Socio-ecological and pharmacy-level factors associated with buprenorphine stocking at pharmacies in New York City.

BACKGROUND: Research is lacking on community and pharmacy-level factors that are associated with stocking buprenorphine. To address these gaps, this study applied a socio-ecological framework to estimate the association between community- and pharmacy-level factors and buprenorphine stocking among a sample of pharmacies in New York City. METHODS: A telephone survey recruitment strategy was used to administer surveys to 662 pharmacies on the New York City Naloxone Standing Order Pharmacy list in 2018. The survey assessed pharmacy-level factors of private spaces to consult with pharmacists, type of pharmacy (chain/independent), size of pharmacy, having buprenorphine in stock and being open on nights and weekends. Socio-ecological variables drawn from census tract and public health data consisted of racial and ethnic composition, rates of poverty, rates of people without insurance, and rates of overdose. Mixed effects logistic regression estimated odds ratios (OR) of carrying buprenorphine in stock after adjusting for socio-ecological and pharmacy-level factors. RESULTS: Fewer than half of the pharmacies reported having buprenorphine in stock (43.81% n = 290). Logistic regression analyses indicate that several pharmacy-level factors - the number of private spaces (aOR=1.67 95% CI=1.20, 2.32 p=.002), large size of the pharmacy (aOR=1.52 95% CI=1.04, 2.22, p=.032), having naloxone in stock (aOR=1.54, 95%CI=1.03, 2.32 p=.037), as well as neighborhood-level factors of higher rates of poverty (aOR=2.07 95%CI=1.07, 4.02 p<.001) and higher rates of uninsured residents were associated with carrying buprenorphine (aOR=0.23 95%CI=0.14,.38). CONCLUSIONS: Using a socio-ecological framework, this study identified inequities in pharmacy stocking of buprenorphine by neighborhood rates of health insurance. At the pharmacy level, increasing private spaces for consultation and encouraging co-stocking of naloxone with buprenorphine stocking may reduce inequalities in buprenorphine availability.

Preventing post-surgical cardiac adhesions with a catechol-functionalized oxime hydrogel.

Post-surgical cardiac adhesions represent a significant problem during routine cardiothoracic procedures. This fibrous tissue can impair heart function and inhibit surgical access in reoperation procedures. Here, we propose a hydrogel barrier composed of oxime crosslinked poly(ethylene glycol) (PEG) with the inclusion of a catechol (Cat) group to improve retention on the heart for pericardial adhesion prevention. This three component system is comprised of aldehyde (Ald), aminooxy (AO), and Cat functionalized PEG mixed to form the final gel (Ald-AO-Cat). Ald-AO-Cat has favorable mechanical properties, degradation kinetics, and minimal swelling, as well as superior tissue retention compared to an initial Ald-AO gel formulation. We show that the material is cytocompatible, resists cell adhesion, and led to a reduction in the severity of adhesions in an in vivo rat model. We further show feasibility in a pilot porcine study. The Ald-AO-Cat hydrogel barrier may therefore serve as a promising solution for preventing post-surgical cardiac adhesions.

Socio-ecological and pharmacy-level factors associated with naloxone stocking at standing-order naloxone pharmacies in New York City.

BACKGROUND: Research on socio-ecological factors that may impede or facilitate access to naloxone in pharmacies remains limited. This study investigated associations between socio-ecological factors, pharmacy participation in the naloxone cost assistance program (NCAP), pharmacy characteristics and having naloxone in stock among pharmacies in New York City. METHODS: Phone interviews were conducted with 662 pharmacies selected from the New York City Naloxone Standing Order List. Multi-level generalized linear modeling estimated associations between neighborhood racial and ethnic composition, poverty rates, overdose fatality rates, pharmacy participation in N-CAP, having private physical spaces within the pharmacy, knowledge of where to refer people to obtain naloxone and adjusted relative risk (aRR) that the pharmacy would have naloxone in stock. RESULTS: Findings from this study supported several of the hypotheses. Greater neighborhood poverty was associated with a lower likelihood of carrying naloxone compared to neighborhoods with less poverty (aRR = .79, CI95 % = .69, .90, p < .001). Pharmacies that provided a private window for consultations (aRR = 1.34, CI95 % = 1.19, 1.51, p < .001), a private room (aRR = 1.42, CI95 % = 1.30, 1.56, p < .001), and a private area (aRR = 1.42, CI95 % = 1.30, 1.56, p < .001) were associated with a higher likelihood of carrying naloxone compared than those that did not. CONCLUSIONS: Findings from this study suggest that community-level socioeconomic marginalization is a contributor to disparities in naloxone availability among pharmacies in New York City. Findings support harm reduction interventions tailored to the built environment of pharmacies that respect privacy to those seeking naloxone.

Evidence for Mechanisms Underlying the Functional Benefits of a Myocardial Matrix Hydrogel for Post-MI Treatment.

BACKGROUND: There is increasing need for better therapies to prevent the development of heart failure after myocardial infarction (MI). An injectable hydrogel derived from decellularized porcine ventricular myocardium has been shown to halt the post-infarction progression of negative left ventricular remodeling and decline in cardiac function in both small and large animal models. OBJECTIVES: This study sought to elucidate the tissue-level mechanisms underlying the therapeutic benefits of myocardial matrix injection. METHODS: Myocardial matrix or saline was injected into infarcted myocardium 1 week after ischemia-reperfusion in Sprague-Dawley rats. Cardiac function was evaluated by magnetic resonance imaging and hemodynamic measurements at 5 weeks after injection. Whole transcriptome microarrays were performed on RNA isolated from the infarct at 3 days and 1 week after injection. Quantitative polymerase chain reaction and histologic quantification confirmed expression of key genes and their activation in altered pathways. RESULTS: Principal component analysis of the transcriptomes showed that samples collected from myocardial matrix-injected infarcts are distinct and cluster separately from saline-injected control subjects. Pathway analysis indicated that these differences are due to changes in several tissue processes that may contribute to improved cardiac healing after MI. Matrix-injected infarcted myocardium exhibits an altered inflammatory response, reduced cardiomyocyte apoptosis, enhanced infarct neovascularization, diminished cardiac hypertrophy and fibrosis, altered metabolic enzyme expression, increased cardiac transcription factor expression, and progenitor cell recruitment, along with improvements in global cardiac function and hemodynamics. CONCLUSIONS: These results indicate that the myocardial matrix alters several key pathways after MI creating a pro-regenerative environment, further demonstrating its promise as a potential post-MI therapy.

Mechanisms of cardiac protection from ischemia/reperfusion injury: a role for caveolae and caveolin-1.

Caveolae, small invaginations in the plasma membrane, contain caveolins (Cav) that scaffold signaling molecules including the tyrosine kinase Src. We tested the hypothesis that cardiac protection involves a caveolin-dependent mechanism. We used in vitro and in vivo models of ischemia-reperfusion injury, electron microscopy (EM), transgenic mice, and biochemical assays to address this hypothesis. We found that Cav-1 mRNA and protein were expressed in mouse adult cardiac myocytes (ACM). The volatile anesthetic, isoflurane, protected ACM from hypoxia-induced cell death and increased sarcolemmal caveolae. Hearts of wild-type (WT) mice showed rapid phosphorylation of Src and Cav-1 after isoflurane and ischemic preconditioning. The Src inhibitor PP2 reduced phosphorylation of Src (Y416) and Cav-1 in the heart and abolished isoflurane-induced cardiac protection in WT mice. Infarct size (percent area at risk) was reduced by isoflurane in WT (30.5+/-4 vs. 44.2+/-3, n=7, P<0.05) but not Cav-1(-/-) mice (46.6+/-5 vs. 41.7+/-3, n=7). Cav-1(-/-) mice exposed to isoflurane showed significant alterations in Src phosphorylation and recruitment of C-terminal Src kinase, a negative regulator of Src, when compared to WT mice. The results indicate that isoflurane modifies cardiac myocyte sarcolemmal membrane structure and composition and that activation of Src and phosphorylation of Cav-1 contribute to cardiac protection. Accordingly, therapies targeted to post-translational modification of Src and Cav-1 may provide a novel approach for such protection.

Role of 12-lipoxygenase in volatile anesthetic-induced delayed preconditioning in mice.

Delayed cardiac protection mediated by 12-lipoxygenase (12-LO) expression and activity has been linked to opioid receptor stimulation. The role of 12-LO in volatile anesthetic-induced delayed cardiac protection has not been determined. We tested the hypothesis that expression and activity of 12-LO mediate delayed cardiac protection induced by isoflurane in the mouse heart in vivo. Mice were pretreated with 1.4% isoflurane for 30 min and allowed to recover for 1, 12, or 24 h. Immunoblot analysis showed isoflurane significantly enhanced 12-LO protein expression at 12 and 24 h after isoflurane exposure, and this induction of 12-LO was confirmed by immunohistochemistry of whole heart sections at 24 h. The induced protein expression appeared to be localized to intercalated disc regions adjoining adjacent cardiac myocytes. Additionally, mice +/- isoflurane (24 h previously) were subjected to 30 min coronary artery occlusion followed by 2 h of reperfusion in the presence and absence of a 12-LO inhibitor. Isoflurane reduced infarct size (27.1 +/- 2.2% of the area at risk; n = 8) compared with the control group (44.6 +/- 3.6%, n = 8). Baicalein (3 mg/kg), a selective 12-LO inhibitor, blocked the delayed protective effects of isoflurane pretreatment on infarct size (40.6 +/- 3.6%, n = 8). These data suggest that 12-LO is an important mediator of isoflurane-induced delayed preconditioning.

Protection of adult rat cardiac myocytes from ischemic cell death: role of caveolar microdomains and delta-opioid receptors.

The role of caveolae, membrane microenvironments enriched in signaling molecules, in myocardial ischemia is poorly defined. In the current study, we used cardiac myocytes prepared from adult rats to test the hypothesis that opioid receptors (OR), which are capable of producing cardiac protection in vivo, promote cardiac protection in cardiac myocytes in a caveolae-dependent manner. We determined protein expression and localization of delta-OR (DOR) using coimmunohistochemistry, caveolar fractionation, and immunoprecipitations. DOR colocalized in fractions with caveolin-3 (Cav-3), a structural component of caveolae in muscle cells, and could be immunoprecipitated by a Cav-3 antibody. Immunohistochemistry confirmed plasma membrane colocalization of DOR with Cav-3. Cardiac myocytes were subjected to simulated ischemia (2 h) or an ischemic preconditioning (IPC) protocol (10 min ischemia, 30 min recovery, 2 h ischemia) in the presence and absence of methyl-beta-cyclodextrin (MbetaCD, 2 mM), which binds cholesterol and disrupts caveolae. We also assessed the cardiac protective effects of SNC-121 (SNC), a selective DOR agonist, on cardiac myocytes with or without MbetaCD and MbetaCD preloaded with cholesterol. Ischemia, simulated by mineral oil layering to inhibit gas exchange, promoted cardiac myocyte cell death (trypan blue staining), a response blunted by SNC (37 +/- 3 vs. 59 +/- 3% dead cells in the presence and absence of 1 muM SNC, respectively, P < 0.01) or by use of the IPC protocol (35 +/- 4 vs. 62 +/- 3% dead cells, P < 0.01). MbetaCD treatment, which disrupted caveolae (as detected by electron microscopy), fully attenuated the protective effects of IPC or SNC, resulting in cell death comparable to that of the ischemic group. By contrast, SNC-induced protection was not abrogated in cells incubated with cholesterol-saturated MbetaCD, which maintained caveolae structure and function. These findings suggest a key role for caveolae, perhaps through enrichment of signaling molecules, in contributing to protection of cardiac myocytes from ischemic damage.