AimsTherapeutic inertia, defined as the failure to initiate or intensify therapy in a timely manner according to evidence‐based clinical guidelines, is a key reason for uncontrolled hyperglycaemia in patients with type 2 diabetes. The aims of this systematic review were to identify how therapeutic inertia in the management of hyperglycaemia was measured and to assess its extent over the past decade.Materials and MethodsSystematic searches for articles published from January 1, 2004 to August 1, 2016 were conducted in MEDLINE and Embase. Two researchers independently screened all of the titles and abstracts, and the full texts of publications deemed relevant. Data were extracted by a single researcher using a standardized data extraction form.ResultsThe final selection for the review included 53 articles. Measurements used to assess therapeutic inertia varied across studies, making comparisons difficult. Data from low‐ to middle‐income countries were scarce. In most studies, the median time to treatment intensification after a glycated haemoglobin (HbA1c) measurement above target was more than 1 year (range 0.3 to >7.2 years). Therapeutic inertia increased as the number of antidiabetic drugs rose and decreased with increasing HbA1c levels. Data were mainly available from Western countries. Diversity of inertia measures precluded meta‐analysis.ConclusionsTherapeutic inertia in the management of hyperglycaemia in patients with type 2 diabetes is a major concern. This is well documented in Western countries, but corresponding data are urgently needed in low‐ and middle‐income countries, in view of their high prevalence of type 2 diabetes.

The therapeutic and toxic effects of drugs are often generated through effects on distinct cell types in the body. Selective delivery of drugs to specific cells or cell lineages would, therefore, have major advantages, in particular, the potential to significantly improve the therapeutic window of an agent. Cells of the monocyte-macrophage lineage represent an important target for many therapeutic agents because of their central involvement in a wide range of diseases including inflammation, cancer, atherosclerosis, and diabetes. We have developed a versatile chemistry platform that is designed to enhance the potency and delivery of small-molecule drugs to intracellular molecular targets. One facet of the technology involves the selective delivery of drugs to cells of the monocyte-macrophage lineage, using the intracellular carboxylesterase, human carboxylesterase-1 (hCE-1), which is expressed predominantly in these cells. Here, we demonstrate selective delivery of many types of intracellularly targeted small molecules to monocytes and macrophages by attaching a small esterase-sensitive chemical motif (ESM) that is selectively hydrolyzed within these cells to a charged, pharmacologically active drug. ESM versions of histone deacetylase (HDAC) inhibitors, for example, are extremely potent anticytokine and antiarthritic agents with a wider therapeutic window than conventional HDAC inhibitors. In human blood, effects on monocytes (hCE-1-positive) are seen at concentrations 1000-fold lower than those that affect other cell types (hCE-1-negative). Chemical conjugates of this type, by limiting effects on other cells, could find widespread applicability in the treatment of human diseases where monocyte-macrophages play a key role in disease pathology.

The copper-catalysed zinc phosphonate chemistry described by Yokomatsu and Shibuya can be used to enter the classical organometallic coupling repertoire via Stille and Suzuki–Miyaura couplings. 1,4-Diiodobenzene underwent coupling with the organozinc reagent derived from diethyl bromodifluoromethylphosphonate with copper(I) catalysis to afford diethyl (4-iodophenyl)difluoromethylphosphonate. Higher yielding couplings were run with (4-trifluoromethylsulfonyloxy)- and (4-nonafluorobutylsulfonyloxy)-iodobenzenes. The iodide and the triflate coupled under palladium-catalysed conditions with a range of stannanes and boronic acids in moderate to excellent yields. Shibuya–Yokomatsu couplings were also successful with more functionalised iodoarenes and heteroarenes presenting the important phosphate mimic on a range of scaffolds

This version is available at https://strathprints.strath.ac.uk/38952/ Strathprints is designed to allow users to access the research output of the University of Strathclyde. Unless otherwise explicitly stated on the manuscript, Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Please check the manuscript for details of any other licences that may have been applied. You may not engage in further distribution of the material for any profitmaking activities or any commercial gain. You may freely distribute both the url (https://strathprints.strath.ac.uk/) and the content of this paper for research or private study, educational, or not-for-profit purposes without prior permission or charge.Any correspondence concerning this service should be sent to the Building block methodology from trifluoroethanol and ringclosing metathesis using a Fürstner modification of Grubbs' conditions allows the rapid synthesis of novel difluorinated cyclooctenones.Difluoroketones are well known for their propensity to undergo the addition of even weak nucleophiles. 1 This behaviour has been exploited by the medicinal chemists for the design and synthesis of protease inhibitors 2 in which the hydrates (or adducts with active site nucleophiles such as serine hydroxy groups) mimic the tetrahedral intermediates traversed in peptide bond cleavage, or the transition states that lead to them. 3 Well established routes allow acyclic difluoroketones to be synthesised 4 but cyclic species are far less common. With the exception of Tius' concise Nazarov route to difluorocyclopentenones, 5 and Portella's intramolecular aldol chemistry entered via Ruppert's reagent, 6 there are few rational methods. We applied the oxy-Cope rearrangement to synthesise cyclodecenones with a highly variable fluorination pattern 7 but we believe this is the only example of a rational route to medium ring fluoroketones. We noted that the ring-closing metathesis 8 appeared to offer access to the eight-membered carbocyclic framework 9 (still a relatively difficult pattern and of increasing interest in carbohydrate mimesis 10 ) and set about exploring the utility of the RCM transformation for the synthesis of a class of novel cyclic fluoroketones.We intercepted the metallated difluoroenol acetal 1 derived from trifluoroethanol 11 with commercial aldehyde 2 and obtained the difluoroallylic alcohol 3 in good (90%) yield after Kugelrohr distillation (Scheme 1). Allylation under phase transfer conditions (91%) followed by [2,3]-Wittig rearrangement 12 afforded ether 4 in moderate but acceptable yield (55%). The hydroxyketone 5 was unmasked (SOCl 2 -MeOH, 65%) 13 and subjected to RCM under standard Grubbs' conditions, returning starting material only. We reduced the hydroxyketone under the Ishihara conditions, 14 obtaining a diastereoisomeric mixture of diols 6 with surprisingly low selectivity. Again the mixture failed to undergo RCM (perhaps because the catalyst decomposes in situ rapidly when two nucl...

Poor adherence to statins increases cardiovascular disease risk. We systematically identified 32 controlled studies that assessed patient-centered interventions designed to improve statin adherence. The limited number of studies and variation in study characteristics precluded strict quality criteria or meta-analysis. Cognitive education or behavioural counselling delivered face-to-face multiple times consistently improved statin adherence compared with control groups (7/8 and 3/3 studies, respectively). None of four studies using medication reminders and/or adherence feedback alone reported significantly improved statin adherence. Single interventions that improved statin adherence but were not conducted face-to-face included cognitive education in the form of genetic test results (two studies) and cognitive education via a website (one study). Similar mean adherence measures were reported for 17 intervention arms and were thus compared in a sub-analysis: 8 showed significantly improved statin adherence, but effect sizes were modest (+7 to +22 % points). In three of these studies, statin adherence improved despite already being high in the control group (82–89 vs. 57–69 % in the other studies). These three studies were the only studies in this sub-analysis to include cognitive education delivered face-to-face multiple times (plus other interventions). In summary, the most consistently effective interventions for improving adherence to statins have modest effects and are resource-intensive. Research is needed to determine whether modern communications, particularly mobile health platforms (recently shown to improve medication adherence in other chronic diseases), can replicate or even enhance the successful elements of these interventions while using less time and fewer resources.Electronic supplementary materialThe online version of this article (doi:10.1007/s40265-016-0640-x) contains supplementary material, which is available to authorized users.