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Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study (4S)

We examined the relation between the risk of major coronary events (coronary death and non-fatal myocardial infarction) and baseline cholesterol levels in patients with coronary heart disease, randomised to placebo or simvastatin therapy in the Scandinavian Simvastatin Survival Study (4S). The relative risk reduction in the simvastatin group was 35% (95% CI 15-50) in the lowest quartile of baseline low-density-lipoprotein cholesterol and 36% (19-49) in the highest. Simvastatin significantly reduced the risk of major coronary events in all quartiles of baseline total, high-density-lipoprotein, and low-density-lipoprotein cholesterol, by a similar amount in each quartile.

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[Impact of statins on clopidogrel platelet inhibition in patients with acute coronary syndrome or stable angina].

This prospective registered study was conducted to investigate the impact of statins (pravastatin, fluvastatin, atorvastatin) on clopidogrel platelet inhibition in patients with acute coronary syndrome (ACS) or stable angina. A total of 1015 consecutive patients with ACS or stable angina underwent coronary angiography/percutaneous coronary intervention (PCI) were allocated to pravastatin group (n = 228), fluvastatin group (n = 179), atorvastatin group (n = 481) or placebo control group (n = 127). Baseline characteristics, coronary angiography/PCI features and acute stent thrombosis, platelet aggregation induced by 2, 5, 10 and 20 micromol adenosine diphosphate (ADP) at 1 minute (ADP-1), 5 minutes (ADP-5) and maximal platelet aggregation (ADP-M) were compared among groups. Baseline and procedural characteristics were comparable among the four groups. Acute stent thrombosis (pravastatin group 0.9%, fluvastatin group 1.1%, atorvastatin group 1.0% and control group 0.8%, all P > 0.05), ADP-1, ADP-5, and ADP-M (all P > 0.05) were also similar among groups. Multivariate liner and ordinal logistic analysis revealed that age (B = 0.21, P = 0.001), dose of clopidogrel (B = 7.30, P = 0.002) and use of low-molecular heparin (OR = 6.71, P = 0.01) were independent factors for platelet aggregation inhibition efficacy by clopidogrel. Inhibition of platelet aggregation with clopidogrel was influenced by age, clopidogrel dose and low-molecular heparin but not by various statin treatments.

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Decrease in suicide among the individuals treated with antidepressants: a controlled study of antidepressants in suicide, Sweden 1995-2005.

Ecological studies have demonstrated a substantial decrease in suicide in parallel with an increase in the use of antidepressants. Causality cannot, however, be inferred from such studies. The aim of this study was to test on the individual level the hypothesis that treatment with antidepressant medication has been a substantially contributing cause of the decrease in suicide. Time trends in the detection of antidepressants and five 'control medications' in the forensic toxicological screening of 16 937 suicides and 33 426 controls in Sweden 1995-2005. The expected number of antidepressant-positive suicides in 2005 was 409 if the hypothesis was true and 603 if it was false. The observed number in 2005 was 420. The control medications were detected to the extent that was expected if not preventing suicide. The observed trend in the number of suicides with antidepressants was well predicted by the hypothesis that the increased use of antidepressants has been a substantially contributing cause of the decrease in suicide.

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Postoperative prophylactic antibiotic treatment in third molar surgery--a necessity?

We evaluated the need for prophylactic postoperative oral antibiotic treatment in the removal of asymptomatic third molars. In a prospective study of more than 30 months, a total of 528 impacted lower third molars were surgically removed in 288 patients. All patients were referred to our department by a dentist or a general practitioner. No patient showed any sign of pain, inflammation, or swelling at the time of removal. Three groups were established. In the first group, antibiotic treatment with amoxicillin/clavulanic acid as an oral medication was carried out for 5 days postoperatively. In the second group, we used clindamycin. In the third group, the patients received no antibiotic treatment. Clinical and radiologic factors were recorded for each case, and the rationale for assigning the patients to the groups was strictly random. The surgical technique was the same in all cases, and the follow-up period was 4 weeks. Parameters that were evaluated were pain, differences in mouth opening, infection, the occurrence of dry socket, and adverse postoperative side effects. We could not find any significant difference between the 3 groups regarding the evaluated parameters, but in 69.6% of the patients with dry socket, the teeth were partially erupted, which showed a significant difference. The results of our study show that specific postoperative oral prophylactic antibiotic treatment after the removal of lower third molars does not contribute to a better wound healing, less pain, or increased mouth opening and could not prevent the cases of inflammatory problems after surgery, respectively, and therefore is not recommended for routine use.

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Impact of high-dose atorvastatin in coronary heart disease patients age 65 to 78 years.

High-dose statin therapy may be underutilized in aged patients due to doubts about efficacy and safety. To investigate outcomes and safety in patients aged 65-78 years compared with patients aged < 65 years in the ALLIANCE study. A total of 2,442 stable coronary heart disease (CHD) patients with dyslipidemia were randomized to either aggressive treatment (low-density lipoprotein cholesterol titration goal of < 80 mg/dL or maximum 80 mg/d of atorvastatin) or usual care (continuation of baseline lipid-lowering therapy, with changes and laboratory analyses directed by treating physicians). A total of 1,001 patients aged 65-78 years were followed for a median period of 53.9 mo. Older, aggressively treated atorvastatin patients experienced a 27% relative risk reduction for the primary composite endpoint of adverse cardiovascular outcomes (hazard ratio [HR]: 0.73; 95% confidence intervals [CI]: 0.57-0.94; p = 0.016). In addition, significant risk reductions were observed for nonfatal myocardial infarction (MI; HR: 0.43; 95% CI: 0.23-0.79; p = 0.006), cardiac revascularization (HR: 0.67; 95% CI: 0.48-0.93; p = 0.017), and the combined endpoint of cardiac death and nonfatal MI (HR: 0.48; 95% CI: 0.32-0.72; p = 0.001). The rate of significant liver transaminase elevations in atorvastatin patients was low and not age related. There were no cases of rhabdomyolysis. The rate of study discontinuations due to serious adverse events was higher in patients aged 65-78 years than in those younger than 65 years, but was similar between the treatment groups. Our data support the efficacy and safety of aggressive lipid management with atorvastatin in older CHD patients.

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The treatment of Hodgkin's disease: emphasizing programs at the Clinic Center, National Institutes of Health.

During the past 10--15 years there has been a dramatic improvement in the prognosis of patients with Hodgkin's diases. More than 80% of all patients now will live 5+ years, many of them free from disease. The well-recognized immediate complications of therapy discussed above, are insignificant compared to the tremendous improvement in patients' survival. The fact that they now probably will survive long enough to potentially be at risk of such long-term complications is a testament to the efficacy of modern-day aggressive therapy.

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Lansoprazole prevents recurrence of erosive reflux esophagitis previously resistant to H2-RA therapy. The Lansoprazole Maintenance Study Group.

This randomized, double-blind study was designed to determine whether the proton pump inhibitor lansoprazole could prevent relapse among patients with healed erosive reflux esophagitis that had been resistant to healing with at least 3 months of H2-receptor antagonist therapy. By the end of the year, 13% of placebo patients remained healed compared with 67% of lansoprazole 15 mg and 55% of lansoprazole 30 mg patients (p < 0.001 for time to first relapse). All placebo patients were symptomatic by the end of the study whereas only one-third of the lansoprazole patients was symptomatic at the end of the 12-month study period. The two lansoprazole doses were comparably effective in maintaining healing and in symptom control and were well tolerated. Fasting serum gastrin values increased significantly to about 1.5-2 times the baseline values over the first 2 months of lansoprazole treatment; no further increase was noted. Erosive relapse can be prevented in most patients for up to 1 yr with lansoprazole 15 mg or 30 mg once daily.

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Cardiac transplantation with corticosteroid-free immunosuppression: long-term results.

To assess the long-term safety of an immunosuppressive regimen without corticosteroids, we retrospectively evaluated 42 long-term (greater than 1 year) survivors of orthotopic cardiac transplantation. We determined the incidence of (1) conversion of the immunosuppressive regimen from cyclosporine and azathioprine alone (group I) to cyclosporine, azathioprine, and prednisone (group II), (2) late acute graft rejection (defined as occurring at greater than 1 postoperative year), and (3) major postoperative complications related to corticosteroids. Of the 42 patients who were started on cyclosporine and azathioprine, 48% remained in group I, and 52% converted to group II. Forty-five percent of group II patients were able to taper and discontinue prednisone in 15.6 +/- 2.2 months. Among the patients on long-term corticosteroid-free immunosuppression, the incidence of late rejection was 2.1% per endomyocardial biopsy. The incidence of late infectious episodes was not significantly different between the two groups of patients, although diabetes mellitus and hypercholesterolemia were more prevalent in group II than in group I. These data suggest that cardiac transplant recipients who chronically remain on corticosteroid-free immunosuppression represent a select group of patients with an acceptably low risk of late graft rejection and associated reduction of potential risk factors of accelerated coronary artery disease.

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The debrisoquine metabolic phenotype and DNA-based assays: implications of misclassification for the association of lung cancer and the debrisoquine metabolic phenotype.

Debrisoquine is an antihypertensive drug that is metabolized by cytochrome P4502D6. Deficient metabolism is inherited as an autosomal recessive condition. We previously reported in a case-control study that extensive metabolizers of debrisoquine were at greater risk of lung cancer compared to poor and intermediate metabolizers. Cloning of the gene that encodes P4502D6 (CYP2D6) led to the identification of both wild-type and mutant forms of the gene. Subsequently, a DNA-restriction fragment length polymorphism (RFLP) was identified, and a Southern hybridization-based test was developed in an attempt to define the genotype. When the DNA-RFLP test was applied to stored DNA from our study subjects there was neither a significant association with the metabolic phenotype nor an association with lung cancer. Further work has demonstrated that the wild-type gene, which was characterized by a 29-kb allele, can also contain mutations that result in nonfunctional or absent proteins. When these mutations are present, individuals exhibit the poor or intermediate metabolizer phenotype in spite of the presence of the 29-kb putative wild-type allele. Sequence determination of the mutants led to the development of techniques to exploit the polymerase chain reaction, which, together with Southern analysis, have been reported to detect as many as 95% of poor metabolizers. This technique is being used to examine the association of the extensive metabolizer genotype with lung cancer in the subjects from the case-control study. Preliminary results indicate a weak association between the homozygous wild-type genotype and lung cancer; in contrast, the extensive metabolizer phenotype is strongly associated with lung cancer in this subset.(ABSTRACT TRUNCATED AT 250 WORDS)

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Treatment of adults with acute lymphoblastic leukaemia in first bone marrow relapse: results of the ALL R-87 protocol.

Sixty-one adults aged <55 years with acute lymphoblastic leukaemia (ALL) in first bone marrow relapse were enrolled in an Italian cooperative study (ALL R-87 protocol) from 12 GIMEMA Institutions. The treatment programme consisted of: (1) an induction phase with intermediate-dose cytarabine (IDARA-C 1 g/m2, 6 h daily infusion x 6 d) plus idarubicin (IDA; 5 mg/m2/d x 6 d) and prednisone (40 mg/m2/d x 21 d), (2) a consolidation phase followed by (3) bone marrow transplant (BMT). Median first complete remission (CR) duration was 8.5 months (range 1-54 months). 34/61 patients achieved CR (56%); 24 (39%) failed to respond and three (5%) died during induction. Most responders (24 patients) could not enter the BMT programme; 15 relapsed early (median time to relapse 2 months); nine were withdrawn due to toxicity and one died in CR of infection. Nine of the 34 CRs underwent BMT (five autologous and four allogeneic). Three of the four allotransplanted patients are alive in continuous CR at 22, 43 and 63 months; only one of the five who underwent an autologous BMT is alive in CR at 46 months. The estimated disease-free survival (DFS +/- SE) at 36 months was 0.16 +/- 0.08 for all responders. Univariate analysis showed that previous therapy was the only prognostic factor influencing DFS. The estimated probabilities of event-free survival (EFS +/- SE) and survival +/- SE at 37 months were 0.09 +/- 0.04 and 0.10 +/- 0.04, respectively. The EFS was significantly better in patients with a preceding CR > or = 24 months, compared to those with a shorter first remission. Our results confirm the tolerance and efficacy of IDARA-C plus IDA in inducing CR in poor-risk adult ALL. Even though the number of transplanted patients was small, allogeneic BMT seems to give a real opportunity of cure in this category of patients.

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A retrospective pilot study examining the use of Acthar gel in sarcoidosis patients.

Acthar was reported as effective for the treatment of pulmonary sarcoidosis in the 1950s. Use of drug waned due to cost and toxicity compared to prednisone. Recent interest has reemerged as an alternative to high dose oral glucocorticoids. Chart review was performed on all advanced sarcoidosis patients seen at two centers who received at least one dose of Acthar gel therapy with at least six months of posttreatment follow up. In all cases prior sarcoidosis therapy and indications for use along with clinical outcome were noted. All patients initially received 80 IU intramuscular or subcutaneous administration twice a week. A total of 47 patients were treated with Acthar gel therapy during the study period, and 18 (37%) discontinued drug within six months due to cost (four patients), death (two patients), or drug toxicity (eleven patients), or noncompliance (1 patient). Of the remaining 29 patients, eleven experienced objective improvement in one or more affected organs. All but two patients noted disease improvement or oral glucocorticoid reduction. Twenty-one patients were treated for more than six months (Median 274 days). Nineteen patients were on prednisone at time of starting Acthar gel: seventeen had their prednisone dosage reduced by more than fifty percent and one patient discontinued cyclophosphamide therapy. In this group of advanced sarcoidosis patients, Acthar gel treatment for at least three months was associated with objective improvement in a third of patients. A third of patients were unable to take at least a three months of treatment.

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Analysis of long-term results and prognostic factors among 138 patients with advanced Hodgkin's disease treated with the alternating MOPP/ABVD chemotherapy.

A prospective study was conducted to assess (a) the long-term results and toxicity of the alternating MOPP/ABVD regimen in advanced Hodgkin's disease; (b) the prognostic value of pretreatment variables and of drug dose intensity. A total 138 consecutive patients with advanced Hodgkin's disease entered this study; patient selection included stages IIB (33% of total), IIIB (26%), IV (25%), and stages IIA-IIIA (16%) with bulky disease and pulmonary hilum involvement. The MOPP/ABVD program was delivered in an 8-month program; adjuvant radiotherapy on sites of bulky disease was delivered in 24 patients. Complete remission was obtained in 106 (77%) patients; significant factors for CR in univariate analysis were stage, symptoms, histology, and bone marrow involvement. The five-year relapse-free survival (RFS) was 83%; in a multivariate analysis, histology only correlated with RFS (p = 0.04). The five-year freedom from tumor mortality and overall survival (OS) were 79% and 67%, respectively. An adverse prognostic significance for OS was observed for B symptoms and bone marrow involvement. The median percentage of relative dose intensity (RDI) was as follows: Adriamycin 86, mechlorethamine 85, vincristine 73, vinblastine 84, bleomycin 79, procarbazine 74, dacarbazine 81. No significant association was found between RDI and clinical outcome. No severe pancytopenia or life-threatening complications occurred during therapy. Alternating MOPP and ABVD cured more than 65% of patients with advanced HD; acute and late toxicity were acceptable. Prognostic analysis defined subgroups with a lower chance of cure which may deserve a more intensive initial therapy.

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Prognostic impact of elevated serum uric acid levels on long-term outcomes in patients with chronic heart failure: A post-hoc analysis of the GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure) trial.

The prognostic impact of hyperuricemia on long-term clinical outcomes in patients with chronic heart failure (HF) has been investigated in observational registries and clinical trials, but the results have been often inconclusive. We examined the prognostic impact of elevated serum uric acid levels on long-term clinical outcomes in the GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure) trial. CLINICALTRIALS. NCT00336336. We assessed the rates of all-cause death, cardiovascular death, cardiovascular hospitalization and the composite of all-cause death or cardiovascular hospitalization over a median follow-up of 3.9 years among 6683 ambulatory patients with chronic HF. Patients in the 3rd serum uric acid tertile (>7.2 mg/dl) had a nearly 1.8-fold increased risk of both all-cause death and cardiovascular death, and a nearly 1.5-fold increased risk of cardiovascular hospitalization and of the composite endpoint compared to those in the 1st uric acid tertile (<5.7 mg/dl). Beyond serum uric acid ≥ 7 mg/dl the risk of outcomes increased sharply and linearly. The significant association between elevated serum uric acid levels and adverse outcomes persisted after adjustment for multiple established cardiovascular risk factors, HF etiology, left ventricular ejection fraction, medication use and other potential confounders, with an adjusted hazard ratio of 1.37 (95% CI 1.22-1.55) for all-cause death, 1.48 (1.29-1.69) for cardiovascular death, 1.19 (1.09-1.30) for cardiovascular hospitalization and 1.21 (1.11-1.31) for the composite endpoint, respectively. Elevated serum uric acid levels are independently associated with poor long-term survival and increased risk of cardiovascular hospitalization in patients with chronic HF.

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Differential prescribing of inhaled corticosteroids in New Zealand general practice.

To determine how inhaled budesonide, beclomethasone and fluticasone are prescribed by general practitioners in New Zealand. Retrospective study of computerised clinical records from 42 general practices in New Zealand for the period 1 July 1997 to 30 June 1998. The study population comprised 174 929 consulting patients, of whom 9878 patients were prescribed budesonide, fluticasone, or beclomethasone with full dosing instructions. The mean daily prescribed dose was higher for patients receiving inhaled budesonide (886 microg) than beclomethasone (547 microg), a difference of 339 microg (95% CI 311 microg to 367 microg), and fluticasone (508 microg), a difference of 378 microg (95% CI 344-412). The difference between mean daily prescribed doses of beclomethasone and fluticasone was 39 microg (95% CI 15-63). The overall difference was consistent across age groups and with different types of inhalation device. Evidence of systematic prescribing of higher doses of budesonide to patients with more severe asthma was not found. Patients prescribed fluticasone were more likely to have been prescribed oral steroids in the preceding year. Conclusions about the relative potencies of inhaled corticosteroids cannot be made with the data presented. However, data presented show that inhaled corticosteroids have not been prescribed in line with their reported relative potencies. This study provides benchmark data for the prescribing of inhaled steroids in New Zealand general practice.

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A double-blind trial of fluoxetine in pathologic skin picking.

Our objective was to determine the efficacy of fluoxetine in the treatment of pathologic skin picking in a double-blind, placebo-controlled, parallel trial. Twenty-one adults with chronic pathologic skin picking agreed to participate and received 10 weeks of placebo or fluoxetine with a flexible dosing schedule up to 80 mg/day. Three skin-picking measures were employed: the Clinical Global Impression-Improvement (CGI-I) scale, the Skin Picking Treatment Scale (SPTS), and a visual analog scale of self-rated change (VAS). In addition, depression, anxiety, and obsessions-compulsions were rated using the Hamilton Rating Scale for Depression (HAM-D), the Hamilton Rating Scale for Anxiety (HAM-A), the Spielberger State-Trait Anxiety Inventory (STAI), and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) for the duration of the study. Seventeen subjects (6 treated with fluoxetine and 11 treated with placebo) completed the trial, at a mean fluoxetine dose of 55 mg/day. Fluoxetine was significantly superior to placebo in the treatment of skin picking according to two of the three measures for the completer analysis and to one of the three measures for the intent-to-treat analysis. Neither baseline level nor change in depression, anxiety, or obsessive-compulsive symptoms was significantly related to change in skin picking. This first controlled trial of the treatment of pathologic skin picking suggests that fluoxetine may be of therapeutic benefit. Larger controlled studies are warranted.

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Comparison of the effect on intragastric pH of a single dose of omeprazole or rabeprazole: which is suitable for on-demand therapy?

An ideal medication for heartburn should have the rapid onset of action needed for on-demand treatment. However, assessment of the onset of action of proton pump inhibitors has been largely subjective. We compared the inhibitory effect on gastric acid secretion of a single oral dose of omeprazole with that of rabeprazole. Fourteen Helicobacter pylori-negative men participated in this randomized, double-masked, two-way cross-over study. Intragastric pH was monitored continuously for 6 h after a single, randomly assigned 20 mg oral dose of either omeprazole or rabeprazole. After a 7-day washout period, the other drug was administered. Each patient's S-mephenytoin 4'-hydroxylase (CYP2C19) genotype was determined by polymerase chain reaction-restriction fragment length polymorphism. Intragastric pH and pH holding time did not differ between treatments when the data were analyzed for the whole group without stratifying for CYP2C19 status. In CYP2C19 homozygous and heterozygous extensive metabolizers (10 subjects), rabeprazole maintained the intragastric at pH > 3 and> 4 for longer than omeprazole during both the 5 and 6 h study periods, and the average pH during the 6 h study period was higher with rabeprazole than with omeprazole. In these extensive metabolizers, rabeprazole maintained the pH > 2,> 3,> 3.5 and> 4 for longer during the 6 h study period than did omeprazole. In H. pylori-negative men who are CYP2C19 homozygous or heterozygous extensive metabolizers, the intragastric pH after a single dose of 20 mg rabeprazole is higher during first 5-6 h than that after a single dose of 20 mg omeprazole.

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No effect of montelukast on asthma-like symptoms in elite ice hockey players.

Controlled clinical trials on the effects of leukotriene antagonists on asthma-like symptoms, bronchial hyperresponsiveness and airway inflammation have not been performed in elite athletes. In 2001, we examined 88 of 102 (86%) players from three junior, national league ice hockey teams in Helsinki. Athletes were included in the intervention if they reported at least two exercise-induced bronchial symptoms (wheeze, cough, shortness of breath) weekly during the previous month on a previously validated respiratory-symptom questionnaire. Sixteen male ice hockey players fulfilled the study criteria. A double-blind, randomized, cross-over, placebo-controlled study included 4-week active treatment (10 mg oral montelukast, bedtime), 1-week washout period, and 4-week placebo treatment. Before entering the study, all patients were clinically examined, skin prick tested, filled in a respiratory symptom questionnaire, performed a spirometry and a histamine challenge test, and gave induced sputum samples. Exhaled NO was measured. These measures were repeated after both treatment periods. During the treatment the athletes kept daily diary on lower respiratory tract symptoms on a scale from 0 (no symptoms) to 10 (most severe symptoms), morning peak expiratory flow (PEF), training amount, and use of study medication. Primary end-point was daily lower respiratory tract symptom score. Montelukast had no effect on daily lower respiratory symptom scores, spirometry parameters [forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, PEF], bronchial hyperresponsiveness, sputum eosinophil or neutrophil cell counts, exhaled NO measurements, or morning PEF. Nine subjects were atopic in skin prick test, but their results did not differ from the nonatopic subjects. A leukotriene antagonist, montelukast, was of no benefit in the treatment of asthma-like symptoms, increased bronchial hyperresponsiveness or a mixed type of eosinophilic and neutrophilic airway inflammation in highly-trained ice hockey players.

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Analysis of hepatitis B virus precore variants in hepatitis B e antibody-positive patients treated with prednisone plus interferon.

To assess the effects of prednisone and interferon on the distribution of hepatitis B virus (HBV) precore mutants, nine hepatitis B e antibody (HBeAb)-positive patients with HBV chronic infection were studied. Patients were treated with prednisone (30 mg day-1 for 4 weeks, followed by 20 mg day-1 for 2 weeks and by 10 mg day-1 for 1 week), followed by recombinant interferon-alpha (15 MU thrice per week) for 6 months, without a clearance period. The HBV precore region was amplified by polymerase chain reaction (PCR) and distribution of the precore mutants was determined by hybridization of PCR products. Moreover, the glucocorticoid-responsive element (GRE) was sequenced to determine whether changes in the sequence were produced at the end of prednisone treatment. During prednisone treatment, changes in alanine transaminase (ALT) were observed in only two patients, in who ALT decreased to nearly normal values. In three patients ALT normalized at the end of interferon treatment. At baseline, wild-type HBV alone was detected in one patient, while seven patients were infected by a mixture of wild-type and precore mutants, predominantly wild type. At the end of prednisone treatment, two patients were infected by only wild-type HBV. The proportion of precore mutants decreased in three cases, while no changes were observed in three. At the end of interferon treatment, the precore mutant proportion decreased in the three responders, while tending to increase or remain unchanged in the rest. No significant changes in GRE sequence were found as a result of prednisone treatment. Our results would appear to confirm the role of the immune system in the selection of precore mutants.

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Simvastatin displays an antioxidative effect by inhibiting an increase in the serum 8-isoprostane level in patients with acute ischemic stroke: brief report.

Oxidative stress plays an important role in ischemic stroke pathophysiology. Some drugs are known to have a substantial influence on oxidative stress. In this study, we examined the antioxidant effect of simvastatin through its influence on patients' serum 8-isoprostane levels. We measured serum 8-isoprostane levels in 67 patients with acute ischemic stroke treated and not treated with simvastatin within 5 days after stroke onset, in comparison with 20 normal controls. Stroke patients from both groups had significantly higher initial serum 8-isoprostane levels than the controls. The median value of serum 8-isoprostane level was significantly lower in the simvastatin-treated group after 5 days of treatment. The results confirm the contribution of oxidative stress to brain ischemia and suggest antioxidative properties of statins in the acute phase of ischemic stroke patients.

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Chemotherapy-induced nausea and vomiting: incidence and characteristics of persistent symptoms and future directions NCCTG N08C3 (Alliance).

Despite newer agents, chemotherapy-induced nausea and vomiting (CINV) continues to remain a distressing side effect to a proportion of patients undergoing systemic anti-cancer therapy. We recently performed an unplanned secondary analysis on a previously reported negative phase III trial (N08C3) looking at the efficacy of gabapentin/placebo in combination with dexamethasone and a 5HT3 receptor antagonist in the prevention of CINV for 413 patients undergoing regimens with highly emetogenic chemotherapy (HEC). In the current study, we attempted to better understand the higher than expected rate of overall patient satisfaction, despite a low complete response rate in both arms. Additionally, we looked at patient variables and their relationship to rates of CINV. Approximately one third of patients experienced more than mild nausea and reported scores on the Functional Living Index-Emesis that indicated interference with activities. Thirty-five percent reported nausea greater than 2.5 on a scale of 0 to 10 (0 being none), 19 % reported at least one emetic episode, and 49 % reported taking rescue medication. Nausea and vomiting on day 1, cisplatin therapy, and history of motion sickness significantly predicted delayed CINV. Age, combination chemotherapy (HEC with moderately emetogenic), and getting treatment for breast cancer predicted CINV on day 1. These data confirm previous reports that subgroups of patients may be more prone to acute and delayed CINV. Future CINV study design may benefit from a more individualized approach to CINV management, targeting those patients who are truly at risk for CINV despite continued drug development efforts.

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Prevalence, long-term prognosis and medical alternatives for patients admitted for acute coronary syndromes and prasugrel contraindication.

Prasugrel is a potent antiplatelet therapy that has demonstrated to be superior to clopidogrel for patients with acute coronary syndromes (ACS) but has three main contraindications. Prospective study of all patients admitted for ACS in two hospitals. Prasugrel contraindication group was defined by the presence of age >75 years, weight <60 kg or previous stroke. We also performed a propensity score matching to obtain a well-balanced subset of patients with the same probability of receiving ticagrelor. We included 8207 patients and 2538 (30.9%) had any contraindication for prasugrel, being age >75 years the most frequent (29.0%). Hospital mortality was 4.4% and it was >2-fold higher in patients with any contraindication for prasugrel (7.9% vs. 2.8%; p < 0.01). Postdischarge follow-up (median 59.9 months) revealed that patients with prasugrel contraindication had higher cardiovascular and all-cause mortality as well as a first major cardiovascular event (MACE). No differences in bleeding rates were found in patients with vs. without prasugrel contraindication. Prasugrel contraindication was independently associated to higher cardiovascular (HR: 1.42) and all-cause mortality (HR: 1.47), as well as higher MACE (HR: 1.25). In the sub-cohort of 482 pairs of patients, obtained by a propensity score matching, ticagrelor treatment was associated with lower cardiovascular death (HR: 0.22), all-cause mortality (HR: 0.30) and first MACE (HR: 0.58) in patients with prasugrel contraindication. Almost one third of ACS patients have prasugrel contraindications and they have worst in in-hospital and post-discharge prognosis. Ticagrelor improved postdischarge outcomes in patients with prasugrel contraindications.

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Acute hemodynamic effects of carvedilol in comparison with propranolol in patients with coronary heart disease.

In a randomized, double-blind study oral doses of 50 mg carvedilol (Dilatrend) were compared with 40 mg propranolol in 16 male patients with coronary heart disease, CHD [12 without significant stenoses following percutaneous transluminal coronary angioplasty (PTCA), 4 with multivessel disease]. Bicycle ergometry in the supine position was performed before and 80 min after drug application; measurements were done at rest, during and after exercise. Clinically, the total exercise time and the onset of angina and exhaustion were noted, while the investigated hemodynamic parameters were heart rate, systemic and pulmonary pressures and resistances, cardiac index, and lower limb blood flow. Clinically, carvedilol improved the exercise tolerance more than propranolol as regards angina and exhaustion. Hemodynamically, carvedilol did not lead, as the classic betablocker propranolol does, to an increase in systemic or pulmonary resistance, to a decrease in cardiac output, or to an increase of the pulmonary capillary wedge pressure during exercise, but instead caused opposite changes. In contrast to propranolol, the post exercise lower limb blood flow had increased significantly. The differences in action between the two betablockers can be explained by the vasodilating properties of carvedilol. Due to these acute effects, carvedilol may be preferred to propranolol in the treatment of CHD patients with hypertension, peripheral occlusive artery disease, and/or coronary vasospasm.

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The serotonin reuptake inhibitor sertraline reduces excessive alcohol consumption in nonhuman primates: effect of stress.

Many monkeys that are reared without adult influence, with only peers, voluntarily consume alcohol in amounts producing intoxication on a relatively regular basis. Using a cross-over design, eight adolescent, peer-reared rhesus monkeys were allowed unfettered access to an 8.4% ethanol solution and treated with 20 mg/kg/24 h of sertraline during three phases: home-cage, social separation, and reunion with cage-mates. Although there was no immediate effect, sertraline reduced alcohol consumption beginning the second week of home-cage treatment, but only in subjects that consumed large amounts of alcohol. Initially, the social separation stress caused the sertaline-treated subjects' alcohol consumption rates to return to baseline levels, but when the stress was repeated, alcohol consumption fell below baseline and placebo levels. Sertraline treatment was ineffective in reducing consumption during the stressful period of home-cage reunion, a period characterized by high levels of aggressive behavior. Behaviorally, sertraline reduced aggression and anxiety-like self-directed behaviors. Our findings provide evidence that sertraline may be an effective pharmacological treatment for excessive alcohol consumption and aggression. On the other hand, stress during treatment may reduce sertraline's effectiveness as a treatment for excessive alcohol consumption.

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Evaluation of health-related quality of life in gastroesophageal reflux disease patients before and after treatment with pantoprazole.

Gastrooesophageal reflux disease (GERD) is highly prevalent in the Western world but its true population prevalence is difficult to estimate without a validated instrument to detect it. The evaluation of health-related quality of life (HRQoL) is an useful tool in this assessment. The aims of this study are to translate and validate a GERD specific HRQoL questionnaire and evaluate HRQoL in a Brazilian population before and after GERD treatment. GERD patients with typical symptoms and Los Angeles Classes A to C esophagitis were included in the study. Two HRQoL questionnaires and upper digestive endoscopy were performed before and after 6 weeks treatment with pantoprazole 40 mg/day followed by 80 mg/day for another 8 weeks if healing did not occur. A generic (SF-36) and one disease-specific questionnaire (GERD score) were used. The latter was translated and validated for Brazilian Portuguese. From January 2002 to December 2003, 100 patients were enrolled. Of these, 78 patients were evaluated in a per protocol analysis (35 men, mean age: 40 years). The translated questionnaire (Brazilian GERD Score, BGERDS) demonstrated adequate psychometric properties (validity, responsiveness and reliability). SF-36 and BGERDS domains significantly improved after treatment (P < 0.01 and P < 0.001 respectively). The BGERDS was shown to be valid and reliable. Patients with esophagitis showed an impaired HRQoL that improved or normalized after treatment with pantoprazole.

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Radioiodine therapy and Graves' disease - Myths and reality.

Autoimmune reactions in Graves' disease (GD) occur not only in the thyroid gland, but also in the orbital connective tissue, eyelids, extraocular muscles. The occurrence of orbitopathy in the course of GD is influenced by environmental factors, e.g. cigarette smoking. The aim of the study was to analyze the effect of cigarette smoking on the efficacy of activity of radioiodine(131I) therapy in patients with GD. We also studied the influence of cigarette smoking and the efficacy of prednisone prophylaxis on the risk of thyroid-associated ophthalmopathy (TAO) development after radioiodine therapy (RIT) during two years of follow-up. Medical records of hyperthyroid patients treated with radioiodine had been included. Patients were scheduled to visit outpatient clinics at baseline and 1, 3, 6, 9, 12, 18, and 24 months after RIT. The studied group consisted of 336 patients (274 women, 62 men) diagnosed with GD and treated with RIT; 130 patients received second therapeutic dose of 131I due to recurrent hyperthyroidism. Among all studied patients, 220 (65.5%) were smokers and 116 (34.5%) non-smokers. In the group of smokers 115 (52.2%) of patients received single RIT, 105 (47.8%) received second dose of RAI due to recurrent hyperthyroidism. In non-smokers 91 (78.6%) received single activity of RAI, while 25 (21.4%) patients required second RIT due to recurrent hyperthyroidism. The ophthalmic symptoms in the group of smokers after RIT were less frequent, if the patient received preventative treatment in the form of oral prednisone (P = 0.0088). The results of our study suggest that cigarette smoking reduces the efficacy of treatment with 131I in patients with GD. The study also confirmed the effectiveness of steroid prophylaxis against TAO development or exacerbation after RIT.

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Treatment of hypercholesterolemia and combined hyperlipidemia with simvastatin and gemfibrozil in patients with NIDDM. A multicenter comparison study.

To compare the lipid-lowering efficacies of simvastatin and gemfibrozil in NIDDM patients with combined (mixed) hyperlipidemia (CHL) or isolated hypercholesterolemia (IHC). Patients with primary dyslipidemia and NIDDM were recruited for this double-blind, double-dummy comparison study from 10 Finnish centers. After a 4-week placebo run-in period, they were randomly assigned to simvastatin or gemfibrozil. The simvastatin group (n = 47) received 10 mg once nightly for 8 weeks, 20 mg for the next 8 weeks, and 40 mg for the third 8-week period. The gemfibrozil group (n = 49) received 600 mg twice daily throughout the 24 weeks. The lipid-lowering efficacies of both drugs were compared in all patients as well as separately in patients with CHL and IHC. In all patients, simvastatin reduced LDL and total cholesterol and the LDL-to-HDL cholesterol ratio more effectively, whereas gemfibrozil was more effective in elevating HDL cholesterol and decreasing triglyceride levels. The drug effects differed according to lipid phenotype at baseline. Simvastatin decreased LDL cholesterol levels by 30-40% in both phenotypes. Gemfibrozil caused a 15% reduction in LDL cholesterol in IHC but no change in CHL patients. Simvastatin produced 15-30% reductions in triglyceride levels in CHL but no change in IHC patients. Gemfibrozil caused reductions in triglycerides in CHL (50% and more) and in IHC (40%) patients, with 12-18% increases in HDL cholesterol in these groups. Simvastatin is useful in both CHL and IHC patients, whereas gemfibrozil can be used in patients with high triglyceride and low or normal LDL cholesterol levels.

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Effectiveness and Adherence to Treatment with Perindopril/Indapamide/Amlodipine Single-Pill Combination in a Greek Population with Hypertension.

Despite the overwhelming evidence and the established benefits of antihypertensive treatment, adherence to treatment remains low. To assess the adherence to treatment with a perindopril/indapamide/amlodipine single-pill combination (SPC), its effectiveness on blood pressure (BP) reduction, as well as the safety and tolerability of this SPC over a 4-month treatment period. This multicenter, non-interventional study prospectively included 2285 hypertensive patients on perindopril/indapamide/amlodipine SPC. The data were recorded at baseline, 1 month, and 4 months. Of the 2285 hypertensive patients included in the study, 50.5% were at "high/very high risk". Mean systolic (SBP)/diastolic (DBP) decreased from 162.3 ± 13.3/93.1 ± 9.3 mmHg at baseline to 129.7 ± 8.3/78.6 ± 7.1 mmHg at 4 months (p < 0.001). Patients with higher baseline BP levels showed greater BP reduction. Patients with hypertension stages 1, 2, and 3 showed mean SBP/DBP reductions of 21.5/10.4 mmHg, 34.2/14.7 mmHg, and 51.2/22.5 mmHg, respectively, at study end (p < 0.001). Only 26 patients (1.1%) prematurely discontinued treatment (0.58% due to an adverse reaction or event). Perindopril/indapamide/amlodipine SPC decreased BP levels rapidly and significantly. The degree of BP reduction was associated with the severity of hypertension and/or with total cardiovascular risk at baseline. Simplifying the drug regimen by using this SPC improved adherence and showed excellent tolerability.

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[Effect of metformin on colorectal carcinoma in type 2 diabetes mellitus patients: a Markov model analysis].

To evaluate the colorectal cancer (CRC) prevention effect of metformin in comparison with that of other T2DM medications from a Markov model perspective. Literature concerning CRC morbidity of T2DM patients with metformin or other diabetes medications treatment was reviewed in PubMed and Cochrane Library database from September 2010 to December 2016. (1)enrolled population was adult patients with T2DM but without CRC; (2) any of the parameters applied in our model was reported; (3) randomized clinical trials (RCTs), quasi-randomized trials, prospective or retrospective cohort studies. With CRC morbidity as endpoint, parameters were extracted to construct Markov model to assess CRC morbidity and cumulative tumor-free survival in each group over 11 years' follow-up period. Finally, Monte Carlo analysis was performed to evaluate the influence of parameter instability on the model. Seven literatures were recruited and 10 000 patients were virtually allocated for each arm. In contrast with non-metformin group, T2DM patients treated with metformin had a lower rate of CRC(1.670% vs. 2.146%, P=0.016). Moreover, cumulative tumor-free survival of metformin group was, slightly but significantly, better than that of non-metformin group (10.908 years vs. 10.882 years, P=0.000). T2DM patients treated with metformin have a lower morbidity of CRC and a better cumulative tumor-free survival than those of non-metformin group. Large scale RCTs are needed to illustrate the role of metformin in the prevention of CRC.

Train

Prazosin once or twice daily?

In 20 patients with long-standing essential hypertension, a comparison was made in a randomized cross-over study of the effect of once and twice daily prazosin administration on blood pressure levels. Concurrent medication (beta-blocker and/or saluretic once daily) remained constant throughout the study. Blood pressure measurements were carried out by a nurse using a Hawksley random zero sphygmomanometer, both in the clinic and at home, and using a Roche Kontron Arteriosonde SR-2 at home. Observations made in the morning and in the evening showed no significant difference in blood pressure between the once and twice daily treatments. Eight patients complained of dizziness and faintness half an hour after taking the once daily dose. However, they felt quite well on the twice daily regimen. The mean daily dose in these 8 patients was prazosin 8.4 mg, range 6-12 mg. No indication was found that the subjective adverse side effects were correlated with the serum prazosin level. The complaints noted may possibly be overcome by taking the once daily dose late in the evening, just before retiring. Better still, the development of a slow-release formulation for daily dosages of 6 mg and over is suggested.

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A feasibility study of the safety and efficacy of a combined clopidogrel and aspirin regimen following off-pump coronary artery bypass grafting.

Effective antiplatelet therapy may decrease the risk of complications following off-pump coronary artery bypass surgery (CABG). We prospectively evaluated the safety and early efficacy of a combined regimen of clopidogrel and aspirin starting immediately after off-pump CABG. One hundred thirty-five consecutive off-pump CABG patients received clopidogrel (75 mg/day) and aspirin (325 mg/day) orally or initially through a nasogastric tube for 3 months, commencing within 6 hours of surgery. Additionally, heparin (10,000 IU/day) was given subcutaneously during the first 4 postoperative days. Clinical events, including death, myocardial infarction (MI), reintervention, angiographically documented graft occlusion, stroke, pulmonary embolism (PE), deep vein thrombosis (DVT), and hemorrhagic events, were recorded. All patients were followed up for 3 months. Thirteen of 135 off-pump CABG patients had treatment discontinued before discharge because of refractory atrial fibrillation requiring warfarin sodium (Coumadin) (6 patients), gastrointestinal bleeding (1 patient), DVT (1 patient), PE (1 patient), and death (4 patients). The remaining patients were followed up for 3 months. At 1 month, the incidences of the following events were: 3.0% cerebrovascular accidents (3 strokes and 1 transient ischemic attack), 3.0% MI, 0.7% DVT, and 0.7% hemothorax. At 3 months, no additional events had occurred except for 1 patient developing DVT and 2 additional patients developing MI. Coronary angiography was indicated in these last 2 patients. All grafts were found to be patent. However, a native vessel required percutaneous intervention (stenting) in one of these patients. Early administration of a combined regimen of clopidogrel and aspirin following off-pump CABG is safe and is associated with a relatively low incidence of major adverse cardiac events, bleeding, PE, and DVT. Consequently, its routine administration after off-pump CABG is recommended.

Train

[Children orbital floor fracture: retrospective study, about 34 cases].

Orbital fractures represent 30 % of children facial fractures. Nausea and vomiting are more predictive of entrapment than local trauma stigmatisms. Entrapment and diplopia are more frequent in adults. Delay for surgery is unclear in literature varying from 6 hours to days. The aim of this study is to summarise the aspects of orbital floor fractures in children with regard to clinical and radiological presentation, management, and outcomes. We conducted a retrospective study including 34 children presenting isolated orbital floor fracture. Clinical, radiological, ophthalmological, surgical data and outcomes were analyzed. Mean age was 9.4 years. In 15% of cases, no local stigmatism of trauma was present. Entrapment fracture was the most frequent, with 81% of fat or muscles entrapment. In all, 27% of the patient had residual diplopia. Residual diplopia developed after trap-door fracture with muscle entrapment and a more than 24 hours delay for surgery. Trap-door fracture is frequent in childhood population. Clinical diagnosis can be difficult. However, surgical treatment should be considered before 24 hours to avoid complication as residual diplopia.

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In vitro dissolution and in vivo gamma scintigraphic evaluation of press-coated salbutamol sulfate tablets.

The aim of this study was to investigate the in vitro and in vivo performance of salbutamol sulfate press-coated tablets for delayed release. The in vitro release behavior of press-coated tablets with the outer layer of PEG 6000/ Eudragit S100 blends (2:1) in pH 1.2 (0.1 mol L-1 HCl) and then pH 6.8 buffer solution was examined. Morphological change of the press-coated tablet during in vitro release was recorded with a digital camera. Release of salbutamol sulfate from press-coated tablets was less than 5 % before 3 h and was completed after 8 h in pH 6.8 phosphate buffer solution. In vivo gamma scintigraphy study carried out on healthy men indicated that the designed system released the drug in lower parts of the GI tract after a lag time of 5 hours. The results showed the capability of the system of achieving delayed release of the drug in both in vitro and in vivo gamma scintigraphy studies.

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Liver injury correlates with biomarkers of autoimmunity and disease activity and represents an organ system involvement in patients with systemic lupus erythematosus.

Liver disease (LD), defined as ≥ 2-fold elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT), was examined in a longitudinal study of systemic lupus erythematosus (SLE) patients. Among 435 patients, 90 (20.7%) had LD with a greater prevalence in males (15/39; 38.5%) than females (75/396; 18.9%; p = 0.01). SLE disease activity index (SLEDAI) was greater in LD patients (7.8 ± 0.7) relative to those without (5.8 ± 0.3; p = 0.0025). Anti-smooth muscle antibodies, anti-DNA antibodies, hypocomplementemia, proteinuria, leucopenia, thrombocytopenia, and anti-phospholipid syndrome were increased in LD. An absence of LD was noted in patients receiving rapamycin relative to azathioprine, cyclosporine A, or cyclophosphamide. An absence of LD was also noted in patients treated with N-acetylcysteine. LFTs were normalized and SLEDAI was diminished with increased prednisone use in 76/90 LD patients over 12.1 ± 2.6 months. Thus, LD is attributed to autoimmunity and disease activity, it responds to prednisone, and it is potentially preventable by rapamycin or N-acetylcysteine treatment.

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Torasemide in the treatment of arterial hypertension.

An important role for diuretics in the treatment of hypertension is assured on the basis of the latest randomized, prospective trials. Although thiazide diuretics have been the mainstay of treatment thus far, they continue to engender debate because of putative, undesirable side effects. Older loop diuretics, such as furosemide, did not establish themselves in the treatment of essential hypertension because of an inferior efficacy profile compared with that of thiazides. Torasemide is a new loop diuretic that is efficacious at low once-daily doses in the treatment of essential hypertension. The drug compares favorably with hydrochlorothiazide and indapamide. Its mechanism of action may not be entirely based on elimination of salt and water from the body. Torasemide exhibits a favorable side-effect profile, particularly because it does not engender hypokalemia, increases in blood sugar, or serum lipid values. When the additional costs of potassium supplements or potassium-retaining medication are considered, torasemide treatment also compares favorably in terms of health-care economics. Torasemide represents a reasonable alternative to conventional diuretic management in patients with essential hypertension.

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Fluoxetine treatment of acral lick dermatitis in dogs: a placebo-controlled randomized double blind trial.

The aim of the study was to assess the efficacy and tolerability of fluoxetine treatment of acral lick dermatitis (ALD) in dogs and to investigate ALD as an animal model of obsessive-compulsive disorder (OCD). Sixty-three dogs with ALD were treated with fluoxetine 20 mg daily, or placebo, for 6 weeks. In the fluoxetine group, owners rated both appearance of the lesion (t = 10.2, df = 29, P < 0.0001) and licking behavior (t = 10.2, df = 29, P < 0.0001) as significantly improved by the end of the trial. Veterinarian-rated pre- and post-treatment photographs showed statistically significant improvement in the fluoxetine group (mean = 2.55). There were no significant changes in the placebo group as rated by owners and veterinarians. These results demonstrate the efficacy of fluoxetine in the treatment of ALD and lend further support to ALD as an animal model of OCD.

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Comparative effectiveness of add-on therapy with newer-generation antiepileptic drugs in Bulgarian patients with refractory epilepsy.

The objective of this study is to perform an open, prospective study on various aspects of comparative effectiveness of newer-generation antiepileptic drugs as add-on therapy in Bulgarian patients with drug-resistant epilepsy. The study was performed with the participation of 1259 patients with epilepsy who attended the Clinic of Neurology at the University Hospital in Plovdiv, Bulgaria for regular visits and completed diaries about seizure frequency, severity, and adverse events. Oxcarbazepine was used in 82 patients, topiramate in 120 patients, lamotrigine in 73 patients, levetiracetam in 135 patients, pregabalin in 47 patients, tiagabine in 43 patients, gabapentin in 18 patients, lacosamide in 12 patients, and retigabine in 6 patients. During the first 24 months of study, improvement of seizure severity and frequency was most frequent in patients on treatment with pregabalin and levetiracetam and rarest in those on treatment with oxcarbazepine. The retention rate of patients on pregabalin and tiagabine was significantly lower compared to the retention rate of patients on most of the other antiepileptic drugs. The frequency of adverse events was higher in patients on treatment with tiagabine and pregabalin. Despite some similar characteristics of newer-generation antiepileptic drugs' effectiveness, levetiracetam stands out with better dynamic improvement of seizure severity and frequency and satisfactory tolerability; typical for pregabalin is a very good dynamic improvement of seizure severity and frequency mainly in patients with focal seizures, but a lower tolerability, and the main advantage of oxcarbazepine is a good tolerability, efficacy, however, is less satisfactory.

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Oral premedication in children: a comparison of chloral hydrate, diazepam, alprazolam, midazolam and placebo for day surgery.

A double-blind study consisting of 339 randomly selected children investigated the effects of several premedicants on the preoperative and postoperative behaviour of children who underwent day-stay surgery. Patients were allocated into two groups. Group 1 consisted of 165 children aged between 6 and 47 months. Group 2 consisted of 174 children aged four years and older to a body weight of 50 kg. Each child received one premedicant. Both groups included alprazolam 0.005 mg/kg, midazolam 0.3 mg/kg and placebo. In addition Group 1 included chloral hydrate 40 mg/kg and Group 2 diazepam 0.25 mg/kg. Chloral hydrate produced superior conditions (more patients calm or asleep) at induction of anaesthesia. Postoperative behaviour and incidence of vomiting were similar for all drugs. No premedicant reduced anxiety in the older group. The time to awaken postoperatively with diazepam was longer than with placebo. Alprazolam and midazolam were unpalatable for children over four years and conferred no advantage over placebo.

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Clinical toxicology of citalopram after acute intoxication with the sole drug or in combination with other drugs: overview of 26 cases.

There is discussion concerning the cardiac safety of citalopram in an overdose. The aim of this study was to investigate the toxic effects and toxicokinetic parameters of citalopram in an overdose as a single drug and in combination with other drugs. Cases observed between 1997 and 2006 were evaluated. Patient demographics, ingested doses, serum concentrations of citalopram, coingested drugs, and clinical parameters were acquired. Outcomes were observed symptoms of the gastrointestinal tract, respiratory tract, central nervous system, and cardiovascular system. Poisoning Severity Score was used to evaluate severity of every intoxicated patient. Individual toxicokinetic parameter values were calculated. Twenty-nine cases of citalopram overdose were observed; three cases had incomplete data so that 26 cases were evaluable. The ingested amount ranged from 200 to 4960 mg. Blood concentrations ranged from 0.21 to 7.5 mg/L with 20 minutes to 8 hours between suggested time of ingestion and blood sampling. Most frequently reported symptoms were drowsiness (seven cases), tachycardia (15 cases), QTc prolongation (eight cases), decrease of consciousness (eight cases), and seizures (four cases). Median length of hospital stay was 3 days (range, 1-8 days). Of the 26 evaluated cases, two fatalities occurred, one because of a cardiac arrest and one as a result of a respiratory arrest. According to Poisoning Severity Score, severity of intoxication was minor in three patients (11%), moderate in nine patients (35%), and severe in 14 patients (54%). Severity was mainly caused by neurologic and respiratory effects. Elimination half-life was prolonged but did not correlate with the amount of ingestion. Citalopram intoxications seem to proceed more severely than is known for other selective serotonin reuptake inhibitor intoxications, causing drowsiness, coma, and seizures in overdose. Cardiac toxicity is generally mild. Therefore, we recommend seizure precautions and intensive care unit admission with cardiac monitoring for citalopram-intoxicated patients. Because elimination half-life is prolonged, normal pharmacokinetics do not apply.

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Determinants of mycophenolic acid levels after renal transplantation.

There are data suggesting an association between mycophenolic acid (MPA) levels and acute rejection and toxicity in renal transplant recipients treated with mycophenolate mofetil (MMF), and therefore, knowledge of factors determining MPA levels may aid in accurate adjustment of MMF dosage. A total of 4970 samples taken 12 hours postdose were analyzed for MPA by immunoassay at regular intervals from the first week posttransplantation in 117 renal transplant patients immunosuppressed with MMF and tacrolimus in a steroid-sparing regimen (prednisolone for the first 7 days only). MPA levels rose in the first 3 months and stabilized thereafter; dose-normalized MPA levels rose throughout the first 12 months and subsequently stabilized. Multivariate analysis by means of a population-averaged linear regression showed positive associations between MPA level and total daily dose (P < 0.001) but not individual dose or total daily dose corrected for body weight. Positive associations were also seen with serum albumin (P = 0.01), tacrolimus trough level (P = 0.01), and female gender (P = 0.002). The association with tacrolimus levels diminished with time. Negative associations were seen between MPA level and higher estimated creatinine clearance (P < 0.001), and also with increasing alanine transaminase levels (P = 0.002), the use of oral antibiotics (P < 0.001), and infective diarrhea (P < 0.001). The latter findings may be related to changes in enterohepatic recirculation of MPA. Many clinical variables show associations with trough MPA levels. An understanding of these factors may aid therapeutic monitoring of MMF.

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[Primary diffuse large B-cell lymphoma of testis: a clinicopathologic study of 14 cases].

To study the clinicopathologic features, immunohistochemical findings and prognosis of primary diffuse large B-cell lymphoma (DLBCL) of testis. Fourteen cases of primary DLBCL of testis, diagnosed according to the 2001 World Health Organization staging standards for hematopoietic and lymphoid tumors, were retrospectively studied. Immunohistochemical study was performed and follow-up information analyzed. The median age of the patients was 62 years. There were 10 patients in stage I, 3 in stage II and 1 in stage IV. Follow-up information was available in 11 patients (78.6%). Three of which were still alive and eight died (with duration of survival ranging from 5 to 19 months). The patients usually presented with unilateral painless enlargement of testis. Histologically, the lymphoma cells of all cases showed a centroblastic appearance. One case belonged to the germinal center B cell-like subtype on immunohistochemical study, while the remaining 13 cases were classified as non-germinal center B cell-like subtype. Ten of the 14 cases (71.4%) showed overexpression of p53 protein. Most cases demonstrated high proliferation index. Six of the 14 cases (42.9%) were positive for bcl-2 protein. The overall 1-year, 2-year and 5-year survival rates were 45.5%, 17.0% and 17.0%, respectively. Most cases with primary DLBCL of testis were of peripheral activated B-cell origin. The prognosis is usually not favorable, with propensity of local relapse and systemic dissemination. Accurate pathologic diagnosis relies on detailed histologic examination and immunohistochemical study.

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Time course of serum Lp(a) in men after coronary artery bypass grafting.

The serum Lp(a) time course was studied in 100 male patients who underwent coronary artery bypass grafting (CABG). The patients were randomized in a placebo (N = 50) and pravastatin treated (N = 50) group. The pravastatin regimen was 10 mg daily from the third postoperative day on and 20 mg daily after 1 week during 11 weeks. Lp(a) levels and serum lipids were analyzed at baseline, at 3 and 10 days, and at 4 and 12 weeks post-CABG. A decrease of serum Lp(a) levels at the third postoperative day was seen which parallels the changes noted with the other serum lipids when using extracorporeal circulation. In contrast with the other serum lipids, a slight but significant Lp(a) overshooting was noticed at day 10 followed by a decrease of the serum Lp(a) levels to preoperative levels 1 month after the acute event. The study clearly depicts that there is a significant time-dependent effect on the serum Lp(a) levels post-CABG and that there is no effect of treatment (pravastatin). The data also reveal that reliable postoperative Lp(a) measurements can be made at earliest 1 month post-CABG.

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Prevention of relapse of reflux oesophagitis after endoscopic healing: the efficacy and safety of omeprazole compared with ranitidine.

The prognosis for the acute healing of patients with persistent, erosive or ulcerative reflux oesophagitis depends upon the choice of drug treatment as well as the severity of the initial oesophagitis. The results of this study show that omeprazole, 40 mg once daily (n = 51), is more effective than ranitidine, 300 mg b.i.d. (n = 47), in the acute healing of reflux oesophagitis (90 and 47% healing, respectively; p less than 0.0001). Omeprazole, 20 mg o.m., is also far more effective than ranitidine, 150 mg b.i.d., in the maintenance treatment of these patients; 67% of the omeprazole-treated patients remained in clinical and endoscopic remission throughout the 12-month study period compared with only 10% of those given ranitidine (p less than 0.0001). This therapeutic advantage was achieved without adverse events and without significant abnormalities in the endocrine or exocrine cell population of the oxyntic mucosa. Basal serum gastrin levels were modestly raised after 4 weeks of omeprazole treatment (the change being from 8.6 to 16.9 pmol/l; p less than 0.05), and remained at this level throughout the study period.

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Treatment results of three consecutive Brazilian cooperative childhood ALL protocols: GBTLI-80, GBTLI-82 and -85. ALL Brazilian Group.

The Brazilian Cooperative Group for Treatment of Childhood Acute Lymphocytic Leukemia (GBTLI) has started clinical activities trials in 1980. Three consecutive multicenter studies in children with unprevious treated ALL have been completed including 994 patients. The first GBTLI-80 accrued 203 children from 1980 to 1982. It was delineated with the standard three drugs induction therapy, CNS protection for all pts comprised cranial irradiation and intrathecal Methotrexate. For low risk pts cranial irradiation with 18Gy was compared in a randomized trial with 24Gy. Maintenance therapy continued for 120 weeks. The 12 years of the event free survival rates for all risk groups is 50% (SD 5%). Regarding CNS relapses there was no significant statistical difference between pts that received 18 or 24Gy. The treatment strategy of GBTLI-82 (n = 360) from 1982 to 1985, consisted of the same previous induction, consolidation, CNS therapy with cranial irradiation 18 Gy (low risk) or 24Gy (high risk), followed by continuous maintenance for 2 years. The main question in this study was the comparison between sequential rotation or pulses of 3 pairs of drugs during maintenance. At a median follow-up of 10 years, the overall event free survival rates for all children is 58% (SD 4%). There was no significant difference between the two maintenance regimens. The successor GBTLI-85 ran from 1985 to 1988 and registered 431 pts. For the first time no cranial radiation was given to children with very good prognosis. For them, CNS protection was done with triple intrathecal therapy during all treatment. A consolidation therapy with high dose ARA-C was introduced for high risk pts and infants The 6.5 years event free survival for all children is 70% (SD 4%). Significant better results were achieved for high risk and infants pts (EFS 50%). Early intensification therapy and rotational combination chemotherapy improved the outcome in childhood ALL in Brazil.

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[Comparison of pantoprazole and omeprazole-based triple therapy regimens in the treatment of Helicobacter pylori infection].

To compare the efficacies of pantoprazole and omeprazole-based triple regimens in the treatment of H. pylori infection for 1-week or 2-week. 147 patients with H. pylori associated gastritis were randomly divided into pantoprazole triple regimen group (pantoprazole 40 mg, amoxicillin 1 g, and metronidazole 400 mg, bid,for 1-week or 2-weeks) and omeprazole triple regimen (omeprazole 20 mg, amoxicillin 1 g, and metronidazole 400 mg, bid, for 1-week or 2-weeks). The eradication was determined by (13)C-UBT at least 4 weeks after antibiotic therapy. The eradication rate of H. pylori for 1-week pantoprazole triple regimen and omeprazole triple regimen were 85.7% (42/49) and 76.9% (20/26) respectively (P > 0.05). The eradication rates of H. pylori for 2-weeks and pantoprazole triple regimen and omeprazole triple regimen were 93.9% (31/33) and 82.1% (32/39) for 2-week respectively (P > 0.05). The eradication rate of H. pylori in pantoprazole (or omerazole) triple therapy regimen for 2-weeks was higher than 1-week. However there were no significant difference between in these two groups (P > 0.05). There were no significant difference between pantoprazole and omeprazole triple therapy regimen in eradication rate of H. pylori for 1-week or 2-weeks (P > 0.05).

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Immune cell response to strenuous resistive breathing: comparison with whole body exercise and the effects of antioxidants.

Whole body exercise (WBE) changes lymphocyte subset percentages in peripheral blood. Resistive breathing, a hallmark of diseases of airway obstruction, is a form of exercise for the inspiratory muscles. Strenuous muscle contractions induce oxidative stress that may mediate immune alterations following exercise. We hypothesized that inspiratory resistive breathing (IRB) alters peripheral blood lymphocyte subsets and that oxidative stress mediates lymphocyte subpopulation alterations following both WBE and IRB. Six healthy nonathletes performed two WBE and two IRB sessions for 45 minutes at 70% of VO₂ maximum and 70% of maximum inspiratory pressure (Pi_max), respectively, before and after the administration of antioxidants (vitamins E, A, and C for 75 days, allopurinol for 30 days, and N-acetylcysteine for 3 days). Blood was drawn at baseline, at the end of each session, and 2 hours into recovery. Lymphocyte subsets were determined by flow cytometry. Before antioxidant supplementation at both WBE end and IRB end, the natural killer cell percentage increased, the T helper cell (CD3+ CD4+) percentage was reduced, and the CD4/CD8 ratio was depressed, a response which was abolished by antioxidants only after IRB. Furthermore, at IRB end, antioxidants promoted CD8+ CD38+ and blunted cytotoxic T-cell percentage increase. CD8+ CD45RA+ cell percentage changes were blunted after antioxidant supplementation in both WBE and IRB. We conclude that IRB produces (as WBE) changes in peripheral blood lymphocyte subsets and that oxidative stress is a major stimulus predominantly for IRB-induced lymphocyte subset alterations.

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The use of amphetamines in U.S. Air Force tactical operations during Desert Shield and Storm.

Today's battleground requires round-the-clock air support. Modern aircraft systems enable tactical aircraft to be flown in all weather conditions, day or night, and for prolonged periods. U.S. Air Force Tactical Air Command (TAC) aircrew who deployed to the Southwest Asia Area of Responsibility (SWA AOR) for Operation Desert Shield/Desert Storm were retrospectively surveyed to determine the extent and effectiveness of dextroamphetamine use in support of sustained flying operations. Surveys were sent in May 1991 to each tactical squadron that participated in Desert Storm. Of pilots who were surveyed, 65% used amphetamines during the deployment to the SWA AOR and/or during Operation Desert Storm. Pilots who used amphetamines in air operations described it as "occasional." The most frequent indications for amphetamine use were "aircrew fatigue" and "mission type." Of pilots who used amphetamines, 58-61% considered their use beneficial or essential to operations. Dextroamphetamine (5 mg every 4 h) was used effectively and without major side effects in tactical flying operations. Amphetamine use enhanced cockpit performance and flight safety by reducing the effect of fatigue during critical stages of flight.

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Thioredoxin-1 as a biological predictive marker for selecting diffuse large B-cell lymphoma patients for etoposide-containing treatment.

In diffuse large B-cell lymphoma (DLBCL), there is an unmet medical need to select patients who would benefit from intensified frontline treatments such as adding etoposide to an R-CHOP regimen. The present work included a retrospective clinical analysis of two patient cohorts and an in vitro study. Primary biopsy samples from DLBCL patients treated with an etoposide-containing high-dose regimen (n = 37) and etoposide-containing frontline treatment (n = 69, R-CHOEP) were studied using immunohistochemical thioredoxin-1 (Trx1) staining. Two DLBCL cell lines expressing Trx1 were cultured, and their expression was silenced using the small interfering RNA knockdown technique. Chemoresistance was tested with doxorubicin, etoposide, vincristine, prednisolone and carboplatin. Thioredoxin-1 knockdown sensitised DLBCL cells to doxorubicin (P < .0001) but decreased etoposide-induced cell death (P < .00001). In DLBCL patients who received etoposide-containing frontline treatment, low cytoplasmic Trx1 expression was associated with inferior 5-year overall survival (46% vs 76%, P = .026) and disease-specific survival (68% vs 90%, P = .026). Strong Trx1 expression appears to increase drug resistance to doxorubicin but sensitises cells to etoposide. This implies that Trx1 expression might be the first predictive biological marker to select the patients who might benefit from adding etoposide to R-CHOP immunochemotherapy.

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Dose-finding study of landiolol hydrochloride: a short-acting β1-blocker for controlling heart rate during coronary computed-tomography angiography in Japan.

Coronary computed-tomography angiography (CCTA) has high diagnostic performance, but it sometimes does not allow evaluation because of artifacts. Currently, the use of a β-blocker is recommended to prevent motion artifacts, but the β-blocker (metoprolol, propranolol, etc.) commonly used has a slow onset and long duration of action. Landiolol hydrochloride is an intravenous β1-blocker with a very short half-life. We investigated the efficacy and optimal dose of this drug for reduction of heart rate in patients undergoing CCTA. Eighty-seven subjects with ischemic heart disease were divided into three groups to receive landiolol hydrochloride at a dose of 0.125 (Group L), 0.25 (Group M), or 0.5 mg/kg (Group H). CCTA was performed at 3-7 min after administration, and heart rate, blood pressure, and image quality were assessed. Heart rate decreased rapidly after completion of landiolol hydrochloride administration in all groups, with a heart rate reduction of 15.55 ± 6.56% in Group L, 16.48 ± 7.80% in Group M, and 21.49 ± 6.13% in Group H (Group L vs Group H, P = 0.0008; Group M vs Group H, P = 0.0109). Since there was no significant difference in heart rate during imaging among the three groups, although there was a significant difference between groups L and H and groups M and H in terms of percent change in heart rate, coronary stenosis was diagnosable in all groups with no significant difference. Landiolol hydrochloride showed a rapid onset and short β-blocking effect, and was most effective at a dose of 0.5 mg/kg. However, the diagnosable proportion had no significant differences among the three groups in CCTA. Therefore, the clinically recommended dose was 0.125 mg/kg or less, considering the heart rate of patients with suspected coronary stenosis during CCTA.

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Liquid chromatography/tandem mass spectrometry for the determination of fluoxetine and its main active metabolite norfluoxetine in human plasma with deuterated fluoxetine as internal standard.

Fluoxetine (F) and its N-demehylated metabolite norfluoxetine (NF) are selective inhibitors of serotonin reuptake in humans. A new sensitive rapid method for the simultaneous determination of F and NF in plasma was established and validated, and was further applied to assess the bioequivalence of two oral formulations of F in 22 healthy Chinese male volunteers who received a single oral dose of each formulation (containing 20 mg of fluoxetine hydrochloride). The new method involves using liquid chromatography/tandem mass spectrometry (LC/MS/MS) in multiple reaction monitoring mode with deuterated fluoxetine (DF) as internal standard. High levels of analytical sensitivity and specificity of MS/MS detection enabled use of a simple liquid-liquid extraction procedure. The combination of a simple sample clean-up procedure and short chromatographic run-time (5 min) considerably increased the productivity of the analytical method. The method was validated for the plasma concentration range 0.27-22 ng/mL for both of the test compounds, and the calibration curves were linear with coefficients of correlation >0.999. The limit of detection was 0.1 ng/mL for plasma F and NF. Taking the plasma sample size (200 micro L) into account the new method for determination of F and NF is more sensitive than those described previously.

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Fascia Iliaca Block Decreases Hip Fracture Postoperative Opioid Consumption: A Prospective Randomized Controlled Trial.

To determine the efficacy of a preoperative fascia iliaca compartment block in decreasing postoperative pain and improving functional recovery after hip fracture surgery. Randomized prospective Level 1 therapeutic. Academic Level 1 trauma center. Geriatric patients with fractures of the proximal femur (neck, intertrochanteric, or subtrochanteric regions) were prospectively randomized into an experimental (A) or control (B) groups. Forty-seven patients met inclusion criteria, 23 randomized to the experimental group and 24 to the control group. Patients randomized to the experimental group received an ultrasound-guided fascia iliaca compartment block administered by a board-certified anesthesiologist immediately before the initiation of anesthesia. Primary outcome measure was postoperative pain medication consumption until postoperative day 3. Secondary outcomes included functional recovery and a study-specific patient-reported satisfaction survey assessed on postoperative day 3. There was no significant difference in consumption of acetaminophen for mild pain, tramadol for moderate pain, or functional recovery between the 2 groups. There was a statistically significant decrease in morphine consumption (0.4 mg vs. 19.4 mg, P = 0.05) and increase in patient-reported satisfaction (31%, P = 0.01). Preoperative fascia iliaca compartment block significantly decreases postoperative opioid consumption while improving patient satisfaction. We recommend the integration of this safe and efficacious modality into institutional geriatric hip fracture protocols as an adjunctive pain control strategy. Therapeutic Level II See Instructions for Authors for a complete description of levels of evidence.

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Fluoxetine for motor recovery after acute intracerebral hemorrhage, the FMRICH trial.

Acute intracerebral hemorrhage (ICH) is a very common cause of disability. Previous evidence suggests that fluoxetine and other selective serotonin reuptake inhibitors improve, the recovery of motor function in patients with cerebral infarct. The purpose of this study was to investigate whether fluoxetine also improves motor recovery in patients with ICH. This is a double blind, placebo controlled, multicenter randomized trial, patients recruited from three centers were assigned to receive 20 mg/day of fluoxetine or matching placebo for three months from within ten days after onset of symptoms. Primary outcome was change in Fugl-Meyer Motor Scale from baseline to day 90. Thirty patients (50 % women) were recruited to the fluoxetine (n = 14) or placebo (n = 16) groups. Median age was 55 years, the cause of the ICH was hypertension in 93.3 %, median volume of the hematomas was 22mm³. Basal ganglia hematoma was present in 67 % and, lobar location in 20 % of the patients. Improvement in FMMS at day 90 was significatively higher in the treatment group (median score 23) than in the placebo group, (median score 48), p = 0.001. No serious adverse events occurred. In addition to standard treatment, early prescription of fluoxetine was safe and helped to increase motor recovery 90 days after ICH. This finding adds to the evidence regarding its beneficial effect upon stroke related disability. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01737541.

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Does eradication of Helicobacter pylori alone heal duodenal ulcers?

Eradication of Helicobacter pylori infection prevents duodenal ulcer (DU) relapse, but it remains uncertain whether eradication of H. pylori alone heals duodenal ulceration. To test the hypothesis that eradication of H. pylori infection is accompanied by healing of duodenal ulcer. A total of 115 consecutive patients with endoscopically confirmed H. pylori-infected duodenal ulcer were randomly assigned to one of two groups. Group BTC patients received a 1-week course of colloidal bismuth subcitrate 220 mg b.d., tinidazole 500 mg b.d., clarithromycin 250 mg b.d. Group OBTC patients received omeprazole 20 mg daily for 4 weeks with the BTC regimen during the first week. Endoscopy with antral biopsies and 13C-urea breath test (UBT) were performed before and 4 weeks after completion of the 7-day triple or quadruple therapy. Eight patients dropped out (four in BTC and four in OBTC). Duodenal ulcer healing rates on an intention-to-treat basis in BTC and OBTC were 86% (95% CI: 77-95%) and 90% (95% CI: 82-98%), respectively. The eradication rates of H. pylori on an intention-to-treat basis in BTC and OBTC were 88% (95% CI: 79-96%) and 91% (95% CI: 84-99%), respectively. There were no statistically significant differences in ulcer healing rates and eradication rates between these two groups (P > 0.05). Epigastric pain resolved more rapidly in patients assigned to OBTC compared with those assigned to BTC. Both of the two regimens were well tolerated with only minor side-effects (3% of the 115 patients) and the compliance was good. BTC is a very effective H. pylori eradication regimen. Almost all duodenal ulcers heal spontaneously after cure of H. pylori infection using a 1-week low-dose bismuth-based triple therapy. Treating duodenal ulcer with simultaneous administration of omeprazole achieves ulcer pain relief more rapidly.

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[Pharmacological treatment of post-traumatic behavioural disorders].

Literature review of the data concerning pharmacologic treatment of post-traumatic behavioural disorders. This review is limited to the treatment of agitation, excitation, mood lability, hostility and agressivity as defined by the NRS and excludes pharmacologic treatment of mental slowness, cognitive disorders and depression. Medline interrogation using keywords Traumatic Brain Injury, Agitation, Agressivity, Behaviour, Pharmacology, Neuroleptics, Benzodiazepines, Carbamazepine, Valproate, Buspirone, SSRI, Propanolol, Methylphenidate and review of recent contents. The data finally includes 29 original studies. The overall level of evidence is quite low as the data mainly consist in open studies and case reports. These data and data from reviews or didactic articles suggest the efficiency of a variety of treatments. Mood-stabilizing antiepileptics, and specially carbamazepine constitute together with SSRI antidepressants the first choices. Some data suggest efficiency of buspirone, methylphenidate and atypic neuroleptics. Lithium requires close monitoring but is probably efficient. It is difficult to conclude concerning propanolol. The available data is in favour of the use of CBZ and SSRI antidepressants. Further studies are required. It is necessary to establish clear evidence of the efficiency of CBZ and assess the effects of methylphenidate, which is almost not prescribed in France.

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Ex-vivo product performance of Diskus and Turbuhaler inhalers using inhalation profiles from patients with severe chronic obstructive pulmonary disease.

Dosing performance of dry powder inhalers is dependent on patient's inspiratory effort. This study compares the inhalation profiles generated by patients with severe obstructive lung disease using Diskus and Turbuhaler inhalers. The patient profiles are subsequently used to determine the dosing performance of fluticasone propionate Diskus and budesonide Turbuhaler inhalers. Inhalation profiles were recorded in COPD patients (FEV1 < or = 30% predicted) as they inhaled with maximal effort through the inhalers. The profiles were used in an inhalation simulator to assess the dosing performance by measuring the total emitted dose and the fine particle mass for each inhaler type. Peak inspiratory flow was significantly higher through the Diskus (mean 82.31 min(-1)) compared with Turbuhaler (mean 53.51 min(-1), difference = 28.8 l min(-1); P < 0.0001). In addition, in direct comparison of the two devices. the Diskus was shown to deliver a more consistent dose irrespective of flow than the Turbuhaler in this patient population. These findings may be of importance in optimising selection of devices for patients with severe airway obstruction.

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Benefits and risks of using clopidogrel before coronary artery bypass surgery: systematic review and meta-analysis of randomized trials and observational studies.

The benefits and risks associated with the use of clopidogrel before coronary artery bypass grafting are controversial, and these were investigated in the present meta-analysis. A systematic literature search was performed to identify studies on the use of clopidogrel before coronary artery bypass grafting. Meta-analysis was performed according to the Cochrane Handbook for Systematic Reviews. The literature search yielded 3 prospective randomized studies and 17 observational studies with valid data. Randomized studies were post hoc analyses of the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY), Clopidogrel for the Reduction of Events During Observation (CREDO), and Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events trials. Meta-analysis based on these data showed a nonsignificant reduced risk of immediate postoperative composite end point (death, myocardial infarction, or stroke) in the clopidogrel group (risk ratio [RR], 0.77; 95% confidence interval [CI], 0.58-1.04). Data from the CREDO and CLARITY trials showed a similar risk of death (RR, 0.81; 95% CI, 0.20-3.37), myocardial infarction (RR, 0.58; 95% CI, 0.25-1.33), and major bleeding according to Thrombolysis in Myocardial Infarction criteria (RR, 1.48; 95% CI, 0.72-3.04). Meta-analysis of observational studies showed that preoperative exposure to clopidogrel was associated with an increased risk of death (RR, 1.30; 95% CI, 1.02-1.67), reoperation for bleeding (RR, 1.88; 95% CI, 1.37-2.58), blood loss (mean difference, 157.8 mL; 95% CI, 61.9-253.6), need of packed red blood cell transfusion (RR, 1.23; 95% CI, 1.10-1.37), and increased use of blood products. A significantly reduced risk of postoperative myocardial infarction was observed among patients taking clopidogrel (RR, 0.63; 95% CI, 0.48-0.82). Contrary to the findings of post hoc analyses of randomized trials, observational studies showed that recent exposure to clopidogrel before coronary artery bypass grafting is associated with increased risk of postoperative death, reoperations for bleeding, blood loss, and need of blood transfusions.

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An open multicenter study to assess the long-term efficacy, tolerance, and safety of the oral angiotensin converting enzyme inhibitor ramipril in patients with mild to moderate essential hypertension.

Three hundred thirty-one patients with mild to moderate essential hypertension, 182 males and 149 females with a mean age of 54 (range, 17-87 years), were studied for 1 year in a clinical trial with ramipril, an angiotensin converting enzyme (ACE) inhibitor. The patients included had completed double-blind trials with ramipril vs. captopril, HCT, atenolol and ramipril plus piretanide. All cases were treated first with 5 mg ramipril and, where appropriate, also with 25 mg HCT. Adjustment of the dose in the range 1.25-20 mg ramipril was left to the investigator. Overall, a consistent reduction in blood pressure was achieved. Only small changes in mean blood pressure were noted during the 12 months (mean diastolic blood pressure 84.3-86.9 mm Hg, mean systolic blood pressure 145.6-148.2 mm Hg). Two hundred sixty-two (82%) of the 331 patients had diastolic values consistently equal to or lower than 95 mm Hg. There was a downward shift in the dosages upon which the investigators finally settled during the 12-month period in the patients receiving ramipril monotherapy. In patients also receiving HCT the initial dose was increased in most cases. Adverse events were observed in 6.7% of patients taking ramipril alone. The most frequent symptoms were dizziness, asthenia, pain in the upper abdomen and headache. Adverse effects occurred more frequently under continuous additional treatment with HCT, the same symptoms being reported. The clinical trial was prematurely terminated in six patients, in only two cases for medical reasons. The analysis of the laboratory findings revealed no general deterioration.(ABSTRACT TRUNCATED AT 250 WORDS)

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Prognostic impact of plasma N-terminal pro-brain natriuretic peptide in severe chronic congestive heart failure: a substudy of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial.

The utility of N-terminal proBNP (NT-proBNP) to predict the occurrence of death and hospitalization was prospectively evaluated in the COPERNICUS study, which enrolled patients with an ejection fraction <25% and symptoms of chronic congestive heart failure at rest or on minimal exertion. Baseline plasma concentrations of NT-proBNP were measured in a subgroup of 814 men and 197 women with symptoms at rest or on minimal exertion who were enrolled in the COPERNICUS study and were randomized to placebo (n=506) or carvedilol (n=505). Values of NT-proBNP were markedly increased despite the requirement that patients be euvolemic before the start of treatment (mean+/-SD, 3235+/-4392 pg/mL; median, 1767 pg/mL). By univariate Cox regression analysis, NT-proBNP was found to be a powerful predictor of subsequent all-cause mortality (relative risk [RR], 2.7; 95% CI, 1.7 to 4.3; P=0.0001 for above versus below median) and all-cause mortality or hospitalization for heart failure (RR, 2.4; 95% CI, 1.8 to 3.4; P=0.0001 for above versus below median). The predictive value of NT-proBNP was similar when both placebo and carvedilol patients were analyzed separately. No significant interaction was found between NT-proBNP and treatment group (P=0.93 for above- versus below-median NT-proBNP). NT-proBNP was consistently associated with increased risk for all-cause mortality and for all-cause mortality or hospitalization for heart failure in patients with severe congestive heart failure, even in those who were clinically euvolemic. This marker therefore may be a useful tool in risk stratification of patients with severe congestive heart failure.

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Specialty-Related Differences in the Acute-Phase Treatment and Prognosis in Patients With Acute Heart Failure　- Insights From REALITY-AHF.

The aim of this study was to assess specialty-related differences in the treatment for patients with acute heart failure (AHF) in the acute phase and subsequent prognostic differences. Methods and Results: We analyzed hospitalizations for AHF in REALITY-AHF, a multicenter prospective registry focused on very early presentation and treatment in patients with AHF. All patients were classified according to the medical specialty of the physicians responsible for contributed most to decisions regarding the initial diagnosis and treatment after the emergency department (ED) arrival. Patients initially managed by emergency physicians (n=614) or cardiologists (n=911) were analyzed. After propensity-score matching, vasodilators were used less often by emergency physicians than by cardiologists at 90 min after ED arrival (29.8% vs. 46.1%, P<0.001); this difference was also observed at 6, 24, and 48 h. Cardiologists administered furosemide earlier than emergency physicians (67 vs. 102 min, P<0.001). However, the use of inotropes, noninvasive ventilation, and endotracheal intubation were similar between groups. In-hospital mortality did not differ between patients managed by emergency physicians and those managed by cardiologists (4.1% vs. 3.8%, odds ratio 1.12; 95% confidence interval 0.58-2.14). Despite differences in initial management, no prognostic difference was observed between emergency physicians and cardiologists who performed the initial management of patients with AHF.

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Role and mechanism of AT1-AA in the pathogenesis of HELLP syndrome.

HELLP syndrome remains a leading cause of maternal and neonatal mortality and morbidity worldwide, which symptoms include hemolysis, elevated liver enzymes and low platelet count. The objective of this study was to determine whether HELLP is associated with AT1-AA. The positive rate and titer of AT1-AA in plasma from pregnant women were determined, and the correlation of AT1-AA titer with the grade of HELLP was analyzed. A HELLP rat model established by intravenous injection of AT1-AA. Our experimental results show the AT1-AA titer and positive rate were significantly higher in HELLP group, and AT1-AA titer were positively correlated with the level of TNF-α and ET-1 in plasma and the grade of HELLP syndrome. The results of animal experiments showed that the typical features of HELLP in the pregnant rats after AT1-AA injection. The levels of TNF-α and ET-1 in plasma and liver tissue were significantly increased in AT1-AA-treated rats compared with control rats. The HELLP syndrome induced by AT1-AA was attenuated markedly after administration of losartan. These data support the hypothesis that one the potential pathway that AT1-AA induce damage to capillary endothelial cells and liver during pregnancy is through activation of TNF-α and ET-1.

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Comparison of the efficacy of culture-based tailored therapy for Helicobacter pylori eradication with that of the traditional second-line rescue therapy in Korean patients: a prospective single tertiary center study.

The effectiveness of Helicobacter pylori therapies has declined with an increase in antibiotic resistance. To overcome this problem, the efficacy of tailored H. pylori eradication therapy based on antimicrobial susceptibility testing was compared with that of empirical second-line rescue regimens. Patients who had persistent H. pylori infection after the first eradication were recommended to undergo culture for determining the minimal inhibitory concentration (MIC) via gastroscopy, which increased the cost by 300%. Fourteen-day esomeprazole, tripotassium dicitrate bismuthate, metronidazole and tetracycline (EBMT) therapy or esomeprazole, moxifloxacin and amoxicillin (MEA) therapy was performed according to the results of antibiotic susceptibility testing. In case of refusal to undergo culture, the participants were treated with either 14-day empirical EBMT or MEA regimen for second eradication after explaining the complexity, side effects and costs associated with each regimen. This trial was registered at ClinicalTrials.Gov (NCT 02349685). In the 219 patients included, the intention to treat (ITT) and per protocol (PP) eradication rates was 75.3% and 79.8% in the 14-day EBMT group (n = 89), 70.8% and 72.4% in the 14-day MEA group (n = 89) and 87.8% and 100.0% in the 14-day tailored therapy group (n = 41), respectively. Based on the PP analysis, the 14-day tailored therapy group showed a significantly higher eradication rate than the 14-day EBMT or MEA group (both p ≤ 0.001). Tailored therapy based on H. pylori culture and MIC test could be an option as a second-line eradication regimen in the presence of high level of antimicrobial resistance.

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[Use of omeprazole and esomeprazole in patients suffering from bronchial asthma with associated gastroesophageal reflux disease].

The purpose of this study is a comparative assessment of the clinical efficiency of Omeprazole and Esomeprazole in patients suffering from bronchial asthma (BA) with associated gastroesophageal reflux disease (GERD). 101 patients with BA and associated GERD being under study were divided into three groups depending on the way of application of the anti-reflux therapy. Patients from the I group were administered Omeprazole--20 mg per day, patients from the II group received Omeprazole--mg per day, and patients from the III group were administered Esomeprazole--40 mg per day, the treatment courses of each group amounting to eight weeks. The clinical efficiency indices of pulmonary (CEIP) and esophageal (CEIE) symptoms were calculated when the results of the study were summed. The decrease of CEIP and CEIE against the background of the anti-reflux therapy (for example, the CEIP of patients from the III group decreased from 14.9 +/- 1.5 (before the treatment) to 2.9 +/- 0.6 points following eight weeks of treatment (p < 0.001), and the CEIE decreased from 9.0 +/- 1.2 (before the treatment) to 1.7 +/- 0.3 points following eight weeks of treatment (p < 0.001)) has demonstrated the reliable improvement of the clinical course of BA with associated GERD. We failed to discover any essential differences between the impact of Omeprazole in the dose equal to 40 mg per day and the impact of Esomeprazole in the same dose on the CEIP. Thus, the CEIP amounted to 10.1 +/- 1.2 points in the II group and 8.5 +/- 1.4 points in the III group (p > 0.05) after the fourth week of treatment. At the same time, we have discovered a reliable advantage of Esomeprazole as compared with Omeprazole for the improvement of the CEIE. The therapy of BA with associated GERD with Omeprazole in the dose equal to 40 mg per day or Esomeprazole in the dose equal to 40 mg per day contributes to the reliable improvement of both pulmonary and esophageal symptoms, and application of Esomeprazole results in a faster reduction of bronchial obstruction and gastroesophageal reflux.

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Patterns and profiles of methylphenidate use both in children and adults.

The aim of the present study was to characterize patterns of use of methylphenidate (MPH), a prescription stimulant medication recommended in the treatment of attention deficit hyperactivity disorder (ADHD) and of narcolepsy, in France, both in children and adults, over a 3-year period. Using the French General Health Insurance database, limited to two areas covering approximately 4 million individuals, we made up a cohort of incident MPH users between July 2010 and June 2013. Splitting them into distinct age groups (18-24, 25-49 and ≥50 years of age for adults and <6, 6-11 and 12-17 years of age for children), we established the characteristics of these populations at MPH initiation and during follow-up according to the duration of treatment, quantities dispensed and coprescription with central nervous system (CNS) drugs. We included a cohort of 3534 incident users, involving 30 238 dispensings of MPH, leading to an annual rate of 29 incident users per 100 000 in 2013. Children (66% of new users) were characterized by long-term use of MPH with few comedications. The group of 25-49-year-old patients were dispensed MPH more frequently than other groups, had the highest mean dose and were more often coprescribed other CNS drugs. The ≥50 year-old group was more often coprescribed antidepressants and antiparkinsonian drugs. Our pharmacoepidemiological study involving incident MPH users with a large number of characteristics showed different patterns of MPH use among children and adults. The results from the 25-49-year-old group suggested that MPH might be being used for medical conditions other than ADHD or narcolepsy in adults, and that it might be subject to misuse and/or abuse.

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Effect of inhalation of salbutamol, beclomethasone dipropionate & ipratropium bromide on mucociliary clearance in some patients with chronic stable bronchial asthma.

Asthma is now regarded as an inflammatory disease and bronchial inflammation may disrupt mucociliary function. Inhaled drugs may act by improving mucociliary function. The aim of the study was to investigate the effect of salbutamol, ipratropium bromide and beclomethasone on mucociliary clearance in patients with chronic stable asthma and to compare the efficacy of these drugs on mucociliary clearance. Ten patients with chronic stable asthma were enrolled in the study, but two patients did not complete the study. Patients with bronchial asthma were chosen on clinical grounds. (99m)Tc phytate radioaerosol generated through a nebulizer, was given to each patient on four days. After each administration the radioactivity over the thorax was constantly measured in sequential frame mode for 120 min. Radioactivity in the thorax was also measured after 24 h. A base-line pulmonary function test with reversibility was obtained. Salbutamol, ipratropium bromide, beclomethasone dipropionate and placebo inhalation were given randomly to each patient on four days. The mean age of patients (n = 8) was 36 +/- 9.3 yr and mean duration of symptoms was 5 +/- 6.6 yr. There was no visual impression that mucociliary clearance was enhanced with any of the drugs. The time activity curves did not show any visually recognisable change in slope. In only one patient the curve tended to show a steeper slope with ipratropium inhalation. In the rest of the patients the curves showed no difference at all with medication when compared with placebo. All the quantitative indices analyzed by two-way ANOVA at the end of one and two hours were comparable for the three test drugs and placebo. None of the three test drugs demonstrated statistically significant mucociliary clearance effect compared with placebo. However, the temporal difference in airways clearance efficiency (ACE) was significant with beclomethasone and ipratropium bromide. Inhalation of any of the three drugs tested did not produce any immediate improvement in mucociliary clearance as compared to placebo in patients with stable bronchial asthma suggesting the need for further studies using higher doses of drugs for longer duration in a large sample.

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Comparative evaluation of subgingivally delivered 1.2% rosuvastatin and 1% metformin gel in treatment of intrabony defects in chronic periodontitis: A randomized controlled clinical trial.

The aim of this study is to explore and compare the clinical efficacy of locally delivered 1.2% Rosuvastatin (RSV) and 1% Metformin (MF) gel as an adjunct to scaling and root planning (SRP) in the treatment of intrabony defects in chronic periodontitis patients. A total of 90 volunteers were randomly assigned to three treatment groups; 1) SRP plus placebo gel; 2) SRP plus 1.2% RSV gel; 3) SRP plus 1% MF gel. Clinical parameters like modified sulcus bleeding index (mSBI), plaque index (PI), pocket probing depth (PD) and clinical attachment level (CAL) were recorded at baseline, 6 and 12 months and the radiologic assessment of bone defect fill was performed at 6 and 12 months. mSBI, BP, PD, and CAL were improved in all the groups, however mean reductions in PD, CAL gain, and percentage of bone fill was found to be higher in RSV and MF groups than placebo group at all visits. Adjunctive use of locally delivered 1.2% RSV and 1% MF gel stimulates a significant PD reduction, CAL gains and improved bone fill when compared with placebo gel. Results were significantly better with the use of 1.2% RSV gel than 1% MF gel.

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Aspirin in Hepatocellular Carcinoma.

Preclinical and clinical studies provide evidence for aspirin as a preventative agent for cancer. Compelling direct evidence supports a chemopreventive effect of aspirin in individuals at high risk of developing colorectal cancer due to Lynch syndrome, while indirect evidence indicates that aspirin may reduce the risk of and mortality from sporadic colorectal cancer. There is weaker evidence for a protective effect of aspirin against all cancers taken as a group. Nevertheless, the results of recent retrospective cohort studies consistently indicate a beneficial effect of aspirin as a chemopreventive or adjuvant chemotherapeutic agent in hepatocellular carcinoma (HCC). Epidemiologic studies conducted in the general population or in selected populations at higher risk for HCC reveal that regular aspirin use is associated with reduced HCC incidence. In addition, aspirin may act as an adjuvant to other therapies in reducing HCC recurrence. According to studies in animal models, the cancer-preventative effect of aspirin may be related to its antiplatelet and anti-inflammatory activities. Prospective studies are warranted to determine whether aspirin should be recommended to diverse populations of patients at risk for HCC.

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Effects of metoprolol vs verapamil in patients with stable angina pectoris. The Angina Prognosis Study in Stockholm (APSIS)

To study long-term treatment effects of metoprolol or verapamil on combined cardiovascular end points and psychological variables in patients with stable angina pectoris. Randomized, double-blind, double-dummy trial. The study included 809 patients under 70 years of age with stable angina pectoris. The mean age of the patients was 59 +/- 7 years and 31% were women. Exclusion criteria were myocardial infarction within the previous 3 years and contraindications to beta-blockers and calcium antagonists. The patients were followed between 6 and 75 months (median 3.4 years and a total of 2887 patient years). The patients were treated with either metoprolol (Seloken ZOC 200 mg o.d.) or verapamil (Isoptin Retard 240 b.i.d.). Acetylsalicylic acid, ACE inhibitors, lipid lowering drugs and long acting nitrates were allowed in the study. Death, non-fatal cardiovascular events including acute myocardial infarction, incapacitating or unstable angina, cerebrovascular or peripheral vascular events. Psychological variables reflecting quality of life i.e. psychosomatic symptoms, sleep disturbances and an evaluation of overall life satisfaction. Combined cardiovascular events did not differ and occurred in 30.8% and 29.3% of metoprolol and verapamil treated patients respectively. Total mortality in metoprolol and verapamil treated patients was 5.4 and 6.2%, respectively. Cardiovascular mortality was 4.7% in both groups. Non-fatal cardiovascular events occurred in 26.1 and 24.3% of metoprolol and verapamil-treated patients, respectively. Psychosomatic symptoms and sleep disturbances were significantly improved in both treatment groups. The magnitudes of change were small and did not differ between treatments. Life satisfaction did not change on either drug. Withdrawals due to side effects occurred in 11.1 and 14.6% respectively. This long term study indicates that both drugs are well tolerated and that no difference was shown on the effect on mortality, cardiovascular end points and measures of quality of life.

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Osteonecrosis in patients with malignant lymphoma: a review of twenty-five cases.

A retrospective study of 25 patients with malignant lymphoma who had osteonecrosis of either the femoral or humeral head(s) was undertaken. The common factor present among all patients was the administration of intermittent steroid-containing combination chemotherapy. Seventeen Hodgkin's disease patients received chemotherapy predominantly consisting of an alkylating agent, vincristine, procarbazine, and moderate amounts of prednisone. The non-Hodgkin's lymphoma patients were on various moderate dosage steroid-containing protocols, except three who received prolonged high-dose steroid-containing chemotherapy regimens. Sixteen of the 17 Hodgkin's disease patients and five of the eight non-Hodgkin's lymphoma patients received radiotherapy to the bones that subsequently developed osteonecrosis. Two of the three non-Hodgkin's lymphoma patients who were not irradiated were treated with high-dose steroid-containing chemotherapy regimens. Symptoms developed in patients 12 months and 32 months after completion of chemotherapy and radiotherapy, respectively. Osteonecrosis was a long-term complication of treatment between 1970 and 1979 and occurred in 1.6% of the Hodgkin's disease and 0.12% of the non-Hodgkin's lymphoma patients treated. The authors conclude that the patients at highest risk for this complication are those who receive both radiotherapy to the affected bone(s) and intermittent steroid-containing multiple drug chemotherapy.

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Double-blind controlled study of rilmenidine versus hydrochlorothiazide in mild hypertension: clinical and renal haemodynamic evaluation.

Clinical and renal haemodynamic parameters were evaluated in 20 mild hypertensive patients after rilmenidine (RIL) administration during a one month double-blind randomised study compared with hydrochlorothiazide (HCT). At the beginning and at the end of the study, BP, heart rate and renal haemodynamic parameters were evaluated. Renal haemodynamic parameters included effective renal plasma flow (ERPF) evaluated by radionuclide study utilising 131I-Hippuran according to Schlegel's method, effective renal blood flow (ERBF = ERPF/(1-Ht)), glomerular filtration rate (GFR) by creatinine clearance, filtration fraction (FF = GFR/ERPF) and renal vascular resistances (RVR = DBP x 80/ERBF). RIL and HCT significantly (P < 0.01) reduced systolic, diastolic and mean blood pressure without relevant change in ERPF, ERBF, GFR and FF. RVR was significantly reduced both in the RIL group (P < 0.002 vs. baseline) and in the HCT group (P < 0.001 vs. baseline). No relevant side-effects were observed in either group. In conclusion, rilmenidine was effective in reducing BP in mild hypertensive patients and produced favourable effects on renal function.

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Interindividual Variability of Apixaban Plasma Concentrations: Influence of Clinical and Genetic Factors in a Real-Life Cohort of Atrial Fibrillation Patients.

(1) Background: Prescribing apixaban for stroke prevention has significantly increased in patients with non-valvular atrial fibrillation (NVAF). The <i>ABCB₁</i> genotype can influence apixaban absorption and bioavailability. The aim of the present study was to assess the factors that influence apixaban's plasma level and to establish if a certain relationship has clinical relevance. (2) Methods: Fifty-three NVAF patients were treated with 5 mg apixaban twice/day (70.0 years, range: 65-77, 60.4% men). Trough and peak plasma concentrations of apixaban were determined by liquid chromatography-tandem mass-spectrometry (LC-MS/MS), and <i>ABCB₁</i> genotyping was performed. (3) Results: Apixaban plasma concentrations varied considerably. They were higher in women than in men (311.2 ng/dL vs. 252.2 ng/dL; <i>p</i> = 0.05) and were lower in patients with heart failure (149.4 ng/dL vs. 304.5 ng/dL; <i>p</i> < 0.01). Creatinine clearance was inversely correlated with the apixaban plasma level (Spearman correlation: <i>r</i> = -0.365; <i>p</i> = 0.007 for trough concentrations). No statistically significant differences between the genotypic groups of <i>ABCB₁</i> rs1045642 and <i>ABCB₁</i> rs4148738 were found in the trough or peak apixaban plasma concentrations. (4) Conclusions: Pharmacokinetic parameters are influenced by several clinical factors of which renal function is the major determinant. Plasma concentrations measured in women had higher values than those measured in men, and heart failure was associated with decreased plasma levels of apixaban.

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Switching from pathogenetic treatment with alpha-lipoic acid to gabapentin and other analgesics in painful diabetic neuropathy: a real-world study in outpatients.

In this retrospective real-world study, we aimed to evaluate whether switching from the pathogenetic treatment option alpha-lipoic acid to drugs for symptomatic treatment of neuropathic pain such as gabapentin would be associated with changes in efficacy, safety, and cost-effectiveness. A cohort of 443 diabetic patients with chronic painful neuropathy were treated with alpha-lipoic acid 600 mg qd orally for a mean period of 5 years. After stopping this treatment, 293 patients were switched to gabapentin (600-2400 mg/day), while 150 patients remained untreated because of no acute symptoms. In the untreated group, 110 (73%) patients developed neuropathic symptoms as soon as 2 weeks after the end of treatment with alpha-lipoic acid. In the group started on gabapentin, 131 (45%) patients had to stop taking the drug due to intolerable side effects. Among the patients treated with gabapentin 132 (45%) were responders on an average dose of 1200 mg/day, whereas 161 (55%) were nonresponders at gabapentin doses up to 2400 mg/day. These patients required an alternative treatment which consisted of pregabalin, carbamazepine, amitriptyline, tramadol, or morphine as monotherapy or in combination. The daily costs for alpha-lipoic acid were considerably lower than those for gabapentin or several frequently used drug combinations. The frequency of outpatient visits was 3.8 times per 3 months during the treatment period with alpha-lipoic acid, while it increased to 7.9 per 3 months after switching to gabapentin or the other pain medications. In conclusion, switching from long-term treatment with alpha-lipoic acid to central analgesic drugs such as gabapentin in painful diabetic neuropathy was associated with considerably higher rates of side effects, frequencies of outpatient visits, and daily costs of treatment. The pathogenic treatment option represents for the practicing diabetologist an effective, safe, and cost-effective treatment option for the majority of patients with diabetic polyneuropathy.

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Dexamphetamine boosts naming treatment effects in chronic aphasia.

To date, minimal research has investigated the effect of combining dexamphetamine with standard naming therapy after stroke. The present study used a double-blind, placebo-controlled, multiple baseline, crossover design with two individuals in the chronic stage of stroke recovery. Each individual attended two 4-week blocks of naming therapy (two to three treatment sessions per week). Dexamphetamine (10 mg) was administered at the start of each session during one therapy block, while a placebo was administered during the other therapy block. Therapy progress on treated and untreated items was assessed by a confrontation naming task during and after each therapy block. Both individuals showed greater progress in therapy and maintenance of therapy gains when behavioral treatment was combined with dexamphetamine rather than placebo, although this gain was only statistically significant in one individual. There was no significant improvement on a control task (nonword reading) in either individual. The results provide preliminary evidence that dexamphetamine paired with combined semantic and phonological therapy may be beneficial for the treatment of naming disorders in chronic aphasia.

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Heart Rate and Heart Rate Difference Predicted the Efficacy of Metoprolol on Postural Tachycardia Syndrome in Children and Adolescents.

To evaluate the ability of heart rate (HR) and HR difference during head-up tilt test (HUTT) and to predict clinical improvement related to metoprolol treatment in children and adolescents with postural tachycardia syndrome (POTS). This was a retrospective cohort study. A total of 53 subjects (27 male, aged 6-12 years old, mean age 11.79 ± 1.50 years old) with POTS treated with metoprolol were involved from July 2012 to September 2019. In total, 52 subjects who underwent health examination during the same period were matched as the control group. Subjects in both groups underwent HUTT. The HR distance between 5 minutes and 0 minutes (HR difference 5) and between 10 minutes and 0 minutes (HR difference 10) during HUTT was calculated. The POTS group was significantly greater than the control group in HR 5, HR 10, HR difference 5, and HR difference 10 (P < .01). There was no statistical difference in HR 0 between the 2 groups (P > .05). In total, 53 subjects with POTS were followed up for 96.0 (IQR, 40.5, 134.5) days during treatment with metoprolol. HUTT results demonstrated that 58.49% of subjects with POTS had a response and symptom scores were reduced after intervention. HR and HR difference were useful in predicting the efficacy of metoprolol on POTS. When HR 5, HR 10, HR difference 5, and HR difference 10, respectively, were ≥110, 112, 34, and 37 beats/min, the sensitivity and specificity were 82.50% and 69.23%, 84.62% and 69.70%, 85.29% and 89.47%, and 97.56% and 64.86%, respectively. HR and HR difference are helpful to predict the efficacy of metoprolol on POTS in children and adolescents.

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Clinical follow-up examination after treatment of canine leishmaniasis.

In 16 dogs, the diagnosis of canine leishmaniasis could be detected by direct microscopic identification, by determination of the antibody titre or by PCR method (peripheral blood/bone marrow). On the basis of the clinical and laboratory diagnostic results 9 cases of the cutaneous type and 7 dogs of the combined cutaneous-visceral type (+ mono- or polyarthritis, hepatopathy and/or renal insufficiency as well as occular manifestation) have been classified. Therapy was: GLUCANTIME in 6 dogs, allopurinol in 3 dogs as single agent, combination-therapy GLUCANTIME and allopurinol in 7 dogs. During GLUCANTIME-treatment the following adverse reactions could be observed: general weakness, reduced food intake up to anorexia, vomiting and diarrhoea. Laboratory parameters showed sporadically leucopenia or pancreatitis. Adverse reactions during allopurinol therapy were: vomitus/diarrhoea or urine concrements. One dog with GLUCANTIME therapy, 2 dogs with allopurinol as well as 2 dogs with combination therapy are clinically symptom-free at the moment (peripheral blood and bone marrow: PCR negative). The remaining 11 patients showed a good to very good improvement of the clinical symptoms. However, since the peripheral blood respectively the bone marrow continue to be PCR positive, relapses have to be expected in these dogs.

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Phase I and pharmacokinetic study of docetaxel, irinotecan, and celecoxib in patients with advanced non-small cell lung cancer.

We studied the toxicities, potential pharmacokinetic interactions, and preliminary antitumor activity of the combination of docetaxel and irinotecan with celecoxib, a selective cyclooxygenase-2 inhibitor. Eligible patients had advanced non-small lung cancer (NSCLC) with measurable disease, good performance status, and adequate end organ function. Docetaxel and irinotecan were administered intravenously on days 1 and 8, every 21 days, and their doses were escalated on successive patient cohorts at three dose levels: 30/50, 30/60, and 35/60 (doses in mg/m2). Celecoxib was administered at a starting dose of 400 mg orally twice daily without interruption, beginning on day 2 of cycle 1. Pharmacokinetic studies were performed on day 1 of cycle 1 and day 1 of cycle 2. Seventeen patients with advanced NSCLC were enrolled and collectively received 78 cycles of therapy. Diarrhea was the most common toxicity; it was noted in 13 patients (76%). Dose-limiting toxicities occurred at dose level 1 (myocardial infarction in a patient with multiple coronary artery disease risk factors) and dose level 3 (grade 4 neutropenia with fatal urosepsis). Other major toxicities were: grade 3 neutropenia (2 patients); grade 3/4 diarrhea (3/1); grade 3 nausea (2); grade 2 rash (1); and grade 3 pneumonitis (1). The maximum tolerated dose was at dose level 3, i.e., docetaxel 35 mg/m2 and irinotecan 60 mg/m2 on days 1 and 8, plus celecoxib 400 mg twice daily, repeated every 21 days. Five of 15 evaluable patients achieved an objective response. The pharmacokinetics of docetaxel were not altered by celecoxib. However, we observed an 18% increase in the average elimination clearance of irinotecan coincident with the addition of celecoxib. The addition of celecoxib to docetaxel and irinotecan was generally well tolerated but unpredictable fatal toxicity occurred. Diarrhea was the most common toxicity. Antitumor activity was promising. The alteration of irinotecan pharmacokinetic parameters observed may not be clinically relevant.

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Predictors of Neurological Outcome of Tuberculous Meningitis in Childhood: A Prospective Cohort Study From a Developing Country.

To assess the long-term outcome of childhood tuberculous meningitis treated with modern 4-drug antitubercular regimens and to determine predictors of survival and morbidity. In this single-center prospective cohort, outcome of children with tuberculous meningitis treated with standard regimens was assessed at 6 months and 12 months after discharge using the Pediatric Cerebral Performance Category Scale. Of 130 children, 38 died in hospital and 34 were either severely disabled or comatose/vegetative at discharge. At 6 and 12 months, 87% of the survivors were either normal (n = 62) or mildly disabled (n = 17, on the Pediatric Cerebral Performance Category scale). On multivariate analysis, the factors associated with poor outcome at 12 months were stage III at admission (adjusted odds ratio 4.4, 95% confidence interval, 1.7-11.2, P = .002) and presence of infarcts on neuroimaging (adjusted odds ratio 2.6, 95% confidence interval, 1.1-6.6, P = .037). Despite the high in-hospital mortality, in resource-constraint settings, the survivors showed remarkable improvement, with two-thirds returning to a normal functional status at 6 months' follow-up.

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Initial therapy for chronic graft-versus-host disease: analysis of practice variation and failure-free survival.

Prior clinical trials largely considered prednisone 1 mg/kg per day with or without calcineurin inhibitor as standard initial therapy for chronic graft-versus-host disease (cGVHD), but uncertainty remains regarding the extent of practice variation and whether this affects subsequent outcomes. We assembled a cohort of 745 patients with cGVHD treated with initial systemic immune suppressive (IS) therapy from 3 prior cGVHD Consortium observational studies. Initial therapy was defined as first IS therapy started for cGVHD or prednisone increased to ≥0.4 mg/kg per day from lower doses within 30 days before cGVHD diagnosis to any time afterward. Initial therapies were nonprednisone IS therapies (n = 137, 18%), prednisone alone (n = 411, 55%), or prednisone plus other IS therapy (n = 197, 26%). In multivariate analysis, initial therapy group was not associated with failure-free survival (FFS; a composite of death, relapse, and new IS therapy), overall survival (OS), or nonrelapse mortality (NRM). Among the prednisone-based approaches, steroid dose was <0.25 (9%), 0.25 to 0.74 (36%), 0.75 to 1.25 (42%), or >1.25 mg/kg per day (13%). Prednisone dose within the patients treated with steroids was not significantly associated with FFS, OS, or NRM. No significant interactions were detected between overall cGVHD severity and either initial therapy group or prednisone dose for the outcomes of FFS, OS, or NRM. These observational data document heterogeneity in more contemporary cGVHD initial treatment practices, including prednisone dose and use of nonsteroid approaches. This variation was not associated with FFS, OS, or NRM. Prospective trials are needed to verify efficacy of reduced-dose prednisone or prednisone-free initial therapy approaches.

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Resistant Hypertension On Treatment (ResHypOT): sequential nephron blockade compared to dual blockade of the renin-angiotensin-aldosterone system plus bisoprolol in the treatment of resistant arterial hypertension - study protocol for a randomized controlled trial.

Resistant hypertension is characterized when the blood pressure (BP) remains above the recommended goal after taking three antihypertensive drugs with synergistic actions at their maximum recommended tolerated doses, preferably including a diuretic. Identifying the contribution of intravascular volume and serum renin in maintaining BP levels could help tailor more effective hypertension treatment, whether acting on the control of intravascular volume or sodium balance, or acting on the effects of the renin-angiotensin-aldosterone system (RAAS) on the kidney. This is a randomized, open-label, clinical trial is designed to compare sequential nephron blockade and its contribution to the intravascular volume component with dual blockade of the RAAS plus bisoprolol and the importance of serum renin in maintaining BP levels. The trial has two arms: sequential nephron blockade versus dual blockade of the RAAS (with an angiotensin converting enzyme (ACE) inhibitor plus a beta-blocker) both added-on to a thiazide diuretic, a calcium-channel blocker and an angiotensin receptor-1 blocker (ARB). Sequential nephron blockade consists in a progressive increase in sodium depletion using a thiazide diuretic, an aldosterone-receptor blocker, furosemide and, finally, amiloride. On the other hand, the dual blockade of the RAAS consists of the progressive addition of an ACE inhibitor until the maximum dose and then the administration of a beta-blocker until the maximum dose. The primary outcomes will be reductions in the systolic BP, diastolic BP, mean BP and pulse pressure (PP) after 20 weeks of treatment. The secondary outcomes will evaluate treatment safety and tolerability, biochemical changes, evaluation of renal function and recognition of hypotension (ambulatory BP monitoring (ABPM)). The sample size was calculated assuming an alpha error of 5% to reject the null hypothesis with a statistical power of 80% giving a total of 40 individuals per group. In recent years, the cost of resistant hypertension (RH) treatment has increased. Thus, identifying the contribution of intravascular volume and serum renin in maintaining BP levels could help tailor more effective hypertension treatment, whether by acting on the control of intravascular volume or sodium balance, or by acting on the effects of the RAAS on the kidney. Sequential Nephron Blockade vs. Dual Blockade Renin-angiotensin System + Bisoprolol in Resistant Arterial Hypertension (ResHypOT). ClinicalTrials.gov, ID: NCT02832973 . Registered on 14 July 2016. First received: 12 June 2016. Last updated: 18 July 2016.

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Left ventricular hypertrophy in elderly hypertensive patients: a report from the European Working Party on High Blood Pressure in the Elderly trial.

In a double-blind, placebo-controlled trial, 840 elderly hypertensive patients were randomly assigned to treatment with a combination of hydrochlorothiazide and triamterene or placebo; methyldopa or matching placebo was added to the treatment regimen if blood pressures remained high. After adjustment for age, gender, and body mass index, initial electrocardiographic (ECG) voltage measures of RaVL and SV1 + RV5 were significantly related to systolic blood pressure; RaVL was also related to diastolic blood pressure. After one year of treatment, the decrease in RaVL and SV1 + RV5 in the treated patients, adjusted for age and body mass index, were not correlated with the changes in systolic blood pressure, but the decreases in SV1 + RV5 were positively related to the decrease in diastolic blood pressure. After four years of treatment, the decreases in RaVL and SV1 + RV5 were significantly and positively related to the decrease in systolic blood pressure after adjustment for age and changes in body mass index. In a four-year cohort of 222 patients, most of the decreases in ECG voltages in the treated patients and the increases in the placebo patients were found to have occurred during the first year of treatment. The type of treatment (diuretics alone or diuretics plus methyldopa) did not affect ECG voltages during the first year of follow-up. Total and cardiovascular mortality were related to initial amplitude of RaVL, but the significant correlation disappeared after adjustment for age.

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Effects of high-dose furosemide and small-volume hypertonic saline solution infusion in comparison with a high dose of furosemide as a bolus, in refractory congestive heart failure.

Diuretics, have been accepted as first-line treatment in refractory heart failure, but a lack of response is a frequent event. A randomised single blind study was performed to evaluate the effects of the combination of high-dose furosemide and small-volume hypertonic saline solution (HSS) infusion in the treatment of refractory NYHA class IV congestive heart failure (CHF). Sixty patients (21 F/39 M) with refractory CHF (NYHA class IV) of different etiologies, unresponsive to high oral doses of furosemide, ACE-inhibitors, digitalis, and nitrates, aged 65-90 years, were enrolled. They had to have an ejection fraction (EF) <35%, serum creatinine <2 mg/dl, BUN </=60 mg/dl, a reduced urinary volume and a low natriuresis. The patients were randomised in two groups (single blind): group 1 (11 F/19 M) received an i.v. infusion of furosemide (500-1000 mg) plus HSS (150 ml of 1.4-4.6% NaCl) b.i.d. in 30 min. Group 2 (10 F/20 M) received an i.v. bolus of furosemide (500-1000 mg) b.i.d., without HSS, during a period lasting 6-12 days. Both groups received KCl (20-40 mEq.) i.v. to prevent hypokalemia. All patients underwent at entry a physical examination, measurement of body weight (BW), blood pressure (BP), heart rate (HR), evaluation of signs of CHF, and controls of serum Na, K, Cl, bicarbonate, albumin, uric acid, creatinine, urea and glycemia and daily during hospitalization, as well as the daily output of urine for, Na, K and Cl measurements. Chest X-ray, ECG and echocardiogram were obtained at entry during and at the discharge. During the treatment and after discharge the daily dietary Na intake was 120 mmol with a drink fluid intake of 1000 ml daily. An assessment of BW and 24-h urinary volume, serum and urinary laboratory parameters, until reaching a compensated state, were performed daily, when i.v. furosemide was replaced with oral administration (250-500 mg/day). After discharge, patients were followed as outpatients weekly for the first 3 months and subsequently once per month. The groups were similar for age, sex, EF, risk factors, treatment and etiology of CHF. All patients showed a clinical improvement. Six patients in both groups had hyponatremia (from 120 to 128 mEq./l) at entry. A significant increase in daily diuresis in both groups was observed (from 390+/-155 to 2100+/-626, and from 433+/-141 to 1650+/-537 ml/24 h, P<0.05). Natriuresis (from 49+/-15 to 198+/-28 mEq./24 h) was higher in group 1 vs. group 2 (from 53.83+/-12 to 129+/-39 mEq./24 h, P<0.05). Serum Na (from 135.9+/-6.8 to 142.2+/-3. 8 mEq./l, P<0.05) increased in the group 1 and decreased in the group 2 (from 134.7+/-7.9 to 130.1+/-4.3 mEq./l). Serum K was decreased (from 4.4+/-0.6 to 3.9+/-0.6, and 4.6+/-9 to 3.6+/-0.5 mEq. /l, P<0. 05) in both groups. BW was reduced (from 73.8+/-9.1 to 63. 8+/-8.8, and from 72.9+/-10.2 to 64.5+/-7.5 kg, P<0. 05) in both groups. Group 2 showed more patients in NYHA class III than group 1 (18 vs. 2 patients, P<0.05). Group 2 showed an increase of serum creatinine. Serum uric acid increased in both groups. BP values decreased, and HR was corrected to normal values in both groups. Group 2 showed a longer hospitalization time than group receiving HHS infusion (11.67+/-1.8 vs. 8.57+/-2.3 days, P<0.001). In the follow-up (6-12 months), none of the patients from group 1 were readmitted to the hospital and they maintained the NYHA class achieved at the discharge. Group 2 showed 12 patients readmitted to hospital and a higher class than at discharge. Our data suggest that the combination of furosemide with HSS is feasible and it appears that this combination produces an improvement of hemodynamic and clinical parameters, reduces the hospitalization time and maintains the obtained results over time in comparison with those receiving high-dose furosemide as bolus.

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Prospective Randomized Study Using Pharmacogenetics to Customize Postoperative Pain Medication Following Hip and Knee Arthroplasty.

The purpose of this study is to determine whether pharmacogenetic testing could be used to effectively customize postoperative pain medicine following total joint replacement. Buccal swabs were collected preoperatively from 107 patients. Pharmacogenetic testing was performed for genetic variants on a panel of 16 genes, including CYP2D6, CYP2C9, OPRM1, and CYP1A2, which affect the pharmacodynamics and pharmacokinetics of non-steroidal anti-inflammatory drugs and many opioids. Patients were randomized to a control group or custom group and blinded to their group. The control group was prescribed oxycodone, tramadol, and celecoxib for postoperative pain management. If any of those were not normally metabolized, they were not prescribed to the patients in the custom group, who were given an alternative drug (hydromorphone for narcotics, meloxicam for non-steroidal anti-inflammatory drugs). Patients recorded their pain level (0-10 numeric scale) and all medications taken daily for the first 10 days following surgery. Medication was converted to milligram morphine equivalents (MMEs). Genetic variations to medications in our standard postoperative pain management protocol occurred in 24 of the 107 patients (22.4%). The 10-day MME consumed by patients in the control group with genetic variants was 162.6 mg. Patients with variants who had custom postoperative medication consumed only 86.7 MME in the same timeframe (P = .126). The control group demonstrated a higher 10-day average pain level of 4.2 vs the custom group pain level of only 3.1 (P < .05). With custom postoperative pain prescriptions based on pharmacogenetic testing, patients were able to achieve lower pain levels while reducing the consumption of pain medication.

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Costs of antidepressant medications associated with inadequate treatment.

To determine the costs of antidepressant medications used during inadequate treatment. Retrospective database analysis of pharmacy claims made by patients who were treated under routine clinical conditions from July 1, 1999, through September 30, 2002. Our participants included 21,632 patients enrolled in a commercial HMO who had a primary care physician associated with our healthcare system. Patients never receiving at least a minimum likely effective antidepressant dose for at least 90 days were defined as having inadequate treatment. This study calculated the costs of antidepressants involved with inadequate treatment at the level of the patient and the medication trial. A majority of patients (51%) received inadequate treatment. Of overall antidepressant costs, 16% were incurred during trials for patients never adequately treated. The majority of inadequate trials were short and unlikely to have been effective. Most patients (64%) had only a single trial of antidepressants. Venlafaxine, fluoxetine, and sertraline had significantly lower first-trial inadequacy rates compared with the most commonly prescribed agent, citalopram. Improved patient care quality and lower antidepressant costs could result if clinicians and healthcare systems focus on reducing short trial rates. Initiating treatment with agents least likely to be discontinued prematurely may be helpful.

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Bronchodilator delivery by metered-dose inhaler in mechanically ventilated COPD patients: influence of tidal volume.

The delivery of bronchodilator drugs with metered-dose inhaler (MDI) and a spacer in mechanically ventilated patients has become a widespread practice. However, the various ventilator settings that influence the efficacy of MDI are not well established. The tidal volume (VT) during drug delivery has been suggested as one of the factors that might increase the effectiveness of this therapy. To test this, the effect of two different VT on the bronchodilation induced by beta 2-agonists administered with MDI and a spacer in a group of mechanically ventilated patients with chronic obstructive pulmonary disease (COPD) was examined. Nine patients with COPD, mechanically ventilated on volume-controlled mode, were prospectively randomised to receive six puffs of salbutamol (S, 100 micrograms/puff) either with a VT of 8 ml/kg (normal VT, 582 +/- 85) or with a VT of 12 ml/kg (high VT, 912 +/- 137). With both modes inspiratory flow was identical. S was administered with an MDI adapted to the inspiratory limb of the ventilator circuit using an aerosol cloud enhancer spacer. After a 6-h washout, patients were crossed-over to receive S by the alternative mode of administration. Static and dynamic airway pressures, minimum (Rint) and maximum (Rrs) inspiratory resistance, the difference between Rrs and Rint (delta R), static end-inspiratory respiratory system compliance (Cst,rs), intrinsic positive end-expiratory pressure (PEEPi) and heart rate (HR) were measured before and at 15, 30 and 60 min after S. S caused a significant decrease in dynamic and static airway pressures, PEEPi, Rint and Rrs. These changes were not influenced by VT and were evident at 15, 30 and 60 min after S. With normal and high VT, Cst,rs, delta R and HR did not change after S. We conclude that S delivered with an MDI and a spacer device induces significant bronchodilation in mechanically ventilated patients with COPD, the magnitude of which is not affected by at least a 50% increase in VT. These results do not support the VT manipulations when bronchodilators are administered in adequate doses during controlled mechanical ventilation.

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[Maintenance therapy with 20 mg fluoxetine. Results of an administration study of 1,737 depressed patients].

An application study was carried out in 1993/94 on the use of fluoxetine for the continuation therapy of depression. 1737 patients received fluoxetine at a dosage of 20 mg per day over a period of 6 months. Diagnosis was made by clinical evaluation of phenomenology and ICD-10 classification. Over the observation period physicians rated the course of illness according to severity of the depression, somatic complaints and therapeutic efficacy on a scale graded 1-4. Side effects and concomitant medication were also noted. Coincidentally, patients recorded subjective satisfaction with therapy, as well as side effects. In a subsample of 423 patients the physicians additionally used a modified version of the Hamilton Depression Rating Scale (HRDS) for behavioural ratings. Standard assessment was performed after the 2nd and 6th weeks of treatment and again after the 3rd and 6th months. The rating scale showed a decrease in depressive symptomatology and somatic complaints at the end of treatment in 53% and 44% of patients, respectively. Treatment efficacy was rated as excellent in 82% of cases, as evaluated by the physicians; patients were satisfied in 89% of cases. These results are strengthened by the reduction from 22.4 +/- 7.0 to 9.2 +/- 6.4 in the subsample of 423 patients according to the HRDS, equivalent to a decrease in depression symptomatology of 59%. This study is the first open phase IV trial in Austria investigating continuation therapy with 20 mg fluoxetine per day and confirms results obtained in international multicentre placebo-controlled studies involving considerably smaller numbers of patients.

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Effect of fluoxetine on the pharmacokinetics of lansoprazole: a two-treatment period study in healthy male subjects.

Fluoxetine is an inhibitor of the main metabolizing enzymes of lansoprazole and could influence the pharmacokinetics of lansoprazole. The changes in lansoprazole pharmacokinetics could have clinical significance concerning the safety of the therapy. The aim of this study was to evaluate the pharmacokinetic interaction between fluoxetine and lansoprazole in healthy subjects. A dose of lansoprazole 30 mg, alone or in combination with fluoxetine 60 mg, was administered to 18 healthy male subjects in a two-treatment study design, separated by an 8-day period in which fluoxetine alone was administered as a single oral daily dose. Plasma concentrations of lansoprazole were determined during a 12-hour period following drug administration. Lansoprazole plasma concentrations were determined by a validated liquid chromatography-mass spectrometry method. The pharmacokinetic parameters of lansoprazole were calculated using non-compartmental analysis. In the two periods of treatment, the mean maximum plasma concentration (C(max)) values were 817 ng/mL (lansoprazole alone) and 1370 ng/mL (lansoprazole in combination with fluoxetine after pre-treatment with fluoxetine for 8 days) [p < 0.0001]. The observed area under the plasma concentration-time curve (AUC) from time zero to time of last measurable concentration values were 2400 and 6220 ng · h/mL (p < 0.0001), respectively, and the AUC from time zero to infinity values were 2480 and 7290 ng · h/mL (p < 0.0001), respectively. The time to reach C(max) values were 2.72 and 2.64 hours, respectively. The elimination rate constant from the central compartment values were 0.50 and 0.21 h-1, respectively (p < 0.0001). The elimination half-life values were 1.47 and 3.56 hours (p < 0.0001), respectively, and the mean residence times were 4.0 and 6.9 hours (p < 0.0001), respectively. The data demonstrate a pharmacokinetic interaction between fluoxetine and lansoprazole and suggest that the observed interaction may be clinically significant, although its clinical relevance has yet to be confirmed.

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Rituximab exposure-response in triweekly R-CHOP treatment in DLBCL: A loading dose is recommended to improve clinical outcomes.

Previous exposure-response analyses for rituximab suggest that higher rituximab concentrations were associated with an improvement in efficacy, however, clinical studies investigating a higher rituximab dose had mixed results. To further explore the exposure-response relationship of rituximab, a prospective observational analysis was performed involving 121 newly diagnosed patients with diffuse large B-cell lymphoma treated with triweekly rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). The trough concentration in the first cycle (C_1-trough ) was significantly higher in patients achieving complete response (CR) compared with patients that did not achieve CR (22.00 μg/ml vs. 16.62 μg/ml, p = 0.0016), however, this difference between the two groups disappeared in later cycles. The relationship between rituximab C_1-trough and achieving a CR was confirmed by matched-pair logistic regression analysis (odds ratio, 0.79; p = 0.0020). In addition, a higher C_1-trough (≥18.40 μg/ml) was associated with longer progression-free survival (p < 0.0001) and overall survival (p = 0.0038). The percentages of patients that did not achieve a CR and had recurrence after CR within 24 months were 35% and 22.50%, respectively, for patients with a C_1-trough less than or equal to 18.40 μg/ml, compared with 12.35% and 6.17% for patients with C_1-trough greater than 18.40 μg/ml. Disease stage was found to be the most significant influencing factor of C_1-trough , with 51.02% of patients at stage IV with an observed C_1-trough less than 18.40 μg/ml. For these advanced patients, population pharmacokinetic simulations using an established model suggest that a loading dose of 800 mg/m²  may help to improve clinical outcomes.

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Bismuth-containing quadruple therapy as second-line treatment for Helicobacter pylori infection: effect of treatment duration and antibiotic resistance on the eradication rate in Korea.

The eradication rate of first-line Helicobacter pylori treatment is only 70-85% and has been decreasing due to the increase in antibiotic resistance. The aim of this study was to evaluate the efficacy of bismuth-containing quadruple therapy as second-line treatment for H. pylori infection based on treatment duration. We prospectively enrolled 227 patients that were found to have persistent H. pylori infection after first-line proton-pump inhibitor-clarithromycin-amoxicillin triple therapy. Patients were randomized to 1-week (112 patients) and 2-week (115 patients) quadruple therapy with tripotassium dicitrate bismuthate 300 mg q.i.d., metronidazole 500 mg t.i.d., and tetracycline 500 mg q.i.d. and esomeprazole 20 mg b.i.d. The eradication rate, drug compliance, and adverse events were compared based on treatment duration. The eradication rates were 72/112 (64.3%, 95% CI: 0.504-0.830) and 71/92 (77.2%, 0.440-0.749) with 1-week group, and 95/115 (82.6%, 1.165-2.449) an 88/94 (93.6%, 1.213-5.113) with 2-week group by intention-to-treat therapy (p = .002) and per-protocol analysis (p = .001), respectively. The adverse events increased as the treatment durations increased from 7 to 14 days (20.0 and 42.5%, respectively, p < .001). However, there was no significant difference in the patient compliance or the rate of major adverse events between the 1- and 2-week groups (6.3 and 12.5%, respectively, p = .133). Two-week bismuth-containing quadruple therapy was more effective than the 1-week treatment, and should be considered for second-line treatment in Korea.

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Double-blind study with dipyrone versus tramadol and butylscopolamine in acute renal colic pain.

To investigate the combined analgesic and spasmolytic effect of dipyrone, 104 patients suffering from "severe" or "excruciating" colic pain due to a confirmed calculus in the upper urinary tract were randomized to receive i.v. either 2.5 g dipyrone (36 patients), 100 mg tramadol (35 patients), or 20 mg butylscopolamine (33 patients) in a multicentre, observer-blind, parallel-group study conducted in 8 German centres. The three treatment groups were homogeneous when analyzed by age, sex, height, and baseline pain intensity. Dipyrone was significantly more effective than tramadol in reducing pain for the primary endpoint, pain intensity differences (PID) at 20, 30, and 50 min after drug administration, and was significantly more effective than butylscopolamine at 30 and 50 min for the secondary efficacy endpoint, pain intensity differences on a categorical scale. Dipyrone had the highest SPID0-2 h of the three drugs (P < 0.05). Only 5 patients receiving dipyrone needed "rescue" medication as compared with 13 patients given tramadol and 11 patients receiving butylscopolamine. Adverse events were observed in 4 patients receiving butylscopolamine and in 1 patient each given dipyrone and tramadol. "Distinct" pain relief as assessed on a visual analogue scale (VAS) is a reliable method of determining the onset of analgesic action in the colic pain model.

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Effect of Oxygen Flow on Aerosol Delivery From a Nebulizer With a Holding Chamber.

A new holding chamber was designed to be used with a vibrating mesh nebulizer to increase the total inhalable dose for patients. It facilitates intermittent and continuous nebulization as well as the optional supply of supplemental oxygen via a T-piece with a mouthpiece adapter. This study aimed to evaluate the effect of oxygen introduction in the new holding chamber on aerosol delivery using a vibrating mesh nebulizer. The study was divided into 2 parts. First, the total inhalable dose of 1 mL of a respirable solution (nominal dose of 5,000 μg-salbutamol) was determined using a breathing simulator set to provide a tidal volume of 500 mL, a breathing frequency of 15 breaths/min, and an inspiratory:expiratory ratio of 1:1 for adults as a quiet-breathing pattern. Three experimental nebulizer setups were used: a vibrating mesh nebulizer with the holding chamber and oxygen set at 6 L/min, a vibrating mesh nebulizer with the holding chamber and no oxygen, and a vibrating mesh nebulizer with the T-piece. Aerodynamic particle size characterizations were determined using cooled Andersen cascade impaction at an inhalation flow of 15 L/min. Second, we performed an in vivo study involving 12 healthy non-smoking subjects (6 female) who were > 18 y old with an average FEV₁ > 90% of predicted. Using normal tidal breathing, subjects inhaled 1 mL of nebulized salbutamol (5,000 μg) through the vibrating mesh nebulizer with the holding chamber with and without oxygen and through the vibrating mesh nebulizer with a T-piece. To analyze salbutamol content, urine samples were obtained 30 min after dosing as an index of lung deposition, and their urine was cumulatively collected for 24 h as an index of systemic absorption. The holding chamber significantly increased the total inhalable dose or amount of salbutamol excreted in the first 30 min, as well as the amount of salbutamol excreted over a 24-h period compared to the dose received with the vibrating mesh nebulizer with a T-piece (<i>P</i> = .005, <i>P</i> = .034, and <i>P</i> = .02, respectively), and relatively decreased the mass median aerodynamic diameter, although the difference was not significant. However, when oxygen was introduced in the holding chamber, the total inhalable dose, or amount of salbutamol excreted in the first 30 min, significantly decreased compared to use without oxygen (<i>P</i> = .003, <i>P</i> = .03 respectively). No significant difference was found between the vibrating mesh nebulizer with the holding chamber with oxygen and the vibrating mesh nebulizer with a T-piece. The vibrating mesh nebulizer with a holding chamber and without oxygen resulted in much better aerosol delivery compared to vibrating mesh nebulizer with a holding chamber and with oxygen delivery and to the vibrating mesh nebulizer with a T-piece. The use of oxygen with the holding chamber significantly decreased aerosol delivery and its benefit, and recommended flow should be reevaluated.

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Stage-adapted treatment of HIV-associated Hodgkin lymphoma: results of a prospective multicenter study.

Although the outcome of patients with HIV-related Hodgkin lymphoma (HIV-HL) has markedly improved since the introduction of combined antiretroviral therapy, standard therapy is still poorly defined. This prospective study investigates a stage- and risk-adapted treatment strategy in patients with HIV-HL. Patients with early favorable HIV-HL received two to four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gy of involved-field (IF) radiation. In patients with early unfavorable HIV-HL, four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP baseline) or four cycles of ABVD + 30 Gy of IF radiation were administered. Six to eight cycles of BEACOPP baseline were given in patients with advanced-stage HIV-HL. In patients with advanced HIV infection, BEACOPP was replaced with ABVD. Of 108 patients (including eight female patients) included in the study, 23 (21%) had early favorable HL, 14 (13%) had early unfavorable HL, and 71 (66%) had advanced-stage HL. The median CD4 count at HL diagnosis was 240/μL. The complete remission rates for patients with early favorable, early unfavorable, and advanced-stage HL were 96%, 100%, and 86%, respectively. The 2-year progression-free survival of the entire study population was 91.7%. Eleven patients (11%) have died, and treatment-related mortality was 5.6%. The 2-year overall survival rate was 90.7% with no significant difference between early favorable (95.7%), early unfavorable (100%), and advanced-stage HL (86.8%). In patients with HIV-HL, stage- and risk-adapted treatment is feasible and effective. The prognosis for patients with HIV-HL may approach that of HIV-negative patients with HL.

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Carvedilol does not modulate moderate exercise-induced hyperkalemia in hemodialysis patients.

Non-selective beta-adrenergic blockers may cause hyperkalemia in patients with end-stage renal failure. In contrast, alpha-adrenergic blockade has been found to decrease the hyperkalemic effect of physical exercise in healthy subjects, although we were unable to confirm this effect in hemodialysis patients. In a crossover design, we studied the effect of carvedilol, a non-selective beta-adrenergic blocker with an additional alpha1-blocking activity, on exercise-induced hyperkalemia in 17 anuric hemodialysis patients. All subjects were given either carvedilol (25 mg/day) or placebo for 2 weeks in a random order with a 2-week wash-out period. At the end of each treatment period they underwent a 30-minute exercise test on a bicycle ergometer with a fixed load of 20 W. The treatment with carvedilol caused a significant decrease in blood pressure. Serum potassium before exercise tests was similar (5.37 +/- 0.2 and 5.24 +/- 0.2 mmol/l on carvedilol and placebo, respectively; mean +/- SE). During the exercise, serum potassium increased significantly (p < 0.001 in both tests) and subsequently decreased during 30 minutes of recovery (p < 0.05). The mean rate of potassium increment during the exercise was similar (23.3 +/- 3.3 micromol/l/min on carvedilol and 20.0 +/- 3.6 micromol/l/min on placebo). During recovery, the mean rate of potassium decrement was 5.0 +/- 3.0 micromol/l/min and 6.7 +/- 2.7 micromol/l/min, respectively. Serum sodium, ionized calcium, insulin and plasma renin activity were similar before the exercise tests and did not change during the exercise. Carvedilol does not enhance the hyperkalemic effect of moderate physical exercise in anuric hemodialysis patients.

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Activity and safety of combination chemotherapy with methotrexate, ifosfamide, l-asparaginase and dexamethasone (MILD) for refractory lymphoid malignancies: a pilot study.

Optimal salvage chemotherapy has not been established for lymphoid malignancy, which is refractory to the conventional cyclophosphamide, doxorubicin, vincristine, and prednisone regimen. To explore an effective regimen, we conducted a phase I pilot study of combination chemotherapy with methotrexate, ifosfamide, l-asparaginase and dexamethasone (MILD), which are unaffected by MDR1-encoded P-glycoprotein. A total of 18 patients with lethal lymphoid malignancy were enrolled over a 2-yr period. The median age was 63 yr. Eleven patients had T/NK-cell malignancies, six had B-cell malignancies, and one was diagnosed with a blastic plasmacytoid dendritic cell neoplasm. Patients aged >/=60 and <60 yr were planned to receive a set of starting doses of methotrexate and ifosfamide, which should induce myelosuppression. Eleven patients completed two courses of MILD therapy. Treatment-related death because of systemic mucormycosis was observed in one patient. Major treatment-related adverse events were grade 3 or more hematologic toxicities, which included lymphopenia corresponding to dose-limiting toxicity. The most common grade 3 non-hematologic toxicity was febrile neutropenia. Of the 14 evaluated patients, three achieved a complete response, and four showed a partial response. The overall response rate was 57%. It was very interesting that all of seven responders had T/NK-cell malignancies. MILD therapy was feasible and presented acceptable toxicity in patients with refractory or lethal lymphoid malignancies. The efficacy for T/NK-cell malignancies should be further evaluated.

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Efficacy of low dose atorvastatin in diabetic dyslipidaemia.

Coronary heart disease (CHD), the commonest cause of morbidity and mortality in patients with type 2 diabetes, requires multipronged approach for management, including especially treating dyslipidaemia with statins. We conducted this study to demonstrate that low dose (10 mg) atorvastatin is effective in reducing LDL cholesterol (LDL-C) to the target levels in patients from Indian subcontinent. Eighty-one subjects with type 2 diabetes mellitus and dyslipidaemia (LDL-C >100 mg/dl in those without coronary artery disease, n=77; LDL-C >70 mg/dl in those with coronary artery disease, n=4) were included. All patients were initiated on 10 mg atorvastatin daily. Serum lipid profile was repeated after 3 months. The mean body mass index among men and women were 25.0 +/- 4 and 26.7 +/- 3.6 kg/m2 respectively. Pretreatment mean HbA(1c) was 7.9 +/- 1.8 % and total cholesterol, triglycerides and HDL cholestrol (HDL-C) and LDL-C was 214 +/- 27 mg/dl, 164 +/- 63 mg/dl, 46 +/- 6 mg/dl and 135 +/- 24 mg/dl respectively. After three months of treatment the mean decrease was 62 +/- 31 mg/dl in total cholesterol (p < 0.001), 31 +/- 57 mg/dl in triglycerides (p < 0.001), 51 +/- 27 mg/dl in LDL-C (p < 0.001) and 4 +/- 8 mg/dl in HDL-C (p < 0.001). The LDL-C level was reduced by 37.6% in these patients, from 135 +/- 24 mg/dl to 84 = 27 mg/dl (p < 0.001) with 10 mg of atorvastatin daily. It was possible to achieve target LDL-C of less than 100 mg/dl in 75.5% (n=58) in subjects without CHD (n=77) and less than 70 mg/dl in 75% (n=3) of those patients with CHD (n=4). The present study showed that in patients with type 2 diabetes mellitus, 10 mg of atorvastatin daily was safe, well tolerated, and effective in reducing LDL-C to target levels.

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Long-term Use of Inhaled Corticosteroids in COPD and the Risk of Fracture.

It is uncertain whether long-term use of inhaled corticosteroids (ICSs), widely used to treat COPD, increases the risk of fracture, particularly in women, in view of the postmenopausal risks. We assessed whether long-term ICS use in patients with COPD increases the risk of hip or upper extremity fractures, and examined sex-related differences. The Quebec health-care databases were used to form a cohort of patients with COPD over 1990 to 2005, followed until 2007 for the first hip or upper extremity fracture. In a nested case-control analysis, each case of fracture was matched with 20 control subjects on age, sex, and follow-up time. The adjusted rate ratio (RR) of fracture with ICS use, by duration and dose, was estimated using conditional logistic regression, with an interaction term to compare the risk in men and women. In the cohort of 240,110 subjects, 19,396 sustained a fracture during a mean 5.3 years (rate, 15.2 per 1,000 per year). Any use of ICSs was not associated with an increased rate of fracture (RR, 1.00; 95% CI, 0.97-1.03). The fracture rate was increased with > 4 years of ICS use at daily doses ≥ 1,000 μg in fluticasone equivalents (RR, 1.10; 95% CI, 1.02-1.19). This risk increase did not differ between men and women. Long-term ICS use at high doses is associated with a modest increase in the risk of hip and upper extremity fractures in patients with COPD. This dose-duration risk increase does not appear to be higher for women.

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Direct hospital resource utilization and costs of treating patients with multiple myeloma in Southwest Sweden: a 5-year retrospective analysis.

Approximately 570 patients are diagnosed with multiple myeloma (MM) in Sweden each year. Few studies have estimated the cost of treatment for these patients. The purpose of this study was to retrospectively investigate the direct hospital resource utilization and costs associated with the treatment of patients with MM in southwest Sweden. Patients aged > or =18 years who initiated first-line chemotherapy in the year 2001 at hospitals in southwestern Sweden were included in this retrospective chart review. Direct hospital-based resources and their corresponding costs (year-2006 euros) for each patient were calculated until the patient's death, or until December 31, 2005. Costs for outpatient and terminal stage care related to MM were not included. Ninety-four patients were included; 20 were still alive at study completion. Mean age at diagnosis was 76 years and patients were followed for a mean of 32.7 months; 55% were males and 74% had at least 1 comorbidity. First-, second-, and third-line treatment lasted a mean of 24.3, 5.8, and 2.6 months, and included 2.8, 2.6, and 3.1 chemotherapy drugs per patient, respectively. Of the 80 patients who received first-line chemotherapy, 72 were prescribed melphalan and 55 patients received a combination of melphalan and prednisone, as recommended by Swedish treatment guidelines. The mean total cost per patient was euro88,199, or euro2770 per patient-month. Therapy-induced and comorbidity-related events constituted 42% of total costs, as much as autologous stem-cell transplantation and inpatient care together. Chemotherapy, bisphosphonate, and blood cell-enhancement drugs each amounted to only 2% of total costs, but chemotherapy drugs increased from euro29/month in first-line therapy to euro453/month in third-line therapy. The cost of treating Swedish patients with MM varied greatly between individuals but, overall, chemotherapy drugs constituted only a minor part of the total monthly cost (2%), whereas costs for inpatient stays and therapy-induced adverse events or comorbidity-related events accounted for 35% and42%, respectively. There was no significant differencein monthly cost between treatment lines.

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Growth during one year of treatment with fluticasone propionate or sodium cromoglycate in children with asthma.

The aim of this study was to compare accurately measured growth over 12 months in asthmatic children treated with either fluticasone propionate (FP) 50 micrograms twice daily (b.i.d.) or sodium cromoglycate (SCG) 20 mg four times daily (q.i.d.). After a 2-week run-in, asthmatic children aged 4-10 years from 15 UK centers were randomized in a 3:4 ratio to open-label FP (n = 52) or SCG (n = 70). After 8 weeks, those whose asthma was not adequately controlled were switched from SCG to FP or withdrawn. Standing height was measured (Holtain stadiometry) at baseline, after 8 weeks and at 6 weeks intervals thereafter for 1 year. Morning peak flows (PEFam) were recorded by patients for 2 weeks during baseline, and 1 week before each visit during treatment. Urinary free cortisol (24 h) was measured at baseline, 6 months, and 1 year. After 8 weeks, 22 patients were withdrawn from SCG group (and were switched to FP), and five patients were withdrawn from the FP group due to poor asthma control. A further 21 and 11 patients were withdrawn from the SCG and FP groups, respectively, during the course of the study. There were no significant differences between patients who received FP and SCG for 1 year (n = 34 and n = 26, respectively) in terms of height velocity adjusted for age and gender (HV), or height velocity standard deviation scores adjusted for gender (HVSDS). Mean HV (mean HVSDS) were 6.0 cm/yr (0.1) and 6.5 cm/yr (0.5) for FP and SCG, respectively. There were no treatment differences in mean 24 h urinary free cortisol levels at 6 and 12 months. Mean % predicted PEFam improved over 1 year in both groups but to a greater degree in the FP group. We concluded that growth was normal in mildly asthmatic children receiving FP (50 micrograms bid) for 1 year. There were fewer withdrawals and lung function improved to a greater extent in FP treated patients than in patients receiving SCG.

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Safety and efficacy of a calcineurin inhibitor avoidance regimen in pediatric renal transplantation.

Thirty-four children were entered into a pilot trial of calcineurin inhibitor avoidance after living-donor kidney transplantation, the CN-01 study. Patients were treated with anti-CD25 mAb, prednisone, mycophenolate mofetil, and sirolimus. Twenty patients were maintained on the protocol for up to 3 yr of follow-up. One enrolled patient did not receive the transplant because of a donor problem, eight terminated because of one or more rejection episodes, four terminated because of adverse events, and one was lost to follow-up. Two grafts were lost, one as a result of chronic rejection and the other as a result of posttransplantation lymphoproliferative disorder. There were no deaths. The 6- and 12-mo acute rejection rates were 21.8 and 31.5%, respectively. GFR were stable throughout the course of the study, with a slight downward trend by 6 mo after transplantation followed by a slight upward trend to a mean of 70 ml/min thereafter. Early surveillance graft biopsies frequently showed focal interstitial mononuclear cellular infiltrates without overt vasculitis or tubulitis, but these infiltrates disappeared without treatment. Anti-HLA class I and II antibodies were detected in three patients before transplantation, and all three had acute rejections, including the two patients who lost their grafts. De novo anti-HLA Ab production occurred in only one patient after transplantation. There were two episodes of Epstein Barr virus-related posttransplantation lymphoproliferative disorder, one of which developed after the patient had been terminated from the study. It is concluded that calcineurin inhibitor-free immunosuppression can be safe and effective in pediatric living-donor renal transplantation. However, further modifications that are designed to lessen early rejection rates and decrease complications should be tested before this approach is used routinely.

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Combination Therapy of Metformin and Statin May Decrease Hepatocellular Carcinoma Among Diabetic Patients in Asia.

Previous studies have shown that metformin or statins may decrease hepatocellular carcinoma (HCC) in diabetic patients. Accordingly, this article evaluates whether combination therapy may further reduce HCC. Newly diagnosed type 2 diabetes mellitus (DM) patients, excluding those with history of malignancy prior to the date of DM diagnosis, were recruited to a DM cohort. DM patients developed HCC as the cancer cohort and the date for HCC diagnosis as index date. Non-cancer cohort was frequency matched with 4:1 according to age, sex, DM-year, and index date as case group from DM cohort. Patients who were treated with statins showed a 63% decreased risk of HCC (odds ratio [OR] = 0.37; 95% confidence interval [CI] = 0.27-0.49). Patients who consumed simvastatin, atorvastatin, or rosuvastatin significantly decreased risk for HCC (OR = 0.32, 0.31, and 0.22; 95% CI = 0.18-0.58, 0.19-0.52, and 0.08-0.61, respectively). Metformin combinations with simvastatin, atorvastatin, or rosuvastatin may decrease HCC (OR = 0.30, 0.30, and 0.24; 95% CI = 0.15-0.59, 0.16-0.54, and 0.08-0.70, respectively). The comorbidities for HCC were decreased by consuming simvastatin and atorvastatin (OR = 0.31 and 0.29; 95% CI = 0.14-0.67 and 0.15-0.57, respectively). Only combination therapy of metformin and simvastatin may significantly decreased HCC comorbidities (OR = 0.26; 95% CI = 0.11-0.60) in our study. In Asia, not all metformin combinations with statins may reduce the incidence of HCC and not all of this kind of combination therapy may decrease the HCC comorbidities.

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QTc interval prolongation in critically ill patients: Prevalence, risk factors and associated medications.

To investigate the prevalence and risk factors of acquired long QT syndrome (LQTS) on admission to a general Intensive Care Unit (ICU), and to assess the risk of LQTS associated with prescribed medications. Prospective observational, cross-sectional study approved by the Institutional Review Board. Between May 2014 and July 2016, 412 patients >18 years-old consecutively admitted to the ICU of a university hospital were included. LQTS was defined as a QT interval on the admission electrocardiogram corrected using Bazett's formula (QTc) >460 ms for men and >470 ms for women. All medications administered within 24 hours before admission were recorded. Logistic regression was used. LQTS prevalence was 27.9%. In LQTS patients, 70.4% had ≥ 1 LQTS-inducing drug prescribed in the 24 hours prior to ICU admission versus 70.4% in non-LQTS patients (p = 0.99). Bradycardia and Charlson morbidity index score are independent risk factors for LQTS. Haloperidol (OR 4.416), amiodarone (OR 2.509) and furosemide (OR 1.895) were associated with LQTS, as well as another drug not yet described, namely clopidogrel (OR 2.241). The LQTS is highly prevalent in critically ill patients, ICU patients are often admitted with LQTS-inducing medications, and patients with slow heart rate or with high Charlson comorbidity index should be evaluated for LQTS.

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Different effects of nifedipine and amlodipine on circulating catecholamine levels in essential hypertensive patients.

To compare the acute and chronic effects of nifedipine retard (NPA), nifedipine gastrointestinal therapeutic system (NGITS) and amlodipine at trough and peak plasma concentrations of drug on blood pressure and heart rate, and on plasma norepinephrine and epinephrine levels in patients with mild-to-moderate hypertension (diastolic blood pressure 95-115 mmHg). After 3-4 weeks' placebo treatment, patients of both sexes were randomly allocated to be administered 10 or 20 mg NPA twice a day, 30 or 60 mg NGITS once a day, and 5 or 10 mg amlodipine once a day for 6 weeks. Initially, for the first 2 weeks, the lowest dose of each drug was used, but higher doses were administered after 2 weeks if sitting diastolic blood pressure was > 90 mmHg. Patients were evaluated after administration of the first dose and after 6 weeks' therapy in a hospital setting. Blood samples were taken for high-performance liquid chromatography measurement of catecholamine and drug levels at various intervals for a period covering trough to peak drug level ranges. Administration of all three drugs reduced clinic blood pressure to the same level after 6 weeks' therapy, but heart rate was increased slightly only with amlodipine (P < 0.05). Administration of NPA reduced blood pressure more abruptly whereas administrations of NGITS and amlodipine induced smoother falls after acute and chronic treatments: a significant increase in heart rate was observed with amlodipine after chronic treatment. Both acute and chronic treatments with NPA (n = 19) increased norepinephrine levels (P < 0.01) transiently (2-4 h). In contrast, administration of NGITS (n = 22) did not increase norepinephrine levels and even induced a slight but significant decrease in norepinephrine levels 5-6 h after chronic treatments. Although administration of amlodipine (n = 22) did not increase norepinephrine levels transiently either after acute or after chronic administration, it did induce a sustained rise in basal norepinephrine levels by more than 50% after chronic therapy (P < 0.01). Plasma epinephrine levels were not increased by any of the treatments and even a slight decrease was observed 4 h after administration of a dose following chronic treatments with NGITS and amlodipine (P < 0.05). The transient increase in norepinephrine levels observed with NPA and the sustained increases in norepinephrine levels observed after chronic treatment with amlodipine suggest that sympathetic activation occurs with those two drugs. The lack of increase in norepinephrine levels after administration of NGITS suggests that this formulation does not activate the sympathetic system. The lowering of epinephrine levels after administrations of NGITS and amlodipine suggests that inhibition of release of epinephrine by the adrenal medulla occurs with longer-acting dihydropyridine formulations.

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Anterior chamber bleeding after laser peripheral iridotomy.

To our knowledge, this is the first study to describe the correlation of anterior chamber bleeding after laser peripheral iridotomy (LPI) and antiplatelet therapy. To determine the incidence and amount of anterior chamber bleeding after laser peripheral iridotomy in patients whose condition is suggestive of primary angle-closure glaucoma (PACS) who continued their antiplatelet or anticoagulant treatment before undergoing LPI compared with when they discontinued treatment. A prospective controlled trial. Patients with suspected bilateral primary angle-closure and no other ocular disease who take antiplatelet or anticoagulant medications regularly (from January 2010-October 2011) were enrolled. The incidence of anterior chamber bleeding with and without antiplatelet and anticoagulant therapy. A total of 104 patients (208 eyes) participated in the study. Thirty-six eyes (34.6%) in the treated and untreated arms bled. The amount of bleeding did not differ significantly when the patient was on or off antiplatelet or anticoagulant treatment, nor did the immediate postprocedure mean intraocular pressure (P = .13). The type of antiplatelet or anticoagulant, total laser energy, age, sex, or color of irides were not risk factors for increased bleeding (P = .156 for all parameters). No indication was noted for discontinuing these medications before a high-powered pulsed laser peripheral iridotomy.

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