Less invasive treatments for pure aortic insufficiency: Are we there yet?

The gold standard for the treatment of pure aortic insufficiency (PAI) is surgical valve repair or replacement.1 With the newest transcatheter heart valve technologies and the accumulating years of experience of heart teams with the current transcatheter aortic valve replacement (TAVR) prostheses, implanters have push the envelope with off-label use of those valves designed and approved for aortic stenosis, in patients with pure aortic insufficiency especially those at higher risks or for compassionate use.3 However, new prostheses are currently under investigation in clinical use and evidences are provided on the safety and efficacy of those latter. It will be discussed in this commentary, the actual clinical evidences and the use of transcatheter heart valves, in and off label, for the treatment of pure aortic insufficiency.

Off-Label Use of Medicines in Children Attending a Secondary Healthcare Facility in Federal Capital Territory

Before a new drug is approved for marketing in any country, it must have undergone three phases of clinical trials designed to assess its efficacy and safety when used according to an approved recommendation. After a drug has been tested and approved by the regulatory authorities, the drug is usually given a ‘label’ or ‘license’ which is a report describing the drug intended use and dosage. This study aimed at evaluating the use of medicines outside the terms stated in the label. The study was conducted using a data collection form to obtain information from patients’ case file. Data were analysed using Statistical Package for Social Sciences. The case notes of 449 patients were included in the study. The ages of the patients ranged from 4 days to 16 years. Females constituted 51.7% (232) and males 48.3% (217). A total of 1866 drugs were administered to patients, of which 469 (25.13%) were off-label prescriptions. The highest category of off-label drug was indication (45%). This study has revealed a considerable prevalence of off-label use of medicines, there is however need for proper pharmaceutical care to be emplaced in healthcare facilities so as to minimize off-label drug use and prevent adverse effect of drugs as a result of inappropriate use of medicines.

Biotechnological therapies and biosimilars for COVID-19: scarcities, poor regulation, and pharmaceutical black market: a case analysis in Ecuador

At the beginning of the COVID-19 pandemic, Ecuador was unprepared for the overwhelming number of COVID-19 cases. As the general population started to see the eff ects of the pandemic, unproven treatments and medications were sought by the population to try to ameliorate the impact of the pandemic. The growing demand for a cure, the fear of dying from COVID-19, and the lack of therapeutic rigour, pushed a signifi cant number of people to seek help outside the traditional healthcare system. Doctors, pharmacists, and patients started prescribing or selfmedicating pharmacological products that were later shown to be ineff ective, toxic or even contraindicated. In Ecuador, most people who developed the severe acute respiratory syndrome associated with infection by the coronavirus 2 (SARS-CoV-2) virus, which causes COVID-19, used antibiotics (azithromycin), antiparasitic medications (hydroxychloroquine or ivermectin), dangerous chemical products (chlorine dioxide) and in some cases, biological medicines, to try to cure or protect themselves from COVID-19. The growing demand for therapies that were unavailable, as well as the rise in misinformation, created the perfect scenario for the misuse of medicines and enabled the appearance of a rampant black market of unregistered biological products. In this manuscript, we describe the Ecuadorian experience in relation to the off -label use of biological and biosimilar products during the COVID-19 pandemic, the role of the pharmaceutical black market, and the lack of national regulations to avoid dangerous practices. To the best of our knowledge this is the fi rst report that has aimed to describe the unapproved and even illegal sale and use of biologicals, biosimilars and related products, with or without approved therapeutic indications in the treatment of COVID-19.

Switzerland’s Narcotics Regulation Jungle: Off-Label Use, Counterfoil Prescriptions, and Opioid Agonist Therapy in the French-Speaking Cantons

The word “narcotic” is often first associated with “illicit drugs”. Yet, many “narcotic” and psychotropic substances are, in fact, medicines. Controlled medicines (CM) are products that meet the legal definition of both a “narcotic” under the Swiss Narcotics Act and of a medicine under the Therapeutic Products Act. We aim to examine how similar and how different, respectively, the implementation of CM regulations is throughout French-speaking Switzerland. Based on a legal analysis of the cantonal regulations, we conducted semi-structured interviews with cantonal pharmacists and cantonal physicians. We asked them how they perceive and implement the federal legal requirements. We find that some of these requirements have fallen into disuse, notably the federal duty to notify off-label use of CM. We observe that counterfoil prescriptions in their current paper format are a veritable data graveyard in the sense that they are not actively used to monitor or supervise the market. Moreover, we detect different conditions for opioid agonist treatment authorization. Some cantons require additional physicians’ training or written commitments by the person treated. Our mapping of the CM regulation implementation can serve as a basis for cantons to review their practices.

Pharmacovigilance Data as a Trigger to Identify Antimicrobial Resistance and Inappropriate Use of Antibiotics: A Study Using Reports from The Netherlands Pharmacovigilance Centre

(1) Background: Antimicrobial resistance (AMR) requires urgent multidisciplinary solutions, and pharmacovigilance has the potential to strengthen current antimicrobial stewardship strategies. This study aimed to characterize AMR-relevant adverse drug reaction (ADR) reports submitted to The Netherlands Pharmacovigilance Centre; (2) Methods: We carried out a descriptive analysis of ADR reports submitted to Lareb, coded with AMR-relevant MedDRA Preferred Terms (PTs); (3) Results: Between 1998 and January 2019, 252 AMR-relevant ADR reports were submitted to Lareb. The most frequent antibiotics were tobramycin (n = 89; 35%), colistin (n = 30; 11.9%), cipro-floxacin (n = 16; 6.3%), doxycycline (n = 14; 5.5%), and aztreonam (n = 12; 4.8%). The PTs used included off label use (n = 91; 36.1%), drug ineffective (n = 71; 28.2%), product use in unapproved indication (n = 28; 11.1%), pathogen resistance (n = 14; 5.6%), and drug resistance (n = 13; 5.2%). 54% of the reports were on Watch antibiotics and 19% were involved in the Reserve group. In the Watch group, “off label use” and “product use in unapproved indication” were the most frequent PTs and the majority of reports on Reserve antibiotics were coded as “Off label”. A sharp increase in the number of reports was observed in the three consecutive years with 21 in 2013, 54 in 2014, and 83 in 2015; (4) Conclusions: In addition to existing AMR monitoring strategies, pharmacovigilance databases can serve as a source of data on suspected resistance and inappropriate use. Future research should explore how these AMR-relevant MedDRA Terms are used in resource-limited settings with less capacity to generate laboratory-confirmed resistance data.

SARS-CoV-2-triggered mast cell rapid degranulation induces alveolar epithelial inflammation and lung injury

SARS-CoV-2 infection-induced hyper-inflammation links to the acute lung injury and COVID-19 severity. Identifying the primary mediators that initiate the uncontrolled hypercytokinemia is essential for treatments. Mast cells (MCs) are strategically located at the mucosa and beneficially or detrimentally regulate immune inflammations. In this study, we showed that SARS-CoV-2-triggered MC degranulation initiated alveolar epithelial inflammation and lung injury. SARS-CoV-2 challenge induced MC degranulation in ACE-2 humanized mice and rhesus macaques, and a rapid MC degranulation could be recapitulated with Spike-RBD binding to ACE2 in cells; MC degranulation altered various signaling pathways in alveolar epithelial cells, particularly, the induction of pro-inflammatory factors and consequential disruption of tight junctions. Importantly, the administration of clinical MC stabilizers for blocking degranulation dampened SARS-CoV-2-induced production of pro-inflammatory factors and prevented lung injury. These findings uncover a novel mechanism for SARS-CoV-2 initiating lung inflammation, and suggest an off-label use of MC stabilizer as immunomodulators for COVID-19 treatments.