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Background: Plane warts, when multiple and recurrent, present a therapeutic challenge acting as a source of reinfection, causing frustration and affecting a patient's quality of life. For large numbers of lesions in cosmetically significant sites, topical treatment is preferred to avoid potential sequelae., Objectives: To evaluate and compare the efficacy and tolerability of tazarotene 0.1% gel vs. imiquimod 5% cream for the treatment of plane warts., Methods: In a parallel three-arm randomized controlled trial, 60 patients were randomized to imiquimod, tazarotene or placebo groups. Patients applied the corresponding treatment once daily at night for a maximum of 12 weeks. Primary outcomes were the percentage of respondents with complete clearance in the three studied groups, and the type and frequency of side-effects in each group., Results: Both active treatments resulted in significant improvement compared with baseline and the placebo group (P = 0.001). The imiquimod 5% treated group showed complete clearance in 50% (10/20) of patients, partial response in 15% (3/20), and no response in 35% (7/20). Tazarotene 0.1% gel showed complete clearance in 40% (8/20) of patients, partial response in 40% (8/20), and no response in 20% (4/20). No significant difference was detected between the imiquimod and tazarotene groups (P = 0.19)., Conclusions: Compared with imiquimod, tazarotene 0.1% gel for the treatment of plane warts seems to offer an equivalent treatment response, it maintained efficacy without recurrence and had a safer profile regarding dyspigmentation with an advantageous cheaper cost., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Oral psoriasis therapies include both older traditional immunosuppressants, such as methotrexate, cyclosporine, and acitretin, as well as newer, more targeted agents, such as apremilast, deucravacitinib, and oral interleukin-23 receptor antagonists. Patients may prefer oral therapies to injectable therapies based on the route of administration. Both older and newer oral psoriasis therapies can be utilized effectively in the treatment of psoriasis. Here, we will review oral agents used in the treatment of psoriasis as well as provide commentary on their role in our current, evolving psoriasis treatment paradigm., Competing Interests: Disclosure Dr J. James has no conflicts of interest. Dr J. Gao received fellowship funding from Abbvie and Janssen. She is an investigator for Abbvie, Bristol Meyers Squibb, UCB, and Novartis. Dr T. Otto is an investigator for Abbvie, Bristol Meyers Squibb, UCB, and Novartis. Dr M.L. Porter is a consultant and/or an investigator for Abbvie, Bristol Meyers Squibb, Eli Lilly, Regeneron, Pfizer, UCB, Moonlake, Acelyrin, Incyte, Trifecta Clinical, and Novartis. She has previously received fellowship funding and honoraria from the National Psoriasis Foundation., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Triple-negative breast cancer (TNBC) is more prone to distant metastasis and visceral recurrence in comparison to other breast cancer subtypes, and is related to dismal prognosis. Nevertheless, TNBC has an undesirable response to targeted therapies. Therefore, to tackle the huge challenges in the diagnosis and treatment of TNBC, Nectin-4 was selected as a theranostic target because it was recently found to be highly expressed in TNBC. We developed anti-Nectin-4 monoclonal antibody (mAb Nectin-4 )-based theranostic pair, 99m Tc-HYNIC-mAb Nectin-4 and mAb Nectin-4 -ICG. 99m Tc-HYNIC-mAb Nectin-4 was applied to conduct immuno-single photon emission computed tomography (SPECT) for TNBC diagnosis and classification, and mAb Nectin-4 -ICG to mediate photothermal therapy (PTT) for relieving TNBC tumor growth., Methods: Nectin-4 expression levels of breast cancer cells (MDA-MB-468: TNBC cells; and MCF-7, non-TNBC cells) were proved by western blot, flow cytometry, and immunofluorescence imagning. Cell uptake assays, SPECT imaging, and biodistribution were performed to evaluate Nectin-4 targeting of 99m Tc-HYNIC-mAb Nectin-4 . A photothermal agent (PTA) mAb Nectin-4 -ICG was generated and characterized. In vitro photothermal therapy (PTT) mediated by mAb Nectin-4 -ICG was conducted under an 808 nm laser. Fluorescence (FL) imaging was performed for mAb Nectin-4 -ICG mapping in vivo. In vivo PTT treatment effects on TNBC tumors and corresponding systematic toxicity were evaluated., Results: Nectin-4 is overexpressed in MDA-MB-468 TNBC cells, which could specifically uptake 99m Tc-HYNIC-mAb Nectin-4 with high targeting in vitro. The corresponding immunoSPECT imaging demonstrated exceptional performance in TNBC diagnosis and molecular classification. mAb Nectin-4 -ICG exhibited favourable biocompatibility, photothermal effects, and Nectin-4 targeting. FL imaging mapped biodistribution of mAb Nectin-4 -ICG with excellent tumor-targeting and retention in vivo. Moreover, mAb Nectin-4 -ICG-mediated PTT provided advanced TNBC tumor destruction efficiency with low systematic toxicity., Conclusion: mAb Nectin-4 -based radioimmunoimaging provides visualization tools for the stratification and diagnosis for TNBC, and the corresponding mAb Nectin-4 -mediated PTT shows a powerful anti-tumor effect. Our findings demonstrate that this Nectin-4 targeting strategy offers a simple theranostic platform for TNBC., (© 2022. The Author(s).)

Not all patients with psoriasis achieve a satisfactory response to their initial biologic monotherapy. Switching to a new biologic may be associated with new safety issues and additional costs. In this study, we assessed the effectiveness and safety of adjunctive halobetasol propionate (HP) 0.01%-tazarotene (TAZ) 0.045% lotion in adult patients with moderate to severe plaque psoriasis who had been receiving biologic monotherapy for 24 weeks or more but had inadequate responses. All participants received HP-TAZ lotion once daily for 8 weeks, then once every other day for 4 weeks, in addition to their ongoing biologics. This real-world study demonstrated that HP-TAZ lotion adjunctive to ongoing biologics is safe and effective and potentially a more economical alternative to switching biologics for patients with psoriasis with inadequate responses to biologic monotherapy.

Aim: Nicomorphine is rapidly metabolized mainly to the biologically active 6-nicotinoyl morphine and morphine. In sport, morphine and nicomorphine use is prohibited whereas codeine use is permitted. Accredited laboratories routinely test for morphine hence must be able to distinguish morphine, as a metabolite of a prohibited substance, from that whose use is permitted. Results: Here we show a relatively simple method to synthesize the nicomorphine metabolites, 3-nicotinoyl and 6-nicotinoyl morphine, and indicate how they may be used to identify nicomorphine administration. Conclusion: This approach should help confirm that it is not codeine, an allowable analgesic in sport, that has been administered.

Introduction: Patients with psoriasis and low body surface area (BSA) involvement often experience substantially reduced quality of life and may be candidates for topical therapies. Fixed-combination halobetasol propionate (0.01%) and tazarotene (0.045%) lotion (HP/TAZ) vs vehicle lotion was evaluated in participants with 3% to 5% BSA involvement., Methods: In two phase 3, multicenter, double-blind, vehicle-controlled, 8-week studies (ClinicalTrial.gov identifiers: NCT02462070/NCT02462122), adults with moderate/severe investigator’s global assessment (IGA) score were randomized 2:1 to once-daily HP/TAZ or vehicle. Pooled post hoc analyses included participants with baseline BSA involvement of 3% to 5%. Measures included treatment success (≥2-grade IGA reduction, clear/almost clear score), reduction in affected BSA, and clinically meaningful improvement (reduction) of ≥4 points on dermatology life quality index (DLQI)., Results: Of 418 participants, 232 had baseline BSA involvement of 3% to 5% (HP/TAZ, n=149; vehicle, n=83). At week 8, 42.7% of HP/TAZ-treated participants achieved treatment success, compared with 11.4% of vehicle-treated participants (P< .001). Participants experienced significantly greater reductions in affected BSA at week 8 with HP/TAZ (-36.0%) vs vehicle (-1.6%; P< .001). Larger proportions experienced clinically meaningful DLQI improvements at week 8 with HP/TAZ (64.2%) vs vehicle (47.4%; P< .05). More participants achieved a ≥2-grade improvement in plaque elevation and scaling with HP/TAZ vs vehicle (each comparison, P< .001). Serious adverse events and discontinuations due to treatment-emergent adverse events were rare., Conclusions: In participants with plaque psoriasis and BSA involvement of 3% to 5%, HP/TAZ provided significantly improved effectiveness after 8 treatment weeks vs vehicle lotion, with clinically meaningful improvements in quality of life. J Drugs Dermatol. 2021;20(8):829-836. doi:10.36849/JDD.6217.

Background: Few studies have examined topical psoriasis therapies in patients with skin of color. Fixed-combination halobetasol propionate (0.01%) and tazarotene (0.045%) lotion (HP/TAZ) was investigated in two phase 3, multicenter, double-blind, vehicle-controlled trials (NCT02462070; NCT02462122). This post hoc analysis evaluated HP/TAZ in subgroups of non-White and White participants, including Hispanic/Latino participants, from these trials., Methods: Adult participants were randomized (2:1) to receive HP/TAZ or vehicle lotion once daily for 8 weeks. Data were pooled and analyzed in non-mutually exclusive subgroups of self-identified non-White or White and Hispanic/Latino participants. Efficacy assessments included treatment success (≥2-grade improvement from baseline in investigator’s global assessment [IGA] and score of clear/almost clear), reduction from baseline in affected body surface area (BSA), and reduction in mean IGA × BSA. Safety was evaluated via treatment-emergent adverse events (TEAEs)., Results: Of 418 participants, 60 and 358 self-identified as non-White and White, respectively; 115 of 418 participants self-identified as Hispanic/Latino. At week 8, a higher percentage of HP/TAZ-treated participants achieved treatment success vs vehicle (non-White, 34.4% vs 19.0%; White, 41.8% vs 8.7%; Hispanic/Latino, 39.3% vs 9.3%); rates for White and Hispanic/Latino participants were statistically significant. Compared with vehicle, HP/TAZ-treated participants in each subgroup experienced numerically greater reductions in affected BSA and IGA × BSA at week 8. The most common TEAEs were contact dermatitis, pruritus, nasopharyngitis, and application-site pain; discontinuations due to TEAEs were few., Conclusions: HP/TAZ reduced disease severity in non-White, White, and Hispanic/Latino participants with psoriasis, with good tolerability and safety over 8 weeks of treatment. J Drugs Dermatol. 2021;20(7):735-744. doi:10.36849/JDD.6158.

Nicotinic acid hydrazide was incorporated into new 4,5-dihydro-5-hydroxy-3,5-diphenylpyrazol-1-yl derivatives. Compounds 6a-h were synthesized, and their antihyperlipidemic activity was evaluated in high cholesterol diet-fed rat model. Compounds 6e, 6f were found to decrease the levels of serum total cholesterol by 14-19% compared to control group. Total triglycerides were also reduced by 24-28% and LDL cholesterol by 16%. As expected from parent niacin, compounds 6e and 6f caused an elevation of HDL cholesterol by 33-41%. Docking study supported the ability of designed compounds to block NPC1L1 active site in a manner similar to that observed with ezetimibe.

Background: Topical agents are still the mainstay for the treatment of mild-to-moderate plaque psoriasis, in which fixed combinations play an important role. Tazarotene/betamethasone dipropionate (Taz/BD) cream is a novel fixed combination approved for treating plaque psoriasis in China, but its efficacy and safety have not been verified in a real-world environment., Objectives: The primary objective was to investigate the efficacy and safety of Taz/BD cream in treating plaque psoriasis. The secondary objectives were to assess its relapse after discontinuation and the efficacy and safety profiles during retreatment., Methods: A prospective, multicenter, large-scale observational study was conducted. Adult patients with chronic plaque psoriasis involving <20% of the body surface area were enrolled. Taz/BD cream was applied once daily for 4 weeks. Patients who achieved ≥90% improvement in the Psoriasis Area and Severity Index (PASI) from baseline to week 4 were followed up to investigate relapse after drug withdrawal. Relapsed patients underwent another 4-week treatment., Results: In total, 2,299 eligible patients were enrolled, and 2,095 patients (91.1%) completed the 4-week study. The mean PASI improvement at week 4 was 53.7%, and the PASI 50/75 response rates were 62.5 and 26.8%, respectively. The mean PASI reduction in plaque induration, desquamation and erythema were 58.3, 61.0 and 40.0%, respectively (p < 0.001). Adverse reactions occurred in 445 patients (20.8%) at week 4. The most frequently reported adverse reactions were local skin irritation, including pruritus (10%), pain (6.7%), erythema (6.1%) and desquamation (1.8%). During the post-treatment period, 47 patients (24.0%) relapsed within 8 weeks after drug discontinuation. Forty-five patients were retreated for another 4 weeks, and the PASI 50/75 response rates were 72.7 and 40.9%, respectively. There were no unexpected safety signals during retreatment., Conclusion: Taz/BD cream is effective and well tolerated in treating mild-to-moderate plaque psoriasis under near real-world conditions and demonstrates efficacy and safety during retreatment., (© 2020 S. Karger AG, Basel.)

Objective: To review phase II and III clinical trial data to evaluate the efficacy and safety of the halobetasol propionate/tazarotene (HP/TAZ) combination lotion (Duobrii), a medication approved by the Food and Drug Administration in April 2019 for adults with plaque psoriasis. Data Sources : A systematic search (January 2005 to July 2019) of MEDLINE (PubMed) and EMBASE databases was performed using the terms halobetasol, tazarotene, halobetasol/tazarotene, Duobrii , and IDP-118 . Study Selection and Data Extraction: Relevant English-language articles reporting on phase II and phase III clinical trials were included. Data from the individual trials were extracted independently and then cross-checked to ensure accuracy. Data Synthesis: HP/TAZ was safe and efficacious compared with HP alone, TAZ alone, or vehicle. More patients achieved treatment success, described as a ≥2-grade improvement on Investigator Global Assessment Scale, over 8 weeks of treatment and at the 4-week follow-up after treatment cessation. The most common adverse events were dermatitis, pain, and pruritus, which occurred more often in the TAZ groups compared with the HP/TAZ cohorts. Relevance to Patient Care and Clinical Practice: The once-daily HP/TAZ combination lotion simplifies psoriasis treatment and may facilitate adherence, which may improve psoriasis outcomes. Conclusions: HP/TAZ combination lotion is efficacious and safe for plaque psoriasis treatment, with more patients achieving end points and fewer side effects than in HP, TAZ, or vehicle-treated controls. Drug synergy may play a role. Importantly, patient adherence to a once-daily combinational therapy is likely to contribute to efficacy.

Background: Acne vulgaris and inflammation-associated sequelae are highly prevalent in black and Hispanic populations. In a phase 2 study, a novel polymeric emulsion formulation of tazarotene 0.045% lotion had relatively fewer adverse events than tazarotene 0.1% cream, but with comparable efficacy. The objective was to evaluate tazarotene 0.045% lotion by race and ethnicity in the pivotal trials. Methods: In two phase 3, double-blind, 12-week studies (NCT03168334; NCT03168321), participants with moderate-to-severe acne were randomized 1:1 to tazarotene 0.045% lotion or vehicle lotion (N=1,614). This pooled, post hoc analysis included subsets of participants that self-identified as white (n=1191) or black (n=262) and Hispanic (n=352) or non-Hispanic (n=1262). Coprimary endpoints were inflammatory/noninflammatory lesion counts and treatment success (defined as at least a 2-grade reduction from baseline in Evaluator's Global Severity Score and a score of 'clear' or 'almost clear'). Treatment-emergent adverse events (TEAEs) and cutaneous safety and tolerability were evaluated. Results: At week 12, tazarotene 0.045% lotion led to significantly greater percent reductions in inflammatory and noninflammatory lesions compared with vehicle in white, Hispanic, and non-Hispanic participants (P<0.05, all). Black participants had significantly greater reductions in noninflammatory lesions following treatment with tazarotene 0.045% versus vehicle (P<0.05). Treatment success rates in all subpopulations were higher with tazarotene 0.045% lotion (29.4-34.1%) versus vehicle (16.4-23.1%). TEAE rates were similar across tazarotene-treated groups and most were mild-to-moderate in severity. The incidence of hyperpigmentation decreased in black tazarotene-treated participants from baseline to week 12. Conclusions: Tazarotene 0.045% lotion demonstrated efficacy and was well tolerated across racial and ethnic subpopulations in this pooled analysis. J Drugs Dermatol. 2020;19(7) doi:10.36849/JDD.2020.5125.

Background: Acne vulgaris is a chronic disfiguring inflammatory disease of adolescents and adults affecting up to 90% of the population around the world. The sequence of etiopathogenesis in acne is not completely understood but involves abnormalities in sebum production, follicular plugging, proliferation of propionibacterium acnes, and chronic inflammation., Aims: This review aims to summarize the features of the topical selective RAR agonists in treating acne vulgaris with a special emphasis on the 4th generation topical retinoid trifarotene., Methods: Studies were identified by searching electronic databases (MEDLINE and PubMed) till August 2019 and reference lists of respective articles. Only articles published in English language were included., Results: Topical retinoids have been first line of treatment for more than 30 years now in treating mild to moderate acne vulgaris. Third generation retinoids like adapalene and tazarotene are selective RAR and γ agonists, having an additional anti-inflammatory action along with their comedolytic effects and work well in combinations with topical antibiotics, due to the stability of chemical composition., Conclusion: Trifarotene is a new 4th generation retinoid with selective action on RAR-γ receptor alone, which is specific for skin, and it is safe for long-term maintenance therapy with good efficacy and tolerability., (© 2020 Wiley Periodicals, Inc.)

Background: The fixed-dose combination foam formulation of calcipotriene 0.005% plus betamethasone dipropionate 0.064% (Cal/BD) has demonstrated efficacy and a favorable safety profile for the treatment of plaque psoriasis. Recently, a topical lotion of the combination of halobetasol 0.01% plus tazarotene 0.045% (HP/TAZ) was approved for treating adult plaque psoriasis. Currently, no head-to-head studies have compared Cal/BD foam with HP/TAZ lotion. Objective: Compare the effectiveness and drug incremental cost per responder (ICPR) of Cal/BD foam vs. HP/TAZ lotion in moderate-to-severe plaque psoriasis. Methods: An anchor-based, matching-adjusted indirect comparison was conducted for PGA treatment success (Physician's Global Assessment of "clear" or "almost clear," [PGA 0/1] with at least a 2-point improvement) using individual patient data from 3 randomized clinical studies of Cal/BD foam and published data from 2 randomized, Phase 3 clinical studies of HP/TAZ lotion. The number needed to treat and ICPR were also calculated. Results: After reweighting of patients in the Cal/BD foam studies to match summary baseline characteristics of the HP/TAZ lotion study patients and anchoring to vehicle effect, 4 weeks of Cal/BD foam produced a significantly greater rate of treatment success than 8 weeks of HP/TAZ lotion treatment (51.4 vs. 30.7%; treatment difference = 20.7%, p  < .001). The number needed to treat with Cal/BD foam was also less than HP/TAZ lotion (1.9 vs. 3.3). Using US wholesale acquisition costs and equal weekly consumption rates, the incremental cost per PGA 0/1 responder relative to vehicle for Cal/BD foam was $3,988 and was 37% lower compared with HP/TAZ lotion ($6,294). Conclusions: The indirect comparison analyses showed that Cal/BD foam was associated with a greater rate of treatment success, lower ICPR, and quicker treatment response than HP/TAZ lotion in adult patients with moderate-to-severe plaque psoriasis.

Background: Acne vulgaris affects approximately 85% of adolescents. Topical tazarotene is efficacious and safe for acne treatment but irritation limits its use. The objective was to evaluate efficacy, safety, and tolerability of a new tazarotene 0.045% lotion formulation in patients aged 10-13 and 14-17 years with moderate-to-severe acne., Methods: In two phase 3, double-blind, vehicle-controlled 12-week studies, patients with moderate-to-severe acne (N=1,614) were randomized (1:1) to receive tazarotene 0.045% lotion or vehicle once-daily. Efficacy assessments included changes from baseline in inflammatory/noninflammatory lesions and treatment success (&ge;2-grade reduction in Evaluator's Global Severity Score [EGSS] and a clear/almost clear score). Quality of life (QoL) and adverse events (AEs) were also assessed., Results: Patients aged 10-13 years (n=136) and 14-17 years (n=548) were pooled. At week 12, mean percent reductions in inflammatory and noninflammatory lesion counts were significantly greater with tazarotene versus vehicle in both age groups (least-squares mean inflammatory 10-13 years: -55.6 vs -37.0%; 14-17 years: -53.3 vs -41.2%; noninflammatory 10-13 years: -47.7 vs -28.2%; 14-17 years: -52.7 vs -32.9%; P&lt;0.01 all). More patients achieved treatment success with tazarotene versus vehicle in both age groups (P&lt;0.05, both). There were no significant differences between tazarotene-treated age groups in lesion counts or treatment success. Acne-QoL scores at week 12 in both age groups were numerically improved in most domains with tazarotene 0.045% lotion versus vehicle. Most treatment-emergent AEs with tazarotene or vehicle were of mild or moderate severity in both age groups., Conclusions: Tazarotene 0.045% lotion was efficacious and well tolerated in pediatric patients with moderate-to-severe acne. J Drugs Dermatol. 2020;19(6): doi:10.36849/JDD.2020.4959.

Background: Plaque psoriasis can occur in all body regions, with the trunk and extremities among the most commonly affected areas. A fixed combination halobetasol propionate 0.01%/tazarotene 0.045% (HP/TAZ) lotion demonstrated efficacy and safety in patients with moderate-to-severe localized plaque psoriasis. This analysis evaluated patients where a psoriatic target lesion was identified on the leg. Methods: In two phase 3, multicenter, double-blind studies, participants were randomized (2:1) to receive HP/TAZ or vehicle lotion once-daily for 8 weeks. This pooled, post hoc analysis included a subset of participants who had a leg target lesion (HP/TAZ, n=148; vehicle, n=71). Efficacy assessments included treatment success (≥2-grade improvement) in psoriasis signs (erythema, plaque elevation, scaling) on the leg target lesion, and overall treatment outcomes, including overall treatment success (≥2-grade improvement in Investigator's Global Assessment [IGA] score and score of clear/almost clear), affected Body Surface Area (BSA), and IGAxBSA composite score. Results: Psoriasis signs were reduced by week 8, with more HP/TAZ treated participants achieving treatment success for erythema (41.6%), plaque elevation (58.5%), and scaling (59.5%) on the leg compared with vehicle (12.5%, 19.2%, and 21.0%, respectively; P<0.001 all). Significantly more participants achieved overall treatment success at week 8 with HP/TAZ versus vehicle (36.4% vs 10.4%; P<0.001). The HP/TAZ group also had a greater mean reduction in affected BSA and IGAxBSA score versus vehicle (P<0.001, both). The most frequently reported treatment-related adverse event (incidence, ≥3%) with HP/TAZ was contact dermatitis. Conclusions: HP 0.01%/TAZ 0.045% lotion was associated with significant reductions in disease severity and good tolerability following 8 weeks of treatment in patients where a psoriatic target lesion was identified on the leg. J Drugs Dermatol. 2020;19(4):389-396. doi:10.36849/JDD.2020.4958.

To develop a 5-aminosalicylic acid (5-ASA)-based anticolitic drug with enhanced therapeutic activity, a colon-targeted codrug constituting 5-ASA and a GPR109A agonist was designed. 5-ASA azo-coupled with nicotinic acid (ASA-azo-NA) was synthesized, and the colon specificity and anticolitic effects were evaluated. Approximately 89% of ASA-azo-NA was converted to 5-aminonicotinic acid (5-ANA) and 5-ASA after 24 h of incubation in the cecal contents. 5-ANA was identified as a GPR109A agonist (concentration that gives half-maximal response (EC 50 ): 18 μM) in a cell-based assay. Upon oral gavage of ASA-azo-NA (oral ASA-azo-NA) and sulfasalazine (oral SSZ), a colon-targeted 5-ASA prodrug, cecal accumulation of 5-ASA was comparable, and 5-ANA was barely detectable in the blood, while it was detected up to 62.7 μM with oral 5-ANA. In parallel, oral ASA-azo-NA did not elicit an adverse skin response. In murine macrophage and human colon carcinoma cells, activation of GPR109A by 5-ANA elevated the level of the anti-inflammatory cytokine IL-10, suppressed NF-κB activation, and potentiated the inhibitory activity of 5-ASA on NF-κB. Oral ASA-azo-NA ameliorated rat colitis and was more effective than oral SSZ, which were substantially blunted following cotreatment with the GPR109A antagonist, mepenzolate. In conclusion, ASA-azo-NA is a colon-targeted anticolitic codrug with a reduced risk of skin toxicity induced by the GPR109A agonist, therapeutically surpassing a current 5-ASA-based anti-inflammatory bowel disease drug in a rat colitis model.

Psoriasis is a chronic, multisystem, inflammatory disease that affects approximately 1% of children, with onset most common during adolescence. This guideline addresses important clinical questions that arise in psoriasis management and provides evidence-based recommendations. Attention will be given to pediatric patients with psoriasis, recognizing the unique physiology, pharmacokinetics, and patient-parent-provider interactions of patients younger than 18 years old. The topics reviewed here mirror those discussed in the adult guideline sections, excluding those topics that are irrelevant to, or lack sufficient information for, pediatric patients., (Copyright © 2019 American Academy of Dermatology, Inc. All rights reserved.)

In 2019, the FDA approved several new drugs for use in primary care. This article highlights the following new drugs: risankizumab-rzaa (Skyrizi); halobetasol and tazarotene (Duobrii); dolutegravir and lamivudine (Dovato); romosozumab-aqqg (Evenity); brexanolone (Zulresso); solriamfetol (Sunosi); aclidinium and formoterol (Duaklir Pressair); and siponimod (Mayzent).

Among the molecular signals underlying cutaneous inflammation is the transcription complex NF-κB, its upstream modulators, and cytokines and chemokines that are the downstream proinflammatory effectors. Central to NF-κB activation is IκB kinase (IKK), which phosphorylates IκBα, releasing NF-κB to the nucleus. In a screening of a kinase inhibitor library, we identified two IKK inhibitors that were high-affinity substrates for p-glycoprotein (ABCB1), the multidrug resistance protein known to facilitate transdermal drug delivery. ACHP (2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)-3-pyridinecarbonitrile) and IKK 16 prevented both nuclear translocation of NF-κB and activation of a NF-κB reporter and reduced the induction of cytokine and chemokine transcripts in human or mouse keratinocytes by IL-1α, tumor necrosis factor-α, and phorbol myristate acetate. ACHP, but not IKK 16, was nontoxic to mouse or human keratinocytes at any dose tested. In mice, topical ACHP prevented the cutaneous inflammation induced by topical phorbol myristate acetate or imiquimod, reduced the inflammation from erythema doses of artificial sunlight, and lowered the tumor incidence of mice treated with 7,12-dimethyl benzanthracene when applied before phorbol myristate acetate. Topical ACHP also reduced the NF-κB and IL-17 inflammatory signature after multiple doses of imiquimod. Thus, ACHP and IKK 16 hit their NF-κB target in mouse and human keratinocytes, and ACHP is an effective topical nonsteroidal anti-inflammatory in mice., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Although the active ingredients of the most frequently used topical therapy for psoriasis have remained the same for many years, the introduction of new vehicles and fixed-dose combination products has increased ease of patient use as well as, in some cases, efficacy and safety. Topical therapies with novel mechanisms of action are under study.

Background: Fixed combinations are commonplace in dermatology, providing significant efficacy and tolerability benefits. In some cases, two active ingredients complement each other providing a cumulative or additive effect. In rarer cases, a synergistic effect may be seen where the sum of the two active ingredients combined action is greater than the sum of the efficacy of the constituent parts. Objective: To determine whether a novel halobetasol propionate 0.01% and tazarotene 0.045% (HP/TAZ) fixed combination lotion provides a synergistic effect in the treatment of moderate-to-severe plaque psoriasis. Methods: Post hoc analysis of 212 patients with moderate-to-severe plaque psoriasis randomized (2:2:2:1) to HP/TAZ lotion, HP, TAZ or vehicle once-daily for 8 weeks, with a 4-week posttreatment follow-up. Treatment success was evaluated based on two outcomes: percent of patients achieving at least a 2-grade improvement in Investigator Global Assessment (IGA) and IGA score equating to ‘clear’ or ‘almost clear’; and percent change from baseline in the IGAxbody surface area (BSA) score, an alternative to assessing response to therapy that is more sensitive to area change than the Psoriasis Area Severity Index (PASI). In addition, a clinically meaningful outcome was reported in patients who achieved a 75% reduction in IGAxBSA. Synergy was established when the benefit of combination HP/TAZ lotion was greater than benefit of HP plus TAZ, with a ratio (HP/TAZ divided by HP+TAZ) >1.0. Results: HP/TAZ lotion was synergistic at week 8, and four weeks posttreatment. At week 8, treatment success with HP/TAZ lotion relative to vehicle was 42.8% compared with 32.5% for HP plus TAZ (ratio 1.3); and percent change from baseline in IGAxBSA score relative to vehicle was 51.6% compared with 40.6% for HP plus TAZ (ratio 1.3). At week 12, treatment success with HP/TAZ lotion relative to vehicle was 31.3% compared with 20.0% for HP plus TAZ (ratio 1.6). Percent change from baseline in IGAxBSA score relative to vehicle was 47.3% compared with 34.2% for HP plus TAZ (ratio 1.4). HP/TAZ lotion also provided synergistic benefits in terms of achieving a clinically meaningful outcome, with a ratio of 1.3 and 2.0 at weeks 8 and 12. Conclusions: Halobetasol propionate 0.01% and tazarotene 0.045% (HP/TAZ) fixed combination lotion provides a synergistic benefit in the treatment of moderate-to-severe plaque psoriasis. In addition, by combining two agents into one once-daily formulation, this novel formulation reduces the number of product applications and may help patient adherence. J Drugs Dermatol. 2019;18(3):279-284.

Background: Psoriasis is a chronic, immune-mediated disease that varies widely in its clinical expression. Treatment options focus on relieving symptoms, reducing inflammation, induration, and scaling, and controlling the extent of the disease. While significant data on tazarotene in psoriasis has been available for over 20 years, its main utility is in acne. Objective: To review the clinical studies with tazarotene in psoriasis and establish its future role in the management of this chronic, incurable condition. Methods: An English language literature review was performed utilizing Medline, EMBASE, and the Web of Science to identify relevant articles, both clinical trials and reviews. Results: Tazarotene is a very effective treatment for plaque psoriasis, with significant reductions in both plaque elevation and scaling after 12 weeks. Efficacy appears to be dose and formulation dependent, and erythema less responsive. Tazarotene sustains clinical response posttreatment and may have an important role in maintenance therapy. The most common side effect is mild-to-moderate local irritation, which limited its role as a single agent for psoriasis. Efficacy is enhanced through combination with topical corticosteroids (TCS). Tazarotene may circumvent the problem of TCS tachyphylaxis, due to its sustained efficacy and provide tolerability benefits; tazarotene increases epidermal thickness and may reduce the risk of steroid-induced atrophy. In addition, tazarotene-induced irritation is reduced by the anti-inflammatory effect of TCS. A new fixed combination, well-tolerated tazarotene/halobetasol topical formulation is now available, which provides synergistic efficacy that is both rapid and sustained posttreatment. Conclusions: Tazarotene is a highly effective psoriasis treatment whose efficacy and tolerability can be enhanced through combination therapy with TCS, and a new fixed combination topical formulation of tazarotene and halobetasol may provide an optimal management approach. J Drugs Dermatol. 2018;17(12):1280-1287.

Background: A unique fixed combination halobetasol propionate 0.01% and tazarotene 0.045% (HP/TAZ) lotion has been shown to be effective in psoriasis using Investigator Global Assessment (IGA) tools to assess erythema, plaque elevation, and scaling. However, these do not consider changes in Body Surface Area (BSA). The IGAxBSA composite tool is a simple, effective, validated alternative for measuring improvement in psoriasis severity. It correlates well with the Psoriasis Area and Severity Index (PASI) and demonstrates sensitivity to changes from baseline in patients with both mild and moderately severe disease. Objective: To further define the role of a fixed combination halobetasol propionate 0.01% and tazarotene 0.045% (HP/TAZ) lotion in moderate-to-severe plaque psoriasis using the IGAxBSA composite tool. Methods: Post hoc analysis of 212 patients with moderate-to-severe plaque psoriasis randomized (2:2:2:1) to HP/TAZ lotion, HP, TAZ, or vehicle once-daily for 8 weeks, with a 4-week posttreatment follow-up. Efficacy assessments using the validated IGAxBSA composite tool. Results: HP/TAZ lotion demonstrated statistically significant superiority at week 8 (versus TAZ and vehicle) and week 12 (versus HP, TAZ, and vehicle). By week 8, HP/TAZ lotion achieved a 63.5% reduction in mean IGAxBSA composite score (P<0.001 versus TAZ and vehicle), that was sustained four weeks posttreatment (P<0.001 versus TAZ and vehicle and P=0.003 versus HP). A 25% and 50% improvement in IGAxBSA was achieved within 1.9 and 4.6 weeks, respectively, and 47.5% of patients achieved IGAxBSA-75 by week 8. Limitations: This post hoc analysis was limited to patients with moderate-to-severe plaque psoriasis with IGA ≥3 and BSA involvement (3%-12%). Conclusions: HP/TAZ lotion was associated with significant and rapid reductions in disease severity as assessed by the IGAxBSA composite tool. The addition of tazarotene affords sustained benefits posttreatment. J Drugs Dermatol. 2018;17(12):1290-1296.

Background: Topical corticosteroids are the mainstay of psoriasis treatment, with long-term safety considerations limiting their use. Combining them with tazarotene may optimize their efficacy and minimize safety and tolerability concerns., Objective: To investigate the safety and efficacy of halobetasol propionate 0.01% plus tazarotene 0.045% (HP/TAZ) lotion in moderate-to-severe plaque psoriasis., Methods: Two multicenter, randomized, double-blind, vehicle-controlled phase 3 studies (N = 418) were conducted. Subjects were randomized (2:1) to HP/TAZ lotion or vehicle once daily for 8 weeks with a 4-week follow-up. The primary efficacy assessment end point was treatment success (at least a 2-grade improvement from baseline in Investigator's Global Assessment score and a score of clear or almost clear). Safety and treatment-emergent adverse events were evaluated throughout., Results: HP/TAZ lotion demonstrated statistically significant superiority over vehicle within as few as 2 weeks. By week 8, 35.8% (study 1) and 45.3% (study 2) of subjects were treatment successes compared with 7.0% and 12.5% of those treated with vehicle (P < .001). HP/TAZ lotion was also superior in reducing signs and symptoms of psoriasis and body surface area affected by psoriasis. The most frequently reported treatment-related adverse events were contact dermatitis (6.3%), application site pain (2.6%), and pruritus (2.2%)., Limitations: Studies did not include subjects with more than 12% of their body surface area affected by psoriasis., Conclusions: HP/TAZ lotion was associated with significant reductions in the severity of the clinical signs of psoriasis, with no safety concerns., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Psoriasis is a chronic, immune-mediated disease that varies widely in its clinical expression. Topical corticosteroids (TCS) are the mainstay of treatment. Long-term safety remains a concern, limiting use, and posttreatment flare is common. Tazarotene has also been shown to be effective in psoriasis, with efficacy maintained several weeks posttreatment. Fixed combination therapy with TCS and tazarotene may improve psoriasis signs and minimize posttreatment flare or rebound., Objective: To investigate the maintenance of effect posttreatment with a once-daily application of halobetasol propionate 0.01%/tazarotene 0.045% (HP/TAZ) lotion in comparison with its active ingredients and vehicle in patients with moderate-to-severe plaque psoriasis., Methods: Multicenter, randomized, double-blind, vehicle-controlled Phase 2 study in moderate or severe psoriasis (N=212). Patients randomized (2:2:2:1 ratio) to receive HP/TAZ, individual active ingredients, or vehicle, once-daily for 8 weeks with a 4-week posttreatment follow-up. Efficacy assessments included treatment success (defined as at least a 2-grade improvement from baseline in the IGA score, and 'clear' or 'almost clear'), and impact on individual signs of psoriasis (erythema, plaque elevation, and scaling) at the target lesion., Results: At the end of the 4-week posttreatment period, 38.2% of patients who had been treated with HP/TAZ were treatment successes; compared with 21.0%, 12.8% and 6.9% of patients who had been treated with HP (P=0.042), TAZ (P=0.004), or vehicle (P=0.002). HP/TAZ lotion was also superior in maintaining reductions in psoriasis signs of erythema, plaque elevation, and scaling at the target lesion. At the end of the 4-week posttreatment period, 49.1%, 54.5%, and 54.5% of patients, respectively, were treatment successes: compared with 38.7% (P=0.26), 48.4% (P=0.51), and 48.4% (P=0.51) of patients who had been treated with HP; 29.8% (P=0.049), 31.9% (P=0.022), and 23.4% (P=0.001) who had been treated with TAZ; and 13.8% (P=0.002), 20.7% (P=0.003), and 20.7% (P=0.003) who had been treated with vehicle. Side effects were minimal and tended to resolve during the posttreatment period., Conclusions: In conclusion, HP 0.01%/TAZ 0.045% lotion provides synergistic efficacy following 8 weeks' therapy that is sustained after a 4-week posttreatment period. J Drugs Dermatol. 2018;17(7):723-726.

Background: Peripheral arterial occlusive disease (PAOD) is a common cause of morbidity and mortality due to cardiovascular disease in the general population. Although numerous treatments have been adopted for patients at different disease stages, no option other than amputation is available for patients presenting with critical limb ischaemia (CLI) unsuitable for rescue or reconstructive intervention. In this regard, prostanoids have been proposed as a therapeutic alternative, with the aim of increasing blood supply to the limb with occluded arteries through their vasodilatory, antithrombotic, and anti-inflammatory effects. This is an update of a review first published in 2010., Objectives: To determine the effectiveness and safety of prostanoids in patients with CLI unsuitable for rescue or reconstructive intervention., Search Methods: For this update, the Cochrane Vascular Information Specialist searched the Specialised Register (January 2017) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 1). In addition, we searched trials registries (January 2017) and contacted pharmaceutical manufacturers, in our efforts to identify unpublished data and ongoing trials., Selection Criteria: Randomised controlled trials describing the efficacy and safety of prostanoids compared with placebo or other pharmacological control treatments for patients presenting with CLI without chance of rescue or reconstructive intervention., Data Collection and Analysis: Two review authors independently selected trials, assessed trials for eligibility and methodological quality, and extracted data. We resolved disagreements by consensus or by consultation with a third review author., Main Results: For this update, 15 additional studies fulfilled selection criteria. We included in this review 33 randomised controlled trials with 4477 participants; 21 compared different prostanoids versus placebo, seven compared prostanoids versus other agents, and five conducted head-to-head comparisons using two different prostanoids.We found low-quality evidence that suggests no clear difference in the incidence of cardiovascular mortality between patients receiving prostanoids and those given placebo (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.41 to 1.58). We found high-quality evidence showing that prostanoids have no effect on the incidence of total amputations when compared with placebo (RR 0.97, 95% CI 0.86 to 1.09). Adverse events were more frequent with prostanoids than with placebo (RR 2.11, 95% CI 1.79 to 2.50; moderate-quality evidence). The most commonly reported adverse events were headache, nausea, vomiting, diarrhoea, flushing, and hypotension. We found moderate-quality evidence showing that prostanoids reduced rest-pain (RR 1.30, 95% CI 1.06 to 1.59) and promoted ulcer healing (RR 1.24, 95% CI 1.04 to 1.48) when compared with placebo, although these small beneficial effects were diluted when we performed a sensitivity analysis that excluded studies at high risk of bias. Additionally, we found evidence of low to very low quality suggesting the effects of prostanoids versus other active agents or versus other prostanoids because studies conducting these comparisons were few and we judged them to be at high risk of bias. None of the included studies assessed quality of life., Authors' Conclusions: We found high-quality evidence showing that prostanoids have no effect on the incidence of total amputations when compared against placebo. Moderate-quality evidence showed small beneficial effects of prostanoids for rest-pain relief and ulcer healing when compared with placebo. Additionally, moderate-quality evidence showed a greater incidence of adverse effects with the use of prostanoids, and low-quality evidence suggests that prostanoids have no effect on cardiovascular mortality when compared with placebo. None of the included studies reported quality of life measurements. The balance between benefits and harms associated with use of prostanoids in patients with critical limb ischaemia with no chance of reconstructive intervention is uncertain; therefore careful assessment of therapeutic alternatives should be considered. Main reasons for downgrading the quality of evidence were high risk of attrition bias and imprecision of effect estimates.

The largest proportion of psoriasis patients are candidates for topical treatment rather than treatment paradigms encompassing systemic, biologic and apremilast, and phototherapy, making skillfulness with topical therapy of paramount importance. As such, numerous studies have been conducted to demonstrate the benefits of using topical therapy in combination with other therapies. In addition, innovative uses of otherwise conventional methods, such as proactive use to minimize flare, have been developed. This article reviews five types of strategies for improved efficacy from topical agents beyond monotherapy. These strategies include proactive use, rotational therapy, sequential therapy, using topical agents to shorten the onset of therapeutic action for slower internal agents or phototherapy, and combination use for added efficacy. Each of these is reviewed in detail.

BACKGROUND: Psoriasis is a chronic, immune-mediated disease that varies widely in its clinical expression. Treatment options focus on relieving symptoms, reducing inflammation, induration, and scaling, and controlling the extent of the disease. Topical corticosteroids are the mainstay of treatment, however long-term safety remains a concern, particularly with the more potent formulations. Combination therapy with a corticosteroid and tazarotene may improve psoriasis signs at a lower corticosteroid concentration providing a superior safety profile., Objective: To investigate the efficacy and safety of a once-daily application of a fixed combination halobetasol propionate 0.01% and tazarotene 0.045% (HP/TAZ) lotion in comparison with its monads and vehicle in subjects with moderate-to-severe plaque psoriasis., Methods: Multicenter, randomized, double-blind, vehicle-controlled Phase 2 study in moderate or severe psoriasis (N=212). Subjects randomized (2:2:2:1 ratio) to receive HP/TAZ, individual monads, or vehicle, once-daily for 8 weeks. Efficacy assessments included treatment success (defined as at least a 2-grade improvement from baseline in the IGA score and a score of 'Clear' or 'Almost Clear'), and impact on individual signs of psoriasis (erythema, plaque elevation, and scaling) at the target lesion. Safety and treatment emergent adverse events (TEAEs) were evaluated throughout., Results: HP/TAZ lotion demonstrated statistically significant superiority over vehicle as early as 2 weeks. At week 8, 52.5% of subjects had treatment success compared with 33.3%, 18.6%, and 9.7% in the HP (P=0.033), TAZ (P less than 0.001), and vehicle (P less than 0.001) groups, respectively. HP/TAZ lotion was superior to its monads and vehicle in reducing the psoriasis signs of erythema, plaque elevation, and scaling at the target lesion. At week 8, a 2-grade improvement in IGA was achieved by 54.2% of subjects for erythema, 67.8% for plaque elevation, and 64.4% for scaling. Most frequently reported TEAEs were application site reactions, and were more likely associated with the tazarotene component. Side effects such as skin atrophy were rare., Conclusions: HP/TAZ lotion was consistently more effective than its monads or vehicle in achieving treatment success and reducing psoriasis signs of erythema, plaque elevation, and scaling at the target lesion. Safety data were consistent with the known safety profile of halobetasol propionate and tazarotene, and did not reveal any new safety concerns with the combination product.

J Drugs Dermatol. 2017;16(3):197-204.

Palmoplantar psoriasis refers to a localized psoriasis variant. The disease can be associated with many clinical forms, including predominantly pustular lesions to thick scaly, hyperkeratotic plaques, or an overlapping of both of them. Palmoplantar psoriasis accounts for 3-4% of all psoriasis cases in most studies. Although it is localized only on the palms and the soles, the fissures, the hardening of the tissue, and hyperkeratosis affect daily routine activities. Taking the body surface area as a measure of severity can sometimes be misleading. In clinical practice, the level of functional impairment should be taken into account rather than relying on traditional instruments to evaluate the severity. Palmoplantar psoriasis is usually managed with topical therapy as a first step. Systemic therapy is needed when the topicals fail or when the disease becomes more severe. Sometimes, biologic agents are required for adequate maintenance of clinical response., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Numerous treatments are available for cutaneous T-cell lymphoma (CTCL), including systemic retinoids. Very few data are available on topical retinoids., Objectives: The aim of this study was to evaluate the safety and efficiency of tazarotene as monotherapy for early-stage CTCL., Methods: An open-label, prospective study of tazarotene as monotherapy for stages IA to IIA CTCL was conducted. Index lesions on 10 patients were followed for 6 months on treatment, plus at least 6 months off treatment., Results: Six patients (60%) showed complete response (CR). Erythema, scaling, thickness, and lesion area decreased progressively throughout treatment. The mean time to CR was 3.8 months; CR was durable for at least 6 months in 83%. Of the 4 patients (40%) without CR, 2 (20%) had stable disease and 2 (20%) stopped the medication because of local side effects; none showed progression., Conclusions: This is the first Canadian trial providing evidence that topical tazarotene has excellent potential as a monotherapy agent for stages I to IIA CTCL., (© The Author(s) 2016.)

Background: Until now, nonivamide/nicoboxil ointment has not been tested in a randomized trial for the treatment of acute non-specific low back pain., Methods: This phase III randomized, double-blind, active- and placebo-controlled, multi-centre trial investigated efficacy, safety and tolerability of topical nicoboxil 2.5%/nonivamide 0.4% for treatment of acute non-specific low back pain [primary endpoint: pain intensity (PI) difference between pre-dose baseline and 8 h after the first application]., Results: Patients (n = 805), 18-74 years of age were treated for up to 4 days with nicoboxil 2.5%/nonivamide 0.4%, nicoboxil 2.5%, nonivamide 0.4% or placebo ointment. Pre-dose baseline pain intensity (6.6 on a 0- to 10-point numerical rating scale) was reduced by 1.049 points with placebo, by 1.428 points with nicoboxil, by 2.252 points with nonivamide and by 2.410 points with nicoboxil/nonivamide after 8 h (p < 0.0001 for nicoboxil/nonivamide vs. placebo, nicoboxil; p = 0.4171 for nicoboxil/nonivamide vs. nonivamide). At the end of treatment, the combination provided more pronounced PI reduction (3.540 points) compared with nicoboxil (2.371, p < 0.0001), nonivamide (3.074, p = 0.0259) and placebo (1.884, p < 0.0001). Low back mobility scores on Day 1 were better for the combination compared with all other treatments (p < 0.044); on Day 2-4, scores were better than for placebo and nicoboxil (p < 0.003). Patients assessed efficacy of the combination as greater than of the comparators (p ≤ 0.0129). All treatments were tolerated well. No treatment-related serious adverse events were reported., Conclusion: Nicoboxil/nonivamide ointment is an effective, well-tolerated medication for the treatment of acute non-specific low back pain., (© 2015 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC®)

Introduction: Acne is a common skin condition of the pilosebaceous units that affects the young and old, ranges from moderate to severe and can be treated with an array of options. Topical retinoids are the initial treatment for acne due to their ability to treat comedones, the starting point of acne., Areas Covered: Tazarotene is a topical retinoid available as a cream, gel and foam. Tazarotene 0.1% foam was FDA approved in 2012 for the treatment of acne in patients ages ≥12 and is the first foam topical retinoid on the market. Phase I and III trials support the efficacy and safety of tazarotene foam for acne., Expert Opinion: The foam vehicles may increase compliance and satisfaction in some patients and as retinoids are commonly first line acne treatments, this new topical retinoid foam may be a useful option for some acne patients.

Alcohol consumption is largely associated with alterations in the extracellular glutamate concentrations in several brain reward regions. We recently showed that glutamate transporter 1 (GLT-1) is downregulated following chronic exposure to ethanol for 5 weeks in alcohol-preferring (P) rats and that upregulation of the GLT-1 levels in nucleus accumbens and prefrontal cortex results, in part, in attenuating ethanol consumption. Cystine glutamate antiporter (xCT) is also downregulated after chronic ethanol exposure in P rats, and its upregulation could be valuable in attenuating ethanol drinking. This study examines the effect of a synthetic compound, (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), on ethanol drinking and expressions of GLT-1 and xCT in the amygdala and the hippocampus of P rats. P rats were exposed to continuous free-choice access to water, 15% and 30% ethanol, and food for 5 weeks, after which they received treatments of MS-153 or vehicle for 5 days. The results show that MS-153 treatment significantly reduces ethanol consumption. It was revealed that GLT-1 and xCT expressions were downregulated in both the amygdala and the hippocampus of ethanol-vehicle-treated rats (ethanol-vehicle group) compared with water-control animals. MS-153 treatment upregulated GLT-1 and xCT expressions in these brain regions. These findings demonstrate an important role for MS-153 in these glutamate transporters for the attenuation of ethanol-drinking behavior., (© 2015 Wiley Periodicals, Inc.)

Background: Distal and lateral onychomycoses are the most frequent forms of onychomycosis, causing subungual hyperkeratosis that usually limits local penetration of antimycotic drugs. Tazarotene exerts anti-inflammatory and immune-modulating activities toward both infective agents and damaged keratinocytes. Given the well-documented efficacy of tazarotene on hyperkeratotic nail psoriasis, we investigated its therapeutic use in onychomycosis., Patients and Methods: We designed a preliminary open clinical trial in patients affected by distal and lateral subungual onychomycosis of the toenails and verified the fungistatic activity of tazarotene in vitro. Fifteen patients were treated with topical tazarotene 0.1% gel once per day for 12 weeks. Mycological cultures and potassium hydroxide stains of nail samples were performed at the beginning and at the end of the study. Treatment was considered effective when clinical healing and negative mycological culture were obtained. Onycholysis, nail bed discoloration, and subungual hyperkeratosis were measured using standardized methodologies and analyzed by means of Mann-Whitney test and analysis of variance. Fungistatic activity of tazarotene was evaluated by disk diffusion assay., Results: Six patients (40%) reached a mycological cure on target nail samples already after 4 weeks of treatment. Complete clinical healing and negative cultures were reached in all patients at week 12, with a significant improvement of all clinical parameters of the infected nails. Disk diffusion assay after 48 hours of incubation with tazarotene solution showed a central area of inhibition in all examined fungal cultures., Conclusion: Our results documented a good clinical outcome using topical tazarotene 0.1% gel in distal and lateral subungual onychomycosis and its fungistatic activity of tazarotene in vitro. The majority of patients appeared cured at a 6-month follow-up. The efficacy and safety of tazarotene must be confirmed on a larger number of patients, although already documented in nail psoriasis patients often affected by onychomycosis.

Purpose: The development of radioimmunotherapy has provided an impressive alternative approach in improving trastuzumab therapy. However, the mechanisms of trastuzumab and radiation treatment combined to increase therapeutic efficacy are poorly understood. Here, we try to examine the efficacy of cytotoxicity and apoptosis induction for (188)Re-HYNIC-trastuzumab in cancer cell lines with various levels of Her2., Materials and Methods: Fluorescence flow cytometry was used to detect the alterations of apoptosis induction after (188)Re-HYNIC-trastuzumab treatment in two breast cancer cell lines with different levels of HER2 (BT-474 and MCF-7) and a colorectal carcinoma cell line (HT-29) for control., Results: Our results indicated that (188)Re-HYNIC-trastuzumab led to cell death of breast cancer cells specifically in HER2 level-dependent and radioactivity dose-dependent fashions. In BT-474 cells, 370 kBq/ml of (188)Re-HYNIC-trastuzumab enhanced the cytotoxicity to a level nearly 100-fold that of trastuzumab-alone treatment. The results also revealed that the mitochondria-dependent pathway attenuated irradiation-induced apoptosis in HER2-expressing breast cancer cells after (188)Re-HYNIC-trastuzumab treatment. In contrast, only after 48 h of (188)Re-HYNIC-trastuzumab treatment, BT-474 cells exhibited typical apoptotic changes, including exposure of phospholipid phosphatidylserine on the cell surface, or fragmented DNA formation, in a radioactivity dose-dependent manner., Conclusion: Briefly, our study demonstrates that (188)Re-labeled HYNIC-trastuzumab not only enhances cell death in a radioactivity dose-dependent fashion, but may also prolong the effects of apoptosis involved with the mitochondria-dependent pathway in HER2-overexpressing breast cancer cells. It is possible that the (188)Re-HYNIC-trastuzumab treatment induced a second round of apoptosis to prolong the effects of cell kill in these cancer cells. These data revealed that (188)Re-HYNIC-trastuzumab has the potential for use as a therapeutic radiopharmaceutical agent in HER2-overexpressing breast cancer cell treatment.

Early diagnosis and therapy of precancerous lesions and malignant tumors belong to the most challenging tasks in modern medicine. Photodynamic diagnosis can help diagnose both precancerous lesions and early carcinoma. Actinic keratosis (AK) is the most common precancerous lesion of the skin. The available data show a high effectiveness of diclofenac in treating multifocal AK. We report a case of a 52-year-old woman who complained of multiple disseminated AK lesions predominantly on the lower limbs and trunk with a significant exacerbation within the last 6 months. Due to the spreading of disease and a high number of AK foci, as well as technical problems with visiting the hospital (PDT Laboratory), photodynamic therapy was not applied. The patient was treated for 2 months with a combination of local administration of 3% diclofenac and 0.1% tazaroten and 3% diclofenac only as a half side (left-right) comparison. The effects of therapy were later clinically evaluated and verified by means of photodynamic diagnosis (PDD) directly after therapy and at a follow-up examination 3 months later. The evaluation of treatment was blinded. Treatment with diclofenac only on the right side of the body resulted in clearing of 55% of all treated lesions, which increased to 60% three months after finishing therapy. On the left side of the body, where combined therapy (diclofenac 2 times daily on uneven dates and diclofenac once a day + tazaroten once a day on even dates) was used, 77.5% pathologic lesions disappeared, but this did not increase at follow up. The treatment of multifocal, disseminated AK is a difficult task and also burdensome for the patient due to side effects like scarring or burning and itching which occur during most therapies. Combined therapy with diclofenac and tazaroten supported by PDD may improve the effects of routine treatment of AK.

Darier-White disease is an uncommon disorder, which presents in a localized pattern in about 10% of patients, usually without nail, mucosa, or acral involvement. Type-1 is the most common of the segmental Darier-White disease types: papules have unilateral distribution along Blaschko lines. A 36-year-old woman diagnosed with type-1 segmental Darier-White disease is reported herein.

Hyperglycemia resulting from type 2 diabetes mellitus (T2DM) is the main cause of diabetic complications such as retinopathy and neuropathy. A reduction in hyperglycemia has been shown to prevent these associated complications supporting the importance of glucose control. Glucokinase converts glucose to glucose-6-phosphate and determines glucose flux into the β-cells and hepatocytes. Since activation of glucokinase in β-cells is associated with increased risk of hypoglycemia, we hypothesized that selectively activating hepatic glucokinase would reduce fasting and postprandial glucose with minimal risk of hypoglycemia. Previous studies have shown that hepatic glucokinase overexpression is able to restore glucose homeostasis in diabetic models; however, these overexpression experiments have also revealed that excessive increases in hepatic glucokinase activity may also cause hepatosteatosis. Herein we sought to evaluate whether liver specific pharmacological activation of hepatic glucokinase is an effective strategy to reduce hyperglycemia without causing adverse hepatic lipids changes. To test this hypothesis, we evaluated a hepatoselective glucokinase activator, PF-04991532, in Goto-Kakizaki rats. In these studies, PF-04991532 reduced plasma glucose concentrations independent of changes in insulin concentrations in a dose-dependent manner both acutely and after 28 days of sub-chronic treatment. During a hyperglycemic clamp in Goto-Kakizaki rats, the glucose infusion rate was increased approximately 5-fold with PF-04991532. This increase in glucose infusion can be partially attributed to the 60% reduction in endogenous glucose production. While PF-04991532 induced dose-dependent increases in plasma triglyceride concentrations it had no effect on hepatic triglyceride concentrations in Goto-Kakizaki rats. Interestingly, PF-04991532 decreased intracellular AMP concentrations and increased hepatic futile cycling. These data suggest that hepatoselective glucokinase activation may offer glycemic control without inducing hepatic steatosis supporting the evaluation of tissue specific activators in clinical trials.

Abnormal cold sensitivity is a common feature of a range of neuropathies. In the murine somatosensory system, multiple aspects of cold sensitivity are dependent on TRPM8, both short term and in response to peripheral nerve injury. The specialized nature of cold-sensitive afferents and the restricted expression of TRPM8 render it an attractive target for the treatment of cold hypersensitivity. This current study examines the effect of a novel TRPM8 antagonist (M8-An) in naive and spinal nerve-ligated rats through behavioral and in vivo electrophysiological approaches. In vitro, M8-An inhibited icilin-evoked Ca(2+) currents in HEK293 cells stably expressing human TRPM8 with an IC(50) of 10.9 nM. In vivo, systemic M8-An transiently decreased core body temperature. Deep dorsal horn recordings were made in vivo from neurons innervating the hind paw. M8-An inhibited neuronal responses to innocuous and noxious cooling of the receptive field in spinal nerve-ligated rats but not in naive rats. No effect on neuronal responses to mechanical and heat stimulation was observed. In addition, M8-An also attenuated behavioral responses to cold but not mechanical stimulation after nerve ligation without affecting the uninjured contralateral response. The data presented here support a contribution of TRPM8 to the pathophysiology of cold hypersensitivity in this model and highlight the potential of the pharmacological block of TRPM8 in alleviating the associated symptoms.

Sporadic human basal cell carcinomas (BCC) are generally well managed with current surgical modalities. However, in the subset of high-risk patients predisposed to developing large numbers of BCCs, there is an unmet need for effective, low-morbidity chemoprevention. This population includes fair-skinned patients with extensive sun exposure and those with genodermatoses such as the basal cell nevus (Gorlin) syndrome (BCNS). Tazarotene (Tazorac, Allergan) is a topical retinoid with relative specificity for RAR-β and RAR-γ receptors. We previously demonstrated tazarotene's robust anti-BCC efficacy in Ptch1(+/-) mice, a murine equivalent of BCNS, and others have found it to have some efficacy against sporadic human BCCs. We report here results of a randomized, double-blind, vehicle-controlled study in patients with BCNS evaluating the efficacy of topically applied tazarotene for BCC chemoprevention (N = 34 subjects), along with an open-label trial evaluating tazarotene's efficacy for chemotherapy of BCC lesions (N = 36 subjects) for a maximum follow-up period of 3 years. We found that only 6% of patients had a chemopreventive response and that only 6% of treated BCC target lesions were clinically cured. Our studies provide no evidence for either chemopreventive or chemotherapeutic effect of tazarotene against BCCs in patients with BCNS.

Inhibition of dihydroorotate dehydrogenase (DHODH) modulates pyrimidine biosynthesis. Effective inhibitors are immunomodulatory drugs clinically useful in the treatment of diseases such as rheumatoid arthritis, psoriatic arthritis and multiple sclerosis. There is limited evidence of their potential utility in treating psoriasis. This patent application claims topical formulations of the non-hepatotoxic DHODH inhibitor 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid for use in the treatment of psoriasis. This inhibitor had previously been claimed to be useful in treating various autoimmune disease.

Background and Purpose: Small molecule glucokinase activators (GKAs) have been associated with potent antidiabetic efficacy and hepatic steatosis in rodents. This study reports the discovery of S 50131 and S 51434, two novel GKAs with an original scaffold and an atypical pharmacological profile., Experimental Approach: Activity of the compounds was assessed in vitro by measuring activation of recombinant glucokinase, stimulation of glycogen synthesis in rat hepatocytes and increased insulin secretion from rat pancreatic islets of Langerhans. Efficacy and safety in vivo were evaluated after oral administration in db/db mice by measuring glycaemia, HbA1c and dyslipidaemia-associated events., Key Results: S 50131 and S 51434 activated GK and stimulated glycogen synthesis in hepatocytes and insulin secretion from pancreatic islets. Unexpectedly, while both compounds effectively lowered glycaemia after acute oral administration, they did not decrease HbA1c after a 4-week treatment in db/db mice. This lack of antidiabetic efficacy was associated with increased plasma free fatty acids (FFAs), contrasting with the effect of GKA50 and N00236460, two GKAs with sustained HbA1c lowering activity but neutral regarding plasma FFAs. S 50131, but not S 51434, also induced hepatic steatosis, as did GKA50 and N00236460. However, a shorter, 4-day treatment resulted in increased hepatic triglycerides without changing the plasma FFA levels, demonstrating dynamic alterations in the lipid profile over time., Conclusions and Implications: In addition to confirming the occurrence of dyslipidaemia with GKAs, these findings provide new insights into understanding how such compounds may sustain or lose efficacy over time., (© 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.)

Psoriasis is an inflammatory skin disorder not uncommonly seen in pregnant patients. Several drugs have been approved for its treatment in non-pregnant patients, but special precautions are necessary when selecting a treatment plan during pregnancy to prevent harm to the fetus and child. This article reviews the treatment options for the treatment of psoriasis in the pregnant and lactating patient., (© 2013 Wiley Periodicals, Inc.)