Figures from the Editor's selected issue highlights will be displayed each month in the journal image carousel on the BJCP homepage http://bpspubs.onlinelibrary.wiley.com/hub/journal/10.1111/(ISSN)1365‐2125/
The British Journal of Clinical Pharmacology is published by the British Pharmacological Society. In December, the Society held its annual scientific conference, Pharmacology 2019. The meeting, this year in the beautiful city of Edinburgh, was a major success and the editorial board of BJCP would hereby like to thank the organizers for such a wonderful event.
2020 is off to a rocky start, to say the least, and it is promising to be a bumpy ride in a rapidly changing climate. We therefore need good and affordable medicines, now more than ever, and we need to use them as well as possible. It will be BJCP's pleasure to help with both.
Nulelìntàm èli Paèkw
Serge Cremers
In his welcome Editorial, our new Editor‐in‐Chief pays tribute and looks back on the journal's accomplishments during his predecessor's tenure. He also addresses the potential challenges and opportunities for the journal in the near and distant future. Diversity will be a major priority for BJCP and over the next few years, we hope to see a considerable change in the composition of the various editorial boards, authors, readers as well as content of the journal. BJCP will be more diverse than ever. To some extent the journal is already diverse, which is nicely illustrated by the various contributions to this current issue. They really come from all over the world!
Drug and therapeutics committees as guardians of safe and rational medicines use
Reecha Sofat, Serge Cremers and R.E. Ferner
In this issue's second editorial, Reecha Sofat and Robin Ferner from London and Birmingham, in the UK, introduce a new series that BJCP will be publishing during the next few years. This most interesting series consists of review and original papers related to the activities of Drugs and Therapeutics Committees (DTCs), participation in which is one of the key‐jobs of any clinical pharmacologist. While the first few papers will be somewhat UK‐centric, the series is open to contributions from committees all over the world.
A novel approach to support implementation of biosimilars within a UK tertiary hospital
Katherine Saxby, Sonali Sanghvi, Pritesh N. Bodalia, Robin E. Ferner, Maria Leandro, Robert Urquhart and Reecha Sofat
The first paper in the DTC series comes from University College London and focuses on switching expensive biologicals (monoclonal antibodies) to less expensive biosimilars. Saxby et al. describe the process that has been undertaken to manage switching to biosimilars within the NHS England 12‐month target at University College London Hospital NHS Foundation Trust (UCLH), a task taken on by the DTC at UCLH. The process is quite successful, to say the least, and clearly demonstrates that DTCs can help to optimize pharmacotherapy while reducing costs.
Hesperidin supplementation has no effect on blood glucose control: A systematic review and meta‐analysis of randomized controlled clinical trials
Shamim Shams‐Rad, Mohammad Mohammadi, Nahid Ramezani‐Jolfaie, Sadegh Zarei, Mohammadali Mohsenpour and Amin Salehi‐Abargouei
Preclinical studies have demonstrated a beneficial effect of the flavonoid hesperidin, a component of many citrus fruits including oranges, lemons, and grapefruits. Study results in humans have been controversial though, which led Shamim Shams‐Rad et al. from Iran to pull all placebo‐controlled studies published in this area and perform a meta‐analysis. The investigators conclude that the data available in the literature does not seem to support a beneficial role of hesperidin on glycaemic control, though there is a need for more high‐quality, longer, randomized controlled trials to further investigate this, especially in patients with type 2 diabetes mellitus.
I am looking at three tangerines which are lying in front of me on my desk. I think I'll take one now …
Impact of the pharmacist‐led intervention on the control of medical cardiovascular risk factors for the primary prevention of cardiovascular disease in general practice: A systematic review and meta‐analysis of randomised controlled trials
Abdullah A. Alshehri, Zahraa Jalal, Ejaz Cheema, M. Sayeed Haque, Duncan Jenkins and Asma Yahyouche
We all know the good and hard work that pharmacists around the world do. Pharmacists play an increasingly important and leading role in optimizing pharmacotherapy of individual patients, but studies investigating the exact benefits of pharmacist interventions are sometimes convoluted. Abdulah Alsherih et al. from Birmingham, in the UK, and Taif, in Saudi Arabia, decided to study pharmacist‐led interventions by exploring the literature on the subject and conducting a meta‐analysis, but limited their studies to pharmacists in general practice and interventions related to primary prevention of cardiovascular disease. Their most important findings suggest that pharmacist‐led interventions in general practice can significantly mitigate risk factors for cardiovascular disease, as well as improve adherence, and are cost‐effective.
I guess we already knew that pharmacists are important players in the management of patients with hypertension, diabetes and dyslipidaemia, but now we also have some data that suggest that their work might improve surrogate parameters of clinical outcome. Next step will hopefully be studies with hard outcomes.
Effectiveness of medication review on the number of drug‐related problems in patients visiting the outpatient cardiology clinic: A randomized controlled trial
Victor Johan Bernard Huiskes, Cornelia Helena Maria van den Ende, Martine Kruijtbosch, Hendrik Tinus Ensing, Marieke Meijs, Veronique Maria Mathea Meijs, David Marinus Burger and Bartholomeus Johannes Fredericus van den Bemt
This issue of BJCP also contains an original study related to pharmacist‐led interventions for cardiovascular diseases. Huiskes et al. from The Netherlands performed a randomized controlled trial, and their findings suggest that a pharmacist‐led medication review of inpatients with a scheduled visit to an outpatient cardiology clinic decreases the number of Drug Related Problems.
Impact of pharmaceutical care on the quality of life of patients with heart failure due to chronic Chagas disease: Randomized clinical trial
Mayara da Costa Chambela, Mauro Felippe Felix Mediano, Fernanda Martins Carneiro, Roberto Rodrigues Ferreira, Mariana Caldas Waghabi, Verônica Gonçalves Mendes, Luciano de Souza Oliveira, Marcelo Teixeira de Holanda, Andréa Silvestre de Sousa, Andréa Rodrigues da Costa, Sérgio Salles Xavier, Gilberto Marcelo Sperandio da Silva and Roberto Magalhães Saraiva
Our world is changing. And thanks to migration and climate change the so‐called western countries on the northern hemisphere are more frequently faced with tropical diseases previously primarily observed in other countries. One of these diseases is Chagas disease (ChD), which is caused by an infection with Trypanosoma Cruzi. One of its complications is chronic chagasic cardiomyopathy, which is characterized by heart failure (HF). Treatment of this specific form of HF can be quite challenging and there is room for improvement. Mayara da Costa Chambela and her colleagues from Rio de Janeiro in Brazil decided to take on this challenge by conducting a randomized controlled trial in 81 patients that investigated the effect of pharmaceutical care. Their important findings demonstrate that pharmaceutical care delivered by pharmacists leads to improved quality of life and less drug related problems, which may be related to the demonstrated improved adherence to medication. The authors would like to see pharmaceutical care implemented for all patient with chronic chagasic cardiomyopathy, and I am sure many of you will agree. They also call for a larger clinical study that looks into the effects of pharmaceutical care on survival.
Investigating the clinical factors and comedications associated with circulating levels of atorvastatin and its major metabolites in secondary prevention
Richard M. Turner, Vanessa Fontana, Richard FitzGerald, Andrew P. Morris and Munir Pirmohamed
Statins are one of the most prescribed drugs in the world and are most effective in the primary and secondary prevention of cardiovascular events. The downside of these drugs are their side effects, one of which, rhabdomyolysis, can be very serious. Anticipating a role of systemic exposure to statins themselves, or their metabolites, Richard Turner and colleagues from Liverpool, in the UK, determined serum trough concentrations of atorvastatin and its metabolites in 571 patients from the Pharmacogenetics of Acute Coronary Syndrome (PhACS) study. They were able to identify multiple factors that determined the levels of the drug and its metabolites, including demographics, co‐medication and co‐morbidities. Interestingly, the influence of proton pump inhibitors on atorvastatin levels was demonstrated to be contingent on CYP2C19 status. This study paves the way to a better understanding of statin‐induced rhabdomyolysis. Let's hope we will see correlations with outcome parameters soon also.
Hydroxychloroquine may be beneficial in preeclampsia and recurrent miscarriage
Claire de Moreuil, Zarrin Alavi and Elisabeth Pasquier
Initially used as an anti‐malarial agent, hydroxychloroquine's anti‐inflammatory and immunomodulatory effects have given the drug a place in the treatment of various auto‐immune diseases such as rheumatoid arthritis and systemic lupus erythematosus. In a most interesting review paper, Claire de Moreuil and colleagues from Brest, in France, discuss the various mechanism of actions that hydroxychloroquine has along with the pathophysiology of two life‐threatening and deadly conditions, pre‐eclempsia and recurrent miscarriages. The authors align mechanisms of action and pathophysiology and elegantly explain why there are currently five clinical studies ongoing that investigate the effect of hydroxychloroquine in preventing preeclampsia and recurrent miscarriage. Hopefully these studies confirm some of the retrospective data that indeed suggest that the drug has a beneficial effect.
Lidocaine as treatment for neonatal seizures: Evaluation of previously developed population pharmacokinetic models and dosing regimen
Laurent M.A. Favié, Alwin D.R. Huitema, Marcel P.H. van den Broek, Carin M.A. Rademaker, Timo R. de Haan, Henrica L.M. van Straaten, Sinno H.P. Simons, Monique Rijken, Debbie H.G.M. Nuytemans, Toine C.G. Egberts, Floris Groenendaal, on behalf of the PharmaCool study group
For the record, I do not mean Marks and Spencer, although some funding from them for neonatal clinical pharmacology research would of course also be very powerful. No, with M&S I am referring to modelling and simulation. Combining serum concentration, efficacy and safety data from two clinical studies and data from patient care, Laurent Favië et al. from Utrecht, The Netherlands, on behalf of the PharmaCool (!) study group, were able to describe the pharmacokinetics (PK) of lidocaine in neonates, together with several factors that alter the drug's PK, which is known to vary and change rapidly in this most vulnerable group of patients. Using the derived model, they were able to simulate and validate lidocaine serum concentrations and thereby derive an optimized dose regimen for the treatment of seizures. With the developed dosing regimen, lidocaine can be a safe and effective add‐on anticonvulsant in preterm and term neonates with and without therapeutic hypothermia.
The association of the optimal bolus of dexmedetomidine with its favourable haemodynamic outcomes in adult surgical patients under general anaesthesia
Cheng‐yu Wang, Fang Chen, Junzheng Wu, Shu‐ying Fu, Xi‐mou Xu, Jia Chen, Yi‐fei Jiang, Qingquan Lian and Hua‐cheng Liu
The specific alpha‐2‐agonist Dexmedetomidine (DEX) can mitigate haemodynamic side effects from surgery and anaesthesia such as hypertension and bradycardia. However, most clinical studies have been performed using a 10‐minute infusion schedule, which can be challenging in a busy operating room. Cheng‐yu Wang et al. from Zhejiang, in China, therefore performed a dose‐finding study using a bolus dose of DEX in 42 adult patients undergoing an elective thyroidectomy. This study with a rather specific design, enabled the investigators to derive the ED50 for an intravenous bolus dose, which in this case means the dose level at which 50% of patients have a favourable haemodynamic response. This study is a first step toward an easier use of DEX in the future.
Using GRADE methodology to assess innovation of new medicinal products in Italy
Filomena Fortinguerra, Giovanni Tafuri, Francesco Trotta and Antonio Addis
Truly innovative new drugs are sometimes rightfully allowed accelerated and conditional approval. The process used by regulatory agencies to determine if a drug warrants such approval, as well as whether drugs should be reimbursed, should be transparent. Filomena Fortinguerra and colleagues from Rome, Italy, describe the methodology used by the Italian Medicine Agency (Agenzia Italiana del Farmaco, IAFA) to reach such conclusions, which was updated in 2017 to make the then sub‐optimally functioning algorithm in use since 2007 more user‐friendly and transparent. Essential, part of the new AIFA criteria is the use of the GRADE methodology to evaluate the quality of evidence within a process of drug innovativeness assessment. The authors, mostly AIFA employees, describe their 2‐year experience with the new system during which 37 full reports were delivered. They conclude that the new AIFA system resulted in a much more flexible and transparent model to define and assess what constitutes a therapeutic innovation.
Food and Drug Administration vs European Medicines Agency: Review times and clinical evidence on novel drugs at the time of approval
Roberta Joppi, Vittorio Bertele, Tommaso Vannini Silvio Garattini and Rita Banzi
Another report from Italy describes the differences between the American Food and Drugs Agency (FDA) and the European Medicines Evaluation Agency (EMA) in terms of expedited review procedures for new drugs. As expected, there are some differences and the short report by Roberta Joppi and colleagues is therefore a nice read.
Adverse events following cannabis for medical use in Tuscany: An analysis of the Italian Phytovigilance database
Giada Crescioli, Niccolò Lombardi, Alessandra Bettiol, Francesca Menniti‐Ippolito, Roberto Da Cas, Maria Parrilli, Martina Del Lungo, Eugenia Gallo, Alessandro Mugelli, Valentina Maggini, Fabio Firenzuoli and Alfredo Vannacci
The third interesting paper from Italy reports on spontaneously reported adverse events (AEs) from medicinal marijuana in Tuscany, from the Italian Phytovigilance database.
Last year I was in Denver, CO, attending a meeting. In the cab from the airport to my hotel, I saw a promotional video for Denver as marijuana capital of the US with a happy visiting couple ready to smoke some pot for a few days, giving a whole new meaning to Denver's denomination as the Mile High City. Even for someone who grew up in The Netherlands that was a bit too much. Italy recognized medical use of cannabis in 2006, when authorizing import of medicinal cannabis from The Netherlands. Since 2016, it is also produced under GMP conditions in Italy itself, in Florence. Its medical use is restricted to various magistral preparations and it is authorised and reimbursed for selected medical conditions. The paper reports on AEs reported between 2006 and 2018. A total number of 103 suspected AEs were reported, 53 of which were reported by healthcare professionals in a manner that allowed a thorough evaluation. The vast majority of AEs were mild and transient. While personally not the biggest fan of medical or recreational marijuana, I think this is good news and an important report as this real world data adds to our growing knowledge on safe medical use of marijuana. It also adds nicely to our previous Themed Issue on Cannabis (BJCP, Volume 84, Issue 11).
Risk factors associated with biochemically detected and hospitalised acute kidney injury in patients prescribed renin angiotensin system inhibitors
Patrick B. Mark, Richard Papworth, Nitish Ramparsad, Laurie A. Tomlinson, Simon Sawhney, Corri Black, Alex McConnachie and Colin McCowan
Angiotensin converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are used successfully in various cardiovascular diseases characterized by renal complications. Unfortunately, the use of these drugs may also be associated with acute kidney injury (AKI). However, the risk for AKI from these drugs is not well described. Using data from the NHS greater Glasgow and Clyde ‘safe haven’, a secure environment whereby health data from different sources on approximately 1.2 million patients can be linked together and made available in de‐identified form for analysis, Patrick Mark and colleagues from Glasgow, London and Aberdeen, in the UK, were able to investigate the risk of acute kidney injury (AKI) in patients on ACE‐inhibitors (ACEis) or angiotensin‐receptor blockers (ARBs). The authors conclude from their analysis of medical, biochemical and prescription data from over 60,000 patients on ACEis or ARBs that, in addition to several factors, the highest risk for AKI in patients on ACEi or ARBs is associated with the very populations for which there is strong evidence‐based indications for their prescription. Worthwhile mentioning also is that socio‐economic status was identified as an often under‐reported risk factor for AKI from these agents. While seemingly slightly confusing for non‐cardiologists and non‐cardiovascular clinical pharmacologists, this most important study no doubt contributes substantially to a better use of these drugs, thereby improving patient care.
Raltegravir pharmacokinetics before and during treatment with ombitasvir, paritaprevir/ritonavir plus dasabuvir in adults with human immunodeficiency virus‐1 and hepatitis C virus coinfection: AIDS Clinical Trials Group sub‐study A5334s
Charles S. Venuto, Yoninah S. Cramer, Susan L. Rosenkranz, Mark Sulkowski, David L. Wyles, Daniel E. Cohen Jeffrey Schmidt, Beverly L. Alston‐Smith and Gene D. Morse
There are many patients co‐infected with Human Immunodeficiency virus‐1 (HIV‐1) and Hepatitis C virus (HCV); treatment poses a challenge since some of the drugs used for these indications share metabolic pathways and drug–drug interactions can be expected. Charles Venuto and colleagues from Rochester, Boston, Baltimore, Denver, Chicago and Buffalo, in the US, addressed this challenge by conducting a drug–drug interaction study in a subset of the AIDS Clinical Trials Group study A5334. Their study showed that HIV‐ and HCV‐medication had an opposite effect in patients when compared with healthy volunteers. During coadministration of raltegravir with ombitasvir, paritaprevir/ritonavir plus dasabuvir (OBV/PTV/r + DSV) in people with HIV and HCV coinfection, a decrease rather than in increase in raltegravir exposure was observed in the majority of participants. Plus, raltegravir PK were higher in participants than previously described in patients living with HIV. Although the changes were not considered clinically significant and effects varied widely, this study does nicely demonstrate that pharmacokinetics and drug–drug interactions can differ between patients, patients and healthy volunteers. I would be most interested in some additional clinical and translational studies, looking both into the mechanism of this influence as well as perhaps biomarkers to identify those patients in which the effects are most pronounced.
A case–control study to assess the ability of the thymine challenge test to predict patients with severe to life threatening fluoropyrimidine‐induced gastrointestinal toxicity
Nuala A. Helsby, John Duley, Kathryn E. Burns, Claire Bonnet, Soo Hee Jeong, Elliott Brenman, Paula Barlow, Katrina Sharples, David Porter and Michael Findlay
Sequencing of the Dehydropyrimidine dehydrogenase (DPYD) gene can be used to identify patients with decreased enzyme activity and thereby those patients who are at increased risk for gastrointestinal side effects from capecitabine or 5‐Fluorouracil therapy. Unfortunately, though, DPYD genotyping has low sensitivity and phenotyping can also identify those patients at increased risk for these potentially lethal side effects. While determining the ratio of basal plasma uracil to its metabolite dihydrouracil has been shown helpful, this test is limited due to varying endogenous uracil concentrations. Nuala Helsby and colleagues from Auckland, NZ, have developed an oral Thymine challenge test with non‐invasive urine sampling instead that might perform better. The current study compared the result of this test between cancer patients who did and did not have side effects from capecitabine and 5‐FU therapy. The authors were able to show that the test can distinguish between those with side effects and those without, provided the test results were corrected for renal function. These results lay the foundation for a larger prospective study that might, hopefully, provide definitive evidence for the use of the oral Thymine challenge to test for tolerance of standard doses of fluoropyrimidine drugs.
High‐risk medicines associated with clinically relevant medication‐related problems in UK hospitals: A prospective observational study
Cathy Geeson, Li Wei and Bryony Dean Franklin
One of the short reports in this issue discusses the results of a prospective observational study to establish associations between the use of high‐risk medicine groups and occurrence of at least one moderate or severe preventable medication‐related problem. Cathy Geeson and colleagues from Luton and London, in the UK, were able to conclude that identification of high‐risk medicine groups has the potential to permit targeting of patients at highest risk of avoidable medication‐related harm. However, multivariate analysis of their data from 1503 admissions in two UK hospitals also suggests that risk is likely to be multifactorial.
Pharmacokinetics of intravenous and inhaled salbutamol and tobramycin: An exploratory study to investigate the potential of exhaled breath condensate as a matrix for pharmacokinetic analysis
Matthijs D. Kruizinga, Willem A.J. Birkhoff, Michiel J. van Esdonk, Naomi B. Klarenbeek Tomasz Cholewinski, Tessa Nelemans, Melloney J. Dröge, Adam F. Cohen and Rob G.J.A. Zuiker
Publication bias makes the world seem nicer than it really is. Publication of negative data makes the world more realistic, may save us all a lot of time, and is therefore welcomed by the journal, even though these papers tend to be cited less frequently. Negative papers in clinical journals usually refer to lack of effect on outcome parameters. The final paper in this issue of BJCP is a short report from Leiden, The Netherlands, and is a negative clinical pharmacokinetics study. Matthijs Kruizinga and colleagues set out to test exhaled breath condensate (EBC) for the study of pharmacokinetics of drugs by measuring salbutamol and tobramycin in this matrix. The drugs were not detectable in EBC after intravenous administrations and a very large variability in the concentrations of these drugs in EBC was observed after inhalation. The authors conclude from this data that EBC may not be a good matrix to study the pharmacokinetics of these two drugs, which is most useful to know and could have implications far beyond the use of these two drugs.
Issue highlights 86–01. Br J Clin Pharmacol. 2020;86:3–7. 10.1111/bcp.14220