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Dexamphetamine normalises electrophysiological activity in attention deficit-hyperactivity disorder during the Stroop task.

A case study was conducted to investigate whether dexamphetamine enhances interference control in an adult with attention deficit/hyperactivity disorder. Continuous electroencephalography was recorded both on and off dexamphetamine during performance on a Stroop task. An age-, gender- and IQ-matched control also completed the same task. Event related potentials for the control participant revealed a positive potential to incongruent stimuli between 270 and 440 ms, whereas for the participant with attention deficit/hyperactivity disorder off medication, the reverse polarity was observed in a later time window. Following administration of dexamphetamine, however, the event-related potentials for the incongruent condition closely resembled those in the control, suggesting that dexamphetamine successfully normalises electroencephalographic activity.

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Effectiveness and safety of salmeterol in nonspecialist practice settings.

To evaluate the effectiveness and safety of inhaled salmeterol in patients managed in nonspecialist practice settings. A randomized, double-blind, 6-month, parallel-group study involving 253 centers. Primarily nonspecialist practices (n = 232). A total of 911 subjects (417 men; 494 women) who met American Thoracic Society asthma criteria were enrolled and randomized to treatment with either twice-daily salmeterol aerosol (50 microg; n = 455) or matching placebo twice daily (n = 456). Both groups were allowed to take salbutamol as needed. All subjects were previously treated with anti-inflammatory maintenance therapy that was continued throughout the study. The primary outcome variable was the proportion of subjects with serious asthma exacerbations defined as an exacerbation requiring hospitalization, emergency department visit, or use of prednisone during the treatment period. A total of 712 subjects competed the study. There was no significant difference in the proportion of subjects experiencing serious exacerbations between the salmeterol and placebo groups (20.8% vs 20.9%, respectively; p = 0.935; power > 88%). Peak expiratory flow was significantly higher in the salmeterol group (398 L/min vs 386 L/min for placebo; p < 0.01). Median daily use of salbutamol was two inhalations for the salmeterol group and three inhalations for placebo (p < 0.001). The proportion of subjects sleeping through the night was significantly higher in the salmeterol group (74%) as compared to placebo (68%; p = 0.028). Salmeterol treatment is effective in subjects typically cared for in the primary-care setting and does not increase the frequency of severe exacerbations.

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Efficacy of transoral fundoplication vs omeprazole for treatment of regurgitation in a randomized controlled trial.

Transoral esophagogastric fundoplication (TF) can decrease or eliminate features of gastroesophageal reflux disease (GERD) in some patients whose symptoms persist despite proton pump inhibitor (PPI) therapy. We performed a prospective, sham-controlled trial to determine if TF reduced troublesome regurgitation to a greater extent than PPIs in patients with GERD. We screened 696 patients with troublesome regurgitation despite daily PPI use with 3 validated GERD-specific symptom scales, on and off PPIs. Those with at least troublesome regurgitation (based on the Montreal definition) on PPIs underwent barium swallow, esophagogastroduodenoscopy, 48-hour esophageal pH monitoring (off PPIs), and high-resolution esophageal manometry analyses. Patients with GERD and hiatal hernias ≤2 cm were randomly assigned to groups that underwent TF and then received 6 months of placebo (n = 87), or sham surgery and 6 months of once- or twice-daily omeprazole (controls, n = 42). Patients were blinded to therapy during follow-up period and reassessed at 2, 12, and 26 weeks. At 6 months, patients underwent 48-hour esophageal pH monitoring and esophagogastroduodenoscopy. By intention-to-treat analysis, TF eliminated troublesome regurgitation in a larger proportion of patients (67%) than PPIs (45%) (P = .023). A larger proportion of controls had no response at 3 months (36%) than subjects that received TF (11%; P = .004). Control of esophageal pH improved after TF (mean 9.3% before and 6.3% after; P < .001), but not after sham surgery (mean 8.6% before and 8.9% after). Subjects from both groups who completed the protocol had similar reductions in GERD symptom scores. Severe complications were rare (3 subjects receiving TF and 1 receiving the sham surgery). TF was an effective treatment for patients with GERD symptoms, particularly in those with persistent regurgitation despite PPI therapy, based on evaluation 6 months after the procedure. Clinicaltrials.gov no: NCT01136980.

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Plasminogen Activator Inhibitor-1 in depression: Results from Animal and Clinical Studies.

Evidence suggests that plasminogen activator inhibitor-1 (PAI-1) is a stress-related factor, and serum PAI-1 levels are increased in patients with major depressive disorders (MDD). Herein, we analysed PAI-1 protein levels in the brain, cerebrospinal fluid (CSF) and serum of rodents exposed to chronic unpredictable mild stress or treated with escitalopram. In addition, we examined PAI-1 concentrations in serum obtained from 17 drug-free depressed patients before and after escitalopram treatment. We found that PAI-1 expression was increased in area 1 of the cingulate cortex and prelimbic cortex of the medial prefrontal cortex as well as in the hippocampal cornu ammonis 3 and dentate gyrus in stressed rats. A downregulation of PAI-1 following chronic escitalopram treatment was also found. PAI-1 levels were higher in the CSF and serum in stressed rats than in controls, although the difference did not reach statistical significance in the serum. Escitalopram treatment significantly decreased PAI-1 levels in the serum, but not in the CSF. MDD patients had significantly greater serum PAI-1 concentrations than controls. Our results suggest that PAI-1 is implicated in the pathophysiology of depression.

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Impact of CYP2C19 Genotype on Escitalopram Exposure and Therapeutic Failure: A Retrospective Study Based on 2,087 Patients.

The antidepressant escitalopram is predominantly metabolized by the polymorphic CYP2C19 enzyme. The authors investigated the effect of CYP2C19 genotype on exposure and therapeutic failure of escitalopram in a large patient population. A total of 4,228 escitalopram serum concentration measurements from 2,087 CYP2C19-genotyped patients 10-30 hours after drug intake were collected retrospectively from the drug monitoring database at Diakonhjemmet Hospital in Oslo. The patients were divided into subgroups based on CYP2C19 genotype: those carrying inactive (CYP2C19Null) and gain-of-function (CYP2C19*17) variant alleles. The between-subgroup differences in escitalopram exposure (endpoint: dose-harmonized serum concentration) and therapeutic failure (endpoint: switching to another antidepressant within 1 year after the last escitalopram measurement) were evaluated by multivariate mixed model and chi-square analysis, respectively. Compared with the CYP2C19*1/*1 group, escitalopram serum concentrations were significantly increased 3.3-fold in the CYP2C19Null/Null group, 1.6-fold in the CYP2C19*Null/*1 group, and 1.4-fold in the CYP2C19Null/*17 group, whereas escitalopram serum concentrations were significantly decreased by 10% in the CYP2C19*1/*17 group and 20% in the CYP1C19*17/*17 group. In comparison to the CYP2C19*1/*1 group, switches from escitalopram to another antidepressant within 1 year were 3.3, 1.6, and 3.0 times more frequent among the CYP2C19Null/Null, CYP2C19*1/*17, and CYP1C19*17/*17 groups, respectively. The CYP2C19 genotype had a substantial impact on exposure and therapeutic failure of escitalopram, as measured by switching of antidepressant therapy. The results support the potential clinical utility of CYP2C19 genotyping for individualization of escitalopram therapy.

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Psychopharmacology in the Pediatric Oncology and Bone Marrow Transplant Units: Antidepressant Treatment.

<b><i>Objectives:</i></b> The aim of this study was to characterize the clinical profiles, tolerability, and efficacy of two groups of antidepressants, selective serotonin reuptake inhibitors (SSRIs), and the atypical antidepressant, mirtazapine, in children and adolescents treated in a large pediatric Hematology-Oncology center. <b><i>Methods:</i></b> A review of computerized medical charts of 32 pediatric patients with cancer, from December 2011 to April 2020, was conducted. Efficacy and tolerability of antidepressant medications were retrospectively analyzed. The Clinical Global Impressions-Severity (CGI-S) and Clinical Global Impressions-Improvement (CGI-I) Scales were used to evaluate psychiatric symptoms severity before and following treatment, while the data on adverse events and drug-drug interactions were retrieved from the computerized medical records. <b><i>Results:</i></b> Thirty-two children and adolescents with cancer, 2-21 years of age (mean 14.1 ± 4.6 years), were treated with antidepressants. Fourteen patients (44%) received mirtazapine, whereas 18 patients (56%) received SSRIs: sertraline (25%), escitalopram (25%), or fluoxetine (6%). Treatment choice was dictated either by physician preference or informed by potential drug-drug interactions. The most common psychiatric diagnoses were major depressive disorders (47%), anxiety disorders (19%), and medication-induced psychiatric disorders (19%). The most common psychiatric-medical symptoms were depressed mood (94%) and anxiety (62%). CGI-S improved significantly (<i>p</i> < 0.05) between pretreatment and on-treatment assessments, with no statistically significant difference between SSRI and mirtazapine-treated patients. CGI-I scores at reassessment indicated improvement in most patients (84%). Adverse events of treatment were mild in all patients. <b><i>Conclusions:</i></b> The antidepressants used in this study, SSRIs and mirtazapine, were effective and well tolerated in children and adolescents with cancer and psychiatric comorbidities. Given the high rates of depression and anxiety in children with cancer, large-scale, multisite, prospective clinical trials of antidepressants are warranted.

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Switching patients from daily citalopram, paroxetine, or sertraline to once-weekly fluoxetine in the maintenance of response for depression.

Major depressive disorder is frequently a chronic, recurrent condition necessitating maintenance treatment. For some patients, compliance with daily pharmacotherapy is difficult over time. As an alternative approach, a once-weekly administered formulation of fluoxetine has recently been made available. This raises the important question of whether once-weekly enteric-coated fluoxetine, 90 mg, is effective for maintenance of response in patients whose depressive symptoms have responded to daily dosing with selective serotonin reuptake inhibitors (SSRIs) such as citalopram, paroxetine, or sertraline. Patients had met DSM-IV criteria for major depressive disorder prior to beginning treatment for their current episode, had received 6 to 52 weeks of treatment with citalopram (20-40 mg/day [N = 83]), paroxetine (20 mg/day [N = 77]), or sertraline (50-100 mg/day [N = 86]), and had responded to that treatment (Clinical Global Impressions-Severity of Illness [CGI-S] score < or = 2, modified 17-item Hamilton Rating Scale for Depression [HAM-D-17] score < or = 10). Patients meeting these criteria (N = 246) continued treatment with their current SSRI for 1 week, then were switched to open-label enteric-coated fluoxetine, 90 mg, taken once weekly for 12 weeks. Safety measures were comparisons of spontaneously reported and solicited treatment-emergent adverse events. Efficacy measures were percentages of patients who discontinued the study for relapse and lack of efficacy and comparison of change from baseline to endpoint in scores on the modified HAM-D-17, subscales of the HAM-D-28, and the CGI-S. Quality of life measures were assessed with the MOS 36-Item Short-Form Health Survey (SF-36). We hypothesized that the once-weekly administration of fluoxetine could be safely and effectively initiated among subjects who had been stabilized on daily SSRI treatment. Seventy-nine percent of patients successfully completed a switch to enteric-coated fluoxetine, 90 mg, with 9.3% discontinuing due to relapse or lack of efficacy. Enteric-coated fluoxetine at a once-weekly dose of 90 mg was well tolerated in all groups. No significant increases were found in the HAM-D-17 total, HAM-D-28 subscores, or CGI-S score. Patients showed improvement from baseline to endpoint in most of the SF-36 health concepts. Enteric-coated fluoxetine taken once weekly appears to be well tolerated and efficacious in patients who responded to acute therapy with other SSRIs and were subsequently switched to fluoxetine once weekly for continuation/maintenance therapy.

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A randomized, open-label, comparative study of simvastatin plus diet versus diet alone on angiographic retardation of coronary atherosclerosis in adult Japanese patients: Japanese utilization of simvastatin therapy (JUST) study.

Cholesterol-lowering therapy reduces the risk of cardiovascular events by slowing the progression or enhancing the regression of coronary atherosclerosis. This study assessed the effects of simvastatin 10 mg/d on progressive coronary atherosclerosis in Japanese patients with coronary artery disease and mild to moderate hypercholesterolemia. In a 2-year, open-label comparative study, patients with coronary atherosclerotic lesions (> or =50% diameter stenosis) and serum total cholesterol levels > or =200 and < or =280 mg/dL were randomly assigned to 2 groups: 1 group received simvastatin 10 mg/d taken orally with diet (S-D) and the other group was assigned to diet alone (D). Atherosclerotic progression in coronary segments was compared in the 2 groups using quantitative coronary angiography (QCA). QCA measurements were done under blinded conditions. The study's primary end point was the comparison of mean changes in each segment's minimum obstruction diameter (MOD) or mean segment diameter (MSD) between the S-D group and the D group. A total of 299 patients were randomized, 146 to the S-D group and 153 to the D group. Mean (SD) age was 58.7 (8.0) years and mean (SD) total cholesterol level was 232.6 (21.6) mg/dL at baseline. After 2 years, serum low-density lipoprotein cholesterol levels decreased by 31.9% in the S-D group and by 2.0% in the D group. QCA showed significant stenotic progression in the D group, with reductions in MOD and MSD both by per-segment-based (P < 0.001 and P = 0.004, respectively) and per-patient-based (both P = 0.004) analyses. Although simvastatin treatment suppressed atherosclerotic progression in both per-segment- and per-patient-based analyses, significant reductions were found only in MOD values with per-segment-based analyses (P = 0.034). In a categorical approach, progression was found in significantly fewer segments in the S-D group compared with the D group (MOD, P = 0.014; MSD, P = 0.003), with odds ratios (S-D) group/D group) of 0.571 for MOD and 0.390 for MSD. Significantly fewer patients with angiographic progression were observed in the S-D group (23.3%) compared with the D group (39.4%) with respect to MSD (P = 0.02). Two years of treatment with simvastatin 10 mg/d improved patients' lipid profile and retarded coronary atherosclerotic progression in Japanese patients with coronary artery disease and mild to moderate hypercholesterolemia

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Treating depression after initial treatment failure: directly comparing switch and augmenting strategies in STAR*D.

Augmenting and switching antidepressant medications are the 2 most common next-step strategies for depressed patients failing initial medication treatment. These approaches have not been directly compared; thus, our objectives are to compare outcomes for medication augmentation versus switching for patients with major depressive disorder in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical trial. We conducted a retrospective analysis of participants aged 18 to 75 years with DSM-IV nonpsychotic depression who failed to remit with initial treatment in the STAR*D clinical trial (N = 1292). We compared depressive symptom remission, response, and quality of life among participants in each study arm using propensity score matching to minimize selection bias. The propensity-score-matched augment (N = 269) and switch (N = 269) groups were well balanced on measured characteristics. Neither the likelihood of remission (risk ratio, 1.14; 95% confidence level, 0.82-1.58) or response (risk ratio, 1.14; 95% confidence level, 0.82-1.58), nor the time to remission (log-rank test, P = 0.946) or response (log-rank test, P = 0.243) differed by treatment strategy. Similarly, quality of life did not differ. Post hoc analyses suggested that augmentation improved outcomes for patients tolerating 12 or more weeks of initial treatment and those with partial initial treatment response. For patients receiving and tolerating aggressive initial antidepressant trials, there is no clear preference for next-step augmentation versus switching. Findings tentatively suggest that those who complete an initial treatment of 12 weeks or more and have a partial response with residual mild depressive severity may benefit more from augmentation relative to switching.

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Clinical efficacy of pravastatin for hyperlipidemia in patients with type 2 diabetes mellitus.

The efficacy of pravastatin (CAS 81131-70-6) on serum lipid levels in 91 type 2 diabetic patients with mean glycosylated hemoglobin of 8.5% was investigated up to 12 weeks. Oral administration of 10 to 20 mg/d of pravastatin significantly decreased total cholesterol by 18.4 +/- 1.5% after 4 weeks. When analyzed separately in type IIa and IIb hyperlipidemia, the reduction of total cholesterol by pravastatin was more prominent in the former. Low-density lipoprotein cholesterol were also significantly decreased 22.2 +/- 2.7% after 4 weeks. The effect of pravastatin in reducing triglyceride was more prominent in patients with higher triglyceride compared to those with lower triglyceride before the administration of the drug. High-density lipoprotein cholesterol showed a slight but significant increase by 4.2 +/- 1.9% after 4 weeks. Among the apolipoproteins examined, apolipoprotein B was significantly decreased after 4 weeks. Atherogenic index and apolipoprotein B/apolipoprotein A-I ratio were also significantly decreased after 4 weeks. The efficacy of pravastatin was also observed after 12 weeks to the same extent as after 4 weeks. No major side effects or abnormalities of laboratory parameters have been observed. These data lead to the conclusion that pravastatin is useful for the treatment of hyperlipidemia in type 2 diabetic patients with poor glycemic control without major adverse effects.

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Circulating monocytes and plasma inflammatory biomarkers in active Crohn's disease: elevated oxidized low-density lipoprotein and the anti-inflammatory effect of atorvastatin.

We investigated inflammatory biomarkers in plasma and in circulating monocytes obtained from patients with Crohn's disease and healthy individuals. Additionally, we assessed the effects of atorvastatin, 10 microM, ex vivo on monocytes cultured for 18 hours from the same subjects. Plasma and blood monocytes from eight patients with active Crohn's disease and eight healthy individuals were analyzed by enzyme-linked immunosorbent and electrophoretic mobility assays. Patients with active Crohn's disease had increased plasma levels of tumor necrosis factor (TNF)-alpha (7.7-fold;p < 0.05), monocyte chemoattractant protein (MCP)-1 (1.3-fold; p < 0.05), and oxidized low density lipoprotein (oxLDL) (1.2-fold; p < 0.05). Monocytes from patients with Crohn's disease showed enhanced secretion of MCP-1 (4.8-fold; p < 0.05) and a markedly suppressed secretion of macrophage migration inhibitory factor (MIF) (93%; p < 0.001). Transcriptional activation of nuclear factor-kappaB did not differ between the groups. Treating monocytes with atorvastatin resulted in the suppression of MCP-1 (42%; p < 0.05) and TNF-alpha (45%; p < 0.05) secretion. These results show increased levels of certain proinflammatory biomarkers, including oxLDL, in plasma and indicate that peripheral blood monocytes in active Crohn's disease are sensitized to chemotaxis. Treatment with atorvastatin may be a potential strategy to reduce oxLDL and inhibit monocyte migration to inflamed tissue, thus attenuating the inflammatory response.

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Effect of oral antiplatelet agents on major bleeding in users of coumarins.

Treatment with vitamin K antagonists (coumarins) is associated with an increased risk of bleeding. In order to elucidate the bleeding risk of users of antiplatelet drugs among users of coumarins, we assessed the odds ratio of major bleeding associated with use of antiplatelet drugs in users of the coumarins acenocoumarol and phenprocoumon. We used data from a Dutch record linkage system, including pharmacy and linked hospitalization records for approximately two million subjects, to conduct a nested case control study in a cohort of new users of coumarins. Cases were patients who were hospitalized with a primary diagnosis of major bleeding while taking coumarin and were matched with up to four control subjects. Conditional logistic regression analysis was used to determine ORs and 95% confidence intervals (CI). We identified 1848 case patients who were matched to 5818 controls. Users of clopidogrel or aspirin showed a significantly increased risk of hospitalization because of major bleeding (OR 2.9, 95% CI 1.2-6.9 and OR 1.6, 95% CI 1.3-1.9, respectively), whereas users of dipyridamole and combinations of antiplatelet drugs showed a strong trend (OR 1.5, 95% CI 1.0-2.3 and OR 1.8, 95 % CI 1.0-3.3, respectively). In all cases, the risks were greater for upper gastrointestinal bleedings than for other bleedings. In conclusion, the use of any antiplatelet drug increases the risk of hospitalization for major bleeding among users of coumarins. Concurrent use of clopidogrel or dipyridamole and coumarins is probably not safer than concurrent use of aspirin and coumarins.

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[Efficacy and metabolic safety of long-term treatment with ethinyl oestradiol/cyproterone and desogestrel/ethinyl oestradiol tablets in women with polycystic ovary syndrome].

To evaluate the efficacy and metabolic safety of long-term treatment with ethinyl oestradiol/cyproteroneand desogestrel/ethinyl oestradiol tablets in women with polycystic ovary syndrome (PCOS). Women with PCOSfrom West China Second Hospital of Sichuan University enrolled between September, 2011 and August, 2013 were randomlyallocated to receive either ethinyl oestradiol/cyproterone tablets (Group A, <i>n</i>=355) or desogestrel/ethinyl oestradiol tablets(Group B, <i>n</i>=357) for a prospective observation period of 6 months. Women with insulin resistance also received metformin. Atbaseline, 3 months, and 6 months, the patients were evaluated for menstruation, acne score, body mass index (BMI), waist-tohip ratio (WHR), plasma levels of sex hormones, fasting blood glucose (FPG), HOMA-insulin resistance index (HOMA-IR), serum lipid, ovarian volume, and the number of ovarian follicles. All the patients had a regular menstrual cycle aftertreatments. Testosterone level, acne score, LH/FSH, ovarian volume, and the number of follicles decreased significantly afterthe treatments without significant differences between the two groups. Significant increases were noted in TG, TCh, LDL, HDL, and AIP, and HDL level in group A as compared with group B (<i>P</i> < 0.001). FPG decreased in both groups, and wassignificantly lower in group B at 6 months (<i>P</i> < 0.05). BMI and WHR decreased in all the patients with insulin resistance aftercombination treatment with metformin (<i>P</i> < 0.05), but increased significantly in patients without insulin resistance (<i>P</i> < 0.05). Ingroup A, HOMA- IR significantly increased in patientswithout insulin resistance at 3 months (<i>P</i> < 0.05), whereas asignificant increase was not observed until 6 months ingroup B (<i>P</i> < 0.05). Both ethinyl oestradiol/cyproterone tablets and desogestrel/ethinyl oestradioltablets can relieve the symptoms of PCOS, but it isadvisable to assess the risk of cardiovascular diseasebefore the treatments.

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Losartan, an angiotensin type 1 receptor antagonist, improves endothelial function in non-insulin-dependent diabetes.

The present study examined the effect on forearm endothelial function of an angiotensin II type 1 receptor antagonist, losartan, in subjects with non-insulin-dependent diabetes mellitus (NIDDM). Angiotensin-converting enzyme (ACE) inhibition with enalapril improves acetylcholine (ACh)-dependent endothelial function in patients with NIDDM. This could be mediated through angiotensin II and the type 1 receptor or could be due to inhibition of kininase II and a bradykinin preserving effect. It is therefore relevant to determine whether a type 1 receptor antagonist improves endothelial function. The influence of losartan (50 mg daily for four weeks) on endothelium-dependent and independent vasodilator function was determined in 9 NIDDM subjects using a double-blinded placebo-controlled crossover protocol. Forearm blood flow was measured using strain-gauge plethysmography. Losartan significantly decreased infused arm vascular resistance in response to three incremental doses of intrabrachial acetylcholine (p < 0.05, ANOVA). The forearm blood flow ratio (flow in infused to noninfused arm) was also increased (p < 0.01). Responses to sodium nitroprusside and monomethyl arginine were not significantly changed. Losartan administration at 50 mg per day improved endothelium-dependent dilation of resistance vessels in patients with NIDDM. That is, blockade of the angiotensin II type 1 receptors improves endothelial function in NIDDM. At least some of the similarly beneficial effect of ACE inhibition is probably mediated also through the angiotensin II-type 1 receptor pathway. The use of a type 1 receptor antagonist seems a reasonable alternative to an ACE inhibitor to maintain endothelial function in NIDDM subjects.

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Comparative pharmacodynamics and plasma levels of beta-adrenoceptor blocking drugs.

1. Metoprolol (ME), pindolol (PI) and propranolol (PR) were studied in nine subjects at different doses and at 'maximum beta-adrenoceptor blockade' at a defined exercise load. Exercise tests were performed after each dosing period; isoprenaline stimulation was studied at the highest dose level. 2. ME and PR reduced heart rate at rest with most doses tested, while PI had no effect on resting heart rate. 3. Exercise heart rate was reduced with the smallest daily doses (ME 75 mg; PI 7.5 mg; PR 60 mg), and maximum reduction was from 163 to 116 beats/min (ME), 124 (PT) and 115 (PR) beats/min with daily doses of 242, 23 and 233 mg, respectively. 4. Resting blood pressure was not significantly affected by any beta-adrenoceptor blocker dose, but exercise induced blood pressure decreased from 166 to 130 (ME), 138 (PI) and 131 (PR) mm Hg, respectively. 5. Mean plasma concentrations at 'maximum beta-adrenoceptor blockade' were 158 (ME), 24 (PI) and 159 (PR) ng/ml without significant differences in the plasma level variation between beta-adrenoceptor blockers. 6. Isoprenaline doses required to increase heart rate by 30 beats/min were 3.8 microgram (control), 22 microgram (ME), 458 microgram (PI) and 200 microgram (PR), respectively. The differences may be due to different ratios of beta 1, beta 2 activity of the beta-adrenoceptor blockers tested.

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[Treatment of acute maxillary sinusitis in adults. Comparison of cefpodoxime-proxetil and amoxicillin-clavulanic acid].

The aim was to demonstrate the equivalence of the clinical efficacy and safety of cefpodoxime-proxetil (200 mg bid for 5 days) to that of amoxicillin-clavulanic acid (1 g/125 mg bid for 8 days) in adults with acute maxillary sinusitis. In this prospective, multicenter, centrally-randomized, open-label study, 73 general practitioners and 11 ear, nose, and throat specialists included 512 patients with unilateral acute maxillary sinusitis. The clinical success rates at day 12-19 in the per-protocol population (primary analysis) were 92.3% (215/233) in the cefpodoxime-proxetil group and 93.6% (204/218) in the amoxicillin-clavulanic acid group. The 95% confidence interval of [6.5%; 3.9%] demonstrated that cefpodoxime-proxetil was not inferior to amoxicillin-clavulanic acid. Cure rates at follow-up (day 25-30) were 90.6% and 92.7%, respectively. Results were similar in the intent-to-treat population. Compliance was significantly better in the cefpodoxime-proxetil group (99.2% versus 95.5%; p=0.011). Tolerance was also significantly better: 1.2% (3/247) of cefpodoxime-proxetil patients reported a treatment-related adverse event, compared with 10.7% (26/244) in the amoxicillin-clavulanic acid group (p<0.001). Most events were gastrointestinal and of mild to moderate intensity. In this study, a 5-day course of cefpodoxime-proxetil at 200 mg bid was as clinically effective as amoxicillin-clavulanic acid 1 g/125 mg bid for 8 days with a significantly better safety profile and compliance.

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Reduction in urinary free cortisol during benzodiazepine treatment of panic disorder.

Urinary free cortisol (UFC) levels were measured at baseline and at four and eight weeks after initiation of treatment in 66 patients who met DSM-III-R criteria for primary panic disorder (PD). Thirty-seven normal control subjects also had UFC levels measured three times at monthly intervals. Patients were randomly assigned to treatment with alprazolam, diazepam, or placebo. At baseline, complicated PD patients (those with agoraphobia and secondary depression) had significantly higher UFC levels than did normal controls. At four and eight weeks, complicated PD patients receiving alprazolam and diazepam had significant reductions in UFC excretion compared to baseline. Patients with uncomplicated PD maintained UFC levels comparable to controls at each sampling period. Treatment with benzodiazepines did not lower UFC levels in this group. These findings suggest that patients with complicated PD demonstrate hyperactivity of the hypothalamo-pituitary-adrenal axis that is decreased by treatment with benzodiazepines.

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Predictive value of interim ¹⁸F-FDG-PET/CT for event-free survival in patients with diffuse large B-cell lymphoma homogenously treated in a phase II trial with six cycles of R-CHOP-14 plus pegfilgrastim as first-line treatment.

The predictive value of interim PET/computed tomography (I-PET/CT) in diffuse large B-cell lymphoma (DLBCL) is controversial. Our aim was to evaluate the predictive value of I-PET/CT for an event-free survival. We analyzed patients with DLBCL included in a prospective clinical trial who were treated with six cycles of dose-dense R-CHOP followed by pegfilgrastim and who had undergone an I-PET/CT (after two cycles) and a final PET [F-PET/CT (60 days after the sixth cycle)]. Event was defined as nonresponse, relapse, or death. A total of 69 patients were included. Their median age was 60 years; 54% were male, 25% had bulky disease, and 67% had an International Prognostic Index of 0-2. The median follow-up duration was 28.8 months. I-PET/CT was positive in 34 (49%) patients and F-PET/CT was positive in 12 (17.4%). The 3-year event-free survival was 86% for patients who were I-PET/CT negative as against 64% for those who were I-PET/CT positive (P=0.036). The negative and positive predictive values, sensitivity, and specificity of I-PET/CT for an event were 83, 32, 65, and 56%, respectively. In a multivariate analysis including baseline characteristics, I-PET/CT, and F-PET/CT, F-PET/CT was the only significant predictor (P<0.0005). In patients with DLBCL treated with dose-dense R-CHOP plus pegfilgrastim, a negative I-PET/CT is highly predictive of a favorable outcome and a positive I-PET/CT is of limited clinical value. These results do not support treatment intensification after a short course of chemotherapy based solely on a positive I-PET/CT.

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Antibiotic treatment of gastric lymphoma of mucosa-associated lymphoid tissue. An uncontrolled trial.

Gastric lymphoma of mucosa-associated lymphoid tissue (MALT) is related to Helicobacter pylori infection and may depend on this infection for growth. To determine the response of gastric MALT lymphoma to antibiotic treatment. Prospective, uncontrolled treatment trial. University hospital referral center and three collaborating university and community hospitals. 34 patients with stage I or stage II N1 gastric MALT lymphoma. Two of three oral antibiotic regimens--1) amoxicillin, 750 mg three times daily, and clarithromycin, 500 mg three times daily; 2)tetracycline, 500 mg four times daily, and clarithromycin, 500 mg three times daily; or 3) tetracycline, 500 mg four times daily, and metronidazole, 500 mg three times daily--were administered sequentially (usually in the order written) for 21 days at baseline and at 8 weeks, along with a proton-pump inhibitor (lansoprazole or omeprazole) and bismuth subsalicylate. Complete remission was defined as the absence of histopathologic evidence of lymphoma on endoscopic biopsy. Partial remission was defined as a reduction in endoscopic tumor stage or 50% reduction in the size of large tumors. 34 patients were followed for a mean (+/-SD) of 41 +/- 16 months (range, 18 to 70 months) after antibiotic treatment. Of 28 H. pylori-positive patients, 14 (50% [95% CI, 31% to 69%]) achieved complete remission, 8 (29%) achieved partial remission (treatment eventually failed in 4 of the 8), and 10 (36% [CI, 19% to 56%]) did not respond to treatment. Treatment failed in all 6 (100% [CI, 54% to 100%]) H. pylori-negative patients. Patients with endoscopic appearance of gastritis (stage I T1 disease) were most likely to achieve complete remission within 18 months. Tumors in the distal stomach were associated with more favorable response than tumors in the proximal stomach. A subset of H. pylori-positive gastric MALT lymphomas, including infiltrative tumors, may respond to antibiotics. The likelihood of early complete remission seems to be greatest for superficial and distal tumors.

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The effect of treatment response on endothelial function and arterial stiffness in depression. A prospective study.

Major depression is associated with endothelial dysfunction and arterial stiffening, which may mediate development of hypertension and increased cardiovascular risk. The effect of response to antidepressant treatment on these vascular parameters has not been elucidated. We aimed to assess the net effect of antidepressant therapy on endothelial function and arterial stiffness in patients with psychotic depression. Thirty-seven patients with major psychotic depression, according to DSM-IV-TR, were treated with titrated citalopram 20-60 mg and risperidone 0.5-1 mg and were followed for 6 months. Twelve additional patients who denied treatment, or were non-compliant, were also followed for the same time period. Vascular function was assessed by flow-mediated dilatation (FMD), carotid-femoral pulse wave velocity (PWV) and augmentation index (AI), at baseline and at the end of follow-up. Aortic and peripheral blood pressure (BP), PWV, FMD and AI (p < 0.05 for all) were significantly improved in the group that received treatment. Overall, only responders to treatment (n = 24) presented significant improvements in all hemodynamic and vascular parameters (p < 0.05 for all), irrespectively of traditional cardiovascular risk factors (TRFs), vasoactive medication and BP lowering. In a secondary analysis, patients with psychotic depression presented worse endothelial function as compared to controls matched for TRFs. Non-randomized study. Patients who respond to therapy for major psychotic depression present sustained improvement in vascular function. Given that depressed patients are considered to be at high cardiovascular risk and are often non-compliant with treatment, further research to assess cardiovascular benefits of vigilant monitoring of antidepressant therapy is warranted.

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Zinc sulfate as an adjunct to methylphenidate for the treatment of attention deficit hyperactivity disorder in children: a double blind and randomized trial [ISRCTN64132371].

Attention-deficit hyperactivity disorder is an early-onset, clinically heterogenous disorder of inattention, hyperactivity, and impulsiveness. The diagnosis and treatment of attention-deficit hyperactivity disorder continues to raise controversy, and, there is also an increase in treatment options. In this 6-week double blind, placebo controlled-trial, we assessed the effects of zinc plus methylphenidate in the treatment of children with attention deficit hyperactivity disorder. To the best of our knowledge, this study is the first double blind and placebo controlled clinical trial assessing the adjunctive role of zinc in ADHD. Our subjects were 44 outpatient children (26 boys and 18 girls) between the ages of 5-11 (mean +/- SD was 7.88 +/- 1.67) who clearly met the DSM IV diagnostic criteria for attention-deficit hyperactivity disorder and they were randomized to methylphenidate 1 mg/kg/day + zinc sulfate 55 mg/day (with approximately 15 mg zinc element) (group 1) and methylphenidate 1 mg/kg/day + placebo (sucrose 55 mg) (group 2) for a 6 week double blind clinical trial. The principal measure of the outcome was the Teacher and Parent ADHD Rating Scale. Patients were assessed by a child psychiatrist at baseline, 14, 28 and 42 days after the medication started. The present study shows the Parent and Teacher Rating Scale scores improved with zinc sulfate over this 6-week, double blind and placebo controlled trial. The behavior of the two treatments was not homogeneous across the time. The difference between the two protocols was significant as indicated by the effect on the group, the between-subjects factor (F = 4.15, d.f. = 1, P = 0.04; F = 4.50, d.f. = 1, P = 0.04 respectively). The difference between the two groups in the frequency of side effects was not significant. This double-blind, placebo-controlled study demonstrated that zinc as a supplementary medication might be beneficial in the treatment of children with attention-deficit hyperactivity disorder. However, further investigations and different doses of zinc are required to replicate these findings in children with ADHD.

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Treatment algorithm for oral anticoagulant and antiplatelet therapy in epistaxis patients.

There is currently little published guidance on the management of anticoagulant and antiplatelet medication in patients admitted with epistaxis. The routine practice of withholding such medication in an attempt to control the epistaxis is common in the UK. However, this practice is not evidence-based, is often unnecessary, and can be associated with significant morbidity. This study introduces a treatment algorithm for oral anticoagulant and antiplatelet therapy in epistaxis patients, validated through a completed audit cycle. One hundred patients admitted with epistaxis to the University Hospital Southampton NHS Foundation Trust were studied via a two-audit cycle covering the implementation of a new treatment algorithm formulated jointly by the otolaryngology and haematology departments. On admission, 58 per cent of patients were taking some form of anticoagulant or antiplatelet medication. The number of patients having such medication withheld decreased significantly between the two audits, for all drugs studied (i.e. aspirin, clopidogrel and warfarin). There was no significant increase in re-bleeding or re-admission rates between the audits. Implementation of this treatment algorithm would help standardise management for epistaxis patients taking anticoagulant or antiplatelet drugs, and should reduce morbidity associated with unnecessary routine discontinuation of such medication.

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The first 20 minutes after a single dose of inhaled salmeterol in asthmatic children.

Very little is known as yet about the effect of salmeterol in pediatric asthma, so a trial was performed on children with mild asthma to compare salmeterol with salbutamol in terms of how quickly they took effect. The double-blind study involved 11 children (mean age 13.4 years) randomly assigned to inhale salmeterol 50 micrograms, salbutamol 200 micrograms, or a placebo three times on alternate days. Peak expiratory flow (PEF), heart rate, and blood pressure were measured before and 5, 10, 15, and 20 min after administering the medication. With salbutamol, PEF was higher at 5 and 10 min, subsequently dropping off at 15 and 20 min; with salmeterol, PEF was better at 10 and 20 min. Forced expiratory volume at 1 s (FEV1) measurements taken at the baseline and after 10 and 20 min revealed an important and consistent rise in values after salmeterol, whereas salbutamol was more effective after 10 min than after 20 min. No significant changes were recorded in heart rate or blood pressure after salbutamol; after salmeterol, there was a significant increase in heart rate after 5 min, but not at subsequent measurements. In conclusion, salmeterol begins to take effect already within 10 min of a single administration in asthmatic children, although the onset of its effect is slower than with salbutamol.

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Predictive value of heart rate in dilated cardiomyopathy treated with metoprolol.

Predictive factors of a favourable response to beta-blocker therapy are still unknown and the role of heart rate remains controversial. To investigate the relation between heart rate and the response to chronic metoprolol treatment in patients with dilated cardiomyopathy (DCM). Ninety-eight consecutive patients with DCM, left ventricular ejection fraction (LVEF) < or = 0.40 and blood pressure < or = 140/90 mmHg were treated with metoprolol, associated with digitalis, diuretics and ACE-inhibitors. After 24 +/- 6 months, 48 patients (49%) were classified as "improved" on the basis of a clinical/instrumental score. Rest, mean 24-hour and maximal exercise heart rate were all significantly and directly related to the probability of improvement, but heart rate at rest, supine and in upright position, showed the highest predictive power. The relationship between heart rate and improvement with metoprolol appeared to be non-linear, with an increasing probability in patients with higher heart rate, but with a fall of the slope in cases with extreme tachycardia. By dividing our study population on the basis of the most important clinical variables, this complex relation was evident only in patients at a more advanced stage of the disease. Our analysis confirms the strict relationship between heart rate and improvement with chronic metoprolol therapy in patients with DCM. This relation seems to be non-linear and is influenced by the severity of the disease.

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Lung bioavailability of chlorofluorocarbon free, dry powder and chlorofluorocarbon containing formulations of salbutamol.

With the future advent of a world wide ban on chlorofluorocarbon containing aerosols, a study was designed to compare the in vivo lung bioavailability of salbutamol via chlorofluorocarbon-containing metered-dose inhaler (CFC), chlorofluorocarbon-free metered-dose inhaler (CFC-free), and dry powder inhaler (DPI). Twelve healthy male subjects were given 1200 micrograms salbutamol and measurements made of plasma and urinary salbutamol. CFC-free produced significantly higher plasma salbutamol levels (ng ml-1; mean and 95% CI for difference) than either CFC or DPI: Cmax, CFC-free 4.18 vs CFC 3.29 (95% CI 0.10-1.68), vs DPI 3.42 (95% CI -0.03-1.56). The ratio for the difference in Cmax between CFC and CFC-free formulations was 1.32 (95% CI 1.02-1.61). There were no significant differences between CFC and DPI formulations. Urinary salbutamol results did not reveal any significant differences between the three inhalers (micrograms 30 min-1): CFC-free 42.4, CFC 43.8, DPI 45.3. Thus, the lung bioavailability of CFC-free was greater than that of CFC or DPI formulations of salbutamol.

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Analysis of montelukast in mild persistent asthmatic patients with near-normal lung function.

Few studies have specifically evaluated controller therapy in patients with mild persistent asthma. We used a subgroup analysis to investigate the effects of montelukast, a potent cysteinyl leukotriene receptor antagonist, on adult patients on the milder end of the asthma severity spectrum. We have identified seven double-blind, randomized, placebo-controlled studies of adult patients with mild-to-moderate chronic asthma in which montelukast was investigated. Subsets of patients with baseline forced expiratory volume in 1 sec (FEV1) > 80% and > 75% predicted or further restricted by less than daily rescue beta-agonist use were included as four cohorts (A, B, C, D), and efficacy measures, including change in FEV1 rescue-free days, beta-agonist use, nocturnal awakenings and blood eosinophil counts were evaluated. Cohorts A to D comprised 21%, 8%, 11%, and 4%, respectively, of patients from these studies. Mean pretreatment FEV1 ranged from 81% to 84% predicted and daily beta-agonist use from 2.4 to 4.5 puffs day(-1) in the four cohorts. Pooled results demonstrated a treatment effect for montelukast over placebo in all cohorts, for all endpoints. There was a significant improvement in FEV1 in montelukast-treated patients (7-8% over baseline) compared with placebo (1-4% over baseline, between-group difference P < or = 0.02) for all cohorts. Similarly, the percentage of rescue-free days increased substantially more with montelukast (22-30%) than with placebo (8-13%). This subgroup analysis indicates that montelukast produced improvements in parameters of asthma control in patients with milder persistent asthma that should be confirmed in additional prospective trials.

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[Alternative Psychoses and Forced Normalization after Seizure Control by Anticonvulsants with Special Consideration of the New Anticonvulsants].

In the case of alternative psychosis and forced normalization, the patient alternates between periods of clinically manifest seizures and normal behavior, and other periods of seizure freedom (or significant seizure reduction) accompanied by psychosis or behavioral disturbances. Unlike the clinically defined alternative psychosis, forced normalization is based on EEG findings. In clinical practice and in the literature, both terms are mostly used synonymously, and they also describe the same clinical pictures. This allowed a joint evaluation of the publications about alternative psychosis and forced normalization. Most often, these two disorders occur after seizure control by anticonvulsants. In the period of older anticonvulsants, the succinimides for the treatment of absence seizures were most often associated with the development of an alternative psychosis or forced normalization. In the era of newer anticonvulsants that started with the introduction of vigabatrin, mostly patients with intractable focal seizures were affected. In 1987 - 31 years ago - paranoid hallucinatory psychosis, triggered by vigabatrin in a patient with epilepsy was reported for the first time. In the following years, reports of alternative psychosis and forced normalization appeared to be related to most of the new anticonvulsants. A comprehensive literature search provided 66 cases with detailed information on such events. More than twice as many women were likely to be affected as compared to men; the reason for this phenomenon is unclear. In four retrospective studies, another 176 alternative events were reported but no details were given. The risk of alternative psychosis and forced normalization seems to be particularly low with the new anticonvulsants oxcarbazepine, eslicarbazepine, gabapentin and pregabalin.

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Risk of Hypoglycemia Following Hospital Discharge in Patients With Diabetes and Acute Kidney Injury.

Hypoglycemia is common in patients with diabetes. The risk of hypoglycemia after acute kidney injury (AKI) is not well defined. The purpose of this study was to compare the risk for postdischarge hypoglycemia among hospitalized patients with diabetes who do and do not experience AKI. We performed a propensity-matched analysis of patients with diabetes, with and without AKI, using a retrospective national cohort of veterans hospitalized between 2004 and 2012. AKI was defined as a 0.3 mg/dL or 50% increase in serum creatinine from baseline to peak serum creatinine during hospitalization. Hypoglycemia was defined as hospital admission or an emergency department visit for hypoglycemia or as an outpatient blood glucose <60 mg/dL. Time to incident hypoglycemia within 90 days postdischarge was examined using Cox proportional hazards models. Prespecified subgroup analyses by renal recovery, baseline chronic kidney disease, preadmission drug regimen, and HbA_1c were performed. We identified 65,151 propensity score-matched pairs with and without AKI. The incidence of hypoglycemia was 29.6 (95% CI 28.9-30.4) and 23.5 (95% CI 22.9-24.2) per 100 person-years for patients with and without AKI, respectively. After adjustment, AKI was associated with a 27% increased risk of hypoglycemia (hazard ratio [HR] 1.27 [95% CI 1.22-1.33]). For patients with full recovery, the HR was 1.18 (95% CI 1.12-1.25); for partial recovery, the HR was 1.30 (95% CI 1.23-1.37); and for no recovery, the HR was 1.48 (95% CI 1.36-1.60) compared with patients without AKI. Across all antidiabetes drug regimens, patients with AKI experienced hypoglycemia more frequently than patients without AKI, though the incidence of hypoglycemia was highest among insulin users, followed by glyburide and glipizide users, respectively. AKI is a risk factor for hypoglycemia in the postdischarge period. Studies to identify risk-reduction strategies in this population are warranted.

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Effect of chronic kidney disease on platelet reactivity to dual-antiplatelet therapy in patients treated with drug-eluting stents.

We investigated the effect of chronic kidney disease (CKD) on platelet function in patients receiving dual-antiplatelet therapy after drug-eluting stent (DES) implantation. We examined 19 patients with CKD and 18 patients without CKD who underwent percutaneous coronary intervention (PCI) with DES. All of the patients had been on chronic aspirin treatment. Blood samples were obtained 20-24 h after a loading dose (300 mg) of clopidogrel. Platelet function was evaluated by measuring the closure time (CT) of a collagen/epinephrine (CEPI) or collagen/adenosine diphosphate (CADP) cartridge in the PFA-100 system. Maximum aggregation of agonist (epinephrine, ADP, collagen, or ristocetin)-induced platelet aggregation was also examined by light transmittance aggregometry. The frequency of the poor responders among CKD (n = 9, 47.4%) patients was significantly higher than that among non-CKD patients (n = 2, 11.1%, P = 0.016) as assessed using a CEPI-CT cartridge. Multiple logistic regression analysis revealed that CKD (odds ratio 7.39, 95% confidence interval 1.38-62.09, P = 0.0183] was the only independent determinant of the poor responders. There were no significant differences between the two groups in the value of CADP-CT or in maximum aggregation of epinephrine-, ADP-, collagen-, and ristocetin-induced platelet aggregation. Compared with non-CKD patients, CKD patients had lower response to aspirin therapy as assessed by the PFA-100 system with a CEPI cartridge. On the other hand, the platelet response to dual-antiplatelet therapy was not different between CKD and non-CKD patients.

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Support for the vascular depression hypothesis in late-life depression: results of a 2-site, prospective, antidepressant treatment trial.

Research on vascular depression has used 2 approaches to subtype late-life depression, based on executive dysfunction or white matter hyperintensity severity. To evaluate the relationship of neuropsychological performance and white matter hyperintensity with clinical response in late-life depression. Two-site, prospective, nonrandomized controlled trial. Outpatient clinics at Washington University and Duke University. A total of 217 subjects aged 60 years or older met DSM-IV criteria for major depression, scored 20 or more on the Montgomery-Asberg Depression Rating Scale (MADRS), and received vascular risk factor scores, neuropsychological testing, and magnetic resonance imaging; they were excluded for cognitive impairment or severe medical disorders. Fazekas rating was conducted to grade white matter hyperintensity lesions. Intervention Twelve weeks of sertraline treatment, titrated by clinical response. Main Outcome Measure Participants' MADRS scores over time. Baseline neuropsychological factor scores correlated negatively with baseline Fazekas scores. A mixed model examined effects of predictor variables on MADRS scores over time. Baseline episodic memory (P = .002), language (P = .007), working memory (P = .01), processing speed (P < .001), executive function factor scores (P = .002), and categorical Fazekas ratings (P = .05) predicted MADRS scores, controlling for age, education, age of onset, and race. Controlling for baseline MADRS scores, these factors remained significant predictors of decrease in MADRS scores, except for working memory and Fazekas ratings. Thirty-three percent of subjects achieved remission (MADRS < or =7). Remitters differed from nonremitters in baseline cognitive processing speed, executive function, language, episodic memory, and vascular risk factor scores. Comprehensive neuropsychological function and white matter hyperintensity severity predicted MADRS scores prospectively over a 12-week treatment course with selective serotonin reuptake inhibitors in late-life depression. Baseline neuropsychological function differentiated remitters from nonremitters and predicted time to remission in a proportional hazards model. Predictor variables correlated highly with vascular risk factor severity. These data support the vascular depression hypothesis and highlight the importance of linking subtypes based on neuropsychological function and white matter integrity. clinicaltrials.gov Identifier: NCT00045773.

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Natural history of more than 20 years of node-positive primary breast carcinoma treated with cyclophosphamide, methotrexate, and fluorouracil-based adjuvant chemotherapy: a study by the Cancer and Leukemia Group B.

Breast cancer heterogeneity dictates lengthy follow-up to assess outcomes. Efficacy differences for three regimens that are based on adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) are presented in this article, but cancer recurrence sites, time of relapse, subsequent primary cancers, and causes of death in the natural history of node-positive breast cancer are emphasized. Beginning in 1975, 905 patients with node-positive cancer were randomly assigned to receive CMF or two regimens of CMF plus other agents. Median follow-up is 22.6 years. The natural-history analysis was performed on a subset of 814 patients. Eighty percent of the 599 women known to have died, died of metastatic breast cancer. Only 8.5% of the deceased women died of a cause other than breast cancer, a second or third cancer, or adjuvant chemotherapy toxicity. One hundred five women (12.8%) developed other primary cancers, with 49 (46.6%) occurring in the contralateral breast. Therapeutic efficacy differences of the CMF regimens reported earlier have been maintained more than 20 years later. For certain subsets, the five-drug regimen had advantages over CMF. Bone was the most common recurrence site. The longest interval to relapse has been 23.5 years, and 18% of those who relapsed did so more than 10 years later. Despite adjuvant chemotherapy, a large majority (80%) of women with node-positive breast cancer die of the disease, and many recurrences develop more than 10 years later. CMF plus vincristine and prednisone provides a benefit compared with CMF, but the magnitude varies with the number of involved nodes. Outcome trends in earlier analyses of this study were maintained even years later.

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Toxicological and pathological findings in a series of buprenorphine related deaths. Possible risk factors for fatal outcome.

Buprenorphine is considered to have little respiratory side effects at therapeutic doses and the partial agonistic properties should produce a "ceiling effect" for respiratory depression at higher doses. Still, there are several reports on buprenorphine related deaths. Most deaths involve drug users and the co-administration of other CNS depressant drugs as well as reduced tolerance have been suggested to be risk factors. The primary aims were to investigate if lack of tolerance and/or co-ingestion of other psychotropic drugs are significant risk factors in buprenorphine fatalities. From July 2005 to September 2009, all autopsy cases where buprenorphine or norbuprenorphine had been detected in femoral blood and where analysis of buprenorphine had been performed in urine were selected. Results from the postmortem examination and toxicology were compiled. Postmortem toxicology was performed using the routine methodology at the laboratory. In total, 97 subjects were included in the study. These were divided into four groups; Intoxication with buprenorphine (N=41), Possible intoxication with buprenorphine (N=24), Control cases where buprenorphine was not the cause of death (N=14), and Unclear (N=18). The metabolite to parent compound ratios in both blood and urine in the Intoxication group were significantly different from those in the Control and Unclear groups. An extensive poly-drug use was seen in all groups with several additional opioids in the Possible group (54%) and in the Unclear group (78%) and hypnotics or sedatives in more than 75% of the Intoxication, Possible, and Unclear cases. Illicit drugs were present in all groups but not to a great extent with amphetamine and tetrahydrocannabinol as the main findings. Interestingly, 4 cases in the Intoxication group presented with no other significant drugs in blood other than buprenorphine. We conclude that a lethal concentration of buprenorphine in blood cannot be defined. Instead the analysis of blood as well as urine can be an important tool to show that the drug was taken shortly before death and to rule out a continuous use of buprenorphine supporting the notion that abstinence is an important risk factor. The presence of alprazolam in more than 40% of the Intoxications and the presence of hypnotics and sedatives in 75% of the Intoxications suggests that these drugs interact with buprenorphine producing toxic effects that buprenorphine alone would not have produced. Still, in 10% of the Intoxications no other drugs were found indicating that under certain circumstances buprenorphine alone may produce respiratory depression resulting in death.

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Propensity for biofilm formation by clinical isolates from urinary tract infections: developing a multifactorial predictive model to improve antibiotherapy.

A group of biofilm-producing bacteria isolated from patients with urinary tract infections was evaluated, identifying the main factors contributing to biofilm formation. Among the 156 isolates, 58 (37.2%) were biofilm producers. The bacterial species (P<0.001), together with patient's gender (P = 0.022), were the factors with the highest influence for biofilm production. There was also a strong correlation of catheterization with biofilm formation, despite being less significant (P = 0.070) than species or gender. In fact, some of the bacteria isolated were biofilm producers in all cases. With regard to resistance profile among bacterial isolates, β-lactam antibiotics presented the highest number of cases/percentages--ampicillin (32/55.2%), cephalothin (30/51.7%), amoxicillin/clavulanic acid (22/37.9%)--although the carbapenem group still represented a good therapeutic option (2/3.4%). Quinolones (nucleic acid synthesis inhibitors) also showed high resistance percentages. Furthermore, biofilm production clearly increases bacterial resistance. Almost half of the biofilm-producing bacteria showed resistance against at least three different groups of antibiotics. Bacterial resistance is often associated with catheterization. Accordingly, intrinsic (age and gender) and extrinsic (hospital unit, bacterial isolate and catheterization) factors were used to build a predictive model, by evaluating the contribution of each factor to biofilm production. In this way, it is possible to anticipate biofilm occurrence immediately after bacterial identification, allowing selection of a more effective antibiotic (among the susceptibility options suggested by the antibiogram) against biofilm-producing bacteria. This approach reduces the putative bacterial resistance during treatment, and the consequent need to adjust antibiotherapy.

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High Ki-67 expression in diffuse large B-cell lymphoma patients with non-germinal center subtype indicates limited survival benefit from R-CHOP therapy.

Rituximab has significantly improved the survival of patients with DLBCL, especially those with non-germinal center B-cell-like (non-GCB) subtype. The impact of Ki-67 expression, an index of proliferation, on the clinical outcomes of patients with DLBCL has largely been unexplored. This study aimed to investigate whether Ki-67 expression is an indicator of outcome in DLBCL patients (especially non-GCB DLBCL patients) treated with standard chemotherapy combined with rituximab. Expression of Ki-67 protein was examined immunohistochemically in 118 tumor specimens from patients newly diagnosed with DLBCL and treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Overall survival (OS) and progression-free survival (PFS) were lower in patients with high Ki-67 expression than in those with low Ki-67 expression (3-year OS: 65.2% vs. 81.7%, P = 0.030; 3-year PFS: 56.4% vs. 73.3%, P = 0.020), similar in patients with GCB subtype and those with the non-GCB subtype (OS: P = 0.330; PFS: P = 0.287). According to Ki-67 expression status by immunophenotype subgroups, patients with high Ki-67 expression in non-GCB subgroup had the most unfavorable PFS and OS, comparing with the other three subgroups (P = 0.004 and P = 0.002, respectively). In multivariate analysis, non-GCB with high Ki-67 expression was an independent prognostic predictor of inferior survival in DLBCL patients treated with R-CHOP. For DLBCL patients with non-GCB DLBCL and high Ki-67 expression, the survival benefit from R-CHOP therapy is limited.

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Statin Use and Survival in Patients with Metastatic Castration-resistant Prostate Cancer Treated with Abiraterone Acetate.

Although statin use has been associated with favorable effects in various solid malignancies, no conclusive evidence is available at present. Statins are safe and inexpensive, and may synergize with novel antiandrogen agents abiraterone via pharmacokinetic interactions and decrease substrate availability for de novo androgen biosynthesis. To determine whether statin use affects survival in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone. Medical records of patients with documented mCRPC between September 2011 and August 2016 were reviewed at multiple participating centers. This research was conducted in ten institutions, including both referral centers and local hospitals. A total of 187 patients receiving abiraterone for mCRPC between September 2011 and August 2016 were eligible for inclusion in this retrospective study. Patients were assessed for overall survival (OS), statin use at the time of treatment initiation, prostate-specific antigen (PSA) variations, and other variables of interest. Univariable and multivariable analysis was used to explore the association of variables of interest with OS and PSA declines. Statin use was a significant prognostic factor for longer OS in univariable (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.37-0.72; p<0.001) and multivariable analysis (HR 0.40, 95% CI 0.27-0.59; p<0.001) and was significantly associated with PSA declines (>50% decline at 12 wk: 72.1% in statin users vs 38.5% in non-users; p<0.001). Our study suggests a prognostic impact of statin use in patients receiving abiraterone for mCRPC. The mechanism of this interaction warrants elucidation, but may include enhancement of the antitumor activity of abiraterone as well as cardioprotective effects. We assessed the effects of statin use in patients with advanced prostate cancer receiving abiraterone. Patients treated with a statin plus abiraterone appeared to live longer than those treated with abiraterone only. Since no negative drug-drug interaction is known and statins are widely used and inexpensive, further studies assessing the use of abiraterone plus statins are warranted.

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Neonatal adaptation in infants prenatally exposed to antidepressants--clinical monitoring using Neonatal Abstinence Score.

Intrauterine exposure to antidepressants may lead to neonatal symptoms from the central nervous system, respiratory system and gastrointestinal system. Finnegan score (Neonatal Abstinence Score, NAS) has routinely been used to assess infants exposed to antidepressants in utero. The purpose was to study neonatal maladaptation syndrome in infants exposed to selective serotonin reuptake inhibitors (SSRI) or serotonin-norepinephrine reuptake inhibitors (SNRI) in utero. Retrospective cohort study of women using antidepressants during pregnancy and their infants. Patients were identified from the electronic health record system at Karolinska University Hospital Huddinge containing pre-, peri- and postnatal information. Information was collected on maternal and infant health, social factors and pregnancy. NAS sheets were scrutinized. 220 women with reported 3rd trimester exposure to SSRIs or SNRIs and who gave birth between January 2007 and June 2009 were included. Seventy seven women (35%) used citalopram, 76 used (35%) sertraline, 34 (15%) fluoxetine and 33 (15%) other SSRI/SNRI. Twenty-nine infants (13%) were admitted to the neonatal ward, 19 were born prematurely. NAS was analyzed in 205 patients. Severe abstinence was defined as eight points or higher on at least two occasions (on a scale with maximum 40 points), mild abstinence as 4 points or higher on at least two occasions. Seven infants expressed signs of severe abstinence and 46 (22%) had mild abstinence symptoms. Hypoglycemia (plasma glucose <2.6 mmol/L) was found in 42 infants (19%). Severe abstinence in infants prenatally exposed to antidepressants was found to be rare (3%) in this study population, a slightly lower prevalence than reported in previous studies. Neonatal hypoglycemia in infants prenatally exposed to antidepressant may however be more common than previously described.

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Coronary heart disease and treatment of hypertension. Some Oslo Study data.

The Oslo Hypertension Study began in 1972; patients were followed for an average of 66 months (range: 60 to 78). A total of 785 healthy men, aged 40 to 49, with mild hypertension was randomly assigned to either a drug-treated group or to an untreated control group. Hydrochlorothiazide was used alone in 36 percent of patients, in combination with propranolol in 26 percent, and with methyldopa in 20 percent. Other drugs, including combinations with hydrochlorothiazide, were used in 18 percent. A total of 95 percent of patients in the drug-treated group received hydrochlorothiazide. Complications of hypertension such as stroke and aneurysm occurred only in the control group. Coronary events were more numerous in the drug-treated group; thus, the total incidence of cardiovascular complications did not significantly differ between the treated and untreated groups. After five and 10 years, total mortality was the same in both groups. However, the coronary heart disease mortality rate at 10 years was significantly greater in the drug-treated group than in the untreated control group (14 versus three, p less than 0.01). This article presents possible reasons for the failure of antihypertensive drug therapy to prevent coronary heart disease. The adverse effect of diuretics and beta-adrenergic blockers, both on lipid and carbohydrate metabolism, is contrasted with the effect of the alpha-adrenergic blocker prazosin, which has been shown to have no adverse effect on the blood lipid profile. In a short-term trial that was part of the Oslo Study, prazosin was found to reduce total serum cholesterol by 9 percent, low-density lipoprotein and very-low-density lipoprotein cholesterol by 10 percent, and total triglycerides by 16 percent. All these changes are statistically significant.

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Low-dose methotrexate may cause air trapping in patients with rheumatoid arthritis.

Both rheumatoid arthritis (RA) and methotrexate (MTX) are reported to be associated with the development of pulmonary disease. To determine whether MTX enhanced the risk of developing abnormalities in pulmonary function in patients with RA, we prospectively studied 31 subjects (12 male, 19 female) with the diagnosis of classic RA for an average period of 4.4 yr (range, 1 to 5 yr). Each subject was placed on low-dose weekly MTX (mean 17 mg, range 2.5 to 40) for control of RA symptoms. Other medications included non-steroidal anti-inflammatory agents and prednisone if required for control of arthritis symptoms. No other immunosuppressive therapy was used. Each subject was evaluated by pulmonary function tests (PFT) and chest X-ray initially, and at 1, 2, 3.5, and 5 yr. Chest X-rays obtained initially and at the end of the study period were found to be normal. The percent predicted values for initial PFTs in the study group were within the normal range. From the beginning to the end of the observation period, the following mean changes in lung function were observed: 1.9% increase in TLC, 5.1% increase in residual volume (RV), 1.8% increase in FVC, 0.71% decrease in FEV1, 14.7% improvement in alveolar-arterial oxygen (A-aO2) difference, and a 12.7% increase in single-breath diffusing capacity (DLCO). To determine whether MTX (average dose, weekly dose, or cumulative dose) was significantly related to changes in pulmonary function, we used multivariate techniques to control for the initial measure of lung function while assessing the relationship between MTX and the subsequent measures of lung function.(ABSTRACT TRUNCATED AT 250 WORDS)

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Pharmacological interventions for smoking cessation among people with schizophrenia spectrum disorders: a systematic review, meta-analysis, and network meta-analysis.

People with schizophrenia have higher rates of smoking than the general population, and lower quit rates. Several randomised controlled trials have investigated the effectiveness of pharmacological interventions for smoking cessation over the past 20 years. We did a systematic review and pairwise and network meta-analysis of smoking abstinence to guide decision making in offering pharmacological interventions for smoking cessation for people with schizophrenia spectrum disorders. We systematically reviewed PubMed, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, and China National Knowledge Infrastructure from inception to Sept 30, 2019, for randomised controlled trials of varenicline, bupropion, and nicotine replacement therapy for smoking cessation for people with schizophrenia spectrum disorders or psychotic disorders who were smokers at the time of study recruitment. Data were extracted from published studies on smoking abstinence outcomes and psychotic symptoms. We did pairwise and network meta-analyses for the primary outcome of smoking abstinence. Sensitivity analyses were done on study inclusion criteria, duration, quality, and location. This study is registered with the international prospective register of systematic reviews PROSPERO, CRD42018102343. A total of 15 111 records were identified by the database searches, and 163 full-text articles were assessed for eligibility. 145 articles were then excluded for several reasons including insufficient data, or abstracts published in later studies, and 18 studies were included in the meta-analysis. In the pairwise meta-analyses, four studies with 394 participants assessed varenicline (RR 3·75, 95% CI 1·96-7·19, p<0·0001; I²=0%), four studies with bupropion and 292 participants (RR 3·40, 95% CI 1·58-7·34, p=0·0002; I²=0%), and three studies with 561 participants assessed nicotine replacement therapy (RR 4·27, 95% CI 1·71-10·65, p=0·0002; I²=0%). All three treatments were deemed superior to placebo. In the network meta-analysis, varenicline was superior to bupropion (RR 2·02, 95% CI 1·04-3·93; p=0·038) but no significant difference was found between varenicline and nicotine replacement therapy, or bupropion and nicotine replacement therapy. No agents were associated with changes in psychiatric symptoms, but varenicline was associated with higher rates of nausea than was placebo. We found evidence to support use of pharmacological agents for smoking cessation for people with psychosis. Varenicline might be superior to bupropion; however, additional direct testing and combination trials of pharmacological agents for smoking cessation are required to inform clinical decision making for people with psychosis. None.

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[A comparison between the effects of albuterol and isoproterenol in bronchodilation test].

To compare albuterol with isoproterenol as a bronchodilator in pulmonary function test and their value in the diagnosis and differential diagnosis of asthma. Two groups (59 patients with asthma and 37 patients with COPD) were included in this study, and the patients of each group were randomly divided into 2 subgroups. The patients in the 2 subgroups inspired the two drugs in a cross-over by odd or even days. The pulmonary functions were evaluated. The changing rates of pulmonary functions induced by the two drugs in the two groups were positively correlated (P < 0.005), The changing rates of FEV1, MMEF, Raw, sGaw induced by albuterol were higher than the ones induced by isoproterenol in patients with asthma(P < 0.02), however the changing rates of FVC and PEF in asthma cases and all the above parameters in COPD cases were not significantly different between the two drugs(P > 0.10). The comparison of positive case number between asthma and COPD cases induced by both drugs showed significant difference(P < 0.005); especially, when the positive rate of sGaw induced by albuterol in asthma cases reached 98%, the positive rates in COPD cases was generally much lower. Bronchodilation test is a valuable diagnostic method for asthma. In this study, albuterol was superior to isoproterenol. The most sensitive index in bronchodilation test was sGaw, then in order, FEV1(92%), MMEF and Raw; the FVC and PEF were relatively insensitive.

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[A study on interval of intravenous cyclophosphamide pulse in the treatment of severe systemic lupus erythematosus].

The aim of this study was to compare the clinical efficacy and adverse effects of intravenous cyclophosphamide pulse therapy between 2-week and 4-week intervals in the treatment of severe systemic lupus erythematosus. 52 patients were involved in the study and were equally divided into two groups. The pulse intervals were 2 weeks for group I and 4 weeks for group II. Each pulse dose of cyclophosphamide was 15 mg/kg. Every patient took prednisone 1 mg/kg daily for first 8 weeks and then tapered. Most of disease indices recovered quicker in group I than in group II. The group with short interval was better than that of long one on total efficacy and remission rate. The cyclophosphamide cumulative doses were not different between two groups as disease activity index dropped 50%. The pulse interval had to be prolonged from 2 weeks to 4 weeks to six patients in group I (23.1%) because of leukopenia, and be shortened from 4 weeks to 2 weeks to five cases in group II (19.2%) because of inefficacy. There was no statistical difference in adverse effects between two groups. Intravenous cyclophosphamide pulse therapy with two-weeks interval is advantageous to recovery of severe systemic lupus erythematosus provided blood test prior to each pulse. We suggest that pulse interval should be individualized.

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Barriers of antiaggregant treatment.

In the present study we aimed to evaluate side effects of antiplatelet therapy in order to establish correlations with medication type, doses and association with other therapies. In the study we prospectively evaluated a cohort of patients who received antiplatelet therapy for different pathologies. We included patients with acute coronary syndromes, valvular disease complicated with supraventricular arrhythmias (especially atrial fibrillation), carotidal critical stenosis, neurologic disease (ischemic or thrombotic), and peripheral artery disease. The study included 125 patients (85 males and 40 females), aged between 45 and 85, and admitted in the 1st Cardiology Department, St Spiridon Hospital, between January 2012 and December 2013, who received antiplatelet therapy for different pathologies. All the patients included in the study received platelet antiaggregant therapy with Clopidogrel in association or not with Aspirin or low weight molecular heparin. Side effects reported (possibly correlated with antiplatelet therapy) were: macroscopic hematuria (7 cases), cutaneous ecchymosis (7 cases), purpuric lesions (9 cases), gingival bleeding (12 cases), upper gastrointestinal bleeding (6 cases), and hemoptysis (2 cases). Hemorrhagic events under the treatment with antiplatelet agents are rare in comparison with the large number of patients treated. Clinical manifestations are very different depending on the drug and also on the drug-associations used. Hemorrhagic accidents may sometimes be very serious, determining the specific therapeutic measures.

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Clinical pharmacokinetics of amoxycillin and theophylline during cotreatment with both medicaments.

The influence of amoxycillin and theophylline on their mutual steady-state pharmacokinetics was studied in healthy adults by comparing the pharmacokinetic parameters as obtained during a 10-day course of each drug alone and after giving the drugs in combination. Amoxycillin and theophylline plasma concentrations were measured by means of HPLC methods. On the 9th day of each of the two periods of drug administration, a concentration-time curve was evaluated. These showed no influence of theophylline on absorption, elimination or volume of distribution of amoxycillin, demonstrating that the mean steady-state plasma concentrations were not significantly different during the two treatments. Amoxycillin also has no significant effect on theophylline steady-state pharmacokinetics. It is concluded that both drugs can be given concomitantly without any dosage adjustment.

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Ofloxacin eardrop treatment for active chronic suppurative otitis media: prospective randomized study.

This report presents a prospective randomized study of 0.3 percent ofloxacin eardrops for the treatment of active chronic suppurative otitis media. Twenty-nine patients were treated with ofloxacin eardrops for 1 week, and another 27 patients were treated with Augmentin for 1 week. One week after completion of treatment, 22 (76%) patients of the group treated with ofloxacin had dry ears, and only seven (26%) patients treated with Augmentin had dry ears. Ofloxacin eardrops were effective in the initial treatment of active chronic suppurative otitis media.

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Relationship of baseline HDL subclasses, small dense LDL and LDL triglyceride to cardiovascular events in the AIM-HIGH clinical trial.

Previous results of the AIM-HIGH trial showed that baseline levels of the conventional lipid parameters were not predictive of future cardiovascular (CV) outcomes. The aims of this secondary analysis were to examine the levels of cholesterol in high density lipoprotein (HDL) subclasses (HDL2-C and HDL3-C), small dense low density lipoprotein (sdLDL-C), and LDL triglyceride (LDL-TG) at baseline, as well as the relationship between these levels and CV outcomes. Individuals with CV disease and low baseline HDL-C levels were randomized to simvastatin plus placebo or simvastatin plus extended release niacin (ERN), 1500 to 2000 mg/day, with ezetimibe added as needed in both groups to maintain an on-treatment LDL-C in the range of 40-80 mg/dL. The primary composite endpoint was death from coronary disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebrovascular revascularization. HDL-C, HDL3-C, sdLDL-C and LDL-TG were measured at baseline by detergent-based homogeneous assays. HDL2-C was computed by the difference between HDL-C and HDL3-C. Analyses were performed on 3094 study participants who were already on statin therapy prior to enrollment in the trial. Independent contributions of lipoprotein fractions to CV events were determined by Cox proportional hazards modeling. Baseline HDL3-C was protective against CV events (HR: 0.84, p = 0.043) while HDL-C, HDL2-C, sdLDL-C and LDL-TG were not event-related (HR: 0.96, p = 0.369; HR: 1.07, p = 0.373; HR: 1.05, p = 0.492; HR: 1.03, p = 0.554, respectively). The results of this secondary analysis of the AIM-HIGH Study indicate that levels of HDL3-C, but not other lipoprotein fractions, are predictive of CV events, suggesting that the HDL3 subclass may be primarily responsible for the inverse association of HDL-C and CV disease.

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Association of heart failure hospitalizations with combined electrocardiography and echocardiography criteria for left ventricular hypertrophy.

The value of performing echocardiography in hypertensive patients with electrocardiographic left ventricular hypertrophy (LVH) is uncertain. Baseline echo- and electrocardiographic data and cardiovascular events over 4.8 years study treatment were assessed in 922 hypertensive patients in the Losartan Intervention For Endpoint reduction in hypertension echocardiography substudy. Patients were grouped according to presence of LVH on both electrocardiogram (ECG) and echocardiogram (n = 515), only on ECG (n = 172), only on echocardiogram (n = 135), or on none tests (n = 100). LVH was diagnosed by Sokolow Lyon and Cornell product criteria by electrocardiography and as LV mass index >116 g/m(2) in men and >104 g/m(2) in women by echocardiography. Patients with LVH on both tests were older, had higher systolic blood pressure and LV mass, lower LV systolic function, and included more patients with aortic regurgitation, albuminuria, and history of ischemic heart disease (all P < 0.05). Incidence of combined myocardial infarction, stroke, or cardiovascular death did not differ between groups. Incidence of hospitalization for heart failure was 5.3 and 2.6 times higher in patients with LVH on both tests compared to patients with LVH on ECG or echocardiogram only (P < 0.01). In Cox regression, LVH on both tests predicted hospitalization for heart failure (hazard ratio 4.29 (95% confidence interval 1.26-14.65), P = 0.020) independent of other covariates including study treatment allocation and history of ischemic heart disease. Our results suggest that combining LVH assessment on a single ECG and echocardiogram provides a simple tool for additional heart failure risk stratification in asymptomatic high-risk hypertensive patients.

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Pharmacokinetics of oral salbutamol controlled-release in Asian patients with asthma.

Using a double blind, double dummy crossover design, single dose and steady state pharmacokinetics of oral controlled release (SCR) salbutamol 4 mg and 8 mg tablets b.d. has been studied in 8 Asian patients. Plasma salbutamol was measured over 12 h. In 8 patients the single dose mean Cmax was 4.2 ng.ml-1 and 7.7 ng.ml-1 after 4 and 8 mg, respectively. In 5 patients the steady state mean Cmax, Cmin and tmax were 8.1 ng.ml-1 and 4.7 ng.ml-1 and 6 h for the 4 mg tablets and 14.1 ng.ml-1 and 7.1 ng.ml-1 and 4 h for the 8 mg tablets. It is concluded that both doses of SCR show features of controlled release and that they produced a relatively constant plasma level of salbutamol in Asian patients.

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Ketorolac is not nephrotoxic in connection with sevoflurane anesthesia in patients undergoing breast surgery.

Ketorolac, which may cause renal vasoconstriction by cyclooxygenase inhibition, is often administered to patients anesthetized with sevoflurane that is metabolized to inorganic fluoride (F(-)), another potential nephrotoxin. We assessed this possible interaction using urine N-acetyl-beta-D-glucosaminidase indexed to urinary creatinine (U-NAG/crea) as a marker of proximal tubular, beta2-microglobulin as a tubular, urine oxygen tension (P(u)O(2)) as a medullary, and erythropoietin as a marker of tubulointerstitial damage. Thirty women (ASA physical status I-II) undergoing breast surgery were included in our double-blinded study. They were allocated into two groups receiving either ketorolac 30 mg IM (Group K) or saline (Group C) at the time of premedication, at the end of, and 6 h after anesthesia maintained with sevoflurane. Urine output, U-NAG/crea, P(u)O(2,) serum creatinine, urea, and F(-) were assessed. Blood loss was larger in Group K (465 +/- 286 mL vs 240 +/- 149 mL, mean +/- SD, P < 0.05). The MAC-doses of sevoflurane were similar. U-NAG/crea increased during the first 2 h of anesthesia and serum F(-) peaked 2 h after the anesthesia without differences between the groups. There were no statistically significant changes in P(u)O(2), erythropoietin, beta2-microglobulin, serum creatinine, urea, or urine output during anesthesia or the recovery period in either group. Our results indicate that the kidneys are not affected by ketorolac administered in connection with sevoflurane anesthesia. The different kinetics of N-acetyl-beta-D-glucosaminidase indexed to urinary creatinine and serum inorganic fluoride during and after sevoflurane anesthesia suggest that the observed mild renal tubular function deterioration is not caused by inorganic fluoride. Administration of ketorolac IM is therefore considered safe in adequately hydrated healthy adult patients given sevoflurane anesthesia.

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Quality of life after response to acute-phase cognitive therapy for recurrent depression.

Adults with major depressive disorder (MDD) often experience reduced quality of life (QOL). Efficacious acute-phase treatments, including cognitive therapy (CT) or medication, decrease depressive symptoms and, to a lesser degree, increase QOL. We tested longer-term changes in QOL after response to acute-phase CT, including the potential effects of continuation treatment for depression and time-lagged relations between QOL and depressive symptoms. Responders to acute-phase CT (N = 290) completed QOL and depressive symptom assessments repeatedly for 32 post-acute months. Higher-risk responders were randomized to 8 months of continuation treatment (CT, fluoxetine, or pill placebo) and then entered a 24-month follow-up. Lower-risk responders were only assessed for 32 months. On average, large gains in QOL made during acute-phase CT response were maintained for 32 months. Continuation CT or fluoxetine did not improve QOL relative to pill placebo. Controlling for residual depressive symptoms, higher QOL after acute-phase CT response was a protective factor against MDD relapse and recurrence. Higher QOL predicted subsequent reductions in depressive symptom severity, but depressive symptom severity did not predict subsequent changes in QOL. Generalization of results to other patient populations, treatments, and measures is uncertain. The clinical trial was not designed to test relations between QOL and depression. Replication is needed before clinical application of these results. Gains in QOL made during response to acute-phase CT are relatively stable and may help protect against relapse/recurrence. Continuation CT or fluoxetine may not further improve QOL among acute-phase CT responders.

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Bioequivalence of two commercially available levothyroxine-Na preparations in athyreotic patients.

The thyroid hormones levothyroxine and levotriiodothyronine are vital for normal growth and development and play an important role in energy metabolism. The bioequivalence of levothyroxine following administration of the test preparation (Eferox 100 tablets, Wyeth Pharma GmbH, Münster, Germany) and a reference preparation (each containing 100 micrograms levothyroxine-Na, the sodium salt of the natural thyroxine isomer) was investigated in 24 male and female patients with a lack of basal thyroid hormone secretion after an ablative thyroidectomy and postoperative radiotherapy. In a randomized, multicentric, open 3-factorial Latin-square (2 x 2 x 2) crossover study the subjects received two pharmaceutical units of the formulations once daily in the morning 30 min before breakfast during two periods of 35-42 consecutive days each. Serum concentrations of total thyroxine and total triiodothyronine were determined on screening day (basal concentrations), on the last 3 days of administration at predose to verify steady-state conditions, and on the last day of administration at 9 predetermined time points up to 24 h postadministration to obtain 24-h hormone profiles. The two formulations proved to be bioequivalent for levothyroxine regarding rate and extent of absorption. The bioequivalence decision was based on CSS,max and AUD0-24h.

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Drug-associated hyperthermia: A longitudinal analysis of hospital presentations.

Hyperthermia occurs when heat accumulation surpasses the body's ability for heat dissipation. Many drugs can affect thermoregulation through mechanisms including altering the neurotransmitters that cause increased heat production or decreased heat loss and may, therefore, be associated with hyperthermia. This study aimed to examine hospitalizations and emergency department (ED) presentations due to hyperthermia and to investigate the potential association with drug therapy. A retrospective analysis of ED presentations and hospitalizations due to hyperthermia in all four major hospitals in Tasmania, Australia, between July 2010 and December 2018 was performed. Data of patients aged ≥18 years were extracted from the hospital digital medical records and analysed for the prevalence, trends and various potential risk factors for hyperthermia, such as age, environmental temperature and drug therapy. This study included 224 patients. The data illustrated a trend with time, albeit not statistically significant, towards increasing hospital presentations due to hyperthermia. Antiepileptics (P = .03) and furosemide (P = .04) were the most frequently used drugs in patients with primary hyperthermia. The high use of levothyroxine in the study population (6.7%) stood out compared with the estimated national average (2.1%). Various drug classes associated with hyperthermia were used significantly more in the age group ≥60 years, suggesting polypharmacy in the elderly as a contributing factor for hyperthermia. This study reports a possible association of some drugs, particularly diuretics (furosemide), antiepileptics and levothyroxine, with hyperthermia. Healthcare professionals should be aware of the increasing prevalence of hyperthermia and the possible involvement of drugs.

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Bridging with glycoprotein IIb/IIIa inhibitors for periprocedural management of antiplatelet therapy in patients with drug eluting stents.

To describe outcomes when glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors are used as bridging antiplatelet therapy for surgical procedures in patients with drug eluting stents (DES). The optimal management of patients with DES who require surgical procedures prior to completion of antiplatelet therapy is unclear. In high risk patients, the use of GP IIb/IIIa inhibitors as bridging therapy while antiplatelet therapy is held has been described, but safety and efficacy data remain sparse. A pharmacy database was used to identify GP IIb/IIIa inhibitor orders at our hospital between January 1, 2007 and July 31, 2009. Indication for GP IIb/IIIa inhibitor administration and other clinical data were gathered through retrospective review of medical records. End points assessed were stent thrombosis, major bleeding, minor bleeding, postoperative acute coronary syndrome, and death within 30 days. Four thousand one hundred seventy-six separate orders for GP IIb/IIIa inhibitors were identified (January 1, 2007 to July 31, 2009). Six patients underwent non-cardiac and thirteen underwent cardiac surgery. Clopidogrel was discontinued a median of 6 days before surgery and 2 days prior to initiating GP IIb/IIIa inhibitor. All bridging patients were treated with eptifibatide infusion prior to procedure. There were no stent thromboses, deaths, or acute coronary syndrome events. Major bleeding occurred in 7 (53.9%) cardiac surgery patients and none of the non-cardiac surgery patients, while minor bleeding occurred in 1 (7.7%) and 1 (16.6%) patients, respectively. In patients with DES, who require cessation of clopidogrel before surgery, bridging with GP IIb/IIIa inhibitors appears effective in preventing adverse cardiac outcomes but may be associated with bleeding in patients undergoing cardiac surgery.

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Possible interaction between exposure to environmental tobacco smoke and therapy in children with asthma.

1. The aim of the study was to determine the carbachol and albuterol responsiveness in treated and untreated asthmatic and allergic children exposed to environmental tobacco smoke assessed by urinary cotinine measurements. 2. Forty-six asthmatic and allergic children with normal spirometric values were recruited. The doubling dose, concentration of carbachol producing a 2-fold increase in specific airway resistance (SRaw) was determined and 200 micrograms of albuterol were administered via a Volumatic(R) spacer. The percentage of bronchodilatation was defined as the difference between the largest obtained SRaw and the post-beta2 SRaw divided by the largest SRaw. Data were compared by a Mann-Whitney U-test. 3. The 23 children with a high urinary cotinine, compared with the 23 children without urinary cotinine, had a decreased doubling dose (108.2+/-14.7 micrograms versus 160.9+/-19.5 micrograms; P=0.04) and an increased percentage of bronchodilatation (74.8+/-1.4% versus 68.8+/-1.8%; P=0.03). A prophylactic anti-inflammatory treatment induced a weaker bronchial reactivity to carbachol and a slightly greater bronchodilatation in children exposed to environmental tobacco smoke. 4. Environmental tobacco smoke increases bronchial reactivity in asthmatic and allergic children. This effect might be reduced by anti-inflammatory therapy. The bronchodilator response may be enhanced in exposed children and may be caused by one or several direct interactions between tobacco smoke compounds and albuterol.

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Frequency of Opioid Dispensing After Vaginal Delivery.

To describe nationwide patterns in outpatient opioid dispensing after vaginal delivery. Using the Truven Health Analytics MarketScan database, we performed a large, nationwide retrospective cohort study of commercially insured beneficiaries who underwent vaginal delivery between 2003 and 2015 and who were opioid-naive for 12 weeks before the delivery admission. We assessed the proportion of women dispensed an oral opioid within 1 week of discharge, the associated median oral morphine milligram equivalent dose dispensed, and the frequency of opioid refills during the 6 weeks after discharge. We evaluated predictors of opioid dispensing using multivariable logistic regression. Among 1,345,244 women undergoing vaginal delivery, 28.5% were dispensed an opioid within 1 week of discharge. The most commonly dispensed opioids were hydrocodone (44.7%), oxycodone (34.6%), and codeine (13.1%). The odds of filling an opioid were higher among those using benzodiazepines (adjusted odds ratio [OR] 1.87, 95% CI 1.73-2.02) and antidepressants (adjusted OR 1.63, 95% CI 1.59-1.66), smokers (adjusted OR 1.44, 95% CI 1.38-1.51), and among those undergoing tubal ligation (adjusted OR 3.77, 95% CI 3.67-3.87), operative vaginal delivery (adjusted OR 1.52, 95% CI 1.49-1.54), and higher order perineal laceration (adjusted OR 2.15, 95% CI 2.11-2.18). The median (interquartile range, 10th-90th percentile) dose of opioids dispensed was 150 (113-225, 80-345) morphine milligram equivalents, equivalent to 20 tablets (interquartile range 15-30, 10th-90th percentile 11-46) of 5 mg oxycodone. Six weeks after discharge, 8.5% of women filled one or more additional opioid prescriptions. Opioid dispensing after vaginal delivery is common and often occurs at high doses. Given the frequency of vaginal delivery, this may represent an important source of overprescription of opioids in the United States.

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Novel assay demonstrates that coronary artery disease patients have heightened procoagulant platelet response.

Essentials Procoagulant platelets can be detected using GSAO in human whole blood. Stable coronary artery disease is associated with a heightened procoagulant platelet response. Agonist-induced procoagulant platelet response is not inhibited by aspirin alone. Collagen plus thrombin induced procoagulant platelet response is partially resistant to clopidogrel. Background Procoagulant platelets are a subset of highly activated platelets with a critical role in thrombin generation. Evaluation of their clinical utility in thrombotic disorders, such as coronary artery disease (CAD), has been thwarted by the lack of a sensitive and specific whole blood assay. Objectives We developed a novel assay, utilizing the cell death marker, GSAO [(4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid], and the platelet activation marker, P-selectin, to identify procoagulant platelets in whole blood by flow cytometry. Patients/Methods Using this assay, we characterized the procoagulant platelet population in healthy controls and a cohort of patients undergoing elective coronary angiography. Results In patients with CAD, compared with patients without CAD, there was a heightened procoagulant platelet response to thrombin (25.2% vs. 12.2%), adenosine diphosphate (ADP) (7.8% vs. 2.7%) and thrombin plus collagen (27.2% vs. 18.3%). The heightened procoagulant platelet potential in CAD patients was not associated with other markers of platelet function, including aggregation, dense granule release and activation of α_2b β₃ integrin. Although dual antiplatelet therapy (DAPT) was associated with partial suppression of procoagulant platelets, this inhibitory effect on a patient level could not be predicted by aggregation response to ADP and was not fully suppressed by clopidogrel. Conclusions We report for the first time that procoagulant platelets can be efficiently detected in a few microliters of whole blood using the cell death marker, GSAO, and the platelet activation marker, P-selectin. A heightened procoagulant platelet response may provide insight into the thrombotic risk of CAD and help identify a novel target for antiplatelet therapies in CAD.

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Better sexual acceptability of agomelatine (25 and 50 mg) compared to escitalopram (20 mg) in healthy volunteers. A 9-week, placebo-controlled study using the PRSexDQ scale.

The present double-blind, placebo-controlled study evaluates the effects of agomelatine and the selective serotonin reuptake inhibitor escitalopram on sexual dysfunction in healthy men and women. A total of 133 healthy volunteers (67 men, 66 women) were randomly assigned to agomelatine (25 or 50 mg) or escitalopram (20 mg) or placebo for nine weeks. Sexual acceptability was evaluated by using the psychotropic-related sexual dysfunction questionnaire 5-items total score and sexual dysfunction relative to each sub-score (in 110 volunteers with sexual activity). Sexual dysfunction was evaluated at baseline and after two, five and eight weeks of treatment and one week after drug discontinuation. The psychotropic-related sexual dysfunction questionnaire 5-items total score was significantly lower in both agomelatine groups versus escitalopram at all visits (p < 0.01 to p < 0.0001) with no difference between agomelatine and placebo nor between both agomelatine doses. Similar results were observed after drug discontinuation. The total score was significantly higher in the escitalopram group than in the placebo group at each post-baseline visit (p < 0.01 to p < 0.001). Similar results were observed regardless of volunteers' gender. Compared to placebo, only escitalopram significantly impaired dysfunction relative to "delayed orgasm or ejaculation" (p < 0.01) and "absence of orgasm or ejaculation" (p < 0.05 to p < 0.01). The percentage of participants with a sexual dysfunction was higher in the escitalopram group than in agomelatine groups (p < 0.01 to p < 0.05) and placebo (p < 0.01). The study confirms the better sexual acceptability profile of agomelatine (25 or 50 mg) in healthy men and women, compared to escitalopram. Evaluation of the effect of agomelatine and escitalopram on emotions and motivation in healthy male and female volunteers. ISRCTN75872983.

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Reduction of cardiovascular structural changes by nifedipine GITS in essential hypertensive patients.

The aim of this study was to evaluate the effect of the calcium antagonist Nifedipine GITS in a double-blind, randomized comparison with the diuretic hydrochlorothiazide (HCTZ) on reduction of left ventricular (LV) mass and minimal vascular resistance in a group of essential hypertensives with left ventricular hypertrophy (LVH). The effects on blood pressure and on echocardiographic LV functional parameters were also analysed. After two months of randomized treatment with Nifedipine GITS or HCTZ, if diastolic blood pressure was > 90 mmHg, a combination of the two drugs was given and was continued for 24 weeks. M-mode, 2D-guided echocardiography was used to measure LV mass index (LVMI) according to the "Penn convention". Minimal vascular resistance was measured in the forearm, from arterial pressure and maximal blood flow, using a strain gauge plethysmography. All examinations were performed before and after 8 and 24 weeks of treatment. Changes in LVMI were analysed at 8 weeks and at 24 weeks in patients receiving monotherapy ("according to protocol" analysis), and also at the end of treatment in patients taking Nifedipine or HCTZ monotherapy or the combination of the two drugs ("intention to treat" analysis). Both Nifedipine and HCTZ significantly reduced systolic and diastolic blood pressure (p < 0.001), without any significant difference between the two drug treatments. Heart rate was not significantly modified by either treatment. A progressive decrease in LVMI was observed after 8 and 24 weeks of treatment with Nifedipine monotherapy (ANOVA, p = 0.03), while the decrease in LVMI during HCTZ treatment did not progress further at 24 weeks (ANOVA, p = 0.49). A significant reduction of minimal vascular resistance was observed in patients treated with Nifedipine GITS monotherapy (ANOVA, p = 0.001), but not in the HCTZ group (ANOVA, p = 0.06). Comparison of changes of forearm minimal vascular resistance, considering baseline values, could demonstrate a greater effect during Nifedipine monotherapy as compared to HCTZ monotherapy. In conclusion, in a group of hypertensive patients with LVH, treatment for 24 weeks with Nifedipine GITS alone or in combination with HCTZ induced a significant reduction in LVMI and of forearm vascular structural changes, as evaluated by minimal vascular resistance. The decrease of minimal vascular resistance was significantly greater in patients treated with Nifedipine monotherapy, as compared to those given HCTZ.

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Metoprolol in the aged hypertensive: a comparison of two dosage schedules.

Thirty-one patients aged 65 y or over suffering from moderate hypertension were studied for 16 weeks using a cross-over design in which metoprolol 100 mg daily and metoprolol 200 mg daily were compared. Both treatment regimes were effective in controlling hypertension and no difference was found between the two with regard to efficacy. The 100 mg regime was, however, better tolerated and we propose this as the preferred metoprolol dose for the aged hypertensive.

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Improving the Translation of Organic Anion Transporting Polypeptide Substrates using HEK293 Cell Data in the Presence and Absence of Human Plasma via Physiologically Based Pharmacokinetic Modeling.

Accurately predicting the pharmacokinetics of compounds that are transporter substrates has been notoriously challenging using traditional in vitro systems and physiologically based pharmacokinetic (PBPK) modeling. The objective of this study was to use PBPK modeling to understand the translational accuracy of data generated with human embryonic kidney 293 (HEK293) cells overexpressing the hepatic uptake transporters organic anion transporting polypeptide (OATP) 1B1/3 with and without plasma while accounting for transporter expression. Models of four OATP substrates, two with low protein binding (pravastatin and rosuvastatin) and two with high protein binding (repaglinide and pitavastatin) were explored, and the OATP in vitro data generated in plasma incubations were used for a plasma model, and in buffer incubations for a buffer model. The pharmacokinetic parameters and concentration-time profiles of pravastatin and rosuvastatin were similar and well predicted (within 2-fold of observed values) using the plasma and buffer models without needing an empirical scaling factor, whereas the dispositions of the highly protein bound repaglinide and pitavastatin were more accurately simulated with the plasma models than the buffer models. This work suggests that data from HEK293 overexpressing transporter cells corrected for transporter expression represent a valid approach to improve bottom-up PBPK modeling for highly protein bound OATP substrates with plasma incubations and low protein binding OATP substrates with or without plasma incubations. SIGNIFICANCE STATEMENT: This work demonstrates the bottom-up approach of using in vitro data directly without employing empirical scaling factors to predict the intravenous pharmacokinetic (PK) profiles reasonably well for four organic anion transporting polypeptide (OATP) substrates. Based on these results, using HEK293 overexpressing cells, examining the impact of plasma for highly bound compounds, and incorporating transporter quantitation for the lot in which the in vitro data were generated represents a valid approach to achieve more accurate prospective PK predictions for OATP substrates.

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Phase II Study of Single/Repeated Doses of Acumapimod (BCT197) to Treat Acute Exacerbations of COPD.

Mitogen-activated protein kinase p38 is a key regulator in the inflammation pathway and is activated in the lungs of chronic obstructive pulmonary disease (COPD) patients. Acumapimod is a potent, selective, oral, p38 inhibitor under investigation for treatment of acute exacerbations of COPD (AECOPD). In this Phase II, double-blind, randomized, placebo-controlled dose-exploration study of acumapimod in patients with moderate or severe AECOPD (NCT01332097), patients presenting with AECOPD were randomized to receive single-dose acumapimod (20 mg or 75 mg) on Day 1, repeated single-dose acumapimod (20 mg or 75 mg) on Days 1 and 6, oral prednisone 40 mg (10 days), or placebo. Primary outcome: improvement in forced expiratory volume in 1 s (FEV₁) versus placebo at Day 5 (single doses) and Day 10 (repeated doses). <i>N</i> = 183 patients were randomized; 169 (92%) patients completed the study. Although the primary endpoint (FEV₁ at Day 10) was not met (<i>p</i> = 0.082), there was a significant improvement in FEV₁ with acumapimod repeat-dose 75 mg versus placebo at Day 8 (<i>p</i> = 0.022) which, though not a prespecified endpoint, was part of an overall trend. Differences at lower doses did not achieve significance. Mean change in FEV₁ AUC from baseline to Day 14 in the 75 mg repeat-dose group was significantly higher versus placebo (<i>p</i> = 0.02), prednisone (<i>p</i> = 0.01), and 20 mg single-dose groups (<i>p</i> = 0.015) (post-hoc analysis). EXACT-PRO showed numerical differences versus placebo that did not reach significance. Acumapimod was well tolerated. In conclusion, repeated single-dose acumapimod showed a clinically relevant improvement in FEV₁ over placebo at Day 8, along with consistent numerical differences in EXACT-PRO. These data can be used to determine dose regimens for a proof-of-clinical-concept trial.

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Treatment with vitamin D and calcium reduces bone loss after renal transplantation: a randomized study.

A decrease in bone mineral density (BMD) is a major complication of renal transplantation (RTx), predominantly occurring within the first 6 mo after RTx. The most important causative factor is the use of corticosteroids, but persisting hyperparathyroidism and abnormalities in vitamin D metabolism play a role too. This study examines the effect of treatment with calcium and active vitamin D on the loss of BMD in the first 6 mo after RTx. A total of 111 renal transplant recipients (65 men, 46 women; age, 47 +/- 13 yr) were randomized to either treatment with active vitamin D (0.25 microg/d) plus calcium (1000 mg/d) (CaD group), or to no treatment (NoT group). Immunosuppressive therapy consisted of cyclosporine, prednisone, and mycophenolate mofetil. Laboratory parameters and BMD (lumbar spine and hip) were measured at 0, 1 (laboratory only), 3, and 6 mo after RTx. Lumbar BMD was nearly normal at the time of RTx. In both groups, a significant decrease in lumbar BMD was observed during the first 3 mo (CaD, -3.3 +/- 4.3%; P < 0.0001; NoT, -4.1 +/- 4.8%; P < 0.0001). Between the third day and sixth month, lumbar BMD slightly recovered in the CaD group, but it decreased further in the NoT group (total loss 0 to 6 mo: CaD, -2.6 +/- 5.0% [P < 0.001]; NoT, -5.0 +/- 4.7% [P < 0.0001]). As a result, the amount of bone loss at 6 mo was significantly lower in the CaD group (P = 0.02). Loss of BMD at the different femoral sites was also significantly reduced in the CaD group. Apart from a trend toward more frequent hypercalcemia in the CaD group, no clinical or biochemical differences existed between the groups. Treatment with a low dose of active vitamin D and calcium partially prevents bone loss at the lumbar spine and proximal femur during the first 6 mo after RTx.

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Effect of pantoprazole on insulin secretion in drug-naïve patients with type 2 diabetes.

To evaluate the effect of pantoprazole during 45 days on insulin secretion in drug-naïve patients with type 2 diabetes, a randomized, double blind, placebo control clinical trial was performed in 14 drug-naïve volunteers. Significant increases in late insulin phase and total insulin secretion, and decreases in HbA1c levels were found.

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Characteristics of asthma resistant to moderate dose inhaled corticosteroid treatment on bronchial hyperresponsiveness.

This study was performed to determine the clinical characteristics of asthmatics with bronchial hyperresponsiveness (BHR) that could not be normalized by 6 months of treatment with a moderate dose of an inhaled corticosteroid (ICS). Thirty-four symptomatic patients with mild to moderate asthma, who had never received any ICS, were treated with 200 mug of inhaled fluticasone propionate twice a day for 6 months. Spirometry, BHR to methacholine, exhaled nitric oxide (NO) and eosinophils in induced sputum were examined before and 2 and 6 months after beginning treatment. FEV1 was increased and bronchial responsiveness, exhaled NO and sputum eosinophilia were significantly decreased 2 and 6 months after starting ICS treatment. Bronchial responsiveness was further decreased at 6 months together with a further increase in FEV1. In 13 patients, BHR was not normalized despite the 6 months of treatment. This group showed a higher prevalence of males, those with a smoking history and airflow limitation, a higher eosinophil count in the sputum following 6 months of treatment and a longer history of asthma. Multiple, stepwise, linear regression analysis showed that sputum eosinophilia and lower FEV1/FVC following 6 months of treatment and a longer history of asthma were significant independent determinants for BHR after 6 months of ICS treatment. These findings suggest that the resistance to a moderate dose of ICS for BHR in asthmatics may be significantly associated with remained airflow limitation, eosinophilic airway inflammation resistive to moderate dose of ICS, and delayed introduction of ICS therapy.

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The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial.

The purpose of this study was to compare urate-lowering (UL) efficacy and safety of daily febuxostat and allopurinol in subjects with gout and serum urate (sUA) > or = 8.0 mg/dL in a six-month trial. Subjects (n = 2,269) were randomized to febuxostat 40 mg or 80 mg, or allopurinol 300 mg (200 mg in moderate renal impairment). Endpoints included the proportion of all subjects with sUA <6.0 mg/dL and the proportion of subjects with mild/moderate renal impairment and sUA <6.0 mg/dL. Safety assessments included blinded adjudication of each cardiovascular (CV) adverse event (AE) and death. Comorbidities included: renal impairment (65%); obesity (64%); hyperlipidemia (42%); and hypertension (53%). In febuxostat 40 mg, febuxostat 80 mg, and allopurinol groups, primary endpoint was achieved in 45%, 67%, and 42%, respectively. Febuxostat 40 mg UL was statistically non-inferior to allopurinol, but febuxostat 80 mg was superior to both (P < 0.001). Achievement of target sUA in subjects with renal impairment was also superior with febuxostat 80 mg (72%; P < 0.001) compared with febuxostat 40 mg (50%) or allopurinol (42%), but febuxostat 40 mg showed greater efficacy than allopurinol (P = 0.021). Rates of AEs did not differ across treatment groups. Adjudicated (APTC) CV event rates were 0.0% for febuxostat 40 mg and 0.4% for both febuxostat 80 mg and allopurinol. One death occurred in each febuxostat group and three in the allopurinol group. Urate-lowering efficacy of febuxostat 80 mg exceeded that of febuxostat 40 mg and allopurinol (300/200 mg), which were comparable. In subjects with mild/moderate renal impairment, both febuxostat doses were more efficacious than allopurinol and equally safe. At the doses tested, safety of febuxostat and allopurinol was comparable. NCT00430248.

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[The effects of captopril and metoprolol on blood pressure and side effects in patients with mild to moderate hypertension].

A material of 76 patients from general practice treated with diuretics for mild to moderate hypertension were randomized to supplementary treatment with captopril (39 patients) and metoprolol (37 patients), respectively, on account of diastolic blood pressure greater than or equal to 95 mmHg. Satisfactory regulation of the blood pressure (diastolic blood pressure less than or equal to 90 mmHg) and acceptable wellbeing was obtained in 29 patients in the captopril group and in 23 patients in the metoprolol group. Six patients in the captopril group were excluded on account of absence of effect on the blood pressure and four dropped out on account of side effects. In the metoprolol group, nine patients were excluded on account of absence of effect on the blood pressure and five on account of side effects. This difference was not significant. In the captopril group, 14 side effects were registered in eight patients while 23 side effects were observed in 15 patients in the metoprolol group. This difference was not statistically significant, p greater than 0.05 (risk for type 2 error = 60%). It is concluded that captopril + a diuretic is just as effective a form of treatment of slight to moderate hypertension as metoprolol + a diuretic and that treatment with captopril + a diuretic is associated with so few side effects that it may be considered as an alternative first choice of treatment in cases of slight to moderate hypertension.

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The Strategic Reperfusion Early After Myocardial Infarction (STREAM) study.

Primary percutaneous coronary intervention (PCI) has emerged as the preferred therapy for acute ST-elevation myocardial infarction (STEMI) provided it is performed in a timely fashion at an expert 24/7 facility. Fibrinolysis is a well-accepted alternative, especially in patients presenting early after symptom onset. The STREAM study will provide novel information on whether prompt fibrinolysis at first medical contact, followed by timely catheterization or rescue coronary intervention in STEMI patients presenting within 3 hours of symptom onset, represents an appropriate alternative strategy to primary PCI. Acute STEMI patients presenting early after symptom onset are eligible if PCI is not feasible within 60 minutes of first medical contact. This is an open-label, prospective, randomized, parallel, comparative, international multicenter trial. Patients are randomized to fibrinolysis combined with enoxaparin, clopidogrel, and aspirin, and cardiac catheterization within 6 to 24 hours or rescue coronary intervention if reperfusion fails within 90 minutes of fibrinolysis versus PCI performed according to local guidelines. Composite efficacy end points at 30 days include death, shock, heart failure, and reinfarction. Safety end points include ischemic stroke, intracranial hemorrhage, and major nonintracranial bleeding. Follow-up is extended to 1 year and includes all-cause mortality. Continuing delays in achieving timely PCI remain a difficult issue. Many patients fail to achieve the desired reperfusion times of 90 to 120 minutes after first medical contact. The STREAM results will provide useful additional data on which to base informed therapeutic decisions.

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Comparative effects of long-acting beta2-agonists, leukotriene receptor antagonists, and a 5-lipoxygenase inhibitor on exercise-induced asthma.

Exercise-induced asthma (EIA) is a common problem that can be controlled with long-acting beta-agonists and leukotriene-modifying compounds. There is, however, limited information on the comparative effectiveness of the two classes of drugs, as well as the relative potencies of the antileukotriene agents. The purpose of the present study was to provide data on the above issues. We performed a random-order, blinded, double-dummy, placebo-controlled trial in 10 patients with EIA. Each subject received standard single doses of salmeterol, montelukast, zafirlukast, zileuton, and placebo on separate days. The participants performed 4 minutes of cycle ergometry while breathing frigid air 1, 4, 8, and 12 hours after administration of the test agents. The primary endpoint was the extent of the decrement in the FEV(1) 10 minutes after exertion. With placebo, symptomatic airway narrowing developed at all times (mean +/- SE decrease in FEV(1) ranged between 21% +/- 5% and 26% +/- 5%). Salmeterol acted quickly and significantly blunted the obstructive response for 12 hours (DeltaFEV(1) first hour: 8% +/- 3%; DeltaFEV(1) twelfth hour: 8% +/- 3%; P <.0001 vs placebo and P =.72 vs time). The leukotriene-modifying agents produced effects within 1 hour of ingestion. Like salmeterol, montelukast and zafirlukast also offered long-lasting protection, and there were no significant differences between them (montelukast DeltaFEV(1) twelfth hour: 9% +/- 4%; zafirlukast DeltaFEV(1) twelfth hour: 11% +/- 2%; P =.75) or the beta(2)-agonist (montelukast vs salmeterol: P =.72; zafirlukast vs salmeterol: P =.48). Zileuton provided equivalent prophylaxis for the first 4 hours (DeltaFEV(1) fourth hour: 11% +/- 2%); however, by 8 hours, it was less efficacious than all of the other active compounds, and by 12 hours it did not differ from placebo (DeltaFEV(1) twelfth hour: 19% +/- 4%; P =.33). Single doses of the currently available leukotriene receptor antagonists provide prompt effective and persistent defense against EIA that equals that seen with a long-acting beta(2)-agonist. The synthesis inhibitor zileuton affords a comparable magnitude of prophylaxis but has a considerably shorter duration of action.

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Ticagrelor Versus Clopidogrel in Patients With STEMI Treated With Fibrinolysis: TREAT Trial.

The efficacy of ticagrelor in the long-term post-ST-segment elevation myocardial infarction (STEMI) treated with fibrinolytic therapy remains uncertain. The purpose of this study was to evaluate the efficacy of ticagrelor when compared with clopidogrel in STEMI patients treated with fibrinolytic therapy. This international, multicenter, randomized, open-label with blinded endpoint adjudication trial enrolled 3,799 patients (age <75 years) with STEMI receiving fibrinolytic therapy. Patients were randomized to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose, 75 mg daily thereafter). The key outcomes were cardiovascular mortality, myocardial infarction, or stroke, and the same composite outcome with the addition of severe recurrent ischemia, transient ischemic attack, or other arterial thrombotic events at 12 months. The combined outcome of cardiovascular mortality, myocardial infarction, or stroke occurred in 129 of 1,913 patients (6.7%) receiving ticagrelor and in 137 of 1,886 patients (7.3%) receiving clopidogrel (hazard ratio: 0.93; 95% confidence interval: 0.73 to 1.18; p = 0.53). The composite of cardiovascular mortality, myocardial infarction, stroke, severe recurrent ischemia, transient ischemic attack, or other arterial thrombotic events occurred in 153 of 1,913 patients (8.0%) treated with ticagrelor and in 171 of 1,886 patients (9.1%) receiving clopidogrel (hazard ratio: 0.88; 95% confidence interval: 0.71 to 1.09; p = 0.25). The rates of major, fatal, and intracranial bleeding were similar between the ticagrelor and clopidogrel groups. Among patients age <75 years with STEMI, administration of ticagrelor after fibrinolytic therapy did not significantly reduce the frequency of cardiovascular events when compared with clopidogrel. (Ticagrelor in Patients With ST Elevation Myocardial Infarction Treated With Pharmacological Thrombolysis [TREAT]; NCT02298088).

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Evaluation of pantoprazole formulations in different dissolution apparatus using biorelevant medium.

The study was developed to compare the in vitro dissolution profiles of pantoprazole (CAS 102625-70-7) formulations in both The United States Pharmacopeia (USP) apparatus 2 and 3 by applying biorelevant medium. Moreover, an in vitro-in vivo relationship was proposed considering in vivo data from a previously published study. In vitro dissolution profiles were evaluated in biorelevant medium in USP apparatus 2 and 3 and the dissolution curves were either compared by the similarity factor (f2) or a model-independent approach. The fraction of drug dissolved in vitro in apparatus 2 was compared with the fraction of drug absorbed in vivo, which was obtained from a retrospective in vivo study. An in vitro-in vivo relationship analysis was then applied to elucidate the overall absorption characteristics of formulations. The dissolution profiles of formulations demonstrated similar disposition in biorelevant medium in both USP apparatus 2 and 3. The dissolution profiles were described by f2 model in apparatus 2 and Weibull's function in apparatus 3. The vitro-in vivo relationship analysis showed that the formulations exhibited permeability rate-limiting absorption. Biorelevant medium in both USP apparatus 2 and 3 may be used as a tool to predict in vivo disposition of formulations of pantoprazole. Furthermore, it can be argued that biowaiver can be granted for enteric coated formulations of pantoprazole on the basis of in vitro dissolution profile.

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Pharmacologic provocation combined with endoscopy in refractory cases of GI bleeding.

The source of GI bleeding may elude us despite exhaustive testing in some cases. Bleeding in these cases is often related to a vascular lesion that is discernible only when actively bleeding. The objective of this study was to determine the efficacy and safety of endoscopy combined with the administration of antiplatelet and/or anticoagulant agents to stimulate bleeding in order to define a source. A retrospective review of a database of device-assisted enteroscopy (DAE) procedures was completed to identify cases in which provocation with antiplatelet or anticoagulant agents was used as part of a GI bleeding evaluation. Procedures were divided into 3 groups based on the method of provocation: patients with a history of bleeding associated with an antiplatelet/anticoagulant (provocation-experienced); patients naïve to these medications (provocation-naïve); and cases of recurrent, overt GI bleeding in which a combination of clopidogrel and intravenous heparin was administered for provocation (Lousiana State University [LSU] protocol). A review of 824 DAE procedures was completed to identify a total of 38 instances in which provocation was attempted in 27 patients. These cases were subdivided into 13 provocation-experienced procedures, 18 provocation-naïve procedures, and 7 LSU protocol procedures. The diagnostic yield of provocative testing per procedure was 53% in the provocation-experienced group, 27% in the provocation-naïve group, and 71% in the full protocol group. Provocative testing was revealing in 15 of 27 patients; angioectasias and Dieulafoy lesions were the most common pathologies. Provocative testing was not beneficial in 4 patients who were eventually diagnosed with bleeding caused by intestinal angioectasias (3) and an aorto-enteric fistula (1). There were no adverse events. Provocative testing combined with endoscopy can be justified as an option in the diagnostic algorithm of complex cases of GI bleeding when intermittent bleeding related to a vascular lesion, such as an angioectasia or Dieulafoy, is suspected. However, this novel technique should be considered only after standard management has failed to define a bleeding source, and bleeding continues to recur. This is the first reported case series of provocative testing combined with endoscopy.

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Left ventricular mass regression and diastolic function improvement in mild and moderate hypertensive patients treated with lisinopril.

Thirty patients (18 male), mean age 49.5 +/- 6.3 years, were treated with lisinopril 10-40 mg once daily for 16 weeks. The effect of treatment on left ventricular mass and improvement in left ventricular diastolic function (measured by echo-Doppler) was assessed. Blood pressure changes were measured conventionally in the clinic and by ambulatory blood pressure monitoring. Clinic blood pressure decreased from 168.3 +/- 13.8/105.5 +/- 5.4 mm Hg to 137.5 +/- 4.1/88.8 +/- 4.1 mm Hg (p < 0.005 for both systolic and diastolic blood pressures), and the heart rate from 75.2 +/- 3.7 to 74.4 +/- 7.6 beats per minute (NS). The frequency of ambulatory systolic blood pressure values > 140 mm Hg decreased in percentage from 63.3 +/- 12.8 to 29.9 +/- 9.1% (p < 0.005) and the frequency of ambulatory diastolic blood pressure values > 90 mm Hg decreased in percentage from 61.1 +/- 12.8 to 28.6 +/- 7.5% (p < 0.005). Septal and left ventricular posterior wall thickness decreased from 11.2 +/- 0.9 to 10.3 +/- 0.6 mm and from 10.9 +/- 0.9 to 10.1 +/- 0.6 mm, respectively (both p < 0.005). Left ventricular diastolic diameter and the shortening fraction did not change significantly. Left ventricular mass, calculated from left ventricular wall thickness and diastolic diameter, decreased from 132.6 +/- 11.5 to 119.9 +/- 6.3 g/m2 (p < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

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On the antioxidant activity of carvedilol in human polymorphonuclear leukocytes in vitro and ex vivo.

In the present study we investigated whether the beta-adrenoceptor antagonist carvedilol (CARV) [Dilatrend] prevented reactive oxygen metabolite (ROM) production in human polymorphonuclear leukocytes (PMNL) or interfered with ROM already generated. To specify the site of action of CARV, we evaluated its effect on extra- and intracellular ROM generation. In addition, we studied the effect of CARV therapy on ROM production in whole blood obtained from patients with congestive heart failure (CHF) combined with type II diabetes mellitus. ROM generation in whole blood and isolated PMNL was determined after phorbol 12-myristate-13-acetate (PMA-0.05 micromol/l) stimulation by luminol/isoluminol-enhanced chemiluminescence (CL) in the microplate luminometer Immunotech LM-01T. CARV significantly decreased CL of human whole blood in the concentrations of 10, 20, 50 and 100 micromol/l, both when applied simultaneously and after stimulation. In isolated PMNL, CARV significantly decreased extracellular CL in the concentrations of 50 and 100 micromol/l, intracellular CL was decreased in the concentrations of 20, 50 and 100 micromol/l. The nonstimulated and PMA stimulated CL of whole blood was increased in patients before therapy in comparison with healthy controls. After CARV therapy, 25 mg/day and 50 mg/day, there was a trend to reduce CL as compared to values before therapy. In human PMNL, CARV interfered in vitro and ex vivo with ROM generation as well as with already generated ROM, suggestive of its both "preventive" and "therapeutic" effect.

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Impact of Point-of-Care Platelet Function Testing Among Patients With and Without Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention With Drug-Eluting Stents (from the ADAPT-DES Study).

We sought to examine if the risk conferred by high on-treatment platelet reactivity (HPR) varies based upon clinical presentation. We examined the relation between HPR (P2Y12 reaction units >208) and adverse ischemic and bleeding events among patients with and without acute coronary syndromes (ACS) from ADAPT-DES; 51.7% of patients had ACS. After clopidogrel loading, ACS patients had higher P2Y12 reaction units and a greater prevalence of HPR based on VerifyNow P2Y12 assay. Of 92 definite or probable stent thrombosis (ST) events at 2 years, 65.2% occurred among patients with ACS. HPR was independently associated with ST in ACS patients (adjusted hazard ratio 2.29, 95% confidence interval 1.32 to 3.98) but not with clinically relevant bleeding. Although no statistical interactions between ACS status and these associations were observed, non-ACS patients exhibited an attenuated association between HPR and ST, and an inverse association between HPR and clinically relevant bleeding. HPR was similarly associated with myocardial infarction, but not with overall mortality in ACS and non-ACS patients. In conclusion, the majority of ST events in the 2 years after drug-eluting stent placement occurred in ACS patients; HPR was strongly associated with ST in these patients. These data support current recommendations for using more potent antiplatelet therapies in ACS patients.

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Facing real-life with direct oral anticoagulants in patients with nonvalvular atrial fibrillation: outcomes from the first observational and prospective study in a Spanish population.

To analyze the effectiveness and safety of direct oral anticoagulants (DOACs) in atrial fibrillation (AF) patients attended in clinical practice. Observational and prospective study of AF patients that started treatment with DOACs. 1443 patients (age 77.2 ± 9.7 years, CHA₂DS₂-VASc = 4.1 ± 1.5) were included. 46.0% were taking rivaroxaban, 24.4% dabigatran, 22.5% apixaban and 7.1% edoxaban. Patients taking dabigatran were younger, had lower CHA₂DS₂-VASc and lesser renal insufficiency. Patients taking apixaban had higher CHA₂DS₂-VASc and more renal insufficiency. Rates of stroke/major bleeding/intracranial bleeding were 0.7/1.3/0.2 events/100 patient-years, respectively. This was the first prospective study that analyzed the use of all DOACs in AF patients in Spain, showing a good profile in terms of safety and effectiveness in accordance with pivotal studies.

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Risks of Adverse Events Following Coprescription of Statins and Calcium Channel Blockers: A Nationwide Population-Based Study.

Some statins (simvastatin, lovastatin, and atorvastatin) are metabolized by cytochrome P450s 3A4 (CYP3A4). Inhibitors of CYP3A4 including some calcium channel blockers (CCBs) might increase statin blood concentration, owing to drug-drug interactions. Risk of adverse events such as acute kidney injury might occur following the coprescription of CYP3A4-metabolized statins and CCBs that inhibit CYP3A4.This was a population-based cohort study. The study analyzed data of patients treated between 1997 and 2011, retrieved from Taiwan's National Health Insurance database. We enrolled 32,801 patients who received coprescription of statins and CCBs that inhibit CYP3A4 (amlodipine, diltiazem, felodipine nicardipine, nifedipine, and verapamil). These patients were divided into 2 groups, according to whether they had received CYP3A4-metabolized statins (lovastatin, simvastatin, and atorvastatin) or non-CYP3A4-metabolized statins (fluvastatin, rosuvastatin, and pitavastatin). These 2 groups were 1:1 matched by age, gender, and Carlson comorbidity index. All outcomes were assessed within 90 days following drug coprescription.In this study, 5857 patients received coprescription of CYP3A4-metabolized statins and CCBs that inhibit CYP3A4. There were no differences in comorbidity or use of antihypertensive drugs between patients who received CYP3A4-metabolized statins and those who received non-CYP3A4-metabolized statins. Patients who received CYP3A4-metabolized statins had significantly higher risk of acute kidney injury (adjusted odds ratio [OR] = 2.12; 95% CI = 1.35-3.35), hyperkalemia (adjusted OR = 2.94; 95% CI = 1.36-6.35), acute myocardial infarction (adjusted OR = 1.55; 95% CI = 1.16-2.07), and acute ischemic stroke (adjusted OR = 1.35; 95% CI = 1.08-1.68) than those who received non-CYP3A4-metabolized statins.This nationwide cohort study demonstrated the increased risk of adverse events following the coprescription of CYP3A4-metabolized statins and CCBs that inhibit CYP3A4. Therefore, it is important to take into account the potential adverse events while coprescribing CYP3A4-metabolized statins and CCBs that inhibit CYP3A4.

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Effect of xuezhikang, a cholestin extract, on reflecting postprandial triglyceridemia after a high-fat meal in patients with coronary heart disease.

The effect of xuezhikang on postprandial triglyceride (TG) level was investigated in patients with coronary heart disease (CHD) after a high-fat meal (800 cal; 50 g fat). Fifty CHD patients were randomly divided into two groups to accept xuezhikang (xuezhikang group) 1200 mg/day (600 mg twice daily) or not (control group) on the base of routine therapy which included aspirin, metoprolol and fosinopril and nitrates during the whole 6 weeks following-up. Xuezhikang significantly reduced fasting serum total cholesterol (TC) (-20%), low-density lipoprotein cholesterol (LDL-C, -34%), TG (-32%) and apoB (-27%) levels, and raised fasting high-density lipoprotein cholesterol (HDL-C, 18%) and apoA-I (13%) levels (P<0.001). The postprandial serum TG levels at 2, 4 and 6 h decreased 32, 38 and 43%, respectively, in xuezhikang group (P<0.001). The TG area under the curve over the fasting TG level (TG-AUC) significantly decreased in CHD patients accepted xuezhikang with normal (less than 1.7 mmol/l) and elevated (1.74 to 2.92 mmol/l) fasting TG levels by 45 and 50%, respectively (P<0.001). Routine therapy had no significant effect on the fasting and postprandial lipid and apolipoprotein levels. The change of TG-AUC was significantly related to the changes of fasting TG, TC, LDL-C, and HDL-C levels after the treatment, which were related to the changes of fasting apoA-I and apoB levels significantly (P<0.001). Xuezhikang was shown to be beneficial in the treatment of reflecting postprandial triglyceridemia in CHD patients with normal and mildly elevated fasting TG levels.

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The concurrent use of antithrombotic therapies and the risk of bleeding in patients with atrial fibrillation.

Patients with atrial fibrillation (AF) often receive, in addition to warfarin, antithrombotic drugs to manage other comorbid conditions. To date, few population-based studies have quantified the bleeding risk associated with the concurrent use of these therapies. The United Kingdom General Practice Research Database was used to identify a cohort of 70,760 patients newly-diagnosed with AF between 1993 and 2008. A nested case-control analysis was conducted within that cohort, and conditional logistic regression was used to estimate adjusted rate ratios (RRs) of bleeding associated with current use of warfarin, aspirin, and clopidogrel in single therapy, as well as in dual and triple therapy, as compared with non-use of any therapy. A total of 10,850 patients experienced a bleeding event during follow-up. In single therapy, warfarin was associated with the highest increased risk (RR: 2.08, 95% confidence interval [CI]: 1.95-2.23), followed by clopidogrel (RR: 1.57, 95% CI: 1.37-1.81) and aspirin (RR: 1.25, 95% CI: 1.17-1.34). In dual therapy, combinations containing warfarin were associated with a higher increased risk (warfarin-aspirin: RR: 2.87, 95% CI: 2.58-3.19, and warfarin-clopidogrel: RR: 2.74, 95% CI: 2.14-3.51), than those not containing warfarin (aspirin-clopidogrel: RR: 1.68, 95% CI: 1.44-1.97). Triple therapy of warfarin-aspirin-clopidogrel was associated with the highest increased risk (RR: 3.75, 95% CI: 2.71-5.19). This large population-based study suggests that while all antithrombotic therapies are associated with an elevated risk of bleeding, the risks increase in an additive fashion with dual and triple therapy, particularly in combinations containing warfarin.

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Adolescent and adult acute lymphoblastic leukemia: prognostic features and outcome of therapy. A study of 293 patients.

The case histories of 293 adolescent and adult patients with acute lymphoblastic leukemia (ALL) first seen and treated between 1969 and 1979 are reviewed. A complete remission (CR) was achieved in 79% of cases. Male sex, advanced age (greater than or equal to 30 yr old), and early CNS involvement were the major determinants of remission failure. Median duration of first CR was 16 mo, with 23 patients (actuarial proportion 25%) alive and relapse-free at 5 yr. The major determinant of first CR length was white blood cell (WBC) count (best cut-off value at 35 X 10(9)/liter). First CR length was also negatively affected by early CNS involvement, morphological FAB L3 subtype, and B-cell (Smlg+) leukemia, but these features were significantly associated with a high WBC count. First CR length in patients 11-15 yr old did not differ significantly from that of patients 16-59 yr old. The negative prognostic value of T-cell (E+) leukemia was not confirmed in this adult series. CNS prophylaxis provided an effective protection against CNS relapse. Maintenance chemotherapy was apparently more effective when 4 or more than 4 drugs were employed. "Low risk" patients (WBC count less than 35 X 10(9)/liter still relapsed rather frequently (32% at 1 yr, 49% at 2 yr), with 33% of them alive and relapse-free at 5 yr. "High risk" patients (WBC count greater than or equal to 35 X 10(9)/liter +/- early CNS involvement +/- morphological L3 subtype +/- B-cell leukemia) relapsed very quickly (50% at 6 mo. 70% at 1 yr), with only 6% of them relapse-free at 5 yr.

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Lessons from combination therapy in Veterans Affairs Studies. Department of Veterans Affairs Cooperative Study Group on antihypertensive agents.

A subset of 102 patients of an original cohort of 1292 with stage 1 to 2 hypertension was characterized by having failed to achieve goal blood pressure (< 90 mm Hg diastolic) after treatment with two single antihypertensive drugs. These patients were given a combination of the two drugs on which they had failed to achieve blood pressure goal when they were administered as single-drug therapy. The drugs were hydrochlorothiazide, atenolol, captopril, diltiazem-SR, clonidine, and prazosin. We examined the responses in each of the drug combination categories by the order that the drugs were administered, by estimated total response rates for the combinations, and by age and race. The order of drug administration did have an effect for some of the drug pairs. This was of two types: 1) different results for each member of the pair, but the same combination result; and 2) different end result of the combination. An example of the first type is that prazosin had only a 6% response rate in patients who had failed on diltiazem, while diltiazem had a 22% response rate in patients who had failed on prazosin. Nevertheless, the combinations yielded the same total responses (86% and 84%) regardless of order. An example of the second type is that captopril-diltiazem was less effective in total response than diltiazem-captopril (88% v 97%). Differences were seen in the response to combinations in the race and age groups. There were ordering differences of type similar to those described above. We conclude that combination drug therapy is highly effective even when the individual components have failed and that some differences in response by order of drug administration may occur.

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Comparison of single-dose and multiple-dose antibiotics for lower urinary tract infection in pregnancy.

To compare the efficacy of fosfomycin trometamol, cefuroxime axetil, and amoxicillin clavulanate antibiotics, and to assess the difference in patient compliance, in the treatment of urinary tract infections during pregnancy. Between September 2007 and May 2008, 90 out of 324 pregnant women with complaints of lower urinary tract infection, who were followed at the outpatient clinic or referred to the emergency department of Vakif Gureba Education and Research Hospital, were enrolled in a prospective study. Patients were randomized into 3 equal groups for treatment with single-dose fosfomycin trometamol, or 5-day courses of amoxicillin clavulanate or cefuroxime axetil. After follow-up, study data were obtained for 28, 27, and 29 patients, respectively. The treatment groups did not differ significantly in terms of demographics, clinical success rate, microbiological cure rate, or adverse effects. Significantly higher drug compliance was observed in the fosfomycin trometamol group than in the other 2 groups (P<0.05). Treatment with a single dose of fosfomycin trometamol was as effective for UTI as the standard course of treatment with amoxicillin clavulanate or cefuroxime axetil. Fosfomycin trometamol may be a preferable treatment for UTI because of its simpler use and better rates of compliance.

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Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole.

Itraconazole increases the risk of skeletal muscle toxicity of some 3-hydroxy-3-methylglutaryl coenzyme A' (HMG-CoA) reductase inhibitors by increasing their serum concentrations. We studied possible interactions of itraconazole with simvastatin and pravastatin. Two randomized, double-blind, two-phase crossover studies were performed with use of an identical design, one with simvastatin (study I) and one with pravastatin (study II). In both studies, 10 healthy volunteers received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, each subject ingested a single 40 mg dose of simvastatin (study I) or pravastatin (study II). Serum concentrations of simvastatin, simvastatin acid, pravastatin, HMG-CoA reductase inhibitors, itraconazole, and hydroxyitraconazole were determined. In study I, itraconazole increased the peak serum concentrations (Cmax) and the areas under the serum concentration-time curve [AUC(0-infinity)] of simvastatin and simvastatin acid at least tenfold (p < 0.001). The Cmax and AUC(0-infinity) of total simvastatin acid (naive simvastatin acid plus that derived by hydrolysis of the lactone) were increased 17-fold and 19-fold (p < 0.001), respectively, and the half-life (t1/2) was increased by 25% (p < 0.05). The AUC(0-infinity) of HMG-CoA reductase inhibitors was increased fivefold (p < 0.001) and the Cmax and t1/2 were increased threefold (p < 0.001). In study II, itraconazole slightly increased the AUC(0-infinity) and Cmax of pravastatin, but the changes were statistically nonsignificant (p = 0.052 and 0.172, respectively). The t1/2 was not altered. The AUC(0-infinity) and Cmax of HMG-CoA reductase inhibitors were increased less than twofold (p < 0.05 and p = 0.063, respectively) by itraconazole. There were no differences in the serum concentrations of itraconazole and hydroxyitraconazole between studies I and II. Itraconazole greatly increased serum concentrations of simvastatin, simvastatin acid, and HMG CoA reductase inhibitors, probably by inhibiting CYP3A-mediated metabolism, but it had only a minor effect on pravastatin. Concomitant use of potent inhibitors of CYP3A with simvastatin should be avoided or its dosage should be greatly reduced.

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Influence of comorbid cardiovascular risk factors on left atrial-left ventricular interaction in asymptomatic patients: clinical application of two-dimensional speckle-tracking echocardiography.

Previous studies have examined the negative impacts of individual cardiovascular risk (CVR) factors on left atrial (LA)-left ventricular (LV) interaction, whereas the combined effects of these risk factors are insufficiently elucidated. We studied 176 asymptomatic patients with CVR factors and age-matched 50 healthy individuals by conventional and 2-dimensional speckle-tracking echocardiography. The patients were classified into 2 groups according to the number of CVR factors: one risk factor (single) group (n = 79) and 2 or more risk factors (comorbid) group (n = 97). The peak early diastolic transmitral flow velocity (E)/peak early diastolic mitral annular motion velocity (e')/peak systolic LA strain (S-LAs) was used as a surrogate for LA stiffness during ventricular systole. The E/e'/S-LAs was greatest in the comorbid group. The peak systolic LV circumferential and radial strains, peak early diastolic LV radial strain rate, and peak early diastolic LA strain and strain rate were lower in the comorbid group than in the single group. Multivariate regression analysis identified age, body mass index, systolic blood pressure, end-systolic LV diameter, peak systolic mitral annular motion velocity (s'), and peak systolic LV radial strain in the comorbid group, and peak atrial systolic transmitral fl ow velocity and s' in the single group, as independent predictors of E/e'/S-LAs. Subtle LA and LV dysfunction with individual CVR factors were more aggravated with the comorbid conditions in asymptomatic patients.

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Metformin and prostate cancer mortality: a meta-analysis.

Observational studies report conflicting results on the association between metformin exposure and prostate cancer outcomes. This meta-analysis summarizes studies reporting overall survival, prostate cancer-specific mortality, and biochemical recurrence. PubMed and Embase were systematically reviewed to identify studies investigating the association between metformin use and clinical endpoints among men with prostate cancer while taking confounding by diabetes diagnosis into account. Pooled risk estimates (hazard ratios, HRs) and 95 % confidence intervals (CIs) were calculated using random-effects models. Sensitivity analyses for quality components and factors for heterogeneity were conducted. Of 549 articles identified, nine retrospective cohort studies representing 9,186 patients were included. There was significant heterogeneity between studies, and studies differed in quality. Metformin use was associated with improved overall survival in studies with clear risk window definition (HR 0.88, 95 % CI 0.86-0.90, p < 0.001) and in studies with potential immortal time bias (HR 0.52, 95 % CI 0.41-0.65, p < 0.001). No significant association with prostate cancer-specific mortality was detected (HR 0.76, 95 % CI 0.44-1.31, p = 0.33). Metformin use was associated with a decreased risk of biochemical recurrence (HR 0.79, 95 % CI 0.63-1.00, p = 0.047). This meta-analysis suggests a benefit of metformin in men with diabetes and prostate cancer. However, further carefully designed studies are needed to confirm findings and to assess potential generalization to non-diabetic, non-white, and less aggressively treated men with prostate cancer.

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Impact of Obesity on Persistent Left Ventricular Hypertrophy After Aortic Valve Replacement for Aortic Stenosis.

Normalization of left ventricular (LV) hypertrophy is expected after successful aortic valve replacement (AVR) in patients with aortic valve stenosis (AS), but is not always observed. We tested the impact of body mass index (BMI) ≥30 kg/m² on persistent post-AVR LV hypertrophy. In the present subanalysis of Simvastatin Ezetimibe in Aortic Stenosis study, clinical and echocardiographic data of 399 patients with severe AS who underwent surgical AVR were analyzed. All patients had a standardized pre- and post-AVR echocardiogram. Patients were grouped by BMI categories into BMI <25 kg/m², BMI 25 to 29.9 kg/m², and BMI ≥30 kg/m². LV hypertrophy was defined as LV mass/height^2.7 >49.2 g/m^2.7 in men and >46.7 g/m^2.7 in women. Predictors of persistent LV hypertrophy after AVR were identified in logistic regression analysis. After a median follow-up of 196 days after AVR, LV hypertrophy was more prevalent in patients with BMI ≥30 kg/m² compared with those with BMI 25 to 29.9 kg/m² and those patients with BMI <25 kg/m² (71% vs 47% and 37%, p <0.01). BMI ≥30 kg/m² patients also remained with lower LV midwall shortening post-AVR compared with patients with normal weight (p <0.01), independent of patient prosthesis mismatch. In multivariable logistic regression analysis, the presence of BMI ≥30 kg/m² before AVR was associated with an almost fourfold higher prevalence of post-AVR LV hypertrophy independent of significant associations with higher systolic blood pressure and lower LV midwall shortening preoperatively (odds ratio 3.75 [95% confidence interval 2.04 to 6.91], p <0.001). In conclusion, the presence of BMI ≥30 kg/m² before AVR in patients with severe AS was strongly and independently associated with persistent post-AVR LV hypertrophy.

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Safety and efficacy of ezetimibe with low doses of simvastatin in heart transplant recipients.

Although statins have proven efficacy in lowering lipids and improving survival in heart transplantation (HT) recipients, potential drug interactions may limit efficacy and reduce tolerability. This observational study explored the efficacy and tolerability of ezetimibe (10 mg/day) combined with simvastatin (10 or 20 mg/day) prescribed to HT recipients with intolerance to statins (n = 11) or inadequate lipid control despite high-dose statins (n = 14). Substantial reductions in lipid levels were apparent after 2 months (total cholesterol, -22%; low-density lipoproteins, -28%; triglycerides, -31%) and were maintained at 6 months. Reductions were significant in both subgroups of recipients; the vast majority (12 of 14, 85%) of recipients with a history of statins intolerance were able to tolerate ezetimibe plus low-dose simvastatin. This study provides suggestive evidence that treatment with ezetimibe plus low-dose simvastatin is well tolerated by HT recipients and may be effective for treatment of dyslipidemia in HT recipients with statins intolerance or resistance.

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Treatment with escitalopram improves the attentional bias toward negative facial expressions in patients with major depressive disorders.

We hypothesized that treatment with escitalopram would improve cognitive bias and contribute to the recovery process for patients with major depressive disorder (MDD). Many previous studies have established that patients with MDD tend to pay selective attention to negative stimuli. The assessment of the level of cognitive bias is regarded as a crucial dimension of treatment outcomes for MDD. To our knowledge, no prior studies have been reported on the effects of treatment with escitalopram on attentional bias in MDD, employing a dot probe task of facial expression. We studied 25 patients with MDD and 25 controls, and used a dot probe task of facial expression to measure cognitive bias. The patients' psychopathologies were rated using the Hamilton Depression Scale (HAMD) at baseline and after 8 weeks of treatment with escitalopram. All participants performed the facial expression dot probe task. The results revealed that the 8 week escitalopram treatment decreased the HAMD scores. The patients with MDD at baseline exhibited an attentional bias towards negative faces, however, no significant bias toward either negative or happy faces were observed in the controls. After the 8 week escitalopram treatment, no significant bias toward negative faces was observed in the patient group. In conclusion, patients with MDD pay more attention to negative facial expressions, and treatment with escitalopram improves this attentional bias toward negative facial expressions. This is the first study, to our knowledge, on the effects of treatment with escitalopram on attentional bias in patients with MDD that has employed a dot probe task of facial expression.

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Efficacy and tolerability of a combination of enalapril and hydrochlorothiazide in the treatment of hypertension measured manually and with an ambulatory blood pressure monitor.

The efficacy and tolerability of an enalapril maleate-hydrochlorothiazide combination (EM-HCTZ) were evaluated in a prospective, open-label study in 26 patients with uncomplicated essential hypertension (mean baseline sitting systolic/diastolic blood pressure: 153/103 mmHg) requiring two agents to reduce sitting diastolic blood pressure (SDBP) below 90 mmHg. Their mean age was 52 years. Patients received enalapril 5 mg daily, which was increased to 10 mg if SDBP was not reduced to < 90 mmHg during a 5-week titration period following washout. If blood pressure did not reach that goal, 25 mg hydrochlorothiazide was added. Only patients who required enalapril 10 mg and hydrochlorothiazide 25 mg for control (SDBP < 90 mmHg) at the end of titration received open-label EM-HCTZ as maintenance therapy for 6 weeks. The SDBP of 19 of the 26 patients (73%) who began titration was controlled at the end of titration, and they received maintenance therapy. During maintenance, the mean SDBP decreased from baseline 13.2 mmHg at week 2, 13.3 mmHg at week 4, and 10.1 mmHg at week 6. All changes from baseline were significant. At the end of the maintenance period, SDBP was controlled in 8 (42%) of 19 patients enrolled. One patient was withdrawn from the study because blood pressure was poorly controlled. Ambulatory blood pressure (ABP) was monitored, average outcome was computed for each patient during the 24-hour interval, and with a paired comparison, baseline and follow-up data were compared with the data measured manually. The mean baseline ABP was 9 mmHg lower than the baseline SDBP measured manually (r = 0.58, P = 0.01). Following treatment with EM-HCTZ, mean diastolic blood pressure fell 10 mmHg and mean systolic blood pressure fell 15 mmHg. In summary, EM-HCTZ was highly effective and generally well-tolerated in a substantial proportion of participants whose SDBP remained > 90 mmHg on enalapril 10 mg. Important differences between blood pressure measured manually and with a monitor were also demonstrated.

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A double-blind study in hypertensive patients of an original new compound, indapamide.

In a double-bind crossover study in 18 patients with essential hypertension, the hypotensive activity of 5 mg. indapamide daily was compared with 40 mg. frusemide daily over a period of 4 months after an initial 15 days on placebo. The overall clinical assessment showed satisfactory blood pressure control in 72% of patients receiving indapamide compared with 57% on frusemide. The weight of patients on active therapy dropped significantly with both products, but to a greater extent with indapamide. Indapamide was well-tolerated by all 18 patients; 3 patients on frusemide developed side-effects. The results of blood chemistry investigations are discussed. Variations in potassium levels during indapamide therapy were modest and did not warrant the use of potassium supplements.

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Incremental cholesterol reduction with ezetimibe/simvastatin, atorvastatin and rosuvastatin in UK General Practice (IN-PRACTICE): randomised controlled trial of achievement of Joint British Societies (JBS-2) cholesterol targets.

The aim of this study was to compare ezetimibe/simvastatin combination therapy with intensified statin monotherapy as alternative treatment strategies to achieve the Joint British Societies (JBS)-2 and National Institute for Health and Clinical Excellence low-density-lipoprotein cholesterol (LDL-C) target of < 2 mmol/l for secondary prevention or JBS-2 LDL-C target of < 2 mmol/l for primary prevention in high-risk patients who have failed to reach target with simvastatin 40 mg. This is a prospective, double-blind study conducted in 34 UK primary care centres; 1748 patients with established cardiovascular disease (CVD), diabetes or high risk of CVD who had been taking simvastatin 40 mg for > or = 6 weeks were screened and 786 (45%) with fasting LDL-C > or = 2.0 mmol/l (and < 4.2 mmol/l) at screening and after a further 6-week run-in period on simvastatin 40 mg were randomised to ezetimibe/simvastatin 10/40 mg (as a combination tablet; n = 261), atorvastatin 40 mg (n = 263) or rosuvastatin 5 mg (n = 73) or 10 mg (n = 189) once daily for 6 weeks. Rosuvastatin dose was based on UK prescribing instructions. The primary outcome measure was the proportion of patients achieving LDL-C < 2 mmol/l at the end of the study. The percentage of patients (adjusted for baseline differences) achieving LDL-C < 2 mmol/l was 69.4% with ezetimibe/simvastatin 10/40 mg, compared with 33.5% for atorvastatin 40 mg [odds ratio 4.5 (95% CI: 3.0-6.8); p < 0.001] and 14.3% for rosuvastatin 5 or 10 mg [odds ratio 13.6 (95% CI: 8.6-21.6); p < 0.001]. Similar results were observed for achievement of total cholesterol < 4.0 mmol/l. All study treatments were well tolerated. Approximately 45% of patients screened had not achieved LDL-C < 2 mmol/l after > or = 12 weeks of treatment with simvastatin 40 mg. In this group, treatment with ezetimibe/simvastatin 10/40 mg achieved target LDL-C levels in a significantly higher proportion of patients during a 6-week period than switching to either atorvastatin 40 mg or rosuvastatin 5-10 mg.

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Effect of statins on platelet PAR-1 thrombin receptor in patients with the metabolic syndrome (from the PAR-1 inhibition by statins [PARIS] study).

We investigated whether, in primary prevention patients with metabolic syndrome, statins affect the platelet protease-activated receptor-1 (PAR-1) thrombin receptor by performing serial measurements of its activity and the antigen expression level by flow cytometry before and during treatment. Recent data from randomized trials of statins are compatible with the possibility of clinically relevant pleiotropic effects. The use of statins is associated with a reduced thrombosis burden and diminished platelet activity, as shown in animal models and in vitro studies. Seventy patients with the metabolic syndrome who were not taking antiplatelet agents were assigned consecutively at starting doses at the discretion of the responsible clinician to 1 of 6 statins (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin) or to a no-statin group for 6 weeks. Platelet expression of intact (SPAN12 antibody) and cleaved (WEDE15) PAR-1 thrombin receptors were assessed by flow cytometry at baseline and at weeks 4 and 6 of treatment. At baseline, no difference was found in receptor expression. However, after 4 weeks of treatment, all statins had significantly inhibited (46% to 55%) the activated epitope of PAR-1 expression. After 6 weeks, inhibition remained, despite a slight rebound (22% to 37%). Also, a delayed pattern of inhibition of the intact PAR-1 receptor epitope was found. In conclusion, all statins inhibited the activity and antigen level of the platelet PAR-1 thrombin receptor, which has a major role in regulating platelet activity and thrombin formation. These observational data offer a plausible mechanism for the recently demonstrated pleiotropic effects of statins that may contribute to early clinical benefit.

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The pravastatin inflammation CRP evaluation (PRINCE): rationale and design.

Randomized, controlled trials demonstrate that HMG CoA reductase inhibition reduces coronary event rates in both primary and secondary prevention. In addition to reducing cholesterol levels, laboratory evidence suggests that statins also have anti-inflammatory activity, a property that may be critical for maintaining plaque stability. Recently, the inflammatory marker high-sensitivity C-reactive protein (hs-CRP) has been shown to predict vascular risk in individuals with and without hyperlipidemia. Furthermore, in the Cholesterol and Recurrent Events (CARE) trial, the relative efficacy of pravastatin in reducing events was greatest among those with elevated levels of hs-CRP. However, the time course and magnitude of this effect in both primary and secondary prevention is controversial. PRavastatin Inflammation CRP Evaluation (PRINCE) is an investigator-initiated, multicenter, community-based trial that will evaluate the effects of pravastatin on hs-CRP in up to 1182 individuals with coronary artery disease and up to 1702 individuals without coronary artery disease. Lipid profiles and hs-CRP levels will be obtained at baseline, 12 weeks, and 24 weeks in all study participants. Patients with known coronary artery disease will receive 40 mg/d pravastatin, whereas those without coronary artery disease will be randomly assigned to receive placebo or 40 mg/d pravastatin. The potential clinical impact of the PRINCE trial is substantial because nearly 50% of myocardial infarctions in the United States occur in persons with normal cholesterol levels, and inflammatory markers such as hs-CRP may provide a means to detect such individuals at high risk who do not currently qualify for statin therapy. The PRINCE trial will determine the time course of effect of this statin on hs-CRP and whether any observed effect on hs-CRP is independent of pravastatin-induced changes in low-density lipoprotein cholesterol.

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Is it useful to add an anticholinergic treatment to beta 2-adrenergic medication in acute asthma attack?

The aim of our study was to determine whether the combination of an anticholinergic treatment with a beta 2-adrenergic medication is a more effective treatment for acute asthma attack than the two treatments individually. The association of salbutamol-ipratropium was compared to treatment with salbutamol and ipratropium alone. It was a prospective double-blind study in children with acute asthma attack, participating as outpatients. Their clinical history and characteristics of bronchial obstruction were recorded on a standard form. Afterwards, they were included in one of the three following study groups: group one, 100 micrograms/inh salbutamol; group two, 20 micrograms/inh ipratropium; group three, 100 micrograms/inh of salbutamol plus 20 micrograms/inh ipratropium. There were 40 patients in each group, with Tal score +/- 5 and PEF < 80% of the predicted value. They were evaluated at the beginning (0 min), and at 15, 30, 45, 60, 80, 100 and 120 min. Each patient was treated with two inhalations of the study medication and was then evaluated for variations in Tal score. The mean age was 7.3 years; Tal score was 5.6, 5.6 and 6.0 at 0 min (p > 0.05). Decrease in Tal score after 15 min meant p < 0.01 for salbutamol-ipratropium and salbutamol vs. ipratropium. At 30 min p < 0.05 for salbutamol-ipratropium vs. salbutamol, and at 45 min p < 0.01 for salbutamol-ipratropium vs. salbutamol. PEF at 0 min was 70.9%, 71.3% and 68.6% (p > 0.05) increasing after 15 min. At 30 min p < 0.05 for salbutamol-ipratropium vs. salbutamol, and p < 0.01 vs. ipratropium. At 45 min p < 0.01 for salbutamol-ipratropium vs. salbutamol and ipratropium. A total 4.7 doses of salbutamol were needed to improve the asthma attack, 5.3 of ipratropium and 3.7 of salbutamol-ipratropium, with p < 0.01 for salbutamol-ipratropium vs. salbutamol and ipratropium. We conclude that the combination of salbutamol and ipratropium is more effective than each medication alone in treating acute asthma attacks in pediatric patients.

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Efficacy of levofloxacin and rifaximin based quadruple therapy in Helicobacter pylori associated gastroduodenal disease: a double-blind, randomized controlled trial.

The aim of this study was to evaluate the efficacy of levofloxacin and rifaximin based quadruple regimen as first-line treatment for Helicobacter pylori infection. A prospectively randomized, double-blinded, parallel group, comparative study was performed. Three hundred consecutive H. pylori positive patients were randomized to receive: omeprazole, amoxicillin, clarithromycin (OAC); omeprazole, amoxicillin, levofloxacin (OAL); and omeprazole, amoxicillin, levofloxacin, rifaximin (OAL-R). The eradication rates in the intention to treat (ITT) and per protocol (PP) analyses were: OAC, 77.8% and 85.6%; OAL, 65.3% and 73.6%; and OAL-R, 74.5% and 80.2%. The eradication rate achieved with OAC was higher than with OAL on the ITT (P = 0.05) and PP analysis (P = 0.04). OAL-R regimen was not inferior to OAC. The frequency of moderate to severe adverse effects was significantly higher in OAC treatment group. Especially, diarrhea was most common complaint, and there was a significantly low rate of moderate to severe diarrhea with the rifaximin containing regimen. In conclusion, the levofloxacin and rifaximin based regimen comes up to the standard triple therapy, but has a limited efficacy in a Korean cohort. The rifaximin containing regimen has a very high safety profile for H. pylori eradication therapy.

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Non-invasive response prediction in prophylactic carvedilol therapy for cirrhotic patients with esophageal varices.

Non-selective beta-blockers (NSBBs) are the mainstay of primary prophylaxis of esophageal variceal bleeding in patients with liver cirrhosis. We investigated whether non-invasive markers of portal hypertension correlate with hemodynamic responses to NSBBs in cirrhotic patients with esophageal varices. In this prospective cohort study, 106 cirrhotic patients with high-risk esophageal varices in the derivation cohort received carvedilol prophylaxis, and completed paired measurements of hepatic venous pressure gradient, liver stiffness (LS), and spleen stiffness (SS) at the beginning and end of dose titration. LS and SS were measured using acoustic radiation force impulse imaging. A prediction model for hemodynamic response was derived, and subject to an external validation in the validation cohort (63 patients). Hemodynamic response occurred in 59 patients (55.7%) in the derivation cohort, and in 33 patients (52.4%) in the validation cohort, respectively. Multivariate logistic regression analysis identified that ΔSS was the only significant predictor of hemodynamic response (odds ratio 0.039; 95% confidence interval 0.008-0.135; p <0.0001). The response prediction model (Model_ΔSS = 0.0490-2.8345 × ΔSS; score = (exp[Model_ΔSS])/(1 + exp[Model_ΔSS]) showed good predictive performance (area under the receiver-operating characteristic curve [AUC] = 0.803) using 0.530 as the threshold value. The predictive performance of the Model_ΔSS in the validation set improved using the same threshold value (AUC = 0.848). A new model based on dynamic changes in SS exhibited good performance in predicting hemodynamic response to NSBB prophylaxis in patients with high-risk esophageal varices. Non-selective beta-blockers are the mainstay of primary prophylaxis to prevent variceal bleeding in patients with cirrhosis and high-risk esophageal varices. This prospective study showed that a prediction model based on changes in spleen stiffness before vs. after dose titration might be a non-invasive marker for response to prophylactic non-selective beta-blocker (carvedilol) therapy in patients with cirrhosis and high-risk esophageal varices. ClinicalTrials.gov Identifier: NCT01943318.

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Comparison of 3 Days Amoxicillin Versus 5 Days Co-Trimoxazole for Treatment of Fast-breathing Pneumonia by Community Health Workers in Children Aged 2-59 Months in Pakistan: A Cluster-randomized Trial.

Globally, most deaths due to childhood pneumonia occur at the community level. Some countries are still using oral co-trimoxazole, despite a World Health Organization recommendation of oral amoxicillin for the treatment of fast-breathing pneumonia in children at the community level. We conducted an unblinded, cluster-randomized, controlled-equivalency trial in Haripur District, Pakistan. Children 2-59 months of age with fast-breathing pneumonia were treated with oral amoxicillin suspension (50 mg/kg/day) for 3 days in 14 intervention clusters and oral co-trimoxazole suspension (8 mg trimethoprim/kg and 40 mg sulfamethoxazole/kg/day) for 5 days in 14 control clusters by lady health workers (LHW). The primary outcome was treatment failure by day 4 for intervention clusters and by day 6 for control clusters. The analysis was per protocol. Out of the 15 749 cases enrolled in the study, 9153 cases in intervention and 6509 cases in control clusters were included in the analysis. Treatment failure rates were 3.6% (326) in intervention clusters and 9.1% (592) in control clusters. After adjusting for clustering, the risk of treatment failure was lower in intervention clusters (risk difference [RD] -5.5%, 95% confidence interval [CI] -7.4--3.7%) than in control clusters. Children with incomplete adherence had a small increase in treatment failure versus those with complete adherence (RD 2.9%, 95% CI 1.6-4.1%). No deaths or serious adverse events occurred. A 3-day course of oral amoxicillin, administered by LHWs, is an effective and safe treatment for fast-breathing pneumonia in children 2-59 months of age. A shorter course of amoxicillin improves adherence to therapy, is low in cost, and puts less pressure on antimicrobial resistance. ISRCTN10618300.

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Effect of metoprolol on chest pain in acute myocardial infarction.

A total of 1395 patients aged 40 to 74 years were included in a double blind trial with the beta 1 selective blocker metoprolol in suspected acute myocardial infarction. Metoprolol was given intravenously (15 mg) as soon as possible after admission to hospital followed by 200 mg daily for three months. A placebo was given in the same manner. The severity of chest pain in the acute phase was calculated by recording the number of injections of analgesics given and the time from the start of blind treatment to the time when the last analgesic was given (duration of pain). The patients receiving metoprolol were given a lower mean number of injections of analgesics during the first four days and after randomisation than those receiving a placebo. The estimated duration of pain was shorter in the metoprolol group than in the placebo group. These effects were related to the initial heart rate, the initial systolic blood pressure, and the final site of the infarct as determined electrocardiographically. Thus metoprolol given in the acute phase of suspected or definite myocardial infarction appears to reduce the severity of chest pain.

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Sequential pharmacotherapy for children with comorbid attention-deficit/hyperactivity and anxiety disorders.

Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by clinically significant anxiety, but few empirical data guide treatment of children meeting full DSM-IV criteria for ADHD and anxiety disorders (ADHD/ANX). This study examined the efficacy of sequential pharmacotherapy for ADHD/ANX children. Children, age 6 to 17 years, with ADHD/ANX were titrated to optimal methylphenidate dose and assessed along with children who entered the study on a previously optimized stimulant. Children with improved ADHD who remained anxious were randomly assigned to 8 weeks of double-blind stimulant + fluvoxamine (STIM/FLV) or stimulant + placebo (STIM/PL). Primary efficacy measures were the Swanson, Nolan, Atkins, and Pelham IV Parent and Teacher Rating Scale ADHD score and the Pediatric Anxiety Rating Scale total score. ADHD, ANX, and overall Clinical Global Impressions-Improvement scores were also obtained. Of the 32 medication-naive children openly treated with methylphenidate, 26 (81%) improved as to ADHD. Twenty-five children entered the randomized trial. Intent-to-treat analysis indicated no differences between the STIM/FLV (n = 15) and STIM/PL groups on the Pediatric Anxiety Rating Scale or Clinical Global Impressions-Improvement-defined responder rate. Medications in both arms were well tolerated. Children with ADHD/ANX have a response rate to stimulants for ADHD that is comparable with that of children with general ADHD. The benefit of adding FLV to stimulants for ANX remains unproven.

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Risk profile of SSrIs in elderly depressive patients with co-morbid physical illness.

So far, most studies on treatment strategies in elderly depressive patients have included only patients in good physical health, thereby excluding and neglecting somatic co-morbidity, which is very prevalent and relevant in geriatric psychiatry. 40 elderly depressive inpatients at the Department of Internal Medicine in Hochzirl who had started on SSRI monotherapy were allocated to this prospective post-marketing surveillance study. A stable medication for their physical illness for at least six months was a prerequisite. A Mini Mental State Exam (MMSE) score of >24 was required for study entry. The four-week study consisted of one baseline and four follow-up examinations, including psychiatric and medical history, as well as ratings for psychopathology and treatment-related adverse events. The antidepressants administered were paroxetine (20 mg/d), citalopram (20 mg/d), fluoxetine (20 mg/d) and sertraline (50 mg/d). Depression was rated using the 21-item Hamilton Depression Scale (HAMD); side effects were evaluated by the UKU Side Effect Rating Scale, and we used the Hillside Akathisia Scale (HAS) to record the incidence of SSRI-induced akathisia. Our results suggest that SSRls are effective and reasonably safe in elderly depressive patients with co-morbid physical illness. Adverse effects are more common, but generally tolerable, than in younger and physically healthy patients. The risk profile of SSRls in this population can be considered favorable.

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Antenatal allopurinol for reduction of birth asphyxia induced brain damage (ALLO-Trial); a randomized double blind placebo controlled multicenter study.

Hypoxic-ischaemic encephalopathy is associated with development of cerebral palsy and cognitive disability later in life and is therefore one of the fundamental problems in perinatal medicine. The xanthine-oxidase inhibitor allopurinol reduces the formation of free radicals, thereby limiting the amount of hypoxia-reperfusion damage. In case of suspected intra-uterine hypoxia, both animal and human studies suggest that maternal administration of allopurinol immediately prior to delivery reduces hypoxic-ischaemic encephalopathy. The proposed trial is a randomized double blind placebo controlled multicenter study in pregnant women at term in whom the foetus is suspected of intra-uterine hypoxia.Allopurinol 500 mg IV or placebo will be administered antenatally to the pregnant woman when foetal hypoxia is suspected. Foetal distress is being diagnosed by the clinician as an abnormal or non-reassuring foetal heart rate trace, preferably accompanied by either significant ST-wave abnormalities (as detected by the STAN-monitor) or an abnormal foetal blood scalp sampling (pH < 7.20).Primary outcome measures are the amount of S100B (a marker for brain tissue damage) and the severity of oxidative stress (measured by isoprostane, neuroprostane, non protein bound iron and hypoxanthine), both measured in umbilical cord blood. Secondary outcome measures are neonatal mortality, serious composite neonatal morbidity and long-term neurological outcome. Furthermore pharmacokinetics and pharmacodynamics will be investigated.We expect an inclusion of 220 patients (110 per group) to be feasible in an inclusion period of two years. Given a suspected mean value of S100B of 1.05 ug/L (SD 0.37 ug/L) in the placebo group this trial has a power of 90% (alpha 0.05) to detect a mean value of S100B of 0.89 ug/L (SD 0.37 ug/L) in the 'allopurinol-treated' group (z-test2-sided). Analysis will be by intention to treat and it allows for one interim analysis. In this trial we aim to answer the question whether antenatal allopurinol administration reduces hypoxic-ischaemic encephalopathy in neonates exposed to foetal hypoxia. Clinical Trials, protocol registration system: NCT00189007.

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Pulmonary lymphangioleiomyomatosis (LAM): progress and current challenges.

Lymphangioleiomyomatosis (LAM), a rare lung disease, is characterized by the progressive proliferation, migration, and differentiation of smooth muscle (SM)-like LAM cells, which lead to the cystic destruction of the lung parenchyma, obstruction of airways and lymphatics, and loss of pulmonary function. LAM is a disease predominantly affecting women and is exacerbated by pregnancy; only a lung transplant can save the life of a patient. It has been discovered that in LAM, somatic or genetic mutations of tumor suppressor genes tuberous sclerosis complex 1 (TSC1) or TSC2 occur and the TSC1/TSC2 protein complex functions as a negative regulator of the mTOR/S6K1 signaling pathway. These two pivotal observations paved the way for the first rapamycin clinical trial for LAM. The recent discoveries that TSC1/TSC2 complex functions as an integrator of signaling networks regulated by growth factors, insulin, nutrients, and energy heightened the interest regarding this rare disease because the elucidation of disease-relevant mechanisms of LAM will promote a better understanding of other metabolic diseases such as diabetes, cancer, and cardiovascular diseases. In this review, we will summarize the progress made in our understanding of TSC1/TSC2 cellular signaling and the molecular mechanisms of LAM; we will also highlight some of the lesser explored directions and challenges in LAM research.

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