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Long-term allopurinol use decreases the risk of prostate cancer in patients with gout: a population-based study.

Clinical observations indicated an increased risk of developing prostate cancer in gout patients. Chronic inflammation is postulated to be one crucial mechanism for prostate carcinogenesis. Allopurinol, a widely used antigout agent, possesses potent anti-inflammation capacity. We elucidated whether allopurinol decreases the risk of prostate cancer in gout patients. We analyzed data retrieved from Taiwan National Health Insurance Database between January 2000 and December 2012. Patients diagnosed with gout during the study period with no history of prostate cancer and who had never used allopurinol were selected. Four allopurinol use cohorts (that is, allopurinol use (>365 days), allopurinol use (181-365 days), allopurinol use (91-180 days) and allopurinol use (31-90 days)) and one cohort without using allopurinol (that is, allopurinol use (No)) were included. The study end point was the diagnosis of new-onset prostate cancer. Multivariable Cox proportional hazards regression and propensity score-adjusted Cox regression models were used to estimate the association between the risk of prostate cancer and allopurinol treatment in gout patients after adjusting for potential confounders. A total of 25 770 gout patients (aged between 40 and 100 years) were included. Multivariable Cox regression analyses revealed that the risk of developing prostate cancer in the allopurinol use (>365 days) cohort was significantly lower than the allopurinol use (No) cohort (adjusted hazard ratio (HR)=0.64, 95% confidence interval (CI)=0.45-0.9, P=0.011). After propensity score adjustment, the trend remained the same (adjusted HR=0.66, 95% CI=0.46-0.93, P=0.019). Long-term (more than 1 year) allopurinol use may associate with a decreased risk of prostate cancer in gout patients.

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The effect of irbesartan in reducing cardiovascular risk in hypertensive type 2 diabetic patients: an observational study in 16,600 patients in primary care.

As arterial hypertension substantially increases the risk of premature death, cardiovascular disease and renal insufficiency in patients with type 2 diabetes, effective and safe antihypertensive therapy is of importance. Therefore, the effect of irbesartan as monotherapy, or in fixed combination with hydrochlorothiazide, on blood pressure, metabolic parameters and microalbuminuria and the safety and tolerability of the drug were assessed. Multicentric, prospective, open phase IV study over 3 months in 16,600 patients with the clinical diagnoses of hypertension and type 2 diabetes. Blood pressure was measured sphygmometrically and albuminuria was assessed with semi-quantitative urine dipsticks. Systolic (SBP) and diastolic (DBP) blood pressure reduction, proportion of patients with microalbuminuria and cardiovascular risk calculated based on the SCORE score, each after a follow-up of 3 months compared to baseline. Number and nature of adverse events (AEs). The sample consisted of 51.3% men, mean age was 62.2+/-10.7 years, 53.9% of patients were overweight and 26.4% were obese. Mean SBP/DBP decrease after 3 months was 22.3/11.2 mmHg. The BP lowering effect was similar in the analyses of various subgroups (according to age group, sex, presence of micro- or macrovascular complications). Irbesartan treatment reduced the percentage of patients with microalbuminuria from 45.6% to 30.6% at 3 months (32.9% relative reduction). Metabolic parameters (lipids, blood glucose, HbA1c) and weight were improved significantly or showed trends for improvement, respectively. The mean 10-year cardiovascular risk as calculated with the SCORE score was decreased from a baseline value of 9.8% to 5.7% (-58% relative reduction). Tolerability was excellent: only 0.3% experienced an AE. Treatment with irbesartan in patients with concomitant hypertension and type 2 diabetes led to large blood pressure reductions. In view of the renoprotective effect documented by the reduced rate of patients with albuminuria, and the improvement of further metabolic parameters, these changes translate into a reduction of cardiovascular risk.

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High primary antibiotic resistance of Helicobacter Pylori strains isolated from dyspeptic patients: A prevalence cross-sectional study in Spain.

The rate of H. pylori resistance to different antibiotics is increasing and determines the selection of eradication therapy. The aim of this study was to determine the resistance patterns of H. pylori strains in our area. Biopsies from gastric corpus for microbiological culture and antibiotic resistance were obtained in patients undergoing upper gastrointestinal endoscopy for dyspepsia. Selective Agar Pylori for isolation of the bacteria and Agar Mueller-Hinton supplemented with blood to test the sensitivity to antibiotics were used. Presence of H. pylori was confirmed using direct observation with phase-contrast microscopy and/or smears stained with acridine orange. In vitro bacterial susceptibility to amoxicillin, clarithromycin, rifampicin, tetracycline, metronidazole, and levofloxacin was tested using diffusion MIC test strips. Minimum inhibitory concentration values were determined based on the 6th version of the EUCAST (European Committee on Antimicrobial Susceptibility Testing) Clinical Breakpoint (2016). Two hundred and seventeen patients were included (58.1% female, median age 64 years, range 25-92). H. pylori was identified in 108 patients (49.8%); culture and antibiogram were completed in 77 of them (71.3% of H. pylori-positive patients). The resistance rates were as follows: levofloxacin 38.7%, rifampicin 33.3%, metronidazole 27% and clarithromycin 22.4%. No case of amoxicillin or tetracycline resistance was identified. Dual clarithromycin-metronidazole resistance was observed in 10% of strains, whereas multiple drug-resistant was observed in 14.2%. Resistance rate of H. pylori to antibiotics is high in the northwest of Spain. The high resistance to levofloxacin and clarithromycin advises against their wide empirical use of these antibiotics in eradication regimens.

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Prevention of adjustment disorders and anticipatory nausea secondary to adjuvant chemotherapy: a double-blind, placebo-controlled study assessing the usefulness of alprazolam.

Although a high prevalence of adjustment disorders and anticipatory nausea secondary to adjuvant chemotherapy (CT) has been reported, little has been done to develop strategies to prevent these problems. A double-blind, placebo-controlled study was therefore designed to assess the usefulness of adding low-dose alprazolam (0.5 mg to 2 mg per day) to a psychologic support program including progressive relaxation training designed to prevent the aforementioned conditions. Fifty-seven women undergoing adjuvant CT for stage II primary breast cancer agreed to participate in the assessment, which was conducted at four time points: before starting CT, 6 weeks after CT, before the fourth CT, and after the fourth CT. The Hospital Anxiety and Depression Scale (HADS), Montgomery and Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Scale (HAS), Revised Symptom Checklist (SCL-90-R), Morrow Assessment of Nausea and Emesis (MANE), and World Health Organization (WHO) grading of acute and subacute toxicities were used to compare the alprazolam (AA) and placebo (PA) arms of the study. At the second evaluation, the results showed a higher rate of anticipatory nausea (18% v 0%) in the PA compared with the AA arm (P = .038). These differences were no more significant at each of the further assessments. Significant differences were found for the intake of hypnotics at each assessment visit, with the rate of hypnotic users being significantly higher in the PA (19%) compared with the AA (0%) arm at the fourth assessment (P < .05). Anxiety and depression scores of self- and observer-report were similar in the two arms. A significant relationship was found between the development of anticipatory nausea and the self-report of anxiety and depression score measured by HADS at baseline. The average HADS total score at baseline was 15.33 (SD = 6.56) for patients who developed anticipatory nausea and 11.23 (SD = 6.67) for other patients. The adjunct of alprazolam to a psychologic support program delays the occurrence of anticipatory nausea and controls sleeping problems secondary to adjunct CT. Although studies are needed to improve the efficacy reported here, physicians may already consider the use of alprazolam for cancer patients undergoing CT.

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Differing Effects of Aliskiren/Amlodipine Combination and High-Dose Amlodipine Monotherapy on Ambulatory Blood Pressure and Target Organ Protection.

The aim of this study was to compare an aliskiren/amlodipine combination with high-dose amlodipine monotherapy on ambulatory blood pressure monitoring (ABPM) and organ protection. The study was a prospective, randomized, multicenter, open-label trial in elderly essential hypertensive patients. A total of 105 patients with clinic BP (CBP) ≥140/90 mm Hg with amlodipine 5 mg were randomly allocated to aliskiren (150-300 mg)/amlodipine (5 mg) (ALI/AML group, n=53) or high-dose amlodipine (10 mg) (h-dAML group, n=52) and treated for 16 weeks. Each patient's CBP, ABPM, urine albumin-to-creatinine ratio (UACR), and brachial-ankle pulse wave velocity (baPWV) were measured at baseline and at the end of the study. The ALI/AML and h-dAML groups showed similarly reduced mean 24-hour SBP, daytime SBP, nighttime SBP, and baPWV. However, UACR reduction was significantly greater in the ALI/AML group (P=.02). ALI/AML was significantly less effective in reducing early-morning BP (P=.002) and morning BP surge (P=.001) compared with h-dAML.

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Effects of Carvedilol Versus Metoprolol on Platelet Aggregation in Patients With Acute Coronary Syndrome: The PLATE-BLOCK Study.

Platelet aggregation plays a pivotal role in acute coronary syndrome (ACS). In this setting, β-blockers (BBs) are used to counteract the effects of catecholamines on heart. Circulating catecholamines can also potentiate platelet reactivity, mainly through α₂- and β₂-adrenoceptors on human platelets' surface, thus BB may affect platelet aggregation; however, the effects of different BBs on platelet aggregation in contemporary-treated patients with ACS have been poorly investigated. One hundred patients with ACS on dual antiplatelet therapy with aspirin and ticagrelor were randomized to receive treatment with carvedilol, a nonselective BB (n = 50), or metoprolol, a selective β₁-blocker (n = 50), at maximum tolerated dose. Light transmission aggregometry was performed at randomization (T0) and at 30-day follow-up (T30), and the results were expressed as a percentage of maximum platelet aggregation (MPA). The primary end point was epinephrine-induced MPA at 30 days. Patients were predominantly men (80%), and mean age was 57.3 ± 9.7 years. The 2 randomized groups were well balanced for baseline characteristics. At T0, mean MPA was similar between the groups (18.96 ± 9.05 vs 18.32 ± 9.21 with 10 µM epinephrine, 14.42 ± 9.43 vs 15.98 ± 10.08 with 20 µM adenosine diphophate (ADP), and 13.26 ± 9.83 vs 14.30 ± 9.40 with 10 µM ADP for carvedilol and metoprolol, respectively, all p = NS). At 30 days, platelet aggregation induced by epinephrine was significantly lower in the carvedilol group than in the metoprolol group (23.52 ± 10.25 vs 28.72 ± 14.37, p = 0.04), with a trend toward the lower values of ADP-induced MPA (20 µM ADP 19.42 ± 13.84 vs 24.16 ± 13.62, p = 0.09; 10 µM ADP 19.12 ± 12.40 vs 22.57 ± 13.59, p = 0.19). In conclusion, carvedilol, a nonselective BB, reduces residual platelet reactivity in patients with ACS compared with the selective BB, metoprolol.

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[Impact of discontinuation of aspirin and clopidogrel before off-pump coronary artery bypass grafting on postoperative bleeding and transfusion requirement].

<b>Objective:</b> To investigate the influence of different discontinuation time of aspirin and clopidogrel before off-pump coronary artery bypass grafting (OPCABG) on postoperative bleeding and blood products transfusion requirement. <b>Methods:</b> Three hundred and fifty-three coronary artery disease patients who underwent OPCABG from January 2017 to January 2018 at Department of Cardiac Surgery, Zhongshan Hospital, Fudan University were retrospectively analysed. There were 268 males and 85 females, aged (66.0±9.1)years. All patients were divided into three groups: (1) guideline-recommended group: patients who discontinued clopidogrel for <i>></i>5 days without discontinuing aspirin before surgery; (2) without discontinuing group: patients who discontinued clopidogrel for ≤5 days without discontinuing aspirin before surgery; (3) discontinuing group: patients who discontinued clopidogrel for <i>></i>5 days with discontinuing aspirin before surgery. Postoperative bleeding recorded as chest tube drainage (CTD) volume and blood products transfusion requirement and perioperative complications were recorded. CTD volumes within 12 hours after surgery between groups were compared by Mann-Whitney <i>U</i> tests, CTD volumes after 12 hours postoperatively were compared by repeated measures analysis of variance and blood products transfusion and complications incidence were compared by χ(2) test or Fisher's precise test. <b>Results:</b> The 12 hours CTD volumes of guideline-recommended group, without discontinuing group, discontinuing group after surgery were 280(153) ml (<i>M</i>(<i>Q(R)</i>)), 291(229) ml, 225(161) ml, respectively. There were no significant differences in postoperative 12 hours CTD volumes (<i>P=</i>0.865), red blood cells transfusion incidence (χ(2)=2.626, <i>P=</i>0.149) and fresh frozen plasma (FFP) transfusion incidence (χ(2)=1.258, <i>P=</i>0.324) between guideline-recommended group and without discontinuing group. However, the 12 hours CTD volumes were significantly higher in guideline-recommended group patients compared with disconutinuing group patients (<i>U</i>=5 247, <i>P=</i>0.002). No significant differences were observed in red blood cells (χ(2)=0.182, <i>P=</i>0.757) and FFP (χ(2)=0.083, <i>P=</i>0.839) transfusion rate between these two groups. Repeated measures analysis of variance indicated that when patients began to take antiplatelet drugs (aspirin and clopidogrel) after 12 hours postoperatively, the change of CTD volumes beyond 12 hours after surgery didn't differ either between guideline-recommended group and without discontinuing group (<i>F=</i>0.019, <i>P=</i>0.941) or between guideline-recommended group and discontinuing group (<i>F=</i>2.447,<i>P=</i>0.113). Besides, the incidence of perioperative arrhythmia was significantly higher in guideline-recommended group patients compared with without discontinuing group patients (4.8% <i>vs</i>. 0, χ(2)=5.073, <i>P=</i>0.038). <b>Conclusions:</b> OPCABG patients who discontinued aspirin before surgery had lower postoperative 12 hours CTD volumes but similar blood products transfusion rate and CTD volumes beyond 12 hours postoperatively compared with patients adhering to the current guideline-recommended protocol. And for patients who discontinued clopidogrel for ≤5 days, postoperative CTD volumes and blood products transfusion requirement were similar but the incidence of perioperative arrhythmia was significantly lower compared with guideline-treated patients.

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A randomized double-blind pilot study comparing Doloteffin and Vioxx in the treatment of low back pain.

This randomized, double-dummy, double-blind pilot study of acutely exacerbated low back pain was aimed to inform a definitive comparison between Doloteffin, a proprietary extract of Harpagophytum, and rofecoxib, a selective inhibitor of cyclo-oxygenase-2 (COX-2). Forty-four patients (phyto-anti-inflammatory drug-PAID-group) received a daily dose of Doloteffin containing, inter alia, 60 mg of harpagoside for 6 weeks and 44 (non-steroidal anti-inflammatory drug-NSAID-group) received 12.5 mg/day of rofecoxib. All were allowed rescue medication of up to 400 mg/day of tramadol. Several outcome measures were examined at various intervals to obtain estimates of effect size and variability that might be used to decide the most suitable principal outcome measure and corresponding numbers required for a definitive study. Forty-three PAID and 36 NSAID patients completed the study. Ten PAID and 5 NSAID patients reported no pain without rescue medication for at least 5 days of the 6th week of treatment. Eighteen PAID and 12 NSAID patients had more than a 50% reduction in the week's average of their pain scores between the 1st and 6th weeks. The mean percentage decrease from baseline in the pain component of the Arhus Index was 23 (S.D. 52) in PAID and 26 (S.D. 43) in NSAID. The corresponding measures for the overall Arhus Index were 11 (31) and 16 (24) and, for the Health Assessment Questionnaire, 7 (8) and 6 (7). Tramadol was used by 21 PAID patients and 13 NSAID patients. Fourteen patients in each group experienced 39 adverse effects, of which 28 (13 in PAID) were judged to some degree attributable to the study medications. Though no significant intergroup differences were demonstrable, large numbers will be needed to show equivalence.

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Effect of steady-state atorvastatin on the pharmacokinetics of a single dose of colchicine in healthy adults under fasted conditions.

Colchicine is commonly prescribed for gout. While minimally metabolized by the cytochrome P450 (CYP) 3A4 isoenzyme, colchicine is a substrate for P-glycoprotein (P-gp). Atorvastatin is metabolized primarily by CYP3A4 and is a P-gp inhibitor. Patients with gout often have dyslipidemia; therefore, the potential for co-administration of atorvastatin and colchicine exists. The objective of this study was to determine the effect of oral atorvastatin on the pharmacokinetics of a single, oral dose of colchicine. Twenty-four healthy adult subjects were enrolled in this single-center, open-label, non-randomized, one-sequence, two-period drug-drug interaction study. On day 1, subjects received a single oral dose of colchicine 0.6 mg. After a 14-day washout, subjects received atorvastatin 40 mg once daily for 14 days followed by a single dose of colchicine 0.6 mg co-administered with atorvastatin 40 mg on day 28. Main outcome measures were colchicine maximum plasma concentration (C max), area under the plasma concentration-time curve (AUC) from time zero to the last measurable concentration (AUC last), and AUC from time zero to infinity (AUC∞), which were compared with and without concurrent atorvastatin. Colchicine AUC last, AUC∞, and C max increased by 27, 24, and 31 %, respectively, when co-administered with atorvastatin. Corresponding 90 % confidence intervals around the ratios were outside the established no-effect 80-125 % interval. Increased colchicine exposure was observed after a single dose of colchicine was administered with steady-state atorvastatin. Additional studies with multiple dosing of both drugs are needed to further determine the clinical implications of these results.

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Inflammatory biomarkers, aspirin, and risk of colorectal cancer: Findings from the physicians' health study.

Chronic inflammation has been implicated in colorectal carcinogenesis. However, the associations between plasma inflammatory markers and risk of colorectal cancer have been inconsistent. In a nested case-control study in the Physicians' Health Study, we prospectively investigated the associations of plasma C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor receptor 2 (TNFR-2) with risk of colorectal cancer, and whether aspirin modified these associations among 268 colorectal cancer patients and 446 age- and smoking-matched controls. In multivariate-adjusted models, plasma levels of CRP, IL-6 and TNFR-2 were not significantly associated with risk of colorectal cancer, although a positive trend was observed for TNFR-2 (RR_{highestvs.lowestquartile}=1.55; 95% CI=0.95-2.54; P_trend=0.05). We observed a statistically significant association between elevated TNFR-2 levels and colorectal cancer risk in the placebo arm (RR_{highestvs.lowesttertile}=1.77; 95% CI=1.02-3.06; P_trend=0.02), but not in the aspirin arm (P_trend=0.72). However, the interaction between TNFR-2 and aspirin was not statistically significant (P_interaction=0.34). Plasma inflammatory markers were not significantly associated with colorectal cancer risk among men, though there was a statistically non-significant positive trend between TNFR-2 and colorectal cancer risk. More studies are required to understand the relationship between the role of TNFα pathway, aspirin, and colorectal cancer risk.

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Patterns of Cognitive Decline Prior to Dementia in Persons with Mild Cognitive Impairment.

Only a limited number of studies have investigated the decline of discrete cognitive domains as individuals progress from mild cognitive impairment (MCI) to dementia. Thus, the goal of this longitudinal study was to evaluate the cognitive changes underway during the years preceding a diagnosis of probable Alzheimer's disease (AD), and to compare these changes to those found in MCI participants who do not progress to dementia. Participants were compared as a function of whether they later converted to AD (n = 47) or not (n = 74). Cognitive change was assessed prior to the conversion year, using that year as a starting point. A combination of polynomial regression analyses and mixed ANOVAs assessed 1) the trajectory of cognitive decline for each domain and 2) the differences between non-progressors and those who had converted to AD. The different cognitive domains demonstrated very different patterns of decline in the group of MCI progressors. A quadratic function, i.e., many years of stable performance followed by a rapid decline just prior to diagnosis, was observed for delayed recall, working memory, and spatial memory. In contrast, a gradual linear decline was observed for immediate recall, executive function, and visuo-spatial abilities. Finally, language in progressors was impaired on all time periods relative to non-progressors, but there was no further change between the first assessments and conversion to AD. Individuals with MCI who progress to AD show abnormal cognition at least two years prior to their dementia diagnosis. The pattern of symptom change observed appears to depend upon the cognitive domain and thus, clinical studies should not assume similar rate of decline across domains. In contrast and, apart from verbal memory, the non-progressors present a performance similar to that of healthy older adults.

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Evaluating the incidence of chemotherapy-induced nausea and vomiting in patients with B-cell lymphoma receiving dose-adjusted EPOCH and rituximab.

Studies evaluating antiemetic prophylaxis have primarily focused on the solid tumor setting and single-day regimens. This study evaluates antiemetic prophylaxis and chemotherapy induced nausea and vomiting (CINV) in patients with lymphoma receiving a multiday doxorubicin-cyclophosphamide containing regimen. This was a retrospective, single center, cohort study evaluating patients with aggressive non-Hodgkin B-cell lymphoma receiving dose-adjusted R-EPOCH in the hospital. Data was collected from the electronic medical record from April 2016 to September 2019. Complete response over 120 hours was the primary outcome. Secondary outcomes included complete response during the acute and delayed phases as well as complete control. A total of 73 patients who received dose adjusted R-EPOCH were identified. Most patients (n = 39, 53%) were male with a the median age was 63 years (range: 21-81). Most patients received ondansetron 16 mg once daily (n = 48, 66%) on days 1-5 as antiemetic prophylaxis with a minority receiving either dexamethasone (n = 8) or an NK1 antagonist (n = 13) in addition to ondansetron. Complete response rate was 32% and the complete response in the acute and delayed phase was also 32%. Control of CINV in patients with lymphoma hospitalized to receive dose-adjusted R-EPOCH was suboptimal, with only 32% of patients achieving complete response. Nearly three-quarters of patients received only a 5HT3 receptor antagonist as scheduled antiemetic therapy without an NK1 receptor antagonist. This data supports the importance of improving awareness of regarding multiday CINV guidelines and ensuring timely update and implementation of these evidence-based guidelines.

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Chronic osteomyelitis of the mandible: diagnosis and management--an institution's experience over 7 years.

The objective of this study was to retrospectively evaluate and report the associated factors with the diagnosis and management of 24 patients with chronic osteomyelitis of the mandible seen at the authors' institution during the past several years. Only cases of chronic osteomyelitis of the mandible not associated with antiresorptive medications or radiotherapy to the maxillofacial region were included in the study. After confirmation of the diagnosis, initial clinical and radiologic findings, treatment approach, and outcome were evaluated for each patient. Fourteen male and 10 female patients (average age, 53.75 yr; range, 22 to 83 yr) were included. The peak incidence of the disease was recorded in the fifth and sixth decades of life. An uneventful healing was observed in 20 patients (83.3%). One of 18 patients (5.5%) who underwent segmental resections developed a secondary infection and was managed with intravenously administered antibiotics. Three of 6 patients (50%) who were treated with marginal resections remained symptomatic after surgery. Independent of the cause and presentation of the disease, complete resolution of the infection should be the main focus of management in patients with chronic osteomyelitis of the mandible, and findings of this retrospective study indicate that a conservative surgical approach is more likely to result in a less than ideal outcome.

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Effect of Losartan or Atenolol on Children and Young Adults With Bicuspid Aortic Valve and Dilated Aorta.

Bicuspid aortic valve aortopathy is defined by dilation of the aortic root (AoRt) and/or ascending aorta (AsAo), and increases risk for aortic aneurysm and dissection. The effects of medical prophylaxis on aortic growth rates in moderate to severe bicuspid aortopathy have not yet been evaluated. This was a single-center retrospective study of young patients (1 day to 29 years) with bicuspid aortopathy (AoRt or AsAo z-score ≥ 4 SD, or absolute dimension ≥ 4 cm), treated with either losartan or atenolol. Maximal diameters and BSA-adjusted z-scores obtained from serial echocardiograms were utilized in a mixed linear effects regression model. The primary outcome was the annual rate of change in AoRt and AsAo z-scores during treatment, compared with before treatment. The mean ages (years) at treatment initiation were 14.2 ± 5.1 (losartan; n = 27) and 15.2 ± 4.9 (atenolol; n = 18). Median treatment duration (years) was 3.1 (IQR 2.4, 6.0) for losartan, and 3.7 (IQR 1.4, 6.6) for atenolol. Treatment was associated with decreases in AoRt and AsAo z-scores (SD/year), for both losartan and atenolol (pre- vs post-treatment): losartan/AoRt: +0.06 ± 0.02 vs -0.14 ± 0.03, p < 0.001; losartan/AsAo: +0.20 ± 0.03 vs -0.09 ± 0.05, p < 0.001; atenolol/AoRt: +0.07 ± 0.03 vs -0.02 ± 0.04, p = 0.04; atenolol/AsAo: +0.21 ± 0.04 vs -0.06 ± 0.06, p < 0.001. Treatment was also associated with decreases in absolute growth rates (cm/year) for all comparisons (p ≤ 0.02). Medical prophylaxis reduced proximal aortic growth rates in young patients with at least moderate and progressive bicuspid aortopathy.

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Predictors of duloxetine response in patients with neuropathic cancer pain: a secondary analysis of a randomized controlled trial-JORTC-PAL08 (DIRECT) study.

Duloxetine has some effect against cancer neuropathic pain (CNP); however, predictors of duloxetine response are unclear. This study sought to identify predictors of duloxetine response in patients with CNP. Patients (N = 70) with CNP unresponsive to or intolerant of opioid-pregabalin combination therapy, with a brief pain inventory-short form (BPI-SF) Item 5 score (average pain) ≥ 4, and with a total hospital anxiety and depression scale score < 20, were randomized to a duloxetine or a placebo group. Multiple linear regression analysis was conducted to identify predictors of duloxetine response as a secondary analysis with the change in the average pain score on day 10 from day 0 as the dependent variable, and the following five covariates; baseline (day 0) average pain score, baseline opioid dose, continuation/discontinuation of pregabalin, and items 20 and 21 score of the short-form McGill pain questionnaire 2 (SF-MPQ-2) as independent variables. Of the four domains (continuous pain, intermittent pain, neuropathic pain, and affective descriptors) score of SF-MPQ-2 on day 0, significant differences were observed in the neuropathic pain domain (p = 0.040) in change on the average pain between day 10 and day 0 in the duloxetine group. Multiple linear regression analysis revealed that patients with a high score for SF-MPQ-2 Item 21 (tingling pain) on day 0 had a significantly greater change in average pain between day 10 and day 0 (p = 0.046). Patients with a high score for SF-MPQ-2 Item 21 might benefit more from duloxetine.

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Hemodynamic interactions between diuretics and calcium antagonists in the treatment of hypertensive patients.

To investigate the hypotensive and hemodynamic effects of plain and extended-release (ER) formulations of felodipine added to a diuretic in the treatment of moderate essential hypertension, we studied 18 patients in a randomized, double-blind, cross-over study. Blood pressure (BP), heart rate (HR), hemodynamics (bioimpedance), foot volume (Archimedes' principle), and symptoms were evaluated after a 1-month placebo washout, after 1-month's treatment with a fixed combination of hydrochlorothiazide 50 mg plus amiloride 5 mg (HA), and then after felodipine 5 mg twice daily (F) or felodipine ER 10 mg daily (FER) (double-blind phase), each given for 2 weeks in a randomized sequence together with the diuretic. All measurements were performed at the end of the dosing interval. At baseline, supine SBP/DBP was 175.6 +/- 12.9/113.4 +/- 8.1 mmHg; HR was 77.3 +/- 7.0 beats/min; CO was 5.3 +/- 1.4 l/min; SVR was 2166 +/- 707 dynes sec. cm5, and foot volume was 433 +/- 195 ml (FV). HA induced a reduction (p less than 0.05) in BP; one patient had a DBP = 90 mmHg and was excluded from the combination study; eight patients had a DBP reduction of greater than or equal to 10 mmHg (responders), and their blood pressure was mainly reduced by a fall in SVR. HR, CO, and FV were unchanged. The addition of felodipine to a diuretic induced a further significant (p less than 0.001) reduction in BP with respect to HA alone, with no differences between F and FER. All patients had a DBP fall greater than 10 mmHg, which had no relationship to their response to the diuretic.(ABSTRACT TRUNCATED AT 250 WORDS)

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Induction prednisone dosing for childhood nephrotic syndrome: how low should we go?

Historically, children with nephrotic syndrome (NS) across British Columbia (BC), Canada have been cared for without formal standardization of induction prednisone dosing. We hypothesized that local historical practice variation in induction dosing was wide and that children treated with lower doses had worse relapsing outcomes. This retrospective cohort study included 92 NS patients from BC Children's Hospital (1990-2010). We excluded secondary causes of NS, age < 1 year at diagnosis, steroid resistance, and incomplete induction due to early relapse. We explored cumulative induction dose and defined dosing quartiles. Relapsing outcomes above and below each quartile threshold were compared including total relapses in 2 years, time to first relapse, and proportions developing frequently relapsing NS (FRNS) or starting a steroid-sparing agent (SSA). Cumulative prednisone was widely distributed with approximated median, 1st, and 3rd quartile doses of 2500, 2000, and 3000 mg/m² respectively. Doses ≤ 2000 mg/m² showed significantly higher relapses (4.2 vs 2.7), shorter time to first relapse (61 vs 175 days), and higher SSA use (36 vs 14%) compared to higher doses. Doses ≤ 2500 mg/m² also showed significantly more relapses (3.9 vs 2.2), quicker first relapse (79 vs 208 days), and higher FRNS (37 vs 17%) and SSA use (28 vs 11%). Relapsing outcomes lacked statistical difference in ≤ 3000 vs > 3000 mg/m² doses. Results strongly justify our development of a standardized, province-wide NS clinical pathway to reduce practice variation and minimize under-treatment. The lowest induction prednisone dosing threshold to minimize future relapsing risks is likely between 2000 and 2500 mg/m². Further prospective studies are warranted.

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[Effects and significance of methacholine bronchial provocation tests and salbutamol bronchial dilation test on measurements of fractional exhaled nitric oxide in patients with asthma].

To study the effects and significance of methacholine (Mch) bronchial provocation tests and salbutamol bronchial dilation test on measurements of fractional exhaled nitric oxide (FeNO) in patients with asthma. This was a prospective study conducted between November 2014 and August 2015. A total of 135 patients with asthma visiting the respiratory clinic of Zhujiang Hospital were enrolled. The patients received either Mch bronchial provocation test or salbutamol bronchial dilation test based on their FEV1/FVC values and cooperative degree. Mch bronchial provocation test was performed by using Astograph Jupiter-21 (Astograh group) or APS-Pro airway reaction testing apparatus (APS group), and salbutamol bronchial dilation test was performed by using Jaeger spirometer (Dilation group). We compared the differences between FeNO values measured before examinations (Pre-FeNO) and 5 min after completion of these examinations (Post-FeNO). The geometric mean of Pre-FeNO and Post-FeNO was 28.07 ppb and 24.08 ppb respectively in the Astograh group, with a significant decrease of the FeNO value after the examination (Z=-3.093, P=0.002). A significant difference between Pre-FeNO and Post-FeNO was found in patients who had positive provocation results in the Astograh group (Z=-2.787, P=0.005), but not in the patients with negative results (Z=-1.355, P=0.176). The geometric mean of FeNO in the APS group decreased significantly from 27.95 ppb to 23.15 ppb after the examination was completed (Z=-5.170, P=0.000); both in patients with positive saline or Mch provocation results and in patients with negative provocation results, the differences between Pre-FeNO and Post-FeNO in the APS group being significant (Z=-2.705, -3.709, -2.371, P=0.002, 0.000, 0.018). No difference of FeNO change(ΔFeNO) was observed between the 2 Mch bronchial provocation test groups (U<918.000, P=0.117). The geometric mean of Pre-FeNO was 36.74 ppb and that of Post-FeNO was 34.79 ppb in the Dilation group; the difference being not significant (Z=-1.281, P=0.200). Our results confirm that salbutamol bronchial dilation test has minor effect on the measurement of FeNO, but Mch bronchial provocation tests can significantly decrease measured FeNO value in patients with asthma, and therefore Post-FeNO values should be interpreted with caution.

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Pharmacokinetic and pharmacodynamic evaluation of fluticasone propionate after inhaled administration.

To evaluate the pharmacokinetic and systemic pharmacodynamic properties of inhaled fluticasone propionate (FP). Single doses of 0.25, 0.5, 1.0 and 3.0 mg FP were administered to groups of six healthy subjects. Serum concentration profiles of FP were monitored over 24 h by means of high-performance liquid chromatography/mass spectrometry (HPLC/MS-MS). Systemic pharmacodynamic effects were evaluated by measuring endogenous serum cortisol and circulating white blood cells, and analyzed with previously developed integrated pharmacokinetic/pharmacodynamic (PK/PD) models. FP showed a dose-independent terminal half-life with a mean (SD) of 6.0 (0.7) h. Maximum serum concentrations occurred 1.0 (0.5) h after administration, ranging from 90 pg.ml(-1) for the 0.25 mg dose to 400 pg.ml(-1) for the 3.0 mg dose. This, together with an estimated mean absorption time of nearly 5 h and a known oral bioavailability of less than 1%, indicates prolonged residence at and slow absorption from the lungs. In the investigated dose range, the cumulative systemic effect was dose-dependent for both markers of pharmacodynamic activity. For doses of 0.25, 0.50, 1.0 and 3.0 mg FP, the PK/PD-based cumulative systemic-effect parameters were 159, 186, 257 and 372% .h for lymphocyte suppression, 107, 186, 202 and 348% .h for granulocyte induction and 23.6%, 33.8%, 51.0% and 73.6% for cortisol reduction, respectively. The time courses of lymphocytes, granulocytes and endogenous cortisol could be sufficiently characterized with the applied PK/PD models. The measured in vivo EC50 values, 30 pg.ml(-1) and 7.3 pg.ml(-1) for white blood cells and cortisol, respectively, were in good agreement with predictions based on the in vitro relative receptor affinity of FP. After inhalation, FP follows linear pharmacokinetics and exhibits dose-dependent systemic pharmacodynamic effects that can be described by PK/PD modeling.

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[Multiple mononeuropathy associated to treatment with pravastatin].

The first reports of neuropathy due to treatment with statins appeared in 1994, although it is an infrequent complication. It usually consists of an axonal polyneuropathy, which is predominantly sensory, distal and symmetric, and may be subacute or chronic. We present here the second case reported in the literature of multiple mononeuropathy associated to the use of statins. A 51-year-old female patient who, after beginning therapy with pravastatin, presented with progressive, asymmetrically distributed, distal paresthesias in the limbs and an unstable gait. An electromyographic study was compatible with multiple mononeuritis. Results of complementary tests that were carried out to preclude other causes of multiple mononeuropathy were normal. The patient's condition improved on withdrawing treatment with the drug and it became worse again when therapy was restarted. When pravastatin therapy was stopped for good, the patient's condition progressively improved until she was practically free of symptoms. The relationship between treatment with statins and the appearance of polyneuropathy has been proved in different epidemiological case-control studies. It does not only appear as the classical distal symmetrical polyneuropathy, but has also been reported as taking on atypical clinical forms including a few cases, like ours, of multiple mononeuropathy. The risk of developing this complication is low and is offset by the cardiovascular benefits offered by statins, although it may become more common in the future due to the increasing rate of use of these agents. It is important to bear this cause of neuropathy in mind, given the fact that it is potentially reversible.

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Thromboelastography with platelet mapping: Limited predictive ability in detecting preinjury antiplatelet agent use.

Preinjury antiplatelet agent (APA) use in trauma patients can increase traumatic hemorrhage and worsen outcomes. Thromboelastography with platelet mapping (TEGPM) has characterized platelet function via arachidonic acid (AA) and adenosine diphosphate (ADP) inhibition in nontrauma settings, but limited data exist in the acute trauma population. A prospective observational study of adult trauma patients with suspected preinjury APA use who received TEGPM testing from 2017 to 2020 was performed. Patients on anticoagulants were excluded. Patients were grouped according to preinjury APA regimen: 81 mg or 325 mg of aspirin daily, 81 mg of aspirin and 75 mg of clopidrogrel daily, 75 mg of clopidrogrel daily, or no antiplatelet. Ability of TEGPM to detect APA use was assessed using predictive statistics and area under receiver operating characteristic curves (AUROCs). A total of 824 patients were included with most patients taking 81 mg of aspirin (n = 558). Patients on no antiplatelet were younger and had higher baseline platelet counts, while patients on 75 mg of clopidrogrel were more likely to be admitted after ground level fall. All other baseline characteristics were balanced. Admission TEG values were similar between groups. Median AA inhibition was higher in patients on aspirin containing regimens (p < 0.0001). Median ADP inhibition was higher in patients on clopidogrel containing regimens and those taking 325 mg of aspirin (p < 0.0001). Arachidonic acid inhibition accurately detected preinjury APA use and aspirin use (AUROC, 0.89 and 0.84, respectively); however, ADP inhibition performed poorly (AUROC, 0.58). Neither AA nor ADP inhibition was able to discern specific APA regimens or rule out APA use entirely. High AA inhibition accurately detects preinjury APA use in trauma patients. High ADP inhibition after trauma is common, limiting its utility to accurately identify preinjury APA use. Further study is needed to identify assays that can reliably detect and further characterize preinjury APA use in trauma populations. Diagnostic test, level II.

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Cardiovascular medicine update 2007: perioperative risk, carotid angioplasty, drug-eluting stents, stronger statins.

Some recent clinical trials have concluded the following: Patients who need noncardiac surgery and who are at risk of major cardiac events should not undergo revascularization with the aim of achieving a better perioperative outcome. They should have an office evaluation only and be prescribed a beta-blocker, if indicated. Except for unusual, high-risk cases, patients at risk of stroke due to atherosclerotic carotid artery stenosis should undergo carotid endarterectomy rather than carotid stenting. Because the technology is still developing, however, carotid stenting may still be appropriate as part of a clinical trial. Although drug-eluting coronary stents reduce the risk of restenosis in the short-term, they pose a small but significant risk of in-stent thrombosis. Clopidogrel (Plavix) should be prescribed for at least a year following drug-eluting stent placement, and perhaps indefinitely. Patients with known coronary heart disease have better outcomes if they receive aggressive statin therapy (eg, atorvastatin [Lipitor] 80 mg/day) to lower their serum levels of low-density lipoprotein cholesterol to less than 70 mg/dL.

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Ephedrine as add-on therapy for patients with myasthenia gravis: protocol for a series of randomised, placebo-controlled n-of-1 trials.

Myasthenia gravis (MG), a rare neuromuscular disease, is often initially treated using acetylcholinesterase inhibitors. Patients who do not respond adequately depend on the use of corticosteroids or other immunosuppressive medication, but these may have serious side effects. Clinical observations suggest that ephedrine can diminish, postpone or even prevent the need for immunosuppressive therapy when added to acetylcholinesterase inhibitors or low-dose prednisone. In the Netherlands, ephedrine is not licensed for MG nor is reimbursement guaranteed. MG is a rare condition, and ephedrine might be indicated only in a subset of patients. Thus, randomised controlled trials comparing large groups are difficult to conduct. We, therefore, aim to aggregate data from a small series of n-of-1 trials (also known as single patient trials) to assess the effect of ephedrine as add-on treatment for MG. Single-centre, placebo-controlled, double-blind, randomised, multiple crossover n-of-1 studies in 4 adult patients with generalised MG who show inadequate improvement on pyridostigmine and/or immunosuppressive drugs. Each n-of-1 trial has 3 cycles of two 5-day intervention periods. 25 mg ephedrine or placebo, twice daily. Quantitative Myasthenia Gravis (QMG) test. fixed effects linear model for QMG for all patients combined. Clinical: effects on MG-Composite and MG-Activities of Daily Living (MG-ADL) scales; QMG at individual level; adverse events. Acceptability of trial design: number of patients eligible and enrolled; number of treatment cycles completed; patients' and caregivers' experiences. This study was approved by the Medical Ethics Committee of Leiden University Medical Center, No. P14.108. Results of the trial will be reported in a peer-reviewed publication. Regulatory stakeholders will comment on the suitability of the trial for market authorisation and reimbursement purposes. This study is registered under EudraCT number 2014-001355-23, protocol no. 40960, V.1.0, registration date 27 March 2014.

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Comparison of 3 different methods of anesthesia before transrectal prostate biopsy: a prospective randomized trial.

Periprostatic nerve block (PNB) is the most common anesthesia technique used before prostate biopsy. However, needle punctures for anesthetic infiltration may be painful and cause higher infectious complications. We assessed whether addition of rectal lidocaine gel would improve its efficacy. We also investigated the efficacy and safety of tramadol, a codeine derivative, as a noninvasive method. A total of 300 patients who underwent prostate biopsies were randomized into 4 groups of controls, PNB, perianal/intrarectal lidocaine gel plus PNB and tramadol. Pain was assessed with a numeric analog scale. Each group consisted of 75 patients, and there was a statistically significant difference among pain scores (p = 0.001). Mean pain scores were 4.63 for controls, 2.57 for PNB, 2.03 for infiltration plus gel group and 3.11 for tramadol. Pain and discomfort were least in PNB plus gel arm. The difference of pain score between PNB alone and tramadol group did not reach statistical significance. Infectious complications were higher in the combination group, whereas there were no complications with tramadol. Any form of analgesia/anesthesia was superior to none. The combination of PNB plus gel provided significantly better analgesia compared to PNB alone or tramadol. If this can be duplicated in other trials, the combination may be accepted as the new gold standard of anesthesia for prostate biopsy. The efficacy of tramadol was similar to that of PNB, and was free of complications. Therefore, tramadol may have a role before prostate biopsy, which needs to be explored.

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In-hospital venous thromboembolism: are glucocorticoids a prime suspect?

The objective of the study was to determine whether glucocorticoid use is associated with an increased incidence of in-hospital VTE. We conducted a case-control study of patients with an in-hospital VTE from October 2015 to December 2019. Adult patient cases were identified by ICD-10 codes for acute venous thromboembolism. Controls were selected from all patients without a VTE diagnosis and matched by hospital length of stay and admission type (medical/surgical). Patients were excluded if they had a history of VTE, received therapeutic anticoagulation, or were pregnant. All patients were evaluated to determine the presence or absence of glucocorticoid exposure. Glucocorticoid dose, duration, and route of administration were assessed for patients with steroid exposure. Overall, 78 patients with VTE and 234 controls were included. Receipt of glucocorticoids within the preceding 90 days was similar between the VTE cases and controls (39.7 vs. 38.9%, P  = 0.89). No differences were noted with regard to oral (21.8 vs. 19.2%, P = 0.62), intravenous (30.8 vs. 29.1%. P = 0.774), or inhaled (6.4 vs. 10.3%, P = 0.31) routes of administration between VTE case and control patients. Cumulative prednisone equivalent doses were similar between cases and controls (877 ± 1366 vs. 697 ± 1963 mg, P = 0.435). The risk of in-hospital venous thromboembolism was not influenced by glucocorticoid exposure within the past 90 days. These results were consistent across all routes of administration, exposure time, and steroid dose. Blood Coagul Fibrinolysis 33:000-000 Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

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Long-term results of upper respiratory syndrome surgery and gastrointestinal tract medical treatment in 51 brachycephalic dogs.

After a first clinical study showing a high prevalence of gastrointestinal tract diseases in brachycephalic dogs presented for upper respiratory syndrome, a prospective study was performed to determine the influence of medical treatment for gastrointestinal tract disorders associated with upper respiratory syndrome surgery. The gastrointestinal tract and respiratory disorders of 61 brachycephalic dogs presented for upper respiratory syndrome were evaluated. Together with surgery of the upper respiratory tract, a specific gastrointestinal medical treatment was administered. A minimal follow-up of six months was required for inclusion. Palatoplasty with rhinoplasty was the most common surgical correction (88.5 per cent). The mortality rate in the perioperative period was 3.3 per cent. Minor complications accounted for 26.2 per cent of cases. No aspiration pneumonia was encountered. A sufficient follow-up was obtained in 51 dogs. The improvement was judged by the owners as excellent or good in 88.3 per cent of the respiratory disorders and in 91.4 per cent of the gastrointestinal disorders. Clinically, a statistically significant improvement was obtained for both respiratory and gastrointestinal disorders. In comparison with other studies, digestive tract medical treatment combined with upper respiratory surgery seems to decrease the complication rate and improve the prognosis of dogs presented for upper respiratory syndrome.

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The Prognostic Role of Circulating Epstein-Barr Virus DNA Copy Number in Angioimmunoblastic T-Cell Lymphoma Treated with Dose-Adjusted EPOCH.

Determine the frequency and prognostic value of circulating Epstein-Barr virus (EBV) DNA copy number in angioimmunoblastic T-cell lymphoma (AITL) patients who were treated with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (DA-EPOCH) regimens. Sixty newly-diagnosed AITL patients were retrospectively enrolled in the present study. All patients were treated with DA-EPOCH regimen. Twenty-two subjects (36.7%) had a EBV DNA-positive test at diagnosis. EBV DNA‒positive patients were associated with lower lymphocyte-monocyte ratio (p=0.024). Median follow-up was 40 months (range, 14 to 100 months). The overall response rate for all the 60 AITL patents were 71.7% (95% confidence interval [CI], 58.6 to 82.5) with 3-year progressive-free survival (PFS) rate of 30.9%±6.1% and overall survival (OS) rate of 60.1%±6.6%. Not only did PFS estimation differ between the EBV DNA‒positive and EBV DNA‒negative group (hazard ratio [HR], 2.24; 95% CI, 1.15 to 4.35; p=0.006), but also worse OS was observed in the pretreatment EBV DNA‒positive group than in the EBV DNA‒negative group (HR, 2.74; 95% CI, 1.22 to 6.19; p=0.006). EBV DNA test positivity was independent prognostic marker for both PFS (HR, 2.17; 95% CI, 1.17 to 4.00; p=0.014) and OS (HR, 3.24; 95% CI, 1.48 to 7.11; p=0.004) after adjusting International Prognostic Index and prognostic index for AITL score. Reduction in EBV copies was significantly associated with therapy-response. Circulating EBV DNA level was an important prognostic and monitoring marker for AITL patients who treated with DA-EPOCH regimens which cannot improve outcomes for AITL patients.

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[Effectiveness of the eradication of Helicobacter pylori by treatment with omeprazol, amoxicillin, and clarithromycin according to dosage and administration schedule].

There are many reports that evaluate the efficacy of the combination of omeprazole, amoxicillin and clarithromycin in the eradication of Helicobacter pylori, but data about effectivity in clinical practice are sparse. The goal of our study is to evaluate the effectivity in the clinical setting of this combination with diverse durations and doses. This is a retrospective analysis of 187 patients (128 male and 59 female), with an endoscopic diagnosis of duodenal ulcer (156), gastric ulcer (25) and both (6) with Helicobacter pylori infection as defined by both: a positive ureasa test and histology. After diagnosis the patient were treated with one of three combinations: a) omeprazole: 20 mg/12 h + amoxicillin: 1 g/12 h + clarithromycin: 500 mg/12 h, during 6 days (n = 60); b) omeprazole: 20 mg/12 h + amoxicillin: 1 g/12 h + clarithromycin: 500 mg/12 h, during 7 days (n = 74), and c) omeprazole: 20 mg/12 h + amoxicillin: 1 g/8 h + clarithromycin: 500 mg/8 h, during 7 days (n = 53). After the 6 or 7 day treatment period the patients did not receive any further treatment until a follow-up control unit. Eradication was evaluated with one of two tests: endoscopy (with ureasa test and at least 4 histologic samples) (n = 90) or urea breath test according to european protocol (n = 97). No patient dropped out because of side effects and compliance was above 80% in all cases. The global eradication rate was 87.2% (CI 95%: 82.4-92%). According to treatment the rate were respectively 80% (CI 95%: 67.7-89.2%) with scheme A; 89.2% (CI 95%: 79.8-95.2%) with scheme B, and 92.5% (CI 95%: 81.8-97.9%) with scheme C, with no statistically significant differences among groups. Difference between schemes and C, however, was almost reached (p = 0.053). The combination of omeprazole, amoxicillin and clarithromycin at standard doses (scheme B) is effective in clinical practice. Higher dose of amoxicillin and clarithromycin does not improve the results, and shorter duration of therapy associated with lower, although not significant rate of eradication.

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Methylphenidate hydrochloride given with or before breakfast: II. Effects on plasma concentration of methylphenidate and ritalinic acid.

Methylphenidate HCl (Ritalin) is often prescribed for the treatment of hyperactivity and is usually administered orally 30 minutes to 1 hour before meals, based on an assumption that meals may interfere with the absorption or metabolism of the drug. Seven boys who were taking methylphenidate regularly for the treatment of hyperactivity were hospitalized and given their established dose of the drug intravenously or orally, either with breakfast or in a fasted state. Blood samples were taken to determine the pharmacokinetics of the drug in each condition. Few differences between the "fed" and "fasted" states were noted, but the statistically significant differences indicated that meals accelerate rather than impede the absorption of methylphenidate.

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Eosinophilic esophagitis in adults: clinical, endoscopic, histologic findings, and response to treatment with fluticasone propionate.

Eosinophilic esophagitis is an increasingly recognized disorder characterized by intense eosinophilic infiltration of the esophageal mucosa. The aim of this study was to define the clinical syndrome, the endoscopic features, and the distribution of the eosinophil infiltrate in adults with eosinophilic esophagitis. We undertook a prospective evaluation of the symptomatic and histologic response to treatment with fluticasone propionate. Twenty-six patients (18 men; mean age 36 years) had symptom assessment and barium studies, esophageal motility recordings, and 24-hour esophageal pH studies. Upper-GI endoscopy was performed with quantitative eosinophil counts of biopsy specimens from the proximal and distal esophagus, the gastric antrum, and the duodenum. Nineteen subjects received 4 weeks of swallowed fluticasone propionate. After treatment, symptom assessment and endoscopic biopsies were repeated. All 26 patients had a history of dysphagia, and 11 presented acutely with food-bolus obstruction. Esophageal peristalsis was normal in most and gastroesophageal reflux coexisted in 10 patients. Characteristic endoscopic findings of furrows (20) and rings (18) were observed. All 19 treated patients had symptom improvement and a significant decrease in esophageal eosinophil counts. Eosinophilic esophagitis is a distinct entity that may coexist with gastroesophageal reflux. Swallowed fluticasone propionate is an effective treatment.

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Fluticasone/formoterol combination therapy is as effective as fluticasone/salmeterol in the treatment of asthma, but has a more rapid onset of action: an open-label, randomized study.

The inhaled corticosteroid (ICS) fluticasone propionate (fluticasone) and the long-acting β2-agonist (LABA) formoterol fumarate (formoterol) are being made available as a combination product (fluticasone/formoterol, flutiform ®) in a single aerosol inhaler. This 12-week, open-label, randomized, active-controlled, parallel-group, multicentre, phase 3 study compared the efficacy and safety of fluticasone/formoterol with the commercially available combination product fluticasone/salmeterol. Patients aged ≥ 18 years (N = 202) with mild-to-moderate-severe, persistent asthma for ≥ 6 months prior to screening were included in the study. After a screening phase (4-10 days), eligible patients were randomized 1:1 to receive fluticasone/formoterol or fluticasone/salmeterol during the 12-week treatment period. The primary objective was to demonstrate non-inferiority of fluticasone/formoterol versus fluticasone/salmeterol, measured by pre-dose forced expiratory volume in the first second (FEV1), at week 12. Fluticasone/formoterol was comparable to fluticasone/salmeterol for the primary efficacy endpoint, mean pre-dose FEV1 at week 12. The new combination was also comparable to fluticasone/salmeterol for change from baseline to week 12 in pre-dose FEV1, change from pre-dose FEV1 at baseline to 2-hour post-dose FEV1 at week 12 and discontinuations due to lack of efficacy. Importantly, fluticasone/formoterol was superior to fluticasone/salmeterol in time to onset of action throughout the duration of the study. The two treatments demonstrated similar results for various other secondary efficacy parameters, including other lung function tests, patient-reported outcomes, rescue medication use, asthma exacerbations and Asthma Quality of Life Questionnaire scores. Fluticasone/formoterol was well tolerated and had a good safety profile that was similar to fluticasone/salmeterol. The results of this study indicate that fluticasone/formoterol is as effective as fluticasone/salmeterol, and has a more rapid onset of action, reflecting the faster bronchodilatory effects of formoterol compared with those of salmeterol. If patients perceive the benefits of therapy with fluticasone/formoterol more rapidly than with fluticasone/salmeterol, this could have a positive impact on preference and adherence.

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Serum biomarkers and clinical outcomes in heart failure patients treated de novo with carvedilol.

The role of inflammatory and hemodynamic stress biomarkers in heart failure (HF) patients treated de novo with beta-blockers has been poorly studied. A total of 86 patients (age 56 ± 9 years, 81 men) with left ventricular ejection fraction (LVEF) < 40% and previously not treated with beta-blockers were initiated on carvedilol. At baseline and 12 months later we performed echocardiography, cardiopulmonary exercise testing, and determined serum levels of B-type natriuretic peptide (BNP), endothelin-1 (ET-1), C-reactive protein (CRP), interleukin-6, and tumor necrosis factor alpha (TNF -a). Patients were followed up over a total period of 9 ± 3 years from baseline. Increased baseline CRP and its on-treatment decrease were associated with improvement of LVEF (est. coefficient per one SD: 1.6; 95% CI: -0.05,3.28; p = 0.056, and -1.80; -3.43, -0.18; p = 0.030, respectively) and diminishing of LV end-systolic volume index [mL/m2] (-6.83; -11.32; -2.34; p = 0.003, and 5.85; 1.23; -10.46; p = 0.014, respectively). Higher baseline ET-1 and on-treatment increase in TNF-a predicted frequent admissions (> 1) for cardiac complications (odds ratio per one SD: 1.98; 95% CI: 1.09-3.59; p = 0.025, and 2.07, 1.12-3.84, p = 0.021, respectively) whereas higher baseline BNP was associated with increased mortality (hazard ratio per one SD: 2.09, 95% CI: 1.26-3.45; p = 0.004). Serum biomarkers may have different roles in prediction of clinical outcomes among HF patients treated de novo with carvedilol.

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[The effect of initial treatment by FP aqueous nasal spray in patients with Japanese cedar pollinosis].

It is well known that an initial treatment with several kinds of antiallergic medicines is useful for patients suffering from Japanese cedar pollinosis to reduce nasal symptoms during the pollen season. Also topical corticosteroids show a preventive effect as antiallergic medicines. In this study, the preventive effect of topical corticosteroids with antiallergic medicine as an initial treatment was evaluated during the 1995 cedar pollen season a season in which a high pollen count was anticipated. Twenty-five patients with cedar pollinosis were selected and divided into two groups. A and B, A topical corticosteroid (fluticasone propionate; Flunase) as well as antiallergic medicine (azelastin) were administered to patients in group A 4 weeks before the beginning of the pollen season. In group B, only antiallergic medicine was given at the same time as group A and a topical corticosteroid was administered after the appearance of the symptoms. Nasal symptoms and mucosal conditions of the nasal cavity were monitored throughout the pollen season. The inflammatory cells in the mucoepithelial layer of the nasal mucosa were also periodically evaluated by immunohistochemical staining. Nasal symptoms and mucosal conditions in group A were significantly improved compared with patients in group B. The infiltration of macrophages in the mucoepithelial layer of the nasal mucosa was strongly inhibited in group A. The numbers of mast cells and EG2-positive cells in group A were not significantly different from those in group B during the pollen season. According to these results, although not all inflammatory cells were inhibited, the initial treatment with Flunase aqueous nasal spray in addition to the conventional initial treatment with antiallergic medicine is very useful for reducing symptoms even in a season with a large amount of cedar pollen.

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Effects of house dust mite avoidance measures on Der p 1 concentrations and clinical condition of mild adult house dust mite-allergic asthmatic patients, using no inhaled steroids.

Exposure to house dust mite (HDM) allergens often results in worsening of asthma. Therefore, avoidance of exposure to HDM allergens is often proposed. Unfortunately, the most effective and feasible avoidance strategy is still not completely assessed. Consequently, we investigated the effects of a combined HDM avoidance strategy on HDM allergen concentrations and clinical condition of allergic, mild asthmatic, patients using no inhaled steroids. Asthmatic patients, allergic to HDM, using no inhaled corticosteroids, were randomly allocated to an active (n = 76) or a placebo allergen-avoidance group (n = 81). Avoidance measures consisted of applying Acarosan(R) (placebo: water) to the living room and bedroom floors, and the use of HDM-impermeable covers for mattresses and bedding (placebo: cotton covers for mattresses only). Effects on allergen concentrations (Der p 1), FEV1, bronchial hyperresponsiveness, peak flow parameters and asthma symptom scores were studied during 20 weeks and controlled for the allergic status of the patients. The active covers reduced Der p 1 concentrations to 9.4% (P = 0.0001), and were always significant lower than in the placebo group (P = 0.0002). Acarosan(R) resulted in slight but significant decreases (twofold, P = 0.0001), both on living room and bedroom floors, but concentrations were never significantly lower than the placebo group. Although the combined avoidance strategy resulted in a considerable reduction in allergen load in the active group, no differences were seen between the two groups in any of the clinical parameters during the follow-up period in this group of allergic asthmatics, using no inhaled corticosteroids. Corrections for the allergic status did not alter these results. The combined avoidance strategy was effective in reducing HDM allergen concentration. This was especially achieved by the allergen-impermeable covers, while the effects of Acarosan(R) were only marginal. However, this allergen reduction was not reflected in a convincing improvement in clinical condition in this group of mild allergic asthmatics, using no inhaled steroids. Perhaps, a longer follow-up period would have resulted in more pronounced effects.

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Therapeutic drug monitoring of posaconazole in hematology patients: experience with a new high-performance liquid chromatography-based method.

Parallel administration of the proton pump inhibitor (PPI) esomeprazole has been shown to decrease oral bioavailability of posaconazole in healthy volunteers. We prospectively analyzed serum samples (n = 59) obtained from hematology patients (n = 27) under posaconazole prophylaxis. Patients treated concomitantly with pantoprazole had significantly lower posaconazole levels than patients without PPI treatment (median levels of 630 microg/liter versus 1,125 microg/liter, respectively). These results suggest that drug monitoring is relevant when posaconazole and pantoprazole are administered concomitantly.

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[Effect of the early administration of pravastatin on C-reactive protein and interleukin-6 levels in the acute phase of myocardial infarction with ST segment elevation].

C-reactive protein (CRP), whose synthesis in the liver is regulated by interleukin 6 (IL-6), is related with the prognosis for ischemic heart disease. The aim of this study was to evaluate the effect of early administration of pravastatin on plasma levels of CRP and IL-6 in patients with acute myocardial infarction and ST segment elevation. 71 patients were randomized during the first 10 hours from the onset of symptoms to receive 40 mg of pravastatin once a day or not. CRP and IL-6 were measured on admission, 48 hours and 7 days later. CRP was also measured 2 months later. On admission, levels of CRP and IL-6 were similar in both groups. After 7 days of treatment the administration of pravastatin was associated with a lower level of CRP (P=.002). Mean and median CRP levels decreased from 48 hours to day 7 by 48.4% and 51.9% respectively in the pravastatin group, and by 32.5% and 15.9% respectively in the control group. In contrast, no significant differences in IL-6 levels were observed between the two groups. After 2 months of follow-up, 50% of the treated patients and 25% of the control patients had CRP levels lower than 6.6 mg/L (P=.039). Early administration of pravastatin in the acute phase of myocardial infarction with ST segment elevation was associated with a lower level of CRP after 7 days of treatment, with no concomitant changes in IL-6 levels.

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Adherence and renal biopsy feasibility in the Renin Angiotensin-System Study (RASS) primary prevention diabetes trial.

Enhancing adherence in research trials is fundamental to the proper testing of treatment hypotheses. Regimen and follow-up adherence as well as factors associated with adherence in the Renin Angiotensin-System Study (RASS) diabetic nephropathy primary prevention trial were evaluated. Adherence to medication (i.e., pill count), follow-up visits, and follow-up renal biopsies was evaluated. 89.8% of subjects completed the second renal biopsy. 96% of follow-up visits were attended within prescribed time windows. Mean medication adherence was 85.6%. Subgroup analyses revealed greater declines in the least adherent participants over time. Factors associated with greater adherence levels included older age, type 1 diabetes (TIDM) duration, lower HbA1c and blood pressure, GFR, ethnicity, and participants', principal investigators' (PI), and trial coordinators' (TC) baseline predictions of adherence. T1DM patients without nephropathy were willing to take experimental medications and undergo repeat renal biopsies. Although overall adherence was excellent, patterns of adherence varied among participants, suggesting the need to better track adherence and to develop customized and targeted approaches for promoting adherence to clinical research regimens. Staff subjective predictions of adherence were imprecise, supporting need for further development of adherence predictors.

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Apixaban for stroke prevention in atrial fibrillation: a review of the clinical trial evidence.

The objective of this review is to summarize data from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trials of apixaban for stroke prevention in patients with atrial fibrillation (AF). The ARISTOTLE trial compared apixaban with warfarin in 18 201 patients with AF and ≥ 1 additional risk factor for stroke. The AVERROES trial compared apixaban with aspirin in 5599 patients with AF who were at increased risk of stroke and for whom vitamin K antagonists were unsuitable. In ARISTOTLE, apixaban reduced the risk of stroke or systemic embolism by 21% compared with warfarin (1.27% vs 1.60% per year; hazard ratio, 0.79; 95% confidence interval, 0.66-0.95). The reduction was significant and demonstrated the superiority of apixaban over warfarin for the primary outcome of preventing stroke or systemic embolism (P = 0.01 for superiority). Apixaban also reduced all-cause mortality by 11% (P = 0.047) and major bleeding by 31% (P < 0.001) compared with warfarin. The benefits of apixaban observed in ARISTOTLE are further supported by the results from AVERROES, which demonstrated a 55% reduction in the risk of stroke or systemic embolism compared with aspirin. Risk of major bleeding was not significantly different between apixaban and aspirin. Subgroup analyses in both trials demonstrated that the effects of apixaban are highly consistent across various patient subpopulations. Discontinuation of study medication was significantly lower with apixaban than with either warfarin in ARISTOTLE or aspirin in AVERROES. Apixaban is the first new oral anticoagulant that has been shown to be superior to warfarin in reducing stroke or systemic embolism, all-cause mortality, and major bleeding in patients with AF. Moreover, in patients with AF who are considered unsuitable for warfarin therapy, apixaban was more effective than aspirin for stroke prevention and had a similar rate of major bleeding.

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Kinetic gait analysis assessment of meloxicam efficacy in a sodium urate-induced synovitis model in dogs.

To examine the ability of meloxicam, a cyclooxygenase inhibitor, to mediate the effects of sodium urate-induced acute stifle synovitis in dogs. 12 clinically normal adult hound-type dogs. A blinded, randomized, controlled single crossover design study was performed to determine the efficacy of meloxicam, using 2 dosage groups. In 2 experimental phases, dogs, according to group, received meloxicam (0.1 or 0.5 mg/kg of body weight) or matched volume of meloxicam vehicle, with a washout period of 21 to 28 days between phases. Blood samples for hematologic and biochemical analysis, as well as synovial fluid or cytologic analysis, were collected immediately before and approximately 24 hours after articular challenge of dogs under propofol anesthesia. Ground reaction forces (GRF) and subjective clinical scores were determined before and at 4, 8, 12, and 24 hours after articular challenge. Vertical force data included peak force, impulse, limb loading, and unloading rates. Craniocaudal data were divided into braking and propulsion phases and consisted of peak force and associated impulses. Except for propulsion impulse at 24 hours, all GRF variables were significantly greater at all post-synovitis induction times in the group receiving the high meloxicam dose. Significant differences in all GRF variables were seen at various times between the low-dose meloxicam group and the corresponding control group, and between the low- and high-dose meloxicam groups. Similar significance was seen in the subjective clinical evaluations. Strong correlations existed between the subjective and objective data. Meloxicam was effective in attenuating the effects of sodium urate-induced acute synovitis in dogs. Kinetic gait data provided an objective measurement of lameness in an experimentally induced arthritis model and quantified lameness improvements in response to medication with a nonsteroidal anti-inflammatory drug.

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Ezetimibe-Simvastatin Therapy Reduce Recurrent Ischemic Stroke Risks in Type 2 Diabetic Patients.

Statin is the main lipid-lowering therapy for type 2 diabetes mellitus patients. Recent evidence suggested the cardiovascular protective effects of ezetimibe-simvastatin in acute coronary syndrome patients. To investigate the effect of ezetimibe-simvastatin combination therapy on stroke prevention among diabetic stroke patients. Design, Setting, Participants, and Outcome Measures: This is a retrospective cohort study. Between March 1, 2009 and December 31, 2011, all patients with type 2 diabetes mellitus in Taiwan's National Health Insurance Research Database were screened. Those admitted for ischemic stroke (IS) were recruited and divided into 10-mg ezetimibe-20-mg simvastatin (EZ-SIM), 40-mg atorvastatin (ATOR), and 20-mg simvastatin (SIM) groups for further analyses. The primary outcomes were IS, myocardial infarction, and death from any cause. Patients were followed from index hospitalization to the date of death, loss of follow-up, or study termination. During the 34-month follow-up period, the risk of recurrent IS in the SIM group was higher than that of the ATOR (hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.46-2.82) and EZ-SIM (HR, 1.69; 95% CI, 1.14-2.50) groups. The risk of recurrent IS was not significantly lower in the EZ-SIM compared with the ATOR group (HR, 1.20; 95% CI, 0.85-1.69). The incidence of composite endpoint was highest in the SIM group (28.2%), followed by the ATOR (16.1%) and EZ-SIM (15.4%) groups. The multivariate adjusted survival curve showed lower trends of recurrent IS in the EZ-SIM and ATOR groups compared with the SIM group. High-potency lipid-lowering therapy effectively reduces the risk of recurrent IS in diabetic patients regardless of ATOR or EZ-SIM combination therapy.

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Intrinsic platelet reactivity before start with clopidogrel as predictor for on-clopidogrel platelet function and long-term clinical outcome.

High on-clopidogrel platelet reactivity is associated with worse clinical outcome. Previous data suggest that intrinsic platelet reactivity before initiation of clopidogrel contributes significantly to on-clopidogrel platelet reactivity. It is unknown whether intrinsic reactivity can sufficiently predict on-clopidogrel reactivity and therefore identify patients with insufficient response to clopidogrel before initiation of treatment and at risk for worse clinical outcome. This analysis included 765 consecutive patients undergoing elective coronary stent implantation. Platelet reactivity was assessed by light transmission aggregometry (5 µM ADP) before administration of clopidogrel 600mg and after intake of first maintenance dose of clopidogrel on day 1 following coronary stenting. Patients were followed for up to seven years. The combined primary endpoint was death of any cause or non-fatal myocardial infarction. Intrinsic and on-clopidogrel platelet reactivity were significant correlated (r=0.31; p < 0.001). Among all tested clinical and genetic factors including the cytochrome P450 2C19*2 polymorphism, intrinsic platelet reactivity was the strongest predictor for on-clopidogrel platelet reactivity. However, intrinsic platelet reactivity could only explain 8 % of variability of on-clopidogrel platelet function. Only on-treatment platelet reactivity was predictive for long-term clinical outcome (HR 1.47, 95 % CI 1.05-2.05; p = 0.02) whereas intrinsic platelet reactivity was not (HR 1.03, 95 % CI 0.74-1.43; p = 0.86). In conclusion, intrinsic platelet reactivity before initiation of clopidogrel is the strongest predictor of early on-clopidogrel platelet reactivity but can only explain a minor proportion of its variability and is not significantly associated with clinical outcome. Thus, baseline testing cannot substitute on-clopidogrel platelet function testing.

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A 16-week fenofibrate treatment increases LDL particle size in type IIA dyslipidemic patients.

The objective of the present study was to compare the effects of a 16-week pharmacotherapy with fenofibrate (200 mg) or pravastatin (initially 20 mg for 8-weeks and, if necessary, increased to 40 mg) on low density lipoprotein (LDL) particle size assessed by gradient gel electrophoresis among patients with type IIa dyslipidemia. For that purpose, type IIa dyslipidemic patients (cholesterol, 7.45+/-1.18 (S.D.) mmol/l; LDL cholesterol, 5.57+/-1.16 mmol/l; triglycerides (TGs), 1.66+/-0.43 mmol/l) were randomized to either fenofibrate (n=36) or pravastatin (n=43) therapy for 16 weeks. Fasting plasma lipoprotein levels as well as the LDL peak particle size (using 2-16% polyacrylamide gel electrophoresis) were assessed at baseline and after the 16-week treatment period. Whereas significant improvements in the plasma lipoprotein-lipid variables were observed with both fenofibrate and pravastatin treatments, LDL peak particle size was only significantly increased with fenofibrate therapy (+2.11+/-5.18 A, P<0.05). Among patients under fenofibrate therapy, changes in TG levels were negatively associated with changes in LDL peak particle size (r=-0.54, P<0.0007), whereas no such association was found in pravastatin-treated patients. The prevalence of patients with small, dense LDL particles (as defined by LDL particle diameter <255.5 A) was reduced from 69.4 to 30.6% (P<0.05) among fenofibrate-treated patients as opposed to 81.4 to 72.1% (NS) in patients who received pravastatin. As pravastatin treatment had no effect on LDL size, it is suggested that the additional effect of fenofibrate therapy on LDL size may contribute to reduce the risk of coronary heart disease (CHD) beyond what can be expected from the reduction in LDL cholesterol concentration in type IIa dyslipidemic patients.

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Cardioprotective effects of perioperative β-blockade in vascular surgery patients: fact or fiction?

Perioperative β-blockade remains a subject of debate. In this review, recent literature and current guidelines for perioperative β-blockade in vascular surgery patients are discussed. Available evidence suggests that perioperative β-blockade may be beneficial in reducing cardiac events. However, in a recent large study, the incidences of stroke and mortality were increased in patients on perioperative β-blockers. Large systematic reviews failed to demonstrate a net beneficial effect of perioperative β-blockers. The 2009 American and the European guidelines for perioperative β-blockade in vascular surgery disagree on the available evidence but do recommend β-blockade for several indications. Most recent, Wallace and colleagues published a large-sized retrospective study, reporting a beneficial effect of the adoption of a protocol for perioperative β-blockade. Perioperative β-blockade reduces cardiac events, but at the expense of increased risk for mortality and stroke. The guidelines seem to be eager to follow positive outcome studies, without considering the effects of β-blockade on other organ systems. Perhaps the main reason for the reported cardioprotective effects of perioperative β-blocker therapy should be sought in failing preoperative β-blocker prophylaxis (irrespective of surgery).

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Efficacy and safety of gabapentin and pregabalin in patients with vasomotor symptoms: a systematic review and meta-analysis.

Vasomotor symptoms are common among postmenopausal women and patients receiving hormone deprivation therapies, and emerging studies are exploring gabapentin's and pregabalin's effects as nonhormonal treatment options. We aimed to assess the efficacy and safety of these 2 drugs. Based on a preregistered protocol (Prospective Register of Systematic Reviews -CRD42019133650), we searched 10 databases (PubMed, Embase, Web of Science, PsycINFO, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Chinese Biological Medical Literature, Chinese National Knowledge Infrastructure, Chinese Journals Full-text Database [VIP], and Wanfang) as well as the World Health Organization international clinical trials registry platform and reference lists of related literatures. Randomized controlled trials and randomized crossover studies exploring gabapentin and pregabalin among women patients with vasomotor symptoms were included. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement was followed. Two reviewers independently selected studies, assessed bias, and extracted data. Mean difference and standardized mean difference with 95% confidence intervals were assessed by random-effects models. Heterogeneities were assessed by I² statistics, and the quality of evidence was evaluated by the Grading of Recommendations Assessment, Development and Evaluation approach. Nineteen randomized controlled trials and 2 randomized crossover trials reporting results from 3519 participants were included. Gabapentin could reduce hot flash frequency (mean difference, -1.62, 95% confidence interval, -1.98 to -1.26 after 4 weeks; mean difference, -2.77, 95% confidence interval, -4.29 to -1.24 after 12 weeks) and composite score (standardized mean difference, -0.47, 95% confidence interval, -0.71 to -0.23 after 4 weeks; standardized mean difference, -0.77, 95% confidence interval, -1.15 to -0.40 after 12 weeks) compared with placebo. Both menopausal participants and patients with breast cancer benefited from treatment. Higher risks of dizziness and somnolence were found in the gabapentin group than in the control group (risk ratio, 4.45, 95% confidence interval, 2.50-7.94; risk ratio, 3.29, 95% confidence interval, 1.97-5.48, respectively). Estrogen was more effective in reducing hot flash frequency than gabapentin. No statistically significant difference in reduction of hot flash severity score was found between gabapentin and antidepressants. The trials comparing gabapentin or pregabalin with the other interventions were too limited to make a conclusion. Favorable effects of gabapentin in relieving vasomotor symptoms were observed, compared with controls, but were less effective than those of estrogen. Evidence supporting the therapeutic effect of pregabalin is still lacking.

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Safety and efficacy of carvedilol in severe heart failure. The U.S. Carvedilol Heart Failure Study Group.

Many patients remain markedly symptomatic despite optimal current therapy for heart failure. Beta-blockers have often been viewed as contraindicated in this group because of their potential adverse short-term effects on cardiac function. One hundred thirty-one patients with severe congestive heart failure were enrolled into a double-blind, placebo-controlled study of the vasodilating beta-blocker carvedilol. All patients had symptomatic, advanced heart failure while on standard triple therapy, as evidenced by a mean ejection fraction of 0.22, marked reduction in distance traveled in a 6-minute corridor walk test, and severe impairment in quality of life measured by the Minnesota Living With Heart Failure Questionnaire. After a 2-week, open-label test of 6.25 mg twice daily carvedilol, 105 patients were randomized (2:1) to receive either carvedilol (up to 25 mg twice daily, n = 70) or matching placebo (n = 35) for 6 months while background therapy with digoxin, diuretics, and an angiotensin-converting enzyme inhibitor remained constant. Ten patients (8%) did not complete the open-label period because of adverse events and 11.4% in both the carvedilol and placebo groups dropped out in the double-blind phase. The study was terminated early by the Data Safety and Monitoring Board and follow-up evaluation was therefore aborted before the projected number of patients and follow-up time was achieved. Quality of life, which was the primary endpoint, improved similarly in the carvedilol and placebo groups, whereas the global assessment by the physicians and the patient exhibited a better response to carvedilol (P < .05). Hospitalization and mortality rate were too low to evaluate a difference, and exercise time and New York Heart Association classification did not change significantly in response to the drug. Left ventricular ejection fraction rose significantly (+0.09) in the carvedilol group compared with the placebo group (+0.02, P = .004). The beta-blocker carvedilol can be safely employed in patients with severe heart failure. Improved left ventricular function with a trend for some improvement in symptoms combined with the experience with the drug in the larger population of less severe patients in this multicenter trial suggests that carvedilol may have a favorable long-term effect in heart failure of diverse severity.

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Study on COgnition and Prognosis in the Elderly (SCOPE).

The Study on COgnition and Prognosis in the Elderly (SCOPE) is a multicentre, prospective, randomized, double-blind, parallel-group study designed to compare the effects of candesartan cilexetil and placebo in elderly patients with mild hypertension. The primary objective of the study is to assess the effect of candesartan cilexetil on major cardiovascular events. The secondary objectives of the study are to assess the effect of candesartan cilexetil on cognitive function and on total mortality, cardiovascular mortality, myocardial infarction, stroke, renal function, hospitalization, quality of life and health economics. Male and female patients aged between 70 and 89 years, with a sitting systolic blood pressure (SBP) of 160-179 mmHg and/or diastolic blood pressure (DBP) of 90-99 mmHg, and a Mini-Mental State Examination (MMSE) score of 24 or above, are eligible for the study. The overall target study population is 4000 patients, at least 1000 of whom are also to be assessed for quality of life and health economics data. After an open run-in period lasting 1-3 months, during which patients are assessed for eligibility and those who are already on antihypertensive therapy at enrolment are switched to hydrochlorothiazide 12.5 mg o.d., patients are randomized to receive either candesartan cilexetil 8 mg once daily (o.d.) or matching placebo o.d. At subsequent study visits, if SBP remains >160 mmHg, or has decreased by <10 mmHg since the randomization visit, or DBP is >85 mmHg, study treatment is doubled to candesartan cilexetil 16 mg o.d. or two placebo tablets o.d. Recruitment was completed in January 1999. At that time 4964 patients had been randomized. All randomized patients will be followed for an additional 2 years. If the event rate is lower than anticipated, the follow-up will be prolonged.

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Oral methotrexate/6-mercaptopurine may be superior to a multidrug LSA2L2 Maintenance therapy for higher risk childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study.

The importance of maintenance therapy for higher risk childhood acute lymphoblastic leukemia (ALL) is uncertain. Between 1992 and 2001 the Nordic Society for Pediatric Haematology/Oncology compared in a nonrandomized study conventional oral methotrexate (MTX)/6-mercaptopurine (6MP) maintenance therapy with a multidrug cyclic LSA2L2 regimen. 135 children with B-lineage ALL and a white blood count > or =50 x 10/L and 98 children with T-lineage ALL were included. Of the 234 patients, the 135 patients who received MTX/6MP maintenance therapy had a lower relapse risk than the 98 patients who received LSA2L2 maintenance therapy, which was the case for both B-lineage (27%+/-5% vs. 45%+/-9%; P=0.02) and T-lineage ALL (8%+/-5% vs. 21%+/-5%; P=0.12). In multivariate Cox regression analysis stratified for immune phenotype, a higher white blood count (P=0.01) and administration of LSA2L2 maintenance therapy (P=0.04) were both related to an increased risk of an event (overall P value of the Cox model: 0.003), whereas neither sex, age at diagnosis, administration of central nervous system irradiation, nor presence of a day 15 bone marrow with > or =25% versus <25% lymphoblasts were of statistical significance. These results indicate that oral MTX/6MP maintenance therapy administered after the first year of remission can improve the cure rates of children with T-lineage or with higher risk B-lineage ALL.

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Allopurinol might improve response to azathioprine and 6-mercaptopurine by correcting an unfavorable metabolite ratio.

Allopurinol potentiates azathioprine and 6-mercaptopurine (6-MP) by increasing 6-thioguanine nucleotide (6-TGN) metabolite concentrations. The outcome might also be improved by adding allopurinol in individuals who preferentially produce 6-methylmercaptopurine nucleotides (6-MMPN), rather than 6-TGN. The aim of the present study was to investigate the effect of allopurinol on concentrations of 6-MMPN and 6-TGN in individuals with a high ratio of these metabolites (>20), which is indicative of a poor thiopurine response. Sixteen individuals were identified who were taking azathioprine or 6-MP, and were commenced on allopurinol to improve a high 6-MMPN:TGN ratio. Metabolite concentrations were compared before and after commencing allopurinol, and markers of disease control were compared. The addition of 100-300 mg allopurinol daily and thiopurine dose reduction (17-50% of the original dose) resulted in a reduction of the median (and range) 6-MMPN concentration, from 11,643 (3,365-27,832) to 221 (55-844) pmol/8×10(8) red blood cells (RBC; P=0.0005), increased 6-TGN from 162 (125-300) to 332 (135-923) pmol/8×10(8) RBC (P=0.0005), and reduced the 6-MMPN:6-TGN ratio from 63 (12-199) to 1 (0.1-4.5) (P=0.0005). There was a significant reduction in steroid dose requirements at 12 months (P=0.04) and trends for improvement in other markers of disease control. One patient developed red cell aplasia that resolved upon stopping azathioprine and allopurinol. In those with a high 6-MMPN:6-TGN ratio (>20), response to thiopurine treatment might be improved by the addition of allopurinol, together with a reduced thiopurine dose and close hematological monitoring.

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Carbamazepine coadministration with fluoxetine or fluvoxamine.

To study the potential interaction between carbamazepine (CBZ) and selective serotonin reuptake inhibitors, fluoxetine (20 mg/day) and fluvoxamine (100 mg/day) were administered for 3 weeks to eight and seven epileptic patients, respectively, on chronic CBZ treatment. No significant changes in steady-state plasma concentrations of CBZ and its active metabolite, carbamazepine-10,11-epoxide (CBZ-E) occurred, suggesting that CBZ metabolism is probably not affected by fluoxetine or fluvoxamine administration.

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[Proliferative mesangial lupus nephritis: description of a cohort of 27 patients].

To describe our cohort of 27 biopsy-proven patients and their long-term follow-up, with special attention to prognostic factors. Twenty seven patients were retrospectively collected. They were controlled in the Internal Medicine Department of the Bellvitge's Hospital (Spain) between 1974 and 2010. Evaluation was performed at one, 3 and 5 year follow-up. There were 22 women (81.5%). Mean age at onset of nephritis was 34.83 years (SD 13.45). Partial or complete remission was achieved by 21 patients (80.77%) in the one-year follow-up, 22 patients (84.61%) in the third-year follow-up and 21 patients (77.77%) in the fifth-year follow-up. A change in the histology class was diagnosed in 4 patients. Seven patients suffered flares of nephritis. Seven patients died in the long term follow-up, 3 out of this 7 died because of systemic erythematosus lupus. Nephritis onset beyond 45 years old is the factor mostly related with a poor prognosis. That is the reason why we recommend co-therapy with immunosuppressors from the beginning in such patients.

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Dual antiplatelet therapy in ACS: time-dependent variability in platelet aggregation during the first week.

Platelets play an important role in the pathogenesis of Acute Coronary Syndrome (ACS). Most of the complications of ACS occur during the initial hours of presentation. We tried to gain an insight into the platelet function during the initial phase of ACS in patients on dual antiplatelet therapy. Platelet aggregation study was performed by light transmittance aggregometry in 64 ACS patients 48 hour and 7 days after initiation of dual antiplatelet therapy with aspirin and clopidogrel. Epinephrine, ADP and collagen induced platelet aggregation was significantly higher at 48 hours, following initiation of dual antiplatelet therapy, in comparison to the profile observed on the 7th day. Diabetics demonstrated a significantly higher aggregation at both the time points and aggregation was also somewhat higher in smokers though it did not reach statistical significance. This study conceptualizes the hypothetical role of alpha-2 adrenoreceptor blockers during the early hours following ACS and also warrants further investigations exploring the optimum loading dose of antiplatelet agents, especially clopidogrel in patients with ACS.

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Fexofenadine decreases sensitivity to and montelukast improves recovery from inhaled mannitol.

We studied, separately, the effects of the histamine antagonist, fexofenadine hydrochloride, and the leukotriene antagonist, montelukast sodium, and their placebos on airway sensitivity to and recovery from inhaled mannitol in subjects with asthma. Two 180-mg doses of fexofenadine were taken over 14 h, and three 10-mg doses of montelukast over 36 h, with the last dose 5 h before challenge. Fexofenadine reduced sensitivity to mannitol and the PD(15) was (mean [95% confidence interval] 138 [95, 201]) mg versus placebo (51 [25, 106] mg) (p < 0.001). The final percent reduction in FEV(1) with fexofenadine was 20.8 +/- 5.4% and not different from placebo (20.1 +/- 5.3%) (p = 0.7); however, recovery was slower with fexofenadine compared with placebo (p < 0.001). By contrast, montelukast had no effect on sensitivity to mannitol and the PD(15) was 71 [36, 144] mg versus placebo (87 [51, 148] mg (p = 0.35). The total dose of mannitol delivered and the final percent reduction in FEV(1) with montelukast were 171 +/- 142 mg and 21 +/- 4% and for placebo were 182 +/- 144 mg and 20 +/- 5% (p = 0.35, p = 0.59, respectively). However, recovery of FEV(1) to baseline was faster with montelukast, with the area under the percent reduction FEV(1)-versus-time curve reduced (220 +/- 121% change.min) compared with placebo (513 +/- 182% change.min) (p < 0.001). We conclude that whereas histamine is important for the initial airway response, leukotrienes are important in sustaining the airway response to inhaled mannitol.

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Evaluating a novel analgesic strategy for ring castration of ram lambs.

To evaluate the analgesic efficacy of the NSAIDs flunixin and meloxicam administered locally to the scrotum before ring castration. Randomised, controlled, prospective study. Forty eight single born male Merino lambs. Lambs, aged approximately 4 weeks, were allocated to four groups for castration. Groups were: sham control; castration + saline; castration + flunixin; castration + meloxicam. Drugs (5 mL) were administered subcutaneously around the circumference of the scrotum immediately before castration. Cortisol, rectal temperature, haematology and plasma haptoglobin were measured before and up to 48 hours after treatment. Behaviour recorded by video for 12 hours after treatment was classified as pain avoidance behaviours in the first hour and postural behaviours in three 4 hour intervals. Ring castration (saline group) induced a bi-phasic increase in cortisol with peaks at 90 minutes and 24 hours but no significant changes in haematology, haptoglobin or rectal temperature. Pain avoidance behaviours were increased and teat seeking decreased. Normal lying and normal standing postures were decreased and abnormal ventral lying, statue standing, abnormal standing and total abnormal postures increased. Flunixin decreased cortisol at 90 minutes (60.3 versus 117.3 nmol L(-1) ) and cortisol AUC (0-6 hours), decreased elevated leg movement (2.5 versus 5.4 events) and sum of pain avoidance behaviours (8.5 versus 16.7 events), improved time spent in normal ventral lying and decreased abnormal ventral lying and total abnormal postures compared to saline treated lambs. In a similar contrast, meloxicam caused non-significant decreases in cortisol at 90 minutes, cortisol AUC (0-6 hours) and pain avoidance behaviours, and significantly improved the postural behaviours normal ventral lying (26.7 versus 15.4%) and normal standing (13.9 versus 7.5%), and reduced abnormal standing and total abnormal postures. Physiological and behavioural responses associated with ring castration for both NSAID treatment groups were generally greater than sham controls. Locally administered NSAIDs provided partial analgesia for ring castration.

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Non-Steroidal Anti-Inflammatory Drug Use and Risk of Anastomotic Leakage after Anterior Resection: A Protocol-Based Study.

Non-steroidal anti-inflammatory drugs (NSAIDs) have been introduced as opioid-sparing analgesics in colorectal surgery. However, recent research has implicated these drugs as risk factors for anastomotic dehiscence. The Swedish Colorectal Cancer Registry was used to identify all patients operated with anterior resection for rectal cancer at centres that performed more than 25 abdominal operations per year, from 2007 to 2012, inclusive. The registry provided individual patient data on demographic variables and symptomatic anastomotic leakage. The patient exposure to NSAIDs was defined according to the protocol of the hospital at which the patient was operated. Logistic regression was employed to estimate ORs and 95% CIs, adjusting for confounders. The study cohort comprised 2,605 patients operated at 21 centres. In the NSAID group, 102/1,458 (7.0%) suffered an anastomotic leak, as compared to 124/1,023 (10.8%) in the non-NSAID group. With adjustment for confounding, patients treated at NSAID hospitals had a reduced risk of developing anastomotic leakage (OR 0.68; 95% CI 0.48-0.96). In this retrospective protocol-based study, NSAIDs did not increase the risk of anastomotic leakage after anterior resection for rectal cancer. The postoperative use of NSAIDs may not be detrimental, but more research is warranted.

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Evidence for adverse phonatory change following an inhaled combination treatment.

Voice problems are reported as a frequent side effect of inhaled combination (IC) treatments. The purpose of this experimental study was to investigate whether IC treatments are detrimental to phonation. We hypothesized that IC treatment would significantly increase phonation threshold pressure (PTP) and perceived phonatory effort (PPE), whereas sham treatment would not. Fourteen healthy adults participated in a repeated-measures design in which they received IC and sham treatments in counterbalanced order. PTP and PPE were measured prior to treatments, immediately following treatments, and at 1 and 2 hr following treatments. IC treatment increased PTP, but sham treatment did not. The increase in PTP was maintained for a 2 hr period following administration. PPE ratings were not significantly correlated with PTP. IC treatments can have acute, adverse effects on phonation. Detrimental phonatory effects were elicited in participants with no self-reported voice problems. IC treatments are being increasingly prescribed across the lifespan. The current data increase our understanding of the nature of phonatory deterioration associated with IC treatment and lay the groundwork for increased research effort to develop IC treatments that effectively control respiratory disease while minimizing an adverse effect on phonation.

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Early and late effects of clopidogrel in patients with acute coronary syndromes.

The risk of ischemic events is high, both early and late after acute coronary syndromes (ACS). We examine the benefits and risks associated with the use of adding clopidogrel to aspirin within the first 30 days and later (31 days to 12 months) in 12 562 patients with ACS. A total of 12 562 ACS patients were randomized to receive clopidogrel (300 mg initially followed by 75 mg/d) or placebo for 3 to 12 months. The proportion of patients experiencing cardiovascular death, myocardial infarction, or strokes (primary outcome) at 30 days was 5.4% in the placebo group and 4.3% in the active group (relative risk 0.79, 95% CI 0.67 to 0.92). Beyond 30 days, the corresponding rates were 6.3% versus 5.2% (relative risk 0.82, 95% CI 0.70 to 0.95). There was no significant excess in life-threatening bleeds in each period (0.97% versus 1.28%, relative risk 1.32, 95% CI 0.95 to 1.84 for 0 to 30 days; 0.83% versus 0.91%, relative risk 1.09, 95% CI 0.75 to 1.59 for 31 days to 12 months). Further subdivision of the early data indicates benefits within 24 hours with consistently lower rates of the primary outcome in combination with refractory or severe ischemia. Clopidogrel reduces the risk of ischemic vascular events, with the benefits emerging within 24 hours of initiation of treatment and continuing throughout the 12 months (mean 9 months) of the study.

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Opposite effects of losartan and atenolol on natriuretic peptides in patients with hypertension and left ventricular hypertrophy: a LIFE substudy.

Secretion of natriuretic peptides is related to cardiac wall stress and influenced by the renin-angiotensin system. Therefore, we investigated the influence of blood pressure (BP) reduction with losartan versus atenolol on N-terminal pro-atrial natriuretic peptide (Nt-proANP) and N-terminal pro-brain natriuretic peptide (Nt-proBNP). In 183 patients with hypertension and electrocardiographic left ventricular (LV) hypertrophy, enrolled in the LIFE Study, we measured BP and serum Nt-proANP and Nt-proBNP by immunoassay after 2 weeks of placebo treatment and after 1, 2, 4, 6, 12, 24, 36 and 48 months of randomized treatment with losartan- or atenolol-based antihypertensive regimens. There was no significant difference in BP at any time point between the two treatment groups. In patients treated with losartan, median Nt-proANP decreased gradually throughout the study, reaching significance after 6 months of treatment (1125-1060 pmol/l, P < 0.001), and Nt-proBNP decreased within the first month (24.7-18.7 pmol/l, P < 0.01) and stayed reduced throughout the study. During losartan-based antihypertensive treatment, Nt-proANP and Nt-proBNP as a percentage of baseline values were correlated to reductions in systolic BP (r = 0.11, P < 0.01 and r = 0.10, P = 0.01) and diastolic BP (r = 0.17, P < 0.001 and r = 0.07, P = 0.09). In atenolol-treated patients, Nt-proANP (1100-1640 pmol/l, P < 0.001) and Nt-proBNP (20.0-37.7 pmol/l, P < 0.001) increased during the first month, and remained elevated throughout the study. During atenolol-based antihypertensive treatment, changes in Nt-proANP (r = -0.16, P < 0.001) and Nt-proBNP (r = -0.07, P = 0.08) were negatively related to change in heart rate. Nt-proANP and Nt-proBNP were reduced in parallel with BP in losartan-treated patients whereas they increased in parallel with decreased heart rate in atenolol-treated patients.

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Cost-effectiveness of ABMT in comparison with CHOP chemotherapy in patients with intermediate- and high-grade malignant non-Hodgkin's lymphoma (NHL).

A prospective randomized clinical trial with simultaneous data collection for an economic appraisal was carried out to assess the effectiveness, quality of life and cost implications of ABMT vs standard chemotherapy in slowly responding patients with intermediate- and high-grade malignant non-Hodgkin's lymphoma (NHL). The patients had a partial response after three cycles of chemotherapy and had no evidence of BM involvement of NHL. The overall and disease-free survival at 3 years were 61% and 60%, respectively, in the ABMT group and 85% and 77% in the CHOP group (P = NS). Moreover, there were more (severe) complications and symptoms in the ABMT than in the CHOP group. The average costs of CHOP chemotherapy were significantly lower than the average costs in the ABMT group (CHOP: US$ 3118 vs ABMT: US$ 34,447). Considering long-term consequences the ABMT group was more expensive (US$ 34,580) and patients experienced 0.14 life years and 0.22 quality adjusted life years less than the CHOP group (discount rate 5%). As a result, changing therapy from CHOP to ABMT, as primary treatment in slow responders to CHOP, can not be recommended as the required additional investment does not produce health gains in terms of survival or quality of life.

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Effects of Group Psychotherapy, Individual Counseling, Methylphenidate, and Placebo in the Treatment of Adult Attention-Deficit/Hyperactivity Disorder: A Randomized Clinical Trial.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high prevalence in adulthood. There is a recognized need to assess the efficacy of psychotherapy in adult ADHD. To evaluate the efficacy of cognitive behavioral group psychotherapy (GPT) compared with individual clinical management (CM) and that of methylphenidate hydrochloride compared with placebo. Prospective, multicenter, randomized clinical trial of 18- to 58-year-old outpatients with ADHD from 7 German study centers. Patients were recruited between January 2007 and August 2010, treatment was finalized in August 2011, and final follow-up assessments occurred in March 2013. Sessions of GPT and CM were held weekly for the first 12 weeks and monthly thereafter (9 months). Patients received either methylphenidate or placebo for 1 year. The primary outcome was the change in the ADHD Index of the Conners Adult ADHD Rating Scale from baseline to the end of the 3-month intensive treatment (blinded observer ratings). Secondary outcomes included ADHD ratings after 1 year, blinded observer ratings using the Clinical Global Impression Scale, and self-ratings of depression. Among 1480 prescreened patients, 518 were assessed for eligibility, 433 were centrally randomized, and 419 were analyzed as randomized. After 3 months, the ADHD Index all-group baseline mean of 20.6 improved to adjusted means of 17.6 for GPT and 16.5 for CM, with no significant difference between groups. Methylphenidate (adjusted mean, 16.2) was superior to placebo (adjusted mean, 17.9) (difference, -1.7; 97.5% CI, -3.0 to -0.4; P = .003). After 1 year, treatment effects remained essentially stable. Descriptive analyses showed that methylphenidate was superior to placebo in patients assigned to GPT (difference, -1.7; 95% CI, -3.2 to -0.1; P = .04) or CM (difference, -1.7; 95% CI, -3.3 to -0.2; P = .03). Regarding depression, no significant differences were found. In contrast, GPT was superior to CM for all visits in the Clinical Global Impression global assessment of effectiveness. Highly structured group intervention did not outperform individual CM with regard to the primary outcome. Psychological interventions resulted in better outcomes during a 1-year period when combined with methylphenidate as compared with placebo. isrctn.org Identifier: ISRCTN54096201.

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High-potency statin and ezetimibe use and mortality in survivors of an acute myocardial infarction: a population-based study.

To determine all-cause mortality in patients with a first myocardial infarct who were treated with simvastatin compared with high-potency statin and simvastatin/ezetimibe combination. Despite statin use, residual cardiovascular risk remains. Therapeutic options include more potent statins or addition of ezetimibe. There is no clinical outcome data on the use of ezetimibe in such patients. Retrospective longitudinal study using the United Kingdom General Practice Research Database. Patients who had survived 30 days after their first acute myocardial infarct (AMI), had not received prior statin or ezetimibe therapy and were started on a statin within 30 days of AMI were included. Three groups were identified according to their follow-up: (i) simvastatin monotherapy; (ii) high-potency statin group (patients who started on simvastatin and switched to atorvastatin or rosuvastatin); and (iii) ezetimibe/statin combination group (patients who received ezetimibe in addition to statin). 9597 patients (57% male, mean age of 65 ± 13 years) matched study criteria: simvastatin (n=6990 (72.8%)); high-potency statin (n=1883, (19.6%)); and ezetimibe/statin combination (n=724 (7.5%)). During a mean follow-up of 3.2 years, there were 1134 (12%) deaths. In the multivariate proportional hazards model, the adjusted HR for high-potency statin and ezetimibe group were 0.72 (95% CI 0.59 to 0.88, p<0.001) and 0.96 (95% CI 0.64 to 1.43, p=0.85), respectively. A similar result was also obtained in the propensity score analysis that took into account covariates that predicted drug treatment groups. Patients switched to a high-potency statin had a significantly reduced mortality compared with simvastatin monotherapy. There was no observed mortality benefit in the ezetimibe group.

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Incidence, presenting features and prognosis of low-grade B-cell non-Hodgkin's lymphomas. Population-based data from a Danish lymphoma registry.

During the period January 1983 to January 1988 1597 newly diagnosed cases of non-Hodgkin's lymphoma (NHL) were included in a Western Danish population-based NHL registry. Of these, 31% (N = 496) were low-grade NHL (LG-NHL) consisting of (Kiel): 9% lymphocytic (LY), 27% lymphoplasmacytic/-cytoid (IC), 53% follicular centroblastic/-centrocytic (CB/CCf) and 11% unclassifiable low-grade. LG-NHL (age range: 26-94 yrs, median: 64 yrs; M/F ratio: 0.8) had an age-standardised incidence rate (IR) of 2.7/10(5)/yr. Age-specific IR's showed an age-related exponential rise in all subtypes except for CB/CCf. Compared with the intermediate (IG)- and high-grade (HG) group, LG-NHL had more female cases (M/F ratio: 0.79 vs. 1.2; p = 0.0002), a higher frequency of stage III-IV disease (66% vs. 53%; p < 0.00005) and of bone marrow involvement (39% vs. 19%; p < 0.00005). A later revision of all IC cases (N = 132) distinguished 79 non-polymorphic (ICnp) from 25 polymorphic (ICp) cases; 28 cases were differently classified. In 34 LG-NHL patients histologic transformation was verified: CB/CCf to CB diffuse (22 pts) and LY to immunoblastic or CB type (6 pts). The 7-yr survival for LG-NHL was 63% (IG: 48%, HG: 38%; p < 0.00005). A Cox-regression analysis identified the following adverse prognostic factors for survival in LG-NHL: age > 50 with a relative risk (RR) of 3.2, hepatic involvement (RR = 2.1), elevated s-LDH (RR = 1.9), B-symptoms (RR = 1.8) and IC histology (ICnp+ICp) (RR = 1.7).(ABSTRACT TRUNCATED AT 250 WORDS)

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Double-blind crossover study of carbuterol and salbutamol in bronchial asthma.

A double-blind crossover comparative study between carbuterol 3 mg thrice daily, carbuterol 2 mg thrice daily and salbutamol 4 mg thrice daily by the oral route was conducted in thirty patients suffering from bronchial asthma, selected at random, with more than 20% reduction in airway obstruction following isoprenaline inhalation. Each patient received all three drugs consecutively, each for 6 days, with a wash-out period in-between. The present study established a relative superiority of carbuterol 3 mg thrice daily over carbuterol 2 mg and salbutamol 4 mg thrice daily as evidenced by a higher percentage of subjective improvement (78.8%), preference shown by more cases (17/27), and need of additional drugs in a minimum number of cases (6/27), and significant improvement in FEV1 and MMEFR (p less than 0.05). Salbutamol is known to produce tachycardia and a rise in blood pressure. There were no adverse side-effects on the cardiovascular system but unlike salbutamol, carbuterol produced a fall in pulse rate and blood pressure which should make carbuterol more acceptable to patients, especially on prolonged usage. There was an absence of significant side-effects on the haemopoietic system and kidneys; other side-effects observed with all three types of treatment were of a minor nature and did not necessitate withdrawal of the drug. Thus, carbuterol is an effective and safe selective beta 2-adrenergic stimulant, is relatively free from side-effects, and has a sustained bronchodilator effect, an advantage in therapeutic application, and is, as a result, a new effective drug in the management of bronchial asthma.

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Are screening serum creatinine levels necessary prior to outpatient CT examinations?

To determine the percentage of outpatients with elevated serum creatinine levels (>/=2.0 mg/dL [177 micromol/L]) and associated reported risk factors for contrast material-induced nephrotoxic reactions (eg, diabetes, renal disease, male, age >/= 60 years, chemotherapy) who undergo computed tomography (CT) and to define a true high-risk population. The serum creatinine levels were obtained in a total of 2,034 consecutive outpatients (969 male, 1,065 female) who underwent contrast material-enhanced CT. In addition, selected patient charts were reviewed to determine the presence of risk factors for contrast material-induced nephrotoxic reactions. Only 66 (3.2%) had an elevated serum creatinine level. Risk factors were identified in 64 of the 66 (97%) patients with an elevated serum creatinine level. Renal disease was present in 62 of the 66 (94%) patients. Two of the 66 patients with an elevated creatinine level had no identifiable risk factors, representing 0.1% of the total number of patients. The data suggest that the majority of patients with a serum creatinine level of at least 2.0 mg/dL (177 micromol/L) will be identified by screening for risk factors. Careful patient screening, especially for renal disease, at the time of scheduling could result in considerable savings in terms of radiology man-hours expended and laboratory costs.

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CHOP plus rituximab therapy in Waldenstrom's macroglobulinemia.

Recently, a consensus panel of experts recommended that patients with Waldenstrom's macroglobulinemia (WM) who are candidates for future autologous transplantation should have limited alkylator or nucleoside analogue exposure due to potential stem cell harm. Cyclophosphamide/doxorubicin/vincristine/prednisone/rituximab (CHOP-R) is a stem cellsparing regimen that has been extensively evaluated in patients without WM or non-Hodgkin's lymphoma. As such, we analyzed the outcome of 13 patients with WM who received CHOP-R at our institution. Patients had a median age of 54 years and a median of 1 previous therapy. Ten of 13 patients (77%) had relapsed (n = 3) or refractory (n = 7) disease. Eight and 6 patients had previously received fludarabine and rituximab, respectively. Intended therapy consisted of 6 cycles of standard-dose CHOP and 6 infusions of rituximab (375 mg/m2). Three patients received additional rituximab as maintenance therapy. Median immunoglobulin M and serum viscosity for all patients decreased from 5230 mg/dL to 1690 mg/dL (P < or = 0.001) and from 2.9 cP to 1.6 cP (P = 0.01), respectively, and the median hematocrit level rose from 30.5% to 39.3% (P < or = 0.001). Clinical responses were as follows: 3 complete responses unconfirmed, 8 partial responses, 1 minor response. At a median follow-up of 9 months (range, 6 to > 37 months), 10 of the 11 patients who had a major response remained in remission. Therapy was well tolerated for most patients. Two patients had febrile neutropenia with documented bacteremia and recovered without complications. Circulating effector cell levels were also evaluated in 6 patients before and after CHOP-R, because rituximab activity is mediated in part by antibody-dependent cell-mediated cytotoxicity activity. No significant change in CD3+, CD4+, CD8+, and CD16+/CD56+ effector cell levels occurred following CHOP-R as assessed by multicolor flow cytometry.

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Nocturnal reduction of blood pressure and the antihypertensive response to a diuretic or angiotensin converting enzyme inhibitor in obese hypertensive patients. TROPHY Study Group.

During a 12-week, multicenter study to evaluate the efficacy and safety of lisinopril and hydrochlorothiazide (HCTZ) for the treatment of obesity-related hypertension, ambulatory blood pressure (ABP) monitoring was performed both at baseline and at study completion in 124 patients. Patients were randomized to three groups: placebo, lisinopril (10, 20, or 40 mg/day), or HCTZ (12.5, 25, or 50 mg/day). All groups were matched with regard to sex, race, age, body mass index, and waist/hip ratio. The primary analysis of ABP data revealed that both lisinopril and HCTZ effectively lowered mean 24-h systolic (SBP) and diastolic (DBP) blood pressure compared with placebo, (mean change from baseline SBP/DBP: -12.0/-8.2, -10.6/-5.5, and -0.3/-0.5 mm Hg, respectively); however, lisinopril lowered DBP better than HCTZ (P < .05). Secondary analyses of groups revealed that men responded better to lisinopril than HCTZ (-11.9/-7.3 v -6.6/-3.5 mm Hg, respectively), whereas women responded well to both drugs. White patients responded better to lisinopril than HCTZ, whereas black patients showed a significant response to HCTZ only. Response to treatment was also influenced by patient classification of 24-h blood pressure profiles, ie, "dipper" or "nondipper." Overall, the majority of obese hypertensives were nondippers. Nondippers (n = 82) responded well to both drugs (-10.4/-6.9 v -12.5/-5.7 mm Hg, P < .05 v placebo), whereas dippers (n = 42) responded to lisinopril (-11.7/ -9.4 mm Hg, P < .05 v placebo and HCTZ), but not HCTZ (-5.6/-4.1 mm Hg, P = NS v placebo). Results of 24-h ABP data show that both lisinopril and HCTZ are effective therapies for obesity-related hypertension and that response to treatment is influenced by sex, race, and dipper/nondipper status.

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Comparison of dry powder versus nebulized beta-agonist in patients with COPD who have suboptimal peak inspiratory flow rate.

A peak inspiratory flow rate (PIFR) of <60 L/min against the internal resistance (resist) of a dry powder inhaler (DPI) may limit the ability of a patient with chronic obstructive pulmonary disease (COPD) to achieve bronchodilation. The hypothesis was that lung function would be higher with a beta-agonist inhaled via nebulization compared with dry powder in patients with COPD who exhibit a PIFRresist of <60 L/min against the Diskus(®). This study was randomized, single-blind, and crossover with spirometry and inspiratory capacity (IC) measured at 15, 30, and 120 min post treatment. The efficacy of arformoterol aerosol solution (15 μg/2 mL) via nebulizer was compared with salmeterol dry powder (50 μg) via Diskus. The primary outcome was the change in lung function from baseline at 2 hr as these two inhaled beta-agonists have the similar peak bronchodilator effect as measured by forced expiratory volume in 1 sec (FEV1). Twenty patients (15 females/5 males) with postalbuterol FEV1 of 0.83±0.31 L (38±12% predicted) and PIFRresist of 53±5 L/min completed the study. At 15 min, improvements in FEV1, forced vital capacity (FVC), and IC were significantly higher with arformoterol than with salmeterol. At 2 hr, changes in FVC and IC, but not FEV1, were significantly higher with arformoterol. At visit 3, patient preference was similar for salmeterol Diskus (n=8) and arformoterol solution (n=7), whereas five patients reported no preference. At peak effect (2 hr), volume responses were greater with arfomoterol via nebulizer compared with dry powder salmeterol in patients with COPD who had a PIFRresist of <60 L/min. Bronchodilator therapy via nebulization should be considered in patients with COPD who have a suboptimal PIFRresist against a particular DPI.

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Paraoxonase-1 Q192R polymorphism is not associated with clopidogrel response in Chinese stroke patients.

It is well known that CYP2C19*2/*2 is associated with attenuated response to clopidogrel, but recent findings indicated that in white patients, paraoxonase-1 (PON1) 192Q/Q was a major determinant of clopidogrel efficacy. The objective of this research was to assess the impact of PON1 Q192R polymorphism on the maximum platelet aggregation (MPA) and the anti-platelet effect of clopidogrel in clopidogrel-treated Chinese stroke patients. The study recruited 183 eligible Chinese stroke patients treated with a loading dose of 300-mg clopidogrel and a 75-mg daily maintenance dose. CYP2C19*2 and PON1 Q192R were genotyped, a subcohort of 13 patients with CYP2C19 *2/*2 genotype was excluded. Finally 170 patients with CYP2C19*1/*1 (wild-type homozygotes, n = 87) or CYP2C19*1/*2 (mutant heterozygotes, n = 83) were enrolled in the study population. These patients were divided into three groups according to their PON1 Q192R genotype: wild-type homozygotes, PON1 192QQ, n = 17; mutant heterozygotes, PON1 192QR, n = 81; mutant homozygotes, PON1 192RR, n = 72. MPA was measured by light transmittance aggregometry (LTA) to assess platelet function after seven 75-mg maintenance doses of clopidogrel before discharge. In those patients who were carriers of 1 mutant allele (PON1 Q/R192), ADP-induced MPA were not significantly different compared with wild-type homozygous patients [30.5% (IQR, 17.5 to 49.1%) versus 25.0% (IQR, 10.0 to 52.5%), respectively; P = 0.910]. In addition, in the patients who were carriers of the 2 mutant allele (PON1 R/R192), MPA were also not significantly different from wild-type homozygous patients [29.2% (IQR, 15.0 to 43.4%) versus 25.0% (IQR, 10.0 to 52.5%), respectively; P = 0.717]. Results of a multivariable linear regression model demonstrated that PON1 192R allele carriage was not independently associated with ADP-induced MPA measurements (P = 0.408). PON1 Q192R polymorphism does not seem to exhibit any impact on MPA and clopidogrel response at all.

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Effects of oral racemic citalopram on neuroendocrine responses.

Citalopram, a selective serotonin reuptake inhibitor (SSRI), has been used as a neuroendocrine probe to assess serotonin (5-HT) function in human subjects. In an effort to characterize the oral citalopram challenge, we hypothesized that oral racemic citalopram would increase plasma cortisol, prolactin and adrenocorticotropic hormone (ACTH) concentrations; ACTH had not been measured in previous studies on the neuroendocrine effects of citalopram. Nine healthy male subjects initially received 20 mg of citalopram in an open-label study, and subsequently received placebo and 40 mg of citalopram in a single-blind, randomized, cross-over study. The administration of citalopram 20 mg failed to produce a significant neuroendocrine response but 40 mg resulted in reliably increased plasma cortisol concentrations. The 40 mg dose, however, did not reliably influence the levels of plasma prolactin or plasma ACTH. The results of this study indicate that caution should be used in accepting oral racemic citalopram as a potential presynaptic serotonergic challenge agent. Further studies are needed to fully determine the validity of racemic citalopram and the active enantiomer, escitalopram, as 5-HT probes.

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The effect of fasting status on lipids, lipoproteins, and inflammatory biomarkers assessed after hospitalization for an acute coronary syndrome: Insights from PROVE IT-TIMI 22.

For decades, fasting for 8 to 12 hours has been recommended for measurement of lipid profiles. The effect of fasting on low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) has been described in healthy cohorts and those with stable disease states. Recently, guidelines suggested that fasting may not be necessary due to its small effect on lipid measures. Little is known, however, regarding whether the impact of fasting is altered in the setting of an acute coronary syndrome (ACS). We hypothesized that the post-ACS period would minimally effect the impact of fasting status on lipid measurements. We evaluated the association of fasting on lipid and other biomarkers at the randomization visit, which occurred at a median of 7 days after the onset of an ACS, as well as during follow-up, in a cohort of 4177 subjects from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial. Fasting samples were independently associated with a higher LDL-C of 4.1 mg/dL and apolipoprotein-B 100 of 2.6 mg/dL as well as a lower TG of 21.0 mg/dL and high-sensitivity C-reactive protein of 0.48 mg/dL. The relative difference was 3.8% for LDL-C and -11.3% for TG. Fasting did not change total cholesterol, high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein(a), or apolipoprotein C-III. Although fasting does impact lipid measurements, the effect on LDL-C is small (about 4 mg/dL), both early after ACS and during follow-up. These data provide support for recent guidelines that no longer advocate for fasting lipid samples, including in the setting of ACS.

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Outcomes of Screening for Prostate Cancer Among Men Who Use Statins.

Prostate-specific antigen (PSA) screening for prostate cancer has resulted in a slight reduction in prostate cancer mortality but also a concomitant overdiagnosis of low-risk tumors. Prostate-specific antigen levels are affected by use of cholesterol-lowering statin drugs, but the association of statin use with PSA screening performance is unknown. To investigate whether statin use was associated with outcomes of a randomized PSA-based prostate cancer screening intervention. This post hoc subgroup analysis of a cohort from a population-based randomized clinical trial used data from the population-based Finnish Randomized Study of Prostate Cancer Screening, which randomized men to PSA screening or routine care from March 1, 1996, to December 31, 1999, with follow-up continuing until December 31, 2015. The population included all men aged 55 to 67 years at baseline and residing in the Tampere or Helsinki districts of Finland. Information on statin purchases from 1996 to 2009 was obtained from a national prescription registry. Eligible men were identified from the population registry of Finland. Prevalent prostate cancer cases at baseline were excluded. Data were analyzed from January 1, 2019 to March 31, 2021. Three invitations for PSA screening at 4-year intervals from 1996 to 2007 vs routine care. Risk for prostate cancer overall, high-risk disease, and prostate cancer mortality in the screening group vs the control group as an intention-to-treat analysis. The analysis was stratified by statin use. The study comprised 78 606 men (median age, 59 years [range, 55-67 years]) with statin purchase data available. Although PSA screening was associated with increased prostate cancer incidence among statin nonusers (screening vs control, 11.2 vs 8.6 per 1000 person-years); rate ratio [RR], 1.31; 95% CI, 1.24-1.38), no similar increase in incidence was observed among statin users (6.9 vs 5.9 per 1000 person-years; RR, 1.02; 95% CI, 0.95-1.10; P < .001 for interaction). Incidence of low-risk (Gleason score 6) and localized tumors was lower among statin users, whereas detection of tumors with a Gleason score of 8 to 10 was similar. Screening was associated with a lower incidence of metastatic tumors regardless of statin use. In this post hoc subgroup analysis of a cohort from a population-based randomized clinical trial, PSA screening among statin users was associated with a decreased incidence of advanced prostate cancer that was similar among statin nonusers, but with less increase in detection of low-grade localized tumors in statin users than in nonusers. These findings suggest that statin use does not materially compromise benefits of PSA-based screening.

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Effect of omeprazole in the treatment of refractory acid-related diseases in childhood: endoscopic healing and twenty-four-hour intragastric acidity.

To determine the clinical efficacy of once-daily treatment with omeprazole in refractory acid-related diseases in children. Endoscopic healing and 24-hour intragastric pH values were assessed in 13 patients with refractory reflux esophagitis (n = 5), refractory and/or giant duodenal ulcer (n = 6), or giant gastric ulcer (n = 2). The mean dose of omeprazole was 0.6 mg/kg per day (range, 0.3 to 0.7 mg/kg per day). Pharmacokinetic studies of omeprazole were performed in seven patients. The cumulative healing rates at 2, 4, 6, and 8 weeks of treatment were 46%, 85%, 92%, and 92%, respectively. Esophagitis in one patient did not heal despite increases in doses of up to 1.6 mg/kg per day (40 mg/day). The mean intragastric pH of omeprazole-treated patients was 5.2 (range, 3.0 to 6.6) and mean hydrogenion activity was 1.78 mmol/L (range, 0.01 to 10.42 mmol/L). There was wide interindividual variation in the reduction of gastric acid production. Mean intragastric H+ activity in omeprazole-treated patients was significantly lower than that of control subjects (p < 0.005) and that of patients treated with histamine type 2(H2)-receptor antagonists (p < 0.05). Mean intragastric H+ activity was not significantly correlated to the area under the concentration-time curve of omeprazole. No severe adverse effects were reported during treatment or at follow-up. Omeprazole has a potent antisecretory effect and is a suitable alternative for short-term treatment of refractory acid-related diseases; a relatively low dose (0.6 mg/kg per day) appears to be optimal in most patients. Unhealed esophagitis at 8 weeks of treatment was considered to be refractory to omeprazole.

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Use of factor-analyzed symptom dimensions to predict outcome with serotonin reuptake inhibitors and placebo in the treatment of obsessive-compulsive disorder.

No consistent predictors of outcome have been identified for the pharmaco-therapy of obsessive-compulsive disorder (OCD). Recent factor analytic studies have identified meaningful symptom dimensions that may be related to response to serotonin reuptake inhibitors and other treatments. A total of 354 outpatients with primary OCD were administered the Yale-Brown Obsessive Compulsive Scale Symptom Checklist, and its 13 main symptom categories were factor analyzed by using principal components analysis. The identified symptom dimensions were then entered into multiple regression models as outcome predictors of response to serotonin reuptake inhibitors and placebo response in a group of 150 nondepressed subjects who completed six double-blind, placebo-controlled trials with a serotonin reuptake inhibitor (clomipramine, fluvoxamine, fluoxetine, sertraline, and paroxetine). Eighty-four patients received a serotonin reuptake inhibitor and 66, placebo. The principal components analysis identified five factors that explained 65.5% of variance in outcome: symmetry/ordering, hoarding, contamination/cleaning, aggressive/checking, and sexual/religious obsessions. Serotonin reuptake inhibitors were significantly superior to placebo on all outcome measures. Initial severity of OCD was related to greater posttreatment severity of OCD. Higher scores on the hoarding dimension predicted poorer outcome following treatment with serotonin reuptake inhibitors, after control for baseline severity. No predictors of placebo response were identified. Exclusion of clomipramine did not modify the overall results, suggesting a cross-serotonin reuptake inhibitor effect. The identified symptom dimensions are largely congruent with those identified in earlier reports. Patients with OCD vary in their response to treatment with serotonin reuptake inhibitors. The presence of hoarding obsessions and compulsions is associated with poorer response to serotonin reuptake inhibitors.

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A novel therapeutic approach in pulmonary arterial hypertension as a complication of adult-onset Still's disease: targeting IL-6.

Adult-onset Still's Disease (AOSD), often though as the adult variant of systemic juvenile idiopathic arthritis (JIA), has an incidence of 1-3 cases per 1 million. Cardinal manifestations include fever, arthritis, skin rash, sore throat, hepatosplenomegaly and lymphadenopathy. Prolongation in diagnosing this disease results from its similarity to infectious, malignant and rheumatic diseases and lack of biomarkers. Pulmonary arterial hypertension (PAH) is a rare pulmonary complication of AOSD, and we are aware of only six cases reported in literature to date. Here we present a patient with AOSD who has developed pulmonary hypertension as a complication. We report a case of AOSD complicated by PAH treated successfully with tocilizumab, a humanized monoclonal antibody to human interleukin (IL)-6 receptor. A Pubmed and Medline search for evidence of pulmonary hypertension in AOSD and use of IL-6 inhibition in management was performed. Data for this study was collected from the patient's chart records. No infectious or neoplastic cause of her disease was identified and after extensive diagnostic workup, the patient was diagnosed with AOSD fulfilling Yamaguchi criteria. After initiation of IL-6 therapy the patient was followed over time to monitor the hemodynamic changes in pulmonary vasculature. Following treatment with Tocilizumab, the patient showed dramatic improvement in her clinical symptoms and remains in remission, through combination of tocilizumab (8 mg/kg), methotrexate and prednisone. Improvement of systemic symptoms, right heart catheterization (RHC) findings and the VECTRA-DA score served as a measure of treatment response. Tocilizumab has been effective in demonstrating marked improvement in both the clinical and laboratory parameters. Tocilizumab is an effective novel treatment for AOSD with PAH. This is the first documented report of successful use of tocilizumab in AOSD patients presenting with PAH. Prospective comparative studies could help validate its efficacy and safety.

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Bone marrow dosimetry and safety of high 131I activities given after recombinant human thyroid-stimulating hormone to treat metastatic differentiated thyroid cancer.

Recombinant human thyroid-stimulating hormone (rhTSH) recently was introduced as a radioiodine administration adjunct that avoids levothyroxine (LT-4) withdrawal and resultant hypothyroidism. The pharmacokinetics of 131I after rhTSH administration are known to differ from those after LT-4 withdrawal but are largely nondelineated in the radioiodine therapy setting. We therefore sought to calculate the red marrow absorbed dose of high therapeutic activities of 131I given after rhTSH administration to patients with metastatic or inoperable locally recurrent differentiated thyroid cancer. We also sought to evaluate the clinical and laboratory effects of this therapy on the bone marrow. Fourteen consecutive patients received in total 17 131I treatments (7.4 GBq). Blood and urine samples were obtained at fixed intervals, and their activities were measured in a well counter. Based on blood activity, renal clearance of the activity, and residence times in red marrow and the remainder of the body, the red marrow absorbed dose was calculated using the MIRD schema. Additionally, we monitored for potential hematologic toxicity and compared platelet counts before and 3 mo after treatment. The mean +/- SD absorbed dose per unit of administered (131)I in the red marrow was 0.16 +/- 0.07 mGy/MBq. The corresponding total red marrow absorbed dose was 1.15 +/- 0.52 Gy (range, 0.28-1.91 Gy). In none of the patients was hematologic toxicity observed. The mean +/- SD platelet count (n = 13 treatments) was 243 +/- 62 x 10(9)/L before treatment and 233 +/- 87 x 10(9)/L 3 mo later, a slight and statistically insignificant decrease. After rhTSH-aided administration of high activities of 131I, the bone marrow absorbed dose remained under 2 Gy, the level long considered the safety threshold for all radioiodine therapy. Our specific findings imply that when clinically warranted, rhTSH should allow an increase in the therapeutic radioiodine activity. Such an increase might improve efficacy while preserving safety and tolerability; this possibility should be assessed in further studies.

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Importance of selected inhaler characteristics and acceptance of a new breath-actuated powder inhalation device.

The degree of patient comfort and satisfaction with an inhaler can have an important effect on compliance with asthma treatment and, hence, therapeutic success. The objective of this study was to assess, from the patient's perspective, the importance of various inhaler characteristics and then evaluate patient satisfaction with a new breath-actuated powder inhaler (Diskhaler) based on those characteristics. Self-administered patient satisfaction questionnaires were completed as part of a randomized, double-blind, placebo-controlled study of fluticasone propionate powder in the treatment of asthma. At baseline, patients rated the importance of five inhaler characteristics (convenient to carry, durability, easy to load, easy to hold and operate, and easy to clean). Following exposure to the Diskhaler over a period of 8 weeks, patients rated the inhaler on those same characteristics. They also rated their comfort using the inhaler and their overall satisfaction with the inhaler. Data were available from 274 patients, the majority of whom expressed a high or very high level of satisfaction with the Diskhaler on each of the five characteristics. These ratings were congruent with their ratings of the importance of those same characteristics; 80-90% rated "convenient to carry," "durability," "easy to load," and "easy to hold and operate" as important or very important characteristics for an inhaler, while "easy to clean" was considered somewhat less important, with 63% rating this characteristic as important or very important. Following the initial exposure to the Diskhaler, 67% of patients were comfortable or very comfortable with the inhaler; that percentage increased to 79% after 8 weeks of use. Following 2 and 8 weeks of use, 61 and 62%, respectively, were satisfied or very satisfied with the Diskhaler. In general, satisfaction ratings were not affected by treatment, indicating that patients were evaluating only the inhaler and not the efficacy of the study drug they received. This study helped to identify which selected inhaler characteristics are most important to patients with asthma. The Diskhaler inhaler performed well on those characteristics deemed important to the patients. From their first exposure to the Diskhaler, patients were comfortable using the device, and this overall acceptance of the inhaler was maintained throughout the study.

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Long-term effectiveness and side effects of acetazolamide as an adjunct to other anticonvulsants in the treatment of refractory epilepsies.

The long-term effectiveness of acetazolamide (AZA) and its side effects, especially the formation of renal calculi, were investigated in a prospective study when AZA was used as an adjunct to other antiepileptic drugs in the treatment of refractory epilepsies. The subjects comprised 37 patients aged from 1 to 17 years (mean age, 8 years and 1 month) whose seizures were hard to control with the use of two or more drugs among sodium valproate, carbamazepine and clonazepam. Thirty-two of the 37 patients were complicated with mental retardation. A daily dose of 10mg/kg of AZA was first administered and then the dosage was increased up to 20mg/kg based on the clinical response and side effects. The maintenance daily dosage of AZA (12.2+/-4.2mg/kg) produced a steady-state plasma concentration of 6.2+/-4.5 microg/ml. Among the 37 patients, complete seizure control for more than 3 years was obtained in four patients. Although there were no significant differences, all of the four patients were classified as having symptomatic localization-related epilepsies. Seizures recurred in five after complete remission for at least 6 months, and six showed >50% decrease in seizure frequency for more than 6 months after the introduction of AZA. Twenty-eight patients, who were taking AZA for 10 months to 14 years (mean, 6 years and 5 months), were examined for the formation of renal calculi. None of them showed evidence of renal calculi. This study reinforces the idea that AZA may be a useful adjunct drug in selected patients with refractory symptomatic localization-related epilepsies.

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Differential effects of oral losartan and enalapril on local venous and systemic pressor responses to angiotensin I and II in healthy men.

This double-blind, placebo-controlled crossover study was designed to differentiate the pharmacodynamic effects of the angiotensin II receptor antagonist losartan from the angiotensin converting enzyme inhibitor enalapril. Effects of placebo, enalapril (10 mg), and losartan (20 and 100 mg) on local venous and systemic pressor responses to angiotensin I and II were compared in eight healthy male subjects. Treatments were administered orally approximately 4 hours before agonist infusions into a dorsal hand vein. Local changes in hand vein diameter and systemic blood pressure were monitored during the infusions. The 100 mg dose of losartan attenuated local venoconstrictor and systemic pressor responses to angiotensin I and II. In contrast, enalapril blocked only responses to angiotensin I. Both losartan and enalapril increased plasma renin concentration compared with placebo. These results are consistent with direct antagonism of angiotensin II receptors by losartan and with indirect effects of enalapril through inhibition of angiotensin converting enzyme.

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Association of common variations in the norepinephrine transporter gene with response to olanzapine-fluoxetine combination versus continued-fluoxetine treatment in patients with treatment-resistant depression: a candidate gene analysis.

To determine whether single-nucleotide polymorphisms (SNPs) in candidate genes are associated with response to olanzapine-fluoxetine combination. A post hoc analysis of a priori-selected SNPs used data from a clinical trial (dates: April 2002-July 2005) of olanzapine-fluoxetine combination, fluoxetine, and olanzapine in patients with major depressive disorder (DSM-IV criteria) and with nonresponse to prestudy antidepressant treatment and nonresponse to fluoxetine treatment during the study. Patients received open-label treatment with fluoxetine for 8 weeks (2 weeks, 25 mg/d; then 6 weeks, 50 mg/d), at the end of which nonresponders (< 25% decline in the 17-item Hamilton Depression Rating Scale score) were randomized to receive double-blind, monotherapy treatment with olanzapine-fluoxetine combination (6/50-18/50 mg/d, n = 71), fluoxetine (50 mg/d, n = 78), or olanzapine (6-18 mg/d, n = 56) for 8 weeks. Statistical significance was assessed at P < .05. The primary efficacy measure for within-study treatment was improvement on the Montgomery-Asberg Depression Rating Scale (MADRS). Rs36024, an intronic SNP in the norepinephrine transporter (SLC6A2), as well as 3 SNPs in melanocortin 3 receptor (MC3R) and 2 SNPs in tryptophan hydroxylase 2 (TPH2), were associated with MADRS-defined response to treatment with olanzapine-fluoxetine combination (adjusted Li-Nyholt P < .05). Except for 1 SNP in TPH2, identified SNPs were not significantly associated with response to continued-fluoxetine or olanzapine treatments. Our findings further support the hypothesis that the synergistic effect of olanzapine and fluoxetine on prefrontal cortical levels of norepinephrine and dopamine might be an underlying mechanism for the efficacy of olanzapine-fluoxetine combination in the treatment of treatment-resistant depression and, if replicated, may form a basis on which response to olanzapine-fluoxetine combination versus continued fluoxetine can be predicted based on variants in SLC6A2. Parent study registered at ClinicalTrials.gov identifier: NCT00035321.

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Everolimus but not mycophenolate mofetil therapy is associated with soluble HLA-G expression in heart transplant patients.

Human leukocyte antigen-G (HLA-G), a protein primarily expressed during pregnancy, helps maintain maternal-fetal immune tolerance. Myocardial and/or soluble HLA-G (sHLA-G) expression confers protection against rejection and vasculopathy after heart transplantation. Although the precise mechanisms remain unclear, immunosuppressive therapy has been reported to influence this expression. We compared sHLA-G expression in heart transplant recipients receiving two different anti-proliferative agents: mycophenolate mofetil (MMF) and everolimus (RAD). Twelve-hour pharmacokinetic (PK) studies were conducted in patients after cyclosporine (CsA) administration in conjunction with RAD or MMF, during which plasma HLA-G concentrations were measured by enzyme-linked immunoassay (ELISA). Among patients receiving RAD, 78% expressed detectable levels of plasma HLA-G (1,002 +/- 511 ng/ml) compared with 25% of patients receiving MMF (612 +/- 438 ng/ml, p = 0.03). In all sHLA-G(+) patients, expression remained constant, with no significant changes in HLA-G levels throughout the 12-hour PK study period. CsA did not appear to influence sHLA-G expression, as there was no correlation between HLA-G levels and CsA exposure (R(2) = 0.43, p = 0.08). These preliminary findings suggest a disproportionate expression of HLA-G in patients under two distinct immunosuppression strategies after heart transplantation. Although CsA administration does not influence sHLA-G levels, RAD but not MMF is associated with sHLA-G expression. Larger prospective clinical investigations are required to confirm whether RAD is independently associated with increased HLA-G expression.

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Effects of fluoxetine treatment in young children with idiopathic autism.

Thirty-seven children, aged between 2 and 7 years, with idiopathic autism underwent an open-label trial of fluoxetine treatment. All had assessment of diagnosis, developmental status, and family psychiatric history. Independent developmental testing before and after starting fluoxetine permitted quantification of language acquisition in a subgroup. Twenty-two of the 37 children had a beneficial treatment response sustained during continuing treatment for 13 to 33 months (mean 21 months). Eleven had an excellent response and were able to attend mainstream classrooms. Eleven had a good response though they remained identifiably autistic. Fifteen children had no benefit. Responders showed behavioral, language, cognitive, affective, and social improvements. Responders with adequate testing showed marked increases in language acquisition at every stage of development as compared with (1) pretreatment status, (2) responses to other treatments, (3) ability in non-language (matching) tasks, and (4) historical controls from the literature. The response to fluoxetine strongly correlated with a family history of major affective disorder. These preliminary findings implicate serotonergic mechanisms in autistic symptomatology and warrant further study with controlled trials.

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Carvedilol therapy in pediatric patients with congestive heart failure: a study investigating clinical and pharmacokinetic parameters.

Our purpose was to evaluate the clinical effect of carvedilol among pediatric patients with congestive heart failure (CHF) who did not respond to standard therapy and to assess the pharmacokinetics of carvedilol among these children. In this prospective, open intervention trial with blinded interpretation of selected end points, patients with CHF who did not improve on standard therapy, including digoxin, angiotensin-converting enzyme inhibitors, and diuretics, were treated with oral carvedilol in a ramped dosing scheme. Clinical parameters (ejection fraction, fractional shortening, and modified Ross score) were assessed before initiation of treatment and monthly for 6 months. Pharmacokinetic profiles of carvedilol were determined over the first 12-hour period after the initial dose in study patients, and for comparison, in 9 healthy adult volunteers. Fifteen patients (aged 6 weeks to 19 years) were enrolled in the study, including 10 patients with dilated cardiomyopathy and 5 with CHF secondary to congenital heart disease. All 15 patients tolerated carvedilol for the duration of the trial, and all achieved maximum target dosing. After 6 months of carvedilol therapy, ejection fraction increased (36% vs 54%; P <.05) and modified Ross Score improved (5 +/- 2 vs 3 +/- 3; P <.05). Elimination half-life was about 50% shorter in pediatric CHF patients compared with healthy adult volunteers (2.9 vs 5.2 hours; P <.05). Pediatric patients with CHF not responding to standard therapy may benefit from oral carvedilol treatment. The observed increased elimination of carvedilol in children suggests that optimal dosing strategies need to be further defined among the pediatric population.

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Fluoxetine does not impair motor function in patients with Parkinson's disease: correlation between mood and motor functions with plasma concentrations of fluoxetine/norfluoxetine.

Selective serotonin reuptake inhibitors are the most commonly chosen antidepressants in patients with Parkinson's disease (PD). The aim of our study was to assess the influence of fluoxetine (Flu) on motor functions in patients with PD. In this prospective, controlled, open-label study, 18 patients with PD and mild depression [(10 < or = Hamilton Rating Scale for Depression (HDRS) < or = 23)] without dementia [(25 < or = Mini-Mental State Examination (MMSE)] were treated with Flu. Both single and repeated dose effects of Flu were assessed on days 1-80. Plasma concentrations of Flu and norfluoxetine (NORFlu) were correlated with the results of selected motor function performance scores: The Unified Parkinsons Disease Rating Score (UPDRS), Finger Tapping Test (FTT) and Purdue Pegboard Test (PPT). Severity of PD, depression and dementia were evaluated using standard tests [(Hoehn and Yahr stages (HY), activity of daily living (ADL), UPDRS, HDRS, MMSE)]. Steady-state for Flu/NORFlu was reached after 18 days of treatment. Such a plateau correlated with significant improvements in both scores of depression and Parkinson's disability (HDRS, UPDRS and ADL, respectively). In addition, FTT and PPT scores also increased until day 18, with further slight fluctuations around the plateau. Optimal motor performances correlated with Flu concentrations of approximately 60-110 microg/L. Flu (20 mg/day) significantly reduced depression in PD patients while it did not impair their motor performances. Because substantial placebo effects may arise in studies of PD and depression, large, prospective, randomized, placebo-controlled clinical trials are warranted.

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Long-term comparison of three combinations of albuterol, theophylline, and beclomethasone in children with chronic asthma.

Three combination regimens, (1) inhaled albuterol (ALB) with oral theophylline (THEO), (2) inhaled ALB with inhaled beclomethasone dipropionate (BDP), or (3) inhaled ALB, inhaled BDP, and oral THEO, were evaluated and compared as optimal pharmacotherapy for chronic asthma in 111 children. In this double-blind, parallel-group, multicenter study, children, aged 6 to 16 years with moderately severe asthma (unstable despite daily medications), were treated with one of the combinations for 12 weeks. Patients were evaluated every 4 weeks by spirometry and serum THEO measurement. Patients kept daily symptom diaries, measured peak flow rates twice daily, and recorded adverse events. Treatment groups did not differ in disease or demographic characteristics at study entry. All three combination treatments provided and maintained significant improvement in FVC, FEV1, and FEF25%-75% volume points, and compared with that of pretreatment, with no significant differences between treatments. Throughout the 12-week treatment period, however, patients receiving BDP had lower symptom scores, fewer had more than one asthma attack, fewer required "bursts" of prednisone (p = 0.001), and fewer required rescue medication (p = 0.009). Significantly more patients receiving BDP said that they felt better than they did at the beginning of the study compared with the number of patients not receiving BDP (p = 0.002). Adverse events were similar among treatment groups.

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Prospective evaluation of a 21-sample needle biopsy procedure designed to improve the prostate cancer detection rate.

To evaluate prospectively the diagnostic yield of a 21-sample ultrasound-guided needle biopsy procedure for prostate cancer in patients with elevated serum prostate-specific antigen and/or abnormal digital rectal examination findings. Between December 2000 and May 2002, 303 patients underwent 21-sample needle biopsy under local anesthesia, comprising sextant biopsies at a 45 degrees angle, 3 biopsies in each peripheral zone at an 80 degrees angle, 3 biopsies in each transition zone (TZ), and 3 biopsies in the midline peripheral zone. Morbidity was assessed clinically. A short questionnaire was filled out by 90 consecutive patients. The cancer detection rate using 6 biopsy samples (sextant biopsies only), 12 samples (sextant plus lateral biopsies), 18 samples (sextant plus lateral plus TZ biopsies), and 21 samples (sextant plus lateral plus TZ, plus midline biopsies) was 22.7%, 28.3%, 30.7%, and 31.3%, respectively. The 21-sample procedure statistically improved the cancer detection rate by 37.9% relative to the 6-sample procedure. The improvement was most marked in patients with a prostate volume of more than 40 cm(3) (48.3%), patients with Stage T1c prostate disease (44.9%), patients undergoing repeat biopsy (66.2%), and patients with prostate-specific antigen levels greater than 10 ng/mL (38.5%). Adverse effects were infrequent (3%), consisting of prostatitis in 3 patients, acute urinary retention in 6 patients, and rectal bleeding requiring hospitalization in 1 patient taking aspirin. Using the questionnaire, 84% of patients reported macroscopic hematuria for an average of 3.4 days and hematospermia for 12.8 days, and 45% reported minor rectal bleeding lasting 1.1 days. The mean pain score, with a visual analog scale ranging between 0 (no pain) and 10 (intense pain), was 4.56. A 21-sample needle biopsy procedure increased the prostate cancer detection rate relative to a 6-sample procedure, without increasing morbidity. Patients with elevated prostate-specific antigen values should undergo sextant biopsies and at least 6 additional biopsies in the peripheral zone and 6 in the TZ.

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Primary mediastinal large B-cell lymphoma: a single-center study of clinicopathologic characteristics.

Primary mediastinal large B-cell lymphoma (PMLBCL) is a subset of LBCL with unique clinicopathologic features. Some studies have raised the question of differences in biological features and clinical course among patients from different parts of the world. We conducted a retrospective clinicopathologic analysis of 24 patients with PMLBCL from a single center in Croatia. We also conducted the first investigation of the frequency of lymphotropic viruses human herpesvirus 6 (HHV-6) and HHV-8 in lymphoid lesions of this disease. The clinical characteristics of the patients were as expected, with high International Prognostic Index scores, elevated serum lactate dehydrogenase (LDH) levels, and bulky disease being adverse prognostic factors. Only 6 patients (25%) showed CD30 expression, and Bcl-6 protein expression was, in our series, prognostically favorable (P = .0401). One patient's tumor had detectable HHV-6 genome sequence, but no HHV-8 sequences were detected in any tumors. Two thirds of the patients received CHOP chemotherapy (cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone) with a relatively low complete remission rate (43.8%; median follow-up, 33.8 months). This study confirmed the moderate preponderance among PMLBCL patients of young females with B symptoms and elevated LDH levels. The CHOP regimen proved effective as first-line therapy only in patients with limited disease. Therefore, other third-generation chemotherapy protocols may be considered for treatment, especially in patients with bulky and advanced disease.

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A comparison of the cost-effectiveness of sertraline versus tricyclic antidepressants in primary care.

There has been considerable debate concerning the cost-effectiveness of selective serotonin re-uptake inhibitors (SSRIs) versus tricyclic antidepressants (TCAs) thus far using crude prescription price comparisons or reductionist decision-analytic models. This paper employs a retrospective quasi-experimental design where data on service utilisation, use of medication and informal care were collected for two groups of patients in general practice settings. The mean cost of treatment was marginally greater for those people receiving TCA medication due to greater use of psychiatric services. Factors such as age, previous depression and concomitant physical illness are all associated with greater treatment costs. Further analysis using a prospective design is recommended.

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The effect of high doses of inhaled salbutamol and ipratropium bromide in patients with stable cystic fibrosis.

The effect of large doses of salbutamol (S) and ipratropium bromide (IB) were tested in a double-blind, randomized, crossover study. Nine patients with cystic fibrosis (CF), aged 12.8 +/- 2 years (mean +/- SE), were studied for 8 h on 2 separate days. Pulmonary function tests (PFTs) included spirometry (FEV1), lung volumes (FRC), and airway resistance (Raw) measured by body plethysmography. Heart rate (HR) and oxygen saturation (SaO2) were measured before each test. On 1 day patients received S 200 micrograms, S 400 micrograms, and IB 80 micrograms, by inhalation at 45-min interval (sequence A). On the other day, the sequence was IB 80 micrograms, S 200 micrograms, and S 400 micrograms (sequence B). The PFTs were obtained at baseline, 45 min after each inhalation, and 4 and 8 h after baseline measurements. Baseline PFTs (mean +/- SE) were not significantly different on the 2 study days (FEV1, 1.48 +/- 0.1 vs 1.42 +/- 0.1 L; FRC, 2.77 +/- 0.6 vs 2.87 +/- 0.6 L; Raw, 4.04 +/- 0.2 vs 4.00 +/- 0.3 cm H2O/L/s). The FEV1 and Raw improved from baseline after each inhalation, and at 4 and 8 h during both days (p < 0.05). Forty-five minutes after S 200 micrograms, plus S 400 micrograms, FEV1, FRC, and Raw were not significantly different compared with the values 45 min after IB 80 micrograms, plus S 200 micrograms (1.67 +/- 0.1 vs 1.63 +/- 0.1 L; 2.81 +/- 0.6 vs 2.65 +/- 0.5 L; and 2.98 +/- 0.2 vs 2.66 +/- 0.1 cm H2O/L/s, respectively). The PFTs were not significantly different after maximal doses of IB (80 micrograms) compared with S (600 micrograms). The HR and SaO2 were not significantly different from baseline throughout the study period. These results indicate that both single and sequential therapy have a similar acute bronchodilator effect provided that large doses are used. We speculate that adrenergic and muscarinic pathways are equally important in airflow obstruction in patients with CF.

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Metered-dose aerosolized bronchodilators in prehospital care: a feasibility study.

The prehospital use of aerosolized bronchodilators was studied in 50 adult patients with bronchospasm. The specific beta 2-agonist, albuterol, was discharged from a metered-dose inhaler (MDI) into the Inhal-aid reservoir-delivery device. No serious adverse effects were encountered, although a substantial proportion of the patients (36%) had difficulty utilizing the device. Ability to use the system properly correlated with improvement in symptoms; inability to use the device was most clearly related to severity of clinical presentation. It is concluded that the use of aerosolized bronchodilators is feasible in prehospital care and most useful in patients with mild or moderately severe symptoms.

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Tramadol for noncancer pain and the risk of hyponatremia.

Case reports have signaled a possible association between tramadol, a weak opioid analgesic, and hyponatremia. The objective of this study was to determine whether the use of tramadol is associated with an increased risk of hyponatremia, when compared with codeine. Using the UK Clinical Practice Research Datalink and Hospital Episodes Statistics database, a population-based cohort of 332,880 patients initiating tramadol or codeine was assembled from 1998 through 2012. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of hospitalization for hyponatremia associated with the use of tramadol, compared with codeine, in the first 30 days after initiation. A similar analysis was conducted within a highly restricted sub-cohort, which additionally excluded patients with any serum sodium level abnormality in the year before cohort entry. All models were adjusted for propensity score quintiles. The incidence rates of hospitalization for hyponatremia were 4.6 (95% CI, 2.4-8.0) and 1.9 (95% CI, 1.4-2.5) per 10,000 person-months for tramadol and codeine users, respectively. In the adjusted model, the use of tramadol was associated with a 2-fold increased risk of hospitalization for hyponatremia, compared with codeine (adjusted HR 2.05; 95% CI, 1.08-3.86). In the highly restricted sub-cohort, the use of tramadol was associated with an over 3-fold increased risk of hospitalization for hyponatremia, compared with codeine (adjusted HR 3.54; 95% CI, 1.32-9.54). In this first population-based study, the use of tramadol was associated with an increased risk of hyponatremia requiring hospitalization.

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The effect of corticosteroid or methotrexate therapy on lung lymphocytes and macrophages in sarcoidosis.

Methotrexate appears to be an effective alternative to corticosteroid therapy for some patients with sarcoidosis. The mechanism of action of methotrexate as an immunosuppressive is unknown. Patients with symptomatic pulmonary sarcoidosis underwent pulmonary function tests and bronchoscopy with bronchoalveolar lavage. Patients were treated with 10 mg methotrexate or prednisone weekly for at least 6 months and repeat studies were performed. A comparison was made between those patients receiving methotrexate (12 patients) and those receiving prednisone (12 patients). For both groups, there was a significant improvement in the vital capacity with therapy (Prednisone: Pre = 2.5 +/- 0.14 L (Mean +/- SEM); Post = 3.1 +/- 0.18 L, p less than 0.01; Methotrexate: Pre = 2.4 +/- 0.14 L; Post = 2.8 +/- 0.18 L, p less than 0.01). In addition, the percentage of lymphocytes in the lavage fell significantly for both the prednisone (Pre: 30 +/- 3.5%; Post: 16 +/- 2.7%, p less than 0.001) and methotrexate (Pre: 37 +/- 3.4%; Post: 13 +/- 2.9%, p less than 0.001) groups. Alveolar macrophages from the symptomatic sarcoid patients were found to be spontaneously releasing hydrogen peroxide and tumor necrosis factor. After treatment with either prednisone or methotrexate, alveolar macrophages retrieved by lavage spontaneously released less of either macrophage product. We found that effective doses of methotrexate for sarcoidosis led to significant changes in lymphocyte and macrophages retrieved by lavage.

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Timolol and metoprolol in glaucoma. A comparison of the ocular hypotensive effect, local and systemic tolerance.

A double-masked cross-over comparison of the ocular hypotensive effect in 19 glaucoma patients between timolol 0.5% - a non-selective beta-blocking agent - and metoprolol 3% - a beta 1-selective blocking agent - disclosed a greater pressure lowering effect (mean 9%, median 7% more) with timolol in a treatment period of 1 month. In patients on timolol treatment 47% - 60% of the eyes could be controlled on an IOP level less than 20 mmHg compared to 34% - 47% of the eyes treated with metoprolol. Metoprolol induced a transitory burning sensation in the eyes of 58% patients compared to 26% treated with timolol. Possible signs of dry eyes manifestations as measured by break-up time, rose bengal and fluorescein 1% staining, tear osmolality and Schirmer test I developed in both the timolol (4 patients) and metoprolol (3 patients) treated group. No significant influence on blood pressure and heart rate was observed. In none had the visual field or visual acuity deteriorated at the end of the study.

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Systematic review: adherence issues in the treatment of ulcerative colitis.

Ulcerative colitis is a chronic inflammatory and debilitating disease requiring lifelong treatment. First-line therapy for ulcerative colitis is 5-aminosalicylic acid, which suffers from poor patient adherence outside the clinical trial setting. Formulations to deliver 5-aminosalicylic acid to the disease activity site, both orally and topically, are often inconvenient and require multiple daily dosing. Such regimens can interfere with normal life and reduce the overall quality of life, negatively impacting on treatment adherence and leading to poorer long-term outcomes. These include increased morbidity with an elevated risk of symptomatic relapse, possible greater risk of colorectal cancer and higher overall costs of care. Ulcerative colitis patients cite treatment regimen complexity, tablet quantity and dose frequency as key negative influencers of adherence. Solutions to these issues include addressing patient concerns, simplifying daily regimens and utilizing new formulations such as micropellet and multimatrix oral formulations, rectal gel and once-daily suppository formulations. This review examines the prevalence and impact of non-adherence to 5-aminosalicylic acid therapy among patients with ulcerative colitis, as well as drug delivery strategies that may enhance dosing regimens to improve patient acceptability, adherence and long-term clinical outcomes. It is a combination of understanding patient behaviour, recognizing signs of non-adherent behaviour and utilizing management strategies to change behaviour that will improve patient outcomes.

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Identification of pharmacogenetic markers in smoking cessation therapy.

Pharmacogenetic clinical trials seek to identify genetic modifiers of treatment effects. When a trial has collected data on many potential genetic markers, a first step in analysis is to screen for evidence of pharmacogenetic effects by testing for treatment-by-marker interactions in a statistical model for the outcome of interest. This approach is potentially problematic because (i) individual significance tests can be overly sensitive, particularly when sample sizes are large; and (ii) standard significance tests fail to distinguish between markers that are likely, on biological grounds, to have an effect, and those that are not. One way to address these concerns is to perform Bayesian hypothesis tests [Berger (1985) Statistical decision theory and Bayesian analysis. New York: Springer; Kass and Raftery (1995) J Am Stat Assoc 90:773-795], which are typically more conservative than standard uncorrected frequentist tests, less conservative than multiplicity-corrected tests, and make explicit use of relevant biological information through specification of the prior distribution. In this article we use a Bayesian testing approach to screen a panel of genetic markers recorded in a randomized clinical trial of bupropion versus placebo for smoking cessation. From a panel of 59 single-nucleotide polymorphisms (SNPs) located on 11 candidate genes, we identify four SNPs (one each on CHRNA5 and CHRNA2 and two on CHAT) that appear to have pharmacogenetic relevance. Of these, the SNP on CHRNA5 is most robust to specification of the prior. An unadjusted frequentist test identifies seven SNPs, including these four, none of which remains significant upon correction for multiplicity. In a panel of 43 randomly selected control SNPs, none is significant by either the Bayesian or the corrected frequentist test.

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Impact of point-of-care testing for CYP2C19 on platelet inhibition in patients with acute coronary syndrome and early dual antiplatelet therapy in the emergency setting.

Only limited data exist about the role of point of care CYP2C19 testing in the acute setting in the early phase of acute coronary syndromes (ACS). Therefore, the present study was designed to investigate the impact of CYP2C19 loss-of-function point-of-care (POC) genotyping in patients presenting with acute coronary syndromes (ACS) and treated with dual antiplatelet therapy in the emergency setting. 137 subjects with ACS scheduled for percutaneous coronary intervention were consecutively enrolled. Pre- and on-treatment platelet aggregation was assessed by multiple electrode aggregometry (MEA) after stimulation with adenosine diphosphate (ADP). Patients were loaded according to current guideline adherent indications and contraindications for use of P2Y12 inhibitors in ACS. POC genotyping for CYP2C19*2 was performed in the emergency room after obtaining a buccal swab using the Spartan RX CYP2C19 system and obtaining patient's informed consent. Prasugrel and ticagrelor treated patients had significantly lower PR compared to clopidogrel-treated patients. The benefits of prasugrel and ticagrelor compared to clopidogrel treated patients in terms of platelet inhibition were more pronounced in CYP2C19*2 carriers. Non-carriers showed similar inhibition regardless of particular P2Y12 inhibitor treatment. Statistical analyses adjusting for factors associated with response (e.g. smoking) revealed that CYP2C19*2 allele carrier status and loading with different type of P2Y12 receptor blockers were significant predictors of on-treatment platelet reactivity in the early phase of ACS. The results of this pilot study of treatment of patients in the early phase of ACS indicate that CYP2C19*2 POC genotyping might help to identify patients at risk with poor response to clopidogrel treatment, thereby benefiting from reloading and switching to alternative P2Y12 receptor inhibition.

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Lung cancer and the debrisoquine metabolic phenotype.

In a case-control study, we tested the hypothesis that the genetically determined ability to metabolize debrisoquine is related to risk of lung cancer. Overall, individuals who were extensive metabolizers of debrisoquine were at significantly greater risk of lung cancer than those who were poor or intermediate metabolizers (odds ratio = 6.1; 95% confidence interval = 2.2-17.1). In this study, case patients had lung cancer, and control subjects had either chronic obstructive pulmonary disease or cancers other than lung cancer. Results were adjusted for age, race, asbestos exposure, and smoking. Both black and white individuals who were extensive metabolizers of debrisoquine were at significantly increased risk after similar adjustment (for blacks, odds ratio = 4.5, 95% confidence interval = 1.1-18.1; for whites, odds ratio = 10.2, 95% confidence interval = 2.0-51.4). Significantly increased risk of lung cancer was also present for individuals who were extensive metabolizers when subjects with chronic obstructive pulmonary disease or other cancers were considered separately. These data confirm that the ability to metabolize debrisoquine is a major determinant of susceptibility to lung cancer. Evaluation of the marker in other case-control settings, further exploration of racial differences, and the prospective evaluation of this marker in subgroups at high risk of lung cancer are areas worthy of further study.

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Clinical efficacy of subgingivally delivered 1.2% atorvastatin in chronic periodontitis: a randomized controlled clinical trial.

Atorvastatin (ATV) is a specific competitive inhibitor of 3-hydroxy-2-methyl-glutaryl coenzyme A reductase. Recently, statins have shown pleiotropic effects such as anti-inflammation and bone stimulation. The aim of the present study is to investigate the effectiveness of 1.2% ATV as an adjunct to scaling and root planing (SRP) in the treatment of intrabony defects (IBDs). Sixty individuals were randomized into two treatment groups: SRP plus 1.2% ATV and SRP plus placebo gel. At baseline and 3, 6, and 9 months, clinical parameters, which included modified sulcus bleeding index, plaque index, probing depth (PD), and clinical attachment level (CAL), were recorded at baseline. Radiologic assessment of IBD fill was done using computer-aided software at baseline and 6 and 9 months. Mean PD reduction and mean CAL gain were greater in the ATV group than the placebo group at 3, 6, and 9 months. A significantly greater mean percentage of radiographic bone fill was found in the ATV group (35.49% ± 5.50%) compared to the placebo group (1.82% ± 1.32%) after 9 months. ATV as an adjunct to SRP can provide a new direction in the management of IBDs.

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A 12-month prospective, observational study of treatment regimen and quality of life associated with ADHD in central and eastern europe and eastern Asia.

This prospective, observational, non-randomized study aimed to describe the relationship between treatment regimen prescribed and the quality of life (QoL) of ADHD patients in countries of Central and Eastern Europe (CEE) and Eastern Asia over 12 months. 977 Male and female patients aged 6-17 years seeking treatment for symptoms of ADHD were assessed using the Child and Adolescent Symptom Inventory-4 Parent Checklists, and the Clinical Global Impressions-ADHD-Severity scale. QoL was assessed using the Child Health and Illness Profile-Child Edition parent report form. Patients were grouped according to whether they were prescribed psycho- and/or pharmacotherapy (treatment) or not (no/'other' treatment). No statistically significant differences were observed between cohorts (treatment vs. no/'other' treatment) in terms of change in QoL, although there was improvement over 12 months, with a greater improvement experienced by patients in the treatment cohort in both study regions (CEE and Eastern Asia). Psychoeducation/counselling and methylphenidate were the predominant ADHD treatments prescribed. Although both treatment and no/'other' treatment cohorts showed improvements in mean QoL over 12 months, the difference was small and not statistically significant. A major limitation was the higher than anticipated number of patients switching treatments, predominantly from the no/'other' treatment cohort.

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The treatment of relapsing primary nephrotic syndrome in children.

To explore better therapy and reduce the rate of re-relapse of primary nephritic syndrome in children who had been treated with corticosteroids but relapsed. Eighty relapsers were enrolled from Jan. 1994 to Apr. 2000, who were randomly divided into two groups. The treatment group (n=39) had been treated with tripterysium glucosides for three months, with the control group (n=41) members were treated with cyclophosphmide (CTX) by intermission intravenous pulse, with total dose of CTX not being more than 150 mg/kg. Prednisone, meanwhile, was given to both groups. The total treatment period of prednisone was prolonged by 12-18 months. After following up for 3-7 years, the re-relapse rates of both groups were observed. The re-relapse rate of the treatment group was 28.2% to 29.3% in the CTX-controlled group. The re-relapse rates between two groups were almost similar, and with no observed significant difference (P>0.05). The side effect of tripterysium glucosides was less than that of CTX. For the treatment of relapsing nephritic syndrome in children, the combination of tripterysium glucosides and prolonged corticosteroid therapy is as effective as the regimen of CTX plus prolonged use of prednisone.

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Early Discontinuation of P2Y₁₂ Antagonists and Adverse Clinical Events Post-Percutaneous Coronary Intervention: A Hospital and Primary Care Linked Cohort.

Background Early discontinuation of P2Y₁₂ antagonists post-percutaneous coronary intervention may increase risk of stent thrombosis or nonstent recurrent myocardial infarction. Our aims were to (1) analyze the early discontinuation rate of P2Y₁₂ antagonists post-percutaneous coronary intervention, (2) explore factors associated with early discontinuation, and (3) analyze the risk of major adverse cardiovascular events (death, acute coronary syndrome, revascularization, or stroke) associated with discontinuation from a prespecified prescribing instruction of 1 year. Method and Results We studied 2090 patients (2011-2015) who were recommended for clopidogrel for 12 months (+aspirin) post-percutaneous coronary intervention within a retrospective observational population cohort. Relationships between clopidogrel discontinuation and major adverse cardiac events were evaluated over 18-month follow-up. Discontinuation of clopidogrel in the first 4 quarters was low at 1.1%, 2.6%, 3.7%, and 6.1%, respectively. Previous revascularization, previous ischemic stroke, and age >80 years were independent predictors of early discontinuation. In a time-dependent multiple regression model, clopidogrel discontinuation and bleeding (hazard ratio=1.82 [1.01-3.30] and hazard ratio=5.30 [3.14-8.94], respectively) were independent predictors of major adverse cardiac events as were age <49 and ≥70 years (versus those aged 50-59 years), hypertension, chronic kidney disease stage 4+, previous revascularization, ischemic stroke, and thromboembolism. Furthermore, in those with both bleeding and clopidogrel discontinuation, hazard ratio for major adverse cardiac events was 9.34 (3.39-25.70). Conclusions Discontinuation of clopidogrel is low in the first year post-percutaneous coronary intervention, where a clear discharge instruction to treat for 1 year is provided. Whereas this is reassuring from the population level, at an individual level discontinuation earlier than the intended duration is associated with an increased rate of adverse events, most notably in those with both bleeding and discontinuation.

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Short- and long-term efficacy of oral cyclophosphamide and steroids in patients with membranous nephropathy and renal insufficiency. Study Group.

Up to half of the patients with idiopathic membranous nephropathy (iMN) will develop renal failure. Preferably, immunosuppressive treatment should be restricted to patients at risk for the development of end-stage renal disease. However, the evidence that immunosuppressive treatment is effective in patients with iMN and renal insufficiency is weak and based on few studies with short follow-up in a limited number of patients. We have analyzed the efficacy of immunosuppressive treatment in a large number of patients with membranous nephropathy and renal insufficiency. Since 1991, we have prospectively treated 39 patients (31 M, 8 F) with membranous nephropathy and evidence of deterioration of renal function. Treatment consisted of oral cyclophosphamide, 1.5-2.0 mg/kg body weight for 12 months, and corticosteroids for 6 months. At regular intervals blood pressure, serum creatinine, serum albumin, and proteinuria were measured. Adverse events were recorded. Average follow-up is 32 months (range 6-104), 18 patients have been followed for more than 3 years. Mean age of the patients was 55 +/- 12 years. In the 6 months before start of therapy, serum creatinine increased from 150 +/- 74 to 226 +/- 108 micromol/l. After start of treatment renal function rapidly improved, serum creatinine at 12 months averaging 143 +/- 62 micromol/l. Proteinuria decreased from 10.3 +/- 4.9 g/10 mmol creatinine at baseline to 2.2 +/- 2.4 g/10 mmol creatinine at month 12. These initial favorable effects have persisted. Overall, 12 patients have developed a complete remission of proteinuria (persistent in 11), and an additional 19 have developed a partial remission of proteinuria (persistent in 15). Thus far, only one treated patient has developed end-stage renal disease. Side effects are a major drawback of the treatment, with 7 patients being admitted, mainly for the treatment of infectious complications. Cyclophosphamide is effective in the treatment of patients with idiopathic membranous nephropathy and deterioration of renal function. The favorable effects are maintained well beyond the one-year treatment period. Therefore, we propose that in patients with iMN immunosuppressive therapy can be restricted to patients at high risk for end-stage renal disease.

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