AimsMizoribine is an oral immunosuppressive agent approved in several countries for prevention of rejection in renal transplantation. Its therapeutic window is based on trough concentrations staying at Ն0.5 but <3 mg ml -1 . It has been postulated that as renal function returns to normal, higher doses may be needed to maintain efficacy than the current clinical dosage of 2-5 mg kg -1 day -1 . The safety, tolerability and pharmacokinetics from two clinical trials of higher-dose mizoribine treatments in healthy male volunteers are presented. MethodsForty-eight healthy White male nonsmokers participated in two randomized, doubleblind, placebo-controlled trials: 32 in a single-dose study (3, 6, 9 and 12 mg kg -1 ) and 16 in a multiple-dose study [6 mg kg -1 day -1 once daily for 5 days or twice daily (12 mg kg -1 day -1 ) for 7 days]. Standard assessments of safety, tolerability and pharmacokinetics were performed. ResultsThe safety profiles of both studies were generally unremarkable, except for elevated serum uric acid concentrations at the highest dose (12 mg kg -1 day -1 ) in the multipledose study. Orally administered mizoribine reached peak concentrations within 2-3 h and was eliminated mostly via the kidney (65-100% of dose) with a 3-h half-life. Only the 12 mg kg -1 day -1 group achieved trough concentrations that were within the therapeutic window. ConclusionsBased on the favourable safety profile and current pharmacokinetic information, a new starting dose in the 6-12 mg kg -1 day -1 range is recommended in the up to 3 months acute phase following transplantation, with dose reduction recommended only if the function of the transplanted kidney is impaired.

BackgroundEarly biomarkers of skeletal muscle anabolism will facilitate the development of therapies for sarcopenia and frailty.Methods and resultsWe examined plasma type III collagen N-terminal propeptide (P3NP), skeletal muscle protein fractional synthesis rate, and gene and protein expression profiles to identify testosterone-induced changes in muscle anabolism. Two placebo-controlled studies enrolled community-dwelling men (study 1, 60–75 years; study 2, 18–40 years) with low to normal testosterone levels. Men were randomized to lower dose (study 1, 100 mg; study 2, 200 mg) or higher dose (study 1, 300 mg; study 2, 600 mg) single intramuscular testosterone or saline injection. After 1 week, testosterone acutely increased plasma P3NP levels in a dose-dependent manner and altered the expression of several skeletal muscle transcripts and proteins. Though not statistically significant, mixed muscle protein fractional synthesis rate tended to increase (1.08-fold with 100 mg testosterone, 1.12-fold with 300 mg testosterone). Testosterone exposure also increased skeletal muscle expression of the collagen type III gene that encodes P3NP.ConclusionP3NP is a potentially useful early biomarker for muscle anabolic therapy. Skeletal muscle protein and RNA profiling are useful tools for the discovery of novel muscle anabolic biomarkers.

Background Growing prevalence of atrial fibrillation (AF) in the ageing population and its associated life-changing health and resource implications have led to a need to improve its early detection. Primary care is an ideal place to screen for AF; however, this is limited by shortages in general practitioner (GP) resources. Recent increases in the number of clinical pharmacists within primary care makes them ideally placed to conduct AF screening. This study aimed to determine the feasibility of GP practice–based clinical pharmacists to screen the over-65s for AF, using digital technology and pulse palpation during the influenza vaccination season. Methods and findings Screening was conducted over two influenza vaccination seasons, 2017–2018 and 2018–2019, in four GP practices in Kent, United Kingdom. Pharmacists were trained by a cardiologist to pulse palpate, record, and interpret a single-lead ECG ( SL ECG). Eligible persons aged ≥65 years (y) attending an influenza vaccination clinic were offered a free heart rhythm check. Six hundred four participants were screened (median age 73 y, 42.7% male). Total prevalence of AF was 4.3%. All participants with AF qualified for anticoagulation and were more likely to be male (57.7%); be older; have an increased body mass index (BMI); and have a CHA 2 DS 2 -VASc (Congestive heart failure, Hypertension, Age ≥ 75 years, Diabetes, previous Stroke, Vascular disease, Age 65–74 years, Sex category) score ≥ 3. The sensitivity and specificity of clinical pharmacists diagnosing AF using pulse palpation was 76.9% (95% confidence interval [CI] 56.4–91.0) and 92.2% (95% CI 89.7–94.3), respectively. This rose to 88.5% (95% CI 69.9–97.6) and 97.2% (95% CI 95.5–98.4) with an SL ECG. At follow-up, four participants (0.7%) were diagnosed with new AF and three (0.5%) were initiated on anticoagulation. Screening with SL ECG also helped identify new non-AF cardiovascular diagnoses, such as left ventricular hypertrophy, in 28 participants (4.6%). The screening strategy was cost-effective in 71.8% and 64.3% of the estimates for SL ECG or pulse palpation, respectively. Feedback from participants (422/604) was generally positive. Key limitations of the study were that the intervention did not reach individuals who did not attend the practice for an influenza vaccination and there was a limited representation of UK ethnic minority groups in the study cohort. Conclusions This study demonstrates that AF screening performed by GP practice–based pharmacists was feasible, economically viable, and positively endorsed by participants. Furthermore, diagnosis of AF by the clinical pharmacist using an SL ECG was more sensitive and more specific than the use of pulse palpation alone. Future research should explore the key barriers preventing th...

A randomized, controlled, open-label, parallel-group, single-center study to determine biomarkers of exposure to nine selected harmful and potentially harmful constituents (HPHC) in cigarette smoke and urinary excretion of mutagenic material in 160 male and female subjects smoking Marlboro cigarettes (6 mg tar, 0.5mg nicotine, and 7.0mg CO) at baseline. Subjects were randomized to continue smoking Marlboro cigarettes, or switch to using an Electrically Heated Cigarette Smoking System (EHCSS) smoking one of two EHCSS series-K cigarettes, the EHCSS-K6 cigarette (5mg tar, 0.3mg nicotine, and 0.6 mg CO) or the EHCSS-K3 cigarette (3mg tar, 0.2mg nicotine, and 0.6 mg CO), or switch to smoking Philip Morris One cigarettes (1mg tar, 0.1mg nicotine, and 2.0mg CO), or to no-smoking. The mean decreases from baseline to Day 8 were statistically significant (p ≤ 0.05) for all determined HPHC including benzene and CO (the primary objectives), and urinary excretion of mutagenic material in the EHCSS-K6 (range -35.5 ± 29.2% to -79.4 ± 14.6% [mean ± standard deviation]), EHCSS-K3 (range -41.2 ± 26.6% to -83.1 ± 9.2%), and PM1 (range -14.6 ± 24.1% to -39.4 ± 17.5%) groups. The largest reductions in exposure occurred in the no-smoking group (range -55.4 ± 45.0% to -100.0 ± 0.0%).

IntroductionAtrial fibrillation (AF) affects >6% of people aged 65 years or older. Left undetected and untreated, patients may develop significant cardiovascular complications and have a fivefold increased risk of suffering a stroke. For 40% of all sufferers, AF can be asymptomatic. Every year in the UK, £2.2 billion is spent on AF-related strokes, so there is an urgent need to improve early detection of AF. This study aims to determine the feasibility of using trained clinical pharmacists based in general practices, to screen for AF, using pulse palpation and a single-lead ECG device on participants aged 65 years or older, attending influenza vaccination clinics.Methods and analysisSeven clinical pharmacists will be trained by a cardiologist to pulse palpate and record single-lead ECGs using the AliveCor Kardia Mobile device. Quantitative analysis will assess the accuracy and ability of the clinical pharmacist to identify pulse irregularities using pulse palpation and to record and interpret a single-lead ECG. The level of agreement of pulse irregularities detected by pulse palpation will be compared with those detected by the single-lead ECG device, as will the level of agreement between the cardiologist and the device’s interpretation of the ECG. The proportion of people identified with AF (confirmed by the cardiologist) will be determined. Additional demographic data will be obtained from all participants through a questionnaire. Qualitative data will be captured from the participants, from the clinical pharmacists and from the general practitioners and practice staff to determine their views on this method of AF screening. We aim to recruit 600 participants across general practices within Kent.Ethics and disseminationThis protocol was approved by the London–Riverside Research Ethics committee. The findings of this study will be disseminated through forums including, but not limited to, peer-reviewed journals, national and international conferences.