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.

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.

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.

MR pulse wave velocity increases with age faster in the thoracic aorta than in the abdominal aorta.

PURPOSE: To assess the difference between thoracic and abdominal aortic pulse wave velocity (PWV) in apparently healthy subjects including young adults to elderly subjects. MATERIALS AND METHODS: We performed PWV and distensibility measurements and analysis of thoracic and abdominal aortic segments in 96 apparently normal subjects aged 20-80 years with magnetic resonance (MR). Both unadjusted correlation and General Linear Model (GLM) analysis of log-transformed PWV (thoracic and abdominal aorta) and distensibility (four aortic cross-sections) were performed. RESULTS: Both thoracic and abdominal PWV values and distensibility values increased with age. In unadjusted analyses the correlation between the ln(thoracic PWV) and age (r = 0.71; P < 0.001) was stronger than between ln(abdominal PWV) and age (r = 0.50; P < 0.001). In GLM analysis, the only determinant of thoracic and abdominal PWV was age (F = 42.5 and F = 14.8, respectively; both P < 0.001). Similarly, correlation between ln(distensibility) and age was strong (r = -0.79, r = -0.67, r = -0.71, and r = -0.65 for ascending, descending, diaphragmatic, and low abdominal aorta, respectively; all P < 0.001). In GLM analysis, age was the major determinant for distensibility of the ascending aorta (F = 81.7; P < 0.001), descending aorta (F = 42.2; P < 0.001), diaphragmatic aorta (F = 39.2; P < 0.001), and low abdominal aorta (F = 32.8; P < 0.001). CONCLUSION: The thoracic aorta is less stiff than the abdominal aorta in young and middle-aged subjects, and stiffens more rapidly with age than the abdominal aorta, resulting in a stiffer thoracic than abdominal aorta at older age.

The impact of chronic benzodiazepine use on cognitive evolution in nursing home residents.

OBJECTIVE: Chronic use of benzodiazepines and Z-drugs (BZD/Zs) has been linked to cognitive decline. In this one-year prospective cohort study, we explored the impact of chronic BZD/Z use on cognitive decline compared to nonusers. METHODS: In cognitively capable BZD/Z users and nonusers in 10 Belgian nursing homes, we investigated cognition with the MiniMentalStateExamination(MMSE) at baseline and one year. A decrease of ≥ 4 points on the MMSE (clinically relevant decrease) was used in multiple logistic regression. We collected baseline demographics, functional, psychometric and social characteristics potentially influencing cognition. RESULTS: In both the 131 BZD/Z users and 95 nonusers, the cognition decreased significantly over time, but without significant difference between the groups. Clinically relevant decrease was present in 34% BZD/Z users and 27% nonusers (NS). Controlled for age, gender, education and BZD/Z use, the significant risk factors for clinically relevant cognitive decline were depression, hearing and functional impairment. Frequent reading was associated with less MMSE decrease. Our findings could not demonstrate with statistical significance that BZD/Z use was associated with fast cognitive decline. The risk factors for fast decline were depression, hearing and functional impairment, and the absence of a reading attitude. In addition, BZD/Z use and depression were associated, indicating a complex relationship.

A European Renal Best Practice (ERBP) position statement on the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for the management of blood pressure in non-dialysis-dependent chronic kidney disease: an endorsement with some caveats for real-life application.

Developing guidelines on a subject as broad as hypertension is difficult, especially when the guidance relates to hypertension in the chronic kidney disease (CKD) population. The Kidney Disease: Improving Global Outcomes Guideline Development Group has applied a rigorous methodology in reviewing all available evidence, and their recommendations are consistent with the evidence-based approach. As a result, the European Renal Best Practice endorses most of its recommendations. However, the Work Group feels that some additional advice could help clinicians in daily practice: (i) individualization of treatment should be taken into account, especially (cardiovascular) co-morbidities, age, gender and race; (ii) side-effects, such as postural dizziness should be monitored closely, particularly in elderly, diabetics and patients with arterial stiffness; (iii) the importance of salt restriction should not be neglected; (iv) although angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blocker (ARBs) remain a cornerstone in the management of hypertension, and especially cardiovascular protection, in some particular situations such as in advanced CKD and in patients without proteinuria, their role is less well defined; (v) as most CKD patients need more than one antihypertensive drug to achieve blood pressure control, the specific (renal) (dis)advantages of other classes than ACE-I or ARB should be taken into account.

Rectal and sublingual administration of tacrolimus: a single-dose pharmacokinetic study in healthy volunteers.

AIMS: The immunosuppressant tacrolimus is usually administered orally. When this is not feasible, other routes of administration may be useful. Previous research suggested that tacrolimus may be applied sublingually or rectally. Pharmacokinetic data are sparse. The aim of this study was to investigate and compare the pharmacokinetics of these alternative formulations with orally administered tacrolimus. METHODS: Three single, fixed-dose formulations of tacrolimus were administered in a random sequence in 18 healthy subjects, using a cross-over study design. For sublingual administration, 3 mg of powder obtained from oral capsules was applied under the tongue for a period of 15 min without swallowing, with mouth rinsing afterwards. For rectal administration, a suppository containing 15 mg of the oral powder was used. Oral administration consisted of 7 mg of instant-release tacrolimus capsules (Prograf). Main pharmacokinetic outcome parameters were compared by anova. RESULTS: Sublingual administration showed no clinically significant exposure, contrary to rectal administration, where all subjects had clinically relevant exposure, with a lower relative bioavailability (78%), a lower maximal blood concentration and a later time of maximal blood concentration compared with oral administration. CONCLUSIONS: Sublingual administration of a single dose of tacrolimus does not result in systemic exposure if care is taken not to swallow saliva and to rinse the oral cavity afterwards. Rectal administration of tacrolimus results in clinically relevant systemic exposure and might represent an alternative formulation in case oral administration is not feasible. When used as a topical agent, systemic side-effects should be considered.

Effectiveness of pharmaceutical care for patients with chronic obstructive pulmonary disease (PHARMACOP): a randomized controlled trial.

AIMS: Few well-designed randomized controlled trials have been conducted regarding the impact of community pharmacist interventions on pharmacotherapeutic monitoring of patients with chronic obstructive pulmonary disease (COPD). We assessed the effectiveness of a pharmaceutical care programme for patients with COPD. METHODS: The pharmaceutical care for patients with COPD (PHARMACOP) trial is a single-blind 3 month randomized controlled trial, conducted in 170 community pharmacies in Belgium, enrolling patients prescribed daily COPD medication, aged ≥ 50 years and with a smoking history of ≥ 10 pack-years. A computer-generated randomization sequence allocated patients to an intervention group (n = 371), receiving protocol-defined pharmacist care, or a control group (n = 363), receiving usual pharmacist care (1:1 ratio, stratified by centre). Interventions focusing on inhalation technique and adherence to maintenance therapy were carried out at start of the trial and at 1 month follow-up. Primary outcomes were inhalation technique and medication adherence. Secondary outcomes were exacerbation rate, dyspnoea, COPD-specific and generic health status and smoking behaviour. RESULTS: From December 2010 to April 2011, 734 patients were enrolled. Forty-two patients (5.7%) were lost to follow-up. At the end of the trial, inhalation score [mean estimated difference (Δ),13.5%; 95% confidence interval (CI), 10.8-16.1; P < 0.0001] and medication adherence (Δ, 8.51%; 95% CI, 4.63-12.4; P < 0.0001) were significantly higher in the intervention group compared with the control group. In the intervention group, a significantly lower hospitalization rate was observed (9 vs. 35; rate ratio, 0.28; 95% CI, 0.12-0.64; P = 0.003). No other significant between-group differences were observed. CONCLUSIONS: Pragmatic pharmacist care programmes improve the pharmacotherapeutic regimen in patients with COPD and could reduce hospitalization rates.

Investigation of combined CYP3A4 inductive/inhibitory properties by studying statin interactions: a model study with the renin inhibitor ACT-178882.

PURPOSE: ACT-178882, a direct renin inhibitor, was used as a model compound in an elaborate drug-drug interaction study with atorvastatin and simvastatin to explore complex CYP3A4 inductive and inhibitory properties. METHODS: Thirty-two healthy male subjects received single doses of 20 mg atorvastatin and 20 mg simvastatin on days 1, 9, 31, and 41. On days 6 to 33, 500 mg ACT-178882 was administered once daily. Plasma concentrations of ACT-178882, simvastatin, and atorvastatin were measured by LC-MS/MS. Routine safety assessments were performed throughout the study. RESULTS: Exposure (as based on area under the curve) to simvastatin and 6ß-hydroxyacid simvastatin increased (90 % confidence interval) 4.63-fold (3.90, 5.50) and 3.71-fold (3.19, 4.32), respectively, when comparing day 9 and day 1. On day 9, exposure to atorvastatin was similar but Cmax decreased, while both variables decreased for ortho-hydroxy atorvastatin when compared to day 1. On day 31, after prolonged administration of ACT-178882, exposure to atorvastatin, ortho-hydroxy atorvastatin, simvastatin, and 6ß-hydroxyacid simvastatin decreased by 14, 19, 21, and 27 %, respectively, when compared to day 9. However, on this day, exposure to simvastatin and its metabolite was still markedly higher when compared to day 1. Effects of ACT-178882 had largely dissipated on day 41. CONCLUSIONS: This design enabled the study of complex time-dependent effects on CYP3A4 activity with clinically relevant substrates.

Feasibility of discontinuing chronic benzodiazepine use in nursing home residents: a pilot study.

PURPOSE: Guidelines discourage chronic benzodiazepines and related Z drugs (BZD/Zs) for sleep problems. However, prevalence among nursing home residents remains high. Discontinuing these drugs is widely recommended but seems difficult to implement. The aim of our study was to evaluate the overall feasibility in the nursing home, in terms of willingness towards discontinuation and success rate at 8 months, together with the impact on withdrawal symptoms, change in sleep quality, quality of life and medication use. METHODS: In a convenience sample of five nursing homes (823 residents), we included cognitively competent residents with chronic BZD/Z use for insomnia. We investigated sleep quality [with Pittsburgh Sleep Quality Index (PSQI)], quality of life (EQ-5D) and withdrawal symptoms [Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ)]. Success rate was analysed with survival analysis. RESULTS: Of the 135 eligible residents, both general physician (GP) and resident were willing to initiate discontinuation in 38 residents. Reasons for refusing to initiate discontinuation among GPs was the unmotivated patient and among residents the reluctance towards change. At 8 months, 66.0% were successful discontinuers, with the subjective PSQI component evolving favourably (p = 0.013) and a decreasing number of midnight awakenings (p = 0.041). In the relapse group (n = 13), the quality of life decreased (p = 0.012), with mainly an increase of problems with activities and pain/discomfort. In both groups, the withdrawal symptoms, functionality and medication use did not change. CONCLUSION: Discontinuation of chronic BZD/Z use is feasible in the nursing home setting without noticeable withdrawal symptoms, without a switch in medication use, without detrimental effect on quality of life and with a positive effect on the self-perceived sleep quality.

Quality of prescribing in Belgian nursing homes: an electronic assessment of the medication chart.

OBJECTIVE: To develop a computerized assessment tool for monitoring the quality of prescribing in Belgian nursing homes. DESIGN: In a observational cross-sectional study of the medication charts of nursing home residents, potentially inappropriate medication (PIM) was investigated using three scoring systems for the elderly (Beers, ACOVE, BEDNURS) complemented with a list of drug-drug interactions. SETTING: A representative stratified sample of Belgian nursing homes (n = 76). PARTICIPANTS: A random sample of nursing home residents with a complete data set (n = 1730) excluding palliative care patients. MAIN OUTCOME MEASURE: A combination of PIM scores to assess inappropriate, under- and overprescribing. RESULTS: Included residents had a mean age of 85, 78% were female. They used a mean of 7.1 chronic medications. Most PIMs were detected by the application of the ACOVE criteria for underprescribing with 58% of patients having at least one PIM. Using the BEDNURS and the Beers criteria, at least one PIM was noticed in 56 and 27% of patients, respectively. Patients' characteristics showing a positive relationship with the PIM score were age, female gender, amount of clinical and nursing care problems, number of prescriptions and the use of psychotropic drugs (multiple regression analysis R(2) = 0.332). CONCLUSIONS: In Belgian nursing homes, the observed high level of drug utilization was associated with potentially inappropriate prescribing. The development of a combined assessment tool and the implementation of a computerized monitoring system of PIMs is highly recommended to improve the quality of prescribing.

Barriers to antipsychotic discontinuation in nursing homes: an exploratory study.

OBJECTIVES: Despite safety warnings on serious adverse effects and guidance advising discontinuation, antipsychotic use in nursing homes remains high. Studies documenting the barriers experienced to antipsychotic discontinuation are rare. This exploratory study investigates the willingness of nurses and general practitioners (GPs) as well as the barriers to undertake antipsychotic discontinuation. DESIGN AND SETTING: A mixed-method study involving an expert meeting, followed by a survey using structured questionnaires distributed to responsible nurses (primary caregivers) and treating GPs on selected nursing home residents in Belgian nursing homes to generate case-specific information. RESULTS: Antipsychotic users (n = 113) had a mean age of 81 years (range 57-97); 62% were female and 81% had moderate to severe cognitive impairment. Nurses and GPs indicated a willingness for antipsychotic discontinuation in a small proportion of residents, 13.8% and 12.2%, respectively, with a shared willingness in only 4.2%. Residents for whom there was a higher willingness to try antipsychotic discontinuation were generally older (mean age 84.6 vs. 80.3, p = 0.07), had high physical dependency (ADL > 14, 93.3% vs. 60.9%, p = 0.01) and resided on a ward with controlled access (80.0% vs. 45.7%, p = 0.02). In contrast, residents for whom there was a significant lower willingness for discontinuation already had a previously failed discontinuation effort, and may present risk of harm to themselves or to others. Nurses working longer on the ward, with lower education, presented higher barriers to discontinuation of antipsychotics. CONCLUSION: Nurses and GPs share a very low willingness and high barriers to antipsychotic discontinuation. To implement discontinuation programs, complex multidisciplinary interventions should be offered taking existing barriers into account.

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.

Oral bioavailability of moxifloxacin after Roux-en-Y gastric bypass surgery.

OBJECTIVES: Roux-en-Y gastric bypass surgery is the most commonly performed procedure for the treatment of morbid obesity. This anatomical alteration may affect the absorption and consequently the bioavailability of oral drugs. This study aims to investigate the oral bioavailability of moxifloxacin in 12 healthy volunteers who underwent gastric bypass surgery. PATIENTS AND METHODS: In this randomized crossover study, each subject received two single standard doses of 400 mg of moxifloxacin orally or intravenously administered on two occasions separated by a washout period of 1 week. Serial venous blood samples were drawn up to 72 h after dosing and moxifloxacin plasma levels were measured by a validated HPLC method with fluorescence detection. [clinicaltrials.gov database (identifier: NCT01130922).] RESULTS: After oral dosing, moxifloxacin plasma concentrations reached a maximum (C(max)) of 3.38 ± 1.41 mg/L after 1.75 h (0.75-4.00). After intravenous dosing, C(max) and T(max) were 4.53 ± 1.43 mg/L and 1.03 h (0.75-2.50), respectively. The mean areas under the plasma concentration time curve extrapolated to infinity (AUC(∞)) were 46.2 ± 1.4 mg ·â€Šh/L after oral dosing and 52.3 ± 1.3 mg ·â€Šh/L after intravenous dosing, resulting in a mean oral bioavailability of 88.32% [90% confidence interval (CI) 85.64%-91.08%]. CONCLUSIONS: This study confirms that exposure to moxifloxacin is equivalent for oral and intravenous administration of 400 mg dosages in healthy volunteers who underwent gastric bypass surgery. But these exposures were more than 50% higher than those described for subjects without gastric bypass. This may suggest a higher enterohepatic recirculation of moxifloxacin after gastric bypass.

Benzodiazepine use in Belgian nursing homes: a closer look into indications and dosages.

AIM: (1) To describe the prevalence of benzodiazepine use in Belgian nursing homes, with specific attention to indications and dosages. (2) To compare actual and recommended dosages of benzodiazepines for anxiety and insomnia. (3) To explore the risk profile for chronic benzodiazepine use in institutionalised older adults. METHODS: Medication charts of 1,730 residents from 76 nursing homes in Belgium were collected and analysed, using the ATC classification. Drug name, indication and daily dosage were recorded. From authoritative international sources, we extracted for each drug and each indication a daily dosage recommended not to be exceeded in older adults for comparison with observed actual dosages. RESULTS: Among the chronic benzodiazepine or z-drug (BZD/Z) users (50% of the residents), the leading indication was 'insomnia' (59% of the users) followed by 'anxiety' (17%) and 'unrest' (10%). In the chronic prescriptions of BZD/Zs indicated for insomnia, the actual daily dose exceeded the geriatric upper limit in 95% of lormetazepam prescriptions, 82% of zolpidem, 78% of zopiclone and 35% of lorazepam prescriptions. For anxiety, daily doses also exceeded the limit but not to the same extent. Multivariate analysis showed BZD/Z use was positively associated with pain (OR 1.58, 95% CI 1.27-1.97), constipation (OR 1.43, 95% CI 1.16-1.76) and depression (OR 1.68, 95% CI 1.35-2.08). Residents with dementia were less likely to receive a BZD/Z (OR 0.60, 95% CI 0.48-0.74). CONCLUSION: Efforts to reduce the use of BZD/Zs in nursing homes should concentrate on insomnia, with interventions aimed at reducing too high prevalence of chronic use and too high daily dosages in this indication.

Naftidrofuryl for intermittent claudication.

BACKGROUND: Lifestyle changes and cardiovascular prevention measures are a primary treatment for intermittent claudication (IC). Symptomatic treatment with vasoactive agents (Anatomic Therapeutic Chemical Classification (ATC) for medicines from the World Health Organisation class CO4A) is controversial. OBJECTIVES: To evaluate evidence on the efficacy and safety of oral naftidrofuryl (ATC CO4 21) versus placebo on the pain-free walking distance (PFWD) of people with IC by using a meta-analysis based on individual patient data (IPD). SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched October 2012) and CENTRAL (2012, Issue 9).For the original review the authors handsearched the European Journal of Vascular and Endovascular Surgery (1984 to 1994) and checked relevant bibliographies. They contacted the registration holder of naftidrofuryl and the authors of identified trials for any unpublished data. SELECTION CRITERIA: We included only randomized controlled trials (RCTs) with low or moderate risk of bias for which the IPD were available. DATA COLLECTION AND ANALYSIS: We collected data from the electronic data file or from the case report form and checked the data by a statistical quality control procedure. All randomized patients were analyzed following the intention-to-treat (ITT) principle. The geometric mean of the relative improvement in PFWD was calculated for both treatment groups in all identified studies.The effect of the drug was assessed compared with placebo on final walking distance (WDf) using multilevel and random-effect models and adjusting for baseline walking distance (WD0). For the responder analysis, therapeutic success was defined as an improvement of walking distance of at least 50%. MAIN RESULTS: We included seven studies in the IPD (n = 1266 patients). One of these studies (n = 183) was only used in the sensitivity analysis so that the main analysis included 1083 patients. The ratio of the relative improvement in PFWD (naftidrofuryl compared with placebo) was 1.37 (95% confidence interval (CI) 1.27 to 1.49, P < 0.001). The absolute difference in responder rate, or proportion successfully treated, was 22.3% (95% CI 17.1% to 27.6%). The calculated number needed to treat was 4.5 (95% CI 3.6 to 5.8). AUTHORS' CONCLUSIONS: Oral naftidrofuryl has a statistically significant and clinically meaningful, although moderate, effect of improving walking distance in the six months after initiation of therapy for people with intermittent claudication. Access by researchers to data from RCTs that are suitable for IPD analysis should be possible through repositories of data from pharmacological trials. Regular formal appraisal of the balance of risk and benefit is needed for older pharmaceutical products.

The influence of tocolytic drugs on cardiac function, large arteries, and resistance vessels.

PURPOSE: Beta-2 adrenoceptor agonistic drugs like ritodrine have been the reference tocolytic drugs, but are associated with cardiovascular side-effects. Atosiban, a newer drug, is a competitive antagonist of oxytocin and has been claimed to have fewer cardiovascular side effects. Until now, there has mainly been a subjective reporting of adverse reactions and few objective cardiovascular data. Evaluation of the acute effects of therapeutic doses of ritodrine and atosiban compared with placebo on cardiac function, large artery properties, blood pressure, and resistance vessels. METHODS: A double-blind, randomized trial was carried out in 20 non-pregnant female volunteers. Hemodynamic measurements were made under standardized conditions during kinetic steady state. Cardiac output was measured with echocardiography, large artery properties with an echo-tracking device. The effect on the microcirculation was estimated using the total peripheral resistance index (TPRI). RESULTS: Atosiban did not differ from placebo. With ritodrine, cardiac function increased by 79% compared with placebo because of a rise in heart rate (91%). TPRI decreased by 48%. Ritodrine increased the distensibility of the common carotid artery by 62% and the compliance by 83%, independent of blood pressure. Compliance of the common femoral artery increased independently of pressure by 33% and the distensibility by 59%. Aortic pulse wave velocity was not influenced by either medication. CONCLUSIONS: The present study shows potential beneficial vascular effects of ritodrine that are counterbalanced by the cardiac effects. Atosiban has no clinically relevant cardiovascular effects and may be a good alternative for ritodrine in pregnant women at risk of cardiovascular complications.