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Angiographic and platelet reactivity outcomes with prasugrel 60 mg pretreatment and clopidogrel 600 mg pretreatment in primary percutaneous coronary intervention.

Pretreatment with 60 mg of prasugrel is more effective than 300 mg of clopidogrel in reducing thrombotic complications with primary percutaneous coronary intervention (PCI). We compared angiographic outcomes and platelet reactivity between treatment with 60 mg of prasugrel and 600 mg of clopidogrel administered before primary PCI. In this single centre non-randomized study, 65 consecutive Asian patients with ST-elevation myocardial infarction (STEMI) received 60 mg of prasugrel before primary PCI. The pre- and post-PCI corrected thrombolysis in myocardial infarction frame count (CTFC) and the 8-h post-treatment platelet vasodilator-stimulated phosphoprotein (VASP) index was compared with a matched historical Asian STEMI cohort (n = 65) receiving 600 mg of clopidogrel pretreatment. Comparing the prasugrel and clopidogrel groups, the mean age was 54.1 ± 10.2 versus 55.5 ± 11.8 years, P = 0.238, and the mean body mass index was 24.6 ± 2.0 versus 24.7 ± 2.8 kg m(-2), P = 0.393. The mean pre-PCI CTFC was 82.1 ± 30.2 versus 86.1 ± 27.6, P = 0.045, and the mean post-PCI CTFC was 21.1 ± 13.9 versus 20.1 ± 9.2, P = 0.309. Pre-PCI coronary thrombi were visualised in 6.3 versus 18.1 %, P = 0.038. The median VASP index was 22.2 ± 24.5 versus 70.5 ± 17.5 %, P < 0.001, and high on-treatment platelet reactivity (VASP index > 50 %) was observed in 13.8 versus 84.3 %, P = 0.001. Rescue intracoronary glycoprotein inhibitors were administered to 29.7 versus 51.0 %, P = 0.018, respectively. Treatment with 60 mg of prasugrel before primary PCI was associated with lower platelet reactivity, a modest trend towards better pre-PCI angiographic outcomes, less pre-PCI coronary thrombi and less rescue glycoprotein inhibitor use compared with 600 mg of clopidogrel. The very high frequency of high on-clopidogrel platelet reactivity with 600 mg of clopidogrel in this Asian STEMI cohort deserves further study.

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Rehospitalization following percutaneous coronary intervention for commercially insured patients with acute coronary syndrome: a retrospective analysis.

While prior research has provided important information about readmission rates following percutaneous coronary intervention, reports regarding charges and length of stay for readmission beyond 30 days post-discharge for patients in a large cohort are limited. The objective of this study was to characterize the rehospitalization of patients with acute coronary syndrome receiving percutaneous coronary intervention in a U.S. health benefit plan. This study retrospectively analyzed administrative claims data from a large US managed care plan at index hospitalization, 30-days, and 31-days to 15-months rehospitalization. A valid Diagnosis Related Group code (version 24) associated with a PCI claim (codes 00.66, 36.0X, 929.73, 929.75, 929.78-929.82, 929.84, 929.95/6, and G0290/1) was required to be included in the study. Patients were also required to have an ACS diagnosis on the day of admission or within 30 days prior to the index PCI. ACS diagnoses were classified by the International Statistical Classification of Disease 9 (ICD-9-CM) codes 410.xx or 411.11. Patients with a history of transient ischemic attack or stroke were excluded from the study because of the focus only on ACS-PCI patients. A clopidogrel prescription claim was required within 60 days after hospitalization. Of the 6,687 ACS-PCI patients included in the study, 5,174 (77.4%) were male, 5,587 (83.6%) were <65 years old, 4,821 (72.1%) had hypertension, 5,176 (77.4%) had hyperlipidemia, and 1,777 (26.6%) had diabetes. At index hospitalization drug-eluting stents were the most frequently used: 5,534 (82.8%). Of the 4,384 patients who completed the 15-month follow-up, a total of 1,367 (31.2%) patients were rehospitalized for cardiovascular (CV)-related events, of which 811 (59.3%) were revascularization procedures: 13 (1.0%) for coronary artery bypass graft and 798 (58.4%) for PCI. In general, rehospitalizations associated with revascularization procedures cost more than other CV-related rehospitalizations. Patients rehospitalized for revascularization procedures had the shortest median time from post-index PCI to rehospitalization when compared to the patients who were rehospitalized for other CV-related events. For ACS patients who underwent PCI, revascularization procedures represented a large portion of rehospitalizations. Revascularization procedures appear to be the most frequent, most costly, and earliest cause for rehospitalization after ACS-PCI.

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Association between cough and angiotensin converting enzyme inhibitors versus angiotensin II antagonists: the design of a prospective, controlled study.

A common adverse experience in hypertensive patients treated with angiotensin converting enzyme (ACE) inhibitors is a tickling dry cough. The aim of the present study was to review clinical observations and mechanisms of cough associated with ACE inhibitors. In addition, since the AT1-type angiotensin II antagonists (represented by losartan, MK954, DuP753) are not expected to influence other systems (kinins, prostaglandins) affected by ACE inhibitors, we explored the hypothesis that antihypertensive therapy with these agents will not be associated with cough at a similar frequency or quality to that seen with ACE inhibitors. Patients with a history of an ACE inhibitor-associated dry cough confirmed by a second challenge with lisinopril were enrolled into an international, multicenter, randomly allocated, double-blind, parallel-group, controlled trial, to be treated with losartan, lisinopril or hydrochlorothiazide. The presence and severity of cough were assessed by a self-administered questionnaire and a visual analog scale, respectively. It is expected that the new class of antihypertensive agents, angiotensin II antagonists, will not be associated with the high incidence of dry cough associated with the use of ACE inhibitors. It appears that this cough is not related to alterations in the renin-angiotensin system but to kininase II effects.

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Excellent uricosuric efficacy of benzbromarone in cyclosporin-A-treated renal transplant patients: a prospective study.

Patients on cyclosporin A (CsA) often develop hyperuricaemia and gout. In transplant patients the use of uricosuric drugs for treating hyperuricaemia may be preferable to allopurinol because of the known interaction of the latter with azathioprine. We therefore prospectively studied the uricosuric efficacy of 100 mg benzbromarone (Bbr;Desuric) daily in 25 CsA-treated renal transplant patients with stable graft function and hyperuricaemia (> 359 mumol/l for females, > 491 mumol/l for males). Benzbromarone decreased plasma uric acid from 579 + 18 mumol/l to 313 +/- 24 mumol/l (mean +/- SEM; P < 0.0001) and thereby normalized plasma uric acid in 21 of 25 patients. The remaining four patients had creatinine clearances between 21 and 25 ml/min, the lowest of the entire study group. Mean fractional clearance of uric acid increased from 5.4 +/- 0.4% to 17.2 +/- 1.0% (P < 0.001). The relative decrease of plasma uric acid closely correlated with baseline creatinine clearance (r = 0.67; P < 0.001). CsA trough values were not influenced. None of the patients experienced any significant side-effects. As an unexpected find-ing, urinary uric acid excretion increased from 2082 +/- 175 mumol/24 h to 3233 +/- 232 mumol/24 h after 4 weeks' treatment with benzbromarone. In conclusion, benzbromarone normalized plasma uric acid in all CsA-treated renal transplant recipients with a creatinine clearance > 25 ml/min. Due to its excellent efficacy and lack of significant side-effects, benzbromarone appears to be preferable to allopurinol in CsA-treated renal transplant recipients with a creatinine clearance over 25 ml/min.

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Associations of HSD11B1 polymorphisms with tacrolimus concentrations in Chinese renal transplant recipients with prednisone combined therapy.

Tacrolimus requires close therapeutic drug monitoring because of its narrow therapeutic index and marked interindividual pharmacokinetic variation. In this study, we investigated the associations of polymorphisms in the gene encoding 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) with tacrolimus concentrations in Chinese renal transplant recipients during the early posttransplantation stage. A total of 258 renal transplant recipients receiving tacrolimus with prednisone (30 mg) combined therapy were genotyped for HSD11B1 rs846908, rs846910, rs4844880, and CYP3A5*3 polymorphisms. Tacrolimus trough concentrations were determined on days 6-9 after transplantation, measured by a chemiluminescent microparticle immunoassay. Among the CYP3A5 expressers, the dose-adjusted trough concentration (C0/D) of tacrolimus in HSD11B1 rs846908 AA homozygous individuals was considerably lower than found in GG+GA carriers [56.2 (23.9-86.6) versus 76.7 (12.6-220.0) (ng/ml)/(mg/kg), P = 0.0204]; HSD11B1 rs846910 AA homozygotes had a lower tacrolimus C0/D compared with GG+GA carriers [51.2 (23.9-86.6) versus 76.3 (12.6-220.0) (ng/ml)/(mg/kg), P = 0.0367]; carriers with the HSD11B1 rs4844880 AA genotype had a significantly lower tacrolimus C0/D with respect to carriers of TT+TA genotypes [61.3 (23.9-97.5) versus 77.2 (12.6-220.0) (ng/ml)/(mg/kg), P = 0.0002]; the HSD11B1 AA-AA-AA haplotype carriers had a lower tacrolimus C0/D than noncarriers [51.2 (23.9-86.6) versus 76.3 (12.6-220.0) (ng/ml)/(mg/kg), P = 0.0367]. These findings illustrate that the HSD11B1 genotypes are closely correlated with tacrolimus trough concentrations, suggesting that these polymorphisms may be useful for safer dosing of tacrolimus.

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Duloxetine vs. placebo in patients with painful diabetic neuropathy.

The aim of this study was to examine the efficacy and safety of duloxetine, a balanced and potent dual reuptake inhibitor of serotonin and norepinephrine, in the management of diabetic peripheral neuropathic pain. Serotonin and norepinephrine are thought to inhibit pain via descending pain pathways. In a 12-week, multicenter, double-blind study, 457 patients experiencing pain due to polyneuropathy caused by Type 1 or Type 2 diabetes mellitus were randomly assigned to treatment with duloxetine 20 mg/d (20 mg QD), 60 mg/d (60 mg QD), 120 mg/d (60 mg BID), or placebo. The diagnosis was confirmed by a score of at least 3 on the Michigan Neuropathy Screening Instrument. The primary efficacy measure was the weekly mean score of the 24-h Average Pain Score, which was rated on an 11-point (0-10) Likert scale (no pain to worst possible pain) and computed from diary scores between two site visits. Duloxetine 60 and 120 mg/d demonstrated statistically significant greater improvement compared with placebo on the 24-h Average Pain Score, beginning 1 week after randomization and continuing through the 12-week trial. Duloxetine also separated from placebo on nearly all the secondary measures including health-related outcome measures. Significantly more patients in all three active-treatment groups achieved a 50% reduction in the 24-h Average Pain Score compared with placebo. Duloxetine treatment was considered to be safe and well tolerated with less than 20 percent discontinuation due to adverse events. Duloxetine at 60 and 120 mg/d was safe and effective in the management of diabetic peripheral neuropathic pain.

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Evaluation of the Helicobacter pylori stool antigen test for monitoring eradication therapy.

We aimed to clarify the time course of the Helicobacter pylori stool antigen (HpSA) level during and after eradication therapy and to determine the appropriate time of measurement of HpSA to evaluate eradication. The subjects were 47 patients who were positive for H. pylori. The patients underwent a 1-wk regimen of triple therapy. The outcome of the eradication therapy was judged by urea breath test, culture, and histology 6 wk after the end of treatment. The HpSA level was serially measured nine times from before therapy until 12 wk after the end of therapy. In the group with successful eradication, HpSA became negative immediately after the end of therapy and the negativity persisted. In contrast, in the noneradication group HpSA became negative immediately after therapy, but became positive again within 2 wk after the end of therapy. The mean absorbance value of the HpSA test on the 4th day after the initiation of eradication therapy was significantly higher in the noneradication group than in the group with successful eradication. The diagnostic accuracy of the HpSA test increased to > or = 90% 2 wk after therapy and thereafter. Comparison of the diagnostic accuracy at 4 wk after the end of therapy showed no significant differences with that at 2, 6, 8, and 12 wk after the end of therapy. The course of the HpSA levels during and after eradication therapy in patients with successful eradication was quite different from that in noneradication patients. Measurement of HpSA was useful to evaluate eradication, and the appropriate evaluation of the outcome of treatment could be made as early as 2 wk after the end of therapy.

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Efficacy of atropine sulfate in combination with albuterol in the treatment for acute asthma.

To determine the efficacy of combination therapy using atropine sulfate and albuterol in the treatment for an acute exacerbation of asthma. A prospective, randomized double-blind, placebo-controlled study was performed in the ED of a large, inner-city, university-affiliated teaching hospital. Participants were a convenience sample of patients presenting to the ED between September 1993 and March 1994 with acute exacerbations of their asthma. Patients judged to be in extremis were excluded. All patients received 3 nebulized treatments with 2.5 mg of albuterol at 0, 30, and 60 minutes. Patients were randomized into 1 of 3 groups with the following added to their nebulizer solutions: 1) saline placebo during all 3 treatments; 2) 2.0 mg atropine sulfate added to the first nebulizer and saline in the second and third; or 3) 2.0 mg atropine to the first and third treatments (with saline in the second). No other medication was administered during the study period. At 90 minutes, the patients were evaluated for admission or release from the ED according to predetermined criteria, and additional medications were given as necessary. Vital signs, peak expiratory flow rate (PEFR), degree of wheezing, level of distress, and side effects were measured before and after each nebulizer treatment. Of the 153 patients eligible for the study, 126 completed the entire study protocol. There was no significant difference between the 3 groups on any parameter studied, including improvement of PEFR, vital signs, or level of distress. There was no difference in the admission rate between the 3 groups, nor was there a difference in the incidence of side effects among the groups. In this study population, combination therapy with atropine sulfate and albuterol offered no significant benefit over the use of albuterol alone in the treatment for acute exacerbation of asthma.

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Efficacy of galactose and adalimumab in patients with resistant focal segmental glomerulosclerosis: report of the font clinical trial group.

Patients with resistant focal segmental glomerulosclerosis (FSGS) who are unresponsive to corticosteroids and other immunosuppressive agents are at very high risk of progression to end stage kidney disease. In the absence of curative treatment, current therapy centers on renoprotective interventions that reduce proteinuria and fibrosis. The FONT (Novel Therapies for Resistant FSGS) Phase II clinical trial (NCT00814255, Registration date December 22, 2008) was designed to assess the efficacy of adalimumab and galactose compared to standard medical therapy which was comprised of lisinopril, losartan, and atorvastatin. Key eligibility criteria were biopsy confirmed primary FSGS or documentation of a causative genetic mutation, urine protein:creatinine ratio >1.0 g/g, and estimated glomerular filtration rate (eGFR) >40 ml/min/1.73 m(2). The experimental treatments - adalimumab, galactose, standard medical therapy-- were administered for 26 weeks. The primary endpoint was a 50 % reduction in proteinuria with stable eGFR. Thirty-two subjects were screened and 21 were assigned to one of the three study arms. While none of the adalimumab-treated subjects achieved the primary outcome, 2 subjects in the galactose and 2 in the standard medical therapy arm had a 50 % reduction in proteinuria without a decline in eGFR. The proteinuria response did not correlate with serial changes in the serum glomerular permeability activity measured by the Palb assay or soluble urokinase plasminogen activator receptor (suPAR). There were no serious adverse effects related to treatments in the study. Recruitment into this trial that addressed patients with resistant FSGS fell short of the enrollment goal. Our findings suggest that future studies of novel therapies for rare glomerular diseases such as FSGS may benefit from enrollment of patients earlier in the course of their disease. In addition, better identification of patients who are likely to respond to a new treatment based on biomarkers suggesting involvement of the disease pathway targeted by the experimental agent may reduce the required sample size and increase the likelihood of a favorable outcome.

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Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and simvastatin.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are effective agents in lowering cholesterol and triglycerides and are being used by human immunodeficiency virus-positive patients to treat the lipid elevation that may be associated with antiretroviral therapy. Many HMG-CoA reductase inhibitors and protease inhibitors are metabolized by the same cytochrome P450 enzyme 3A4 (CYP3A4). In addition, many protease inhibitors are potent inhibitors of CYP3A4. Therefore, coadministration of these two classes of drugs may cause significant drug interactions. This open-label, multiple-dose study was performed to determine the interactions between nelfinavir, a protease inhibitor, and two HMG-CoA reductase inhibitors, atorvastatin and simvastatin, in healthy volunteers. Thirty-two healthy subjects received either atorvastatin calcium (10 mg once a day) or simvastatin (20 mg once a day) for the first 14 days of the study. Nelfinavir (1,250 mg twice a day) was added on days 15 to 28. Pharmacokinetic assessment was performed on days 14 and 28. The study drugs were well tolerated. Nelfinavir increased the steady-state area under the plasma concentration-time curve during one dosing period (AUC(tau)) of atorvastatin 74% and the maximum concentration (C(max)) of atorvastatin 122% and increased the AUC(tau) of simvastatin 505% and the C(max) of simvastatin 517%. Neither atorvastatin nor simvastatin appeared to alter the pharmacokinetics of nelfinavir. It is recommended that coadministration of simvastatin with nelfinavir should be avoided, whereas atorvastatin should be used with nelfinavir with caution.

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Trends in use of ezetimibe after the ENHANCE trial, 2007 through 2010.

Results from the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial, announced in January 2008, demonstrated that ezetimibe use lowered cholesterol levels but did not slow the progression of atherosclerosis. To examine the association of this announcement with national patterns of ezetimibe prescribing, including medication initiation and discontinuation, as well as predictors of use. Retrospective analysis of a national sample of adults 18 years or older who were continuously enrolled in plans of a large US pharmacy benefit manager from 2007 to 2010. Lipid-lowering therapy prescription claims were categorized as ezetimibe-containing treatments or any other lipid-lowering agent. Initiation was defined as an ezetimibe claim without another in the prior 180 days; discontinuation, as an ezetimibe claim without another in the subsequent 180 days. From 2007 to 2010, 29.1% of the 10,597,296 continuously eligible adults obtained at least 1 lipid-lowering agent prescription. Among these adults, 17.8% were prescribed ezetimibe and 95.3% another lipid-lowering agent, predominantly statins. Ezetimibe use peaked in January 2008, when 2.5% of all adults were ezetimibe users, but declined to 1.8% by December 2010. The ENHANCE trial announcement was associated with a nonsignificant 0.16% fewer monthly ezetimibe users (P = .11) but a significant 0.14% more monthly monotherapy users and 0.30% fewer users of ezetimibe concomitant with other lipid-lowering agents (both P = .01). The ENHANCE trial was also associated with 0.44% fewer monthly ezetimibe initiations (P = .002) and 10.4% more monthly ezetimibe discontinuations (P < .001), particularly of ezetimibe monotherapy for both. More than half of adults who initiated ezetimibe use did so without first being prescribed another lipid-lowering agent, both before (50%-60%) and after (60%-70%) the trial. Those aged 50 to 64 years and those living in the East South Central US Census division were both more likely to initiate and less likely to discontinue ezetimibe after the ENHANCE trial. After announcement of the results of the ENHANCE trial, nearly 2% of all continuously enrolled adult beneficiaries within a large US pharmacy benefit manager used ezetimibe, although ezetimibe initiations declined and discontinuations increased.

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Benzodiazepine Use During Hospitalization: Automated Identification of Potential Medication Errors and Systematic Assessment of Preventable Adverse Events.

Benzodiazepines and "Z-drug" GABA-receptor modulators (BDZ) are among the most frequently used drugs in hospitals. Adverse drug events (ADE) associated with BDZ can be the result of preventable medication errors (ME) related to dosing, drug interactions and comorbidities. The present study evaluated inpatient use of BDZ and related ME and ADE. We conducted an observational study within a pharmacoepidemiological database derived from the clinical information system of a tertiary care hospital. We developed algorithms that identified dosing errors and interacting comedication for all administered BDZ. Associated ADE and risk factors were validated in medical records. Among 53,081 patients contributing 495,813 patient-days BDZ were administered to 25,626 patients (48.3%) on 115,150 patient-days (23.2%). We identified 3,372 patient-days (2.9%) with comedication that inhibits BDZ metabolism, and 1,197 (1.0%) with lorazepam administration in severe renal impairment. After validation we classified 134, 56, 12, and 3 cases involving lorazepam, zolpidem, midazolam and triazolam, respectively, as clinically relevant ME. Among those there were 23 cases with associated adverse drug events, including severe CNS-depression, falls with subsequent injuries and severe dyspnea. Causality for BDZ was formally assessed as 'possible' or 'probable' in 20 of those cases. Four cases with ME and associated severe ADE required administration of the BDZ antagonist flumazenil. BDZ use was remarkably high in the studied setting, frequently involved potential ME related to dosing, co-medication and comorbidities, and rarely cases with associated ADE. We propose the implementation of automated ME screening and validation for the prevention of BDZ-related ADE.

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The interscan variation of CT coronary artery calcification score: analysis of the Calcium Acetate Renagel Comparison (CARE)-2 study.

In the Calcium Acetate Renagel Evaluation (CARE)-2 study, the effects of calcium acetate plus atorvastatin (Lipitor) on the progression of coronary artery calcifications (CACs) are evaluated versus those of Renagel, monitored using dual electron beam tomography (EBT) scans (two scans at study initiation and two at follow up). The aim of this study is to estimate the interscan variation for the Agatston score and for the volume score determined in patients with end-stage renal disease (ESRD) in the CARE-2 study. CAC score and volume were measured at study initiation in 463 ESRD subjects (mean age: 59.4 +/- 12.5 years, 48.3% female). All patients underwent dual scanning using an EBT, as first scan of two needed to measure the progression of CAC when treated with sevelamer (Renagel) compared with calcium acetate with or without atorvastatin. All scans in all participants were completed by using an EBT system (GE Imatron, South San Francisco, CA). Interscan variability was defined by the following formula: abs (scan A - scan B) / (0.5 x scan A + 0.5 x scan B) x 100%, where A and B denote the first and second scan, respectively, of the dual scan procedure performed before treatment. We evaluated the reproducibility of the cutpoints commonly used for calcium scores clinically, namely 1-30, 31-100, 101-400, and >400. The CAC interscan variability was 11.8% using the Agatston score and 10.3% using the volume score. The reproducibility was then assessed using cutpoints 1-30, 31-100, 101-400, and >400. Agatston score variability for the four subgroups was 61.3%, 23%, 16.1%, and 8.2%, respectively (mean variability, 11.8%). Volume score variability was 60.0%, 14.4%, 14.6%, and 7.7%, respectively (mean variability, 10.3%). The correlation coefficient for scan A to scan B goes up significantly with increasing calcium scores and reaches 0.99 for scores greater than 400 (P < .0001). Interscan variability was sufficiently small for patients with calcium scores greater than 30. Our study thus demonstrates a sufficient reproducibility of the calcium score using EBT. This score allows for accurate serial assessment of these patients and for comparing different therapies.

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Characteristics of children with non-hodgkin lymphoma associated with primary immune deficiency diseases: descriptions of five patients.

An increased incidence of non-Hodgkin lymphoma (NHL) has been seen in various primary immune deficiency (PID) cases. The present study aimed to evaluate the clinical characteristics and treatment outcomes of five cases with NHL associated with primary immunodeficiency. We retrospectively evaluated five patients with primary immunodeficiency who developed NHL. Two patients had ataxia-telangiectasia (A-T), one patient had common variable immunodeficiency (CVID), one patient had Bloom's Syndrome, and one patient had Wiskott-Aldrich syndrome (WAS). All patients were male (median age, 8 years). Stage distribution was stage III in three patients and stage IV in two patients. Three patients had B-cell lymphoma and two had T-cell lymphoma. Reduced doses of Berlin-Frankfurt-Münster (BFM) and French Society of Pediatric Oncology (SFOP) regimens were used in four patients according to histopathological subtype. The two patients with ataxia and one patient with Bloom's Syndrome died of progressive/relapsed disease at months 5, 19, and 6, respectively. The patient with CVID associated with T-cell lymphoma has been in remission for 7 years. A full-dosage regimen of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) was successfully used in the patient with WAS and B-cell lymphoma; he was still in remission after 3 years. Primary immunodeficiency diseases are one of the strongest known risk factors for the development of NHL. Management of these patients remains problematic. There is a great need to develop new therapeutic approaches in this group. The use of rituximab in combination with CHOP may provide a promising treatment option for B-cell lymphomas associated with immunodeficiency.

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Resistance of Helicobacter pylori to antibiotics: the main limitation of current proton-pump inhibitor triple therapy.

Data showing the clinical relevance of Helicobacter pylori resistance, as well as recent data gathered from the MACH2 study, are presented. Despite the problems associated with testing for metronidazole resistance, a correlation between resistance and eradication failure is found in most studies of proton-pump inhibitor triple therapy, in which either amoxycillin or clarithromycin is used as the second antibiotic with metronidazole. Clarithromycin resistance is still low in most communities. Current data are scarce, but indicate that when present it has a higher negative impact on treatment outcome than metronidazole resistance. Resistance frequently emerges with treatment failure, although it is not clear to what extent resistant organisms will spread. In the MACH2 study, culture was used as one of the diagnostic tests and its sensitivity compared with the urea breath test was 99%. In addition, susceptibility tests could be performed on almost all strains. The overall rates of resistance to clarithromycin and metronidazole were found to be 3% (range 1-5%) and 24% (range 16-41%), respectively. There was a 15% decrease in success rate with omeprazole-metronidazole-clarithromycin treatment (from 91 to 76%) for metronidazole-resistant strains. The addition of omeprazole improved the efficacy of metronidazole-clarithromycin dual therapy. The best way to prevent resistance is to obtain the highest possible eradication rate.

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The effect of fibrin clot inhibitors on the immunomodulatory efficacy of Bacillus Calmette-Guérin therapy for non-muscle-invasive bladder cancer.

To determine if there is a difference in clinical outcomes among non-muscle-invasive bladder cancer patients taking fibrin clot-inhibiting (FCI) medications (aspirin, clopidogrel, or warfarin) while receiving Bacillus Calmette-Guérin (BCG) therapy compared with their counterparts not taking anticoagulation. Our Investigational Review Board-approved database was queried for patients who received an induction course of BCG from 2001 to 2011. The analysis included 224 patients with a minimum of 3 months of follow-up. Recurrence-free survival (RFS), cystectomy-free survival, overall survival, and disease-specific survival were analyzed using the Kaplan-Meier method stratified by FCI status. Logistic regression was used to predict the initial response rate to BCG and progression by FCI status. Of the 224 patients analyzed, 68, 19, and 23 patients were taking aspirin, clopidogrel and warfarin, respectively, at BCG induction. No specific FCI was associated with differences in cystectomy-free survival, overall survival, disease-specific survival, or the likelihood of progression at recurrence. Neither warfarin nor clopidogrel affected RFS. Patients taking aspirin trended toward increased RFS, although this was not statistically significant (P = .058). Multivariate analysis showed aspirin use was associated with an increased initial response to BCG (odds ratio, 2.41; P = .031) Contrary to the postulated inhibitory molecular effect of FCI on BCG-binding activity, this study did not substantiate a significant impact on BCG efficacy of the concomitant use of these medications during BCG induction. The observation that aspirin use potentiates an increased initial response to BCG may warrant further analysis.

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Treatment of hiccups in stroke rehabilitation with gabapentin: A case series and focused clinical review.

Persistent and intractable hiccups have a major impact on quality of life and can be a barrier to stroke rehabilitation. The first-line treatment for intractable hiccups, chlorpromazine, can have sedating effects, which may negatively affect rehabilitation participation. Gabapentin has been reported in several cases to be effective in hiccup treatment in both the general and post-stroke populations. To describe the use of gabapentin for treatment of persistent or intractable hiccups in post-stroke patients. Four cases were identified by clinicians for a retrospective review. A literature review was concurrently conducted. This case series presents four patients with improvement or resolution of intractable hiccups on gabapentin in a stroke rehabilitation setting. Therapeutic dose ranged from 100 mg TID to 400 mg BID. Treatment duration ranged from 2 days to 5.5 weeks. Adjuncts were used in three of the cases. A potential side effect was worsened confusion in one case. Evidence on the use of gabapentin for persistent or intractable hiccups is limited. This case series expands on the current literature by examining and comparing the current literature to our cases and exploring issues related to dosing, titration, side effects, and adjuncts to gabapentin.

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Results of a multicenter, 8-week, parallel-group, randomized,double-blind, double-dummy, Phase III clinical trial to evaluate the efficacy and tolerability of amlodipine maleate versus amlodipine besylate in Korean patients with mild to moderate hypertension.

Recently, amlodipine maleate was developed and tested in preclinical and Phase I clinical trials in Korea. The studies found pharmacokinetics and pharmacodynamics similar to those of amlodipine besylate. The aim of this study was to compare the efficacy and tolerability of amlodipine maleate with those of amlodipine besylate in Korean patients with mild to moderate hypertension. This was a multicenter, 8-week, parallel-group, randomized, double-blind, double-dummy, Phase III clinical trial. Eligible patients were Korean, aged 18 to 75 years, had hypertension, and were either taking antihypertensive medications or had a documented sitting diastolic blood pressure of 90 to 109 mm Hg. After a washout period of 2 weeks, patients were randomized to amlodipine maleate or amlodipine besylate for 8 weeks. In both groups, the medications were initiated at 5 mg QD. At day 29, the medication dose was increased to 10 mg QD if sitting diastolic blood pressure (SiDBP) was > or = 90 mm Hg. One hundred eighteen patients were enrolled. Fifty-seven patients received amlodipine maleate (29 men, 28 women; mean [SD] age, 49.0 [11.4] years) and 61 received amlodipine besylate (35 men, 26 women; mean [SD] age, 51.6 [9.4] years). Baseline mean (SD) values for sitting systolic blood pressure and SiDBP were 152.0 (12.2) mm Hg and 98.1 (5.6) mm Hg, respectively, for the amlodipine maleate group and 153.4 (14.0) mm Hg and 98.1 (5.5) mm Hg, respectively, for the amlodipine besylate group. In this population, amlodipine maleate was not inferior to amlodipine besylate: the lower limit of the 2-sided 95% CI for the treatment difference in SiDBP was greater than -4 mm Hg. The between-group difference in SiDBP response rate (the proportion of patients who experienced adequate SiDBP reductions) did not reach statistical significance: 85.7% (42/49) for the amlodipine maleate group and 91.8% (45/49) for the amlodipine besylate group. Compliance rates were similar between groups, with mean (SD) compliance rates of 97.4% (2.8%) and 97.1% (3.6%) in the amlodipine maleate and amlodipine besylate groups, respectively. Also, there were no significant differences in the incidences of drug-related clinical and laboratory adverse events; the most common were headache, flushing, facial edema, and paresthesia. In this population, the efficacy and tolerability observed with amlodipine maleate were similar to those seen with amlodipine besylate.

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Beneficial ex vivo immunomodulatory and clinical effects of clarithromycin in COVID-19.

Macrolide antibiotics have immunomodulatory properties which may be beneficial in viral infections. However, the precise effects of macrolides on T cell responses to COVID, differences between different macrolides, and synergistic effects with other antibiotics have not been explored. We investigated the effect of antibiotics (amoxicillin, azithromycin, clarithromycin, and combined amoxicillin with clarithromycin) on lymphocyte intracellular cytokine levels and monocyte phagocytosis in healthy volunteer PBMCs stimulated ex vivo with SARS-CoV-2 S1+2 spike protein. A retrospective cohort study was performed on intensive care COVID-19 patients. Co-incubation of clarithromycin with spike protein-stimulated healthy volunteer PBMCs ex vivo resulted in an increase in CD8⁺ (p = 0.004) and CD4⁺ (p = 0.007) IL-2, with a decrease in CD8⁺ (p = 0.032) and CD4⁺ (p = 0.007) IL-10. The addition of amoxicillin to clarithromycin resulted in an increase in CD8⁺ IL-6 (p = 0.010), decrease in CD8⁺ (p = 0.014) and CD4⁺ (p = 0.022) TNF-alpha, and decrease in CD8⁺ IFN-alpha (p = 0.038). Amoxicillin alone had no effect on CD4⁺ or CD8⁺ cytokines. Co-incubation of azithromycin resulted in increased CD8⁺ (p = 0.007) and CD4⁺ (p = 0.011) IL-2. There were no effects on monocyte phagocytosis. 102 COVID-19 ICU patients received antibiotics on hospital admission; 62 (61%) received clarithromycin. Clarithromycin use was associated with reduction in mortality on univariate analysis (p = 0.023), but not following adjustment for confounders (HR = 0.540; p = 0.076). Clarithromycin has immunomodulatory properties over and above azithromycin. Amoxicillin in addition to clarithromycin is associated with synergistic ex vivo immunomodulatory properties. The potential benefit of clarithromycin in critically ill patients with COVID-19 and other viral pneumonitis merits further exploration.

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A comparative study on the effectiveness of losartan/hydrochlorothiazide and telmisartan/hydrochlorothiazide in patients with hypertension.

Long-term effects of a low-dose hydrochlorothiazide (HCTZ) with losartan (LOS) on uric acid (UA) metabolism as well as glucose metabolism have been studied in hypertensive patients in comparison with those of a low-dose HCTZ with telmisartan (TEL). Fifty-nine hypertensive patients were allocated to a combination therapy with either losartan (50 mg/day)/HCTZ (12.5 mg/day) (LOS + HCTZ group: n = 37) or telmisartan (40 mg/day)/HCTZ (12.5 mg/day) (TEL + HCTZ group: n = 22), respectively. Before and 1 year after the treatment, blood pressure and biochemical parameters of blood and urine were evaluated. Both systolic and diastolic blood pressures significantly decreased in two groups, without any statistical differences among them. LOS + HCTZ caused no changes in the serum UA level or the ratio of UA clearance to creatinine clearance (CUA/Ccr), whereas TEL + HCTZ significantly increased the serum UA level and reduced CUA/Ccr. LOS + HCTZ did not influence CUA/Ccr in patients with their serum UA below 5.4 mg/dl, while LOS + HCTZ significantly increased CUA/Ccr in patients with their serum UA above 5.5 mg/dl. TEL + HCTZ significantly reduced CUA/Ccr in patients with their serum UA below and above 5.4 mg/dl to increase serum UA level significantly. Neither combination therapies caused any changes in fasting plasma glucose, HbA1c and HOMA-R. In patients with their serum UA level above 5.4 mg/dl, TEL + HCTZ increased HOMA-R, whereas LOS + HCTZ did not. LOS + HCTZ did not influence UA metabolism as well as glucose metabolism, likely because of inhibitory action of losartan on URAT1, although TEL + HCTZ were accompanied with impairment of the UA metabolism and glucose metabolism.

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Comparison of two methods of presenting risk information to patients about the side effects of medicines.

To determine whether the use of verbal descriptors suggested by the European Union (EU) such as "common" (1-10% frequency) and "rare" (0.01-0.1%) effectively conveys the level of risk of side effects to people taking a medicine. Randomised controlled study with unconcealed allocation. 120 adults taking simvastatin or atorvastatin after cardiac surgery or myocardial infarction. Cardiac rehabilitation clinics at two hospitals in Leeds, UK. A written statement about one of the side effects of the medicine (either constipation or pancreatitis). Within each side effect condition half the patients were given the information in verbal form and half in numerical form (for constipation, "common" or 2.5%; for pancreatitis, "rare" or 0.04%). The estimated likelihood of the side effect occurring. Other outcome measures related to the perceived severity of the side effect, its risk to health, and its effect on decisions about whether to take the medicine. The mean likelihood estimate given for the constipation side effect was 34.2% in the verbal group and 8.1% in the numerical group; for pancreatitis it was 18% in the verbal group and 2.1% in the numerical group. The verbal descriptors were associated with more negative perceptions of the medicine than their equivalent numerical descriptors. Patients want and need understandable information about medicines and their risks and benefits. This is essential if they are to become partners in medicine taking. The use of verbal descriptors to improve the level of information about side effect risk leads to overestimation of the level of harm and may lead patients to make inappropriate decisions about whether or not they take the medicine.

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Steroid-antiviral treatment improves the recovery rate in patients with severe Bell's palsy.

The extent of facial nerve damage is expected to be more severe in higher grades of facial palsy, and the outcome after applying different treatment methods may reveal obvious differences between severe Bell's palsy and mild to moderate palsy. This study aimed to systematically evaluate the effects of different treatment methods and related prognostic factors in severe to complete Bell's palsy. This randomized, prospective study was performed in patients with severe to complete Bell's palsy. Patients were assigned randomly to treatment with a steroid or a combination of a steroid and an antiviral agent. We collected data about recovery and other prognostic factors. The steroid treatment group (S group) comprised 107 patients, and the combination treatment group (S+A group) comprised 99 patients. There were no significant intergroup differences in age, sex, accompanying disease, period from onset to treatment, or results of an electrophysiology test (P >.05). There was a significant difference in complete recovery between the 2 groups. The recovery (grades I and II) of the S group was 66.4% and that of the S+A group was 82.8% (P=.010). The S+A group showed a 2.6-times higher possibility of complete recovery than the S group, and patients with favorable electromyography showed a 2.2-times higher possibility of complete recovery. Combined treatment with a steroid and an antiviral agent is more effective in treating severe to complete Bell's palsy than steroid treatment alone.

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De novo anti-HLA antibodies in renal allograft recipients: a cross-section study.

The occurrence of anti-HLA antibodies plays a well established role in solid organ rejection. The development of x-MAP multiple bead technology (Luminex) has enabled more accurate detection and definition of these alloantibodies. In 267 kidney transplant patients with stable allograft function for ≥3 years, we analyzed the presence of anti-HLA antibodies by Luminex technology. These patients had no alloantibodies before transplantation, and the immunosuppression treatment was: tacrolimus, cyclosporine, mycophenolate mofetil, prednisone, everolimus, and/or sirolimus. Fifteen of the 267 patients showed anti-HLA class I antibodies and 12 showed anti-HLA class II antibodies, Seven patients had donor-specific antibodies (DSA): 1 anti-HLA class I, 5 anti-HLA class II, and 1 with both classes. No differences were found between DSA and the use or not of any specific therapy. However, in the retrospective review, we found a higher incidence of acute rejection episodes in the immediate posttransplant period among patients who developed class II DSA than those without DSA. The prevalence of patients with normal renal function who develop DSA beyond 3 years after transplantation was relatively low. Steroid or withdrawal replacement of calcineurin inhibitors with inhibitors of mammalian target of rapamycin seem to not be risk factors to increase the development of DSA. The finding that patients who developed DSA showed a higher rate of previous acute rejection episodes suggested that they should be monitored more frequently for HLA antibodies.

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Oral etoposide and oral prednisone for the treatment of castration resistant prostate cancer.

Treatment options for patients with castration-resistant prostate cancer (CRPC) are limited. The purpose of our study was to investigate the safety and efficacy in terms of prostate-specific antigen (PSA) response of a low-dose oral combination of etoposide and prednisone in patients with CRPC. Thirty-nine patients with prostate cancer (median age, 77.9 years) with progressive disease after standard hormonal therapy were enrolled. Etoposide (25 mg, twice daily) and prednisone (5 mg, twice daily) were administered orally. Each cycle comprised 21 consecutive days of treatment followed by a 7-day drug holiday. All patients previously treated with an antiandrogen were required to undergo antiandrogen withdrawal prior to entry into the study. A total of 226 cycles were administered with a median of 6.7 cycles per patient (range, 1-18 cycles). Sixteen of 39 patients (41%) with elevated PSA levels at baseline achieved at least a 50% reduction in PSA levels. Median progression-free survival for all patients was 5.9 months (range, 1-17 months). No Grade 4 toxicities were observed. The predominant toxicities were mucositis, nausea, fatigue, and anemia in twelve, nine, eight, and seven patients, respectively. Hematologic toxicity was infrequent, with no episodes of febrile neutropenia. The combination of low-dose etoposide and prednisone is an efficacious and reasonably well-tolerated oral regimen in the treatment of elderly patients with CRPC. This regimen can be easily administered in an outpatient setting and does not require frequent patient visits.

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Reduction of oral toxicity of 5-fluorouracil by allopurinol mouthwashes.

5-Fluorouracil (5-FU) is the most effective drug in gastrointestinal cancer. Mucositis and bone marrow toxicity are the two major limiting side effects. In our effort to reduce mucositis we administered 'Allopurinol' mouthwash in 16 patients who had experienced oral mucositis during prior treatment with 5-FU. In all patients significant reduction of oral toxicity was noticed as well as prolonged pain relief. This observation must be tested by controlled clinical trial.

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The effect of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes: results from a prospective pharmacological study.

Thiopurine therapy is often discontinued in inflammatory bowel disease (IBD) patients. The xanthine oxidase (XO) inhibitor allopurinol has previously shown to enhance thiopurine efficacy and to prevent adverse reactions, the mechanism of this beneficial interaction is not completely clarified. The aim of this study is to observe possible effects of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes. A prospective study of IBD patients failing thiopurine therapy due to a skewed thiopurine metabolism was performed. Patients were treated with allopurinol and azathioprine or mercaptopurine. Xanthine oxidase, hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and thiopurine S-methyl transferase (TPMT) activities, and thiopurine metabolites concentrations were measured during thiopurine monotherapy, and after 4 and 12 weeks of combination therapy. Of fifteen IBD patients, XO activity decreased from 0.18 (IQR 0.08-0.3) during thiopurine monotherapy to 0.14 (IQR 0.06-0.2) and 0.11 (IQR 0.06-0.2; p=0.008) mU/hour/ml at 4 and 12 weeks, respectively. HGPRT activity increased from 150 (IQR 114-176) to 180 (IQR 135-213) and 204 nmol/(h×mg protein) (IQR 173-213; p=0.013). TPMT activity seemed not to be affected. 6-Thioguanine nucleotide concentrations increased from 138 (IQR 119-188) to 235 (223-304) and to 265 pmol/8×10^8 (IQR 188-344), whereas 6-methyl mercaptopurine ribonucleotides concentrations decreased from 13230 (IQR 7130-17420) to 690 (IQR 378-1325) and 540 (IQR 240-790) pmol/8×10^8 at 4 and 12 weeks of combination therapy (both p<0.001). Allopurinol and thiopurine combination-therapy seems to increase HGPRT and decrease XO activity in IBD patients, which at least in part may explain the observed changes in thiopurine metabolite concentrations.

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Cardiotoxicity of epirubicin and doxorubicin: a double-blind randomized study.

24 patients with non-Hodgkin lymphoma were randomized into two multidrug regimens including either epirubicin (N = 12) or doxorubicin (N = 12) to establish the cardiotoxicity of each treatment modality. At cumulative doses of 400-500 mg/m2 left ventricular ejection fraction (LVEF) at rest determined by radionuclide angiocardiography decreased significantly more in the doxorubicin (-15 +/- 11%) than in the epirubicin group (0 +/- 13%, p less than 0.005). During epirubicin therapy no clinically significant cardiotoxicity developed, but a decrease larger than 10% in LVEF was seen in 4 of 12 patients at a mean cumulative level of 450 mg/m2. During doxorubicin therapy 1 patient developed a heart failure at a cumulative level of 200 mg/m2 and, altogether, in 7 patients LVEF decreased more than 10%. The monitoring of cardiac toxicity is imperative in patients treated with doxorubicin and is advisable if the patient is expected to receive epirubicin at more than 450 mg/m2.

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Preoperative transversus abdominis plane block decreases intraoperative opiate use during pancreatoduodenectomy.

Multimodal analgesia and regional anesthetic blocks, such as transversus abdominis plane (TAP) block, decrease postoperative opiate consumption but their effect on intraoperative opiates is unknown. This was a retrospective review of patients undergoing pancreatoduodenectomy between June 2018 and February 2021, in which perioperative data, operative times, and medication administration data were collected. Intraoperative opiate use was calculated in total morphine equivalent doses (MED) for each patient and adjusted for operative time. Univariate analysis and multivariate linear regression were performed to determine factors affecting intraoperative opiate requirements. Of the 169 patients in the study, 51 (30.2%) received pre-surgical TAP blocks and 118 (69.8%) did not. There were no statistically significant differences in intraoperative opiate use with preoperative acetaminophen (p = 0.527), celecoxib (p = 0.553), gabapentin (p = 0.308), intraoperative ketorolac (p = 0.698) or epidural placement (p = 0.086). Minimally invasive surgery had lower intraoperative opiate use compared to open (p = 0.011), as well as pre-surgical TAP block compared to no pre-surgical block (5.24 vs 7.27 MED/hour, p < 0.001). On multivariate linear regression, pre-surgical TAP block (p = 0.001) was independently associated with decreased intraoperative opiate use. Preoperative TAP blocks were associated with decreased intraoperative opiate use during pancreatoduodenectomy and should be considered for routine use.

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Probiotic supplementation with Lactobacillus plantarum and Pediococcus acidilactici for Helicobacter pylori therapy: A randomized, double-blind, placebo-controlled trial.

To evaluate the safety, tolerability and efficacy of a probiotic supplementation for Helicobacter pylori (H. pylori) eradication therapy. Consecutive adult naive patients with a diagnosis of H. pylori infection who were prescribed eradication therapy according to clinical practice (10-day triple or nonbismuth quadruple concomitant therapy) randomly received probiotics (1 × 10⁹ colony-forming units each strain, Lactobacillus plantarum and Pediococcus acidilactici) or matching placebo. Side effects at the end of the treatment, measured through a modified De Boer Scale, were the primary outcome. Secondary outcomes were compliance with therapy and eradication rates. A total of 209 patients (33% triple therapy, 66% non-bismuth quadruple therapy) were included [placebo (n = 106) or probiotic (n = 103)]. No differences were observed regarding side effects at the end of the treatment between groups (β -0.023, P 0.738). Female gender (P < 0.001) and quadruple therapy (P 0.007) were independent predictors of side effects. No differences in compliance were observed, regardless of the study group or eradication therapy. Eradication rates were similar between groups [placebo 95% (95% confidence interval (CI), 89% to 98%) vs probiotic 97% (95% CI, 92% to 99%), P 0.721]. There were no relevant differences in cure rates (>90% in all cases) between triple and quadruple concomitant therapy. Probiotic supplementation containing Lactobacillus Plantarum and Pediococcus acidilactici to H. pylori treatment neither decreased side effects nor improved compliance with therapy or eradication rates.

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Treatment response for acute depression is not associated with number of previous episodes: lack of evidence for a clinical staging model for major depressive disorder.

Mental illness has been observed to follow a neuroprogressive course, commencing with prodrome, then onset, recurrence and finally chronic illness. In bipolar disorder and schizophrenia responsiveness to treatment mirrors these stages of illness progression, with greater response to treatment in the earlier stages of illness and greater treatment resistance in chronic late stage illness. Using data from 5627 participants in 15 controlled trials of duloxetine, comparator arm (paroxetine, venlafaxine, escitalopram) or placebo for the treatment of an acute depressive episode, the relationship between treatment response and number of previous depressive episodes was determined. Data was dichotomised for comparisons between participants who had >3 previous episodes (n=1697) or ≤3 previous episodes (n=3930), and additionally for no previous episodes (n=1381) or at least one previous episode (n=4246). Analyses were conducted by study arm for each clinical trial, and results were then pooled. There was no significant difference between treatment response and number of previous depressive episodes. This unexpected finding suggests that treatments to reduce symptoms of depression during acute illness do not lose efficacy for patients with a longer history of illness.

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Valproic Acid significantly lowers serum concentrations of olanzapine-an interaction effect comparable with smoking.

Preliminary reports have indicated that valproic acid (VPA) reduces serum concentrations of olanzapine (OLZ). The aim of this study was to investigate the impact of VPA and other antiepileptic drugs (AEDs) on serum concentrations of OLZ and 3 of its major metabolites in a large-scale material of therapeutic drug monitoring samples. OLZ-treated patients were stratified into subgroups according to coadministration of various AEDs, that is, lamotrigine (LTG; 110 patients/153 samples), VPA (92/166), LTG + VPA (7/12), carbamazepine (CBZ) (8/8), oxcarbazepine (2/3), gabapentin (3/4), levetiracetam (2/3), and topiramate (2/2). A control group treated with OLZ without AEDs was also included (205/247). Dose-adjusted serum concentrations (C:D ratios) of OLZ and its major metabolites (N-desmethyl, N-oxide, and 10-N-glucuronide) were compared between AED subgroups and controls, using linear mixed model analyses with age, gender, and cigarette smoking as covariates. Significantly lower OLZ C:D ratios were found in patients comedicated with VPA (-32%, P < 0.001), VPA + LTG (-31%, P < 0.01), and CBZ (-50%, P < 0.001), compared with controls. The 10-N-glucuronide concentration was significantly lower in patients comedicated with VPA (-26%, P < 0.001), whereas CBZ significantly lowered N-desmethyl (-42%, P = 0.001) and N-oxide (-52%, P < 0.001) metabolite concentrations. C:D ratios of OLZ and metabolites were not significantly affected by comedication with LTG or any of the other AEDs. All covariates were significant determinants of OLZ C:D ratio, that is, age 60 years or above +35% (P < 0.001), female gender +11% (P < 0.01) and smoking -32% (P < 0.001). Concurrent use of VPA significantly decreases serum concentrations of OLZ to an extent comparable with smoking. The mechanism behind the interaction could not be derived from the results of this study.

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Safety and effectiveness of direct oral anticoagulants in patients with nephrotic syndrome: a report of 21 cases.

Nephrotic syndrome (NS) is associated with increased risk of thromboembolic events (TE) adding to the morbidity and mortality. International guidelines recommend prophylactic anticoagulation in patients with NS and high risk of TE, but no studies have identified the optimal type of anticoagulation in NS. We aimed to assess the effectiveness and safety of direct oral anticoagulant (DOAC) by analyzing the thromboembolic and bleeding events in NS patients prescribed DOAC as primary prophylaxis to prevent TE or as treatment for TE occurring in relation to NS. We performed a single-center, retrospective study including patients with NS, a plasma albumin less than 25 g/L and prophylactic anticoagulation treatment with DOAC at the Department of Renal Medicine at Aarhus University Hospital, Denmark from July 2016 to June 2021. Patients treated with DOAC as thromboprophylaxis for other indications than NS were excluded. Baseline characteristics and outcomes, including TE, bleeding and other adverse effects associated with DOAC were obtained from medical records. We identified 268 patients treated with DOAC of which 21 patients with NS were included in the study. Nineteen patients were prescribed DOAC as thromboprophylaxis and two patients received DOAC due to previous TE, which was considered associated with the NS. The type of DOAC prescribed was apixaban (n = 10) and rivaroxaban (n = 11). No patients experienced TE during DOAC treatment, while five patients had a minor bleeding episode. Patients who experienced bleeding episodes were older (median 62 vs 51 years), more often female (80%) and had been on DOAC for a longer period (204 days vs 47 days). Neither the HAS-BLED score nor GN-risk-score predicted the risk of minor bleedings in this population. In this case series, no new TE and only minor bleeding complications were observed among adult NS patients treated with DOAC.

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Respiratory effects of four adrenergic blocking agents combined with a diuretic in treating hypertension with concurrent chronic obstructive lung disease.

The study was a comparison of the effects on respiratory function produced by four antihypertensive agents with receptor-blocking properties (atenolol, oxprenolol, labetalol, metoprolol), when used in combination with a diuretic (chlorthalidone) in four homogeneous groups of hypertensive patients also suffering from chronic obstructive lung disease. All the agents with the exception of labetalol caused systematic and considerable worsening of functional parameters monitored in the trial. Treatment with labetalol, on the other hand, led to an improvement in respiratory function. Labetalol thus proved to be the most reliable and selective of the drugs tested for administration to patients with severe chronic airflow limitation.

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Metformin Triggers Autophagy to Attenuate Drug-Induced Apoptosis in NSCLC Cells, with Minor Effects on Tumors of Diabetic Patients.

The biologic plausibility of an association between type 2 diabetes mellitus (T2D) and lung cancer has received increasing attention, but the results of investigations remain largely inconclusive. In the present study we investigated the influence of the anti-diabetic drug metformin on the cytotoxic effects of EGFR targeted therapy and chemotherapy in 7 non-small cell lung cancer (NSCLC) cell lines and a cohort of lung cancer patients with/without T2D. In vitro cell viability assays indicated that metformin didn't potentiate the growth inhibitory effects of erlotinib at different doses in cell lines that are of distinct genetic background. EGFR downstream signaling evaluation further demonstrated that metformin, at its IC₅₀ value, modified apoptosis caused in erlotinib or chemotherapeutic agent-treated cells via AKT activation and the inhibition of caspase 3 and PARP cleavages. These regulations were driven independently from EGFR, LKB1, KRAS, PTEN and p53 status. Metformin triggered autophagy (LC3B expression) was identified to interplay with apoptosis to attenuate the drug effect and postpone cancer cell death. In the retrospective study of 8 NSCLC patients, the administration of metformin did not induce statistically significant changes as assessed by immunohistochemical staining of pERK, pAKT and cleaved PARP. Consequently, the application of metformin for T2D NSCLC patients receiving chemo or EGFR targeted therapy should be considered with caution.

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High-dose intensity cyclophosphamide, epidoxorubicin, vincristine and prednisone by shortened intervals and granulocyte colony-stimulating factor in non-Hodgkin's lymphoma: a phase II study.

Twenty patients with non-Hodgkin's lymphoma were treated with a combination of cyclophosphamide (750 mg m(-2), day 1), epidoxorubicin (60 mg m(-2), day 1), vincristine (1.4 mg m(-2), day 1) and prednisone (100 mg m(-2), days 1-5) every 14 days. Shortening of intervals was associated with the prophylactic employment of granulocyte colony-stimulating factor (G-CSF; specifically, filgrastim) administered at a dose of 300 microg subcutaneously from day 6 to day 11. The ratio between actually delivered dose intensity and planned dose intensity was 1.0 in 18 out the 20 patients. Toxicity was acceptable; response rate and survival are in the expected range. The present study demonstrated the feasibility of acceleration of chemotherapy cycles to obtain dose intensification in non-Hodgkin's lymphoma.

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The rational use of diuretics in the treatment of arterial hypertension.

The development of modern pharmacologic diuretic agents has revolutionized the therapy of arterial hypertension. The diuretics currently available are easily administered orally, are effective in the presence of alkalosis or acidosis, are non-toxic and have a low incidence of side effects which are readily circumvented or treated. Loop diuretics such as furosemide have the capacity to be effective in patients with diminished renal function or clinical situations that have a powerful stimulus to sodium retention. In clinical circumstances when renal potassium loss is to be prevented such as in patients receiving digitalis, the addition of a potassium-sparing diuretic to either a thiazide or furosemide will achieve the clinical goal of providing an effective diuresis while inhibiting potassium excretion. The mechanism of antihypertensive activity of the diuretic agents appears to be the reduction of extracellular fluid volumes and plasma volumes. Hence, the clinical dictum that to be effective as an antihypertensive agent, diuretics should be administered in diuretic doses. Besides being the cornerstone of initial antihypertensive therapy, diuretics also play an important role in antihypertensive therapy of patients with moderate to severe hypertension who are receiving potent antihypertensive drugs of the vasodilator or sympatholytic class of compounds. Indeed, one of the most important steps in the successful therapy of these patients receiving multiple drugs, is the re-assessment of the diuretic agent. The sodium retention and consequent fluid volume expansion associated with the administration of these potent antihypertensive agents may often cause these patients to develop apparent drug resistance since the thiazide diuretics are not potent enough to counteract the powerful stimulus to sodium retention caused by these antihypertensive agents. The re-evaluation of the diuretic agent at this point will usually necessitate the substitution of furosemide for thiazide or the doubling of the dose of the present loop diuretic. A working knowledge of the physiology of urine formation and the sites of action of currently available diuretic agents will enable the clinician to tailor the diuretic agent to the clinical circumstances of an individual patient and allow the clinician to rationally select a diuretic for the treatment of arterial hypertension.

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Gabapentin effect on spasticity in multiple sclerosis: a placebo-controlled, randomized trial.

To investigate the effect of gabapentin on subject self-report and physician-administered spasticity scales in individuals with multiple sclerosis. Prospective, double-masked, placebo-controlled, crossover design. The Multiple Sclerosis Center at the Denver Veterans Affairs Medical Center. Subjects were titrated to either 900 mg gabapentin orally three times a day or placebo over a 6-day period. Subjects underwent a 14-day washout and then were crossed over. No other changes were made to their medication regimen. The outcome measures were divided into two categories: subject self-report scales physician-administered scales. Subject self-report scales included the spasm frequency scale, spasm severity scale, interference with function scale, painful spasm scale, and global assessment scale. Physician-administered scales included the Modified Ashworth Scale, clonus scale, deep tendon reflexes, plantar stimulation response, and the Kurtzke Expanded Disability Status (EDSS) Scale. Digit Span and Digit Symbol subtests of the WAIS-R Intelligence Scale were administered to assess for possible impaired concentration. The Fatigue Impact Scale was administered to assess for changes in fatigue. The adjective generation technique was administered to assess for alterations in mood. A statistically significant reduction in the impairment of spasticity was found in the gabapentin-treated subjects compared with placebo as measured by the self-report scales of the spasm severity scale, interference with function scale, painful spasm scale, and global assessment scale and by the physician-administered scales of the Modified Ashworth and plantar stimulation response. No significant difference was noted in the Digit Span, Digit Symbol, adjective generation technique, and EDSS. Gabapentin reduces the impairment of spasticity, compared with placebo, without the side effects of worsening concentration and fatigue.

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[Effect of the Helicobacter pylori eradication in patients with functional dyspepsia: randomised placebo-controlled trial].

The Helicobacter pylori eradication in patients with functional dyspepsia has been the subject of controversy because trials come to contradictory conclusions. The objective of this trial was to evaluate the effect, compared with placebo, of the eradication treatment in patients with functional dyspepsia. Randomized double blind placebo controlled trial. We included 158 patients attended by family physicians (Area 10 Primary Care, Health Institute of Madrid) with functional dyspepsia and Helicobacter pylori infection detected by the ureasa test in endoscopy. An OCA (ameprazole clarithromycin and amoxicillin group (n = 79) and a placebo group (n = 79) were randomized. During 7 days, patients at the OCA group received omeprazole (20 mg bid), clarithromycin (500 mg bid) and amoxicillin (1000 mg bid) daily, and patients at the control group received the placebo agent twice daily. Dyspepsia improvement according to a Likert scale (5 steps), and eradication of H. pylori by 13C-urea breath test were evaluated during one year. Both groups were homogeneous in relation to age, sex and dyspepsia degree. The average age (standard deviation) of studied patients was 41.99 (13.93) years. At one year of follow up, H. pylori was eradicated in 81.01% (64/79) of the OCA group and 5.06% (4/79) of the placebo group. The difference of dyspepsia improvement (22.78%; 95% confidence interval [CI], 7.62-37.79) between the OCA group (41.77%; 95% CI, 30.77-53.41), and the placebo group (18.99%; 95% CI 11.03-29.38) was significant (p = 0.0018). Eradication of Helicobacter pylori in patients with functional dyspepsia is more effective improving symptoms than placebo.

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Switching from allopurinol to febuxostat for the treatment of hyperuricemia and renal function in patients with chronic kidney disease.

Hyperuricemia is a frequent complication of chronic kidney disease (CKD). Febuxostat is a novel xanthine oxidase inhibitor that is metabolized by many metabolic pathways in the kidney and the liver. We performed a 1-year cohort study of 73 hyperuricemic patients who had an estimated glomerular filtration rate (eGFR) below 45 ml/min and were being treated with urate-lowering therapy. In 51 patients, treatment was changed from allopurinol to febuxostat, and the other 22 patients were continued on allopurinol. The serum levels of uric acid (UA) level, creatinine, and other biochemical parameters were measured at baseline and after 3, 6, 9, and 12 months of treatment. The serum UA levels significantly decreased from 6.1 ± 1.0 to 5.7 ± 1.2 mg/dl in the febuxostat group and significantly increased from 6.2 ± 1.1 to 6.6 ± 1.1 mg/dl in the allopurinol group. The eGFR decreased 27.3 to 25.7 ml/min in the febuxostat group and from 26.1 to 19.9 ml/min in the allopurinol group. The switch from allopurinol to febuxostat was significantly associated with the changes in eGFR according to a multiple regression analysis (β = -0.22145, P < 0.05). Febuxostat reduced the serum UA levels and slowed the progression of renal disease in our CKD cohort in comparison with allopurinol.

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A Comparative Study of High-intensity Rosuvastatin Versus Atorvastatin Therapy Post-acute Coronary Syndrome Using Real-world Data.

A high-intensity statin is recommended for the secondary prevention of cardiovascular diseases (CVD). However, real-world evidence of the effectiveness of rosuvastatin following acute coronary syndrome (ACS) is scarce. This retrospective cohort study included patients diagnosed with ACS to compare between the 2 high-intensity statin therapies (rosuvastatin vs atorvastatin) in terms of a primary composite outcome of CVD-associated death, non-fatal ACS, and non-fatal stroke at 1 month and 12 months post discharge. The primary effectiveness outcome did not differ between the 2 groups at 1 month (1.3% vs 1%; aHR = 1.64, 95% CI 0.55-4.94, P= 0.379) and at 12 months (4.8% vs 3.5%; aHR = 1.48, 95% CI 0.82-2.67, P= 0.199). Similarly, the 2 groups had comparable safety outcomes. In conclusion, the use of high-intensity rosuvastatin compared to high-intensity atorvastatin therapy in patients with ACS had resulted in comparable cardiovascular effectiveness and safety outcomes.

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Is perforated marginal ulcer after the surgery of gastroduodenal ulcer associated with inadequate treatment for Helicobacter pylori eradication?

A marginal ulcer developing after an initial operation for gastroduodenal ulcer is a serious threat to the patient, and a challenge to surgeons. Helicobacter pylori is the primary cause of peptic ulcer disease. However, its role in ulcer recurrence, especially of marginal ulcer (MU), after peptic ulcer surgery is unclear. This study aimed to determine any association between H. pylori infection and perforated MU by comparing the prevalence of H. pylori and nonsteroidal anti-inflammatory drugs (NSAIDs) use in patients with perforated (PMU) and in those with nonperforated MU (NPMU). The study retrospectively evaluated the records of 16 patients with PMU who underwent surgical treatment and 24 patients with NPMU who underwent medical treatment in Atatürk University, School of Medicine, Department of General Surgery and Gastroenterology, between January 1995 and December 2004. The rate of H. pylori in the PMU group was significantly higher than that of the NPMU group (P < 0.01). There was a significant relationship between NSAID consumption and PMU compared with NPMU patients (P < 0.01). There was also a significant relationship between NSAID consumption and H. pylori and PMU (P < 0.01). Eradication of H. pylori after the first PMU operation especially in cases with impaired hemodynamics, severe peritoneal contamination, and/or a diameter smaller than 1 cm and avoiding the use of NSAIDs will surely reduce the risk of relapsing ulcers.

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Acute lymphoblastic leukemia in the elderly.

We report our findings in 18 patients with acute lymphoblastic leukemia (ALL) aged 60 years or older. A preleukemic syndrome was observed in 2 patients. Compared to younger adults with ALL, L3 morphology was unexpectedly frequent (4/16). T-ALL was not observed. Other criteria of poor prognosis (high white blood cell count, CNS involvement, organomegaly, high serum LDH) were similar to those reported in young adults. 12 patients were treated with an OPAL-derived regimen, 4 with the MAV regimen, 1 with vincristine and prednisone, 1 with 6-mercaptopurine. Complete remission was achieved in 8 patients but proved short-lived. 5 patients died in aplasia and 5 failed to achieve remission. Median survival for the whole group was 3 months. ALL in the elderly raises the dilemma of an aggressive disease in patients with poor tolerance to intensive therapy.

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Chemiluminescent Measurement of Hydrogen Peroxide in the Exhaled Breath Condensate of Healthy and Asthmatic Adults.

Reactive oxygen species are centrally involved in the pathophysiology of airway diseases such as asthma and chronic obstructive pulmonary disease. This study reports the development of a chemiluminescence assay and a device for measuring hydrogen peroxide in the exhaled breath condensate of asthma patients and healthy participants. A stand-alone photon detection device was constructed for use with an optimized chemiluminescence assay. Calibrations using a catalase control to scavenge residual hydrogen peroxide in calibrant solutions provided analytically sensitive and specific measurements. We evaluated exhaled breath condensate hydrogen peroxide in 60 patients (ages 20-83; 30 healthy patients and 30 asthma patients) recruited from the John Peter Smith Hospital Network. The exhaled breath condensate hydrogen peroxide concentrations trended toward higher values in asthma patients compared to healthy participants (mean 142.5 vs 115.5 nM; <i>p</i> = 0.32). Asthma patients who had not used an albuterol rescue inhaler in the past week were compared to those who had and showed a trend toward higher hydrogen peroxide levels (mean 172.8 vs 115.9 nM; <i>p</i> = 0.25), and these patients also trended toward higher hydrogen peroxide than healthy participants (mean 172.8 vs 115.5 nM; <i>p</i> = 0.14). This pilot study demonstrates the ability of the newly developed assay and device to measure exhaled breath condensate hydrogen peroxide in asthma patients and healthy participants. The trends observed in this study are in agreement with previous literature and warrant further investigation of using this system to measure exhaled breath condensate hydrogen peroxide for monitoring oxidative stress in asthma.

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Effect of alirocumab on coronary atheroma volume in Japanese patients with acute coronary syndromes and hypercholesterolemia not adequately controlled with statins: ODYSSEY J-IVUS rationale and design.

Serial intravascular ultrasound (IVUS) imaging can be used to evaluate the effect of cholesterol-lowering on coronary atheroma progression and plaque volume, with evidence of potential incremental effects with more aggressive lipid-lowering treatments. Alirocumab is a highly specific, fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9). This study will investigate the effect of alirocumab on coronary artery plaque volume in Japanese patients with a recent acute coronary syndrome (ACS) and hypercholesterolemia while on stable statin therapy. ODYSSEY J-IVUS is a phase IV, open-label, randomized, blinded IVUS analysis, parallel-group, multicenter study in Japanese adults recently hospitalized for an ACS and who have elevated low-density lipoprotein cholesterol (LDL-C) values [≥100mg/dL (2.6mmol/L)] at ACS diagnosis and suboptimal LDL-C control on stable statin therapy. Patients will be randomized (1:1) to receive alirocumab or standard-of-care (SOC). The alirocumab arm will receive alirocumab 75mg every 2 weeks (Q2W) added to statin therapy (atorvastatin ≥10mg/day or rosuvastatin ≥5mg/day), with a dose increase to 150mg Q2W in patients whose LDL-C value remains ≥100mg/dL at week 12. The SOC arm will receive atorvastatin ≥10mg/day or rosuvastatin ≥5mg/day, with dose adjustment to achieve LDL-C <100mg/dL. Post-treatment IVUS imaging will be done at week 36±2. The primary objective is to compare the effect of alirocumab versus SOC on coronary atheroma progression (percent change in normalized total atheroma volume) after 9 months of treatment. ODYSSEY J-IVUS will provide insights into the effect of alirocumab on coronary atherosclerotic plaque volume in patients with a recent ACS and hypercholesterolemia while on stable statin therapy. ClinicalTrials.gov number: NCT02984982.

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Perioperative Use of Nonsteroidal Anti-inflammatory Drugs Decreases the Risk of Recurrence of Cancer After Colorectal Resection: A Cohort Study Based on Prospective Data.

Perioperative use of nonsteroidal anti-inflammatory drugs (NSAIDs) is known to reduce inflammatory response in relation to surgery. Inflammation may promote recurrence of cancer, thus inhibition by use of NSAIDs could reduce recurrence after surgery. The aim of this study was to examine the association between perioperative use of NSAIDs and cancer recurrence, as well as disease-free survival (DFS) and mortality after colorectal cancer surgery. This was a cohort study based on data from a prospective clinical database, electronic medical records, and nationwide registers, and included patients from six major colorectal centers in Denmark. The primary outcome was cancer recurrence, while secondary outcomes included 5-year mortality and DFS. Overall, 2308 patients undergoing colorectal cancer surgery between 1 January 2006 and 31 December 2009 were included. A total of 909 patients received at least 2 days of treatment with NSAIDs, of whom 702 (77.2%) received ibuprofen and 204 (22.4%) received diclofenac. Cox regression analysis adjusting for NSAIDs resulted in decreased recurrence risk (adjusted hazard ratio [HR_adjusted] 0.84, 95% confidence interval [CI] 0.72-0.99; p = 0.042). Competing risk analysis confirmed the finding, with an HR_adjusted of 0.76 (95% CI 0.60-0.97; p = 0.026). There was no significant effect on mortality or DFS. Sensitivity analysis of the effect of ibuprofen reported an HR_adjusted of 0.83 (95% CI 0.70-1.00; p = 0.047). In restricted analyses of localized disease only (Union for International Cancer Control [UICC] I-II) and elective surgery only, no effect was found (localized: HR_adjusted 0.81, 95% CI 0.62-1.06, p = 0.12; elective: HR_adjusted 0.85, 95% CI 0.72-1.01, p = 0.063). Perioperative use of NSAIDs was associated with a reduced risk of cancer recurrence after resection for colorectal cancer. No effect on 5-year mortality or DFS was found.

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Variability in platelet responsiveness to clopidogrel among 544 individuals.

We sought to describe the responses of patients to clopidogrel using ex vivo measures of platelet aggregation and activation in a large, heterogeneous population. Recently, a number of reports, using various definitions, have dichotomized patients who are treated with clopidogrel into a minority of "non-responders" and a majority of "responders." Such classifications imply that treatment leads to an all-or-none response, with potentially important clinical implications. We conducted secondary post-hoc analyses of a dataset consisting of volunteers (n = 94) and patients after coronary stenting (n = 405), with heart failure (n = 25), and after stroke (n = 20). The response of subjects to clopidogrel followed a normal, bell-shaped distribution, with a mean and standard deviation of 41.9 +/- 20.8% when aggregation was induced by 5 mumol/l of adenosine diphosphate. When hyporesponsiveness and hyper-responsiveness to clopidogrel were considered to be two standard deviations less than and greater than the mean, respectively, the prevalence of hyporesponsiveness and hyper-responsiveness in these patients was 4.2% and 4.8%, respectively. Pretreatment platelet activity and clinical characteristics were not associated with responsiveness to clopidogrel. Individuals receiving clopidogrel exhibit a wide variability in response that follows a normal distribution. The clinical implications of this variability are unknown but potentially are important. Clinical trials are needed to define whether hyporesponders to clopidogrel are at increased risk for thrombotic events and whether hyper-responders are at increased risk for bleeding. If so, the individualization of antiplatelet therapy, including clopidogrel dosing, may be possible in the future but will require the ability to easily and reproducibly measure responsiveness by a method that has been proven to be predictive of clinical events.

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Prevention of Cardiovascular Events and Mortality With Icosapent Ethyl in Patients With Prior Myocardial Infarction.

REDUCE-IT was a double-blind trial that randomized 8,179 statin-treated patients with controlled low-density lipoprotein cholesterol and moderately elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in the primary endpoint, including death from cardiovascular (CV) causes. The specific impact of IPE among patients with prior myocardial infarction (MI) was unknown. Our goal was to examine the benefit of IPE on ischemic events among patients with prior MI in REDUCE-IT. We performed post hoc analyses of patients with prior MI. The primary endpoint was CV death, MI, stroke, coronary revascularization, or hospitalization for unstable angina. The key secondary endpoint was CV death, MI, or stroke. A total of 3,693 patients had a history of prior MI. The primary endpoint was reduced from 26.1% to 20.2% with IPE vs placebo; HR: 0.74 (95% CI: 0.65-0.85; P = 0.00001). The key secondary endpoint was reduced from 18.0% to 13.3%; HR: 0.71 (95% CI: 0.61-0.84; P = 0.00006). There was also a significant 35% relative risk reduction in total ischemic events (P = 0.0000001), a 34% reduction in MI (P = 0.00009), a 30% reduction in CV death (P = 0.01), and a 20% lower rate of all-cause mortality (P = 0.054), although there was a slight increase in atrial fibrillation. Sudden cardiac death and cardiac arrest were also significantly reduced by 40% and 56%, respectively. Patients with a history of prior MI in REDUCE-IT treated with IPE demonstrated large and significant relative and absolute risk reductions in ischemic events, including CV death. (A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients With Hypertriglyceridemia and on Statin. The Primary Objective is to Evaluate the Effect of 4 g/Day AMR101 for Preventing the Occurrence of a First Major Cardiovascular Event. [REDUCE-IT]; NCT01492361).

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Illicit drug use correlates with negative urine drug test results for prescribed hydrocodone, oxycodone, and morphine.

A number of studies indicate that 10.8%-34% of patients with chronic pain use illicit drugs. One hypothesis for this occurrence is that some patients may be supplementing their prescription medications with illicit drugs. The primary purpose of this retrospective data analysis was to test the hypothesis that people whose urine specimens are positive for the medications that have been listed as being prescribed to them are positive for fewer illicit substances than those whose specimens were negative for their prescribed medications. The secondary purpose of the study was to correlate the use of illicit drugs and the amount of prescribed medications excreted in urine. A retrospective study of the incidence of patients using illicit drugs versus their consistency with reported medications. Using urine specimens from a cohort of nearly 400,000 patients whose identities had been redacted, and who were being treated for chronic pain with opioid therapy, this study was performed to correlate the patients' positivity with their prescribed medication to the prevalence of illicit substance use. A secondary study was conducted to correlate the amount of prescribed medication excreted in urine (measured in ng/mL) with the incidence of illicit drug use. The specific prescription medications analyzed were hydrocodone, morphine, and oxycodone. Specimens defined as negative for prescribed hydrocodone (27.3%), morphine (11.5%) or oxycodone (19%) were more likely to contain illicit drugs than those found to be positive for the prescribed medication. The illicit drug prevalence among the inconsistent specimens was 15.3% for hydrocodone, 23.8% for morphine, and 24.4% for oxycodone. The secondary study showed no statistically significant difference in the excretion level of prescribed medication between those patients using and not using illicit drugs. The study is limited in that no data was obtained to determine the causal relationships of illicit drug use. This work supports the hypothesis that people who are positive for their prescribed medications use fewer illicit drugs than those who do not take their medications. It may be beneficial for physicians to test more thoroughly for illicit drugs when patients' drug tests are negative for their prescribed medications.

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R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma.

The benefit of radiotherapy (RT) after chemotherapy in limited-stage diffuse large B-cell lymphoma (DLBCL) remains controversial. We conducted a randomized trial in patients with nonbulky limited-stage DLBCL to evaluate the benefit of RT after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients were stratified according to the modified International Prognostic Index, including lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, age, and disease stage. The patients received 4 or 6 consecutive cycles of R-CHOP delivered once every 2 weeks, followed or not by RT at 40 Gy delivered 4 weeks after the last R-CHOP cycle. All patients were evaluated by fluorodeoxyglucose-positron emission tomography scans performed at baseline, after 4 cycles of R-CHOP, and at the end of treatment. The primary objective of the trial was event-free survival (EFS) from randomization. The trial randomly assigned 165 patients in the R-CHOP arm and 169 in the R-CHOP plus RT arm. In an intent-to-treat analysis with a median follow-up of 64 months, 5-year EFS was not statistically significantly different between the 2 arms, with 89% ± 2.9% in the R-CHOP arm vs 92% ± 2.4% in the R-CHOP plus RT arm (hazard ratio, 0.61; 95% confidence interval [CI], 0.3-1.2; <i>P</i> = .18). Overall survival was also not different at 92% (95% CI, 89.5%-94.5%) for patients assigned to R-CHOP alone and 96% (95% CI, 94.3%-97.7%) for those assigned to R-CHOP plus RT (<i>P</i> = not significant). R-CHOP alone is not inferior to R-CHOP followed by RT in patients with nonbulky limited-stage DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT00841945.

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[Clinical effect and mechanism of nitroglycerin patch on arresting preterm labor].

To observe the effect of nitroglycerin patch on treatment of preterm labour and to identify the mechanism responsible for arrest of preterm labour with nitroglycerin patch. Sixty women diagnosed as threatened preterm labour were divided into two groups: group of nitroglycerin patch therapy (n = 30), and group of magnesium sulfate and salbutamol sulfate therapy (n = 30). Nitroglycerin patch was applied to the abdomen of patients. Measurement of cortictrophin-releasing hormone (CRH) levels in maternal plasma was performed by radioimmunoassay. The mean time of pregnancy prolongation was 25 days in the nitroglycerin patch group, and 8 days in the magnesium sulfate and salbutamol sulfate group. The mean level of CRH concentration in nitroglycerin patch group before treatment was (257 +/- 61) ng/L, and it was decreased sharply to (38 +/- 17) ng/L after treatment. Those were (248 +/- 60) ng/L and (56 +/- 22) ng/L respectively in the magnesium sulfate and salbutamol sulfate group. Reduction of CRH secretion may be the mechanism of nitroglycerin patch on preterm labour therapy. It may act as an effective, safe, well-tolerated, and non-invasive method for treatment of preterm labour.

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Effect of calcium channel blocker amlodipine on the intimal-medial thickness of carotid arterial wall in type 2 diabetes.

Although several reports have suggested that calcium channel blockers may inhibit progression of atherosclerosis in animals, it is still controversial whether they have any clinically significant antiatherogenic action in humans. The measurement of intimal-medial thickness (IMT) of the common carotid artery by B-mode ultrasound technique has been recognized as a powerful and noninvasive method to evaluate early atherosclerotic lesions. We investigated the effect of treatment with amlodipine, a powerful calcium channel blocker, on IMT. Twenty-two hypertensive patients with type 2 diabetes were enrolled in a prospective open study. An amlodipine group (amlodipine, 5 mg; n = 11) and a control group receiving angiotensin-converting enzyme inhibitors (n = 11) were studied before and 6 months after treatment. Amlodipine treatment caused a significant decrease in IMT compared with control (-0.052 +/- 0.017 vs. 0.011 +/- 0.021 mm; p < 0.05). Although the exact mechanisms remain to be elucidated, our preliminary result suggests that amlodipine has an antiatherogenic action in type 2 diabetes.

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[Predictive value of the GRACE discharge score on the long-term out-of-hospital coronary thrombotic events after implantation of drug-eluting stents].

<b>Objective:</b> To evaluate the predictive value of GRACE discharge score on the long-term out-of-hospital coronary thrombotic events (CTE) after percutaneous coronary intervention (PCI) with drug-eluting stents. <b>Methods:</b> Present study was a prospective, observational, single center study. 10 724 consecutive patients underwent PCI in Fuwai Hospital between January and December 2013 were included, stents were implanted with conventional method. After PCI, patients were prescribed aspirin 100 mg once daily indefinitely, and either clopidogrel 75 mg once daily or ticagrelor 90 mg twice daily for at least 1 year. A total of 9 782 patients were included in the final analysis after excluding patients who did not undergo successful stent implantation, who were not discharged on dual anti-platelet therapy (DAPT), who only underwent bare-metal stents, who experienced in-hospital major bleeding, stent thrombosis, myocardial infarction (MI) or death,and who lost follow up. Clinical data were collected from all patients. 9 543 patients with complete baseline data were further analyzed for risk stratification and predictive value of GRACE discharge score. CTE was defined as stent thrombosis or spontaneous myocardial infarction. All patients were followed through Fuwai Hospital Follow-up Center, and evaluated either by phone, letter, or clinic visits or at 1, 6, 12 and 24 months after PCI. Risk stratification was performed according to the GRACE discharge score, and the predictive value of the GRACE discharge score was assessed using the receiver operating characteristic (ROC) curve. <b>Results:</b> After 2 years follow-up, there were 95 CTE among the 9 782 patients. The patients were divided into 2 groups according to the presence or absence of CTE: CTE group (95 cases) and no CTE group (9 687 cases). GRACE discharge score was significantly higher in CTE group than no CTE group (82.98±27.58 vs. 75.51±22.46, <i>t</i>=-2.57, <i>P=</i>0.012). According to risk stratification of GRACE discharge score, the patients were divided into low-risk (≤88) group (<i>n=</i>6 902), moderate-risk (89-118) (<i>n=</i>2 988) and high-risk (>118) (<i>n=</i>343) groups. As compared to the low-risk group, CTE risk in moderate- and high-risk groups was 1.59 times (<i>HR</i> 1.59, 95%<i>CI</i> 1.01-2.52, <i>P=</i>0.046) and 3.89 times higher (<i>HR</i> 3.89, 95%<i>CI</i> 1.98-7.65, <i>P<</i>0.001), respectively. Further analysis showed that the GRACE score had predictive value in the total cohort for CTE (area under the receiver operating characteristic (AUROC) 0.576, 95%<i>CI</i> 0.512-0.640, <i>P=</i>0.012) and in the acute coronary syndromes(ACS) subgroup for CTE: (AUROC 0.594, 95%<i>CI</i> 0.509-0.680, <i>P=</i>0.019), but not in the non-ACS subgroup: (AUROC 0.561, 95%<i>CI</i> 0.466-0.657, <i>P=</i>0.187). <b>Conclusion:</b> GRACE discharge score can predict the long-term out-of-hospital CTE in patients undergoing PCI with drug-eluting stents and treated with DAPT, and patients can be stratified into the low-, moderate- and high-risk groups of CTE by the GRACE discharge score.

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Combining psychotherapy and antidepressants in the treatment of depression.

To compare the efficacy of antidepressants with that of antidepressants plus psychotherapy ("combined therapy") in the treatment of depression. 6 month randomised clinical trial of antidepressants (N=84) and combined therapy (N=83) in ambulatory patients with Major Depression and a 17-item HDRS baseline score of at least 14 points. The antidepressant protocol provides for three successive steps in case of intolerance or inefficacy: fluoxetine, amitriptyline and moclobemide. The combined therapy condition consists, in addition to pharmacotherapy, of 16 sessions of Short Psychodynamic Supportive Psychotherapy. Efficacy is assessed using the 17-item HDRS, the CGI of Severity and of Improvement, the depression subscale of the SCL-90, and the Quality of Life Depression Scale. The data analysis is conducted on three samples: the intention-to-treat sample, the per protocol sample and the observed cases sample. After randomisation, 32% of the patients refused the proposed pharmacotherapy while 13% refused the proposed combined therapy. In 24 weeks, 40% of the patients who started with the pharmacotherapy stopped medication; 22% of those receiving the combined therapy did so. The difference in success rates is statistically significant, favouring combined therapy, in 23%, 31% and 62% of the patients after 8, 16 and 24 weeks of treatment, respectively. At week 24, the mean success rate is 40.7% in the pharmacotherapy group and 59.2% in the combined therapy group. Patients found combined treatment significantly more acceptable, they were significantly less likely to drop out of combined therapy and, ultimately, significantly more likely to recover. Combined therapy is preferable to pharmacotherapy in the treatment of ambulatory patients with major depression.

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Clinical, procedural, and pharmacologic correlates of acute and subacute stent thrombosis: results of a multicenter case-control study with 145 thrombosis events.

The aim of this study was to determine correlates of acute/subacute coronary stent thrombosis among unselected patients treated in the era of routine dual antiplatelet therapy and specifically to investigate the influence of prophylactic administration of glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitors and use of clopidogrel versus ticlopidine on the development of coronary stent thrombosis (ST). Because of a relative infrequency of ST events and relatively uniform practice patterns within randomized trials, previous studies have had a limited ability to address whether the use of different antiplatelet regimens at the time of coronary stenting is associated with differences in ST. We performed a multicenter, case-control study to evaluate clinical, angiographic, and pharmacologic/procedural correlates of ST. Between 1996 and 2000, all cases of angiographically-confirmed ST (n = 145) among patients receiving dual antiplatelet therapy were identified from 10 participating clinical sites and were matched with a control without ST randomly selected from the same institution. Multivariable conditional logistic regression identified higher pre-procedure platelet count, stenting for acute myocardial infarction, use of a coil or self-expanding stent, and overt angiographic thrombus prior to the procedure, as independent predictors of ST (all P < .05). After adjusting for these factors, the use of clopidogrel (vs ticlopidine) was independently associated with an increased risk of ST (OR 2.1, 95% CI 1.0-4.1, P = .04). The use of prophylactic glycoprotein IIb/IIIa inhibitors was not associated with reduced ST in the overall analysis, but appeared to confer some protection against ST within the first 24 hours post procedure (OR 0.5 [95% CI 0.2-1.1] for ST during first day, OR 1.7 [95% CI 0.7-4.3] for ST on subsequent days). Both biologic and pharmacologic factors are independently associated with acute/subacute ST. The association between clopidogrel use (vs ticlopidine) and increased ST in this analysis requires confirmation in adequately powered clinical trials and suggests a potential role for newer and more potent antiplatelet agents.

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The relative efficacy of methylphenidate (ritalin) and behavior-modification techniques in the treatment of a hyperactive child.

Drug versus placebo effects were contrasted with those of contingency management in the treatment of a hyperactive child. Several criterion behaviors were monitored in two different settings to gauge the breadth and generalizability of drug and behavior-management effects. Medication and contingency management effects were both found to be situation specific. No interaction effects were found. Accuracy of task performance, amount of eye contact with the experimenters, frequency of repetitive hand movements, and distractible behavior were apparently unaffected by medication (Ritalin versus placebo) within the clinic. A multiple-baseline design incorporating contingency reversals revealed the reinforcement contingencies to be the crucial variable controlling behavior within the clinic. Medication effects were shown to be significant within the home setting where reinforcement contingencies were not changed. While aggressive behavior decreased as a function of Ritalin, repetitive hand movements increased.

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Anticoagulant-related gastrointestinal bleeding: a real-life data analysis on bleeding profiles, frequency and etiology of patients receiving direct oral anticoagulants versus vitamin K antagonists.

Vitamin K antagonists (VKA) continue to be the standard of long-term anticoagulation. Direct oral anticoagulants(DOAC) are increasingly used. In many trials DOAC were at least as effective as VKA. In this study we evaluate the bleeding profiles, frequencies and etiologies of patients receiving DOAC versus VKA in a real-life setting. All patients presenting with suspected gastrointestinal bleeding (GIB) in the emergency department of the University Hospital Erlangen in one year were enrolled in this study. They were looked up for the intake of either DOAC (dabigatran, rivaroxaban and apixaban) or VKA. The results showed that 406 patients with suspected GIB were admitted to the emergency unit of the University Hospital Erlangen. In 228 of those patients GIB could be verified (56.2%). Fifty four of those patients (23.7%) were administered either VKA or DOAC. In 35 of those 54 patients (64.8%) GIB was classified as 'major bleeding'. In 27 patients with administration of VKA upper GIB was recorded and lower GIB was detected four times. In 16 patients with administration of DOAC upper GIB was found and lower GIB was found in 7 patients. The presented data do not show higher GIB rates for DOAC (mainly dabigatran and rivaroxaban), but do also not indicate a significantly higher safety of DOAC concerning GIB than VKA. This finding represents a clear contrast to the reduced bleeding rates of DOAC for intracerebral bleeding and other non-GIB events. According to our study, the absolute number of DOAC-associated GIB events is lower than in the VKA group.

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Preliminary investigations into a novel, long-acting, injectable, intramuscular formulation of omeprazole in the horse.

Pilot investigations have suggested that a novel, long-acting, injectable i.m. formulation of omeprazole (LA-OMEP) can induce acid suppression for up to 7 days following a single injection. To investigate the pharmacodynamics and assess the clinical efficacy of the LA-OMEP formulation. Part A comprised a pharmacodynamic study. Part B consisted of a pilot clinical trial. Part A enrolled six adult Thoroughbred horses with percutaneous gastrotomy tubes. Intragastric pH was measured for continuous 23-h periods (08.00-07.00 h) for eight consecutive days (days 0-7). A single 2.0-g dose of a 100 mg/mL LA-OMEP formulation was administered at 08.00 h on day 1. In Part B, 26 horses with squamous or glandular gastric disease were enrolled based on routine gastroscopic evaluation. Once enrolled, horses received 2.0 g of the 100 mg/mL LA-OMEP formulation by i.m. injection on days 0 and 7. Repeat gastroscopy was performed on days 14 (23 horses) or 16 (one horse). In Part A, the percentage of time during which pH was above 4 exceeded 66% for days 1-4 in all horses and days 1-7 in four of the six horses studied. In Part B, healing was observed in all 22 (100%, 95% confidence interval [CI] 89-100%) horses with squamous disease and in nine of 12 (75%, 95% CI 47-92%) horses with glandular disease. Improvement, by at least one grade, was observed in all 22 (100%, 95% CI 89-100%) horses with squamous disease and in all 12 (100%, 95% CI 81-100%) horses with glandular disease. No worsening of lesions was observed. Lesion grade decreased over time in both the squamous (P<0.0001) and glandular (P = 0.0024) mucosa. Small sample sizes. The results of the present study compare favourably with previous reports on the pharmacodynamics of omeprazole and the clinical outcomes of trials reporting response to oral omeprazole therapy.

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A prospective follow-up study of 5669 users of lansoprazole in daily practice.

Immediately after the introduction of the proton pump inhibitor lansoprazole, a 2-year follow-up study was started to evaluate patterns of use, safety and effectiveness of this drug in naturally occurring groups of patients in the Netherlands. Medical data were recorded by participating physicians while medication listing were provided by pharmacists. The study was designed according to the Safety Assessment of Marketed Medicines guidelines. The only inclusion criterion was the use of lansoprazole prior to entry into the study. A total of 5669 lansoprazole users was included by 374 general practitioners and 117 specialists. Lansoprazole was mostly prescribed in patients with reflux oesophagitis (55.1%), 'gastritis' (26.8%) and duodenal ulcers (11.4%), sometimes as part of a Helicobacter pylori eradication therapy (8.5%). For their complaints most patients (91.1%) had previously used acid-related drugs. Improvement or disappearance of complaints was achieved in 88.9% and 90.5% of patients after 4 and 8 weeks of treatment, respectively. Diarrhoea (4.1%), headache (2.9%) and nausea (2.6%) were the most frequently reported adverse events. The patterns of use of lansoprazole in daily practice deviated from the recommendations in the information leaflet. Nevertheless, lansoprazole was found to be safe in this naturally occurring group of users. Effectiveness appeared to be comparable to results found in clinical trials of the registered indications for lansoprazole.

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Influence of omeprazole and famotidine on the antiplatelet effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes: a prospective, randomized, multicenter study.

It remains unclear whether concomitant use of omeprazole attenuates platelet function as compared with that of famotidine in patients with acute coronary syndromes (ACS) who receive clopidogrel. In this prospective study, 130 ACS patients treated with aspirin and clopidogrel who underwent stent implantation were randomly assigned to receive a Japanese standard dose of omeprazole 10mg daily or famotidine 20mg daily for at least 4 weeks. Between 14 and 28 days after enrollment, there was no significant difference in the platelet reactivity index (PRI) measured with vasodilator-stimulated phosphoprotein phosphorylation assay between the omeprazole group (n=65) and famotidine group (n=65) (55±17% vs. 51±19%; P=0.26). The cumulative rate of adverse cardiovascular events at 12 months was similar in the groups (13% vs. 17%; P=0.81). The PRI was similar (54.9±17.9% vs. 54.0±17.8%; P=0.83) in the omeprazole group (n=33) and the famotidine group (n=39) among patients with ST-elevation myocardial infarction (STEMI). However, there was a trend toward a higher PRI (55.2±15.9% vs. 46.4±19.4%; P=0.06) in the omeprazole group (n=32) as compared with the famotidine group (n=26) among patients without persistent ST-segment elevation ACS. As compared with famotidine, concomitant use of low-dose omeprazole does not significantly attenuate the antiplatelet effects of clopidogrel in patients with ACS, especially in those with STEMI.

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Duloxetine for the treatment of major depressive disorder in women ages 40 to 55 years.

The efficacy of duloxetine in the treatment of major depressive disorder in women of approximately perimenopausal age (40-55 years; 62 placebo subjects and 55 subjects taking duloxetine, 60 mg/day) was compared with that observed in cohorts of younger (<40 years, 94 placebo subjects and 85 duloxetine subjects) and older (>55 years, 26 placebo subjects and 25 duloxetine subjects) women. Women (ages 40-55 years) receiving duloxetine demonstrated significantly greater improvement in total scores on the 17-item Hamilton Rating Scale for Depression compared with placebo at the study endpoint (week 9). Significant advantages for duloxetine over placebo were observed on 17-item Hamilton depression scale subscales (core, Maier, anxiety, retardation, and sleep), in addition to the Clinical Global Impression severity and Patient Global Impression of Improvement Scale, the Quality of Life in Depression Scale, and Visual Analog Scales assessing pain severity. The magnitude of duloxetine's treatment effect in women ages 40-55 years was similar to that observed in younger (age <40 years) and older (age >55 years) female patients. In the placebo treatment groups, however, mean changes differed substantially by age group with the smallest placebo responses observed in the 40-55 age group. Duloxetine (60 mg/day) was demonstrated to be an effective treatment for major depressive disorder in this cohort of women ages 40-55 years.

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Influence of postoperative immobilization on pain control of patients with distal radius fracture treated with volar locked plating: A prospective, randomized clinical trial.

The purpose of this study was to compare the pain scores and the rates and doses of opioid use in patients undergoing volar locked plate fixation of intra-articular distal radius fractures using or not postoperative immobilization. This was a prospective randomized controlled trial. Thirty-nine patients with distal radius fractures scheduled to receive volar plate fixation were randomly assigned to receive a short forearm splint for two weeks postoperatively or conventional bandage with early wrist mobilization. Thirty-six patients completed the follow-up. The outcome measurements included pain scores (0-10 points); rates and doses of tramadol use; DASH score; wrist range of motion; patient satisfaction; and complication rates. The last follow-up assessment was performed at 6 months. The pain scores were similar between the groups during hospital stay, as well as after hospital discharge within the first week and in subsequent assessments up to six months. The rates of tramadol use were greater in the No splint group during hospital stay, but this difference was not statistically significant (No splint = 65%; Splint = 47%; p = 0.296). Likewise, the doses of tramadol intake were higher in the No splint group during hospital stay (No splint = 218 mg; Splint = 167 mg; p = 0.273) and after discharge (2^nd day: No splint = 112 mg; Splint = 75 mg; p = 0.286), with no statistically significant differences. The functional results and complication rates were similar between the groups. In this study, there was a trend to a greater use of tramadol in patients who did not use immobilization and started early wrist mobilization after volar locked plating of distal radius fracture, compared with patients who were immobilized for two weeks. The pain scores were similar but may have been influenced by the unbalanced use of opioids between the groups. The functional results and complication rates were not influenced by the use of immobilization. Therapeutic Level I.

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Apoptotic impact of alpha1-blockers on prostate cancer growth: a myth or an inviting reality?

Pharmacological manipulation or genetic targeting of the major apoptosis regulators, such as bcl-2, caspases, and inhibitors of apoptosis (IAPs), represent clinically attractive avenues towards effective therapeutic strategies for advanced prostate cancer. A wealth of evidence established the alpha(1)-adrenoceptor antagonists to be clinically effective in relieving the symptoms associated with benign prostatic hyperplasia (BPH) by relaxing prostatic smooth muscle tone. This action alone however does not fully account for the long-term clinical response to these drugs in BPH patients. Experimental and retrospective clinical studies provided new evidence supporting a differential growth-suppressing function of two alpha(1)-adrenoceptor antagonists against prostate cancer, independent of an alpha(1)-adrenoceptor mechanism. The quinazoline-based antagonists, doxazosin and terazosin, induce apoptosis, inhibit cell adhesion to the extracellular matrix (by activating anoikis), and prevent cell invasion and migration of prostate tumor epithelial cells and vascular endothelial cells. Tamsulosin, a sulphonamide-based, clinically effective alpha(1)-adrenoceptor antagonist for BPH treatment, fails to exert a similar apoptotic action against prostate cells. Furthermore, at pharmacologically relevant doses, doxazosin suppresses benign and malignant prostate growth in in vivo experimental models. The effect is characterized by three intriguing features: (a) it is mediated by an alpha(1)-adrenoceptor-independent action, (possibly related to the quinazoline nucleus); (b) it is targeted at the apoptotic process without affecting cell proliferation; and (c) the elevated apoptotic index correlated with symptom score improvement in BPH patients. This evidence challenges conventional knowledge of the mechanism of action of alpha(1)-adrenoceptor antagonists, and points to a new therapeutic value for these drugs by providing a differential molecular basis for their anti-tumor efficacy. The present review focuses on the characterization of the apoptotic/anti-angiogenic effect of quinazoline-based alpha(1)-adrenoceptor antagonists against prostate cancer cells and discusses the clinical significance of this action in the prevention and treatment of prostate cancer.

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The outcome of fluticasone nasal spray on anosmia and triamcinolone oral paste in dysgeusia in COVID-19 patients.

To study the outcome of fluticasone nasal sprays in smell disorders and triamcinolone paste in taste dysfunction in a population of laboratory-confirmed SARS-CoV-2 patients as the test group. The control group will not be given any intervention and only monitoring of these symptoms will be done to compare the recovery time. This prospective interventional study was conducted from June to Nov 2020 at, Datta Meghe University during the COVID-19 outbreak. The 120 enrolled patients were tested at days 1 and 5 after proven infection by RT-PCR test. The mean age for all cases is 50.88 ± 15.93 years, whereas for the controls mean age is 51.2 ± 14.89. 2. Among cases 45 (75%) were males and 15 (25%) were females, among controls 43 (71.66%) were males and 17 (28.33%) were females. Among the case group, after the use of fluticasone spray in the nose and triamcinolone paste in the mouth there was a statistically significant improvement in recognizing all the odours and taste on day 5 compared to day 1. On comparing the smell and taste of cases and control group, either there is no improvement or worsening in smell or taste on day 5 in the control group. The use of fluticasone nasal spray and triamcinolone paste had immensely influenced the basic senses such as smell and taste. Our study showed that olfactory and taste function significantly improved in patients with COVID-19. For all anosmia and dysgeusia cases who received fluticasone nasal spray and triamcinolone medications the recovery of smell senses and the taste was within a week.

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Metabolic effects of beta-blockers in critically ill patients: A retrospective cohort study.

Beta-blockers have potential protective features during critical illness. Heart rate reduction, with limited effect on blood pressure and beneficial effects on metabolism, organ function and inflammation have been reported. We examined metabolic effects of beta-blockers among ICU patients, to address the effect on the estimated energy expenditure, measured by carbon dioxide production (VCO₂). Furthermore, we investigated effects on organ function and inflammation. A retrospective study in adult patients admitted to our 17-beds mixed medical-surgical ICU from January 2013 to March 2016. Mechanically ventilated patients who commenced beta-blockers were eligible for inclusion. Exclusion criteria were: beta-blocker therapy in the 7 previous days, treatment duration <48 h, therapeutic hypothermia, and no VCO₂ measurements. Outcome parameters were obtained at 6 different time points from 24 h before until 48 h after beta-blocker commencement. Linear mixed models were used to evaluate trends. In total 58 patients were included. Various types of beta-blockers were administered, with a median equivalent daily dose to metoprolol of 50.0 mg (IQR 25.0-62.5). The mean heart rate decreased from 103 ± 20 to 91 ± 19 beats per minute after 48 h (p < 0.001), with unaltered blood pressures. Metabolic and other parameters did not show significant differences over time, or parameter changes were due to trends that had already started before beta-blocker commencement. No changes in VCO₂ after beta-blocker commencement were demonstrated suggesting no alterations in energy expenditure. Heart rates significantly decreased with unaltered blood pressures. Other parameters did not show trends that could be attributed to beta-blockers effects.

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Outcome of chickenpox in 66 pediatric renal transplant recipients.

Although chickenpox can cause severe morbidity and mortality in pediatric renal transplant recipients, published reports describing treatment of these patients are few, especially in the cyclosporine era. Sixty-nine episodes of chickenpox occurring in 66 patients were diagnosed in our transplant population between January 1984 and May 1996. Immunosuppression consisted of prednisone and azathioprine (30 cases); prednisone, azathioprine, and cyclosporine (38 cases); or prednisone alone (1 case). Azathioprine was temporarily discontinued in 66 of 68 cases. Cyclosporine was continued at the preexisting dose in 36 of 38 cases. Acyclovir was administered parenterally in 62 of 69 cases. Sixty-five of 66 patients survived. Cyclosporine use did not increase the incidence of severe disease (p > 0.1). Acute allograft rejection occurred in three patients and responded to prednisone. Chickenpox in children with renal transplants can be successfully treated with intravenous acyclovir and temporary withdrawal of azathioprine. Allograft rejection is uncommon with this approach. Patients receiving cyclosporine do not appear to experience increased morbidity or mortality with chickenpox.

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Antibiotic treatment and prophylaxis of periprosthetic infections: Evaluation of 666 consecutive breast implant removals.

Periprosthetic infections are feared complications in esthetic and reconstructive breast surgery. The purpose of our study is to evaluate our institution's specific culture data and to identify most common organisms and suitable antibiotics for prophylaxis and first-line treatment. We evaluated all patients with a change or removal of breast implants from 01.01.2012 to 31.12.2017 retrospectively. Based on the medical records, the surgical indications were identified and specifically analyzed for signs of infection, reasons for primary and secondary surgery, and all available microbiological data of these interventions. A total of 666 implant removals or exchanges were performed in 431 patients. Microbiological smears were gathered from 291 patients (449 implants). Bacteria were cultured from 63 implants (56 patients). In six additional patients (ten implants), a periprosthetic infection was seen, without bacteria detection. Advanced capsular contracture correlated with a higher proportion of positive swabs (p<0.05). In 11.5% of smears, bacterial contamination was found despite absence of clinical signs of infection. Coagulase-negative staphylococci were the dominant pathogen in clinical inapparent infections, while Staphylococcus aureus was when there was clinical evidence of infection. All pathogens were sensitive to vancomycin. In the majority of cases, bacterial contamination was an incidental finding, which was more common in the presence of advanced capsular contracture. In our institution, cefuroxime and amoxicillin/clavulanic acid have been proven to be reasonable choices for prevention and treatment of periprosthetic infections. In the treatment of fulminant infections and for the prophylaxis during implant replacement due to advanced capsular contracture, vancomycin became our first choice.

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Early onset of antidepressant action of venlafaxine: pattern analysis in intent-to-treat patients.

Pattern analysis has been used to distinguish between the true effect of an antidepressant and a placebo effect. The placebo effect constitutes clinical improvement that is attributable to the caregiver, treatment setting, or placebo substance. Pattern analysis allows identification of patients who have early persistent responses, delayed persistent responses, or no responses to a drug. In our study, we used this method to assess the onset and persistence of antidepressant activity of high daily doses of venlafaxine. Our analysis considered scores on the Global Improvement item of the Clinical Global Impressions scale for intent-to-treat patients in two double-masked, placebo-controlled studies of at least 6 weeks' duration. Dosages in both studies were rapidly titrated upward so patients received at least 200 mg/d within the first week of treatment. Improvement within the first 2 weeks was considered early, and improvement not followed by a relapse through the scheduled end of treatment was considered persistent. Significantly greater percentages of patients in the venlafaxine group (27% and 20% in study 1 and study 2, respectively) than in the placebo group (9% and 2%, respectively) had a clinically meaningful drug response within the first 2 weeks of treatment. This early response persisted for the duration of each trial. We concluded that venlafaxine in dosages of at least 200 mg/d demonstrates an early and persistent onset of efficacy compared with placebo.

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Management of and prophylaxis against status epilepticus in children with severe myoclonic epilepsy in infancy (SMEI; Dravet syndrome)--a nationwide questionnaire survey in Japan.

The aim of this study was to establish strategies for prophylaxis against status epilepticus (SE) associated with high fever and for management of ongoing SE in children with severe myoclonic epilepsy in infancy (SMEI). The investigation was performed retrospectively using a questionnaire, asking about medications, which was distributed to epilepsy specialists throughout Japan. All respondents were members of the Japan Epilepsy Society (JES) and/or the Japanese Society of Child Neurology (JSCN). Data from 109 SMEI patients (51 males and 58 females), 1-37 (M+/-SD, 10.7+/-6.53) years old, were used for this study. Of these 109 patients, 10 were excluded because they had not experienced SE, such that data from 99 patients were analyzed. Among the anti-epileptic drugs (AEDs) used daily, excellent efficacy against SE evolution was obtained with the following: potassium bromide (KBr) (41.7%), zonisamide (ZNS) (13.5%), clobazam (CLB) (10.0%), valproate (VPA) (8.0%), phenobarbital (PB) (6.7%), and phenytoin (PHT) (2.6%). Excellent efficacy was not obtained with either clonazepam (CZP) or carbamazepine (CBZ). The diazepam (DZP) suppository was the most frequently given drug for prophylaxis against SE triggered by fever, but only 2 (2.4%) cases showed excellent results. Excellent efficacy in terminating ongoing SE was obtained with the following medications; intravenous barbiturates (75-100%), intravenous midazolam (MDZ) (68.8%), intravenous DZP (54.3%), intravenous lidocaine (Lid) (21.4%), and intravenous PHT (15.4%). Daily KBr was most efficacious for controlling seizures in SMEI patients. Early use of intravenous barbiturates is the most effective strategy in stopping SE in a subset of patients. Reliable efficacy in SE was not obtained with prophylactic DZP, intravenous benzodiazepines (BZPs), PHT and Lid.

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Variability of mycophenolic acid elimination in the renal transplant recipients – population pharmacokinetic approach.

The aim of this study was to develop a population pharmacokinetic (PK) model for clearance of mycophenolic acid (MPA) in adult renal transplant recipients, to quantify the PK parameters and the influence of covariates on the MPA pharmacokinetic parameters. Parameters associated with plasma concentrations of MPA at steady-state were analyzed in 70 renal transplant recipients (mean age 42.97 years; mean total body weight 75.33 kg) using nonlinear mixed-effect modeling (NONMEM). Characteristics of patients screened for influence on the pharmacokinetic parameters were gender, age, body weight, time after transplantation, whether the patient was diagnosed as having diabetes mellitus, organ source (living or deceased donor), biochemical parameters and co-therapy (tacrolimus, cyclosporine, prednisolone, omeprazole, bisoprolol, carvedilol, nifedipine). A validation set of 25 renal transplant recipients was used to estimate the predictive performance of population pharmacokinetic model. Typical mean value of MPA oral clearance, estimated by base model (without covariates) was 0.741 L h(-1). During population modeling, the full model showed that clearance of the MPA was significantly influenced by age, total daily dose of MPA, creatinine clearance, albumin level, status and gender of a donor, and the nifedipine and tacrolimus co-therapy. In the final model, clearance of MPA was reported to be significantly influenced by age, total daily dose of MPA and thenifedipine co-therapy. The derived model describes adequately MPA clearance in terms of characteristics of our patients, offering basis for individual pharmacotherapy approach.

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A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors.

To characterize safety and tolerability of the selective PI3Kβ inhibitor AZD8186, identify a recommended phase II dose (RP2D), and assess preliminary efficacy in combination with abiraterone acetate or vistusertib. This phase I open-label study included patients with advanced solid tumors, particularly prostate cancer, triple-negative breast cancer, and squamous non-small cell lung cancer. The study comprised four arms: (i) AZD8186 monotherapy dose finding; (ii) monotherapy dose expansion; (iii) AZD8186/abiraterone acetate (with prednisone); and (iv) AZD8186/vistusertib. The primary endpoints were safety, tolerability, and identification of the RP2D of AZD8186 monotherapy and in combination. Secondary endpoints included pharmacokinetics (PK), pharmacodynamics, and tumor and prostate-specific antigen (PSA) responses. In total, 161 patients were enrolled. AZD8186 was well tolerated across all study arms, the most common adverse events being gastrointestinal symptoms. In the monotherapy dose-finding arm, four patients experienced dose-limiting toxicities (mainly rash). AZD8186 doses of 60-mg twice daily [BID; 5 days on, 2 days off (5:2)] and 120-mg BID (continuous and 5:2 dosing) were taken into subsequent arms. The PKs of AZD8186 were dose proportional, without interactions with abiraterone acetate or vistusertib, and target inhibition was observed in plasma and tumor tissue. Monotherapy and combination therapy showed preliminary evidence of limited antitumor activity by imaging and, in prostate cancer, PSA reduction. AZD8186 monotherapy had an acceptable safety and tolerability profile, and combination with abiraterone acetate/prednisone or vistusertib was also tolerated. There was preliminary evidence of antitumor activity, meriting further exploration of AZD8186 in subsequent studies in PI3Kβ pathway-dependent cancers.

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[Tolerance of amlodipine in left ventricular dysfunction of ischemic origin].

The aim of this study was to assess the effects of amlodipine on left ventricular function at rest and on effort, at least 30 days after myocardial infarction. The 30 patients included in the study had resting isotopic ejection fractions of 40 to 60%. At inclusion and after 15 days treatment with 10 mg of amlodipine, the patients underwent exercise stress testing with a standard Bruce protocol and resting and exercise isotopic left ventricular ejection fractions were measured. The association of betablockers was allowed but vasodilator therapy was prohibited. During the second exercise stress test, the duration of exercise increased (437 +/- 167 to 518 +/- 154 s; p < 0.002) and the work level rose from 140 +/- 56 to 169 +/- 60 Watts; p < 0.04. The number of electrically positive tests did not change significantly (33 vs 26.7%; NS). The resting ejection fraction did not increase after 15 days treatment with amlodipine (47.4 +/- 6.7 vs 48.3 +/- 8.9%; NS). Similar results were observed with respect to the exercise ejection fraction (51.4 +/- 10.4 vs 52.6 +/- 8.6%; NS). These patients may however be divided into two subgroups. In the first subgroup of 10 patients, the resting ejection fraction rose by more than 5% with amlodipine whereas the exercise ejection fraction remained unchanged (54.4 +/- 7.7% vs 54.5 +/- 7.5% with amlodipine). In the second subgroup of 20 patients, the resting ejection fraction decreased slightly with amlodipine (48 +/- 6.9% vs 45.3 +/- 8%; p = 0.04) but increased significantly on exercise (45.3 +/- 8% vs 51.7 +/- 9.1%; p < 0.0002). Therefore, amlodipine, a new generation calcium antagonist, does not induce any deleterious effect after myocardial infarction with mild left ventricular dysfunction.

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The effects of preinjury clopidogrel use on older trauma patients with head injuries.

This study was designed to determine whether or not older trauma patients on clopidogrel have an increased risk of morbidity and mortality. A retrospective review was performed on all trauma patients > or =50 years of age between January 1, 2002, and August 31, 2005. The charts of those patients who had documented preinjury use of clopidogrel were further reviewed. A control group of patients with no history of clopidogrel use was matched for age, sex, mechanism of injury, and injury severity score. During this time period, there were 1,020 trauma patients > or =50 years of age admitted, 43 of which had documented preinjury clopidogrel use (P). A higher percentage of patients in the P group underwent cranial surgery, had episodes of rebleeds, and required transfusions of blood products than in the control group. The mortality and length of stay were comparable in both groups. This study indicates that the preinjury use of clopidogrel may cause significant morbidity in patients with closed-head injuries. Further studies are needed to suggest specific treatment modalities.

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[The saluretic effect of xipamide (4-chloro-5-sulfamoyl-2',6'-salicyloxylilide) in normal subjects].

The diuretic and saluretic effectiveness of xipamide (4-chloro-5-sulfamoyl-2',6'-salicyloxylidide, Aquaphor) is determined and compared to those of chlortalidone and furosemid in normal subjects. The substance is revealed as a potent diuretic agent. In the range of 0.035--0.750 mg/kg body weight the dose-response curve of orally administered xipamide for the increase of excretion of urine, sodium and potassium ion and chloride during 24 h is described. Observing the renal activity over a period of 3 days after a single administration the duration of action is found to be up to 24 h with its maximum within the first 12 h. In the following 2 days the degree of the physiological rebound effect depends on the preceding saluretic effect and thus on the given dose. The pattern of ion-excretion (Na

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Comparison of carprofen and meloxicam for 72 hours following ovariohysterectomy in dogs.

To compare the peri- and post-operative (72 hours) analgesic effects of injectable and orally administered carprofen and meloxicam for ovariohysterectomy in dogs. Prospective, randomized clinical study. Forty-three dogs undergoing elective ovariohysterectomy. Dogs were randomly assigned to receive pre-operative carprofen, meloxicam or sterile saline by subcutaneous injection. Pre-anaesthetic medication was intramuscular acepromazine (0.02 mg kg(-1)) and methadone (0.2 mg kg(-1)). Anaesthesia was induced with either thiopentone or propofol injected to effect, and maintained with isoflurane in oxygen. Visual analogue scores (VAS) for pain and sedation were recorded at 1, 2, 3, 4 and 6 hours following tracheal extubation. Oral medication with the same treatment was continued post-operatively for 3 days, with VAS scores for pain being recorded before, and 2 hours after treatment on each day. Differences between group age, body mass, duration of general anaesthesia, time from treatment injection to tracheal extubation and time from treatment injection to first oral treatment were analysed using one-way analysis of variance and Kruskal-Wallis test. Visual analogue scores for pain and sedation were analysed using a re-randomization method. The significance level was set at p < 0.05. Meloxicam-treated subjects had lower mean VAS than the control group at 2 and 6 hours following tracheal extubation. Control group VAS were more varied than meloxicam scores (at 6 hours) and carprofen scores (at 3 and 6 hours). On the first post-operative day, pre- to post-treatment VAS scores decreased significantly after meloxicam. On day 3, scores in the meloxicam-treated group were significantly lower than control values after treatment. Changes in pre- to post-treatment VAS were greater in animals receiving either meloxicam or carprofen compared with those given saline. Both carprofen and meloxicam provided satisfactory analgesia for 72 hours following ovariohysterectomy in dogs.

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Rationale and design of AXAFA-AFNET 5: an investigator-initiated, randomized, open, blinded outcome assessment, multi-centre trial to comparing continuous apixaban to vitamin K antagonists in patients undergoing atrial fibrillation catheter ablation.

Catheter ablation is the most efficacious rhythm control therapy in atrial fibrillation (AF) patients. There is growing evidence that catheter ablation procedures are best performed during continuous oral anticoagulation, but outcomes are variable depending on the anticoagulation strategy or agent chosen. Specifically, there is a need to evaluate the peri-procedural use of non-vitamin K antagonist oral anticoagulants (NOACs) in patients undergoing catheter ablation of AF. The AXAFA-AFNET 5 trial will test whether peri-procedural anticoagulation therapy using apixaban is a safe alternative to vitamin K antagonist (VKA) therapy for patients undergoing catheter ablation of AF. AXAFA-AFNET 5 is a randomized, prospective multi-centre study conducted in Europe and the USA. A total of 650 patients scheduled for AF ablation will be randomized 1:1 to undergo AF ablation on continuous treatment with the NOAC apixaban or with a VKA. Patients can undergo AF ablation after at least 30 days of continuous effective anticoagulation or after exclusion of atrial thrombi by transoesophageal echocardiogram. The trial includes a post-ablation magnetic resonance imaging substudy that will quantify silent brain lesions that can occur in neurologically asymptomatic patients after AF ablation. Patients will be followed on continuous anticoagulation for 3 months after the ablation. The primary outcome parameter of AXAFA-AFNET 5 is a composite of all-cause death, stroke, and major bleeding events. The results of AXAFA-AFNET 5 will provide evidence informing about the safety of apixaban in ablation patients and on its efficacy including effects on silent brain lesions. AXAFA - AFNET 5 is an investigator-initiated trial sponsored by AFNET. The trial is supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research) and by Bristol-Myers Squibb/Pfizer Alliance.

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Does behavioral improvement with haloperidol or trazodone treatment depend on psychosis or mood symptoms in patients with dementia?

Several previous studies have examined the effects of pharmacological interventions for agitated behavior in patients with dementia. However, the choice of medication in clinical practice continues to be directed largely by local pharmacotherapy culture rather than empirical treatment guidelines. We examined the relationship between behavioral improvement and co-occurring delusions and mood symptoms in patients with dementia who were treated with haloperidol, an antipsychotic medication, or trazodone, a serotonergic antidepressant. Randomized, double-blind, parallel-group, 9-week treatment trial. Inpatient geropsychiatry unit. Twenty-eight patients with dementia and agitated or aggressive behaviors. Haloperidol 1 to 5 mg/day or trazodone 50 to 250 mg/day. Cohen-Mansfield Agitation Inventory (CMAI), Hamilton Depression Rating Scale (Ham-D), and delusional thoughts subscale and hallucinations subscale of the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD). CMAI scores improved in each treatment group over the 9 weeks of treatment (P < .001 in each group). Within the haloperidol treatment group, CMAI improvement was not associated with baseline delusional thoughts score or with change in delusional thoughts score over the course of treatment. Within the trazodone treatment group, CMAI improvement was associated with baseline score on total Ham-D (r = -0.60, P = .02), Ham-D items measuring subjective mood symptoms (r = -0.50, P = .07), and Ham-D items measuring neurovegetative signs (r = -0.49, P = .08). CMAI improvement was also associated with improvement in Ham-D total score over the course of treatment (r = 0.62, P = .02). Mild depressive symptoms in patients with dementia and agitated behavior are associated with greater behavioral improvement by trazodone-treated patients. In contrast, the presence of delusions in concert with behavioral disturbance does not necessarily predict greater behavioral improvement with haloperidol treatment than in subjects without signs of psychosis.

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Systemic steroids have a role in treating esophageal strictures in pediatric eosinophilic esophagitis.

The role of systemic steroids in the treatment of esophageal strictures in children with Eosinophilic Esophagitis (EoE) is poorly defined. To describe a cohort of children with EoE-associated esophageal strictures responding to systemic steroids. Retrospective review of medical records of children with EoE and moderate (<9 mm) to severe (<6 mm) strictures, who responded clinically and endoscopically to systemic steroids. Twenty children (median age 10.6 ± 4.2 years; 17 males) from nine centers in six countries were included in the analysis; 16 had moderate and four, severe strictures; 18 had dysphagia or bolus impaction; median diagnostic delay was 8 months (IQR 3.5-35). Eighteen patients received oral systemic steroids (mean dose 1.4 mg/kg/day) for a median of 4 weeks, while two initially received IV steroids. All patients showed clinical improvement and 15/20 became asymptomatic. Stricture resolution at endoscopy was found in 19/20, while histological resolution of EoE (<15 eos/hpf) in 13/20. Only minor side effects were reported: hyperphagia (10/20); weight gain (5/20); hyperactivity (2/20) and acne (1/20). Esophageal dilation was required in 3/20 patients during a median follow-up of 48.5 months (IQR 26.7-73.2). Children with EoE and esophageal strictures, may benefit from the use of a short course of systemic steroids, avoiding mechanical dilation.

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Lack of Cumulative Toxicity Associated With Cabazitaxel Use in Prostate Cancer.

Cabazitaxel provided a survival advantage compared with mitoxantrone in patients with castration-resistant prostate cancer refractory to docetaxel. Grade 3 to 4 (G3-4) neutropenia and febrile neutropenia were relatively frequent in the registrative XRP6258 Plus Prednisone Compared to Mitoxantrone Plus Prednisone in Hormone Refractory Metastatic Prostate Cancer (TROPIC) trial, but their incidence was lower in the Expanded Access Program (EAP). Although cumulative doses of docetaxel are associated with neuropathy, the effect of cumulative doses of cabazitaxel is unknown. In this retrospective review of prospectively collected data, the authors assessed "per cycle" incidence and predictors of toxicity in the Italian cohort of the EAP, with a focus on the effect of cumulative doses of cabazitaxel.The study population consisted of 218 Italian patients enrolled in the cabazitaxel EAP. The influence of selected variables on the most relevant adverse events identified was assessed using a Generalized Estimating Equations model at univariate and multivariate analysis."Per cycle" incidence of G 3 to 4 neutropenia was 8.7%, whereas febrile neutropenia was reported in 0.9% of cycles. All events of febrile neutropenia occurred during the first 3 cycles. Multivariate logistic regression analysis showed that higher prior dose of cabazitaxel was associated with decreased odds of having G3 to 4 neutropenia (OR = 0.90; 95% CI: 0.86-0.93; P < 0.01), febrile neutropenia (OR = 0.52; 95% CI: 0.34-0.81; P < 0.01) and G3 to 4 anemia (OR = 0.93; 95% CI: 0.86-1; P = 0.07). Patients with a body surface area >2 m2 presented increased odds of having G 3 to 4 neutropenia (OR = 0.93; 95% CI: 0.86-1; P = 0.07), but decreased odds of having G3 to 4 anemia.Among the toxicities assessed, the authors did not identify any that appeared to be associated with a higher number of cabazitaxel cycles delivered. Prior cumulative dose was associated with reduced G3 to 4 neutropenia and anemia. The apparent protective effect associated with higher doses of cabazitaxel is likely to be affected by early dose reduction and early toxicity-related treatment discontinuation. Because this analysis is limited by its retrospective design, prospective trials are required to assess the optimal duration of cabazitaxel treatment.

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Apixaban in Comparison With Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: Findings From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial.

Apixaban is approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. However, the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial included a substantial number of patients with valvular heart disease and only excluded patients with clinically significant mitral stenosis or mechanical prosthetic heart valves. We compared the effect of apixaban and warfarin on rates of stroke or systemic embolism, major bleeding, and death in patients with and without moderate or severe valvular heart disease using Cox proportional hazards modeling. Of the 18 201 patients enrolled in ARISTOTLE, 4808 (26.4%) had a history of moderate or severe valvular heart disease or previous valve surgery. Patients with valvular heart disease had higher rates of stroke or systemic embolism and bleeding than patients without valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in patients with and without valvular heart disease in reducing stroke and systemic embolism (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.51-0.97 and HR, 0.84; 95%, CI 0.67-1.04; interaction P=0.38), causing less major bleeding (HR, 0.79; 95% CI, 0.61-1.04 and HR, 0.65; 95% CI, 0.55-0.77; interaction P=0.23), and reducing mortality (HR, 1.01; 95% CI, 0.84-1.22 and HR, 0.84; 95% CI, 0.73-0.96; interaction P=0.10). More than a quarter of the patients in ARISTOTLE with nonvalvular atrial fibrillation had moderate or severe valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in reducing stroke or systemic embolism, causing less bleeding, and reducing death in patients with and without valvular heart disease. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.

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Conversion from glipizide to glyburide: long-term follow-up of a cost-impact survey focusing on the elderly.

The appropriate use of second-generation oral hypoglycemic agents is limited by the lack of definitive guidelines for their use in elderly diabetic patients and controversy over relative dosing equivalence. We previously conducted a survey to determine the feasibility and cost of converting diabetic patients from glipizide to glyburide. This new survey provides an extended, 24-month follow-up in 210 patients and focuses on findings in elderly patients. The mean final daily dose of glyburide (11.6 mg) was lower than the preconversion dose of glipizide (18.7 mg) (P < or = 0.0001). One hundred forty-one (67%) patients successfully continued glyburide for 24 months, including 103 (73%) patients who were 65 years of age or older. There was no apparent correlation between age and final dose of glyburide, ability to continue glyburide, or risk of stopping glyburide. The conversion program reduced the mean daily dose after switching from glipizide to glyburide, which was preserved throughout the observation period. The program also conferred a 49% savings in the projected 2-year expenditures for second-generation oral hypoglycemic agents.

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[Outcomes using two preservation solutions (UW/HTK) in liver transplantation from brain death donors].

Preservation solutions are critical for organ transplantation. In liver transplant (LT), the solution developed by the University Of Wisconsin (UW) is the gold-standard to perfuse deceased brain death donor (DBD) grafts. Histidine-Tryptophan-Ketoglutarate (HTK), formerly a cardioplegic infusion, has been also used in solid organ transplantation. To compare the outcomes of LT in our center using either HTK or UW solution. Retrospective study including 93 LT DBD liver grafts in 89 patients transplanted between March 1994 and July 2010. Forty-eight grafts were preserved with UW and 45 with HTK. Donor and recipient demographics, total infused volume, cold ischemia time, post-reperfusion biopsy, liver function tests, incidence of biliary complications, acute rejection and 12-month graft and patient survival were assessed. Preservation solution costs per liver graft were also recorded. Donor and recipient demographics were similar. When comparing UW and HTK, no differences were observed in cold ischemia time (9.6 ± 3 and 8.7 ± 2 h respectively, p = 0.23), biliary complications, the incidence of acute rejection, primary or delayed graft dysfunction. Histology on post-reperfusion biopsies revealed no differences between groups. The infused volume was significantly higher with HTK than with UW (9 (5-16) and 6 (3-11) l, p < 0.001). The cost per procurement was remarkably lower using HTK. Perfusion of DBD liver grafts with HTK is clinically equivalent to UW, with a significant cost reduction.

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Safety of 12 core transrectal ultrasound guided prostate biopsy in patients on aspirin.

To prospectively assess safety outcome of TRUS guided prostate biopsy in patients taking low dose aspirin. Consecutive patients, who were planned for 12 core TRUS guided prostate biopsy and satisfied eligibility criteria, were included in the study and divided into two Groups: Group A: patients on aspirin during biopsy, Group B: patients not on aspirin during biopsy, including patients in whom aspirin was stopped prior to the biopsy. Parameters included for statistical analysis were: age, serum prostate specific antigen (PSA), prostate volume, hemoglobin (Hb %), number of hematuria episodes, number of patient reporting hematuria, hematuria requiring intervention, number of patient reporting hematospermia and number of patient reporting rectal bleeding. Of 681 eligible patients, Group A and B had 191 and 490 patients respectively. The mean age, prostate volume, serum PSA and pre-biopsy hemoglobin were similar in both Groups with no significant differences noted between them. None of the post-biopsy complications, including number of hematuria episodes (p=0.83), number of patients reporting hematuria (p=0.55), number of patients reporting hematospermia (p=0.36) and number of patients reporting rectal bleeding (p=0.65), were significantly different between Groups A and B respectively. None of the hemorrhagic complication in either group required intervention and were self limiting. Continuing low dose aspirin during TRUS guided prostate biopsy neither alters the minor bleeding episodes nor causes major bleeding complication. So, discontinuation of low dose aspirin prior to TRUS guided prostate biopsy is not required.

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A retrospective study of patients with systemic lupus erythematosus combined with Pneumocystis jiroveci pneumonia treated with caspofungin and trimethoprim/sulfamethoxazole.

Systemic lupus erythematosus (SLE) complicated with Pneumocystis jiroveci pneumonia (PCP) is a clinical complex with unsatisfying treatment efficacy and poor prognosis which is difficult to be diagnosed at early stage. The present study aimed to investigate the clinical features of SLE with PCP, recognize the early onset indicating factors, and evaluate the treatment efficacy of combined caspofungin and trimethoprim/sulfamethoxazole (coSMZ).We reviewed data of 9 patients admitted with SLE-PCP and treated with caspofungin combined with coSMZ at Tangshan Gongren Hospital from January 2013 to December 2017. Patients' clinical manifestation and laboratory data [leucocyte, lymphocyte, cluster of differentiation 4 (CD4)T cell, lactate dehydrogenase (LDH), blood gas, etc] were compared before and after treatments. And the early onset factors of SLE-PCP, treatment efficacy of combined caspofungin and CoSMZ were analyzed.Among these 9 patients, 8 patients suffered renal impairment, and all of them had been taking prednisone in the past 3 months at an average dose of 29.4 ± 13.6 mg/day. In addition, they had taken at least one kind of immunosuppressants. Laboratory data (leucocyte, lymphocyte, CD4T cell, PaO2, LDH) were remarkably abnormal at hospital admission, but they were improved significantly after 2 weeks of treatment, which is also statistically significant (P < .05), except that leukocyte had no significance change to the value at admission (P = .973). In addition, none of the studied patients died.The results of the study indicated that long-term use of glucocorticoids and immunosuppressants, low CD4T cell count, and renal impairment are the early-onset factors for SLE-PCP, caspofungin, when combined with CoSMZ, it could be a promising and effective strategy to treat SLE with PCP.

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Differences in Toxicity and Outcomes in Clinical Trial Participants From Minority Populations.

Black men have a higher prevalence of and mortality rate from prostate cancer compared with White men and have been shown to present with more aggressive and later-stage disease. How prostate cancer treatment affects these racial disparities is still unclear. Several studies have shown that Black men who receive treatment have a more pronounced decrease in prostate cancer-specific death; however, there remains a large disparity in all-cause mortality. This disparity may be in part related to a higher risk of death resulting from comorbidities, given the higher rates of cardiovascular disease and diabetes in Black men, both of which are complicated by the use of androgen-deprivation therapy. To further understand these disparities, it is important that we analyze the racial differences in adverse event rates and severity. Increasing the percentage of Black men in clinical trials will improve the understanding of the biologic drivers of racial disparities in prostate cancer. To evaluate the potential differences in adverse event reporting and demonstrate the feasibility of enrolling equal numbers of Black and White men in trials, we performed a prospective, multicenter study of abiraterone plus prednisone with androgen-deprivation therapy in men with metastatic castration-resistant prostate cancer, stratified by race. Racial differences in prostate-specific antigen kinetics and toxicity profile were demonstrated. Higher rates and severity of adverse events related to adrenal hormone suppression, including hypertension, hypokalemia, and hypomagnesemia, were seen in the Black cohort, not previously reported. Increased enrollment of Black men in prostate cancer clinical trials is imperative to further understand the impact of race on clinical outcomes and treatment tolerability.

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Interventions to increase adherence to medications for tobacco dependence.

Pharmacological treatments for tobacco dependence, such as nicotine replacement therapy (NRT), have been shown to be safe and effective interventions for smoking cessation. Higher levels of adherence to these medications increase the likelihood of sustained smoking cessation, but many smokers use them at a lower dose and for less time than is optimal. It is important to determine the effectiveness of interventions designed specifically to increase medication adherence. Such interventions may address motivation to use medication, such as influencing beliefs about the value of taking medications, or provide support to overcome problems with maintaining adherence. To assess the effectiveness of interventions aiming to increase adherence to medications for smoking cessation on medication adherence and smoking abstinence compared with a control group typically receiving standard care. We searched the Cochrane Tobacco Addiction Group Specialized Register, and clinical trial registries (ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform) to the 3 September 2018. We also conducted forward and backward citation searches. Randomised, cluster-randomised or quasi-randomised studies in which adults using active pharmacological treatment for smoking cessation were allocated to an intervention arm where there was a principal focus on increasing adherence to medications for tobacco dependence, or a control arm providing standard care. Dependent on setting, standard care may have comprised minimal support or varying degrees of behavioural support. Included studies used a measure that allowed assessment of the degree of medication adherence. Two authors independently screened studies for eligibility, extracted data for included studies and assessed risk of bias. For continuous outcome measures, we calculated effect sizes as standardised mean differences (SMDs). For dichotomous outcome measures, we calculated effect sizes as risk ratios (RRs). In meta-analyses for adherence outcomes, we combined dichotomous and continuous data using the generic inverse variance method and reported pooled effect sizes as SMDs; for abstinence outcomes, we reported and pooled dichotomous outcomes. We obtained pooled effect sizes with 95% confidence intervals (CIs) using random-effects models. We conducted subgroup analyses to assess whether the primary focus of the adherence treatment ('practicalities' versus 'perceptions' versus both), the delivery approach (participant versus clinician-centred) or the medication type were associated with effectiveness. We identified two new studies, giving a total of 10 studies, involving 3655 participants. The medication adherence interventions studied were all provided in addition to standard behavioural support.They typically provided further information on the rationale for, and emphasised the importance of, adherence to medication or supported the development of strategies to overcome problems with maintaining adherence (or both). Seven studies targeted adherence to NRT, two to bupropion and one to varenicline. Most studies were judged to be at high or unclear risk of bias, with four of these studies judged at high risk of attrition or detection bias. Only one study was judged to be at low risk of bias.Meta-analysis of all 10 included studies (12 comparisons) provided moderate-certainty evidence that adherence interventions led to small improvements in adherence (i.e. the mean amount of medication consumed; SMD 0.10, 95% CI 0.03 to 0.18; I² = 6%; n = 3655), limited by risk of bias. Subgroup analyses for the primary outcome identified no significant subgroup effects, with effect sizes for subgroups imprecisely estimated. However, there was a very weak indication that interventions focused on the 'practicalities' of adhering to treatment (i.e. capabilities, resources, levels of support or skills) may be effective (SMD 0.21, 95% CI 0.03 to 0.38; I² = 39%; n = 1752), whereas interventions focused on treatment 'perceptions' (i.e. beliefs, cognitions, concerns and preferences; SMD 0.10, 95% CI -0.03 to 0.24; I² = 0%; n = 839) or on both (SMD 0.04, 95% CI -0.08 to 0.16; I² = 0%; n = 1064), may not be effective. Participant-centred interventions may be effective (SMD 0.12, 95% CI 0.02 to 0.23; I² = 20%; n = 2791), whereas those that are clinician-centred may not (SMD 0.09, 95% CI -0.05 to 0.23; I² = 0%; n = 864).Five studies assessed short-term smoking abstinence (five comparisons), while an overlapping set of five studies (seven comparisons) assessed long-term smoking abstinence of six months or more. Meta-analyses resulted in low-certainty evidence that adherence interventions may slightly increase short-term smoking cessation rates (RR 1.08, 95% CI 0.96 to 1.21; I² = 0%; n = 1795) and long-term smoking cessation rates (RR 1.16, 95% CI 0.96 to 1.40; I² = 48%; n = 3593). In both cases, the evidence was limited by risk of bias and imprecision, with CIs encompassing minimal harm as well as moderate benefit, and a high likelihood that further evidence will change the estimate of the effect. There was no evidence that interventions to increase adherence to medication led to any adverse events. Studies did not report on factors plausibly associated with increases in adherence, such as self-efficacy, understanding of and attitudes toward treatment, and motivation and intentions to quit. In people who are stopping smoking and receiving behavioural support, there is moderate-certainty evidence that enhanced behavioural support focusing on adherence to smoking cessation medications can modestly improve adherence. There is only low-certainty evidence that this may slightly improve the likelihood of cessation in the shorter or longer-term. Interventions to increase adherence can aim to address the practicalities of taking medication, change perceptions about medication, such as reasons to take it or concerns about doing so, or both. However, there is currently insufficient evidence to confirm which approach is more effective. There is no evidence on whether such interventions are effective for people who are stopping smoking without standard behavioural support.

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Duloxetine Reduces Pain and Improves Quality of Recovery Following Total Knee Arthroplasty in Centrally Sensitized Patients: A Prospective, Randomized Controlled Study.

Unexplained postoperative pain is one of the most feared complications of total knee arthroplasty (TKA). A persistent noxious peripheral stimulus, such as the pain of chronic knee osteoarthritis, can cause central sensitization in which the central nervous system becomes hyperexcitable, resulting in hypersensitivity to both noxious and non-noxious stimuli. Patients with central sensitization may be more susceptible to unexplained pain after TKA. Duloxetine, a selective serotonin norepinephrine reuptake inhibitor (SNRI), can ameliorate the pain associated with central sensitization, and we aimed to determine whether it could reduce postoperative pain and improve quality of recovery after TKA in patients with central sensitization. Patients undergoing TKA were screened for central sensitization preoperatively with use of the Central Sensitization Inventory (CSI). Among 464 patients with primary osteoarthritis who were scheduled for primary unilateral TKA, 80 were identified as being centrally sensitized and were included in the study. Forty patients were randomly assigned to the duloxetine group (30 mg 1 day before surgery and for 6 weeks after surgery), and 40 were randomized to the control group (no duloxetine). Pain and quality of recovery were assessed with use of the Brief Pain Inventory (BPI), the Short Form-36 (SF-36), the Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP), and the Hamilton Depression Scale. The prevalence of adverse medication effects was also noted. The patients in the duloxetine group had better performance across pain metrics during the initial 2 to 12-week postoperative period (p < 0.05). The duloxetine group also had a superior quality of recovery 2 weeks after TKA, as indicated by emotional and physical functioning (all p < 0.05). There was no difference between groups in the prevalence of adverse events. A substantial number of patients are centrally sensitized before TKA. Surgeons should consider selective incorporation of duloxetine into the multimodal postoperative analgesic protocol, according to the severity of central sensitization, to minimize the possibility of persistent pain following TKA. Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

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Indomethacin versus meloxicam for prevention of heterotopic ossification after total hip arthroplasty.

Heterotopic ossification (HO) is a recognized postsurgical complication after total hip arthroplasty. Brooker et al. [6] established a grading system to define the degree of HO. The results of several studies have shown that non-steroidal anti-inflammatory drugs (NSAID) and radiation therapy reliably reduce the occurrence of severe HO. The exact cause and mechanism of bone formation are not known. The efficacy of indomethacin versus meloxicam for the prevention of heterotopic periarticular ossification and clinical NSAID side-effects after primary, cementless total hip arthroplasty was evaluated. Probands underwent cementless total hip replacements at the Orthopaedic Department, Hospital Wiener Neustadt, from January 1997 to January 1998, did not take NSAID up to 4 weeks preoperatively and had no NSAID contraindications. Patients were separated into two groups by different hospitalisation floors. All patients selected for this study suffered from primary or secondary coxarthrosis. Data were collected as a prospective, randomised, parallel group study. Patients were given 50 mg indomethacin 2 times daily ( n=58) vs 7.5 mg meloxicam ( n=58) in a 12-day treatment course. A two-sided Cochran-Armitage trend test showed no statistically significant difference ( p<0.05) for one of the drugs regarding influence on ectopic bone formation according to the grading system of Brooker et al. Our study demonstrates that there is no statistically significant trend that indomethacin or meloxicam protects a hip arthroplasty better from heterotopic bone formation. We prefer indomethacin therapy because it is almost half the price of meloxicam therapy, and we recommend indomethacin in a 12-day treatment course given 50 mg 2 times daily as an effective, inexpensive and easily administered HO prophylaxis.

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The effects of omeprazole on gastro-oesophageal sphincter pressure, intragastric pH, and the migrating motor complex in fasting healthy subjects.

Placebo and omeprazole (80 mg) were administered by intravenous injection in a random, double-blind, cross-over manner. Phase I and phase II of the MMC were divided into segments, and phase III constituted a single segment. The highest and lowest sphincter pressures were recorded in each segment. In the placebo group only one of the lowest values was significantly different from phase I,1. Among the highest values all means from phase II,1 to phase III were significantly higher. In the omeprazole group all means from phase II,4 to phase III in the upper demarcation were significantly higher. When the pressure profiles of placebo and omeprazole in each segment were compared, no differences were found. An unchanged pressure profile in all segments of the MMC in connection with a substantial reduction of acid secretion indicates that omeprazole shows great promise for use in patients with oesophagitis.

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Potential interaction between troglitazone and atorvastatin.

Troglitazone is a CYP3A4 isoenzyme inducer known to decrease the plasma concentration of drugs metabolized by CYP3A4. Atorvastatin, a known substrate of the CYP3A4 pathway, is often used in combination with troglitazone for diabetic patients with dyslipidemia. The purpose of this study was to investigate the clinical effects of troglitazone on the fasting lipid profiles of patients receiving atorvastatin. We retrospectively reviewed the medical records of patients who received concomitant troglitazone and atorvastatin therapy during a 24-month period. Patients were included in the analysis if during the study period, complete laboratory data were available (fasting lipid profile and glycosylated haemoglobin), the dose of atorvastatin remained unchanged, there were no changes in the diabetic drug regimen, patients received at least 3 months of combination therapy and patients were adherent with their medication. Four out of 31 (13%) patients satisfied the inclusion criteria. All of these patients were male, with a mean age of 63. All patients were receiving insulin only for diabetes control when the troglitazone was added. There was an increase in LDL-cholesterol and triglycerides of 23.3% and 21.3%, respectively. The increase in LDL-cholesterol and triglycerides on atorvastatin and troglitazone combination therapy compared with atorvastatin mono-therapy is suggestive of a drug interaction. Further studies involving troglitazone and atorvastatin may be warranted to substantiate this interaction.

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Escitalopram treatment of trichotillomania.

With the understanding that serotonergic drugs might curb compulsive hair pulling, we conducted a preliminary investigation examining the effectiveness of escitalopram, a potent and selective serotonin uptake inhibitor, in the treatment of trichotillomania. Twenty women meeting the Diagnostic and Statistical Manual-IV-Text revision criteria for trichotillomania participated in a 12-week open-label trial of treatment with escitalopram 10-30 mg/day. Response was prospectively defined as meeting the following criteria: (i) clinician version of clinical global impressions-improvement scale score of 1 or 2 (very much improved or much improved), and (ii) > or =50% reduction from baseline in the National Institute of Mental Health trichotillomania severity scale total score. Sixteen individuals, who had at least one postbaseline assessment, were included in the intention-to-treat analysis. Eight individuals (50%) were judged to be responders. Trichotillomania severity scale mean (SE) total score decreased significantly over time in the intention-to-treat analysis [15.4 (0.9)-9.4 (1.4); F=7.3; P<0.0001] and for completers [15.8 (1.0)-7.5 (1.2); F=10.1; P<0.0001]. Side effects were mild. Escitalopram treatment for 12 weeks led to significant improvement of trichotillomania in some patients in this small open-label trial.

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Drug effects on aldosterone/plasma renin activity ratio in primary aldosteronism.

Primary aldosteronism is a specifically treatable and potentially curable form of secondary hypertension. The aldosterone/plasma renin activity ratio (ARR) is routinely used as a screening test. Antihypertensive therapy can interfere with the interpretation of this parameter, but a correct washout period can be potentially harmful. We have investigated the effects of therapy with atenolol, amlodipine, doxazosin, fosinopril, and irbesartan on the ARR in a group of 230 patients with suspected primary aldosteronism. The percent change from control of ARR in patients taking amlodipine was -17%+/-32; atenolol, 62%+/-82; doxazosin, -5%+/-26; fosinopril, -30%+/-24; and irbesartan, -43%+/-27. The ARR change induced by atenolol was significantly higher compared with that induced by all other drugs (P<0.0001), and the ARR change induced by irbesartan was significantly lower than that induced by doxazosin (P<0.0001). One of 55 patients from the group taking amlodipine (1.8%) and 4/17 of the patients taking irbesartan (23.5%) gave a false-negative ARR (<50). None of the patients of the groups taking fosinopril, doxazosin, and atenolol displayed a false-negative ARR. Doxazosin and fosinopril can be used in hypertensive patients who need to undergo aldosterone and PRA measurement for the diagnosis of primary aldosteronism; amlodipine gave a very small percentage of false-negative diagnoses. beta-Blockers also do not interfere with the diagnosis of primary aldosteronism, but they can be responsible for an increased rate of false-positive ARRs. The high rate of false-negative diagnoses in patients undergoing irbesartan treatment requires confirmation in a higher number of patients.

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Myasthenia gravis with ocular involvement in older patients.

There has been little previous study reporting the eye findings and presentation of elderly patients with myasthenia gravis. The purpose of this study was to review the findings and course of myasthenia gravis after the sixth decade of life. Retrospective observational case series. The authors reviewed the clinical records of 27 patients with onset of myasthenia gravis at age 60 years or more who were seen at a tertiary care academic ophthalmology centre in Houston between January 1992 and March 1999. The diagnosis of myasthenia gravis was based on conventional clinical and laboratory criteria. Twenty patients (74%) were men. Of the 16 patients who underwent testing for anti-acetylcholine receptor antibodies, 11 (69%) were seropositive. Concurrent thyroid disease was found in seven patients (26%), including five (71%) of the seven women. No patient had thymoma. Sixteen patients (59%) manifested generalized symptoms during follow-up; 12 did so within 1 year of disease onset. Patients responded well to both anticholinesterase and corticosteroid therapy. At the most recent follow-up visit 18 patients (67%) were clinically improved, and no patient was clinically worse. Myasthenia gravis in this study was characterized by a male predominance, high rate of concurrent thyroid disease, high rate of progression to mild generalized symptoms, absence of thymoma, good response to medical therapy and minimal life-threatening complications. Clinicians should consider the diagnosis of myasthenia gravis in an older patient presenting with diplopia or ptosis.

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Therapeutic response to benzodiazepine in panic disorder subtypes.

This study makes a comparison between two subtypes of panic disorder regarding the clinical efficacy of clonazepam, a benzodiazepine. To evaluate the clinical efficacy of clonazepam in a fixed dosage (2 mg/day), compared to placebo, in the treatment of panic disorder patients and to verify whether there are any differences in the responses to clonazepam between panic disorder patients with the respiratory and non-respiratory subtypes. Randomized study with clonazepam and placebo. Outpatient Anxiety and Depression Unit of the Institute of Psychiatry, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. 34 patients with a diagnosis of panic disorder with agoraphobia, between 18 and 55 years old. Administration of clonazepam or placebo for 6 weeks, in panic disorder patients, after they were classified within two subtypes of panic disorder: respiratory and non-respiratory. Changes in the number of panic attacks in comparison with the period before the beginning of the study; Hamilton Anxiety Scale; Global Clinical Impression Scale; and Patient's Global Impression scale. In the group that received clonazepam, by the end of the 6th week there was a statistically significant clinical improvement, shown by the remission of panic attacks (p < 0.001) and decrease in anxiety (p = 0.024). In the group that received clonazepam there was no significant difference between the respiratory and non-respiratory subtypes of panic disorder, regarding the therapeutic response to clonazepam. Clonazepam was equally effective in the treatment of the respiratory and non-respiratory subtypes of panic disorder, suggesting there is no difference in the therapeutic response between the two subtypes.

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Differential co-expression and regulation analyses reveal different mechanisms underlying major depressive disorder and subsyndromal symptomatic depression.

Recent depression research has revealed a growing awareness of how to best classify depression into depressive subtypes. Appropriately subtyping depression can lead to identification of subtypes that are more responsive to current pharmacological treatment and aid in separating out depressed patients in which current antidepressants are not particularly effective. Differential co-expression analysis (DCEA) and differential regulation analysis (DRA) were applied to compare the transcriptomic profiles of peripheral blood lymphocytes from patients with two depressive subtypes: major depressive disorder (MDD) and subsyndromal symptomatic depression (SSD). Six differentially regulated genes (DRGs) (FOSL1, SRF, JUN, TFAP4, SOX9, and HLF) and 16 transcription factor-to-target differentially co-expressed gene links or pairs (TF2target DCLs) appear to be the key differential factors in MDD; in contrast, one DRG (PATZ1) and eight TF2target DCLs appear to be the key differential factors in SSD. There was no overlap between the MDD target genes and SSD target genes. Venlafaxine (Efexor™, Effexor™) appears to have a significant effect on the gene expression profile of MDD patients but no significant effect on the gene expression profile of SSD patients. DCEA and DRA revealed no apparent similarities between the differential regulatory processes underlying MDD and SSD. This bioinformatic analysis may provide novel insights that can support future antidepressant R&D efforts.

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Comparative effect of telmisartan vs lisinopril on blood pressure in patients of metabolic syndrome.

The present study was planned to focus on comparative effects of telmisartan vs lisinopril on blood pressure in patients of metabolic syndrome The study was carried out on 62 patients of metabolic syndrome from Dec 2010 to Oct 2012 in OPD of Institute. There were two groups, A and B. Group A- Telmisartan (31 patients) and Group B- Lisinopril (31 patients) receiving Telmisartan 40 mg and lisinopril 5 mg orally once a day respectively for 12 weeks. The diagnosis of essential hypertension was made by the physician based on two measurements of blood pressure on two different occasions using auscultatory method and was done at initial stage and repeated after 6 weeks and 12 weeks of treatment in Group A and Group B patients. Our study found that telmisartan or lisinopril treatment for 12 weeks leads to statistically significant (p<0.001) reduction in both SBP and DBP at 6 and 12 weeks when compared with baseline, whereas comparison between telmisartan and lisinopril treatment failed to show any statistically significant effect. Treatment of metabolic patients with telmisartan or lisinopril for the management of hypertension reduced both Systolic blood pressure (SBP) as well as Diastolic blood pressure (DBP) statistically significantly during 12 weeks treatment. However, telmisartan and lisinopril treatment were found effective.

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Clinical experience with ketanserin in the treatment of hypertension.

Ketanserin (K), a selective and specific S2-receptor antagonist, has been compared with metoprolol (M), a cardioselective beta-blocker, in a double-blind study in order to assess its efficacy and safety in the treatment of essential hypertension. After a placebo run-in period of 4 weeks, hypertensive patients [supine diastolic blood pressure (DBP) greater than or equal to 100 mmHg] were treated with K, 40 mg twice daily (n = 18), or with M, 100 mg twice daily (n = 14). Systolic pressure (SBP) and DBP, both supine and standing, were significantly reduced from the first month of treatment by both drugs and remained stable for the whole study period (12 weeks). About two-thirds of the patients treated with K responded to the therapy (drop in DBP of at least 10%) and half were normalized (DBP less than or equal to 90 mmHg). In the M group, 50% of patients responded and 30% were normalized. A significant decrease in the heart rate was observed with M, but not with K. Ten patients treated with K were followed for 1 year. The antihypertensive effect of K was maintained throughout the study with evidence of tolerance. No serious adverse reaction was observed.

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New single capsule of bismuth, metronidazole and tetracycline given with omeprazole versus quadruple therapy consisting of bismuth, omeprazole, amoxicillin and clarithromycin for eradication of Helicobacter pylori in duodenal ulcer patients: a Chinese prospective, randomized, multicentre trial.

To assess the efficacy and safety of omeprazole given with the new single capsule of bismuth, metronidazole and tetracycline (OBMT) compared with quadruple treatment consisting of omeprazole, bismuth, amoxicillin and clarithromycin (OBAC) for Helicobacter pylori eradication in duodenal ulcer patients. This single-blind, randomized multicentre trial was conducted in 10 tertiary hospitals in China between January 2013 and April 2014. Patients were randomized to receive 10 days of OBMT therapy or 10 days of OBAC therapy. Our primary outcome was the H. pylori eradication rate, confirmed by negative [13C]urea breath tests 20-25 days after the end of omeprazole maintenance. Antibiotic resistance was determined by Etest. This study is registered with ClinicalTrials.gov, number ChiCTR-TRC-13003143. One hundred and ninety-two patients received OBMT therapy and 192 received OBAC therapy. There was no significant difference between the eradication rates achieved by OBMT and OBAC in either the ITT analysis (86.46% versus 87.50%, P = 0.762) or the PP analysis (94.58% versus 93.06%, P = 0.563). The efficacies of OBMT and OBAC were not affected by metronidazole or clarithromycin resistance. Treatment-emergent adverse events (TEAEs) for both treatments were similar; gastrointestinal and CNS symptoms were the most commonly reported. The new single-capsule OBMT quadruple therapy is as effective and well tolerated as the widely used OBAC therapy for treatment of H. pylori in clinical practice in China. In addition, this OBMT therapy largely overcomes H. pylori metronidazole and clarithromycin resistance.

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Pre- and post-treatment urinary tract findings in children with nephrogenic diabetes insipidus.

Nephrogenic diabetes insipidus (NDI) is characterized by the kidney's inability to concentrate urine, which causes intense polyuria that may lead to urinary tract dilation. We report the morphological findings of the urinary tract in ten boys with NDI specifically addressing the presence and changes of urinary tract dilation during treatment. Patients were diagnosed at a median age of 1.6 years (range, 0.16-6.33 years) and treated with a low osmotic diet, hydrochlorothiazide-amiloride and indomethacin, which decreased the diuresis from a median of 10.5 ml/kg/h to 4.4 ml/kg/h (p < 0.001). Three patients showed normal renal ultrasound before treatment until last control, while the remaining seven showed urinary tract dilation. In this second group, dilation was reduced with treatment in four patients and disappeared in the remaining three. Children without dilation or in whom the dilation disappeared were diagnosed and treated earlier than those with persistent dilation (median 1.66 versus 4.45 years, respectively). After a median of 10.4 (range, 2.3-20.3) years of follow-up, no patients showed urological complications. Medical treatment of the disease improved the dilation in all cases, preventing its potential complications. Regardless of the good outcome of our patients, periodic urologic follow-up is recommended in NDI patients.

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Efficacy and safety of DALI-LDL-apheresis in two patients treated with the angiotensin II-receptor 1 antagonist losartan.

Direct adsorption of lipids (DALI) is the first low-density lipoprotein (LDL)-apheresis technique capable of adsorbing LDL and lipoprotein (a) directly from whole blood. The adsorber consists of negatively charged polyacrylate ligands linked to a Eupergit matrix. Negatively charged ligands give rise to activation of bradykinin, which is rapidly degraded by the angiotensin converting enzyme (ACE). Thus, angiotensin converting enzyme inhibitors are contraindicated in DALI-LDL-apheresis. This is the first paper to describe the efficacy and safety of DALI-LDL-apheresis in patients treated with 50 mg of the angiotensin II-receptor 1 antagonist (ARA) losartan. Two hypercholesterolemic patients were treated for 79 patient months with weekly or biweekly DALI sessions (N = 221 sessions). Approximately 1.4 patient blood volumes were treated per session. Acute reductions of LDL-cholesterol (63%) and lipoprotein (a) (62%) exceeded 60% and laboratory safety parameters remained in the apheresis typical range. Mean bradykinin plasma levels peaked in the efferent line post-adsorber at 1000 mL of treated blood volume; 467 fmol/mL (N = 6 sessions) in the ARA-treated patients and 671 fmol/mL (N = 9 sessions) in a control group of three DALI patients without ARA medication (P = 0.69, n.s.). Clinically, the DALI sessions for the ARA-treated patients were completely uneventful and blood pressure was not significantly different in the two groups. In summary, according to this retrospective pilot study, DALI-LDL-apheresis was shown for the first time to be safe and effective in patients on ARA medication.

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A retrospective analysis of the etiologic agents and antibiotic susceptibility pattern of uropathogens isolated in the Jigme Dorji Wangchuck National Referral Hospital, Thimphu, Bhutan.

Urinary tract infection is one of the major public health problems. Specific population studies to understand the common etiologic agents and antibiotic susceptibility patterns are important to determine the empirical treatment of urinary tract infections. This is the first study in Bhutan to analyze the etiologic agents and antibiotic susceptibility pattern of uropathogens isolated from patients visiting Jigme Dorji Wangchuck National Referral Hospital with the ultimate goal of guiding empirical treatment. Hospital based (inpatients/outpatients) retrospective cross sectional study of 6030 clinically suspected patients with urinary tract infections who have submitted urine samples for culture in a 6 months period was done. Urine samples were collected and processed as per standard microbiological procedures and antibiotic susceptibility testing performed by CLSI guidelines. Significant bacteriuria were detected in 14.9 % of the total patients. The most common uropathogens isolated were Escherichia coli (79.3 %) followed by Klebsiella pneumoniae. Females around the age group of 18-26 have the highest prevalence of urinary tract infection. The highest rate of antibiotic resistance was seen in amoxicillin (71.4 %) and nalidixic acid (80.3 %), and resistance were lower in nitrofuration (3.4 %) and gentamycin (17.5 %). The third generation cephalosporin resistance (which is a surrogate marker of ESBL) was 16.1 % in outpatient and 16.7 % approximately in inpatient setting. Escherichia coli was the predominant uropathogen making up 79.3 % (outpatient 81.1 % and inpatient 69.5 %) of the total and its antibiotic susceptibility pattern needs to be considered for treating community-acquired UTIs empirically. The third generation cephalosporin resistance (which is a surrogate marker of ESBL) is alarmingly high among the isolates and there is need for further studies.

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