Novel drugs approved by the EMA, the FDA, and the MHRA in 2023: A year in review.

In 2023, seventy novel drugs received market authorization for the first time in either Europe (by the EMA and the MHRA) or in the United States (by the FDA). Confirming a steady recent trend, more than half of these drugs target rare diseases or intractable forms of cancer. Thirty drugs are categorized as "first-in-class" (FIC), illustrating the quality of research and innovation that drives new chemical entity discovery and development. We succinctly describe the mechanism of action of most of these FIC drugs and discuss the therapeutic areas covered, as well as the chemical category to which these drugs belong. The 2023 novel drug list also demonstrates an unabated emphasis on polypeptides (recombinant proteins and antibodies), Advanced Therapy Medicinal Products (gene and cell therapies) and RNA therapeutics, including the first-ever approval of a CRISPR-Cas9-based gene-editing cell therapy.

Guidance for the use and reporting of anaesthetic agents in BJP manuscripts involving work with animals.

Scientists who plan to publish in the British Journal of Pharmacology (BJP) should read this article before undertaking studies utilising anaesthetics in mammalian animals. This editorial identifies certain gaps in the reporting of details on the use of anaesthetics in animal research studies published in the BJP. The editorial also provides guidance, based upon current best practices, for performing in vivo experiments that require anaesthesia. In addition, mechanisms of action and physiological impact of specific anaesthetic agents are discussed. Our goal is to identify best practices and to provide guidance on the information required for manuscripts submitted to the BJP that involve the use of anaesthetic agents in studies with experimental animals.

Guiding principles for the use of knowledge bases and real-world data in clinical decision support systems: report by an international expert workshop at Karolinska Institutet.

INTRODUCTION: Technical and logical breakthroughs have provided new opportunities in medicine to use knowledge bases and large-scale clinical data (real-world) at point-of-care as part of a learning healthcare system to diminish the knowledge-practice gap. AREAS COVERED: The article is based on presentations, discussions and recommendations from an international scientific workshop. Value, research needs and funding avenues of knowledge bases and access to real-world data as well as transparency and incorporation of patient perspectives are discussed. EXPERT OPINION: Evidence-based, publicly funded, well-structured and curated knowledge bases are of global importance. They ought to be considered as a public responsibility requiring transparency and handling of conflicts of interest. Information has to be made accessible for clinical decision support systems (CDSS) for healthcare staff and patients. Access to rich and real-world data is essential for a learning health care ecosystem and can be augmented by data on patient-reported outcomes and preferences. This field can progress by the establishment of an international policy group for developing a best practice guideline on the development, maintenance, governance, evaluation principles and financing of open-source knowledge bases and handling of real-world data.

A rational roadmap for SARS-CoV-2/COVID-19 pharmacotherapeutic research and development: IUPHAR Review 29.

In this review, we identify opportunities for drug discovery in the treatment of COVID-19 and, in so doing, provide a rational roadmap whereby pharmacology and pharmacologists can mitigate against the global pandemic. We assess the scope for targeting key host and viral targets in the mid-term, by first screening these targets against drugs already licensed, an agenda for drug repurposing, which should allow rapid translation to clinical trials. A simultaneous, multi-pronged approach using conventional drug discovery methods aimed at discovering novel chemical and biological means of targeting a short list of host and viral entities which should extend the arsenal of anti-SARS-CoV-2 agents. This longer term strategy would provide a deeper pool of drug choices for future-proofing against acquired drug resistance. Second, there will be further viral threats, which will inevitably evade existing vaccines. This will require a coherent therapeutic strategy which pharmacology and pharmacologists are best placed to provide. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.

Experimental design and analysis and their reporting II: updated and simplified guidance for authors and peer reviewers.

This article updates the guidance published in 2015 for authors submitting papers to British Journal of Pharmacology (Curtis et al., 2015) and is intended to provide the rubric for peer review. Thus, it is directed towards authors, reviewers and editors. Explanations for many of the requirements were outlined previously and are not restated here. The new guidelines are intended to replace those published previously. The guidelines have been simplified for ease of understanding by authors, to make it more straightforward for peer reviewers to check compliance and to facilitate the curation of the journal's efforts to improve standards.

Effects of the cannabinoid CB1 agonist ACEA on salicylate ototoxicity, hyperacusis and tinnitus in guinea pigs.

Cannabinoids have been suggested as a therapeutic target for a variety of brain disorders. Despite the presence of their receptors throughout the auditory system, little is known about how cannabinoids affect auditory function. We sought to determine whether administration of arachidonyl-2'-chloroethylamide (ACEA), a highly-selective CB1 agonist, could attenuate a variety of auditory effects caused by prior administration of salicylate, and potentially treat tinnitus. We recorded cortical resting-state activity, auditory-evoked cortical activity and auditory brainstem responses (ABRs), from chronically-implanted awake guinea pigs, before and after salicylate + ACEA. Salicylate-induced reductions in click-evoked ABR amplitudes were smaller in the presence of ACEA, suggesting that the ototoxic effects of salicylate were less severe. ACEA also abolished salicylate-induced changes in cortical alpha band (6-10 Hz) oscillatory activity. However, salicylate-induced increases in cortical evoked activity (suggestive of the presence of hyperacusis) were still present with salicylate + ACEA. ACEA administered alone did not induce significant changes in either ABR amplitudes or oscillatory activity, but did increase cortical evoked potentials. Furthermore, in two separate groups of non-implanted animals, we found no evidence that ACEA could reverse behavioural identification of salicylate- or noise-induced tinnitus. Together, these data suggest that while ACEA may be potentially otoprotective, selective CB1 agonists are not effective in diminishing the presence of tinnitus or hyperacusis.

Isolation and epithelial co-culture of mouse renal peritubular endothelial cells.

BACKGROUND: Endothelial-mesenchymal transition (EndoMT) has been shown to be a major source of myofibroblasts, contributing to kidney fibrosis. However, in vitro study of endothelial cells often relies on culture of isolated primary endothelial cells due to the unavailability of endothelial cell lines. Our recent study suggested that peritubular endothelial cells could contribute to kidney fibrosis through EndoMT. Therefore, successful isolation and culture of mouse peritubular endothelial cells could provide a new platform for studying kidney fibrosis. This study describes an immunomagnetic separation method for the isolation of mouse renal peritubular endothelial cells using anti-CD146 MicroBeads, followed by co-culture with mouse renal proximal tubular epithelial cells to maintain endothelial phenotype. RESULTS: Flow cytometry showed that after isolation and two days of culture, about 95% of cells were positive for endothelial-specific marker CD146. The percentage of other cells, including dendritic cells (CD11c) and macrophages (F4/80), was less than 1%. Maintenance of endothelial cell phenotype required vascular endothelial growth factor (VEGF) and co-culture with mouse proximal tubular epithelial cells. CONCLUSION: In this study, we established a method for the isolation of mouse renal peritubular endothelial cells by using immunomagnetic separation with anti-CD146 MicroBeads, followed by co-culture with mouse renal proximal tubular epithelial cells to maintain phenotype.

End-stage renal disease and cardiomyopathy in children: cardiac effects of renal transplantation.

BACKGROUND: The occurrence and progression of cardiomyopathy is well known in patients with end-stage renal disease (ESRD). However, the feasibility of renal transplantation in the setting of cardiac dysfunction and the effect of renal transplantation on this progression remain poorly studied in pediatric patients. METHODS: A single-center, retrospective review of pediatric renal transplants between January 1, 2001, and December 31, 2010, was conducted. Six children with ESRD and severe systolic dysfunction underwent renal transplantation. Clinical data were collected and compared for the pretransplant, peritransplant, and posttransplant periods. RESULTS: Nutritional support, dialysis, and chronic kidney disease and heart failure therapy led to improved cardiac function before transplantation (ejection fraction 28.8%±9.6% vs. 44.4%±11.5%; fractional shortening 12.7%±5.1% vs. 23.6%±6.2%); however, normal systolic function was not achieved before transplantation in any patient. After transplantation, two patients had normalization of systolic function by hospital discharge, while the systolic function of the remaining four patients normalized during the first posttransplant year. Mean ejection fraction 1 year posttransplant was 22 units greater than before transplant. All patients experienced excellent allograft function in the peritransplant period. Mean estimated creatinine clearance 1 year posttransplant was 93.2±33.3 mL/min/1.73 m(2). CONCLUSIONS: Renal transplantation can be performed safely in children with ESRD and severe systolic dysfunction. After transplantation, systolic function continues to improve and may reach normal levels during the first posttransplant year. The presence of severe systolic dysfunction in pediatric dialysis patients should not deter referral for renal transplantation.

A technique for rapid exchange of continuous renal replacement therapy.

Re-initiation of continuous renal replacement therapy (CRRT) in neonates and young infants weighing less than 15 kg often necessitates a blood prime of the blood circuit path or a concurrent packed red blood cell (PRBC) transfusion to avoid causing hemodynamic instability due to acute hemodilution. The significant amount of time required for a routine CRRT circuit change can be associated with worsening electrolyte and acid-base abnormalities, fluid retention, greater hemodynamic instability and reducing effective hemofiltration time. In an attempt to limit the time without CRRT and to eliminate the requirement for additional blood exposure, a new technique, rapid exchange of continuous renal replacement therapy (RECRRT), was developed. Rapid exchange of continuous renal replacement therapy is a sequential technique that transfers citrated blood from one CRRT machine to another machine connected in series. The technique effectively negates the requirement for CRRT circuit path blood priming or PRBC transfusion. The amount of time without CRRT is markedly reduced by RECRRT to 2-3 min. The RECRRT technique has been utilized more than 30 times for at least 15 patients without an adverse event. RECRRT may benefit children who weigh less than 15 kg and in those patients who experience hemodynamic or clinical instability while CRRT is discontinued for only a brief period.