Improved Satisfaction While Maintaining Safety and High Time in Range (TIR) With a Medtronic Investigational Enhanced Advanced Hybrid Closed-Loop (e-AHCL) System.

OBJECTIVE: To determine feasibility and compare acceptance of an investigational Medtronic enhanced advanced hybrid closed-loop (e-AHCL) system in adults with type 1 diabetes with earlier iterations. RESEARCH DESIGN AND METHODS: This nonrandomized three-stage (12 weeks each) exploratory study compared e-AHCL (Bluetooth-enabled MiniMed 780G insulin pump with automatic data upload [780G] incorporating an updated algorithm; calibration-free all-in-one disposable sensor; 7-day infusion set) preceded by a run-in (non-Bluetooth 780G [670G V4.0 insulin pump] requiring manual data upload; Guardian Sensor 3 [GS3] requiring calibration; 3-day infusion set), stage 1 (780G; GS3; 3-day infusion set), and stage 2 (780G; calibration-free Guardian Sensor 4; 3-day infusion set). Treatment satisfaction was assessed by Diabetes Technology Questionnaire (DTQ)-current (primary outcome) and other validated treatment satisfaction tools with glucose outcomes by continuous glucose monitoring metrics. RESULTS: Twenty-one of 22 (11 women) participants (baseline HbA1c 6.7%/50 mmol/mol) completed the study. DTQ-current scores favored e-AHCL (123.1 [17.8]) versus run-in (101.6 [24.2]) and versus stage 1 (110.6 [20.8]) (both P < 0.001) but did not differ from stage 2 (119.4 [16.0]; P = 0.271). Diabetes Medication System Rating Questionnaire short-form scores for "Convenience and Efficacy" favored e-AHCL over run-in and all stages. Percent time in range 70-180 mg/dL was greater with e-AHCL versus run-in and stage 2 (+2.9% and +3.6%, respectively; both P < 0.001). Percent times of <70 mg/dL for e-AHCL were significantly lower than run-in, stage 1, and stage 2 (-0.9%, -0.6%, and -0.5%, respectively; all P < 0.01). CONCLUSIONS: e-AHCL was feasible. User satisfaction increased compared with earlier Medtronic HCL iterations without compromising glucose control.

Fast-Acting Insulin Aspart Versus Insulin Aspart Using a Second-Generation Hybrid Closed-Loop System in Adults With Type 1 Diabetes: A Randomized, Open-Label, Crossover Trial.

OBJECTIVE: To evaluate glucose control using fast-acting insulin aspart (faster aspart) compared with insulin aspart (IAsp) delivered by the MiniMed Advanced Hybrid Closed-Loop (AHCL) system in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS: In this randomized, open-label, crossover study, participants were assigned to receive faster aspart or IAsp in random order. Stages 1 and 2 comprised of 6 weeks in closed loop, preceded by 2 weeks in open loop. This was followed by stage 3, whereby participants changed directly back to the insulin formulation used in stage 1 for 1 week in closed loop. Participants chose their own meals except for two standardized meal tests, a missed meal bolus and late meal bolus. The primary outcome was the percentage of time sensor glucose values were from 70 to 180 mg/dL (time in range; [TIR]). RESULTS: Twenty-five adults (52% male) were recruited; the median (interquartile range) age was 48 (37, 57) years, and the median HbA1c was 7.0% (6.6, 7.2) (53 [49, 55] mmol/mol). Faster aspart demonstrated greater overall TIR compared with IAsp (82.3% [78.5, 83.7] vs. 79.6% [77.0, 83.4], respectively; mean difference 1.9% [0.5, 3.3]; P = 0.007). Four-hour postprandial glucose TIR was higher using faster aspart compared with IAsp for all meals combined (73.6% [69.4, 80.2] vs. 72.1% [64.5, 78.5], respectively; median difference 3.5% [1.0, 7.3]; P = 0.003). There was no ketoacidosis or severe hypoglycemia. CONCLUSIONS: Faster aspart safely improved glucose control compared with IAsp in a group of adults with well-controlled type 1 diabetes using AHCL. The modest improvement was mainly related to mealtime glycemia. While the primary outcome demonstrated statistical significance, the clinical impact may be small, given an overall difference in TIR of 1.9%.

Open-label, randomised, multicentre crossover trial assessing two-layer compression bandaging for chronic venous insufficiency: results of the APRICOT trial.

Compression bandaging is the mainstay therapy for chronic venous insufficiency and venous leg ulcers, but patient compliance can be challenging due to associated discomfort. The study discussed here aimed to compare AndoFlex TLC Calamine and Coban2 compression bandaging in relation to patient comfort and pruritus symptomology, with severity of pruritus as the primary outcome. This was a multi-centre, prospective, non-blinded, randomised controlled crossover trial involving 39 randomised patients with chronic venous insufficiency patients. In two periods, the patients wore AndoFlex TLC Calamine or Coban2 for 3 weeks each. No significant differences in validated pruritus outcome measures were observed, including a non-significant treatment effect for the severity of pruritus scale (n=35 trial completers; p-value=0.24, Wilcoxon test). However, after trying both bandages, 21 of the 35 patients (60%) definitely preferred AndoFlex TLC Calamine, whereas 4 patients (11%) definitely preferred Coban2. Thus, AndoFlex TLC Calamine compression bandage therapy was preferred by most patients, although this observation could not be confirmed using validated patient-reported outcome measures for pruritus. Further research is indicated to establish if patient preference translates into favourable clinical outcomes. ISRCTN number: ISRCTN95282887.

A plantar flexion device exercise programme for patients with peripheral arterial disease: a randomised prospective feasibility study.

OBJECTIVES: To determine if the use of a plantar flexion device (Step It pedal) in a newly developed exercise programme is of benefit to patients with peripheral arterial disease. DESIGN: Prospective feasibility trial with patients randomised to either standard care or the Step It exercise programme plus standard care. SETTING: Physiotherapy Department at Cumberland Infirmary, Carlisle, UK. PARTICIPANTS: Patients were identified from the vascular team's referral list. In total, 42 patients agreed to take part; 18 in the control group and 24 in the intervention group. INTERVENTIONS: Eligible participants were randomised and received either standard care or took part in a plantar flexion resistance exercise programme, involving the Step It pedal, for a period of 12 weeks. MAIN OUTCOME MEASURES: Maximum walking distance, claudication distance and ankle brachial pressure index. RESULTS: Eighty-three percent of patients completed the study. Improvements in median distance to claudication symptoms and maximum walking distance were observed in the intervention group but not in the control group. Nine out of 15 (60%) participants in the control group and 14 out of 20 (70%) participants in the intervention group improved their walking distance. Ankle brachial pressure index remained virtually unchanged in both groups. CONCLUSIONS: Due to the variability of patients' fitness in the sample, it cannot be concluded whether use of the Step It pedal has additional benefits to patients over standard care. However, the study completion rate implies that patients with peripheral arterial disease are receptive to undertaking exercise programmes.

Total synthesis of rapamycin.

For over 30 years, rapamycin has generated a sustained and intense interest from the scientific community as a result of its exceptional pharmacological properties and challenging structural features. In addition to its well known therapeutic value as a potent immunosuppressive agent, rapamycin and its derivatives have recently gained prominence for the treatment of a wide variety of other human malignancies. Herein we disclose full details of our extensive investigation into the synthesis of rapamycin that culminated in a new and convergent preparation featuring a macro-etherification/catechol-templating strategy for construction of the macrocyclic core of this natural product.

Effect of omeprazole on the pharmacokinetics of saquinavir-500 mg formulation with ritonavir in healthy male and female volunteers.

INTRODUCTION: Recent studies have described reduced absorption of certain protease inhibitors when administered with agents known to increase gastric pH. No clinically significant interactions between saquinavir absorption and gastric pH have previously been shown. We evaluated the effect of omeprazole, a proton-pump-inhibitor, on the pharmacokinetics of the recently developed saquinavir-500 mg formulation co-administered with ritonavir. METHODS: Eighteen healthy subjects (n = 6 women and 12 men) received 1000/100 mg saquinavir/ritonavir twice daily in an open-label study for 15 days. On days 11-15, subjects were administered omeprazole 40 mg daily with the morning dose. Serial plasma samples were collected for 12-h pharmacokinetic profiles of saquinavir and ritonavir on days 10 and 15 and safety analysis on days 1, 4, 10, 15 and 29. RESULTS: The geometric mean and 95% confidence interval (CI), for the area under time-concentration curve (AUC; ng h/ml), trough plasma concentration (C trough; ng/ml) and maximum observed plasma concentration (Cmax; ng/ml) of saquinavir were 20599 (14396-29360) and 37511 (28733-48970); 737 (482-1127) and 1521 (1039-2227); 3227 (2370-4393) and 5611 (4507-7710) on days 10 and 15, respectively, with geometric mean ratios of 1.82, 2.06 and 1.75. No significant changes were observed in saquinavir elimination half life, ritonavir pharmacokinetic parameters or in safety laboratory tests. No unexpected adverse events attributed to study medication were noted. CONCLUSIONS: In the presence of omeprazole, total saquinavir plasma exposure is significantly increased (82% increase in AUC). The mechanism of this interaction requires elucidation. Despite the significant increase in saquinavir exposure, no short term toxicities were observed.

Simultaneous determination of HIV protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir in human plasma by high-performance liquid chromatography-tandem mass spectrometry.

We report a precise and accurate method for simultaneous quantification of protease inhibitors (PIs) amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir in plasma. An internal standard was added to samples prior to protein precipitation with acetonitrile followed by addition of ammonium formate buffer. Analysis was by HPLC-MS/MS. Calibration curves were validated over concentration ranges encompassing both subtherapeutic and potentially 'toxic' drug concentrations. Inter- and intra-assay variation were below 11% and PI recovery was above 87%. The bioanalytical method described is successfully applied to measure PI concentrations obtained from clinical pharmacokinetic studies and routine therapeutic drug monitoring (TDM).