A qualitative study on pharmacy policies toward over-the-counter syringe sales in a rural epicenter of US drug-related epidemics

Background Expanding access to sterile syringes in rural areas is vital, as injection-related epidemics expand beyond metropolitan areas globally. While pharmacies have potential to be an easily accessible source of sterile syringes, research in cities has identified moral, legal and ethical barriers that preclude over-the-counter (OTC) sales to people who inject drugs (PWID). The current study builds on prior urban-based research by elucidating (1) pharmacy OTC policies and (2) pharmacists’ rationale for, and barriers and facilitators to, OTC syringe sales in a US rural area hard hit by drug-related epidemics. Methods We conducted 14 semi-structured interviews with pharmacists recruited from two Eastern Kentucky health districts. Interview domains included experiences with, and attitudes toward, selling OTC syringes to PWID. Constructivist grounded theory methods were used to analyze verbatim transcripts. Results Most pharmacists operated “restrictive OTC” pharmacies (n = 8), where patients were required to have a prescription or proof of medical need to purchase a syringe. The remainder (n = 6) operated “open OTC” pharmacies, which allowed OTC syringe sales to most patients. Both groups believed their pharmacy policies protected their community and pharmacy from further drug-related harm, but diverging policies emerged because of stigma toward PWID, perceptions of Kentucky law, and belief OTC syringe sales were harmful rather than protective to the community. Conclusion Our results suggest that restrictive OTC pharmacy policies are rooted in stigmatizing views of PWID. Anti-stigma education about substance use disorder (SUD), human immunodeficiency virus (HIV), and Hepatitis C (HCV) is likely needed to truly shift restrictive pharmacy policy.

Where Are We with RPE Replacement Therapy? A Translational Review from the Ophthalmologist Perspective

The retinal pigmented epithelium (RPE) plays a pivotal role in retinal homeostasis. It is therefore an interesting target to fill the unmet medical need of different retinal diseases, including age-related macular degeneration and Stargardt disease. RPE replacement therapy may use different cellular sources: induced pluripotent stem cells or embryonic stem cells. Cells can be transferred as suspension on a patch with different surgical approaches. Results are promising although based on very limited samples. In this review, we summarize the current progress of RPE replacement and provide a comparative assessment of different published approaches which may become standard of care in the future.

Behavioral Effects of Buspirone in Juvenile Zebrafish of Two Different Genetic Backgrounds

Anxiety continues to represent a major unmet medical need. Despite the availability of numerous anxiolytic drugs, a large proportion of patients do not respond well to current pharmacotherapy, or their response diminishes with chronic drug application. To discover novel compounds and to investigate the mode of action of anxiolytic drugs, animal models have been proposed. The zebrafish is a novel animal model in this research. It is particularly appropriate, as it has evolutionarily conserved features, and drug administration can be employed in a non-invasive manner by immersing the fish into the drug solution. The first step in the analysis of anxiolytic drugs with zebrafish is to test reference compounds. Here, we investigate the effects of buspirone hydrochloride, an anxiolytic drug often employed in the human clinic. We utilize two genetically distinct populations of zebrafish, ABSK, derived from the quasi-inbred AB strain, and WT, a genetically heterogeneous wild-type population. We placed juvenile (10–13-day, post-fertilization, old) zebrafish singly in petri dishes containing one of four buspirone concentrations (0 mg/L control, 5 mg/L, 20 mg/L or 80 mg/L) for 1 h, with each fish receiving a single exposure to one concentration, a between subject experimental design. Subsequently, we recorded the behavior of the zebrafish for 30 min using video-tracking. Buspirone decreased distance moved, number of immobility episodes and thigmotaxis, and it increased immobility duration and turn angle in a quasi-linear dose dependent but genotype independent manner. Although it is unclear whether these changes represent anxiolysis in zebrafish, the results demonstrate that behavioral analysis of juvenile zebrafish may be a sensitive and simple way to quantify the effects of human anxiolytic drugs.

Antioxidants as Therapeutic Agents in Acute Respiratory Distress Syndrome (ARDS) Treatment—From Mice to Men

Acute respiratory distress syndrome (ARDS) is a major cause of patient mortality in intensive care units (ICUs) worldwide. Considering that no causative treatment but only symptomatic care is available, it is obvious that there is a high unmet medical need for a new therapeutic concept. One reason for a missing etiologic therapy strategy is the multifactorial origin of ARDS, which leads to a large heterogeneity of patients. This review summarizes the various kinds of ARDS onset with a special focus on the role of reactive oxygen species (ROS), which are generally linked to ARDS development and progression. Taking a closer look at the data which already have been established in mouse models, this review finally proposes the translation of these results on successful antioxidant use in a personalized approach to the ICU patient as a potential adjuvant to standard ARDS treatment.

Pharmacophore Modelling and Virtual Screening Studies for the Discovery of Potential Natural Products Based PDE1B Inhibitor Lead Compounds

Aim: The aim of the present study was to apply pharmacophore based virtual screening to a natural product database to identify potential PDE1B inhibitor lead compounds for neurodegenerative and neuropsychiatric disorders. Background: Neurodegenerative and neuropsychiatric disorders are a major health burden globally. The existing therapies do not provide optimal relief and are associated with substantial adverse effects. This has resulted in a huge unmet medical need for newer and more effective therapies for these disorders. Phosphodiesterase (PDEs) enzymes have been identified as potential targets of drugs for neurodegenerative and neuropsychiatric disorders, and one of the subtypes, i.e., PDE1B, accounts for more than 90 % of total brain PDE activity associated with learning and memory process, making it an interesting drug target for the treatment of neurodegenerative disorders. Objectives: The present study has been conducted to identify potential PDE1B inhibitor lead compounds from the natural product database. Methods: Ligand-based pharmacophore models were generated and validated; they were then employed for virtual screening of Universal Natural Products Database (UNPD) followed by docking with PDE1B to identify the best hit compound. Results: Virtual screening led to the identification of 85 compounds which were then docked into the active site of PDE1B. Out of the 85 compounds, six showed a higher affinity for PDE1B than the standard PDE1B inhibitors. The top scoring compound was identified as Cedreprenone. Conclusion: Virtual screening of UNPD using Ligand based pharmacophore led to the identification of Cedreprenone, a potential new natural PDE1B inhibitor lead compound.

De-Escalating Breast Cancer Surgery: Should We Apply Quality Indicators from Other Jurisdictions in Canada?

Quality Indicators (QIs), including the breast-conserving surgery (BCS) rate, were published by the European and American Breast Cancer Societies and this study assesses these in a Canadian population to look for opportunities to de-escalate surgery. A total of 2311 patients having surgery for unilateral, unifocal breast cancer between 2013 and 2017 were identified and BCS QIs calculated. Reasons for mastectomy had been prospectively collected with synoptic operative reporting. Our BCS rate for invasive cancer < 3 cm was 77.1%, invasive cancer < 2 cm was 84.1%, and DCIS < 2 cm was 84.9%. There was no statistically significant change in BCS rates over a five-year period, but there was a reduction in contralateral prophylactic mastectomies (CPM) from 28% in 2013 to 16% in 2017 (p < 0.001). Trend analysis looking at tumour size and medical need for mastectomy indicated that 80% of patients at our centre would be eligible for BCS with tumour cut off of 2.5 cm. Our institution met American but not European QI standards for BCS rates, potentially indicating a difference in patient demographics compared to Europe. Our results support the understanding that BCS rates are influenced by multiple factors and are challenging to compare across jurisdictions. CPM rates may offer a more actionable opportunity to de-escalate surgery for breast cancer.

Venetoclax in Relapsed/Refractory Acute Myeloid Leukemia: Are Supporting Evidences Enough?

Despite the progress in the development of new therapeutic strategies, relapsed/refractory (R/R) acute myeloid leukemia (AML) still represents a high unmet medical need. Treatment options in this setting include enrollment into clinical trials, allogeneic stem cell transplantation and/or targeted therapy. Nevertheless, it is associated with poor outcomes. Thus, the development of new treatments, which could ameliorate the prognosis of these patients with a good safety profile are highly demanded. Recently, venetoclax (VEN) has been approved for naïve AML patients unfit for intensive chemotherapy. In this regard, regimens including VEN could represent a valuable treatment option even in those with R/R disease and several studies have been conducted to demonstrate its role in this clinical setting. This review aims to summarize the current evidence on the use of VEN regimens in the treatment of R/R AML.

Combined Treatment with Immunotherapy-Based Strategies for MSS Metastatic Colorectal Cancer

In recent years, deepening knowledge of the complex interactions between the immune system and cancer cells has led to the advent of effective immunotherapies that have revolutionized the therapeutic paradigm of several cancer types. However, colorectal cancer (CRC) is one of the tumor types in which immunotherapy has proven less effective. While there is solid clinical evidence for the therapeutic role of immune checkpoint inhibitors in mismatch repair-deficient (dMMR) and in highly microsatellite instable (MSI-H) metastatic CRC (mCRC), blockade of CTLA-4 or PD-L1/PD-1 as monotherapy has not conferred any major clinical benefit to patients with MMR-proficient (pMMR) or microsatellite stable (MSS) mCRC, reflecting 95% of the CRC population. There thus remains a high unmet medical need for the development of novel immunotherapy approaches for the vast majority of patients with pMMR or MSS/MSI-low (MSI-L) mCRC. Defining the molecular mechanisms for immunogenicity in mCRC and mediating immune resistance in MSS mCRC is needed to develop predictive biomarkers and effective therapeutic combination strategies. Here we review available clinical data from combinatorial therapeutic approaches using immunotherapy-based strategies for MSS mCRC.

Secondary Immunodeficiency Related to Kidney Disease (SIDKD) - Definition, Unmet Need and Mechanisms

Kidney disease is a known risk factor for poor outcome of COVID-19 and many other serious infections. Vice versa, infection ranks second as cause of death in patients with kidney disease. However, little is known about the underlying secondary immunodeficiency related to kidney disease (SIDKD). In contrast to cardiovascular disease related to kidney disease, which has triggered countless epidemiological, clinical, and experimental research activities or interventional trials, investments in tracing, understanding, and therapeutically targeting SIDKD have been sparse. As a call for more awareness of SIDKD as an immanent unmet medical need that requires rigorous research activities at all levels, too, we review the epidemiology of SIDKD and the numerous aspects of the abnormal immunophenotype of patients with kidney disease. We propose a definition of SIDKD and discuss the pathogenic mechanisms of SIDKD known so far, including more recent insights into the unexpected immunoregulatory roles of elevated levels of FGF23 and hyperuricemia as well as shifts in the secretome of the intestinal microbiota in kidney disease. As an ultimate goal, we should aim to develop therapeutics that can reduce mortality due to infections in patients with kidney disease by normalizing host defense to pathogens and immune responses to vaccines.