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Objective: To compare the effects of lorazepam, a benzodiazepine-type anxiolytic agent, with those of captodiamine, a non-benzodiazepine anxiolytic agent, on vigilance and on driving behaviour. Design: Randomised, double-blind, crossover trial. Study Participants: Sixteen healthy male volunteers, aged 29 to 44 years, medically qualified to drive, holding a driving licence for more than 5 years, and driving more than 15 000km per year. Intervention: Lorazepam 0.5mg in the morning and at lunchtime, 1mg at bedtime, for 7 days; captodiamine 50mg in the morning, at lunchtime and at bedtime, for 7 days. Outcome Measures: Principal criterion: driving test on a 900m circuit with assessment of the number of errors resulting from clumsiness, excessive inhibition and disinhibition. Other criteria: psychometric tests (visual and auditory reaction times, tremometric test) and measurement by visual analogue scales of the degree of internal stress, anxiety, drowsiness and reduction of physical and mental capacity. All measurements were made before and after 7 days of treatment. Results: During the driving test a reduction in the number of errors resulting from clumsiness and disinhibition was observed with captodiamine, whereas an increase in the number of errors was seen with lorazepam (p < 0.001). A trend towards a shortening of auditory reaction time was noted in favour of captodiamine (p < 0.10). The reduction in internal stress was significantly greater with lorazepam compared with captodiamine (p < 0.05). Atendency to drowsiness was noted with lorazepam (p < 0.10). No other trend or significant difference was observed between the two drugs. Conclusion: Compared with lorazepam, captodiamine improved the concentration and dexterity of individuals when driving, without inducing a tendency to drowsiness.

Objective: The JADE (Jornada de Análisis de Dislipemias en España) study aimed to analyse the impact of dyslipidaemia and other cardiovascular risk factors in primary care and to establish the attitude of physicians in treating dyslipidaemic patients. Participants and Methods: The JADE study was an observational study conducted in primary care centres throughout the Spanish territory over 1 day of activity. Physicians recorded the data of each patient who visited on the day selected and who provided laboratory tests on a previous visit (i.e. for reasons not related to the study) including the measurement of some lipid parameters. 3841 physicians participated, and collected information from 10 641 patients, of whom 7832 met predefined criteria for dyslipidaemia (73.6%). Results and Conclusion: In the group of patients with dyslipidaemia, 55.6% of patients received lipid-lowering treatment. When the degree of control achieved by patients on lipid-lowering drug treatment was analysed, it was found that only 14.7% had ideal low density lipoprotein levels, while in the group of patients considered to be nondyslipidaemic, 38.1% met criteria for lipid-lowering drug intervention but were not receiving treatment. Therefore, it would be advisable to perform programmes promoting the better diagnosis and treatment of dyslipidaemias.

Warfarin-related nephropathy is an unexplained acute kidney injury, and may occur in patients with supratherapeutic INR, in the absence of overt bleeding. Similar findings have been observed in rats treated with dabigatran etexilate. We conducted a prospective study in dabigatran etexilate-treated patients to assess the incidence of dabigatran-related nephropathy and to investigate the possible correlation between dabigatran plasma concentration (DPC) and worsening renal function. One hundred and seven patients treated long term with dabigatran etexilate for non-valvular atrial fibrillation (NVAF) were followed up for 90 days. DPC, serum creatinine (SCr) and serum cystatin C were prospectively measured. Ninety five patients had complete follow-up data and were evaluable for primary endpoint. Eleven patients had supratherapeutic DPC, defined as DPC higher than 200 ng/ml at study enrolment, but at the end of follow-up no patient showed a persistent increase in SCr. No patients experienced acute kidney injury. Our study shows that no persistent renal detrimental effect is associated with dabigatran treatment. An increase in SCr during dabigatran treatment is reversible and it seems to be unrelated to dabigatran itself.

Objective: The clinical efficacy, tolerability and acceptability of a new multidose powder inhaler (MDPI) [Easyhaler®, Orion Pharma, Finland] containing a high dose (500 μg/dose) of beclomethasone dipropionate (BDP) were compared with those of BDP metered dose inhaler administered with a large volume spacer (MDI-spacer). Patients and Study Design: Recruited patients were adult asthmatics currently receiving 800 to 1000 μg/day of inhaled corticosteroid. The dose of BDP during the study was 1000 μg/day The study was an open, randomised, parallel-group multicentre study and included a 2-week run-in period followed by a 12-week treatment period. Results: 74 patients were randomised to both groups. During the run-in period the mean morning peak expiratory flow (PEF) was 489 and 478 L/min in the MDPI and MDI-spacer groups, respectively. During the last 2 weeks of the study the morning PEF was 485 L/min in the MDPI group and 477 L/min in the MDI-spacer group. Asthma symptom scores and use of rescue medication were low in both groups. The median dose of histamine required to decrease forced expiratory volume in 1 second (FEV1) by 15% was 1.05mg in the MDPI group and 0.64mg in the MDI-spacer group. The most frequent adverse events were hoarseness and sore throat. Mean serum cortisol levels were not affected in either treatment group. Patients’ personal opinion regarding acceptability of the devices clearly favoured the MDPI. Conclusion: In conclusion, the novel powder inhaler was well tolerated and at least equally effective compared with the conventional MDI-spacer combination in the treatment of asthma with BDP. However, in everyday use the patients clearly favoured the powder inhaler.

Combined pulmonary fibrosis and emphysema (CPFE) is a computed tomography (CT)-defined syndrome of combined pulmonary fibrosis and emphysema, characterized by subnormal spirometry, impairment of gas exchange, and high prevalence of pulmonary hypertension. Although endothelin-1 (ET-1) plays an important role in the development of lung fibrosis as well as in pulmonary hypertension, no ET-1-targeted therapy is currently recommended. Here we report a case of CPFE successfully treated with ambrisentan, an endothelin-A receptor antagonist, and also discuss the biologic mechanisms underlying the observed therapeutic effects. A 79-year-old man with chronic obstructive pulmonary disease (COPD) was referred to our respiratory unit as an outpatient for dyspnea. Clinical, radiologic, and laboratory findings suggested a diagnosis of chronic hypoxemic, type 1 respiratory failure, due to combined pulmonary fibrosis and emphysema, complicated by severe, precapillary pulmonary hypertension. Pharmacologic treatment with ambrisentan induced an initial improvement in clinical symptoms that proved to be very relevant 9 months later. In order to investigate the biologic mechanisms underlying the clinical effects of ambrisentan, we performed an “in vitro” study on primary cultures of fibrotic human lung fibroblasts, as well as on human umbilical vein endothelial cells, incubated for 24 and 48 h with ET-1, in the absence or presence of an overnight treatment with ambrisentan. ET-1 significantly increased cell proliferation and mitogen-activated protein kinase activation (P < 0.01). These effects were significantly (P < 0.01) inhibited by ambrisentan in both cell cultures. In conclusion, we hypothesize that the clinical benefits induced by ambrisentan in this patient with CPFE can be attributed to its vasodilator and anti-proliferative actions, exerted on pulmonary the vascular bed and lung fibroblasts.

Sacubitril-valsartan is effective in reducing the N-terminal pro-B-type natriuretic peptide level of hospitalized patients with acute decompensated heart failure, with a high acquisition cost compared with enalapril treatment. This study aimed to determine the cost utility of sacubitril-valsartan compared with enalapril for acute decompensated heart failure treatment. A Markov model was constructed to project the total costs, life-years, quality-adjusted life-years (QALYs) of early initiation, and a 2-month delay of sacubitril-valsartan treatment and enalapril treatment in hospitalized patients with acute decompensated heart failure over a lifetime horizon from a Thai healthcare system perspective. Clinical inputs were mainly derived from the PIONEER-HF and PARADIGM-HF trials, together with Thai epidemiological data. Cost data were based on the Thai population. All costs and outcomes were discounted at 3% annually. A series of sensitivity analyses were performed. Compared with enalapril, sacubitril-valsartan incurred a higher total cost per year (THB 42,994 [US$1367.48] vs THB 19,787 [US$629.37]), and it gained more QALYs (4.969 vs 4.755). The incremental cost-effectiveness ratio was THB 108,508/QALY (US$3451.26/QALY). Early initiation of sacubitril-valsartan treatment was more cost effective than delayed treatment. Sensitivity analyses revealed that at a level of willingness to pay of THB 160,000/QALY (US$5089/QALY), sacubitril-valsartan was a cost-effective strategy of about 60%. Sacubitril-valsartan is cost effective in patients with acute decompensated heart failure. However, the results are highly dependent on the long-term cardiovascular mortality, and they are applicable only to Thailand or countries with a similarly structured healthcare system. Long-term registries should be pursued to decrease the uncertainty around long-term mortality.