Roflumilast 0.3% Cream: a Phosphodiesterase 4 Inhibitor for the Treatment of Chronic Plaque Psoriasis.

BACKGROUND: Plaque psoriasis is a chronic dermatologic autoimmune disease that affects adults and children. Roflumilast 0.3% cream is currently the only topical phosphodiesterase 4 inhibitor indicated for the treatment of plaque psoriasis in patients 12 years or older. PHARMACODYNAMICS AND PHARMACOKINETICS: Roflumilast inhibits phosphodiesterase 4 inhibitor enzyme leading to the accumulation of cyclic adenosine monophosphate, which suppresses the inflammatory mediators interferon-γ and tumor necrosis factor-α. Roflumilast, applied once daily, reaches steady state by day 15 and has a half life of approximately 4 days in adults. Roflumilast undergoes extensive hepatic metabolism by cytochrome P450 enzymes and conjugation. Roflumilast is 99% bound to plasma proteins. CLINICAL TRIALS: Roflumilast efficacy and safety were evaluated in the DERMIS-1 and DERMIS-2 clinical trials. These identically designed, double-blind, vehicle-controlled phase 3 trials randomized 881 patients to roflumilast 0.3% cream or vehicle, applied once daily for 8 weeks. In DERMIS-1, the Investigator Global Assessment success rate was 42.4% with roflumilast 0.3% cream compared with 6.1% with the vehicle (32.3%-46.9%; P <0.001). Similarly, in DERMIS-2, the Investigator Global Assessment success rate was 37.5% with roflumilast 0.3% cream compared with 6.9% with the vehicle (20.8%-36.9%; P <0.001). Of 881 participants, 1% discontinued treatment with roflumilast cream due to adverse reactions compared with 1.3% treated with vehicle. Urticaria at the application site (0.3%) was the most common adverse reaction that led to discontinuation of roflumilast. THERAPEUTIC ADVANCE: To date, topical corticosteroids are the most commonly used agents to treat mild plaque psoriasis. Sensitive areas are often challenging to treat with existing topical therapy, including corticosteroids. Topical roflumilast has shown to be effective in treating sensitive areas, including skin folds, and may be an alternative to systemic therapy for some patients. The Food and Drug Administration approved topical roflumilast for the treatment of plaque psoriasis, including intertriginous areas, for patients 12 years or older.

Vascular smooth muscle ROCK1 contributes to hypoxia-induced pulmonary hypertension development in mice.

Rho kinase (ROCK) is implicated in the development of pulmonary arterial hypertension (PAH) in which abnormal pulmonary vascular smooth muscle (VSM) contractility and remodeling lead to right heart failure. Pharmacologic ROCK inhibitors block experimental pulmonary hypertension (PH) development in rodents but can have off-target effects and do not distinguish between the two ROCK forms, ROCK1 and ROCK2, encoded by separate genes. An earlier study using gene knock out (KO) in mice indicated that VSM ROCK2 is required for experimental PH development, but the role of ROCK1 is not well understood. Here we investigated the in vivo role of ROCK1 in PH development by generating a VSM-targeted homozygous ROCK1 gene KO mouse strain. Adult control mice exposed to Sugen5416 (Su)/hypoxia treatment to induce PH had significantly increased right ventricular systolic pressures (RVSP) and RV hypertrophy versus normoxic controls. In contrast, Su/hypoxia-exposed VSM ROCK1 KO mice did not exhibit significant RVSP elevation, and RV hypertrophy was blunted. Su/hypoxia-induced pulmonary small vessel muscularization was similarly elevated in both control and VSM ROCK1 KO animals. siRNA-mediated ROCK1 knock-down (KD) in human PAH pulmonary arterial SM cells (PASMC) did not affect cell growth. However, ROCK1 KD led to reduced AKT and MYPT1 signaling in serotonin-treated PAH PASMC. The findings suggest that like VSM ROCK2, VSM ROCK1 actively contributes to PH development, but in distinction acts via nonproliferative pathways to promote hypoxemia, and thus may be a distinct therapeutic target in PH.

The Economy of Shark Conservation in the Northeast Pacific: The Role of Ecotourism and Citizen Science.

Historically sharks have been seen either as a source of income through harvesting, or as a nuisance and danger. The economic value of sharks has traditionally been measured as the total value of sharks caught for liver oil, fins, or meat for consumption. Sharks have also been killed to near extinction in cases where they were seen as a threat to fisheries on other species. This is illustrated by the mass extermination of Basking Sharks (Cetorhinus maximus) in British Columbia. They were seen as a nuisance to fishermen as they got entangled in gill nets during the salmon fishing season. However with the development of the SCUBA diving industry, and ecotourism in general, increased awareness of the role sharks play in marine ecosystems has resulted in changes in how they are perceived and utilized. Despite an ongoing harvest of sharks such as the North Pacific Spiny Dogfish (Squalus suckleyi), sharks now generate economic value through SCUBA diving enthusiasts who travel the globe to see, swim with, and photograph them. The use of digital cameras and other digital media has brought sharks into households around the world and increased awareness of the conservation issues facing many species. This renewed appreciation has led to a better understanding of sharks by the public, resulting in advocates calling for better protections and conservation. In particular, a growing part of the SCUBA diving community wants to contribute to conservation and research projects, which has led to participation in citizen science projects. These projects provide scientific data but also gain ground as ecotourism activities, thus adding to both economic value of tourism and conservation efforts.

Pharmacist Counseling and the Use of Nonsteroidal Anti-Inflammatory Drugs by Older Adults.

OBJECTIVE: To determine the impact a medication review has on the detection and use of nonsteroidal anti-inflammatory drugs (NSAIDs) by older adults compared with non-NSAID users in regard to interacting drug classes, interacting comorbidities, and prior counseling by providers. DESIGN: Prospective, quasi-experiment without control. SETTING: Ambulatory. PATIENTS: Patients 60 years of age and older who contacted the pharmacy outreach program. In total, 83 patients consented. Twenty-eight patients were eligible for three-month follow-up. INTERVENTIONS: Pharmacists and pharmacy students provided NSAID counseling. MAIN OUTCOME MEASURES: Patient-reported changes of NSAID use, change from inappropriate to appropriate use, impression of risk awareness, and further discussion with health care providers. RESULTS: NSAID use was reported by 39 (47.6%) of 83 patients. Inappropriate use was detected in 28 (71.8%) of NSAID users; of these, 18 (64.3%) were reached for post-counseling follow-up. The number of appropriate users increased to 20 (51.3%), with a concomitant reduction of inappropriate users to 19 (48.7%). Nine (50%) reported change in the use of NSAIDs, 13 (72.2%) had a better understanding of the risks associated with NSAID use, and 10 (55.6%) had a more meaningful conversation with providers. CONCLUSIONS: Older adults who use NSAIDs may be unaware of potential risks. Counseling older adults may reduce potentially inappropriate use and increase patient risk awareness. Pharmacists can improve their role in recognizing and counseling patients on NSAIDs.

Alpha-Catulin Co-Localizes With Vimentin Intermediate Filaments and Functions in Pulmonary Vascular Endothelial Cell Migration via ROCK.

The ubiquitous α-catulin acts as a scaffold for distinct signalosomes including RhoA/ROCK; however, its function is not well understood. While α-catulin has homology to the cytoskeletal linkers α-catenin and vinculin, it appears to be functionally divergent. Here we further investigated α-catulin function in pulmonary vascular endothelial cells (VEC) on the premise that α-catulin has a unique cytoskeletal role. Examination of endogenous α-catulin intracellular localization by immunofluorescence revealed a highly organized cytosolic filamentous network suggestive of a cytoskeletal system in a variety of cultured VEC. Double-immunofluorescence analyses of VEC showed endogenous α-catulin co-localization with vimentin intermediate filaments. Similar to vimentin, α-catulin was found to distribute into detergent-soluble and -insoluble fractions. Treatment of VEC with withaferinA, an agent that targets vimentin filaments, disrupted the α-catulin network distribution and altered α-catulin solubility. Vimentin participates in cell migration, and withaferinA was found to inhibit VEC migration in vitro; similarly, α-catulin knock-down reduced VEC migration. Based on previous reports showing that ROCK modulates vimentin, we found that ROCK depletion attenuated VEC migration; furthermore, α-catulin depletion was shown to reduce ROCK-induced signaling. These findings indicate that α-catulin has a unique function in co-localization with vimentin filaments that contributes to VEC migration via a pathway that may involve ROCK signaling. J. Cell. Physiol. 231: 934-943, 2016. © 2015 Wiley Periodicals, Inc.

Evolution of Staphylococcus aureus under vancomycin selective pressure: the role of the small-colony variant phenotype.

Staphylococcus aureus small-colony variants (SCVs) often persist despite antibiotic therapy. Against a 10(8)-CFU/ml methicillin-resistant S. aureus (MRSA) (strain COL) population of which 0%, 1%, 10%, 50%, or 100% was an isogenic hemB knockout (Ia48) subpopulation displaying the SCV phenotype, vancomycin achieved maximal reductions of 4.99, 5.39, 4.50, 3.28, and 1.66 log10 CFU/ml over 48 h. Vancomycin at ≥16 mg/liter shifted a population from 50% SCV cells at 0 h to 100% SCV cells at 48 h, which was well characterized by a Hill-type model (R2>0.90).

The Lbc Rho guanine nucleotide exchange factor α-catulin axis functions in serotonin-induced vascular smooth muscle cell mitogenesis and RhoA/ROCK activation.

Serotonin (5-hydroxytryptamine, 5-HT) is mitogenic for several cell types including pulmonary arterial smooth muscle cells (PASMC), and is associated with the abnormal vascular smooth muscle remodeling that occurs in pulmonary arterial hypertension. RhoA/Rho kinase (ROCK) function is required for 5-HT-induced PASMC mitogenesis, and 5-HT activates RhoA; however, the signaling steps are poorly defined. Rho guanine nucleotide exchange factors (Rho GEFs) transduce extracellular signals to Rho, and we found that 5-HT treatment of PASMC led to increased membrane-associated Lbc Rho GEF, suggesting modulation by 5-HT. Lbc knockdown by siRNA attenuated 5-HT-induced thymidine uptake in PASMC, indicating a role in PASMC mitogenesis. 5-HT triggered Rho-dependent serum response factor-mediated reporter activation in PASMC, and this was reduced by Lbc depletion. Lbc knockdown reduced 5-HT-induced RhoA/ROCK activation, but not p42/44 ERK MAP kinase activation, suggesting that Lbc is an intermediary between 5-HT and RhoA/ROCK, but not ERK. 5-HT stimulation of PASMC led to increased association between Lbc, RhoA, and the α-catulin scaffold. Furthermore, α-catulin knockdown attenuated 5-HT-induced PASMC thymidine uptake. 5-HT-induced PASMC mitogenesis was reduced by dominant-negative G(q) protein, suggesting cooperation with Lbc/α-catulin. These results for the first time define a Rho GEF involved in vascular smooth muscle cell growth and serotonin signaling, and suggest that Lbc Rho GEF family members play distinct roles. Thus, the Lbc/α-catulin axis participates in 5-HT-induced PASMC mitogenesis and RhoA/ROCK signaling, and may be an interventional target in diseases involving vascular smooth muscle remodeling.

Transgender health education for pharmacy students and its effect on student knowledge and attitudes.

BACKGROUND AND PURPOSE: Increased student pharmacist education on health issues and concerns of the underserved Lesbian, gay, bisexual, transgender, and queer (LGBTQ) population is needed. We incorporated pharmacy-specific, transgender-focused education into the curriculum and sought to identify whether pharmacy students' knowledge and attitudes towards LGBTQ individuals were affected by: (1) required online module or in-class lecture and (2) student demographics. Educational activity and setting: Pharmacy student attitudes and perceptions towards transgender individuals and the LGBTQ population were assessed before and after online (video) and in-person education using a modification of the Attitudes towards Lesbian Gay Bisexual Transgender Patients Scale. Wilcoxon test for non-parametric paired data was used to test for statistically significant changes between the pre- and post-education surveys, while two-way analysis of variance was used to analyze correlations between student demographics and responses. FINDINGS: Changes in students' knowledge and attitudes were observed after exposure to either online or in-person education. Increases in students' perceived competence to provide care to patients identifying as LGBTQ were associated with both teaching methods. Significant demographic associations were seen with specific attitudes; female students and students who knew a transgender person were more likely to strongly disagree that discussing sexual behavior with LGBTQ patients is challenging. SUMMARY: Delivery of transgender-focused education produced observable changes in student pharmacist perceptions and attitudes towards working with the LGBTQ patient population. Demographic characteristics, such as being female or knowing a transgender individual, positively correlated with student pharmacists' feeling more comfortable discussing sexual behavior with LGBTQ persons.

Rhinorrhea as a Result of Alzheimer's Disease Treatment: A Case Report.

This report describes a case of persistent rhinorrhea caused by donepezil and successfully treated with azelastine in an 84-year-old male treated with donepezil for Alzheimer's disease (AD) who experienced excessive rhinorrhea. After initiation of donepezil for AD the patient showed increased discomfort with rhinorrhea. A trial with an oral second-generation antihistamine provided no benefit. Azelastine 0.1% nasal spray was initiated and successfully reduced the rhinorrhea. A less-oftenreported side effect of donepezil that may impact patients is rhinorrhea, also described as rhinitis or nasopharyngitis.
Cholinergic mechanisms of rhinorrhea have been previously described in the condition of vasomotor rhinitis and are not allergy-mediated though symptomatology overlaps. Azelastine is a histamine H1 antagonist indicated for vasomotor rhinitis. To our knowledge there are no previous descriptions in the literature that recommend azelastine to manage symptoms of rhinorrhea caused by treatments for AD. The adverse side effect of rhinorrhea, resulting from treatment with donepezil, can be disregarded as allergy symptoms. Instead, a trial of azelastine 0.1% nasal spray, one spray each nostril daily then titrated up to two sprays in each nostril twice daily as tolerated, may be warranted. Patients and caregivers should be aware of epistaxis as a potential side effect of azelastine, especially for patients on antithrombotic therapy.

Impact of geriatrics elective courses at three colleges of pharmacy: Attitudes toward aging and eldercare.

INTRODUCTION: One in five Americans will be 65 years and older by 2030. Training student pharmacists to provide quality eldercare as healthcare professionals is essential. The objective of the study was to assess pharmacy students' attitudes toward aging and eldercare before and after a geriatrics-focused elective course. METHODS: The University of Arizona Aging and Health Care (UA AHC) survey was modified for pharmacy and administered pre and post to students enrolled in a geriatrics elective course at three United States (US) colleges of pharmacy. Pre and post means were calculated to examine attitudinal changes after course participation. Factor analysis was performed to examine construct validity by identifying the dimensions being measured. RESULTS: Sixteen of 37 questions differed significantly from pre-course to post-course demonstrating improved attitudes after course participation. Students also reported an awareness of how older adults are viewed and treated. Factor analysis identified seven factors with a range of behaviors, skills, training, and attitudes perceived to be important in geriatric care. Two factors, importance of learning about geriatric care and experience/comfort with older adults, showed significant changes confirming positive impact of the course. CONCLUSIONS: Geriatrics-focused elective courses in three colleges of pharmacy had a positive impact on students' perceived importance of learning about geriatric care and experience/comfort with elders. Further research to adapt and validate the UA AHC survey to pharmacy education is needed. The identification of the skills and attitudes necessary to meet the growing needs of older adults is necessary for pharmacy curriculum implementation and practice.

Perspectives in Marine Citizen Science.

Citizen science can be defined as the process by which any non-scientist collects data or uses the scientific method under the guidance or mentorship of a scientist. This article presents an overview of several marine citizen-science projects as practiced by three non-profit organizations.