A Clinical Perspective of Canagliflozin in the Management of Type 2 Diabetes Mellitus

Objective To assess the real-world efficacy and safety of the first sodium-glucose cotransporter-2 inhibitor, canagliflozin, in the treatment of patients with type 2 diabetes mellitus (T2DM). Methods This observational study assessed the efficacy and tolerability of canagliflozin in T2DM patients. Primary study outcomes were changes in HbAlC and weight, and percentage of patients reporting adverse effects of therapy. Results The study criteria were met by 111 patient records. Baseline patient characteristics were: average age, 59 ± 9 years; mean duration of T2DM, 11.9 ± 7.3 years; 57.6% of patients were male; 92.8% were Caucasian; baseline BMI, 38.9 ± 11 kg/m 2 ; and mean baseline HbAlC, 7.53 (58.8 mmol/mol) ± 1.08%. HbAlC and weight were significantly reduced by 0.37% and 4.4 kg, respectively. Adverse effects were reported by 21 patients, and 17 (15.3%) discontinued canagliflozin because of adverse reactions. Conclusion Canagliflozin was generally well tolerated and significantly reduced HbAlC levels and body weight in patients with T2DM when added to a regimen of other anti-hyperglycemic agents

Failure to fail – Perspective from junior faculty preceptors on the challenges of evaluating underperforming students in the experiential learning environment

Introduction: Preceptors serve as the gatekeepers between individuals progressing from student pharmacist to independent practitioner. This responsibility is challenging if a student is not progressing as required and is at risk of failure. In this article, we will review the potential consequences and barriers of “failing to fail” a student, share the emotions that come with the decision, and suggest actions that may aid in preceptor decision-making. Commentary: A preceptor\u27s failure to fail a student has a global impact on many parties including the student, their future employer and patients, the preceptor, and the school or college of pharmacy. Despite supportive factors, preceptors may experience an internal struggle about the ripple effect of failing or not failing an experiential student. Implications: Underperformance in the experiential setting is a complex issue that remains largely unseen due to “failure to fail,” a concept that should be researched further in the pharmacy setting. Empowering preceptors, particularly newer preceptors, to assess and manage failing students is possible through increased discussion around the topic and focused preceptor development programs

Alternate NF-\u3baB-Independent Signaling Reactivation of Latent HIV-1 Provirus

Current combination antiretroviral therapies (cART) are unable to eradicate HIV-1 from infected individuals because of the establishment of proviral latency in long-lived cellular reservoirs. The shock-and-kill approach aims to reactivate viral replication from the latent state (shock) using latency-reversing agents (LRAs), followed by the elimination of reactivated virus-producing cells (kill) by specific therapeutics. The NF-\u3baB RelA/p50 heterodimer has been characterized as an essential component of reactivation of the latent HIV-1 long terminal repeat (LTR). Nevertheless, prolonged NF-\u3baB activation contributes to the development of various autoimmune, inflammatory, and malignant disorders. In the present study, we established a cellular model of HIV-1 latency in J-Lat CD4+ T cells that stably expressed the NF-\u3baB superrepressor I\u3baB-\u3b1 2N\u3944 and demonstrate that conventional treatments with bryostatin-1 and hexamethylenebisacetamide (HMBA) or ionomycin synergistically reactivated HIV-1 from latency, even under conditions where NF-\u3baB activation was repressed. Using specific calcineurin phosphatase, p38, and MEK1/MEK2 kinase inhibitors or specific short hairpin RNAs, c-Jun was identified to be an essential factor binding to the LTR enhancer \u3baB sites and mediating the combined synergistic reactivation effect. Furthermore, acetylsalicylic acid (ASA), a potent inhibitor of the NF-\u3baB activator kinase I\u3baB kinase \u3b2 (IKK-\u3b2), did not significantly diminish reactivation in a primary CD4+ T central memory (TCM) cell latency model. The present work demonstrates that the shock phase of the shock-and-kill approach to reverse HIV-1 latency may be achieved in the absence of NF-\u3baB, with the potential to avoid unwanted autoimmune- and or inflammation-related side effects associated with latency-reversing strategies.IMPORTANCE The shock-and-kill approach consists of the reactivation of HIV-1 replication from latency using latency-reversing agents (LRAs), followed by the elimination of reactivated virus-producing cells. The cellular transcription factor NF-\u3baB is considered a master mediator of HIV-1 escape from latency induced by LRAs. Nevertheless, a systemic activation of NF-\u3baB in HIV-1-infected patients resulting from the combined administration of different LRAs could represent a potential risk, especially in the case of a prolonged treatment. We demonstrate here that conventional treatments with bryostatin-1 and hexamethylenebisacetamide (HMBA) or ionomycin synergistically reactivate HIV-1 from latency, even under conditions where NF-\u3baB activation is repressed. Our study provides a molecular proof of concept for the use of anti-inflammatory drugs, like aspirin, capable of inhibiting NF-\u3baB in patients under combination antiretroviral therapy during the shock-and-kill approach, to avoid potential autoimmune and inflammatory disorders that can be elicited by combinations of LRAs