dermatologists to evaluate for any suspicious changes. Large-scale, prospective, multi-center studies should be performed to definitively determine the risk of cSCC and vismodegib. It has been proposed that vismodegib may select for tumor cells utilizing the Ras/MAPK pathways.