BackgroundWhite-coat hypertension (WCH) is also referred to as 'isolated clinic hypertension'. While it is a frequently encountered phenomenon, WCH is not systematically evoked, and its management remains unclear due to the contradictory guidelines provided by professional societies.AimTo examine WCH management by GPs in Europe and Canada.Design & settingA clinical vignette of a possible case of WCH was created from the literature, and the responses of GPs to WCH-specific questions in a cross-sectional electronic questionnaire were compared.MethodComplete electronic questionnaire responses from Europe and Canada were systematically analysed.ResultsAmong 770 eligible questionnaires (useful response rate: 10.6%), 43.5% were from France, 19.2% from Belgium, 7.8% from England, 19.5% from Switzerland, and 10.0% from Canada. Based on the clinical information provided in the vignette, GPs overall diagnosed hypertension and WCH equally (50.7% versus 49.3%, respectively). Canadian GPs suggested hypertension more frequently than European GPs in general (64.2% versus 46.1%, P<10–4), and more frequently used ambulatory blood pressure monitoring ([ABPM] 42.3% versus 26.1%, P = 0.01). In both groups of GPs, WCH was managed similarly (no treatment, 100% versus 97.3%, P = 0.39). Generally, the GPs all followed WCH patients for 3–6 months (51.3% versus 66.2%, P = 0.1), and they were not aware of the WCH guidelines (47.3% versus 52.1%, P = 0.54).ConclusionAlthough WCH guidelines are different, WCH management by GPs is very similar except for diagnosis. Homogeneity in WCH guidelines is required and should be systematically implemented in hypertension guidelines to avoid inappropriate management of the condition.

PurposeThis clinical trial investigated the effectiveness, pharmacokinetic properties, and safety profile of leuprolide acetate 22.5-mg depot, a new 3-month leuprolide depot formulation, as androgen deprivation therapy for patients with prostate cancer. MethodsA Phase III, open-label, multicenter study design for patients with prostate cancer, with patient inclusion assessed by the investigative site as patient's appropriate for androgen deprivation therapy. Patients received 2 separate intramuscular injections of leuprolide acetate 22.5-mg depot for a 3-month depot interval of therapeutic effect. Plasma testosterone concentrations were determined throughout the study. The primary efficacy analysis was the percentage of patients who achieve and maintain castrate testosterone levels (≤50 ng/mL) from days 28–168. Secondary end points included luteinizing hormone, follicle-stimulating hormone, prostate-specific antigen, and safety assessments. A pharmacokinetic study was also conducted in a subset of 30 patients. FindingsAll 163 patients enrolled in the study received at least 1 dose of study drug; 162 of them were fully evaluable and 151 completed the study. Castrate levels of testosterone were achieved and maintained from days 28–168 in 96.8% (95% CI, 92.5%–98.7%) of patients. Five patients presented with sporadic testosterone levels >50 ng/dL. By day 28, of the 161 patients, 150 (99.4%) had achieved castrate levels, and 127 (78.9%) had achieved testosterone concentrations ≤20 ng/dL. At study end, 149 of 151 patients (98.7%) patients achieved castrate testosterone levels, with 142 of 151 (94.0%) having testosterone levels ≤20 ng/dL. At study end, mean luteinizing hormone and follicle-stimulating hormone concentrations had decreased from baseline to below the lower limit of quantitation and below baseline levels, respectively, whereas mean serum prostate-specific antigen was reduced by 94.7% from baseline. Most patients (>96%) had no change in their World Health Organization/Eastern Cooperative Oncology Group score, whereby 84.0% of patients had a baseline score of 0. Bone pain, urinary pain, and urinary symptoms were infrequent and remained so throughout the study. After administration, leuprolide concentrations increased rapidly. The peak was followed by a decline up to day 28, maintaining sustained drug levels until the following dose on day 84. The most common related treatment-emergent adverse events, detected in >5% of patients, were hot flushes, fatigue, and injection site pain reported by 77.3%, 9.8%, and 9.2% of patients, respectively. ImplicationsLeuprolide acetate 22.5-mg depot was effective in achieving and maintaining testosterone suppression. Safety and tolerability profiles were consistent with established profiles of androgen deprivation therapy. Clinical Trials.gov identifier: NCT01415960.

This personal viewpoint lays out the development of a silver-catalyzed kinetic resolution of alpha-allenic alcohols inspired by the biomimetic synthesis of natural products. The corresponding selectivity factor (s) indicates that this resolution protocol can deliver chiral allenic alcohols and 2,5-dihydrofurans in high enantioselectivity with synthetically applicable isolated yields. The broad substrate scope makes it an attractive approach for building synthetically useful chiral building blocks. From the recent progress in allene chemistry, silver was considered as an anion metathesis reagent to prepare highly efficient Au catalysts. Our discovery of the unique reactivity of a chiral silver phosphate should stimulate more interesting discoveries in this field.

Aim: Lercanidipine, a long-acting dihydropyridine with a good antihypertensive efficacy and tolerability. The aim of the ELYPSE trial was to determine the efficacy and tolerability of this medication in daily clinical practice. Methods: Patients with Stage 1-2 essential hypertension, in whom their physicians considered to prescribe a dihydropyridine, were administered lercanidipine 10 mg once daily, with a 3-month follow-up. The study included 9059 patients (mean age 63±11 years; 58% women, 60% over 60 years, 56% with Stage 2 hypertension, and 69% previously treated with other antihypertensive drugs). A subgroup of 1267 patients (14%) experienced adverse reactions, related to pre-administered antihypertensive therapy. Electronic case-report forms and a central Internet database were used for the data collection. Results: Baseline levels of blood pressure (BP) and heart rate (HR) were 160,1±10,2/95,6±6,6 mm Hg and 77,3±9,3 bpm, respectively. Significant reductions in both systolic and diastolic BP were attained at 1 month, with some additional reduction 2 months later. At 3 months, BP level was 141,4±11,3/83,1±6,9 mm Hg, and HR level was 75,2±8,2 bpm (p <130/85 mm Hg) was achieved only in 16,4%. The overall incidence of adverse events was 6,5%; the most frequent ones were headache (2,9%), ankle edema (1,2%), flushing (1,1%), and palpitations (0,6%). Withdrawal rate was<1%. The efficacy and tolerability of lercanidipine in the subgroup of patients included in the study due to adverse events of other antihypertensive drugs were similar to those in the whole study population. Conclusion: In this study, lercanidipine has demonstrated good efficacy and tolerability in daily clinical practice. These findings are consistent with the results of randomized controlled trials.

Background: A microencapsulated, sustained-release formulation of leuprolide acetate 3.75 mg has been developed. Objective: This study investigated the effectiveness, pharmacokinetics, and safety profile of a 1-month leuprolide acetate 3.75-mg depot formulation for suppressing testosterone concentrations in patients with prostate cancer. Methods: This was a Phase III, open-label, international multicenter clinical trial. Patients with prostate cancer who, in the judgment of the investigators, could benefit from androgen deprivation therapy received 6 monthly intramuscular injections of leuprolide acetate 3.75-mg depot. Plasma testosterone concentrations were determined at specific times throughout the study. The primary end point was the proportion of successful patients over the total number of evaluable patients (ie, patients with evaluable testosterone concentrations at all monthly assessments and no missing values due to treatment-related adverse events). Treatment success was defined as testosterone suppression below the clinical castration level (ie, ≤0.5 ng/mL) at day 28 and maintenance of clinical castration until study completion (day 168). The frequency of patients with testosterone concentrations ≤0.2 ng/mL was also studied. Results: The study included 160 patients with a mean (SD) age of 71.6 (9.2) years, weight of 83.7 (15.5) kg, and predominantly white race (87.5% [140/160]). All 160 patients received at least one dose of study drug; 157 of them were fully evaluable, and 152 completed the study. The proportion of successful patients over the total number of evaluable patients was 96.8% (152/157; 95% CI,92.7%–99.0%). Five of the 157 evaluable patients (3.2%) did not achieve the primary end point of testosterone concentration ≤0.5 ng/mL by day 28. Of the evaluable patients, 78.7% (122/155) achieved testosterone suppression by day 21. By day 28, 96.8% (151/156) of the evaluable patients had achieved castrate levels, and 73.1% (114/156) achieved testosterone concentrations <0.2 ng/mL. At study end, 100% (152/152) of the patients completing the study maintained castrate levels, and 92.8% (141/152) had testosterone concentrations ≤0.2 ng/mL. The pharmacokinetic profile of leuprolide during the first 3 months of treatment, evaluated in a subset of the study population (n = 12), showed sustained release of leuprolide from the formulation. Values for AUC 0−t calculated from day 0 to day 28, days 28 to 56, and days 56 to 84 were 25,976.5 (7892.0), 30,685.5 (9348.4), and 31,030.9 (10,745.0) pg/mL per day, respectively. The most common treatment-related adverse event was hot flashes (45.0% [72/160]). Fatigue, hyperhidrosis, night sweats, and headache each occurred in ≤6.3% (10/160) of the patients. The most frequently reported local adverse reaction was pain at the injection site, experienced by 8.1% (13/160) of the patients. Conclusions: Leuprolide acetate 3.75-mg depot was effective in achieving and maintaining testosterone suppression and was well tolerated throughout the study in this cohort of patients with prostate cancer. ClinicalTrials.gov identifier: NCT00128531.

As a dose-finding phase I study of a new liposomal formulation of doxorubicin (LipD), patients (n = 39; median age: 60 years; range, 41–75; median ECOG performance status, 1; range, 0–2) with refractory cancer had a starting dose of LipD administered at 30 mg/m2 as a 1-hour iintravenous infusion. Cycle duration was 21 days. At the recommended dose (RD), patients received a first cycle of nonliposomal doxorubicin (non-LipD) to evaluate intrapatient pharmacokinetic differences between non-LipD and LipD. The most frequent diagnosis was head and neck tumor (7 patients). Tolerance and safety of dose levels of 30, 40, 50, 60, 70, 80, and 90 mg/m2 were evaluated. A total of 131 cycles were administered (median per patient, 3; range, 1–6). Of the 39 patients, 8 completed the planned six cycles. Febrile neutropenia was dose limiting and defined the toxic dose of LipD as 70 mg/m2. Other significant toxicities included asthenia (G2: 31%; G3: 8%), neutropenia (G3: 35%; G4: 29%), thrombopenia (G3: 15%; G4: 2%), anemia (G1–G2: 67%; G3–G4: 5%), mucositis (G1–G2: 32%, G3: 4%), and acute allergic reactions (G1–G2: 36%). Comparison of pharmacokinetic profiles of non-LipD and LipD showed that higher exposure was achieved with LipD. Stable disease was observed in 14 patients. We conclude that the LipD regimen, given as a 1-hour infusion every 3 weeks, is well tolerated and has a favorable pharmacokinetic profile. The recommended dose is 70 mg/m2 with prophylactic antihistamines and corticoids to preempt allergic reaction.