Severe Acute Respiratory Syndrome Coronavirus 2 and the Use of Biologics in Patients With Psoriasis [Formula: see text].

Coronavirus disease (COVID-19), a respiratory disease caused by a novel coronavirus designated severe acute respiratory syndrome coronavirus 2, has rapidly spread worldwide and has been recognized as a pandemic by the World Health Organization. Patients with altered immunologic function are at higher risk of acquiring COVID-19. In patients with psoriasis, inhibition of select pro-inflammatory cytokines through the use of biologic agents has been shown to be an effective treatment option. Pro-inflammatory cytokines have key immunomodulatory effects and are known to be involved in the hosts' immune response to a variety of viral infections. Though little is currently known about the role of inflammatory cytokines in COVID-19, early reports have shown patients with severe disease to have elevated serum levels of select inflammatory cytokines such as tumor necrosis factor alpha. This review will summarize key information that is currently known about COVID-19, the role of select cytokines in viral defense, and important considerations for patients with psoriasis using biologic agents during this pandemic. Currently, there is insufficient evidence to discontinue biologic therapy in patients with psoriasis who have not tested positive for COVID-19. The decision to pause biologic therapy should be considered on a case-by-case basis in patients in higher risk populations, and should take into account individual risk and benefit. Until more is known about the impact of biologic therapy on COVID-19 outcomes, we recommend patients with psoriasis who test positive for COVID-19 be instructed to discontinue or postpone biologic treatment until they have recovered from infection.

Short-Term Evaluation of the Real-World Efficacy and Safety of Dupilumab for the Treatment of Moderate-to-Severe Atopic Dermatitis: A Canadian Multicenter Retrospective Cohort Study [Formula: see text].

BACKGROUND: Systemic therapy for atopic dermatitis (AD) has been challenging with limited safe and efficacious long-term treatment options. In 2017, dupilumab was approved in the United States, Europe, and Canada as the first targeted therapy for patients with moderate-to-severe AD. Despite promising efficacy and safety results in clinical trials, our understanding of dupilumab in clinical practice remains limited with few studies outside clinical trials in literature. OBJECTIVE: The aim of this study is to evaluate the efficacy and safety of dupilumab in clinical practice and discuss any differences in results between clinical trials and real-world results. METHODS: A retrospective chart review was conducted of consecutive patients receiving dupilumab treatment at two tertiary hospitals in Toronto, Canada, between December 2017 and May 2019. The primary efficacy endpoint was measured by Investigator's Global Assessment (IGA) score of 0/1 at 16 weeks and all adverse events (AEs) experienced by patients were recorded. RESULTS: Of the 93 patients included in the study, 51 (55%) reached IGA 0/1 and 38 (41%) experienced ≥1 AE. There were no severe AEs or discontinuation prior to 16 weeks due to an AE. CONCLUSIONS: These findings suggest a higher IGA-based efficacy profile with no newly identified safety concerns in patients treated with dupilumab at two tertiary hospitals in Toronto, Canada, compared to those in randomized controlled trials.

Dose optimization of brodalumab in moderate-to-severe plaque psoriasis: A case report.

Brodalumab, a monoclonal antibody that targets the interleukin-17 receptor, is a new treatment option for moderate-to-severe plaque psoriasis with a unique mechanism of action. The current recommended dosing regimen is a 210-mg subcutaneous injection at weeks 0, 1, and 2, and every 2 weeks thereafter. We present a case of a patient with recalcitrant moderate-to-severe plaque psoriasis who required a higher maintenance dose frequency of 210 mg of brodalumab subcutaneously every week to achieve disease clearance. To our knowledge, this is the first report of a patient receiving a maintenance dose of 210 mg of brodalumab weekly. In patients with refractory plaque psoriasis only partially responsive to the recommended maintenance dose, an increase in frequency to every week may be worth consideration. Further research is required to elucidate the effectiveness and long-term safety of this regimen.

Off-label Uses of Topical Pimecrolimus.

Pimecrolimus is a topical calcineurin inhibitor currently approved for second-line use in the management of mild-to-moderate atopic dermatitis in patients age 2 years and older. Given the safety profile and nonsteroidal mechanism of pimecrolimus, there has been significant interest in its use in the treatment of a variety of dermatological conditions. This article reviews research that has been published on the off-label uses of topical pimecrolimus, with a focus on published RCTs. Convincing evidence exists supporting pimecrolimus' efficacy in oral lichen planus and seborrheic dermatitis. For other conditions studied to date, pimecrolimus may prove to be a useful treatment alternative when conventional agents fail. Adverse events seen with its off-label use were typically application site reactions, the most common being a transient burning sensation. In summary, pimecrolimus appears to be an effective agent in the treatment of multiple dermatological conditions and may be worth considering as a pharmacologic alternative in several conditions when first-line treatment fails, or for areas that are more susceptible to the adverse effects of topical corticosteroids.

Ambulatory Medication Reconciliation in Dialysis Patients: Benefits and Community Practitioners' Perspectives.

BACKGROUND: Ambulatory medication reconciliation can reduce the frequency of medication discrepancies and may also reduce adverse drug events. Patients receiving dialysis are at high risk for medication discrepancies because they typically have multiple comorbid conditions, are taking many medications, and are receiving care from many practitioners. Little is known about the potential benefits of ambulatory medication reconciliation for these patients. OBJECTIVES: To determine the number, type, and potential level of harm associated with medication discrepancies identified through ambulatory medication reconciliation and to ascertain the views of community pharmacists and family physicians about this service. METHODS: This retrospective cohort study involved patients initiating hemodialysis who received ambulatory medication reconciliation in a hospital renal program over the period July 2014 to July 2016. Discrepancies identified on the medication reconciliation forms for study patients were extracted and categorized by discrepancy type and potential level of harm. The level of harm was determined independently by a pharmacist and a nurse practitioner using a defined scoring system. In the event of disagreement, a nephrologist determined the final score. Surveys were sent to 52 community pharmacists and 44 family physicians involved in the care of study patients to collect their opinions and perspectives on ambulatory medication reconciliation. RESULTS: Ambulatory medication reconciliation was conducted 296 times for a total of 147 hemodialysis patients. The mean number of discrepancies identified per patient was 1.31 (standard deviation 2.00). Overall, 30% of these discrepancies were deemed to have the potential to cause moderate to severe patient discomfort or clinical deterioration. Survey results indicated that community practitioners found ambulatory medication reconciliation valuable for providing quality care to dialysis patients. CONCLUSIONS: This study has provided evidence that ambulatory medication reconciliation can increase patient safety and potentially prevent adverse events associated with medication discrepancies.

CONTEXTE: Le bilan comparatif des médicaments en soins ambulatoires peut réduire les divergences au chapitre des médicaments et les événements indésirables liés aux médicaments. Les divergences relatives aux médicaments représentent un risque élevé pour les patients dialysés, car ils souffrent normalement de multiples troubles comorbides, ils prennent souvent de nombreux médicaments et ils sont soignés par bon nombre de praticiens. Peu d'information existe sur les possibles avantages du bilan comparatif des médicaments en soins ambulatoires pour ces patients. OBJECTIFS: Déterminer le nombre et la catégorie des divergences concernant les médicaments constatées lors d'un bilan comparatif des médicaments en soins ambulatoires ainsi que la gravité potentielle des préjudices consécutifs. De plus, établir la position des pharmaciens communautaires et des médecins de famille sur cette modalité du bilan comparatif des médicaments. MÉTHODES: La présente étude de cohorte rétrospective a été menée auprès de patients amorçant un traitement par hémodialyse pour qui un bilan comparatif des médicaments en soins ambulatoires a été réalisé dans le cadre d'un programme hospitalier des maladies du rein, entre juillet 2014 et juillet 2016. Les divergences trouvées dans les formulaires de bilan comparatif des médicaments ont été classées par catégorie et selon la gravité potentielle des préjudices. Le niveau du préjudice a été déterminé de manière indépendante par un pharmacien et un membre du personnel infirmier praticien à l'aide d'un système de notation défini. En cas de désaccord, le score final était établi par un néphrologue. Des sondages ont été envoyés à 52 pharmaciens communautaires et à 44 médecins de famille prodiguant des soins aux participants afin qu'ils expriment leurs opinions et leurs points de vue sur le bilan comparatif des médicaments en soins ambulatoires. RÉSULTATS: En tout, 296 bilans comparatifs des médicaments en soins ambulatoires ont été effectués auprès de 147 patients hémodialysés. Le nombre moyen de divergences constatées par patient était de 1,31 (écart-type de 2,00). Dans l'ensemble, 30 % de ces divergences ont été considérées comme une source potentielle d'un inconfort allant de modéré à grave ou de dégradation clinique. Selon les résultats du sondage, les praticiens communautaires ont jugé le bilan comparatif des médicaments en soins ambulatoires utile à la prestation de soins de qualité aux patients dialysés. CONCLUSIONS: D'après les résultats de l'étude, le bilan comparatif des médicaments en soins ambulatoires augmenterait la sécurité des patients et pourrait prévenir les événements indésirables liés aux divergences relatives aux médicaments.

The Effects of CKD on Cytochrome P450-Mediated Drug Metabolism.

CKD affects a significant proportion of the world's population, and the prevalence of CKD is increasing. Standard practice currently is to adjust the dose of renally eliminated medications as kidney function declines in effort to prevent adverse drug reactions. It is increasingly becoming recognized that CKD also impacts nonrenal clearance mechanisms such as hepatic and intestinal cytochrome P450 (CYP) enzymes and drug transport proteins, the latter of which is beyond the scope of this review. CYPs are responsible for the metabolism of many clinically used drugs. Genetics, patient factors (eg, age and disease) and drug interactions are well known to affect CYP metabolism resulting in variable pharmacokinetics and responses to medications. There now exists an abundance of evidence demonstrating that CKD can impact the activity of many CYP isoforms either through direct inhibition by circulating uremic toxins and/or by reducing CYP gene expression. Evidence suggests that reductions in CYP metabolism in ESRD are reversed by kidney transplantation and temporarily restored via hemodialysis. This review summarizes the current understanding of the effects that CKD can have on CYP metabolism and also discusses the impact that CYP metabolism phenotypes can have on the development of kidney injury.

Jadomycin breast cancer cytotoxicity is mediated by a copper-dependent, reactive oxygen species-inducing mechanism.

Jadomycins are natural products biosynthesized by the bacteria Streptomyces venezuelae which kill drug-sensitive and multidrug-resistant breast cancer cells in culture. Currently, the mechanisms of jadomycin cytotoxicity are poorly understood; however, reactive oxygen species (ROS)-induced DNA cleavage is suggested based on bacterial plasmid DNA cleavage studies. The objective of this study was to determine if and how ROS contribute to jadomycin cytotoxicity in drug-sensitive MCF7 (MCF7-CON) and taxol-resistant MCF7 (MCF7-TXL) breast cancer cells. As determined using an intracellular, fluorescent, ROS-detecting probe, jadomycins B, S, SPhG, and F dose dependently increased intracellular ROS activity 2.5- to 5.9-fold. Cotreatment with the antioxidant N-acetyl cysteine lowered ROS concentrations to below baseline levels and decreased the corresponding cytotoxic potency of the four jadomycins 1.9- to 3.3-fold, confirming a ROS-mediated mechanism. Addition of CuSO4 enhanced, whereas addition of the Cu(II)-chelator d-penicillamine reduced, the ROS generation and cytotoxicity of each jadomycin. Specific inhibitors of the antioxidant enzymes, superoxide dismutase 1, glutathione S-transferase, and thioredoxin reductase, but not catalase, enhanced jadomycin-mediated ROS generation and anticancer activity. In conclusion, the results indicate that jadomycin cytotoxicity involves the generation of cytosolic superoxide via a Cu(II)-jadomycin reaction, a mechanism common to all jadomycins tested and observed in MCF7-CON and drug-resistant MCF7-TXL cells. The superoxide dismutase 1, glutathione, and peroxiredoxin/thioredoxin cellular antioxidant enzyme pathways scavenged intracellular ROS generated by jadomycin treatment. Blocking these antioxidant pathways could serve as a strategy to enhance jadomycin cytotoxic potency in drug-sensitive and multidrug-resistant breast cancers.