Central blood pressure estimation in type 1 diabetes: impact and implications of peripheral calibration method.

OBJECTIVE: Peripheral blood pressure (BP) waveforms are used for noninvasive central BP estimation. Central BP could assist in cardiovascular risk assessment in patients with type 1 diabetes mellitus (T1DM). However, correct calibration of peripheral BP waveforms is important to accurately estimate central BP. We examined differences in central BP estimated by radial artery tonometry depending on which brachial BP (SBP/DBP vs. MAP/DBP) is used for calibration of the radial waveforms, for the first time in T1DM. METHODS: A cross-sectional study in T1DM patients without known cardiovascular disease. Radial artery BP waveforms were acquired using applanation tonometry ( SphygmoCor ) for the estimation of central SBP, central pulse pressure (PP) and central augmentation pressure, using either brachial SBP/DBP or MAP/DBP for the calibration of the radial pressure waveforms. RESULTS: Fifty-four patients (age: 46 ±â€Š9.5 years; T1DM duration: 27 ±â€Š8.8 years) were evaluated. Central BP parameters were significantly higher when brachial MAP/DBP-calibration was used compared with brachial SBP/DBP-calibration (7.5 ±â€Š5.04, 7.5 ±â€Š5.04 and 1.5 ±â€Š1.36 mmHg higher central SBP, central PP and central augmentation pressure, respectively, P  < 0.001). CONCLUSION: In patients with T1DM, there are significant differences in central BP values estimated with radial artery tonometry, depending on the method used for calibration of the radial waveforms. Brachial MAP/DBP-calibration resulted in consistently higher central BP as compared to using brachial SBP/DBP, leading to patient re-stratification. Hence, the accuracy of noninvasive estimation of central BP by radial tonometry is dependent on calibration approach, and this problem must be resolved in validation studies using an invasive reference standard to determine which method best estimates true central BP.

Arterial stiffness in patients with type 1 diabetes and its comparison to cardiovascular risk evaluation tools.

BACKGROUND: Arterial stiffness is a potential biomarker for cardiovascular disease (CVD) risk in patients with type 1 diabetes (T1D). However, its relation with other CV risk evaluation tools in T1D has not been elucidated yet. This study aimed to evaluate arterial stiffness in T1D patients free from known CVD, and compare it to other CV risk evaluation tools used in T1D. METHODS: Cross-sectional study in adults with a T1D duration of at least 10 years and without established CVD. Patients were categorized in CVD risk groups based on 2019 European Society of Cardiology (ESC) guidelines, and the STENO T1D risk engine was used to estimate 10-year risk for CV events. Arterial stiffness was evaluated with carotid-femoral pulse wave velocity (cf-PWV). Coronary artery calcium (CAC) score was assessed and carotid ultrasound was performed. Ambulatory 24-h blood pressure and central hemodynamic parameters were evaluated. Data on renal function and diabetic kidney disease was retrieved. RESULTS: 54 patients (age: 46 ± 9.5 years; T1D duration: 27 ± 8.8 years) were included. One-fourth of patients showed prematurely increased aortic stiffness based on cf-PWV (24%). Cf-PWV was significantly associated with CAC score, carotid intima-media thickness, central hemodynamic parameters and diabetic kidney disease. Based on STENO, 20 patients (37%) were at low, 20 patients (37%) at moderate, and 14 patients (26%) at high 10-year risk for CV event. Cf-PWV was strongly associated with the STENO score (rs = + 0.81; R2 = 0.566, p < 0.001), increasing with each higher STENO group (p < 0.01). However, cf-PWV was not significantly different between the two CV risk groups (high versus very high) based on ESC criteria, and ESC criteria compared to STENO classified 10 patients more as having > 10% 10-year risk for CV events (n = 44/54; 81.5% versus n = 34/54; 63%). CONCLUSIONS: This study demonstrated that a substantial proportion of long-standing T1D patients free from known CVD show premature arterial stiffening. Cf-PWV strongly associates with the STENO risk score for future CV events and with cardiovascular imaging and function outcomes, thereby illustrating the clinical importance of arterial stiffness. The data, however, also show considerable heterogeneity in CV risk and differences in risk categorisation between the STENO tool and ESC criteria.There is a need for refinement of CV risk classification in T1D, and future studies should investigate if evaluation of arterial stiffness should be implemented in T1D clinical practice and which patients benefit the most from its assessment.

Propionyl-L-carnitine for intermittent claudication.

BACKGROUND: Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis. Intermittent claudication is a symptomatic form of PAD that is characterized by pain in the lower limbs caused by chronic occlusive arterial disease. This pain develops in a limb during exercise and is relieved with rest. Propionyl-L-carnitine (PLC) is a drug that may alleviate the symptoms of PAD through a metabolic pathway, thereby improving exercise performance. OBJECTIVES: The objective of this review is to determine whether propionyl-L-carnitine is efficacious compared with placebo, other drugs, or other interventions used for treatment of intermittent claudication (e.g. exercise, endovascular intervention, surgery) in increasing pain-free and maximum walking distance for people with stable intermittent claudication, Fontaine stage II. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and the ClinicalTrials.gov trials register to July 7, 2021. We undertook reference checking and contact with study authors and pharmaceutical companies to identify additional unpublished and ongoing studies. SELECTION CRITERIA: Double-blind randomized controlled trials (RCTs) in people with intermittent claudication (Fontaine stage II) receiving PLC compared with placebo or another intervention. Outcomes included pain-free walking performance (initial claudication distance - ICD) and maximal walking performance (absolute claudication distance - ACD), analyzed by standardized treadmill exercise test, as well as ankle brachial index (ABI), quality of life, progression of disease, and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted data, and evaluated trials for risk of bias. We contacted study authors for additional information. We resolved any disagreements by consensus. We performed fixed-effect model meta-analyses with mean differences (MDs) and 95% confidence intervals (CIs). We graded the certainty of evidence according to GRADE. MAIN RESULTS: We included 12 studies in this review with a total number of 1423 randomized participants. A majority of the included studies assessed PLC versus placebo (11 studies, 1395 participants), and one study assessed PLC versus L-carnitine (1 study, 26 participants). We identified no RCTs that assessed PLC versus any other medication, exercise, endovascular intervention, or surgery. Participants received PLC 1 grams to 2 grams orally (9 studies) or intravenously (3 studies) per day or placebo. For the comparison PLC versus placebo, there was a high level of both clinical and statistical heterogeneity due to study size, participants coming from different countries and centres, the combination of participants with and without diabetes, and use of different treadmill protocols. We found a high proportion of drug company-backed studies. The overall certainty of the evidence was moderate. For PLC compared with placebo, improvement in maximal walking performance (ACD) was greater for PLC than for placebo, with a mean difference in absolute improvement of 50.86 meters (95% CI 50.34 to 51.38; 9 studies, 1121 participants), or a 26% relative improvement (95% CI 23% to 28%). Improvement in pain-free walking distance (ICD) was also greater for PLC than for placebo, with a mean difference in absolute improvement of 32.98 meters (95% CI 32.60 to 33.37; 9 studies, 1151 participants), or a 31% relative improvement (95% CI 28% to 34%). Improvement in ABI was greater for PLC than for placebo, with a mean difference in improvement of 0.09 (95% CI 0.08 to 0.09; 4 studies, 369 participants). Quality of life improvement was greater with PLC (MD 0.06, 95% CI 0.05 to 0.07; 1 study, 126 participants). Progression of disease and adverse events including nausea, gastric intolerance, and flu-like symptoms did not differ greatly between PLC and placebo. For the comparison of PLC with L-carnitine, the certainty of evidence was low because this included a single, very small, cross-over study. Mean improvement in ACD was slightly greater for PLC compared to L-carnitine, with a mean difference in absolute improvement of 20.00 meters (95% CI 0.47 to 39.53; 1 study, 14 participants) or a 16% relative improvement (95% CI 0.4% to 31.6%). We found no evidence of a clear difference in the ICD (absolute improvement 4.00 meters, 95% CI -9.86 to 17.86; 1 study, 14 participants); or a 3% relative improvement (95% CI -7.4% to 13.4%). None of the other outcomes of this review were reported in this study. AUTHORS' CONCLUSIONS: When PLC was compared with placebo, improvement in walking distance was mild to moderate and safety profiles were similar, with moderate overall certainty of evidence. Although In clinical practice, PLC might be considered as an alternative or an adjuvant to standard treatment when such therapies are found to be contraindicated or ineffective, we found no RCT evidence comparing PLC with standard treatment to directly support such use.

Indirect implications of COVID-19 prevention strategies on non-communicable diseases : An Opinion Paper of the European Society of Hypertension Working Group on Hypertension and Cardiovascular Risk Assessment in Subjects Living in or Emigrating from Low Resource Settings.

BACKGROUND: After its outbreak in China, the novel COronaVIrus Disease 19 is spreading across the globe. It is an emergency the world has never seen before. MAIN TEXT: The attention of health systems is mainly focused on COronaVIrus Disease 19 patients and on the risk that intensive care units might be overwhelmed by the serious pulmonary complications. Different countries are also attempting to establish infection prevention and control strategies which proved effective in China where the outbreak was initially reported. We reflect on important lessons to be learnt from different countries. The effects that infection prevention and control strategies, such as social distancing or isolation, can have on the care of millions of patients with non-communicable diseases, who may be indirectly affected, have not been taken into consideration so much. CONCLUSIONS: When dealing with COronaVIrus Disease 19, policy makers and healthcare personnel should consider the indirect effects on the treatment of non-communicable diseases.

Eye drop technique and patient-reported problems in a real-world population of eye drop users.

OBJECTIVE: To assess eye drop technique and patient-reported problems with eye drop instillation in a primary care sample of eye drop users. METHODS: Cross-sectional observational study in 136 community pharmacies in Belgium. Patient inclusion criteria were being age ≥ 18 years and using eye drops for ≥ 1 month (to ensure that patients were already familiar with eye drop instillation). Participants demonstrated their eye drop technique and completed a self-administered questionnaire. RESULTS: Participants (n = 678) had a mean age of 68.9 ± 12.4 years. During the demonstration, almost everyone (98.0%) successfully instilled at least one drop in the eye, although 14% required multiple attempts to achieve this. Only 3% of the sample exhibited perfect drop technique, meaning that they performed correctly all the steps. Most common deviations were touching the bottle to the eye or eyelid (40.7% of patients), and failing to close the eye (67.8%) and perform nasolacrimal occlusion for at least 1 min (94.7%) after drop instillation. Importantly, we found that 20% of ophthalmic suspensions were not shaken before use. Forty percent of patients reported ≥ 1 problem with eye drop instillation. Most common problems were difficulties with getting a drop in the eye (18.3% of patients), too many drops coming out of the bottle (14.6%), and difficulty squeezing the bottle (12.2%). About half of the sample recalled having had education in eye drop instillation technique. CONCLUSION: This study showed suboptimal eye drop technique in real-world clinical practice. A proactive role of community pharmacists in detecting and resolving these problems could be helpful.

Doravirine and the Potential for CYP3A-Mediated Drug-Drug Interactions.

Identifying and understanding potential drug-drug interactions (DDIs) are vital for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. This article discusses DDIs between doravirine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), and cytochrome P450 3A (CYP3A) substrates and drugs that modulate CYP3A activity. Consistent with previously published in vitro data and DDI trials with the CYP3A substrates midazolam and atorvastatin, doravirine did not have any meaningful impact on the pharmacokinetics of the CYP3A substrates ethinyl estradiol and levonorgestrel. Coadministration of doravirine with CYP3A inhibitors (ritonavir or ketoconazole) increased doravirine exposure approximately 3-fold. However, these increases were not considered clinically meaningful. Conversely, previously published trials showed that coadministered CYP3A inducers (rifampin and rifabutin) decreased doravirine exposure by 88% and 50%, respectively (K. L. Yee, S. G. Khalilieh, R. I. Sanchez, R. Liu, et al., Clin Drug Investig 37:659-667, 2017 [https://doi.org/10.1007/s40261-017-0513-4]; S. G. Khalilieh, K. L. Yee, R. I. Sanchez, R. Liu, et al., J Clin Pharmacol 58:1044-1052, 2018 [https://doi.org/10.1002/jcph.1103]), while doravirine exposure following prior efavirenz administration led to an initial reduction in doravirine exposure of 62%, but the reduction became less pronounced with time (K. L. Yee, R. I. Sanchez, P. Auger, R. Liu, et al., Antimicrob Agents Chemother 61:e01757-16, 2017 [https://doi.org/10.1128/AAC.01757-16]). Overall, the coadministration of doravirine with CYP3A inhibitors and substrates is, therefore, supported by these data together with efficacy and safety data from clinical trials, while coadministration with strong CYP3A inducers, such as rifampin, cannot be recommended. Concomitant dosing with rifabutin (a CYP3A inducer less potent than rifampin) is acceptable if doravirine dosing is adjusted from once to twice daily; however, the effect of other moderate inducers on doravirine pharmacokinetics is unknown.

Switchability of Gabapentin Formulations: A Randomized Trial to Assess Bioequivalence Between Neurontin and Gabasandoz on the Individual Subject Level.

Generic substitution of antiepileptic drugs is generally not advised by neurologists. The present study investigated the switchability of gabapentin 800 mg tablets (Neurontin and Gabasandoz) using an individual bioequivalence (IBE) study design with two batches of each product and assessed whether between-batch and between-formulation variability in exposure play a significant role in the within-subject variability. The trial was analyzed according to the US Food and Drug Administration (FDA) framework to establish IBE. The IBE was shown between both products with the 95% upper confidence bound of the IBE criterion being -2.01 and -2.31 for area under the concentration-time curve from zero to infinity (AUC0-inf ) and peak plasma concentration (Cmax ), respectively. Subject-by-formulation variability (1.35%) was negligible compared with the within-subject variability of AUC0-inf with Neurontin (19.0%) and Gabasandoz (23.6%). Inclusion of an additional batch did not significantly change this within-subject variability (20.2% and 23.6%, respectively). This study shows that substitution of gabapentin 800 mg tablets of Neurontin and Gabasandoz should be possible without affecting clinical outcomes.

Self-Medication With Over-the-Counter Analgesics: A Survey of Patient Characteristics and Concerns About Pain Medication.

Pain is a common reason for self-medication with over-the-counter (OTC) analgesics. However, this self-treating population has remained largely uncharacterized. This cross-sectional observational study investigated individuals who self-medicate their pain with OTC analgesics to elucidate their pain characteristics and medication use. In addition, presence of and risk factors for concerns about pain medication were examined. The clinical profile of the participants (n = 1,889) was worse than expected with long-standing pain complaints (median pain duration of 9 years), pain located at multiple body sites (median of 4, and 13% with ≥10 painful body areas), about one-third suffering from daily pain and about 40% experiencing substantial pain-related disability. Head (58.6% of sample), low back (43.6%), and neck (30.7%) were the most common pain locations. About 73% had a physician diagnosis, mainly migraine and osteoarthritis. Paracetamol (used by 68.6% of patients) and nonsteroidal anti-inflammatory drugs (46.8%) were the most frequently used pain medications. About 40% of our sample showed substantial concern about the perceived need for pain medication and the perceived potential for harmful effects (eg, fear for addiction). These findings highlight the importance for health professionals to systematically probe pain patients about their self-medication practices and explore attitudes about pain medication. Perspective: This study found that the clinical picture of people who self-medicate their pain with OTC analgesics looked worse than expected. We also identified substantial concerns about pain medication. Therefore, we recommend that health professionals systematically probe pain patients about their self-medication practices and explore concerns about pain medication.

Arterial stiffness in black African ancestry patients with chronic kidney disease living in Cameroon.

BACKGROUND: Increased aortic pulse wave velocity (PWV), a direct measure of arterial stiffness (AS) is an independent predictor of cardiovascular events (CVEs) in chronic kidney disease (CKD) patients. This study assessed the patterns of PWV among Cameroonian patients with CKD in whom that marker of early vascular aging has not been explored so far. METHODS: We enrolled 150 Black African patients (mean age: 52±15 years, 56.7% males) with CKD in a cross-sectional study conducted at Douala General Hospital, Douala, Cameroon. Sociodemographic, anthropometric and biologic variables, blood pressure (BP) and PWV were recorded in all participants. Estimated aortic PWV was measured using a Mobil-O-Graph automatic brachial oscillometric device. RESULTS: PWV increased with aging (P<0.0001), and PWV adjusted for age, sex, body mass index and mean arterial BP (MAP) was higher in non-dialysed (n=90) than in hemodialysed (n=60) patients, even in pre-dialysis: 8.5±2.0 vs. 7.9±1.4 m/s (P=0.026); and in post-dialysis: 8.5±2.0 vs. 7.8±1.5 m/s (P=0.008). The mean PWV of all study participants was 8.2±1.8 m/s, with 61.3% of patients having a PWV ≥8.2 m/s, indicative of subclinical damage to the aorta, which was more pronounced in non-dialysis (67.8%) than in hemodialysis (53.3%) patients (P=0.033). Multivariable analysis performed in all participants revealed that advanced age, MAP and tobacco use were independently associated with PWV (all P<0.05). CONCLUSIONS: Our findings suggest increased AS in Cameroonian CKD non-dialyzed as compared to dialyzed patients. Slower PWV in patients on maintenance hemodialysis suggests improvement of aortic distensibility following dialysis. However, further large-scale studies are needed to confirm our findings and to improve understanding of the underlying mechanisms of arterial stiffening in black African ancestry patients with CKD.

Arterial stiffness and cardiometabolic phenotype of Cameroonian Pygmies and Bantus.

BACKGROUND: Pygmies living in the Central African rainforest with a traditional hunter-gatherer lifestyle have a low incidence of cardiovascular diseases. Because of progressive loss of traditional habitat and ancestral lands, some Pygmies have migrated to urban areas and adopt specific Bantu lifestyles such as increased salt consumption and a sedentary way of life. We tested the hypothesis that migrant Pygmies could present with hemodynamic and metabolic characteristics different from those of traditional in-situ Pygmies and possibly closer to those of Bantu farmers. PATIENTS AND METHODS: The study included 148 Pygmies (94 traditional and 54 migrants) and 164 Bantus. Peripheral and central hemodynamics, aortic pulse wave velocity (PWV), and augmentation index corrected for heart rate (AIx) were measured, as well as fasting lipid profile. Urinary sodium and potassium excretion was also measured on a morning spot. RESULTS: Compared to Bantus, Pygmies had lower height (even between men and women, but men were taller than women in the three groups), weight, waist and hip circumference, peripheral and central blood pressure, total, low-density lipoprotein, and high-density lipoprotein cholesterol and apolipoprotein B100 levels, sodium urinary excretion, and lower prevalence of the metabolic syndrome. By contrast, they had a higher waist-to-hip ratio, and higher triglycerides levels, as compared to Bantu farmers. PWV and AIx did not differ between Bantus and Pygmies. Compared to traditional in-situ Pygmies, migrant Pygmies were not taller when adjusted for sex, had lower brachial and central blood pressure, higher PWV (adjusted for mean arterial pressure, BMI, and sex), and higher apolipoprotein B100 levels. In the whole population, multivariable analysis revealed that PWV was independently associated with age, weight, height, mean arterial pressure, total cholesterol, and hip circumference, whereas AIx was independently related to age, sex, height, heart rate, diastolic blood pressure, and group (from Bantu farmers to Pygmies). CONCLUSION: Comparisons between Bantus and Pygmies, and between migrant Pygmies and traditional in-situ Pygmies, showed mixed results, with favorable and deleterious hemodynamic and metabolic characteristics in all groups. This could be due to increased contacts between these populations, which blunt the expected differences and because the beneficial effects of the hunter-gatherer subsistence mode of traditional in-situ Pygmies are counterbalanced by unhealthy behavioral habits.

KH176 under development for rare mitochondrial disease: a first in man randomized controlled clinical trial in healthy male volunteers.

BACKGROUND: Mitochondrial disorders are a clinically, biochemically and genetically heterogeneous group of multi-system diseases, with an unmet medical need for treatment. KH176 is an orally bio-available small molecule under development for the treatment of mitochondrial(-related) diseases. The compound is a member of a new class of drugs, acting as a potent intracellular redox-modulating agent essential for the control of oxidative and redox pathologies. The aim of this randomized, placebo controlled, double-blinded phase 1 study was to test safety, tolerability and pharmacokinetics of single and multiple doses of KH176 in healthy male volunteers. Putative effects on redox related biomarkers were explored. RESULTS: KH176 was well tolerated up to and including a single dose of 800 mg and multiple doses of 400 mg b.i.d. for 7 Days. However, when the QT interval was corrected for heart rate, administration of single doses of 800 and 2000 mg and at a multiple dose of 400 mg KH176 had marked effects. Post-hoc analysis of the ECGs showed clear changes in cardiac electrophysiology at single doses of 800 and 2000 mg and multiple doses of 400 mg b.i.d.. At lower doses, detailed ECG analysis showed no changes in electrophysiology compared to placebo. Exposure-response modelling of the cardiac intervals revealed an exposure range of KH176 without effects on cardiac conduction and provided a threshold of 1000 ng/mL above which changes in intervals could occur. After single- and multiple-dose administration, the pharmacokinetics of KH176 was more than dose proportional. KH176 accumulated to a small extent and food only slightly affected the pharmacokinetics of KH176, which was considered clinically irrelevant. Renal excretion of unchanged KH176 and its metabolite represents a minor pathway in the elimination of KH176. As expected in healthy volunteers no effects on redox biomarkers were observed. CONCLUSION: The study deemed that KH176 is well tolerated up to single doses of 800 mg and multiple doses of 400 mg b.i.d. and has a pharmacokinetic profile supportive for a twice daily dosing. Only at high doses, KH176 causes clinically relevant changes in cardiac electrophysiology, including prolonged QTc interval and changes in T wave morphology. A Phase 2 clinical trial (100 mg b.i.d., orally) has been conducted recently of which the final results are expected Q1 2018. TRIAL REGISTRATION: NCT02544217 . Registered. ISRCTN43372293 . Retrospectively registered.

Proximal aortic stiffening in Turner patients may be present before dilation can be detected: a segmental functional MRI study.

BACKGROUND: To study segmental structural and functional aortic properties in Turner syndrome (TS) patients. Aortic abnormalities contribute to increased morbidity and mortality of women with Turner syndrome. Cardiovascular magnetic resonance (CMR) allows segmental study of aortic elastic properties. METHOD: We performed Pulse Wave Velocity (PWV) and distensibility measurements using CMR of the thoracic and abdominal aorta in 55 TS-patients, aged 13-59y, and in a control population (n = 38;12-58y). We investigated the contribution of TS on aortic stiffness in our entire cohort, in bicuspid (BAV) versus tricuspid (TAV) aortic valve-morphology subgroups, and in the younger and older subgroups. RESULTS: Differences in aortic properties were only seen at the most proximal aortic level. BAV Turner patients had significantly higher PWV, compared to TAV Turner (p = 0.014), who in turn had significantly higher PWV compared to controls (p = 0.010). BAV Turner patients had significantly larger ascending aortic (AA) luminal area and lower AA distensibility compared to both controls (all p < 0.01) and TAV Turner patients. TAV Turner had similar AA luminal areas and AA distensibility compared to Controls. Functional changes are present in younger and older Turner subjects, whereas ascending aortic dilation is prominent in older Turner patients. Clinically relevant dilatation (TAV and BAV) was associated with reduced distensibility. CONCLUSION: Aortic stiffening and dilation in TS affects the proximal aorta, and is more pronounced, although not exclusively, in BAV TS patients. Functional abnormalities are present at an early age, suggesting an aortic wall disease inherent to the TS. Whether this increased stiffness at young age can predict later dilatation needs to be studied longitudinally.

Multicenter Randomized Double-Blind Comparison of Nebivolol plus HCTZ and Irbesartan plus HCTZ in the Treatment of Isolated Systolic Hypertension in Elderly Patients: Results of the NEHIS Study.

INTRODUCTION: The present study was aimed at comparing the antihypertensive efficacy, tolerability, and side effects profile of nebivolol/hydrochlorothiazide (NH) vs irbesartan/hydrochlorothiazide (IH) combination in elderly patients with isolated systolic hypertension (ISH). METHODS: 124 ISH patients aged 69.1 ± 5.1 years (mean ± SD) were enrolled by 13 general practitioners in Netherlands and Belgium and randomized in a double-blind fashion to receive either NH (5/12.5 mg day, n = 62) or IH (150/12.5 mg day, n = 62) for a 12-week period. The primary efficacy endpoint of the study was the comparison of the two combinations in terms of sitting office systolic blood pressure (BP) reduction after 12 weeks of treatment. In addition ambulatory BP, 24-h BP variability, tolerability, and safety profile were also investigated. RESULTS: 122 patients were included in the intention-to-treat analysis. After 12 weeks of treatment the reduction of systolic BP with NH was significantly greater than IH (-25.8 ± 12 vs -21.2 ± 14 mm Hg, P < 0.03). Diastolic BP reduction was significantly greater with NH after 4 and 8 weeks of treatment but similar at the end of the study (or after 12 weeks). In contrast, the magnitude of the 24-h, daytime, and nighttime systolic and diastolic BP reduction was almost similar in the two groups, while heart rate reduction induced by NH was significantly (P < 0.001) greater during the 24-h, daytime, and nighttime period than that induced by IH. NH caused a reduction in 24-h BP variability significantly greater than IH (standard deviation -4.4 ± 2.7 vs -2.2 ± 5.1 mm Hg, P < 0.02, variation coefficient -2.0 ± 2.6 vs -0.3 ± 3.4%, P < 0.01). Both treatment regimens were well tolerated. CONCLUSIONS: These data provide evidence that NH reduces office BP more than IH but has similar effects on 24-h BP. NH reduces 24-h systolic and diastolic BP variability more than IH, suggesting a greater protective effect on a variable known to adversely affect prognosis. TRIAL REGISTRATION: EU clinical Trials Register identifier, 2010-023104-28. FUNDING: Menarini International Operations Luxembourg.

Dried blood spot analysis of gabapentin as a valid alternative for serum: a bridging study.

We evaluated the applicability of a validated GC-MS method for the determination of gabapentin in dried blood spots (DBS). Important for the acceptance of DBS sampling as an alternative sampling strategy is the possibility to base solid conclusions on the quantification. Therefore, bridging studies -studies in which the correlation between both DBS and a reference matrix (e.g. serum) is evaluated statistically- need to be conducted. To this end, a comparative study was set up to quantify gabapentin in both blood (DBS) and serum samples. Statistically significant differences between DBS and serum concentrations were found (p<0.001). A mean blood-to-serum ratio of 0.85 was observed, which is in line with expectations. Calculated serum concentrations (obtained by dividing the DBS concentrations by 0.85) demonstrated a good correlation with measured serum concentrations, with 87% of samples fulfilling the criterion for incurred sample reanalysis. Furthermore, our data indicate a good correlation between capillary and venous concentrations. Conclusively, this study demonstrated that DBS are a valid alternative to serum for the determination of gabapentin.

EUFEMED London Conference 2017: Exploratory Medicines Development: Innovation and Risk Management.

The first formal conference of the EUropean Federation for Exploratory MEdicines Development (EUFEMED) held in London was the result of a collaborative effort of its founding associations: the Association for Applied Human Pharmacology (AGAH; Germany), the Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI; UK), the Belgian Association of Phase-I Units (BAPU; Belgium), and Club Phase-I (France). The conference focused on innovation and risk management in early clinical drug development. Among other innovations, immunotherapy in oncology and inflammatory diseases were discussed as well as the importance of adaptive trial designs in early clinical drug development. Consideration was given to assessing and mitigating risk in early clinical drug development, and included a preconference workshop. Different measures to minimize risks in healthy volunteers and patients in first-in-human trials were discussed in addition to the importance of non-clinical data, the need for reliable biomarkers, improved communication on adverse events (AEs) and well-trained study sites with ready access to intensive care units and clinical specialists. The need for a European-wide system for prevention of over-volunteering was also discussed. The conference provided opportunity to discuss these developments and concerns and the changing regulatory environment with stakeholders from academia, industry, and regulatory agencies including the European Medicines Agency (EMA). Presentations given by invited speakers are published on http://www.eufemed.eu/london-conference-2017/.

Microwave-assisted on-spot derivatization for gas chromatography-mass spectrometry based determination of polar low molecular weight compounds in dried blood spots.

Dried blood spot (DBS) sampling and analysis is increasingly being applied in bioanalysis. Although the use of DBS has many advantages, it is also associated with some challenges. E.g. given the limited amount of available material, highly sensitive detection techniques are often required to attain sufficient sensitivity. In gas chromatography coupled to mass spectrometry (GC-MS), derivatization can be helpful to achieve adequate sensitivity. Because this additional sample preparation step is considered as time-consuming, we introduce a new derivatization procedure, i.e. "microwave-assisted on-spot derivatization", to minimize sample preparation of DBS. In this approach the derivatization reagents are directly applied onto the DBS and derivatization takes place in a microwave instead of via conventional heating. In this manuscript we evaluated the applicability of this new concept of derivatization for the determination of two polar low molecular weight molecules, gamma-hydroxybutyric acid (GHB) and gabapentin, in DBS using a standard GC-MS configuration. The method was successfully validated for both compounds, with imprecision and bias values within acceptance criteria (<20% at LLOQ, <15% at 3 other QC levels). Calibration lines were linear over the 10-100µg/mL and 1-30µg/mL range for GHB and gabapentin, respectively. Stability studies revealed no significant decrease of gabapentin and GHB in DBS upon storage at room temperature for at least 84 days. Furthermore, DBS-specific parameters, including hematocrit and volume spotted, were evaluated. As demonstrated by the analysis of GHB and gabapentin positive samples, "microwave-assisted on-spot derivatization" proved to be reliable, fast and applicable in routine toxicology. Moreover, other polar low molecular weight compounds of interest in clinical and/or forensic toxicology, including vigabatrin, beta-hydroxybutyric acid, propylene glycol, diethylene glycol, 1,4-butanediol and 1,2-butanediol, can also be detected using this method.

Polypharmacy in a Belgian cohort of community-dwelling oldest old (80+).

OBJECTIVES: Polypharmacy is highly prevalent among older people (65+), but little is known on the medication use of the oldest old (80+). This study explores the medication use of the Belgian community-dwelling oldest old in relation to their demographic, clinical and functional characteristics. METHODS: Baseline data was used from the BELFRAIL study; a prospective, observational population-based cohort of Belgian community-dwelling patients (80+). General practitioners recorded clinical problems and medications. Medications were coded by the Anatomic Therapeutic Chemical classification. RESULTS: Participants' (n = 503) mean age was 84.4 years (range 80-102) and 61.2% was female. Median chronic medication use was 5 (range 0-16). Polypharmacy (≥5 medications) was high (57.7%), with excessive polypharmacy (≥10 medications) in 9.1%. Most commonly used medication group were antithrombotics, but also benzodiazepines and antidepressants were frequently consumed. Demographics related to polypharmacy (univariate analysis) were female gender, low education and moderate alcohol use. Age, care dependency and cognitive impairment showed no association with polypharmacy. In multivariate analysis, the predominant association with polypharmacy was found for multimorbidity (OR 1.78, 95% CI 1.5-2.1), followed by depression (OR 3.7, 95% CI 4.4-9.7) and physical activity (OR 0.8, 95% CI 0.7-0.9). CONCLUSIONS: Polypharmacy was high among Belgian community-dwelling oldest old (80+). Determinants of polypharmacy were interrelated, but dominated by multimorbidity. On top of the burden of multimorbidity, polypharmacy was independently associated with less physical activity, and with depressive symptoms.