Permissive Regulation: A Critical Review of the Regulatory History of Buprenorphine Formulations in Canada

Suboxone (buprenorphine-naloxone) is an opioid product approved in the US and Canada for the treatment of opioid use disorder. The drug is considered an important response to the opioid overdose epidemic with consistent calls for wider prescribing and deregulation. The history of Suboxone regulation in Canada has not been critically examined. Part of the rationale for doing so stems from the US regulatory experience, with documented irregularities, or what some have called abuses, that support profit-making by Suboxone\u27s manufacturers. This regulatory analysis allows us to determine how opportunities to address health crises through drug innovation are managed at a federal level. We used public drug and patent registries to critically examine Suboxone\u27s Canadian history. First, we investigated Suboxone\u27s entry into the Canadian market to understand how it achieved market exclusivity. Second, we examined Health Canada\u27s risk mitigation process to address extramedical use and diversion to understand the intersection of regulation and brand promotion. Insights from these two analyses were then extended to the recent approval of two related buprenorphine-containing products and their specific pathways to Canadian market exclusivity. We identified inconsistencies in Suboxone\u27s regulatory history that suggest Health Canada\u27s functions of health protection and promotion were compromised in favour of an “innovations” agenda that supports profit-making. Despite six years of market exclusivity in Canada, there was no evidence suggesting Suboxone achieved formal exclusivity (i.e., through patent or data protection). Health Canada\u27s process to address safety concerns of Suboxone were compromised by reliance on the manufacturer to carry out post-market education, allowing the manufacturer to create and market a branded “education” program for its product. Similar inconsistencies have afforded market exclusivity for two related products despite marginal innovation. These analyses reveal a case of permissive regulation, where principles of health protection are compromised by economic imperatives. Such a regulatory approach has the potential to adversely impact public health due to unnecessarily high costs for medicines deemed essential to stem a major health crisis. Alternative pharmaceutical policies are urgently needed to safely and efficiently expand treatment access for opioid use disorder

Report from the 6th International Meeting on Bone Marrow Adiposity (BMA2020)

The

ARC Newsletter May 2017

https://digitalcommons.lasalle.edu/arc_newsletter/1004/thumbnail.jp

The effects of high dose interferon-β1a on plasma microparticles: Correlation with MRI parameters

<p>Abstract</p> <p>Objectives</p> <p>We previously reported a correlation between levels of microparticles carrying CD31 (PMP ^CD31+) and disease activity in MS. However, the effects of long term (12 month) treatment with high dose, high frequency interferon-β1a (Rebif™) on plasma levels of PMP^CD31+, PMP^CD146+, and PMP^CD54+and MRI measures of disease activity have not yet been assessed.</p> <p>Methods</p> <p>During this prospective 1-year study, we used flow cytometry to measure changes in plasma microparticles (PMP) bearing CD31 (PMP^CD31+), CD146 (PMP^CD146+), and CD54/ICAM-1 (PMP^CD54+) in 16 consecutive patients with relapsing-remitting MS (RRMS) before and after 3, 6, and 12 months of subcutaneous therapy with interferon-beta1a (44 micrograms, 3X weekly). At each visit, clinical exams and expanded disability status scale (EDSS) scores were recorded.</p> <p>Results</p> <p>Plasma levels of PMP^CD31+, and PMP^CD54+were significantly reduced by treatment with IFN-β1a. PMP^CD146+appeared to decrease only at 3 months and did not persist at 6 and 12 months (p = 0.0511). In addition, the decrease in plasma levels of PMP^CD31+and PMP^CD54+levels at 12 months were associated with a significant decrease in the number and volume of contrast enhancing T1-weigthed lesions.</p> <p>Conclusion</p> <p>Our data suggest that serial measurement of plasma microparticles (PMP), particularly in the initial stages of MS (when neuro-inflammatory cascades are more intense), may serve as reliable and reproducible surrogate markers of response to IFN-β1a therapy for MS. In addition, the progressive decline in plasma levels of PMP^CD31+and PMP^CD54+further supports the concept that IFN-β1a exerts stabilizing effect on the cerebral endothelial cells during pathogenesis of MS.</p

Use of Impella Devices for Acute Cardiogenic Shock in the Perioperative Period of Cardiac Surgery

Introduction: The Impella ventricular support system is a device that can be inserted percutaneously or directly across the aortic valve to unload the left ventricle. The purpose of this study is to determine the role of Impella devices in patients with acute cardiogenic shock in the perioperative period of cardiac surgery. Methods: A retrospective single-surgeon review of 11 consecutive patients who underwent placement of Impella devices in the perioperative period of cardiac surgery was performed. Patient records were evaluated for demographics, indications for placement, and postoperative outcomes. Results: Impella devices were placed for refractory cardiogenic shock preoperatively in 6 patients, intraoperatively in 4 patients, and postoperatively as a rescue in 1 patient. Seven patients received Impella CP, 1 Impella RP, 1 Impella CP and RP, and 2 Impella 5.0. Additionally, 3 patients required preoperative venovenous extracorporeal membrane oxygenation (VV-ECMO), and 1 patient required intraoperative venoarterial extracorporeal membrane oxygenation (VA-ECMO). All Impella devices were removed 1 to 28 days after implantation. Length of stay in the intensive care unit stay ranged from 2 to 53 days (average 23.9±14.6). The 30-day and 1-year mortality were 0%. Ten of 11 patients were alive at 2 years. Also, 1 patient died 18 months after surgery from complications of coronavirus disease (Covid-19). Device-related complications included varying degrees\u3e of hemolysis in 8 patients (73%) and device malfunction in 1 patient (9%). Conclusions: The Impella ventricular support system can be combined with other mechanical support devices for additional hemodynamic support. All patients demonstrated myocardial recovery with no deaths in the perioperative period and in 1-year of follow-up. Larger studies are necessary to validate these findings

Loss of histone methyltransferase Ezh2 stimulates an osteogenic transcriptional program in chondrocytes but does not affectcartilage development

Ezh2 is a histone methyltransferase that suppresses osteoblast maturation and skeletal development. We evaluated the roleof Ezh2 in chondrocyte lineage differentiation and endochondral ossification. Ezh2 was genetically inactivated in the mesenchymal, osteoblastic, and chondrocytic lineages in mice using the Prrx1-Cre,Osx1-Cre, and Col2a1-Cre drivers, respectively. Wild-type and conditional knockout mice were phenotypically assessed by grossmorphology, histology, and micro-CT imaging. Ezh2-deficient chondrocytes in micromass culture models were evaluated usingRNA-sequencing, histologic evaluation, and western blotting. Aged mice with Ezh2 deficiency were also evaluated for prematuredevelopment of osteoarthritis using radiographic analysis. Ezh2 deficiency in murine chondrocytes reduced bone density at 4 weeks of age, although caused no other gross developmentaleffects. Knockdown of Ezh2 in chondrocyte micromass cultures resulted in a global reduction in trimethylation of histone 3lysine 27 (H3K27me3) and altered differentiation in vitro. RNA-seq analysis revealed enrichment of an osteogenic gene expressionprofile in Ezh2 deficient chondrocytes. Joint development proceeded normally in the absence of Ezh2 in chondrocytes withoutinducing excessive hypertrophy or premature osteoarthritis in vivo. In summary, loss of Ezh2 reduced H3K27me3 levels, increased expression of osteogenic genes in chondrocytes, and resulted ina transient post-natal bone phenotype. Remarkably, Ezh2 activity is dispensable for normal chondrocyte maturation and endochondralossification in vivo, even though it appears to have a critical role during early stages of mesenchymal lineage-commitment

Generalisability of vaccine effectiveness estimates: an analysis of cases included in a postlicensure evaluation of 13-valent pneumococcal conjugate vaccine in the USA

External validity, or generalisability, is the measure of how well results from a study pertain to individuals in the target population. We assessed generalisability, with respect to socioeconomic status, of estimates from a matched case–control study of 13-valent pneumococcal conjugate vaccine effectiveness for the prevention of invasive pneumococcal disease in children in the USA