British Journal of Clinical Pharmacology

Interest in patient adherence has increased in recent years, with a growing literature that shows the pervasiveness of poor adherence to appropriately prescribed medications. However, four decades of adherence research has not resulted in uniformity in the terminology used to describe deviations from prescribed therapies. The aim of this review was to propose a new taxonomy, in which adherence to medications is conceptualized, based on behavioural and pharmacological science, and which will support quantifiable parameters. A systematic literature review was performed using MEDLINE, EMBASE, CINAHL, the Cochrane Library and PsycINFO from database inception to 1 April 2009. The objective was to identify the different conceptual approaches to adherence research. Definitions were analyzed according to time and methodological perspectives. A taxonomic approach was subsequently derived, evaluated and discussed with international experts. More than 10 different terms describing medication‐taking behaviour were identified through the literature review, often with differing meanings. The conceptual foundation for a new, transparent taxonomy relies on three elements, which make a clear distinction between processes that describe actions through established routines (‘Adherence to medications’, ‘Management of adherence’) and the discipline that studies those processes (‘Adherence‐related sciences’). ‘Adherence to medications’ is the process by which patients take their medication as prescribed, further divided into three quantifiable phases: ‘Initiation’, ‘Implementation’ and ‘Discontinuation’. In response to the proliferation of ambiguous or unquantifiable terms in the literature on medication adherence, this research has resulted in a new conceptual foundation for a transparent taxonomy. The terms and definitions are focused on promoting consistency and quantification in terminology and methods to aid in the conduct, analysis and interpretation of scientific studies of medication adherence.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n‐3 fatty acids found in oily fish and fish oil supplements. These fatty acids are able to inhibit partly a number of aspects of inflammation including leucocyte chemotaxis, adhesion molecule expression and leucocyte‐endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n‐6 fatty acid arachidonic acid, production of inflammatory cytokines and T cell reactivity. In parallel, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonioc acid and EPA and DHA give rise to anti‐inflammatory and inflammation resolving resolvins and protectins. Mechanisms underlying the anti‐inflammatory actions of n‐3 fatty acids include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro‐inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes, activation of the anti‐inflammatory transcription factor NR1C3 (i.e. peroxisome proliferator activated receptor γ) and binding to the G protein coupled receptor GPR120. These mechanisms are interlinked. In adult humans, an EPA plus DHA intake greater than 2 g day^–1 seems to be required to elicit anti‐inflammatory actions, but few dose finding studies have been performed. Animal models demonstrate benefit from n‐3 fatty acids in rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and asthma. Clinical trials of fish oil in patients with RA demonstrate benefit supported by meta‐analyses of the data. Clinical trails of fish oil in patients with IBD and asthma are inconsistent with no overall clear evidence of efficacy.

1 A total of three hundred and nineteen new chemical entities (NCEs) were investigated in man for the first time between 1964 and 1985 by seven UK‐owned pharmaceutical companies. The majority (96.2%), were self‐originated by the UK company or one of its overseas subsidiaries. 2 There was an increase in the number of NCEs investigated each year in man, doubling from an average of 12 per year up to 1980, to over 20 per year between 1981 and 1985. The majority of first drug evaluations in human volunteers were carried out in the UK (92.2%), in contrast to evaluation of new medicines in patients, where 42.9% were first tested outside the UK. 3 The majority of NCEs evaluated in man (78%), were in four therapeutic classes: anti‐infectives (32%), anti‐allergics (22%), drugs acting on the central nervous system (13%) and cardiovascular system agents (11%). 4 By the end of 1985, 49 (15.4%) of these NCEs had been marketed in the UK and 198 (62.0%) discontinued from further development. The main reasons for termination were inappropriate pharmacokinetics in man (39.4%), and lack of clinical efficacy (29.3%). 5 Average development times increased from less than 2 years between 1964 and 1965, to around 8 years in the 1980s with a consequent reduction in the effective patent life.

Poisoning by paraquat herbicide is a major medical problem in parts of Asia while sporadic cases occur elsewhere. The very high case fatality of paraquat is due to inherent toxicity and lack of effective treatments. We conducted a systematic search for human studies that report toxicokinetics, mechanisms, clinical features, prognosis and treatment. Paraquat is rapidly but incompletely absorbed and then largely eliminated unchanged in urine within 12–24 h. Clinical features are largely due to intracellular effects. Paraquat generates reactive oxygen species which cause cellular damage via lipid peroxidation, activation of NF‐κB, mitochondrial damage and apoptosis in many organs. Kinetics of distribution into these target tissues can be described by a two‐compartment model. Paraquat is actively taken up against a concentration gradient into lung tissue leading to pneumonitis and lung fibrosis. Paraquat also causes renal and liver injury. Plasma paraquat concentrations, urine and plasma dithionite tests and clinical features provide a good guide to prognosis. Activated charcoal and Fuller's earth are routinely given to minimize further absorption. Gastric lavage should not be performed. Elimination methods such as haemodialysis and haemoperfusion are unlikely to change the clinical course. Immunosuppression with dexamethasone, cyclophosphamide and methylprednisolone is widely practised, but evidence for efficacy is very weak. Antioxidants such as acetylcysteine and salicylate might be beneficial through free radical scavenging, anti‐inflammatory and NF‐κB inhibitory actions. However, there are no published human trials. The case fatality is very high in all centres despite large variations in treatment.