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/
Another set of highlights written at a time when there is still considerable uncertainty as to whether the UK will remain an EU member state. Whatever happens the BJCP will remain a journal that recruits its authors and readers from around the globe.
Anti‐IL‐7 receptor α monoclonal antibody (GSK2618960) in healthy subjects – a randomized, double‐blind, placebo‐controlled study
Joanne Ellis, Andre van Maurik, Lea Fortunato, Sophie Gisbert, Keguan Chen, Ann Schwartz, Simon McHugh, Andrew Want, Sara Santos Franco, Joao‐Joaquim Oliveira, Jeffrey Price, Alasdair Coles, Kim Brown, Donggang Su, Jenny L. Craigen, Jiansong Yang, Sara Brett, Bill Davis, Joseph Cheriyan, Onajite Kousin‐Ezewu, Frank Gray, Paul W. Thompson and Disala Fernando
Joanne Ellis and an eclectic team from all over the globe decided to eliminate IL‐7 by administering a monoclonal antibody against the alpha‐subunit (CD127) of the IL‐& receptor. This target is interesting because it is of importance for the proliferation of cytotoxic T‐cells but spares the regulatory T‐cells. Blocking the action of IL‐7 could therefore be of use in autoimmune conditions. The authors have done an excellent job in combining the pharmacokinetics of this compound with receptor occupancy in vitro and in vivo. They also studied intracellular signaling and in fact such studies more or less define the dose to be used in a subsequent clinical trial without much further dose ranging. They also established that there was a certain amount of paradoxical agonist activity, but all this is available before the interesting trials in patients with autoimmune conditions. With such excellent examples as this study we wonder why we still receive submissions of Phase I trials where there is not even an attempt to measure drug effects, even when it is well feasible.
The Developing Regorafenib Eye drops for neovascular Age‐related Macular degeneration (DREAM) study: an open‐label phase II trial
Antonia M. Joussen, Sebastian Wolf, Peter K. Kaiser, David Boyer, Thomas Schmelter, Rupert Sandbrink, Oliver Zeitz, Gesa Deeg, Annett Richter, Torsten Zimmermann, Joachim Hoechel, Ulf Buetehorn, Walter Schmitt, Brigitte Stemper and Michael K. Boettger
Neovascular age‐related macular degeneration is now treatable by intraocular injections with VEGF blockers like bevacizumab. This treatment places a large burden on patients and clinics and a local, self‐administered treatment is eagerly awaited. Regorafenib is among other things a potent small molecule VEGF blocker. Would it reach the retina from an eye drop? This appeared to be the case preclinically and a group of multinational authors, spearheaded by Antonia Joussen from Berlin, undertook a multicenter study in patients, which they (perhaps with some foresight) named the DREAM study. Although the team did an exemplary job in demonstrating that they probably administered the correct dose, there was no effect on vision. Rescue with an intraocular preparation of a regular VEGF inhibitor did the trick, so the patients were potentially treatable. Consequently this dream did not come true, but it was a very well performed piece of complicated clinical science and sets an example of how to do this for the next compound that comes along.
The role of vascular endothelium in nitroglycerin‐mediated vasodilation
Kangbin Zhou and John D. Parker
Just when you thought nothing new could be reported about glyceryl trinitrate (GTN), there appear Kangbin Zhou and John Parker from Toronto with a moderately explosive piece of human vascular pharmacology. The model they used was intraarterial infusion of agonists and antagonists with measurement of the flow in the forearm by venous occusion plethysmography. Basically you measure how the arm circumference increases when you block venous outflow as a measure of inflow of blood. With a beautiful series of experiments they demonstrate that the GTN vasodilation is largely endothelium independent.
Efficacy of DPP‐4 inhibitors, GLP‐1 analogues, and SGLT2 inhibitors as add‐ons to metformin monotherapy in T2DM patients: a model‐based meta‐analysis
Hiroyuki Inoue, Yoko Tamaki, Yushi Kashihara, Shota Muraki, Makoto Kakara, Takeshi Hirota and Ichiro Ieiri
Meta‐analysis is normally a fairly standard affair in which studies are collected and responses amalgamated. Hiroyuki Inoue and his colleagues from Fukuoka in Japan performed a model based meta‐analysis in which they modelled the response of different modern antidiabetic drugs used in diabetic patients inadequately controlled with metformin. This advanced technique, which alone it is good to learn more about, allowed them more extensive conclusions than from the traditional meta‐analysis.
Thrombotic microangiopathy associated with gemcitabine use: Presentation and outcome in a national French retrospective cohort
Florence Daviet, Franck Rouby, Pascale Poullin, Julie Moussi‐Francès, Marion Sallée, Stéphane Burtey, Julien Mancini, Florence Duffaud, Renaud Sabatier, Bertrand Pourroy, Aurélie Grandvuillemin, Steven Grange, Véronique Frémeaux‐Bacchi, Paul Coppo, Joëlle Micallef and Noémie Jourde‐Chiche
Thrombotic microangiopathy in the kidney is a rare side effect of treatment with gemcitabine and is particularly distressing, as the drug is often used to treat serious forms of cancer. A potentially reduced lifespan is not improved by the need for dialysis. Florence Daviet, a nephrologist from Aix, and colleagues studied all cases referred to the French Pharmacovigilance network and other sources. They report useful figures about treatment indications and the outcome of this disastrous side effect in 120 patients. Remission did occur in 40% of patients and plasma exchange did not improve the prognosis (but increased the adverse events). The TMA appears to be entirely caused by endothelial damage and complement abnormalities do not appear to play a role.
A clinical trial on the acute effects of methadone and buprenorphine on actual driving and cognitive function of healthy volunteers
Maren Cecilie Strand, Vigdis Vindenes, Hallvard Gjerde, Jørg Gustav Mørland and Johannes G. Ramaekers
The effect of medicines on driving are difficult to measure. After all the most relevant outcome is accidents and one can hardly imagine a trial that would demonstrate an effect (or absence of an effect) on accident rates. Studies in the psychopharmacological laboratory may be yielding sensitive results but the relevance of these tests to real driving (including driving simulator tests) is still being studied. On‐road instrumented cars can measure the amount of lateral position as the driver loses the ability to drive straight when for instance being drunk, as every policeman knows. The amount of instability is expressed as the standard deviation of the lateral position (relative to the white line on the side of the motorway). This research team tested buprenorphine and methadone and found little effect on this aspect of driving other than after buprenorphine 0.4 mg, for which they also found effects on a psychomotor test battery. But the test battery also showed effects of the other opioids. Therefore the conclusion may be that the effect of these treatments is mild, at least in healthy people who do not normally receive them. It may also be that the tests used are less sensitive than hoped, because some of the subjects felt they were unable to drive and discontinued because of sleepiness after taking the opiods. Better to take public transport when you are on such drugs, unless you are driving the public transport.
Issue highlights. Br J Clin Pharmacol. 2019;85:283–284. 10.1111/bcp.13854