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Effectiveness and safety of citalopram in hospitalized adolescents with major depression: a preliminary, 8-week, fixed-dose, open-label, prospective study.

Citalopram is widely used in adolescents with major depressive disorder (MDD) and anxiety; however, data on efficacy and safety are still limited and inconsistent. The aim of this study was to evaluate both the efficacy and the safety of citalopram for treatment of MDD and anxiety symptoms in adolescent inpatients. An open-label, prospective design of an 8-week trial with a fixed dose of 20 mg/d of citalopram was performed in 10 hospitalized adolescents. Clinical state was assessed by Hamilton Depression (HAM-D 17) and Hamilton Anxiety scales, Beck Depression Inventory (BDI), and the Clinical Global Impression-Severity Scale for depression. Suicidal risk was assessed by the Suicide Risk Scale. A 30% improvement in the rating scales was considered as being a response to the treatment. After 8 weeks, depression levels as measured by the HAM-D 17 (P = 0.002), the BDI (P = 0.011), and the Clinical Global Impression-Severity Scale (P = 0.002) showed significant improvement. So did anxiety levels, as measured by the Hamilton Anxiety (P = 0.026) at end point. Subjective depression level (BDI) decreased significantly between week 2 and 4 (Z = -2.36, P = 0.018), whereas objective depression level (HAM-D 17) decreased significantly between week 4 and 6 (Z = -2.53, P = 0.012). Suicide risk, as assessed by the Suicide Risk Scale, however, increased significantly after 8 weeks (P = 0.011). This pilot small-scale trial found that citalopram was effective for both depressive and anxiety symptoms in adolescents with MDD and that response started as early as the second week. However, suicidal risk was elevated for some of the subjects. Larger randomized placebo-controlled trials are needed.

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Chemotherapy of invasive thymoma. A retrospective study of 22 cases.

The authors report on combination chemotherapy in 22 patients (seven men, 15 women; age 20-67, median 38.5 years) with incompletely resected invasive thymoma. Twelve of 22 patients have had prior radiotherapy of the tumor (four of 12 local failure, eight of 12 remote metastases). By subsequent chemotherapy five of 12 obtained complete remission (CR). One of them died by relapsed tumor, another by an intercurrent infection. At 5 years after diagnosis the survival rate of the 12/22 patients was 33% (Kaplan-Meier). Ten of 22 patients received chemotherapy as primary treatment of incompletely resected thymoma. Four of 10 obtained CR. One of them was lost during follow-up, the others received adjuvant irradiation of the mediastinum and are free of disease. Two of ten obtained partial remission (PR), but relapsed within 6 months after chemotherapy. At 3 years after diagnosis the survival rate of the 10/22 patients was 34%. Thirteen of 22 patients received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP/bleomycin as first chemotherapeutic regimen. Five of them achieved CR. Cyclophosphamide, vincristine, and prednisone (COP) or COP plus procarbazine (COPP) was administered to six of 22. Three of them obtained a CR and one a PR. In an alternating manner COPP and Einhorn regimens were given to two of 22, one of which had a CR. In one of 22 the doxorubicin, bleomycin, cisplatin, prednisone (BAPP) regimen was followed by a PR. The authors conclude that combination chemotherapy is effective in the first-line postsurgical treatment of incompletely resected thymoma and also in the treatment of local or metastatic relapses after radiotherapy.

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Zofenopril plus hydrochlorothiazide and irbesartan plus hydrochlorothiazide in previously treated and uncontrolled diabetic and non-diabetic essential hypertensive patients.

In most treated patients with hypertension, a two or more drug combination is required to achieve adequate blood pressure (BP) control. In our study we assessed whether the combination of zofenopril + hydrochlorothiazide (HCTZ) was at least as effective as irbesartan + HCTZ in essential hypertensives with at least one additional cardiovascular risk factor, uncontrolled by a previous monotherapy. After a 2-week placebo washout, 361 treated hypertensive patients [office sitting diastolic BP (DBP), ≥90 mmHg], aged 18-75 years, were randomized double blind to 18-week treatment with zofenopril 30 mg plus HCTZ 12.5 mg or irbesartan 150 mg plus HCTZ 12.5 mg once daily, in an international, multicenter study. After the first 6 and 12 weeks, zofenopril and irbesartan doses could be doubled in non-normalized subjects. The primary study end point was the office sitting DBP reduction after 18 weeks of treatment. Secondary end points included office systolic BP (SBP), ambulatory BP and high sensitivity C-reactive protein (hs-CRP). The between-treatment difference for office DBP averaged to +1.0 (95% CI -0.4, +0.8) mmHg (P = 0.150), the upper limit of the 95% confidence interval being inferior to the protocol-defined non-inferiority limit (3 mmHg). In the subset of patients with valid ambulatory BP, no difference in 24-h average DBP [n = 181; 6.7 (8.7, 4.6) zofenopril + HCTZ vs. 6.3 (8.8, 3.7) mmHg irbesartan + HCTZ, P = 0.810] and SBP reductions [11.7 (15.4, 8.0) vs. 12.6 (17.2, 8.0) mmHg, P = 0.758] were observed between the two treatment groups. hs-CRP was reduced by zofenopril + HCTZ [-0.52 (-1.05, 0.01) mg/L], while it was increased by irbesartan plus HCTZ [0.97 (0.29, 1.65) mg/L, P = 0.001 between treatments]. In previously monotherapy-treated, uncontrolled patients with hypertension, zofenopril 30-60 mg + HCTZ 12.5 mg is as effective as irbesartan 150-300 mg plus HCTZ 12.5 mg, with the added value of a potential protective effect against vascular inflammation.

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Serum TGF-beta1 correlates with chronic histopathological lesions in protocol biopsies of kidney allograft recipients.

Transforming growth factor-beta (TGF-beta) is a well-known profibrotic factor playing a role in chronic kidney allograft nephropathy. Cyclosporine (CsA)-sparing immunosuppressive regimens may improve long-term graft function. Our aim was to study the influence of immunosuppressive treatment with versus without calcineurin inhibitors on serum TGF-beta levels and histological changes in protocol biopsies of kidney allograft recipients. In this prospective, randomized study of 42 low-rejection risk patients we randomized two groups: group A: mycophenolate mofetil (MMF), prednisone, daclizumab, and reduced CsA dose for 7 months (5 mg per kg per day) followed by complete withdrawal (n = 21); and group B: normal CsA dose (10 mg per kg per day adjusted according to C2 levels), MMF, prednisone, and no daclizumab (n = 21). In both groups we performed histological assessments (Banff 97) and measured serum TFG-beta levels before as well as, at 3 and 12 months after transplantation. We found a relationship between immunosuppressive regimen and the TGF-beta concentration over 1 year of observation. Before transplant the TGF-beta1 levels did not differ between the groups (P = .29); at 3 months they were 33 +/- 9 vs 49 +/- 15 pg per mL, respectively, in groups A and B (P = .08), and at 12 months they were 39.5 +/- 4 versus 55.5 +/- 11 pg per mL, respectively, in groups A and B (P = .03). Protocol biopsies at 12 months in group B showed chronic tubular lesions more pronounced than in group A. TGF-beta1 concentrations were significantly higher among group B than A. We conclude that TGF-beta1 concentration may predict the development of kidney graft fibrosis; early CsA withdrawal may achieve a reduction in chronic tubular and interstitial injury of cadaveric kidney allografts.

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Efficacy of a fixed dose combination of irbesartan and atorvastatin (Rovelito^®) in Korean adults with hypertension and hypercholesterolemia.

Coexistence of hypertension (HTN) and hypercholesterolemia is a major synergistic and modifiable risk factor for cardiovascular disease (CVD). Thus, a fixed-dose combination (FDC) of anti-HTN drugs and statins may be useful for treating CVD. This study evaluated the efficacy of an FDC of irbesartan and atorvastatin (Rovelito^®) in Korean patients. Patients with HTN and hypercholesterolemia were screened for this prospective, observational, descriptive, multi-center, phase IV study. Eligible patients were administered with Rovelito for 3 months. Dose adjustment was allowed based on the physician's discretion. Blood pressure (BP) goal was <140/90 mmHg, and blood lipid goal was based on Adult Treatment Panel III. Compliance with therapeutic lifestyle modification and safety of the study drugs were evaluated. Of the 2,777 patients enrolled in this study, 931 were analyzed for clinical efficacy. BP and low-density lipoprotein cholesterol (LDL-C) goals were achieved in 801 (86.04%) and 797 (85.61%) patients, respectively. For the BP goal, higher baseline BP and higher body mass index were risk factors for treatment failure. For LDL-C goal, baseline LDL-C level, number of concomitant drugs, smoking status, and alcohol consumption were risk factors for treatment failure. Of the 931 participants, 694 (74.54%) achieved the treatment goals for both BP and LDL-C. Smoking status, alcohol consumption, number of concomitant drugs, and higher baseline LDL-C and BP levels were risk factors for treatment failure in both BP and LDL-C goals. Adherence with Rovelito was 97.90%±5.79%, and incidence of adverse events was 4.19% (116). FDC of irbesartan and atorvastatin (Rovelito) could be extremely helpful in treating patients with both HTN and hypercholesterolemia. Poor metabolic profiles were risk factors for poor treatment response and the reason for choosing Rovelito. Therapeutic lifestyle modification should still be underscored despite the 75% treatment success rate with Rovelito for both conditions.

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Atorvastatin lowers lipoprotein(a) but not apolipoprotein(a) fragment levels in hypercholesterolemic subjects at high cardiovascular risk.

The effect of statins on Lp(a) levels is controversial; furthermore, the potential action of statins on apo(a) fragmentation is indeterminate. We therefore determined the circulating levels of Lp(a) and of apo(a) fragments in hypercholesterolemic patients before and after treatment (6 weeks) with Atorvastatin 10 mg/day (A10) or Simvastatin 20 mg/day (S20). In a double blind study, hypercholesterolemic patients (n=391) at high cardiovascular risk (LDL-C>=4.13 mmol/l; TG<2.24 mmol/l; 34% with documented CHD; 45% hypertensive; and 29% current smokers) were assigned to treatment with A10 (n=199) or S20 (n=192). Plasma Lp(a) and apo(a) fragment levels (n=206) were measured prior to and after treatment. At baseline, A10 and S20 groups did not differ in plasma levels of lipids, Lp(a) (A10: 0.45+/-0.48 mg/ml, S20: 0.46+/-0.5), and apo(a) fragments (A10: 3.88+/-5.22 microg/ml; S20: 3.25+/-3), and equally in apo(a) isoform size (A10: 26+/-5 kr, S20: 25.5+/-5.3). After treatment, both statins significantly reduced Lp(a) levels (A10: 0.42+/-0.47 mg/ml, 6% variation, P<0.001; S20: 0.45+/-0.53 mg/ml, 0.02% variation, P=0.046). A10 and S20 did not significantly differ in their efficacy to lower Lp(a) levels. In a multivariate logistic regression analysis, the reduction of Lp(a) levels was independently associated with Lp(a) baseline concentration, but not to other variables, including LDL-C reduction. Plasma levels of apo(a) fragments were not modified by either statin. In conclusion, both A10 and S20 significantly lowered Lp(a), although this effect was of greater magnitude in atorvastatin-treated patients.

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Can daily intake of aspirin and/or statins influence the behavior of non-muscle invasive bladder cancer? A retrospective study on a cohort of patients undergoing transurethral bladder resection.

This study aimed to evaluate the behavior of non-muscle-invasive bladder cancer (NMIBC) in patients submitted to transurethral bladder resection (TURB) comparing subjects in chronic therapy with aspirin, statins, or both drugs to untreated ones. This retrospective study was conducted on 574 patients diagnosed with NMIBC who underwent TURB between March 2008 and April 2013. The study population was divided into two main groups: treated (aspirin and/or statins) and untreated. The treated group was further divided into three therapeutic subgroups: Group A (100 mg of aspirin, daily for at least two years); Group B (20 mg or more of statins, daily for at least two years); and Group C (100 mg of aspirin and 20 mg of statins together). The mean follow-up of patients was 45.06 months. No significant differences were observed among the different groups at baseline. On multivariate analysis, statin treatment, smokers and high stage disease (T1) achieved the level of independent risk factor for the occurrence of a recurrence. When patients were stratified according to the different treatment; patients treated with statins (Group B) presented an higher rate of failure (56/91 patients; 61.5%) when compared to Group A (42/98 patients; 42.9%), Group C (56/98; 57.1%) and (133/287 patients; 46.3%). This difference corresponds to a significant difference in recurrence failure free survival (p = 0.01). Our results suggest that long-term treatment with aspirin in patients with NMIBC might play a role on reducing the risk of tumor recurrence. In contrast, in our investigation data from statins and combination treatment groups showed increased recurrence rates. A long-term randomized prospective study could definitively assess the possible role of this widely used drugs in NMIBC.

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Growth after renal transplantation in prepubertal children: impact of various treatment modalities.

A retrospective study evaluated posttransplant growth of 70 prepubertal children during the first 2 y after renal transplantation (RTx). Immunosuppressive treatment consisted of prednisone administered either daily or on alternate days in combination with either azathioprine or cyclosporin A. The increment in height standard deviation score for chronologic age during the first 2 y after RTx was less than 0.5 SD for 70% of the study population. The predictive factors for posttransplant growth were determined by evaluating several factors and treatment modalities singly and simultaneously in a multiple regression analysis. Patients with the most severe growth retardation at RTx appeared to have the most pronounced growth spurt after RTx, but even they never had complete catch-up growth, and 2 y after RTx they were still shorter than those with less severe growth retardation at RTx. Alternate-day instead of daily prednisone administration had a significantly positive influence, whereas a high cumulative dose of prednisone, azathioprine instead of cyclosporin A therapy, and a persistently reduced GFR (GFR < 50 mL/min/1.73 m2) had a significantly negative influence on catch-up growth during the 2 y after RTx. Other factors, such as gender, chronologic and bone age at RTx, primary renal disease, duration of initial dialysis, repeat RTx, and target height SD score for chronologic age, whether evaluated singly or simultaneously with other significant factors, appeared to have no significant influence on post-RTx growth. Thus, 70% of the prepubertal children do not experience appreciable catch-up growth during the first 2 y after RTx. Optimization of pretransplant height appears very important. Immunosuppressive treatment with cyclosporin therapy in combination with a minimal dose of alternate-day prednisone would then result in optimal post-transplant growth, particularly if the GFR remains above 50 mL/min/1.73 m2).

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No adverse effects of statins on muscle function and health-related parameters in the elderly: an exercise study.

The aim of the present study was to investigate the effects of a repeated bout of eccentric exercise on health-related parameters and muscle performance on subjects undergoing atorvastatin therapy. Twenty-eight elderly men participated in the investigation and were assigned either in a control (n = 14) or in a statin therapy group (n = 14). All participants performed two isokinetic eccentric exercise bouts separated by 3 weeks. Muscle damage indices, resting energy expenditure, substrate metabolism, lipid and lipoprotein profile, as well as insulin sensitivity, were evaluated before and after eccentric. No differences in muscle function were observed between the two groups either at rest or after exercise. Eccentric exercise increased resting energy expenditure, increased fat oxidation, improved lipid profile, and increased insulin resistance 2 days after both eccentric exercise bouts. However, these changes appeared to lesser extent after the second bout. No differences were observed in the responses in the health-related parameters in the control and in the statin therapy group. Eccentric exercise affected similarly the control and the atorvastatin-treated individuals. The present results indicate that atorvastatin-treated elderly individuals may participate in various physical activities, even high-intensity muscle-damaging activities, without negative impact on muscle function and adaptation.

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Bupropion "Abuse" Reported to US Poison Centers.

Bupropion use to obtain nonmedical psychoactive effects has been reported. The objective was to determine the prevalence, characteristics, clinical effects, and outcomes of bupropion "abuse." A 14-year retrospective review was conducted of single substance bupropion cases with "intentional abuse" as the coded reason for exposure in individuals 13 and older reported to the National Poison Data System. Data were evaluated for prevalence, demographics, clinical effect, route, final management site, and coded outcome. There were 975 bupropion abuse cases, which accounted for 3.3% of single substance bupropion cases reported to US poison centers. The prevalence of abuse increased by 75%, from 2000 to 2012, declining slightly in 2013. The majority of cases were 13 to 29 years old (67.4%). The most frequent clinical effects were tachycardia (57.0%), seizures (33.5%), agitation/irritable (20.2%), hallucinations/delusions (14.0%), and tremor (13.1%). Most exposures were ingestions (745) followed by insufflation (166), parenteral (17), and other/unknown (17); 30 cases involved 2 routes. Seizure frequency was not significantly different between routes (P = 0.783) or exposure chronicity (P = 0.264). Final management sites were predominantly emergency department (36.9%) and admission to critical care unit (27.3%) or noncritical care unit (20.1%). Outcomes were major (11.4%), moderate (48.2%), minor (24.5%), and no effect (15.5%). There were 4 deaths. Most bupropion abuse occurs in adolescents and young adults. Tachycardia and seizures are common indicating the potential for serious effects. Seizures occur regardless of route. Providers should be aware of risk of bupropion abuse.

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Effect of prednisone priming followed by alfa-interferon in treatment of children with chronic hepatitis B: an interim analysis of a controlled trial.

A six-month analysis of a controlled trial on the treatment of chronic hepatitis B in children shows that prednisone priming followed by alpha-interferon 2A was effective in 6 of 9 treated patients in reducing HBV replication and disease activity.

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Response to aerosol salbutamol, SCH 1000, and placebo in cystic fibrosis.

The responses of 20 patients with cystic fribrosis to a B2 agonist, salbutamol, to an anticholinergic agent, SCH 1000, and to a placebo containing difluorodichloroethane and soya lecithin delivered by metered aerosol were compared. Flow rates decreased significantly after placebo (p < 0.05). FEV1 increased significantly after salbutamol (p < 0.05), but the degree of these changes was small. There was a small but significant increase in FVC but no change in flow rates after SCH 1000. Specific conductance increased significantly (p < 0.01) after both salbutamol and SCH 1000. Thoracic gas volume remained unchanged with both drugs and placebo. Four of 20 patients had a clinically significant increase in flow rates with SCH 1000 and three with salbutamol. The consistent increases in sGaw coupled with minimal changes in flow rates, suggest that the physiological effects of both agents is to increase the compressibility of the airway. The results after placebo demonstrate the increased airway reactivity to irritants in cystic fibrosis. In view of this, attention should be paid to the possible irritant effects of inhaled medications.

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Drug-Drug Interaction Potential of Darolutamide: In Vitro and Clinical Studies.

Darolutamide is a novel androgen receptor (AR) antagonist approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC). Accordingly, the drug-drug interaction (DDI) potential of darolutamide was investigated in both nonclinical and clinical studies. In vitro studies were performed to determine the potential for darolutamide to be a substrate, inducer or inhibitor for cytochrome P450 (CYP) isoforms, other metabolizing enzymes and drug transporters. A phase I drug-interaction study in healthy volunteers evaluated the impact of co-administering rifampicin [CYP3A4 and P-glycoprotein (P-gp) inducer] and itraconazole [CYP3A4, P-gp and breast cancer resistance protein (BCRP) inhibitor] on the pharmacokinetics of darolutamide. Two further phase I studies assessed the impact of co-administering oral darolutamide on the pharmacokinetics of midazolam (sensitive CYP3A4 substrate) and dabigatran etexilate (P-gp substrate) and the impact on the pharmacokinetics of co-administered rosuvastatin [a substrate for BCRP, organic anion-transporting polypeptide (OATP)1B1, OATP1B3 and organic anion transporter (OAT)3]. In vitro, darolutamide was predominantly metabolized via oxidative biotransformation catalyzed by CYP3A4 and was identified as a substrate for P-gp and BCRP. The enzymatic activity of nine CYP isoforms was not inhibited or slightly inhibited in vitro with darolutamide, and a rank order and mechanistic static assessment indicated that risk of clinically relevant DDIs via CYP inhibition is very low. In vitro, darolutamide exhibited no relevant induction of CYP1A2 or CYP2B6 activity. Inhibition of BCRP-, P-gp-, OAT3-, MATE1-, MATE2-K-, OATP1B1- and OATP1B3-mediated transport was observed in vitro. Phase I data showed that darolutamide exposure increased 1.75-fold with co-administered itraconazole and decreased by 72% with rifampicin. Co-administration of darolutamide with CYP3A4/P-gp substrates showed no effect or only minor effects. Rosuvastatin exposure increased 5.2-fold with darolutamide because of BCRP and probably also OATPB1/OATPB3 inhibition. Darolutamide has a low potential for clinically relevant DDIs with drugs that are substrates for CYP or P-gp; increased exposure of BCRP and probably OATP substrates was the main interaction of note.

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[Comparative trial of 3-day azithromycin versus 10-day coamoxilav course efficacy in acute sinusitis].

To investigate the validity of a short-term course of azitromycin in acute sinusitis (AS). Comparison of clinical and bacteriological effects, tolerance of azitromycin and co-amoxiclav. 50 AS patients were given a single 500 mg daily dose of axitromycin for 3 days and 50 such patients received co-amoxiclav 625 mg 3 times a day for 10 days. The examination performed before the treatment, 72 hours, 10-12 and 26-30 days after its beginning assessed the presence of fever, head ache, pain at palpation at the site of the sinuses projection, nasal breathing and discharge. X-ray examination and microbiological analysis of the puncture biopsy from the nasal sinuses were conducted before treatment and on its day 10-12. On the treatment hour 72 and day 10-12 azitromycin efficiency was significantly higher than that of co-amoxiclav. Recovery on the treatment day 10-12 was registered in 41(82%) and 26(52%) patients, improvement--in 6(12%) and 21(42%), no effect--in 3(6%) and 2(4%) patients, respectively, for azitromycin and co-amoxiklav. On the treatment days 26-30, 45 and 43 patients recovered, respectively. The causative agents were mainly S.aureus and Str.pyogenes. Eradication of the pathogens in response to azitromycin occurred in 29, to co-amoxiclav in 18 patients. The latter caused side effects more frequently. Azitromycin vs. co-amoxiclav provides cure in acute sinusitis for a shorter time, is better tolerated and less toxic.

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Acute antithrombotic effect of a front-loaded regimen of clopidogrel in patients with atherosclerosis on aspirin.

There is a need for a rapid antithrombotic effect after the administration of antiplatelet drugs in the setting of acute coronary syndromes and percutaneous interventions. Clopidogrel, a new thienopyridine derivative, is an efficient antiplatelet agent. However, the standard regimen of clopidogrel (75 mg/d) requires 2 to 3 days before significant antithrombotic effects. Patients with stable arterial disease on chronic aspirin therapy (n=20) were treated with clopidogrel either with a front-loaded regimen, 300 mg the first day and 75 mg/d the next 7 days, or with a standard regimen, 75 mg/d for 8 days. Blood thrombogenicity was assessed by quantification of platelet-thrombus formation in an ex vivo perfusion chamber, by ADP-induced platelet aggregation, and by ADP-induced fibrinogen binding. At 2 hours, mean total thrombus area with the standard regimen was not significantly reduced. In contrast, at 2 hours, the mean total thrombus area with the front-loaded regimen was significantly decreased by 23.1+/-8.5% versus baseline (P<0.05). ADP-induced platelet aggregation (with 5 and 10 micromol/L) was also significantly (P<0.05) reduced with the front-loaded regimen at 2 hours, with the mean platelet aggregation being 82.2+/-4.4% and 81.8+/-4.5%, respectively, versus baseline. Similarly, flow cytometry demonstrated a significant decrease (P<0. 05) in the ADP-induced fibrinogen binding (with 0.12 and 0.6 micromol/L) at 2 hours in this front-loaded regimen group (36.1+/-2. 0% and 53.2+/-9.3%). With the standard regimen, platelet activity was not significantly reduced at 2 hours. Our data suggest that a front-loaded regimen of clopidogrel added to aspirin achieves a significant antithrombotic effect at 2 hours in patients with known atherosclerotic disease on chronic aspirin therapy. This provides a rationale for using front-loaded clopidogrel in combination with aspirin in percutaneous coronary interventions.

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Initial Severity Effects on Residual Symptoms in Response and Remission: A STAR*D Study During and After Failed Citalopram Treatment.

The effects of initial severity on the time to and course of residual symptoms based on response or remission periods, and during and after failed response to citalopram in major depressive disorder are unknown. STAR*D data during and after failed citalopram treatment were reanalyzed to examine the effect of initial severity on the time to and course of residual symptoms using the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR). During and after failed citalopram treatment, Cox regression and Generalized Estimating Equation models were computed to examine mild and moderate residual symptoms during (1) response based on at least a 50% QIDS-SR reduction, as well as (2) remission based on a QIDS-SR score below 6. Generally, initial severity significantly (P < 0.05) increased the time to and course of residual symptoms at the time of response and remission. The course of select mild and moderate residual symptoms was significantly (P < 0.05) more likely to persist in the presence of initial severity during response than remission (eg, energy) across treatment levels. It is concluded that initial severity is a predictor of the time to and course of residual symptoms. The presence of residual symptoms is more likely during response than remission, thereby directing their definition as a treatment target.

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Dexamethasone and Dexmedetomidine as an Adjuvant to Intraarticular Bupivacaine for Postoperative Pain Relief in Knee Arthroscopic Surgery: A Randomized Trial.

Knee arthroscopy causes minimal trauma, however, good analgesia is required for early rehabilitation and return to normal life in the patients. We aimed to compare the analgesic effects of intraarticular dexamethasone and dexmedetomidine added to bupivacaine with those of bupivacaine alone. This study uses a double-blind, randomized, controlled design with allocation concealment in a 3-armed parallel group format among patients undergoing arthroscopic meniscal surgery. The study was conducted at Assiut University Hospital in Asyut, Egypt. The study duration was from July 2016 to February 2017. After the ethics committee approval, 60 patients, with the American Society of Anesthesiologists (ASA) physical status of I or II, 20 - 50 years old, and scheduled for arthroscopic meniscal surgery were randomized in a double-blind manner to receive 18 mL intraarticular bupivacaine 0.25% with either dexamethasone 8 mg (group I), dexmedetomidine 1 ug/kg (group II), or 2 mL of normal saline (group III). The total volume of injectate used in each group was 20 mL. All of the patients received spinal anesthesia. Postoperatively, oral paracetamol 1000 mg was given every 8 hours, and oral tramadol 50 mg was administered, as needed, for rescue analgesia. The visual analog scale (VAS) pain scores, time to first analgesic request, and total dose of postoperative analgesics were recorded for 3 days postoperatively. The VAS scores were lower in groups I and II compared with group III. The time to the first analgesic was significantly shorter in group III compared with groups I and II (P = 0.001). The total dose of rescue paracetamol was higher in group III compared with groups I and II (P = 0.001). No need for tramadol rescue analgesia was recorded in any of the groups. No significant differences between groups I and II were noticed. The limitations of this study include the lack of previous research to compare the effect of both intraarticular dexamethasone and dexmedetomidine added to bupivacaine for postoperative analgesia in arthroscopic knee surgery. Additionally, there was a short observation period for the detection of chondrotoxicity, if occurred. The addition of dexamethasone or dexmedetomidine to a solution of bupivacaine 0.25% provided better analgesia than using bupivacaine alone. NCT02818985. Intraarticular, knee arthroscopy, bupivacaine, dexmedetomidine, dexamethasone, postoperative pain.

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Chronic cough and gastroesophageal reflux disease: experience with specific therapy for diagnosis and treatment.

To evaluate experience using a therapeutic trial of proton-pump inhibitor therapy with or without a prokinetic agent in diagnosis and treatment of gastroesophageal reflux disease (GERD)-related cough. A review of experience with 214 patients with cough of > or = 3 weeks referred over 3.5 years. An anatomic diagnostic protocol was used to identify and treat those with GERD-related cough. A pulmonary specialty practice affiliated with the University of Rochester School of Medicine and Dentistry. One hundred eighty-three patients were identified with chronic cough and were included in the study. Thirty-one patients were disqualified because of abnormal chest radiographic findings, inadequate follow-up, or cough being not the primary complaint. Fifty-six patients were identified as having GERD-related cough. A once-daily dose of a proton-pump inhibitor was prescribed. A prokinetic agent was added if esophageal dysfunction was suspected or response was inadequate. Those who did not respond underwent 24-h esophageal pH monitoring. GERD was the single cause of cough in 24 patients (43%). Twenty-nine patients (52%) had GERD plus another cause, and 3 patients (5%) had GERD with more than two causes. Twenty-four patients (43%) had cough only, while 32 patients (57%) had other symptoms of GERD. Proton-pump therapy was successful in 42 patients (79%). Twenty-four patients responded to proton-pump inhibitor therapy, and 18 patients responded when metoclopramide or cisapride was added. The remaining two patients responded to a histamine type-2 blocker or cisapride alone. The cough was eliminated or markedly improved in 38 patients (86%) after 4 weeks and by 8 weeks in the remaining 6 patients. Six of the nonresponders had aspiration diagnosed by bronchoscopy. Four patients had fundoplication recommended, and two patients responded to alternative interventions. Four to 6 weeks of a proton-pump inhibitor alone or in combination with a prokinetic agent successfully diagnoses and treats four of five patients with GERD-related cough. Twenty-four-hour esophageal pH monitoring will confirm the diagnosis in the others. These patients may be candidates for fundoplication. Nonresponders often aspirate as an additional aggravating factor.

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Prescribing patterns of target-specific oral anticoagulants: an academic hospital perspective.

Target-specific oral anticoagulants have been rapidly adopted into clinical practice for stroke prophylaxis and venous thromboembolism treatment, raising concerns about off-label prescribing practices. We conducted a retrospective review of consecutive patients prescribed dabigatran, rivaroxaban or apixaban prior to inpatient hospitalization over an 18-month period to examine the off-label prescribing frequency, contraindications and related complications. Chart review included baseline demographics, hospital admitting service, outpatient prescribing service, renal function, therapeutic indication, echocardiographic findings, contraindications, major bleeding events and vital status. We identified 160 patients who received a target-specific oral anticoagulant prior to hospitalization. Over half (53.1%) of the patients received rivaroxaban, 43.7% received dabigatran and 3.1% received apixaban. Atrial fibrillation (68.1%) and venous thromboembolism treatment (25.6%) were the most common indications. Ninety percent of patients had a U.S. Foods and Drugs Administration (FDA)-approved indication for therapy. Major bleeding events occurred in 4.4% of patients. Cardiology was the most common prescribing and admitting service (43.8 and 31.3%), and more frequently adhered to FDA-approved indications (97 vs. 84%, P = 0.01). There were no significant differences between prescribing services regarding major contraindications (P = 0.14) and major bleeding events (P = 0.77). Off-label prescription rates for target-specific oral anticoagulants were infrequent and not associated with increased adverse events.

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Effects of two selective serotonin reuptake inhibitor antidepressants, sertraline and escitalopram, on aldosterone/renin ratio in normotensive depressed male patients.

Plasma aldosterone to renin ratio (ARR) is the most popular screening test for primary aldosteronism (PAL). Certain medications are known to cause false-negative or -positive ARRs by affecting renin and aldosterone levels. There are no previously published data on the effects of antidepressants on ARR. Normotensive, depressed male patients (n = 26) underwent measurement (seated, midmorning) of plasma aldosterone, direct renin concentration (DRC), renin activity (PRA), electrolytes and creatinine and urinary aldosterone, cortisol, electrolytes, and creatinine at baseline and after 2 and 6 wk treatment with sertraline (n = 14) or escitalopram (n = 12). For both antidepressants, treatment was associated with rises in aldosterone [sertraline: baseline, mean ± sd, 243 ± 34; 2 wk, 256 ± 33; 6 wk, 267 ± 34 pmol/liter (P < 0.01 by ANOVA); escitalopram, 261 ± 36, 269 ± 38, 282 ± 40 pmol/liter (P < 0.05)], DRC [19.5 ± 2.2, 33.5 ± 2.0, 39.0 ± 2.4 mU/liter (P < 0.001); 24.5 ± 2.4, 34.0 ± 2.7, 42.8 ± 2.4 mU/liter (P < 0.001)], and PRA [2.24 ± 0.21, 2.58 ± 0.26, 4.68 ± 0.42 ng/ml · h (P < 0.001); 4.31 ± 0.22, 5.57 ± 0.36, 6.42 ± 0.53 ng/ml · h (P < 0.001)]. ARR fell significantly whether calculated using DRC [sertraline, 13.7 ± 2.2, 7.5 ± 0.7, 6.8 ± 0.7 (P < 0.001); escitalopram, 11.5 ± 1.9, 8.0 ± 1.1, 6.6 ± 1.0 (P < 0.001)], or PRA [116.6 ± 15.8, 108.4 ± 15.6, 60.4 ± 6.2 (P < 0.001); 61.2 ± 8.1, 50.0 ± 7.7, 45.6 ± 6.0 (P < 0.01)]. Selective serotonin reuptake inhibitor antidepressants can significantly reduce ARR and therefore potentially increase the risk of false-negative results when screening for PAL. Further studies in hypertensive patients, including patients with confirmed PAL, are required.

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Generic Clopidogrel: Has Substitution for Brand Name Plavix® Been Effective?

Following the expiration of brand name exclusivity of Plavix® in 2012, generic clopidogrel bisulfate was approved. As a widely prescribed medication with significant inter-patient pharmacokinetic and pharmacodynamic variability, data regarding the impact of switching to generic clopidogrel bisulfate on patients is needed. The objective of this study was to determine whether generic clopidogrel bisulfate is as efficacious as Plavix® for the inhibition of platelet aggregation. Patients treated with Plavix® monotherapy (n = 254) or generic clopidogrel bisulfate monotherapy (n = 185) were included in this retrospective review. Confounding factors previously found to affect clopidogrel responsiveness (diabetes, female sex, and smoking) were assessed, as well as medications classified as substrates, inducers, and inhibitors of enzymes involved in clopidogrel metabolism. Whole blood impedance aggregometry was used to measure platelet aggregation in response to adenosine diphosphate. Patients were tested after ≥2 weeks of treatment and designated as non-responders if aggregation response exceeded sensitivity thresholds of 6 ohms of impedance. The introduction of generic clopidogrel bisulfate was associated with a decrease in antiplatelet resistance (44% to 31%, p < 0.01) and decreased mean ohms of resistance (5.06 ± 4.55 to 3.32 ± 4.03, p < 0.01). Prior to analysis of secondary outcomes, 217 patients were eliminated due to antiplatelet usage for longer than 3 years (n = 123 for Plavix® and n = 118 for clopidogrel). There was no statistically significant finding in prevalence of secondary events. Resistance rates to the antiplatelet, clopidogrel are significantly lower since the switch to generic formulations. Further investigation into the impact of variability between clopidogrel bisulfate formulations is needed.

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Metoprolol metabolism via cytochrome P4502D6 in ethnic populations.

The objective of this study was to determine whether metabolism via cytochrome P4502D6 (CYP2D6) was higher in Black subjects than White subjects. Ten Black and 10 White healthy male volunteers who were phenotyped CYP2D6 extensive metabolizer phenotypes participated in this randomized, cross-over study in which metoprolol was used as a model CYP2D6 substrate. In both study phases, subjects received oral rac-metoprolol tartrate (200 mg); during one phase, subjects also took quinidine sulfate (100 mg) daily beginning 3 days before the dose of metoprolol. Plasma samples were collected for 12 and 24 hr after the dose in the metoprolol and metoprolol plus quinidine phases, respectively. Metoprolol enantiomer concentrations were determined by chiral HPLC with fluorescence detection. S-metoprolol areas under the concentration vs. time curves during the metoprolol phase were 879 +/- 600 ng/ml*hr in White subjects vs. 984 +/- 653 ng/ml*hr in Black subjects. During inhibition of CYP2D6-mediated metabolism with quinidine, S-metoprolol areas under the concentration vs. time curves were 2515 +/- 749 and 2719 +/- 742 in White and Black subjects, respectively. Metoprolol elimination half-lives in both groups were approximately doubled by quinidine. Mean S-metoprolol/R-metoprolol ratios were 1.39 in both racial groups during the metoprolol phase, and during the metoprolol plus quinidine phase were 0.89 and 1.03 in White subjects and Black subjects, respectively (p < 0.05, Blacks vs. Whites). The percentage of metoprolol metabolism inhibited by quinidine was similar between Blacks and Whites (e.g., 66 +/- 15% and 64 +/- 25% of S-metoprolol apparent oral clearance in Blacks and Whites, respectively). We conclude that there are no differences between Black subjects and White subjects in metabolism via CYP2D6. There were also no racial differences in the contribution of CYP2D6 to overall metoprolol metabolism. The results of this study suggest that drugs are primarily metabolized by CYP2D6 will not exhibit racial differences in their disposition.

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Direct oral anticoagulants in hypercoagulable states.

Direct oral anticoagulants have been shown safe and effective in the treatment of pulmonary emboli and deep vein thrombi. Their role in the treatment of patients with hypercoagulability is uncertain. We designed a retrospective exploratory analysis of all patients with definite heparin induced thrombocytopenia (HIT) and antiphospholipid syndrome (APS) that were treated with either apixaban or rivaroxaban from September 2011 through November 2015. Patients were reviewed for several clinico-pathologic features, including efficacy and safety. 23 patients were identified (12 patients with HIT and 11 patients with APS). Sixteen patients (70 %) were treated with apixaban and seven patients (30 %) were treated with rivaroxaban over a median follow up of 7 months (range 2-39). Zero patients developed recurrent thrombi. Two patients being treated for HIT developed major bleeding leading to discontinuation of all anticoagulation. Therefore, apixaban and rivaroxaban appear safe and effective for treatment of patients with HIT and APS in this small retrospective cohort and should be considered on an individual basis for patients who refuse, fail or are intolerant of warfarin. There were no sources of funding.

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β2-Adrenergic receptor agonists activate CFTR in intestinal organoids and subjects with cystic fibrosis.

We hypothesized that people with cystic fibrosis (CF) who express CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations associated with residual function may benefit from G-protein coupled receptor (GPCR)-targeting drugs that can activate and enhance CFTR function.We used intestinal organoids to screen a GPCR-modulating compound library and identified β2-adrenergic receptor agonists as the most potent inducers of CFTR function.β2-Agonist-induced organoid swelling correlated with the CFTR genotype, and could be induced in homozygous CFTR-F508del organoids and highly differentiated primary CF airway epithelial cells after rescue of CFTR trafficking by small molecules. The in vivo response to treatment with an oral or inhaled β2-agonist (salbutamol) in CF patients with residual CFTR function was evaluated in a pilot study. 10 subjects with a R117H or A455E mutation were included and showed changes in the nasal potential difference measurement after treatment with oral salbutamol, including a significant improvement of the baseline potential difference of the nasal mucosa (+6.35 mV, p<0.05), suggesting that this treatment might be effective in vivo Furthermore, plasma that was collected after oral salbutamol treatment induced CFTR activation when administered ex vivo to organoids.This proof-of-concept study suggests that organoids can be used to identify drugs that activate CFTR function in vivo and to select route of administration.

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Suppression of exercise-induced asthma by salbutamol, theophylline, atropine, cromolyn, and placebo in a group of asthmatic children.

A number of drugs are known to inhibit exercise-induced asthma (EIA), but the results in some cases have been difficult to interpret due to the techniques employed. A comparative study was carried out in a group of children to investigate the effects of salbutamol, choline theophyllinate, cromolyn sodium, atropine, and placebo. The exercise test took the form of six minutes of standardized treadmill running. All the drugs, but not the placebo, were able to inhibit EIA ti a significant degree, the effect being most marked with salbutamol. Cromolyn sodium caused no bronchodilatation at rest, while all the other drugs were brondhocilators, the effect being most marked with the atropine during exercise. It was impossible to distinguish the type of drug used for inhibition of EIA if it caused bronchodilatation at rest. The manner in which an exercise test can be used to investigate the duration of action or site of action of drugs is noted.

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Acute intervention with metoprolol in myocardial infarction.

Studies in experimental and clinical myocardial infarction support the idea that sympathetic activity and myocardial noradrenaline release play a significant role in the development of myocardial ischemic damage. Betablockade has been shown to limit infarct size and lower the incidence of ventricular fibrillation in experimental models. Betablockade to patients (pts) with acute myocardial infarction (AMI) has been shown to reduce ischemia reflected as reduction of ischemic chest pain, decrease ST-segment elevation and increase lactate extraction. Whether this treatment in the clinical situation can prevent development of infarction, reduce infarct size and early mortality in man remains to be proven. In Gøteborg a double-blind study on metoprolol and placebo was started four and a half years ago. Inclusion of pts. in the study has been terminated and survival data will be available on May 1, 1981. 1395 pts. were included of whom 800 developed AMI. Metoprolol 15 mg was given IV followed by a total daily dose of 200 mg/day. The tolerance for betablockade was generally good. Analysis of serum enzyme estimations of maximal LD I + II showed a significant reduction by metoprolol when the treatment was given within 12 hours of onset of pain. In a subgroup consisting of 103 pts. with AMI metoprolol had no clearcut effects on the ventricular arrhythmias during the first 24 hours in hospital. The betablockade resulted in a 15% reduction in heart rate. The main objective of this study, the mortality during three months of blind treatment will be published late in 1981.

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Fluoxetine for hypochondriacal patients without major depression.

Hypochondriasis without concomitant depression is often considered to be unresponsive to pharmacotherapy. Given marked similarities between hypochondriasis and obsessive-compulsive disorder, we decided to conduct an open trial of high-dose fluoxetine for patients with DSM-III-R hypochondriasis who did not meet criteria for major depression. Ten of 16 patients were much improved at the end of 12 weeks. A comparison of baseline and week 12 scores by the use of a paired-samples t-test revealed a statistically significant reduction in hypochondriacal concerns, as measured by the Heightened Illness Concern Clinical Global Impression Severity scale, the Whiteley Index of Hypochondriasis, and the Heightened Illness Concern Questionnaire. These results suggest that fluoxetine may be a useful therapy for hypochondriacal patients without marked depressive features--a group previously considered to be treatment refractory.

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Effect of atorvastatin on in vitro expression of resistin in adipocytes and monocytes/macrophages and effect of atorvastatin treatment on serum resistin levels in patients with type 2 diabetes.

Resistin is a novel cysteine-rich protein that plays a role in the development of insulin resistance and atherosclerosis. HMG-CoA reductase inhibitors (statins) possess anti-inflammatory properties that are independent of their lipid-lowering action. The aims of this study were to investigate the effect of atorvastatin on expression of resistin in vitro and to determine the effect of 6 months of treatment with atorvastatin on serum levels of resistin in patients with type 2 diabetes. 3T3-L1 adipocytes and human monocytes/macrophages and preadipocytes were incubated with 1 and 10 micromol/l atorvastatin for 24 and 48 h, followed by measurement of resistin mRNA by the quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Serum resistin concentration in the patients with type 2 diabetes was measured at baseline and after 6 months of atorvastatin treatment (10 mg/day). qRT-PCR analysis revealed that atorvastatin decreased resistin mRNA expression in a dose- and time-dependent manner. Serum resistin concentration tended to decrease after 6 months of atorvastatin treatment, although this decrease did not reach statistical significance. In conclusion, the findings of our in vitro study contribute to the growing volume of evidence on the anti-inflammatory and anti-atherosclerotic effects of statins, and led us to suggest that statins may control inflammatory responses by inhibiting expression of resistin mRNA. It is necessary to confirm the findings of our in vitro study by an appropriately designed large-scale clinical study.

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Antibiotic prescription patterns in Spanish cystic fibrosis patients: results from a national multicenter study.

Information about antibiotic prescription patterns for cystic fibrosis (CF) patients and, specifically, about inhaled treatment strategies for their management is lacking in Spain due to the absence of a national patient registry. In this study we present data about antibiotic prescription in the Spanish CF context that were obtained in a multicenter study, being inhaled treatment strategies the special focus of this work. Twenty-four specialized CF units (12 adult, 12 pediatric) from 17 tertiary-care hospitals covering all Spanish Autonomous Communities provided sputa and clinical data from 15 consecutive patients. Data about antibiotic and non-antibiotic therapies prescribed to these patients during the year prior inclusion (2013) were retrospectively collected. The multicenter study included 341 CF patients from all age groups and clinical status. The prevalence of oral, inhaled and intravenous therapies was 89% (n = 302), 80% (n = 273) and 31% (n = 105), respectively. The most prevalent oral agents were ciprofloxacin (n = 177, 59%), cotrimoxazole (n = 109, 36%) and amoxicillin-clavulanate (n = 99, 33%), whereas ceftazidime (n = 53, 50%), tobramycin (n = 43, 41%) and meropenem (n = 41, 49%) were the most prevalent intravenous ones. Two or more different inhaled antibiotics were administered to 67 patients (24%), 51 of them receiving 2 drugs continuously in alternating schemes. Nebulization of intravenous specific antibiotics was common (n = 39) and, in some cases, was used for maintenance purposes. These results show that the treatment of CF patients is evolving more rapidly than clinical consensus guidelines. Clinical trials evaluating new specific inhaled combinations and new alternative treatment regimes of the existing ones are needed.

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A controlled study of the effects of carvedilol on clinical events, left ventricular function and proinflammatory cytokines levels in patients with dilated cardiomyopathy.

Carvedilol is known to decrease the severity of ventricular dysfunction, to increase the left ventricular ejection fraction (LVEF), and, consequently, to reduce morbidity and mortality in patients with dilated cardiomyopathy. There is accumulating evidence that inflammatory cytokines have an important role in the pathogenesis of heart failure. To establish whether the addition of carvedilol has an additive beneficial effect on cytokines in patients with dilated cardiomyopathy who are already receiving treatment with angiotensin-converting enzyme (ACE) inhibitors, digoxin and diuretics. In this single-centre, prospective, randomized study, 60 patients with dilated cardiomyopathy with an LVEF less than 40% and already receiving digoxin, ACE inhibitors and diuretics for six months as the standard therapy were randomly assigned to receive either carvedilol (n=30) or placebo (n=30). Patients received an initial dosage of 3.125 mg carvedilol or placebo twice daily for two weeks, which was then increased at two-week intervals (if tolerated), first to 6.25 mg, then to 12.5 mg, and, finally, to a target dosage of 25 mg twice daily. Clinical examinations, radionuclide studies, and determinations of plasma levels of tumour necrosis factor-alpha (TNF-a), interleukin (IL)-2 and IL-6 were performed at baseline and repeated four months after random assignment. Primary end points were New York Heart Association functional class, LV function and plasma cytokines levels. Eight patients died (seven in the placebo group, P=0.05). Patients treated with carvedilol had a significant improvement in functional class compared with the baseline values (P=0.001), with a decrease in the levels of cytokines (IL-6 [P=0.001] and TNF-a [P=0.001]). LVEF increased from 22.14+/-7.85% to 27.85+/-11.80% (P=0.002), but diastolic function did not change in the carvedilol group. In patients with dilated cardiomyopathy, the addition of carvedilol to treatment with digoxin, ACE inhibitors and diuretics is associated with a significant improvement in symptoms and in LV function, and suppression of inflammatory cytokines.

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Long-term follow-up and analysis for prognostic factors for patients with limited-stage diffuse large-cell lymphoma treated with initial chemotherapy with or without adjuvant radiotherapy.

In order to assess long-term outcome of patients with localized (stage I or II) diffuse large-cell lymphoma treated with initial combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or without involved-field radiotherapy following chemotherapy, we combined data from two prospective trials in Tucson (64 patients) and Vancouver (78 patients). Follow-up on 142 patients was updated and a variety of potential pretreatment prognostic factors were analyzed for impact on outcome. One hundred forty patients (99%) achieved a complete remission and there were no differences in outcome between institutions. Twenty-three patients have relapsed and 22 have died from lymphoma at a median follow-up of 4.4 years, resulting in an overall relapse-free survival of 82% at 5 years. There was no treatment-related mortality and were no instances of late cardiac toxicity or leukemia. Of the following potential pretreatment prognostic factors (age, stage, "B" symptoms, extranodal disease, gastrointestinal tract involvement, bulky disease, or disease above or below the diaphragm), only stage affected relapse-free survival (RFS) (P = .16) and survival (.003). Among 34% of patients over age 65, outcome was similar to younger patients. RFS for 108 patients treated with CHOP plus radiotherapy was not significantly superior to the use of CHOP alone in 34 patients (P = .2).

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Modified ProMACE-MOPP hybrid regimen with moderate-dose methotrexate for patients with primary CNS lymphoma.

The object of this study was to assess the estimation of 2- and 5-year overall survival and tumor response and the frequency and severity of treatment morbidity with a modified ProMACE-MOPP hybrid protocol in patients with primary CNS lymphoma (PCNSL). Thirty-two immunocompetent patients were treated with a regimen of pirarubicin, cyclophosphamide, etoposide, vincristine, and methotrexate (500 mg/m(2)) administered in 21-day cycles. Intraventricular 10 mg of methotrexate was given for eight cycles once a week. Patients received 20 Gy of whole brain radiotherapy after three cycles of chemotherapy. A single cycle of chemotherapy was repeated every 4 months for 2 years. Older patients (aged >60) received a reduced dose of chemotherapeutic agents. Eighteen patients were followed up with neuroimaging and neuropsychological assessments for evidence of CNS toxicity. Sixteen patients completed the regimen as planned. The response rate was 87.5% after the initial chemoradiotherapy. The cumulative survival and progression-free survival rates at 5 years were 56 and 31%, respectively. The median survival time was 68 months. The median progression-free survival time was 39 months. Toxicity included grade 3 or 4 leukopenia in 33% of the cycles administered. There were eight grade 3 or 4 pulmonary toxicities. There were three deaths during chemotherapy: one as a result of sepsis and two of pneumonitis. Three patients (25%) experienced delayed neurologic toxicity while on the complete regimen. Maintaining the dose of methotrexate while adding chemotherapeutic agents improved disease control and overall survival in patients with PCNSL, but early toxicity and delayed neurotoxicity are still a risk of this approach.

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Use of imidazole-based eradication regimens for Helicobacter pylori should be abandoned in North India regardless of in vitro antibiotic sensitivity.

The purpose of this study was to compare the efficacy of tinidazole- versus clarithromycin-based triple regimens for eradication of Helicobacter pylori in North Indian patients of peptic ulcer disease, and to correlate the outcome with in vitro antibiotic susceptibility. One hundred and forty-six H. pylori-infected patients with active ulcer were included in the prospective, randomized study. A total of 70 patients received lansoprazole 30 mg b.d., amoxycillin 1000 mg b.d. and tinidazole 500 mg b.d. (LAT), and 76 patients received lansoprazole 30 mg b.d., amoxycillin 1000 mg b.d. and clarithromycin 500 mg b.d. (LAC) for 14 days. The H. pylori status was assessed by urea breath test, rapid urease test, and histology and antibiotic sensitivity pattern by Epsilometer test. In per-protocol analysis of 112 patients the H. pylori eradication rate was 42.3% (95% confidence interval (CI): 0.29-0.56) in LAT, and 64.8% (95%CI: 0.52-0.78) in LAC (95%CI of difference of proportions: 0.13-0.33, P = 0.01). Ulcer healed in 69.2% in the LAT group (95%CI: 0.57-0.82) and 81.7% in the LAC group (95%CI: 0.72-0.92; P = 0.02). Antibiotic susceptibility testing was done in 31 patients. Metronidazole resistance was present in 41.9% isolates but was unrelated to the outcome of the LAT regimen. Imidazole-based eradication regimens should be abandoned in North India regardless of in vitro susceptibility results.

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Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial.

Spastic paraplegia type 5 (SPG5) is a rare subtype of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative disorders defined by progressive neurodegeneration of the corticospinal tract motor neurons. SPG5 is caused by recessive mutations in the gene CYP7B1 encoding oxysterol-7α-hydroxylase. This enzyme is involved in the degradation of cholesterol into primary bile acids. CYP7B1 deficiency has been shown to lead to accumulation of neurotoxic oxysterols. In this multicentre study, we have performed detailed clinical and biochemical analysis in 34 genetically confirmed SPG5 cases from 28 families, studied dose-dependent neurotoxicity of oxysterols in human cortical neurons and performed a randomized placebo-controlled double blind interventional trial targeting oxysterol accumulation in serum of SPG5 patients. Clinically, SPG5 manifested in childhood or adolescence (median 13 years). Gait ataxia was a common feature. SPG5 patients lost the ability to walk independently after a median disease duration of 23 years and became wheelchair dependent after a median 33 years. The overall cross-sectional progression rate of 0.56 points on the Spastic Paraplegia Rating Scale per year was slightly lower than the longitudinal progression rate of 0.80 points per year. Biochemically, marked accumulation of CYP7B1 substrates including 27-hydroxycholesterol was confirmed in serum (n = 19) and cerebrospinal fluid (n = 17) of SPG5 patients. Moreover, 27-hydroxycholesterol levels in serum correlated with disease severity and disease duration. Oxysterols were found to impair metabolic activity and viability of human cortical neurons at concentrations found in SPG5 patients, indicating that elevated levels of oxysterols might be key pathogenic factors in SPG5. We thus performed a randomized placebo-controlled trial (EudraCT 2015-000978-35) with atorvastatin 40 mg/day for 9 weeks in 14 SPG5 patients with 27-hydroxycholesterol levels in serum as the primary outcome measure. Atorvastatin, but not placebo, reduced serum 27-hydroxycholesterol from 853 ng/ml [interquartile range (IQR) 683-1113] to 641 (IQR 507-694) (-31.5%, P = 0.001, Mann-Whitney U-test). Similarly, 25-hydroxycholesterol levels in serum were reduced. In cerebrospinal fluid 27-hydroxycholesterol was reduced by 8.4% but this did not significantly differ from placebo. As expected, no effects were seen on clinical outcome parameters in this short-term trial. In this study, we define the mutational and phenotypic spectrum of SPG5, examine the correlation of disease severity and progression with oxysterol concentrations, and demonstrate in a randomized controlled trial that atorvastatin treatment can effectively lower 27-hydroxycholesterol levels in serum of SPG5 patients. We thus demonstrate the first causal treatment strategy in hereditary spastic paraplegia.

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Walking capacity of patients with intermittent claudication during chronic antihypertensive treatment with metoprolol and methyldopa.

In a placebo-controlled double-blind crossover trial, the effect of a 3-week course of treatment with metoprolol (100-200 mg daily) and methyldopa (500-1000 mg daily) on walking capacity on a treadmill with increasing work load was studied in 14 hypertensive patients with intermittent claudication. The walking capacity was not affected by the antihypertensive treatment.

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Orbital Cellulitis Following Uncomplicated Aqueous Shunt Surgery.

To date, there have only been 5 reported cases of orbital cellulitis following implantation of an aqueous tube shunt for glaucoma. Previously reported cases have involved eyes with significant comorbidities and successful management has often required the removal of the device alongside systemic antibiotic therapy. We present a 53-year-old man with severe orbital cellulitis, 3 months after routine implantation of a Baerveldt tube shunt for primary open angle glaucoma. The patient was managed medically, with topical and systemic antibiotic therapy. The patient went on to make a full recovery with the tube in situ. We report that a more conservative approach (without tube removal) to be successful in a case where there is no evidence of tube exposure. It is important to appreciate that in some cases of orbital cellulitis without clear signs of intraocular involvement, a tube can be left in situ.

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A place for ipratropium bromide in the treatment of severe acute asthma.

Twenty-four consecutive patients admitted to hospital with severe acute asthma were studied. Eleven were given 10 mg salbutamol by nebulizer followed 2 hours later by 500 micrograms of nebulized ipratropium bromide. These patients had a greater response in PEFR than 13 patients given two doses of 10 mg salbutamol 2 hours apart.

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Statins for Graves' orbitopathy (STAGO): a phase 2, open-label, adaptive, single centre, randomised clinical trial.

A protective action of statins on development of Graves' orbitopathy suggests that statins might be used for treatment of the disease. We aimed to assess the efficacy of the addition of a statin, atorvastatin, to intravenous glucocorticoids (ivGCs) on Graves' orbitopathy outcomes in patients with hypercholesterolaemia. We did a randomised, open-label, phase 2, adaptive, clinical trial at a single, tertiary, referral hospital in Pisa, Italy. Patients with moderate-to-severe, active Graves' orbitopathy, with a low-density lipoprotein cholesterol concentration between 2·97 and 4·88 mmol/L were eligible for inclusion. Patients were randomly assigned (1:1) in 11 blocks of eight, using a computer-based system, to the ST group or the NST group. The ST group received ivGCs (methylprednisolone 500 mg once a week for 6 weeks followed by 250 mg once a week for an additional six weeks) for 12 weeks and oral atorvastatin (20 mg once a day) for 24 weeks. The NST group only received the ivGC regimen. Patients were unmasked to group allocation; however, the ophthalmological investigator was masked to randomisation. The primary endpoint was the Graves' orbitopathy outcome (composite evaluation of exophthalmos, clinical activity score, eyelid aperture, and diplopia) at 24 weeks in the modified intention-to-treat (ITT) population (patients who attended the week 12 visit). Patients were considered responders when at least two of the following criteria were fulfilled in the most affected eye, without worsening in any of the same measures in both eyes: (1) reduction in exophthalmos of 2 mm or more, with no increase by 2 mm or more in the other eye; (2) reduction of clinical activity score by two or more points; (3) reduction in eyelid aperture by 2 mm or more, with no increase by 2 mm or more in the other eye; and (4) disappearance or improvement (change from constant to inconstant, intermittent, or absent, or from inconstant to intermittent or absent) of diplopia, and (5) improvement in visual acuity by 0·2 decimals or more. The trial is registered with EUDRACT, 2018-001317-33, and ClinicalTrials.gov, NCT03110848. Between June 1, 2020, and Nov 30, 2020, 119 patients were screened for inclusion, of whom 88 (74%) patients were enrolled and randomly assigned to one of the two treatment groups (44 [50%] to the ST group and 44 [50%] to the NST group). Eight (9%) patients did not attend the 12 week visit; 80 (91%) patients (18 [23%] men and 62 [78%] women) were included in the modified ITT population (41 [51%] in the ST group and 39 [49%] in the NST group]. The proportion of Graves' orbitopathy composite evaluation responders at 24 weeks was higher in the ST group (21 [51%] of 41 patients) than the NST group (11 [28%] of 39 patients; attributable risk 0·23 [95% CI 0·02-0·44]; p=0·042). 26 adverse events occurred in 21 (24%) of 88 patients in the safety population. One (2%) of 44 patients in each group required treatment discontinuation, with no serious adverse events and no difference between groups. Addition of oral atorvastatin to an ivGC regimen improved Graves' orbitopathy outcomes in patients with moderate-to-severe, active eye disease who were hypercholesterolaemic. Future phase 3 studies, which could potentially recruit patients regardless of low-density lipoprotein cholesterol concentration, are required to confirm this association. Associazione Allievi Endocrinologia Pisana.

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[Tunisian pemphigus. Apropos of 70 cases. (Experience of the dermatology department of La Rabta Hospital 1974-1992)].

Pemphigus frequently seen in Tunisia has specific characteristics distinguishing it from the European or American forms. Between 1974 and 1992, we observed 70 cases in the dermatology unit of the La Rabta University Hospital in Tunis. Most patients were young (mean age 39 yr), predominantly women (80%). Deep pemphigus (pemphigus vulgaris and vegetans) occurred in 56% and superficial pemphigus (seborrheic and foliaceus) in 44%. High-dose corticosteroids were given as initial treatment (1.4 mg/kg/day). Infectious complications were frequent. Mortality was 14%. Pemphigus in Europe and North America usually occurs in adults in the 50-60 year age range. Superficial forms are rare (2-10%). In Tunisia, pemphigus is similar to Brazilian pemphigus with high frequency and predominant superficial forms (pemphigus foliaceus).

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Increased Mortality Rates With Prolonged Corticosteroid Therapy When Compared With Antitumor Necrosis Factor-α-Directed Therapy for Inflammatory Bowel Disease.

Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) that compromise quality of life and may increase mortality. This study compared the mortality risk with prolonged corticosteroid use vs. antitumor necrosis factor-α (anti-TNF) drugs in IBD. A retrospective cohort study was conducted among Medicaid and Medicare beneficiaries from 2001 to 2013 with IBD prescribed either >3,000 mg of prednisone or equivalent within a 12-month period or new initiation of anti-TNF therapy, each treated as time-updating exposures. The primary outcome was all-cause mortality. Secondary outcomes included common causes of death. Marginal structural models were used to determine odds ratios (ORs) and 95% confidence intervals (CIs) for anti-TNF use relative to corticosteroids. Among patients with CD, 7,694 entered the cohort as prolonged corticosteroid users and 1,879 as new anti-TNF users. Among patients with UC, 3,224 and 459 entered the cohort as prolonged CS users and new anti-TNF users, respectively. The risk of death was statistically significantly lower in patients treated with anti-TNF therapy for CD (21.4 vs. 30.1 per 1,000 person-years, OR 0.78, 0.65-0.93) but not for UC (23.0 vs. 30.9 per 1,000 person-years, OR 0.87, 0.63-1.22). Among the CD cohort, anti-TNF therapy was also associated with lower rates of major adverse cardiovascular events (OR 0.68, 0.55-0.85) and hip fracture (OR 0.54, 0.34-0.83). Compared with prolonged corticosteroid exposure, anti-TNF drug use was associated with reduced mortality in patients with CD that may be explained by lower rates of major adverse cardiovascular events and hip fracture.

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The Importance of the Mean Platelet Aggregation Degree in Long-term Dual Antiplatelet Therapy Following Drug-Eluting Stent Implantation.

The dual antiplatelet therapy (DAPT) and the response of clopidogrel were two pivotal issues in drug-eluting stent (DES) era. To analyze the combined impacts of DAPT and the response to clopidogrel to evaluate their long-term effect on patients undergoing DES implantation. Platelet aggregation was serially measured by light transmission aggregometry in all eligible patients during the course of treatment with DAPT, and the mean platelet aggregation degree of each participant was calculated. Based on the duration of DAPT and the mean platelet aggregation degree, all the enrolled patients were then divided into four groups. The primary endpoint was a composite of major adverse cardiovascular events. We analyzed 1245 suitable patients in this study. They were divided into four groups: Group A (12-month DAPT & low platelet aggregation degree) with 233 subjects, Group B (12-month DAPT & high platelet aggregation degree) with 260 subjects, Group C (>12-month DAPT & low platelet aggregation degree) with 374 subjects, and Group D (>12-month DAPT & high platelet aggregation degree) with 378 subjects. Group C was associated with a decreased incidence of primary endpoints [HR 0.512, 95%CI (0.27-0.97); P = 0.040]. The Cox proportional hazard model was further analyzed with Groups A and B combined as the reference category [HR for Group C vs. Group A, 0.84, 95%CI (0.33-2.15); P = 0.719; HR for Group C vs. Group B, 0.45, 95%CI (0.21-0.98); P = 0.043]. Their respective multivariate Cox proportional hazard regressions confirmed these trends. The mean platelet aggregation degree is of importance in long-term use of DAPT; extension of DAPT beyond 1 year should be implemented cautiously in patients implanted with DESs.

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Varenicline: a first-line treatment option for smoking cessation.

Varenicline acts as a partial agonist/antagonist with affinity and selectivity for alpha(4) beta(2) nicotinic acetylcholine receptors. This activity at the nicotine-receptor level may help patients achieve smoking cessation by reducing cravings/withdrawal symptoms and smoking satisfaction. This article reviews the literature on the pharmacologic properties, therapeutic efficacy, and tolerability of varenicline for smoking cessation. Pertinent controlled clinical trials, meta-analyses, meeting abstracts, case reports, and review articles published in English between 1966 and May 2008 were identified through searches of MEDLINE and OVID using the terms varenicline, smoking, tobacco cessation, and CP 526555. Eight clinical trials were identified that compared <or=12 weeks of varenicline treatment with placebo and/or bupropion sustained release (SR); one of the trials reported follow-up data to 24 weeks, and the remainder reported data to 52 weeks. During treatment with oral varenicline titrated to 1 mg BID, CO-confirmed 4-week continuous quit rates/continuous abstinence rates (CQRs/CARs) in weeks 9 through 12 ranged from 43.9% (odds ratio [OR] = 3.85 [95% CI, 2.69-5.50; P < 0.001 vs placebo]; OR = 1.90 [95% CI, 1.38-2.62; P < 0.001 vs bupropion SR]) to 65.4% (OR = 2.98 [95% CI, 1.78-4.99; P < 0.001 vs placebo]). In 4 of these trials, varenicline 1 mg BID was associated with significantly higher CQRs/CARs compared with placebo at week-52 follow-up, ranging from 21.9% (P < 0.001) to 34.6% (P = 0.036). One trial reported a significantly higher CAR at 52 weeks with varenicline compared with bupropion SR (23.0% vs 14.6%, respectively; P = 0.004), and another reported a significantly higher CAR at 52 weeks with varenicline compared with nicotine replacement therapy (25.9% vs 19.8%, respectively; P = 0.040). In a relapse-prevention study that included a 12-week extension period for participants who were abstinent after the initial 12 weeks of treatment, CARs were significantly improved at 24 weeks with varenicline relative to placebo (70.5% vs 49.6%, respectively; OR = 2.48; 95% CI, 1.95-3.16; P < 0.001). Treatment with varenicline was generally well tolerated in study populations with no major comorbidities. In a pooled analysis of 2 Phase III trials, the most commonly reported adverse events (AEs) with varenicline, bupropion SR, and placebo were nausea (28.8%, 9.9%, and 9.1%, respectively), insomnia (14.2%, 21.5%, and 12.6%), and headache (14.2%, 11.1%, and 12.4%). In a pooled analysis of 2 identically designed Phase III trials, bupropion SR was associated with the highest overall rates of discontinuation due to all-cause AEs compared with varenicline and placebo (13.9%, 9.5%, and 8.2%, respectively) and due to AEs considered related to study drug (12.1%, 7.9%, and 6.4%). In double-blind clinical trials of varenicline, nausea was the most frequently reported AE (16.3%-41.9%). Varenicline treatment should begin 7 days before the proposed smoking quit date; dose titration is recommended to minimize dose-related nausea. Based on postmarketing reports of serious AEs in vareniclinetreated patients, caution is recommended when operating vehicles or heavy machinery. Patient education and monitoring for potential AEs are also recommended, particularly in patients with a history of psychiatric illness. Varenicline has a unique mechanism of action compared with other first-line options for smoking cessation. Available clinical-trial data support its use as an effective and generally well-tolerated therapy for smoking cessation in healthy adult smokers, although there is a need for further efficacy and safety evaluation in the general population, particularly those with comorbid conditions.

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Curability of advanced Hodgkin's disease with chemotherapy. Long-term follow-up of MOPP-treated patients at the National Cancer Institute.

The results of treatment of 198 patients with Hodgkin's disease with MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) were analyzed. Eighty percent attained complete remission, and 68% of patients achieving a complete remission have remained disease free beyond 10 years from the end of treatment. Results of autopsy on patients who died of other causes while in clinical complete remission did not show evidence of residual tumors except in one patient. Asymptomatic patients and patients with mixed-cellularity or lymphocytic-depleted Hodgkin's disease do significantly better than symptomatic patients and those with nodular sclerosing histologic type. Advanced Hodgkin's disease appears to be curable by chemotherapy.

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Chemoprophylaxis of bacterial infections in granulocytopenic patients with ciprofloxacin vs ciprofloxacin plus amoxicillin.

Ciprofloxacin was compared to ciprofloxacin plus amoxicillin as antibacterial prophylaxis in 53 evaluable patients with neutropenic episodes, because an oral penicillin may help to decrease the incidence of gram-positive infections. The two groups were randomized and evaluated in a number of febrile episodes, in days at fever/at risk, in mean interval of first febrile episode, in duration of antibiotic therapy and in causative organisms in febrile episodes. In conclusion, no significant difference was observed between the two groups in prevention of gram-positive bacteremias.

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NHL-3 protocol. Six-drug combination chemotherapy for non-Hodgkin's lymphoma.

Combination chemotherapy and radiotherapy (RT) were administered to 73 adults with non-Hodgkin's lymphoma (NHL). Ten cycles of the following drugs were given: intravenous Adriamycin (doxorubicin) (25 mg/m2), cyclophosphamide (700 mg/m2) and vincristine (1.5 mg/m2) on day 1; arabinosylcytosine (100 mg/m2) and methotrexate (10 mg/m2) on days 3 to 5; and oral prednisone (60 mg/m2) on days 1 to 5. Radiotherapy was given to resistant or initially bulky disease (2000 rad). Patients were also randomized to receive pseudomonas vaccine or no immunotherapy. Of 61 evaluable patients, 33 (54%) achieved a complete response (CR) and 18 (30%) a partial response (PR). Among 44 evaluable patients with diffuse histiocytic lymphoma (DHL), 22 (50%) had a CR, and 15 (34%) a PR. For 17 evaluable patients with nodular (4) and diffuse (11) mixed and poorly differentiated lymphocytic and diffuse "undifferentiated" (2) lymphomas, CR and PR rates were 65% and 18%, respectively. No statistically significant differences in response rate or duration and survival have been observed between the patients randomized to receive pseudomonas vaccine or no immunotherapy. Median follow-up time from start of treatment was 47.5 months. Median survival for all 73 patients (including inevaluables ) and for 52 DHL patients was 30.7 months. Poor prognostic features influencing survival included: female sex (P = 0.003), poor response to therapy (CR versus PR; P = 0.001), prior chemotherapy, (P = 0.01) and high levels of lactic dehydrogenase (P = 0.001). It can be concluded that this combination of cycle and phase-active agents is of similar efficacy to other reported regimens in inducing major responses and that it has the potential to prolong disease-free survival. The analysis of prognostic factors has been used to dissect poor prognostic categories that might require different modalities of treatment.

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Effectiveness of methotrexate with step-down glucocorticoid remission induction (COBRA Slim) versus other intensive treatment strategies for early rheumatoid arthritis in a treat-to-target approach: 1-year results of CareRA, a randomised pragmatic open-label superiority trial.

Combining disease-modifying antirheumatic drugs (DMARDs) with glucocorticoids (GCs) is an effective treatment strategy for early rheumatoid arthritis (ERA), yet the ideal schedule and feasibility in daily practice are debated. We evaluated different DMARD combinations and GC remission induction schemes in poor prognosis patients; and methotrexate (MTX) with or without GC remission induction in good prognosis patients, during the first treatment year. The Care in ERA (CareRA) trial is a 2-year investigator-initiated randomised pragmatic open-label superiority trial comparing remission induction regimens in a treat-to-target approach. DMARD-inexperienced patients with ERA were stratified into a high-risk or low-risk group based upon presence of erosions, disease activity, rheumatoid factor and anticitrullinated protein antibodies. High-risk patients were randomised to a COBRA Classic (MTX + sulfasalazine + prednisone step-down from 60 mg), COBRA Slim (MTX + prednisone step-down from 30 mg) or COBRA Avant Garde (MTX + leflunomide + prednisone step-down from 30 mg) scheme. Low-risk patients were randomised to MTX tight step-up (MTX-TSU) or COBRA Slim. Primary outcome was the proportion of patients in 28 joint disease activity score calculated with C-reactive protein remission at week 52 in an intention-to-treat analysis. Secondary outcomes were safety and effectiveness (ClinicalTrial.gov identifier NCT01172639). 98 COBRA Classic, 98 COBRA Slim (high risk), 93 COBRA Avant Garde, 47 MTX-TSU and 43 COBRA Slim (low risk) patients were evaluated. Remission was achieved in 64.3% (63/98) COBRA Classic, 60.2% (59/98) COBRA Slim (high risk) and 62.4% (58/93) COBRA Avant Garde patients at W52 (p=0.840); and in 57.4% (27/47) MTX-TSU and 67.4% (29/43) COBRA Slim (low risk) patients (p=0.329). Less adverse events occurred per patient with COBRA Slim (high risk) compared with COBRA Classic or COBRA Avant Garde (p=0.038). Adverse events were similar in MTX-TSU and COBRA Slim (low risk) patients (p=0.871). At W52, 76.0% patients were on DMARD monotherapy, 5.2% used GCs and 7.5% biologicals. MTX with a moderate-dose GC remission induction scheme (COBRA Slim) seems an effective, safe, low-cost and feasible initial treatment strategy for patients with ERA regardless of their prognostic profile, provided a treat-to-target approach is followed. EudraCT-number 2008-007225-39 and NCT01172639; Results.

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Gabapentin for the treatment of spasticity in patients with spinal cord injury.

Our serendipitous observations suggested that some patients with spasticity appeared to have improved following the administration of the anticonvulsant drug gabapentin. As some patients with spasticity are either refractory to or intolerant of established medical treatments, we conducted this study to investigate the effect of gabapentin on spasticity in patients with spinal cord injury. Twenty-five patients with spinal cord injury and spasticity received oral gabapentin (2400 mg over 48 h) in a randomized, double blind, placebo-controlled crossover study. We assessed responses by measuring the Ashworth spasticity scale, muscle stretch reflexes, presence of clonus and reflex response to noxious stimuli. Patient ratings were obtained using a Likert Scale. Administration of gabapentin, but not placebo, was associated with an 11% reduction in spasticity as measured by the Ashworth Scale (P = 0.04) and by a 20% reduction in the Likert Scale (P = 0.0013). Significant changes were not obtained for the other measures. The data obtained suggest that gabapentin may be useful in the management of spasticity associated with spinal cord injury.

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[Gastroesophageal reflux and obstructive sleep apnea syndrome].

Patients with mild or moderate Sleep Apnea Syndrome (SAS) need wider therapeutic scope options according to their disease severity. To consider including proton pump inhibitors (PPI) to the therapeutical alternatives of these patients. A prospective study was designed, among patients with SAS. Nocturnal polysomnography and double channel pHmetry were performed simultaneously. From the 18 patients included in this preliminary phase, in three (16.7%) nocturnal proximal ph monitoring was positive. These 3 patients were treated with PPI during at least 3 months with a very satisfactory outcome in two of them. Treatment with PPI may be a useful therapeutical alternative in patients with mild to moderate SAS.

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[Comparative Randomized Study of the Effects of Long-Term Therapy With Rosuvastatin and Combination of Atorvastatin and Ezetimibe on Carbohydrate Metabolism and Adipokines Levels in Patients With Coronary Artery Disease and Diabetes Mellitus].

This open randomized study compares the effects of 24-week-long treatment with rosuvastatin and with atorvastatin coadministered with ezetimibe on the parameters of carbohydrate metabolism and the plasma levels of adipokynes in patients with coronary artery disease and type 2 diabetes mellitus or impaired glucose tolerance (IGT). A total of 31 patients with coronary artery disease and type 2 diabetes mellitus or IGT were recruited in the study. Patients were randomized into two groups: group 1 included patients who received rosuvastatin therapy in an average dose of 12.5 mg/day (n = 16); group 2 included patients who received combination treatment with atorvastatin in an average dose of 13.3 mg/day and ezetimibe (10 mg) (n = 15). Plasma levels of lipids, apoB, apoA1, glucose, insulin, leptin, and adiponectin were evaluated; HOMA-IR index (an empty stomach insulin, mu/l x fasting glucose, mmol/l)/22.5) was calculated. During the therapy, the LDL-C and apoB levels decreased by 51.7% and 42.3% in group 1 and by 51.8% and 44.9% in group 2, respectively. Reduction in the triglyceride levels was significantly more pronounced in group 2 than in group 1: 43.2% vs 17.4% (p < 0.02), whereas we did not observed significant changes of HDL-C and apoA1 in either group. The increases in basal glycemia, basal insulinemia, HbA1c levels (from 6.47% [6.10-7.02%] to 6.98% 16.23-8.18%]), and HOMA-IR (from 2.14 [1.68-3.51] to 4.30 [2.31-5.77]) were found only in group 2 (p < 0.05 for all). These changes were observed in 75% of patients of group 2 independently of the presence of diabetic state or IGT, but the changes were more pronounced in patients with disturbed carbohydrate metabolism. Changes of leptin levels during the therapy were diverse: 73% patients of group 1 demonstrated decrease in the leptin levels, whereas 67% of patients in group 2 experienced 57%-increase in the leptin concentrations. Degree of increased basal glycemia was associated with increase in the leptin levels (r = 0.37, p = 0.04) in the entire group of patients (n = 31). Furthermore, changes in leptin levels were negatively associated with decreased adiponectin levels (r = -0.57, p = 0.034). In case of equivalent degree of the decrease in LDL-C levels, 24-week combination therapy with atorvastatin and ezetimibe, unlike rosuvastatin treatment, induced increases in basal glycemia, insulinemia, HbA1c, and HOMA-IR index irrespective of the presence of carbohydrate metabolism disturbances before treatment. Our data suggest that adiponectin and leptin are involved in the mechanisms of adverse metabolic effects of the combination of atorvastatin and ezetimibe.

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Vonoprazan non-inferior to lansoprazole in treating duodenal ulcer and eradicating Helicobacter pylori in Asian patients.

Duodenal ulcers, especially caused by increasingly drug-resistant Helicobacter pylori, are a concern in Asia. We compared oral vonoprazan versus lansoprazole for efficacy (healing duodenal ulcers) and safety in non-Japanese Asian patients. In this phase 3, randomized (1:1), double-blind, double-dummy, parallel-group, non-inferiority study (April 5, 2017, to July 19, 2019), patients with ≥ 1 endoscopically confirmed duodenal ulcer, at 52 hospitals (China, South Korea, and Taiwan), received vonoprazan 20 mg once daily (QD) or lansoprazole 30 mg QD for 6 weeks maximum. Patients with H. pylori received bismuth-containing quadruple therapy including vonoprazan 20 mg twice daily (BID) or lansoprazole 30 mg BID, for 2 weeks, followed by vonoprazan or lansoprazole monotherapy QD (4 weeks maximum). Endpoints were endoscopically confirmed duodenal ulcer healing (Week 4/6; primary) and H. pylori eradication (4 weeks post-treatment; secondary); non-inferiority margins were -6% and -10%, using a two-sided 95% confidence interval (CI). Of 533 enrolled patients, one was lost to follow-up and one withdrew (full analysis set: 531 patients [vonoprazan, n = 263; lansoprazole, n = 268]; 85.4% = H. pylori positive). Vonoprazan was non-inferior to lansoprazole for duodenal ulcer healing (96.9% vs 96.5%; difference 0.4% [95% CI -3.00, 3.79]). H. pylori eradication rates were 91.5% (vonoprazan) and 86.8% (lansoprazole; difference 4.7% [95% CI -1.28, 10.69]). Vonoprazan and lansoprazole were well tolerated, with similar safety profiles, no new safety signals; no deaths occurred. Vonoprazan was well tolerated and non-inferior to lansoprazole for duodenal ulcer healing and achieved H. pylori eradication above the clinically meaningful threshold (90%), in non-Japanese Asian patients.

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Phase II study of oral methyl-CCNU and prednisone in previously treated alkylating agent-resistant multiple myeloma.

Thirteen patients with multiple myeloma (MM) who either failed to respond to or who were relapsing from standard agents and who received four or more courses of methyl-CCNU + prednisone (adequate drug trial) are reported in this paper. Methyl-CCNU was given orally before breakfast at 6-week intervals at a starting dose of 50 mg/m2 with the intention of increasing the dose to 100, 150, and 200 mg/m2 with each subsequent course. The dose of prednisone was 75 mg/day x 7 with each course. The response rate was 46% (six of 13 patients). No patient had better than a fair response. Drug toxicity, severe enough to prevent further dose escalation, was observed in every case. Prior BCNU therapy or the lack of response to previous alkylating agents did not prevent a response to methyl-CCNU + prednisone. The response rate of methyl-CCNU + prednisone in MM is comparable to the results achieved with other agents in similar groups of patients.

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Rationale and Design of the Genotype-Blinded Trial of Torasemide for the Treatment of Hypertension (BHF UMOD).

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) near the uromodulin gene (UMOD) affecting uromodulin excretion and blood pressure (BP). Uromodulin is almost exclusively expressed in the thick ascending limb (TAL) of the loop of Henle and its effect on BP appears to be mediated via the TAL sodium transporter, NKCC2. Loop-diuretics block NKCC2 but are not commonly used in hypertension management. Volume overload is one of the primary drivers for uncontrolled hypertension, so targeting loop-diuretics to individuals who are more likely to respond to this drug class, using the UMOD genotype, could be an efficient precision medicine strategy. The BHF UMOD Trial is a genotype-blinded, multicenter trial comparing BP response to torasemide between individuals possessing the AA genotype of the SNP rs13333226 and those possessing the G allele. 240 participants (≥18 years) with uncontrolled BP, on ≥1 antihypertensive agent for ≥3 months, will receive treatment with Torasemide, 5 mg daily for 16 weeks. Uncontrolled BP is average home systolic BP (SBP) >135 mmHg and/or diastolic BP >85 mmHg. The primary outcome is the change in 24-hour ambulatory SBP area under the curve between baseline and end of treatment. Sample size was calculated to detect a 4 mmHg difference between groups at 90% power. Approval by West of Scotland Research Ethics Committee 5 (16/WS/0160). The study should conclude August 2021. If our hypothesis is confirmed, a genotype-based treatment strategy for loop diuretics would help reduce the burden of uncontrolled hypertension. https://clinicaltrials.gov/ct2/show/NCT03354897.

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Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL): a randomised, double-blind, placebo-controlled phase 3 trial.

Patients with metastatic castration-resistant prostate cancer have few treatment options. We investigated the safety and efficacy of lenalidomide, an immunomodulatory agent with anti-angiogenic properties, in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. In this randomised, double-blind, placebo-controlled, phase 3 study, we randomly assigned chemotherapy-naive patients with progressive metastatic castration-resistant prostate cancer in a 1:1 ratio to receive docetaxel (75 mg/m(2)) on day 1 and prednisone (5 mg twice daily) on days 1-21 and either lenalidomide (25 mg) or placebo once daily on days 1-14 of each 21 day treatment cycle. Permuted block randomisation was done with an interactive voice response system and stratified by Eastern Cooperative Oncology Group performance status, geographic region, and type of disease progression. Clinicians, patients, and investigators were masked to treatment allocation. The primary endpoint was overall survival. Efficacy analysis was by intention to treat. Patients who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00988208. 1059 patients were enrolled and randomly assigned between Nov 11, 2009, and Nov 23, 2011 (533 to the lenalidomide group and 526 to the control group), and 1046 patients received study treatment (525 in the lenalidomide group and 521 in the placebo group). At data cutoff (Jan 13, 2012) after a median follow-up of 8 months (IQR 5-12), 221 patients had died: 129 in the lenalidomide group and 92 in the placebo group. Median overall survival was 17·7 months (95% CI 14·8-18·8) in the lenalidomide group and not reached in the placebo group (hazard ratio [HR] 1·53, 95% CI 1·17-2·00, p=0·0017). The trial was subsequently closed early due to futility. The number of deaths that occurred during treatment or less than 28 days since the last dose were similar in both groups (18 [3%] of 525 patients in the lenalidomide group vs 13 [2%] of 521 patients). 109 (21%) patients in the lenalidomide group and 78 (15%) in the placebo group died more than 28 days from last dose, mainly due to disease progression. At least one grade 3 or higher adverse event was reported in 381 (73%) of 525 patients receiving lenalidomide and 303 (58%) of 521 patients receiving placebo. Grade 3-4 neutropenia (114 [22%] for lenalidomide vs 85 [16%] for placebo), febrile neutropenia (62 [12%] vs 23 [4%]), diarrhoea (37 [7%] vs 12 [2%]), pneumonia (24 [5%] vs five [1%]), dyspnoea (22 [4%] vs nine [2%]), asthenia (27 [5%] vs 17 [3%]), and pulmonary embolism (32 [6%] vs seven [1%]) occurred more frequently in the lenalidomide group than in the placebo group. Overall survival with the combination of lenalidomide, docetaxel, and prednisone was significantly worse than with docetaxel and prednisone for chemotherapy-naive men with metastatic, castration-resistant prostate cancer. Further research with this treatment combination is not warranted. Celgene Corporation.

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Taxane and epothilone-induced peripheral neurotoxicity: From pathogenesis to treatment.

Taxane-induced peripheral neurotoxicity (TIPN) is the most common non-hematological side effect of taxane-based chemotherapy, and may result in dose reductions and discontinuations, having as such a detrimental effect on patients' overall survival. Epothilones share similar mechanism of action with taxanes. The typical TIPN clinical presentation is mainly comprised of numbness and paresthesia, in a stocking-and-glove distribution and may progress more proximally over time, with paclitaxel being more neurotoxic than docetaxel. Motor and autonomic involvement is less common, whereas an acute taxane-induced acute pain syndrome is frequent. Patient reported outcomes questionnaires, clinical evaluation, and instrumental tools offer complementary information in TIPN. Its electrodiagnostic features include reduced/abolished sensory action potentials, and less prominent motor involvement, in keeping with a length-dependent, axonal dying back predominately sensory neuropathy. TIPN is dose-dependent and may be reversible within months after the end of chemotherapy. The single and cumulative delivered dose of taxanes is considered the main risk factor of TIPN development. Apart from the cumulative dose, other risk factors for TIPN include demographic, clinical, and pharmacogenetic features with several single-nucleotide polymorphisms potentially linked with increased susceptibility of TIPN. There are currently no neuroprotective strategies to reduce the risk of TIPN, and symptomatic treatments are very limited. This review critically examines the pathogenesis, incidence, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of TIPN.

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Low-dose venlafaxine treatment in panic disorder.

Venlafaxine, a structurally novel antidepressant that combines mechanisms of action of both the cyclic antidepressants and SSRIs, may be effective in the treatment of panic disorder. Thirteen patients with DSM-IV panic disorder with or without agoraphobia participated in an open-label, fixed-flexible dose treatment study with venlafaxine. All patients who completed the 10-week trial exhibited statistically significant decreases in scores on anxiety symptoms as well as complete cessation of panic attacks at an effective mean daily dose of 47 mg per day. Venlafaxine was well tolerated in all completers. Venlafaxine may be an effective antipanic agent, even at lower than typical antidepressant dosages.

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Effect of Duloxetine on Urethral Resting Pressure and on Sphincter Contractility in Response to Coughing and Magnetic Stimulation in Healthy Women.

As a proof-of-mechanism (POM) study of drugs developed to treat stress urinary incontinence (SUI) has not been conducted, this urodynamic study in healthy women was performed to determine an appropriate method to confirm POM, and to evaluate the effect of duloxetine, a serotonin and noradrenaline reuptake inhibitor, on urethral resting pressure and on sphincter contractility in response to coughing and magnetic stimulation. The urethral pressure profiles at rest, during coughing and during sacral root magnetic stimulation (SMS), and the motor threshold (MT) for urethral sphincter contraction in response to transcranial magnetic stimulation (TMS) were measured before and 6 h after the administration of 40 mg duloxetine in 10 healthy female subjects. Oral administration of duloxetine significantly increased the mean and maximal urethral closure pressures at rest over the proximal and middle third of the urethra. During coughing, duloxetine marginally significantly increased the mean distal urethral pressure and significantly reduced the mean delay in the distal urethral pressure peak relative to the vesical peak. Although duloxetine did not change amplitudes of pressure spikes in response to SMS, this drug significantly lowered the MT in response to TMS. The proposed method for measuring the urethral resistance in healthy women can be used in POM studies of new drugs developed to treat SUI. UMIN000009096.

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The pharmacokinetics of lisinopril in hospitalized patients with congestive heart failure.

1. The pharmacokinetics of the angiotensin converting enzyme inhibitor, lisinopril, were studied in an open, randomized, balanced, two-period, crossover design in 12 in-patients with stable, chronic congestive heart failure (CHF). 2. To evaluate the pharmacokinetics of lisinopril in CHF, lisinopril was administered orally (10 mg) and intravenously (5 mg) in each patient. Each dose was followed by a 72 h period with frequent blood sampling and fractional urine collections for radioimmunoassay of lisinopril. 3. Mean urinary recovery of lisinopril was 15 and 88% following oral and intravenous administration, respectively; absorption/bioavailability of lisinopril based on urinary recovery ratios was 16%, less than that found in normal subjects. 4. Serum concentrations of lisinopril following intravenous administration were higher in this study than those previously observed in normal subjects. 5. The results of this study suggest a reduced absorption of lisinopril in CHF and altered disposition, possibly associated with age as well as the disease state.

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Comparing the effects of peritonsillar infiltration of tramadol before and after the surgery on post-tonsillectomy pain.

The aim of the study was to compare the effects of peritonsillar infiltration of tramadol before and after the surgery on post-tonsillectomy pain. In this double-blinded clinical trial study, 80 children aged 5-12 years old with ASA (American Society of Anesthesiologists) class I or II undergoing tonsillectomy involved. In group A (n = 40), after anesthesia induction and before starting the surgery, tramadol 2 mg/kg diluted in normal saline up to 2 cc total volume was injected into the tensile bed by the anesthesiologist using a 25 gauge needle. Surgery began 3 min later and the tonsils were removed using the sharp dissection method. In children of group B (n = 40), anesthesia induction was performed. When surgery was completed, tramadol 2 mg/kg diluted in normal saline up to 2 cc total volume was injected at the site of removing each tonsil using a 25 gauge needle by the anesthesiologist. Using the CHEOPS (Children's Hospital of Eastern Ontario Pain Scale) Scale, pain recorded at different times. Patient sedation was recorded using the RAMSAY Sedation Scale. All the data were analyzed using SPSS 17 statistical software. Two groups significantly felt different pain intensities at different times following the surgery. At the three times, the mean sedation score in the group receiving tramadol infiltration before surgery was a little higher compared to the other group, but this difference was not significant (p > 0.05). As for the relative frequency of nausea and vomiting, the difference was not significant (p = 0.793). Request for analgesics between the groups was not significant (p = 0.556). The mean time of the first feeding after the surgery was not significant between the groups (p = 0.062). Surgical duration was almost the same for both groups (p > 0.05). Systolic blood pressures (before surgery, before extubation, and after extubation) were statistically the same in both groups (p < 0.05). Furthermore, systolic blood pressures 10, 15, and 30 min after entry into the recovery room were the same in both groups. We concluded that peritonsillar infiltration of tramadol before surgery controlled postoperative pain better from 8 h after the surgery to hospital discharge (late effect), but that local infiltration of tramadol after surgery controlled postoperative pain better up to 2 h after the operation (early effect).

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Effects of losartan and captopril on left ventricular volumes in elderly patients with heart failure: results of the ELITE ventricular function substudy.

The mechanism by which angiotensin-converting enzyme inhibitors reduce mortality rates and disease progression in patients with heart failure is likely mediated in part through prevention of adverse ventricular remodeling. This study examined the effects of the angiotensin-converting enzyme inhibitor captopril and the angiotensin II type 1 receptor antagonist losartan on ventricular volumes and function in elderly patients with heart failure and reduced left ventricular ejection fraction (< or =40%). Patients underwent radionuclide ventriculograms (RVG) at baseline and were randomized to either captopril (n = 16) or losartan (n = 13). After 48 weeks, another RVG was obtained. Therapy was then withdrawn for at least 5 days, and the RVG was repeated while the patient was not receiving the drug. At 48 weeks both captopril and losartan significantly reduced left ventricular (LV) end-diastolic volume index (135 +/- 26 to 128 +/- 23 mL/m(2) for losartan, P <.05 vs baseline; 142 +/- 25 to 131 +/- 20 mL/m(2) for captopril, P <.01; mean (SD). Captopril also reduced LV end-systolic volume index (98 +/- 24 to 89 +/- 21 mL/m(2), P <.01 vs. baseline), whereas a nonsignificant trend was observed for the losartan group (97 +/- 23 to 90 +/- 16 mL/m(2), P = not significant). The between-group differences in the changes in LV volumes were not statistically significant. After drug withdrawal, LV end-diastolic volume index remained significantly lower than baseline in the captopril group (P <.01). Both captopril and losartan prevent LV dilation, representing adverse ventricular remodeling, previously seen with placebo treatment. Reverse remodeling was observed in the captopril group. On the basis of these results, the relative effects on LV remodeling do not provide a rationale for a survival benefit of losartan over captopril.

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Executive Function Predicts Antidepressant Treatment Noncompletion in Late-Life Depression.

To examine whether executive function (EF) is associated with nonremission and noncompletion of antidepressant pharmacotherapy in older adults with depression. In this prospective study (July 2009 to May 2014), older adults (aged ≥ 60 years; n = 468) with a DSM-IV-defined major depressive episode diagnosed via structured interview received 12 weeks of venlafaxine extended release with the goal of achieving remission. A hypothesis was made that worse baseline EF would predict both nonremission and noncompletion (primary outcomes). Treatment-related factors, including side effects and nonadherence, were also studied. Baseline EF, including response inhibition and set-shifting, was assessed with subtests of the Delis-Kaplan Executive Function System and the semantic fluency subtest of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Attention, immediate memory, delayed memory, visuospatial ability, and global cognition were also assessed with the RBANS. Of 468 participants, 96 (21%) failed to complete the treatment trial, 191 (41%) completed and remitted, and 181 (39%) completed and did not remit. Univariate analyses indicated that some EFs (set-shifting and semantic fluency) and other cognitive variables (attention, immediate memory, visuospatial ability, and global cognition) predicted treatment noncompletion, whereas no cognitive variables predicted nonremission. In a multivariate logistic regression model, semantic fluency (P = .003), comorbid medical burden (P < .001), and early nonadherence (P < .001) were significant predictors of treatment noncompletion. Poorer EF predicted treatment noncompletion. These findings suggest that EFs of initiation and set maintenance (examined by the semantic fluency task) may allow depressed elderly individuals to engage and stay in treatment. Identification of those at risk for noncompletion may help implementation strategies for personalized care. ClinicalTrials.gov identifier: NCT00892047.

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Is Apixaban Safe and Effective for Venous Thromboembolism Prophylaxis After Primary Total Hip and Total Knee Arthroplasties?

Venous thromboembolism (VTE) is a serious complication of total hip arthroplasty (THA) and total knee arthroplasty (TKA). Apixaban is approved for VTE prophylaxis. This study seeks to ascertain the risk of VTE and bleeding complications in patients undergoing primary THA and TKA receiving apixaban for postoperative VTE prophylaxis for one of the following indications: high risk for VTE, previously on apixaban, and contraindication to the use of aspirin. This is a retrospective cohort study of patients who underwent primary THA or TKA over a 17-month period and were prescribed apixaban for thromboprophylaxis postoperatively. 230 patients were included in the study, 110 TKA and 120 THA. The primary reasons for high-risk VTE status included personal and family history of VTE, and 13% were taking apixaban preoperatively for atrial fibrillation. 1 patient (0.43%) who underwent TKA had a DVT with PE. 2.6% of patients had wound complications requiring operative treatment, and 0.87% of THA patients underwent revision arthroplasty. The use of apixaban for VTE prophylaxis after primary THA and TKA in patients at high risk for VTE, in patients previously on apixaban, and in patients with a contraindication to the use of aspirin is associated with a low risk of VTE and bleeding complications.

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A multinational study of the effects of low-dose pravastatin in patients with non-insulin-dependent diabetes mellitus and hypercholesterolemia. Pravastatin Multinational Study Group for Diabetes.

This multinational, 16-week, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of low-dose pravastatin in 325 patients with non-insulin-dependent diabetes mellitus (NIDDM) and hypercholesterolemia [serum total cholesterol concentrations of 5.2-7.8 mmol/l (200 to 300 mg/dl)]. Patients were randomized to receive pravastatin 10 mg or matching placebo with doubling of the dose after 8 weeks if predefined target levels for total cholesterol [(i.e., < 5.2 mmol/l (200 mg/dl) or > 15% decrease from baseline] had not been achieved. At Week 16, pravastatin-treated patients showed a 21.4% decrease in serum low-density lipoprotein cholesterol (LDL-C) and a 13.5% reduction in serum total cholesterol (TC) concentrations (p < 0.001 compared with placebo). Levels of triglycerides (TG) were reduced 9.6% during pravastatin treatment (p < 0.05 compared with placebo) while high-density lipoprotein cholesterol (HDL-C) levels were increased 4.4% (p = NS). Adverse events and laboratory test abnormalities were similar among patients treated with pravastatin or placebo. Glycosylated hemoglobin (HbA1C) levels remained unchanged. The results of this study demonstrate that low-dose pravastatin is effective and well tolerated for lowering elevated cholesterol concentrations during short-term treatment of patients with NIDDM and hypercholesterolemia.

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Atorvastatin reduced soluble receptors of TNF-alpha in systemic lupus erythematosus.

The aim of this study was to evaluate the efficacy of atorvastatin to reduce the plasma levels of TNF system molecules (TNF-α, sTNFR1 and sTNFR2) and to assess their association with risk factors for accelerate atherosclerosis and clinical disease activity scores in SLE patients. In a previous study, 64 female SLE patients received 20 mg/day of atorvastatin and 24 SLE patients (non-treated group) were followed for 8 weeks. Plasma levels of TNF-α, sTNFR 1 and sTNFR 2 were measured by ELISA, at baseline and at the end of the study. The plasma levels of sTNFR1 and sTNFR 2 showed a positive correlation with SLEDAI score. We also found a positive correlation between TNF-α and sTNFR 1 levels and SLICC score. Patients with current nephritis and patients with anti-ds-DNA antibodies presented higher sTNFR1 and sTNFR2 levels. Patients with abdominal obesity and arterial hypertension also had higher plasma levels of soluble receptors. At the end of 8 weeks, we observed a significant decrease in sTNFR1 plasma levels in patients receiving atorvastatin [median (percentile), 876.5 (717-1284 pg/ml) vs. 748 (629.6-917.3 pg/ml), p=0.03], without difference regarding TNF-α and sTNFR2 plasma levels. The SLEDAI and SLICC scores were independent determinants of the plasma levels of sRTNF1. Atorvastatin reduced soluble receptors of TNF-α. The plasma levels of TNF-α, sTNFR1 and sTNFR2 may play a role in SLE activity and atherosclerosis, and might be evaluated as targets for new therapies.

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A third generation regimen VACOP-B with or without adjuvant radiotherapy for aggressive localized non-Hodgkin's lymphoma: report from the Italian Non-Hodgkin's Lymphoma Co-operative Study Group.

The objective of this multicenter prospective study was to determine the clinical efficacy and toxicity of a polychemotherapeutic third generation regimen, VACOP-B, with or without radiotherapy as front-line therapy in aggressive localized non-Hodgkin's lymphoma. Ninety-three adult patients (47 males and 46 females, median age 45 years) with aggressive localized non-Hodgkin's lymphoma, 43 in stage I and 50 in stage II (non-bulky), were included in the study. Stage I patients received VACOP-B for 6 weeks plus involved field radiotherapy and stage II patients received 12 weeks VACOP-B plus involved field radiotherapy on residual masses. Eighty-six (92.5%) achieved complete remission and 4 (4.3%) partial remission. Three patients (3.2%) were primarily resistant. Ten-year probability of survival, progression-free survival and disease-free survival were 87.3, 79.9 and 83.9%, respectively. Eighty-four patients are surviving at a median observation time of 57 months (range: 6-126). Statistical analysis showed no difference between stages I and II in terms of response, ten-year probability of survival, progression-free survival or disease-free survival. Side effects and toxicity were negligible and were similar in the two patient groups. The results of this prospective study suggest that 6 weeks of VACOP-B treatment plus radiotherapy may be the therapy of choice in stage I aggressive non-Hodgkin's lymphoma. Twelve weeks of VACOP-B treatment with or without radiotherapy was shown to be effective and feasible for stage II. These observations need to be confirmed by a phase III study comparing first and third generation protocols in stage I-II aggressive non-Hodgkin's lymphoma.

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Simultaneous hybrid revascularization by carotid stenting and coronary artery bypass grafting: the SHARP study.

In an attempt to reduce post-operative events we investigated a new therapeutic strategy consisting of a simultaneous hybrid revascularization by carotid artery stenting (CAS), immediately followed by an on-pump coronary artery bypass graft (CABG). Preventing stroke and cardiovascular events after coronary artery revascularization in patients with elevated surgical risk is a complex and multifaceted problem. One hundred-one consecutive patients with severe carotid and coronary artery disease and a standard EuroSCORE >or=5 were included in this multicenter study. Immediately after CAS, patients underwent CABG. The primary end point was the incidence of stroke, acute myocardial infarction (AMI), or death at 30 days. Secondary outcomes were transient ischemic attacks; major local complications; bleeding and systemic complications within 30 days after treatment; and any stroke, AMI, or death occurring from the 31st day to the end of the 12-month follow-up. All clinical outcomes were assessed by an independent monitoring board. The rate of procedural success was 98%. The 30-day cumulative incidence of disabling stroke, AMI, or death was 4%: 2 patients died (2%) in the post-operative period, and 2 patients (2%) had a stroke immediately after CAS and before CABG. Three patients died from the 31st day to the 12th month after the procedure. Our findings indicate that in high-risk patients with coronary artery disease suitable for CABG and carotid artery disease, the hybrid revascularization by CAS immediately followed by CABG is a promising and feasible therapeutic strategy.

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Treatment of Sydenham's chorea with intravenous immunoglobulin, plasma exchange, or prednisone.

Sydenham's chorea has been established as a postinfectious autoimmune neuropsychiatric disorder. Corticosteroids have been used to treat patients with severe disease but are not always effective, and relapses are frequent after cessation. Eighteen subjects were entered into this randomized-entry controlled trial designed to determine if intravenous immunoglobulin or plasma exchange would be superior to prednisone in decreasing the severity of chorea. Mean chorea severity for the entire group was significantly lower at the 1-month follow-up evaluation (overall 48% improvement). Although the between-group differences were not statistically significant, clinical improvements appeared to be more rapid and robust in the intravenous immunoglobulin and plasma exchange groups than in the prednisone group (mean chorea severity scores decreased by 72% in the intravenous immunoglobulin group, 50% in the plasma exchange group, and 29% in the prednisone group). Larger studies are required to confirm these clinical observations and to determine if these treatments are cost-effective for this disorder.

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Increased insulin-like growth factor-I levels in women with polycystic ovary syndrome, and beneficial effects of metformin therapy.

We aimed to investigate whether metformin would reverse the endocrinopathy of polycystic ovary syndrome (PCOS), allowing resumption of cyclic ovulation and regular menses, and whether metformin causes any change in the serum concentration of insulin-like growth factor-I (IGF-I) in patients with PCOS. Fifty-eight women with PCOS participated in the study and received metformin at a dose of 850 mg three times a day (total 2550 mg) for 16 weeks. Serum concentrations of luteinizing hormone, follicle stimulating hormone, estradiol, free testosterone, total testosterone, 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, fasting insulin, IGF-I, sex hormone binding globulin and insulin-like growth factor binding protein-1 (IGFBP-1) were evaluated before and after metformin treatment. Patients were divided into two groups as responders and non-responders according to the achievement of regular menstrual periods. The mean IGF-I levels decreased significantly on metformin therapy. After 16 weeks of metformin treatment, 55.17% of PCOS patients achieved regular menses. Only the change in serum levels of progesterone and IGF-I on metformin were statistically significant between responders and non-responders; metformin-induced decremental change in IGF-I levels were greater in responders. In conclusion, we observed that elevated IGF-I levels may have a crucial role in many consequences of PCOS in addition to hyperinsulinemia. By decreasing insulin and IGF-I levels, metformin therapy offers additional beneficial effects in resumption of regular menses. Thus, in PCOS patients with elevated levels of IGF-I, metformin may be considered as an appropriate agent to be used for the regulation of menstrual cycles.

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Serum levels of soluble CD40 ligand at flare and at remission in patients with systemic lupus erythematosus.

To perform a prospective evaluation of soluble CD40 ligand (sCD40L) levels according to the activity of systemic lupus erythematosus (SLE). Two serum samples were taken from 53 patients with SLE: at flare and at remission. Clinical and biological measures (sCD40L levels were measured by a commercial ELISA) were evaluated in both situations. Patients with SLE had significantly lower median levels of sCD40L during flare than during remission [3365 (6157) vs 7125 (4122) pg/ml; p < 0.001]. The multivariate analysis to explain those patients with lower values of sCD40L during flare than during remission included 3 variables: 2 related to flare (prednisone dose received <or= 15 mg/day and platelet counts > 192,000 x 10(6)/l) and one related to lower changes in SLE Disease Activity Index (SLEDAI) score. We regrouped patients with the 2 characteristics related to flare as Group 4, and the others were Group 123. All patients with low SLEDAI scores at flare had statistically significant lower sCD40L levels during flare than during remission. When flare SLEDAI scores were higher than the 50th percentile, patients of Group 123 showed the same behavior and even more diminished levels of sCD40L during flare than patients of Group 123 with low SLEDAI scores (p = 0.023); and patients of Group 4 showed no differences in the values of sCD40L between flare and remission (p = 0.241). sCD40L plays a biologically active role, with decreased levels at flare at low SLEDAI scores. At high SLEDAI scores there are mechanisms that involve platelets and that are inhibited by high doses of prednisone that lead to increased serum values of sCD40L at flare.

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Myonecrosis after elective percutaneous coronary intervention: effect of clopidogrel-statin interaction.

A recent ex vivo study suggests that the metabolic activation of clopidogrel is catalyzed by cytochrom P450 (CYP) 3A4 and is competitively inhibited by atorvastatin, but not pravastatin. To determine whether the incidence of procedure-related myocardial injury, assessed by cardiac troponin T (cTnT) release, is altered when clopidogrel is coadministered with a statin that is predominantly CYP3A4-metabolized. Of the 211 consecutive patients who underwent coronary stenting after pretreatment with clopidogrel, 114 were receiving a CYP3A4-metabolized statin (59 simvastatin and 55 atorvastatin, Group 1), and 37 were receiving a non-CYP3A4-metabolized statin (30 pravastatin and 7 fluvastatin, Group 2) whereas 60 patients were not taking any statins (Control). All were troponin-negative before the procedure. The overall incidence of postprocedural cTnT positivity (> 0.10 ng/ml) was 30.8%. Group 2 patients were less likely to exhibit cTnT rise relative to Group 1 patients (8% versus 41.6%; p = 0.004) and relative to controls (8% versus 32.5%; p < 0.001). Multivariate analysis identified the use of a non-CYP3A4-metabolized statin before coronary stenting as the sole independent predictor for lower incidence of procedure-related cTnT elevation with estimated Odds ratios of 0.16 relative to no statin therapy (95% CI: 0.04-0.59; p = 0.006) and 0.18 relative to CYP3A4-metabolized statin therapy (95 CI: 0.053-0.637; p = 0.008) Benefit derived from the preprocedural use of pravastatin and fluvastatin but not atorvastatin and simvastatin suggest that the ex vivo finding of a negative interaction when coadministering a CYP3A4-metabolized statin with clopidogrel may be of clinical significance.

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The possible role of antiovary antibodies in repeated in vitro fertilization failures.

The study was conducted to investigate the possible role of circulating ovarian autoantibodies (ov-ab) in patients with repeated in vitro fertilization embryo transfer (IVF-ET) failure and to evaluate the effectiveness of immunosuppression treatment in these patients. The study group comprised 80 IVF patients who had five or more failed treatment cycles (mean 10.2; range 7-22). The presence of ov-ab was compared between these women and 1) 50 IVF patients who conceived during the first three treatment cycles; 2) 50 healthy nulligravidae. All participants were seronegative to nonorgan-specific and antithyroid autoantibodies. Patients in the study group who were positive for ov-ab were treated with 10 mg/day prednisone starting 1 month before ovulation induction. Embryo grading was compared in the IVF cycles before and after treatment. Ov-ab were found in ten patients (12.5%) in the study group, compared to none in the control groups (P = 0.01). Nine of the patients positive for ov-ab were treated with prednisone for their following cycle. A statistically significant improvement in embryo grading was noted. Three patients conceived after treatment (33%), with a take-home baby rate of 22%, compared to only six patients (8.6%) who conceived among the rest of the seronegative study group, with a take-home baby rate of 7.1% (P = 0.05). Ov-ab are a possible marker of an autoimmune disorder that may be one of the causes of repeated IVF failures. Immunosuppression treatment may prove efficient in ov-ab seropositive patients with repeated IVF failures by improving embryo grading and pregnancy rate.

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Pretreatment with low-dose β-adrenergic antagonist therapy does not affect severity of Takotsubo cardiomyopathy.

Takotsubo cardiomyopathy is a syndrome of transient left ventricular dysfunction following acute emotional or physical stress without obstructive coronary artery disease. The leading hypothesis for the etiology is stress-induced catecholamine surge. People taking outpatient β-adrenergic receptor antagonist therapy have less-severe presentation and clinical course of Takotsubo cardiomyopathy. We identified patients diagnosed with Takotsubo cardiomyopathy from October 2005 to January 2011 by analyzing our cardiac-catheterization database. Clinical records and angiograms were reviewed by 2 experienced observers independently to confirm the diagnosis. We collected clinical, demographic, laboratory, and angiographic data for the identified patients. We then compared the severity of myocardial dysfunction or damage (cardiac enzymes, left ventricular end diastolic pressure, and left ventricular ejection fraction) between patients taking outpatient β-adrenergic antagonist therapy upon admission vs those who were not. Arrival and peak values for cardiac enzymes were analyzed when available. Analysis of parameters related to the severity of myocardial dysfunction or damage was conducted using the Mann-Whitney U test. Means for age were compared using the Student t test. Statistical significance was set at P < 0.05 (2-tailed). Out of 64 patients identified, 16 (25%) were on one of 3 β-adrenergic antagonists on presentation: metoprolol succinate, metoprolol tartrate, or atenolol, with mean doses of 75 mg daily, 52.5 mg twice daily, and 37.5 mg daily, respectively. Patients on β-blockers were older (mean age 73.1 years vs 66 years; P < 0.05). There was no statistically significant difference in levels of cardiac enzymes, left ventricular end diastolic pressure, or left ventricular ejection fraction between the 2 groups. Prior therapy with low-dose β-adrenergic antagonists does not affect the severity of presentation and clinical course of Takotsubo cardiomyopathy as measured by common markers of myocardial dysfunction.

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Idarucizumab Reversal of Dabigatran in Patients with Acute Ischemic Stroke and Intracranial Hemorrhage: Comparison with Non-idarucizumab-Treated Patients.

Idarucizumab reverses the anticoagulant dabigatran; it is recommended during intravenous thrombolysis treatment of dabigatran-treated patients with acute ischemic stroke (AIS) and in dabigatran-treated patients with intracranial hemorrhage (ICH). Outcomes of consecutive idarucizumab/dabigatran-treated patients with intravenous thrombolysis-treated AIS (n = 22) were compared with consecutive similar intravenous thrombolysis-treated patients with AIS who were not anticoagulated (n = 182) [primary aim]; idarucizumab/dabigatran-treated patients with ICH (n = 13) were compared with patients with ICH who received the anticoagulants rivaroxaban or apixaban (n = 24) [secondary aim]. Efficacy was estimated by National Institutes of Health Stroke Scale score changes between admission and discharge and by the modified Rankin score after 3 months; safety was assessed by symptomatic ICH and mortality. Basal neurological impairment was similar in both idarucizumab/dabigatran-treated and control groups of patients with AIS and ICH. The idarucizumab/dabigatran-treated patients with AIS with subsequent intravenous thrombolysis showed a mean National Institutes of Health Stroke Scale improvement of 84% vs 68% in the control group (p < 0.05). A favorable outcome (modified Rankin score ≤ 2 after 3 months) was achieved significantly more frequently than in the control group (86% vs 57%; p < 0.05). The complication rate was similar in both groups. In patients with ICH, a positive functional outcome (modified Rankin score ≤ 3 after 3 months) was achieved more often in the idarucizumab/dabigatran-treated group than in the control group (70% vs 42%; p = 0.109). The complication rate was similar. Idarucizumab use in dabigatran-treated patients with AIS resulted in significantly more efficacious intravenous thrombolysis treatment and a non-significantly better outcome in dabigatran-treated patients with ICH compared with controls. There was no difference regarding complications.

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A randomized, double-blind, double-dummy, parallel-group, multicenter, dose-reduction trial of the minimal effective doses of budesonide and fluticasone dry-powder inhalers in adults with mild to moderate asthma.

Inhaled corticosteroids are established first-line anti-inflammatory treatment for asthma. Clinical trials comparing inhaled corticosteroids must take into consideration that because of their excellent effect at low doses, they typically induce a near-maximal response in asthma patients. The aim of the present dose-response study was to estimate the minimal effective doses (MEDs) of budesonide and of fluticasone propionate via dry-powder inhaler in adults with mild to moderate asthma. This was a randomized, double-blind, double-dummy, parallel-group, multicenter, dose-reduction trial performed in adults to compare these 2 inhaled corticosteroids. After a 4- to 6-week run-in period with beclomethasone dipropionate 2000 pg/d, patients fulfilling defined criteria for asthma control were randomly allocated to treatment with budesonide or fluticasone, both administered BID at a total of 800 pg/d. At 5-week intervals, the dose was reduced to 400 and then 200 pg/d (200 and 100 pg BID) if asthma control was maintained according to further defined criteria. The MED was defined as the last dose level before deterioration of asthma control. Subjects were 197 asthmatic patients with a mean age of 40.6 years in the budesonide group and 41.5 years in the fluticasone group. In both groups, baseline mean forced expiratory volume in 1 second (FEV(1)) was 79.4% of the predicted normal volume and baseline mean FEV(1) reversibility was 22.3%. The median MED for both groups was 400 microg/d, with no detectable difference in dis-tributions. The budesonide-to-fluticasone ratio for the geometric mean MED was 123% (95% CI, 99-153 [not significant]). No statistically significant differences regarding lung function, symptom scores, or rescue medication usage were found between the treatment groups during the first treatment period. Adverse-event profiles were similar in both groups, and no unexpected adverse events were considered to be caused by the study drugs. This effect-controlled study did not detect a statistically significant difference between the MEDs for budesonide and fluticasone via dry-powder inhaler in adults with mild to moderate asthma.

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An analysis of the safety and efficacy of dexmedetomidine in posterior spinal fusion surgery for adolescent idiopathic scoliosis: a prospective randomized study.

To evaluate whether use of dexmedetomidine, a centrally acting α2 adrenergic agonist, reduces opioid consumption in PSF. Adolescent idiopathic scoliosis patients who underwent PSF were randomized into morphine (M) and dexmedetomidine (D) group. M group received a 10 μg/kg/h IV infusion of morphine for 24 h post-surgery, while the D group received a 0.4 μg/kg/h IV infusion of dexmedetomidine. Trained nursing staffs recorded hourly vital parameters (blood pressure, pulse rate, respiratory rate, and oxygen saturation). Pain, postoperative nausea/vomiting (PONV), and sedation were rated using: the numerical rating scale (NRS), the PONV scale, and sedation status scale (SS). Preemptive analgesia with gabapentin and postoperative analgesia with ketorolac and paracetamol were used in both the groups. Any complications in the study groups were recorded. No significant difference was noted between the groups (M vs D) with respect to NRS (3.1 ± 0.8 vs 2.7 ± 0.5) (p = 0.07) and breakthrough analgesia requirements (0.78 vs 0.45) (p = 0.17). A significant difference was noted between the groups with respect to the secondary outcome measures of time to ambulation (56.6 ± 12.7 h vs 45.2 ± 7.7 h), time to oral analgesics (84.3 ± 20 h vs 64.0 ± 15.4 h), and time to liquid intake (8.3 ± 1.3 h vs 7.2 ± 1.2 h). The M group had a higher PONV score (0.46 ± 0.3 vs 0.16 ± 0.1) (p < 0.001) and mean time to bowel opening (112.7 ± 28.4 h vs 90.1 ± 20.5 h) (p < 0.001). Additionally, the enema or suppository requirements for bowel opening were significantly more (0.59 ± 0.6 vs 0.26 ± 0.4) (p = 0.01) in the M group. Dexmedetomidine provided analgesia comparable to morphine with lower PONV scores. It also reduced the opioid requirements in the PSF patients without additional complications and can therefore be incorporated in pain management protocols.

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Relationship of Prescribed Drugs with the Risk of Fall in Inpatients.

Falls are common in elderly patients and are often serious. Several drugs have been associated with an increased risk of fall. Older adults often take multiple drugs for chronic diseases, and thus may be at increased risk from drugs associated with fall. We investigated the association between drug use and falling in hospitalized older people, with the goal of identifying medications that may increase the risk of a fall. A retrospective case control study was performed at the National Hospital Organization Kumamoto Saishunso Hospital in Japan. Medications taken by patients who fell (n=57) were compared with those taken by patients who did not fall (n=63). The median age (interquartile range; IQR) of the fall and non-fall groups were 75.0 (67.0-83.0) and 80.0 (70.3-84.5) years, respectively. The characteristics of the two groups were similar, with no significant differences in age, sex, or body weight. The probability of falling increased when the patients used zolpidem [odds ratio (OR)=2.47; 95%CI: 1.09-5.63; p<0.05] and calcium channel antagonists (OR=0.299; 95%CI: 0.13-0.68; p<0.01), and was also related to physical factors (OR=2.27; 95%CI: 1.01-5.09; p<0.05). Elderly patients taking zolpidem may fall due to sleepiness, and blood pressure control may be important to prevent orthostatic high blood pressure. In the treatment of elderly people, medical staff should try to choose drugs that prevent fall or are not associated with falling.

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High response rate to low-dose rituximab plus high-dose dexamethasone as frontline therapy in adult patients with primary immune thrombocytopenia.

Corticosteroids as initial therapy for primary immune thrombocytopenia achieve a low rate of sustained remission. We prospectively evaluated the efficacy, safety, and response duration of low-dose rituximab plus high-dose dexamethasone as frontline therapy in newly diagnosed primary immune thrombocytopenia patients. One cycle of dexamethasone, 40 mg/d/intravenously for four consecutive days, plus weekly intravenous rituximab, 100 mg for four doses, was delivered. Twenty-one consecutive adults were enrolled. The overall response at day +28 was 90.5%. Complete sustained response at 6 months and relapse rate were 76.2% and 15.8%, respectively, compared with 30% and 62.5% for a historical group who had received standard treatment with prednisone (P = 0.005 and P = 0.004). There was a 9.5% incidence of adverse effects. The combination of low-dose rituximab and high-dose dexamethasone as frontline therapy for adults with primary immune thrombocytopenia was effective and had a high overall response rate and a low incidence of relapse.

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Correlation between point-of-care platelet function testing and bleeding after coronary angiography according to two different definitions for bleeding.

Platelet function testing could be useful when assessing the risk for bleeding during treatment with antiplatelet drugs. This has been indicated in several studies, including the Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty-Bleeding (ARMYDA-BLEEDS) study, which demonstrated that testing with a point-of-care assay correlated with bleeding events after percutaneous coronary intervention. To standardize bleeding definitions, the Bleeding Academic Research Consortium (BARC) published a consensus report, which is in need of data-driven validation. Hence, the investigators conducted an observational, prospective, single-center study of 474 patients receiving clopidogrel and aspirin who underwent coronary angiography with or without percutaneous coronary intervention from October 2006 to May 2011. Platelet reactivity was measured with adenosine diphosphate-induced single-platelet function testing (Plateletworks) at the start of coronary angiography. The primary end point was the 30-day incidence of bleeding as defined by BARC and ARMYDA-BLEEDS. The aim of the present study was to investigate the relation between on-treatment platelet reactivity and the 30-day incidence of bleeding complications according to the BARC and ARMYDA-BLEEDS definitions. Patients in the first platelet aggregation quartile had a higher frequency of type 2 or higher BARC bleeding and ARMYDA-BLEEDS-defined bleeding <30 days after coronary angiography compared with the fourth quartile (16.9% vs 6.7%, p = 0.014, and 8.5% vs 1.7%, p = 0.016, respectively) and the third quartile (16.9% vs 7.7%, p = 0.031, and 8.5% vs 2.6%, p = 0.048, respectively). In conclusion, patients with low on-treatment platelet reactivity at the time of intervention had a significantly higher incidence of bleeding according to the BARC and ARMYDA-BLEEDS definitions <30 days after coronary angiography with or without percutaneous coronary intervention.

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[Eradication of Helicobacter pylori in patients with end-stage renal disease undergoing dialysis treatment].

The aim of the present study was to examine the efficacy and safety of combination therapy with amoxicillin (AMPC), lansoprazole, and plaunotol for the eradication of H. pylori in dialysis patients. The subjects consisted of 15 dialysis patients (10 men and 5 women, mean age of 56 +/- 2.4 years) in whom H. pylori was found in the stomach. H. pylori status was evaluated by histology, culture and rapid urease test with biopsy specimens of the gastric mucosa. The patients were treated with AMPC 500 mg once a day for 3 weeks, lansoprazole 30 mg once a day for 8 weeks and plaunotol 80 mg three times a day for 24 weeks. In addition, the concentrations of serum gastrin and gastric juice ammonia were measured. Fourteen patients completed the treatment schedule, while one discontinued treatment because of nausea and diarrhea. Among the 14 patients, H. pylori was eradicated in 11 without any side effects (eradication rate 78.6%). Concentrations of gastric juice ammonia and serum gastrin were reduced significantly in patients who became H. pylori-negative. The present study indicates that combination therapy with AMPC, lansoprazole and plaunotol is safe and efficient for the eradication of H. pylori in dialysis patients. The results also suggested that elevated concentrations of gastric juice ammonia and serum gastrin in dialysis patients can be attributed, at least in part, to H. pylori infection.

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Impact of Apolipoprotein(a) Isoform Size on Lipoprotein(a) Lowering in the HPS2-THRIVE Study.

Genetic studies have shown lipoprotein(a) (Lp[a]) to be an important causal risk factor for coronary disease. Apolipoprotein(a) isoform size is the chief determinant of Lp(a) levels, but its impact on the benefits of therapies that lower Lp(a) remains unclear. HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) is a randomized trial of niacin-laropiprant versus placebo on a background of simvastatin therapy. Plasma Lp(a) levels at baseline and 1 year post-randomization were measured in 3978 participants from the United Kingdom and China. Apolipoprotein(a) isoform size, estimated by the number of kringle IV domains, was measured by agarose gel electrophoresis and the predominantly expressed isoform identified. Allocation to niacin-laropiprant reduced mean Lp(a) by 12 (SE, 1) nmol/L overall and 34 (6) nmol/L in the top quintile by baseline Lp(a) level (Lp[a] ≥128 nmol/L). The mean proportional reduction in Lp(a) with niacin-laropiprant was 31% but varied strongly with predominant apolipoprotein(a) isoform size (<i>P</i>_Trend=4×10^-29) and was only 18% in the quintile with the highest baseline Lp(a) level and low isoform size. Estimates from genetic studies suggest that these Lp(a) reductions during the short term of the trial might yield proportional reductions in coronary risk of ≈2% overall and 6% in the top quintile by Lp(a) levels. Proportional reductions in Lp(a) were dependent on apolipoprotein(a) isoform size. Taking this into account, the likely benefits of niacin-laropiprant on coronary risk through Lp(a) lowering are small. Novel therapies that reduce high Lp(a) levels by at least 80 nmol/L (≈40%) may be needed to produce worthwhile benefits in people at the highest risk because of Lp(a). URL: https://clinicaltrials.gov. Unique identifier: NCT00461630.

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Usefulness of platelet response to clopidogrel by point-of-care testing to predict bleeding outcomes in patients undergoing percutaneous coronary intervention (from the Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty-Bleeding Study).

Platelet reactivity predicts ischemic outcomes in patients who undergo percutaneous coronary intervention (PCI), but the correlation of heightened platelet response with bleeding has not been characterized. The aim of this study was to evaluate whether low platelet reactivity by point-of-care measurement after clopidogrel administration correlates with bleeding complications of PCI. A total of 310 patients receiving clopidogrel before PCI were prospectively enrolled. Platelet reactivity was measured with the VerifyNow P2Y12 assay. The primary end point was the 30-day incidence of major bleeding or entry-site complications according to quartile distribution of P2Y12 reaction units (PRU). The primary end point occurred more frequently in patients with preprocedural PRU levels in the lowest quartile compared to those in the highest quartile (10.1% vs 1.3%, p = 0.043), due mainly to entry-site hemorrhages. Absolute PRU levels were lower in patients with major bleeding (171 ± 49 vs 227 ± 68 in patients without, p = 0.002). On multivariate analysis, pre-PCI PRU levels in the first quartile were associated with a 4.5-fold increased risk for major bleeding (odds ratio 4.5, 95% confidence interval 1.9 to 25.9, p = 0.01). By receiver-operating characteristic curve analysis, the optimal cutoff for the primary end point was a pre-PCI PRU value ≤ 189 (area under the curve 0.76, 95% confidence interval 0.66 to 0.87, p = 0.001). In conclusion, this study suggests that an enhanced response to clopidogrel may be associated with higher risk for early major bleeding or entry-site complications in patients who undergo PCI. Point-of-care monitoring of platelet reactivity after clopidogrel administration may help identify patients in whom individualized strategies are indicated to limit bleeding complications after coronary intervention.

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How do cardiologists select patients for dual antiplatelet therapy continuation beyond 1 year after a myocardial infarction? Insights from the EYESHOT Post-MI Study.

Current guidelines suggest to consider dual antiplatelet therapy (DAPT) continuation for longer than 12 months in selected patients with myocardial infarction (MI). We sought to assess the criteria used by cardiologists in daily practice to select patients with a history of MI eligible for DAPT continuation beyond 1 year. We analyzed data from the EYESHOT Post-MI, a prospective, observational, nationwide study aimed to evaluate the management of patients presenting to cardiologists 1 to 3 years from the last MI event. Out of the 1633 post-MI patients enrolled in the study between March and December 2017, 557 (34.1%) were on DAPT at the time of enrolment, and 450 (27.6%) were prescribed DAPT after cardiologist assessment. At multivariate analyses, a percutaneous coronary intervention (PCI) with multiple stents and the presence of peripheral artery disease (PAD) resulted as independent predictors of DAPT continuation, while atrial fibrillation was the only independent predictor of DAPT interruption for patients both at the second and the third year from MI at enrolment and the time of discharge/end of the visit. Risk scores recommended by current guidelines for guiding decisions on DAPT duration are underused and misused in clinical practice. A PCI with multiple stents and a history of PAD resulted as the clinical variables more frequently associated with DAPT continuation beyond 1 year from the index MI.

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Comparing Deflazacort and Prednisone in Duchenne Muscular Dystrophy.

Deflazacort and prednisone/prednisolone are the current standard of care for patients with Duchenne muscular dystrophy (DMD) based on evidence that they improve muscle strength, improve timed motor function, delay loss of ambulation, improve pulmonary function, reduce the need for scoliosis surgery, delay onset of cardiomyopathy, and increase survival. Both have been used off-label for many years (choice dependent on patient preference, cost, and geographic location) before FDA approval of deflazacort for DMD in 2017. In this review, we compare deflazacort and prednisone/prednisolone in terms of their key pharmacological features, relative efficacy, and safety profiles in patients with DMD. Differentiating features include lipid solubility, pharmacokinetics, changes in gene expression profiles, affinity for the mineralocorticoid receptor, and impact on glucose metabolism. Evidence from randomized clinical trials, prospective studies, meta-analyses, and post-hoc analyses suggests that patients receiving deflazacort experience similar or slower rates of functional decline compared with those receiving prednisone/prednisolone. Regarding side effects, weight gain and behavior side effects appear to be greater with prednisone/prednisolone than with deflazacort, whereas bone health, growth parameters, and cataracts appear worse with deflazacort.

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The effect of ezetimibe, administered alone or in combination with simvastatin, on lymphocyte cytokine release in patients with elevated cholesterol levels.

Studies assessing the extra-lipid effects of ezetimibe have provided contrasting results. In the present study, we compared the effects of ezetimibe and simvastatin, administered alone or in combination, on the secretory function of human lymphocytes, systemic inflammation and endothelial function in subjects with elevated cholesterol levels. A prospective study involving a group of 178 ambulatory patients with isolated hypercholesterolaemia who were randomly assigned in a double-blind fashion to 90days of treatment with ezetimibe (10mg), simvastatin (40mg), ezetimibe (10mg) plus simvastatin (4mg) or placebo. A total of 170 patients completed the study. Lymphocyte cytokine release and plasma levels of high-sensitivity C-reactive protein (hsCRP) and intercellular adhesion molecule 1 (ICAM-1). Although both drugs reduced lymphocyte release of tumour necrosis factor-α, interferon-γ and interleukin-2 in a lipid-independent manner, only the effect of simvastatin was statistically significant (P<0.001). This lymphocyte-suppressing effect, which was accompanied by a decrease in plasma levels of hsCRP and ICAM-1 (P<0.001), was strongest in patients receiving both simvastatin and ezetimibe. There were no differences in lymphocyte-suppressing, systemic anti-inflammatory and endothelial protective effects of simvastatin between insulin-resistant and insulin-sensitive subjects, whereas the effects of ezetimibe and the combined treatment were greater in the former group of patients (P<0.01 and P<0.001, respectively). The results of this study indicate that simvastatin is superior to ezetimibe in producing lymphocyte-suppressing, systemic anti-inflammatory and endothelial protective effects in patients with elevated cholesterol levels. Hypercholesterolaemic patients with high cardiovascular risk may receive the greatest benefits from concomitant treatment with a statin and ezetimibe.

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Analgesic efficacy of lysine clonixinate plus tramadol versus tramadol in multiple doses following impacted third molar surgery.

This study compared the analgesic and anti-inflammatory efficacy, trismus control, and tolerability of the combination of lysine clonixinate and tramadol (LCT) versus tramadol (T) alone after surgical removal of impacted mandibular third molars. This study was a double-blind, randomized clinical trial, including two study groups of 20 patients each, who exhibited acute pain subsequent to surgical extraction of two mandibular third molars. Pain intensity was quantified over a 96-h period using a visual analogue scale and a 5-point verbal rating scale. Secondary indicators of analgesic and anti-inflammatory efficacy, trismus control, and tolerability were determined. Patients administered LCT exhibited better therapeutic effects that those administered T. Fifty percent of patients in the LCT group rated this therapy as 'excellent analgesia' compared with only 10% in the T group. The onset of the analgesic effect of LCT was significantly faster, without any therapeutic failures. There were no significant differences between the groups with regard to anti-inflammatory effect or trismus. The results of this study suggest that the postsurgical analgesic efficacy of LCT in combination (LC 125 mg + T 25 mg) is superior to that obtained with T alone, administered at the standard dose of 50 mg, for up to 96 h after the extraction of both impacted mandibular third molars.

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Prevalence and risk factors for delayed adrenal insufficiency after liver transplantation.

Liver transplantation (LT) recipients are at risk for early and delayed adrenal insufficiency for multiple reasons. Although early adrenal insufficiency is known to occur in a high proportion of recipients maintained on steroid-free immunosuppressive regimens, the prevalence and risk factors associated with delayed functional adrenal gland atrophy (FAGA) are unknown because routine evaluation for this condition is not standard practice among LT centers. We investigated a group of 87 patients (64 males) transplanted for end-stage liver disease related to different etiologies. All underwent a standard corticotropin stimulation test (CST) when, after gradual steroid tapering, they had been maintained for at least 1 week on oral prednisone at a daily dose of 5 mg. FAGA, defined by a serum cortisol concentration that, 60 minutes after corticotropin administration, did not double the baseline level and remained <20 mug/dL, was diagnosed in 23/87 patients (26.4%). Stepwise logistic regression analysis selected as significant predictors of FAGA the cumulative dosage of corticosteroids administered (P < 0.01), the increase in the body mass index after LT (P < 0.01), a low serum cholesterol concentration (P = 0.005), and a high adrenocorticotropin hormone (ACTH) serum level (P < 0.05) at the time CST was performed. In conclusion, FAGA is a common condition among LT recipients who are maintained on prolonged corticosteroid immunosuppressive treatment. Factors associated with FAGA include the cumulative steroid dose, weight changes after LT, and ACTH and cholesterol levels at the time of steroid withdrawal.

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Does obesity confer an increased risk and/or more severe course of post-ERCP pancreatitis?: a retrospective, multicenter study.

Pancreatitis is the most common major complication of endoscopic retrograde cholangiopancreatography (ERCP). Recent studies have suggested that obesity may serve as a prognostic indicator of poor outcome in non-ERCP-induced acute pancreatitis. However, to our knowledge, no one has ever investigated the potential association of obesity and ERCP-induced pancreatitis. Thus, the purpose of our study was to determine whether obesity conferred an increased risk and/or more severe course of post-ERCP pancreatitis. A 160 variable database was prospectively collected by a defined protocol on patients undergoing diagnostic or therapeutic ERCP at 15 centers in the Midwest Pancreaticobiliary Group and participating in a randomized controlled study, evaluating whether prophylactic corticosteroids reduces the incidence of post-ERCP pancreatitis. Body mass indices (BMIs) were available on 964 of the 1115 patients from the original study. A BMI > or = 30 kg/m2 was defined as obese (World Health Organization) and used as a cutoff point in this study. BMIs were analyzed in a retrospective fashion to determine whether obesity confers an increased risk and/or more severe course of post-ERCP pancreatitis. Data were collected before the ERCP, at the time of procedure, and 24 to 72 hours after discharge. Standardized criteria were used to diagnose and grade the severity of postprocedure pancreatitis. Nine hundred sixty four patients were enrolled in the study. Pancreatitis occurred in 149 patients (15.5%) and was graded as mild in 101 (67.8%), moderate in 42 (28.2%), and severe in 6 (4.0%). The patients were categorized by BMI (kg/m2) using the following breakdowns: BMI < 20, 20 to < 25, 25 to < 30, and > or = 30, as well as BMI < 30 or > or = 30. The groups were similar with respect to the patient and procedure risk factors for post-ERCP pancreatitis except the group with BMI > or = 30 had a higher frequency of females, were younger, had less frequent chronic pancreatitis, a lower number of pancreatic duct injections, and fewer patients received more than 2 pancreatic duct injections. Of the patients with a BMI < 30, 119 (16.4%) developed post-ERCP pancreatitis compared with 30 (12.5%) of those with a BMI > or = 30 (P=0.14). There was no association between the presence of obesity and the severity of pancreatitis (P=0.74). Patients with a BMI < 20, 20 to < 25, 25 to < 30, and > or = 30 had a similar incidence of post-ERCP pancreatitis. Obesity did not seem to confer an increased risk for ERCP-induced pancreatitis. A statistically significant association between obesity and the severity of ERCP-induced pancreatitis was not apparent.

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Low-dose aspirin and survival in men with prostate cancer: a study using the UK Clinical Practice Research Datalink.

Aspirin use is associated with reduced risk of, and death from, prostate cancer. Our aim was to determine whether low-dose aspirin use after a prostate cancer diagnosis was associated with reduced prostate cancer-specific mortality. A cohort of newly diagnosed prostate cancer patients (1998-2006) was identified in the UK Clinical Practice Research Datalink (confirmed by cancer registry linkage). A nested case-control analysis was conducted using conditional logistic regression to compare aspirin usage in cases (prostate cancer deaths) with up to three controls (matched by age and year of diagnosis). Post-diagnostic low-dose aspirin use was identified in 52 % of 1,184 prostate cancer-specific deaths and 39 % of 3,531 matched controls (unadjusted OR 1.51, 95 % CI 1.19, 1.90; p < 0.001). After adjustment for confounders including treatment and comorbidities, this association was attenuated (adjusted OR  1.02 95 % CI 0.78, 1.34; p = 0.86). Adjustment for estrogen therapy accounted for the majority of this attenuation. There was also no evidence of dose-response association after adjustments. Compared with no use, patients with 1-11 prescriptions and 12 or more prescriptions had adjusted ORs of 1.07 (95 % CI 0.78, 1.47; p = 0.66) and 0.97 (95 % CI 0.69, 1.37; p = 0.88), respectively. There was no evidence of a protective association between low-dose aspirin use in the year prior to diagnosis and prostate cancer-specific mortality (adjusted OR 1.04 95 % CI 0.89, 1.22; p = 0.60). We found no evidence of an association between low-dose aspirin use before or after diagnosis and risk of prostate cancer-specific mortality, after potential confounders were accounted for, in UK prostate cancer patients.

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Twice-a-day PPI, tetracycline, metronidazole quadruple therapy with Pylera® or Lactobacillus reuteri for treatment naïve or for retreatment of Helicobacter pylori. Two randomized pilot studies.

Bismuth is no longer available in Europe except as part of combination therapy. Lactobacillus reuteri has also been used as an adjuvant for Helicobacter pylori therapy. We aimed to investigate the efficacy of a b.i.d. quadruple therapy containing Pylera® or L reuteri for H pylori infection. We performed two open-label randomized pilot studies. Adult patients positive for H pylori were randomly assigned to b.i.d therapy with quadruple therapy containing bismuth (2 capsules of Pylera® plus 250 mg each of tetracycline and metronidazole for a total of 500 mg of each), or the same dose of antibiotics plus 2 × 10⁸  CFU L reuteri DSM 17 938 plus 2 × 10⁸  CFU L reuteri ATCC PTA 6475 (Gastrus®) once daily and pantoprazole 20 mg b.i.d. Regimens were given with meals for 10 days. Cure was defined by negative 13C-UBT or stool antigen test. A total of 99 subjects (29% men) were enrolled; 92 completed the study. In the Pylera® group, H pylori infection was cured in 95.7%; 95% CI = 85%-99% (44/46) PP and 88%; 95% CI = 75%-95% (44/50) ITT vs. 84.8%; 95% CI = 71%-95% (39/46) PP and 79.6%; 95% CI = 65%-89% (39/49) ITT in the Gastrus® group, respectively. Cure rates in naїve patients were 100%; 95% CI = 85%-100% (25/25) PP with Pylera®, and 89.7%; 95% CI = 72%-97% (26/29) with Gastrus®. Compliance was excellent and side effects mild with both regimens. B.i.d. bismuth quadruple therapy was highly effective for H pylori eradication in treatment of naïve patients in Sardinia. Replacement of bismuth with Gastrus® might be considered when bismuth is contraindicated or unavailable.

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Metoprolol Versus Carvedilol in Patients With Heart Failure, Chronic Obstructive Pulmonary Disease, Diabetes Mellitus, and Renal Failure.

This study compared the survival and the risk of heart failure (HF), chronic obstructive pulmonary disease (COPD), diabetes mellitus (DM), hypoglycemia, and renal failure (RF) hospitalizations in geriatric patients exposed to carvedilol or metoprolol. Data sources were Danish administrative registers. Patients aged ≥65 and having HF, COPD, and DM were followed for 1 year from the first β-blocker prescription redemption. Patients' characteristics were used to 1:1 propensity score match carvedilol and metoprolol users. A Cox regression model was used to compute the hazard ratio (HR) of study outcomes. For statistically significant associations, a conditional inference tree was used to assess predictors most associated with the outcome. In total, 1,424 patients were included. No statistically significant differences were observed for survival (HR 0.86; 95% confidence interval [CI] 0.67 to 1.11, p = 0.240) between carvedilol/metoprolol users. The same applied to COPD (HR 0.88; 95% CI 0.75 to 1.05, p = 0.177), DM (HR 0.95; 95% CI 0.82 to 1.10, p = 0.485), hypoglycemia (HR 0.88; 95% CI 0.47 to 1.67, p = 0.707), and RF (HR 1.25; 95% CI 0.93 to 1.69, p = 0.142) hospitalizations. Carvedilol users had a 38% higher hazard then metoprolol users of HF hospitalization during the follow-up period (HR 1.38; 95% CI 1.19 to 1.60, p <0.001). Artificial intelligence identified carvedilol exposure as the most important predictor for HF hospitalization. In conclusion, we found an increased risk of HF hospitalization for carvedilol users with this triad of diseases but no statistically significant differences in survival or risk of COPD, DM, hypoglycemia, and RF hospitalizations.

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Hydroxylation index of omeprazole in relation to CYP2C19 polymorphism and sex in a healthy Iranian population.

Polymorphism of CYP2C19 gene is one of the important factors in pharmacokinetics of CYP2C19 substrates. Omeprazole is a proton pump inhibitor which is mainly metabolized by cytochrome P450 2C19 (CYP2C19). The aim of present study was to assess omeprazole hydroxylation index as a measure of CYP2C19 activity considering new variant allele (CYP2C19*17) in Iranian population and also to see if this activity is sex dependent. One hundred and eighty healthy unrelated Iranian individuals attended in this study. Blood samples for genotyping and phenotyping were collected 3 hours after administration of 20 mg omeprazole orally. Genotyping of 2C19 variant alleles *2, *3 and *17 was performed by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and semi-nested PCR methods. Plasma concentrations of omeprazole and hydroxyomeprazole were determined by high performance liquid chromatography (HPLC) technique and hydxroxylation index (HI) (omeprazole/ hydroxyomeprazole) was calculated. The CYP2C19*17 was the most common variant allele in the studied population (21.6%). Genotype frequencies of CYP2C19*17*17, *1*17, and *2*17 were 5.5%, 28.8% and 3.3% respectively. The lowest and the highest median omeprazole HI was observed in *17*17 and *2*2 genotypes respectively (0.36 vs. 13.09). The median HI of omeprazole in subjects homozygous for CYP2C19*1 was 2.16-fold higher than individuals homozygous for CYP2C19*17 (P < 0.001) and the median HI of CYP2C19*1*17 genotype was 1.98-fold higher than CYP2C19 *17*17 subjects (P < 0.001). However, subjects with CYP2C19*2*17 (median HI: 1.74) and CYP2C19*1*2 (median HI: 1.98) genotypes and also CYP2C19*1*17 (median HI: 0.71) and CYP2C19*1*1 (mean HI: 0.78) did not show any significantly different enzyme activity. In addition, no statistically significant difference was found between women and men in distribution of CYP2C19 genotypes. Furthermore, the hydroxylation index of Omeprazole was not different between women and men in the studied population. Our data point out the importance of CYP2C19*2 and CYP2C19*17 variant alleles in metabolism of omeprazole and therefore CYP2C19 activity. Regarding the high frequency of CYP2C19*17 in Iranian population, the importance of this new variant allele in metabolism of CYP2C19 substrates shall be considered.

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Rationale and Design of the H-REPLACE Study: Safety and Efficacy of LMWH Versus Rivaroxaban in ChinEse Patients HospitaLized with Acute Coronary SyndromE.

Acute coronary syndrome (ACS) is a serious and life-threatening condition. Anticoagulation during the acute phase of ACS is effective in reducing ischemic events. The most widely used parenteral anticoagulation agent in ACS patients is enoxaparin. Rivaroxaban is a novel oral anticoagulant with potent anti-Xa activity, which might be an attractive alternative drug to enoxaparin. In fact, rivaroxaban was consistently shown to be non-inferior to enoxaparin therapy in terms of reduction of recurrent venous thromboembolism events. This prospective, randomized, open-label, active-controlled, multicenter study is designed to compare the safety and efficacy of rivaroxaban versus enoxaparin in patients with ACS, who missed the primary reperfusion therapy window and before selective revascularization. Up to 2055 participants receiving background treatment of aspirin plus clopidogrel or ticagrelor will be randomly assigned to either oral rivaroxaban 2.5 mg twice daily or rivaroxaban 5 mg twice daily or subcutaneous enoxaparin 1 mg/kg twice daily until hospital discharge for a maximum of 8 days or 12 h before revascularization therapy. The primary safety endpoint is the International Society on Thrombosis and Hemostasis definition of bleeding events [minor, clinically relevant non-major and major bleeding]. The primary efficacy endpoint is a composite of major adverse cardiac events (MACE), including cardiac death, myocardial infarction, re-revascularization or stroke, and major bleeding events. Secondary endpoints include cardiac-related rehospitalization and all-cause death. Patients will be followed for 12 months after randomization. The H-REPLACE trial offers an opportunity to assess clinical outcomes of rivaroxaban versus enoxaparin during the acute phase of ACS and may provide an alternative anticoagulation strategy for ACS patients, who missed the primary reperfusion therapy window and before selective revascularization. ClinicalTrials.gov; NCT03363035.

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[Beta blocking agents in the treatment of dilated cardiomyopathy: review of the literature and clinical experience with 67 patients].

Several reports suggest that chronic beta blockade, most often with the beta 1 selective agent metoprolol, may improve hemodynamic and clinical function in patients with idiopathic dilated cardiomyopathy. However, controlled trials are limited and some studies have not shown beneficial effects in short term trials. Mechanisms of effectiveness are still debated and probably concern the capacity to avoid toxic myocardial damage by catecholamines, to induce receptor up-regulation, to contribute to the control of arrhythmias, to improve diastolic relaxation and other mechanisms. After a revision of the literature, a preliminary clinical experience with metoprolol in dilated cardiomyopathy diagnosed according to the WHO definition is reported. Sixty-seven patients symptomatic for congestive heart failure or with complex ventricular arrhythmias associated with severe left ventricular dysfunction were submitted to test dose with metoprolol 5 mg bid for 2-7 days. All patients were completely studied, including coronary angiography and endomyocardial biopsy to exclude ischemic heart disease and active myocarditis. Four pts (6%) did not tolerate the first test dosage of metoprolol and twenty-two patients were excluded from analysis because of inadequate follow-up or because they were enrolled in an international trial. Forty-one patients underwent long-term treatment with metoprolol at a final mean dosage of 150 mg a day (range 50-200 mg) and are presently analyzed. The dosage was gradually increased during the first seven weeks. After 6 +/- 2 months and 12 +/- 2 months, 34 patients were stable or ameliorated (Group 1) and experienced an overall significant improvement of functional class (all pts in class I-II NYHA), of left and right ventricular ejection fraction (from 28 +/- 8.8% to 35.8 +/- 13.7% to 33.2 +/- 12.3% and from 38.6 +/- 11.8% to 42.4 +/- 5.8% to 45.2 +/- 12.2% respectively), of clinical signs of congestive heart failure, of cardiothoracic index, of left ventricular diameters and of arrhythmic pattern. Furthermore, the rate of ventricular couplets > 20/24h and of non-sustained ventricular tachycardia changed respectively from 46% and 54% to 4% and 21% at 12 +/- 2 months. None in Group 1 died nor is any waiting for heart transplantation. Eleven patients (Group 2) did not tolerate the drug acutely (4 pts) or deteriorated during the first 6 +/- 2 months (7 pts) of the treatment. In this group a worsening or an insignificant variation of all clinical and instrumental parameters was observed. During follow-up four patients of this group underwent heart transplantation (one died shortly after the operation because of infective complications), one died while waiting, two are currently waiting for heart transplantation, and three are still in heart failure (class III NYHA). No cases of sudden death occurred in any group of patients (15 pts with follow-up > 12 mo). Our uncontrolled study seems to confirm the beneficial effect of betablockers in a subgroup of patients with idiopathic dilated cardiomyopathy. The characterization of responders to this therapy is still undefined and will constitute the aim of future analyses.

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Bioavailability of a crushed pantoprazole tablet after buffering with sodium hydrogencarbonate or magaldrate relative to the intact enteric coated pantoprazole tablet.

The aim of this study was to determine the bioavailability of orally administered, crushed pantoprazole tablets after buffering with either 1.4% sodium hydrogencarbonate or 1600 mg magaldrate relative to the intact enteric coated pantoprazole tablet. A single dose, three-period crossover study was performed with 18 healthy male volunteers. The crushed pantoprazole suspension, together with either sodium hydrogencarbonate or magaldrate, was administered via a nasogastral tube. Tmax of crushed pantoprazole was earlier as compared to the intact tablet (0.5 h vs. 3 h) and Cmax was approximately 10% higher due to faster absorption. The bioavailability of the crushed pantoprazole tablet relative to the intact pantoprazole tablet was 93% when using sodium hydrogencarbonate as the buffering agent, and 88% when using magaldrate. Based on the internationally approved confidence intervals for AUC (0.80-1.20) and Cmax (0.70-1.43), the crushed tablet buffered with sodium hydrogencarbonate was shown to be bioequivalent with the intact tablet (point estimates for AUC or Cmax: 0.93 or 1.10). For the crushed tablet buffered with magaldrate (point estimates for AUC or Cmax: 0.88 or 1.12) bioequivalence with the intact tablet could not be formally demonstrated, although the lower confidence limit for AUC of 0.78 was only slightly below the lower limit of the equivalence range of 0.80.

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Comparison between the bronchodilator and cardiovascular effects of inhaling 0.5 mg. rimiterol ('Pulmadil') and 0.2 mg. salbutamol.

A comparison between the acute effects of rimiterol (0.5 mg) and salbutamol (0.2 mg.) has been made using metered dose aerosols. In this dosage it was found that the peak effect of the two drugs was the same but that the effect of rimiterol was less prolonged than that of sulbutamol. No increase in blood pressure occurred and heart rate changes were minimal after both drugs. Rimiterol is an acceptable alternative to the short-acting isoprenaline but lacks the cardiovascular effects of isoprenaline and is an alternative to salbutamol where very prolonged action is unnecessary.

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Concomitant Use of Antiplatelets and Anticoagulants in Patients with Coronary Heart Disease and Atrial Fibrillation: What Do Recent Clinical Trials Teach Us?

Coronary heart disease (CHD) and atrial fibrillation (AF) are among the most common cardiovascular diseases. A significant proportion of patients have both CHD and AF and are at increased risk for thrombotic complications. Current therapy for CHD and AF includes antiplatelet and anticoagulant medications, respectively. Patients with concurrent CHD and AF may be prescribed dual antiplatelet therapy (DAPT) in addition to anticoagulation, which increases their bleeding risk. Controversy remains on how to balance risks and benefits in patients with CHD and AF in which multiple antithrombotic therapies may be indicated. We review clinical trials and current guidelines for antiplatelet and anticoagulant therapy in CHD and AF. Aspirin and P2Y₁₂ inhibitors are the mainstay of antiplatelet therapy. Vitamin K antagonists (VKAs) are the most commonly used anticoagulant, although the use of non-VKA oral anticoagulants (NOACs) in patients with AF is increasing. Recent studies provide guidance on how to address antithrombotic therapies in patients with concomitant CHD and AF. To date, we have evidence that in patients with AF who undergo percutaneous coronary intervention (PCI), clopidogrel with VKA may be used safely without aspirin. Also, low-dose rivaroxaban in combination with either clopidogrel only or DAPT is as effective as the traditional regimen of triple therapy with VKA and DAPT with lower bleeding risk. Dabigatran with a P2Y₁₂ inhibitor was also found to be safe with less bleeding compared to triple therapy with VKA and DAPT. Use of a single antiplatelet agent with anticoagulation has become a viable choice in patients with CHD and AF, but more clinical trial data is needed to confirm therapy and duration regimens.

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Randomized phase III trial in childhood high-grade astrocytoma comparing vincristine, lomustine, and prednisone with the eight-drugs-in-1-day regimen. Childrens Cancer Group.

In a previous randomized trial, the addition of adjuvant chemotherapy to postoperative radiotherapy proved beneficial in the treatment of childhood high-grade astrocytomas. The present study tests the hypothesis that an eight-drug adjuvant chemotherapy regimen would improve survival in such children compared with the three-drug regimen of the prior study. Between April 1985 and May 1990, patients between the ages of 18 months and 21 years with newly diagnosed high-grade astrocytomas were eligible for this study, as determined by the treating institution's histopathologic diagnosis. Treatment consisted of postoperative local-field radiotherapy and adjuvant chemotherapy, either lomustine (CCNU), vincristine, and prednisone (control regimen) or eight-drugs-in-1-day chemotherapy (experimental regimen). Two cycles of postoperative preirradiation chemotherapy were administered in the experimental regimen. Patients were evaluated radiographically every 3 months after irradiation. Eighty-five eligible patients were randomized to the control regimen and 87 to the experimental regimen. The progression-free survival (PFS) and overall survival (OS) at 5 years were 33% (SE = 5%) and 36% (SE = 6%), respectively. There was no statistical difference in outcome between the two chemotherapy regimens. In patients with confirmed diagnoses of anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM), anaplastic astrocytoma, greater than 90% resection, and nonmidline tumor location were characteristics predictive of an improved PFS. There was a difference in toxicity between the two chemotherapeutic regimens, with greater myelosuppression and hearing loss in the experimental regimen. Tumor recurrence occurred primarily within the primary tumor site. There is no benefit to the treatment of high-grade astrocytomas in children with eight-drugs-in-1-day chemotherapy compared with CCNU, vincristine, and prednisone. Extent of tumor resection and histopathologic diagnosis are significant prognostic variables. The overall outcome for children with high-grade astrocytomas remains poor.

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The effect of beta-adrenoceptor agonists and antagonists on gastric emptying in man.

1. The effect of beta-adrenoceptor agonists and antagonists on gastric emptying of a solid meal labelled with Indium113m was measured by a gamma camera in healthy volunteers or patients with hypertension. Each subject acted as his own control. 2 In ten subjects given isoprenaline (10 or 20 mg) sublingually 30 min before the meal, gastric emptying half-times were significantly prolonged (P less than 0.05). No effect was observed when isoprenaline was given immediately before the meal. 3 Salbutamol, 4 mg four times daily for 1 week also significantly prolonged gastric emptying in four subjects (P less than 0.05). 4 The effect of isoprenaline on gastric emptying was blocked by propranolol 40 mg four times daily for 1 week. 5 In ten subjects propranolol 40 mg four times daily alone for 1 week was found to significantly speed up gastric emptying (P less than 0.005), suggesting that emptying of the normal stomach is subject to some degree of adrenergic inhibition.

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Childhood asthma clusters and response to therapy in clinical trials.

Childhood asthma clusters, or subclasses, have been developed by computational methods without evaluation of clinical utility. To replicate and determine whether childhood asthma clusters previously identified computationally in the Severe Asthma Research Program (SARP) are associated with treatment responses in Childhood Asthma Research and Education (CARE) Network clinical trials. A cluster assignment model was determined by using SARP participant data. A total of 611 participants 6 to 18 years old from 3 CARE trials were assigned to SARP pediatric clusters. Primary and secondary outcomes were analyzed by cluster in each trial. CARE participants were assigned to SARP clusters with high accuracy. Baseline characteristics were similar between SARP and CARE children of the same cluster. Treatment response in CARE trials was generally similar across clusters. However, with the caveat of a smaller sample size, children in the early-onset/severe-lung function cluster had best response with fluticasone/salmeterol (64% vs 23% 2.5× fluticasone and 13% fluticasone/montelukast in the Best ADd-on Therapy Giving Effective Responses trial; P = .011) and children in the early-onset/comorbidity cluster had the least clinical efficacy to treatments (eg, -0.076% change in FEV1 in the Characterizing Response to Leukotriene Receptor Antagonist and Inhaled Corticosteroid trial). In this study, we replicated SARP pediatric asthma clusters by using a separate, large clinical trials network. Early-onset/severe-lung function and early-onset/comorbidity clusters were associated with differential and limited response to therapy, respectively. Further prospective study of therapeutic response by cluster could provide new insights into childhood asthma treatment.

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Beta-lactam versus beta- lactam/macrolide therapy in pediatric outpatient pneumonia.

The objective was to evaluate the comparative effectiveness of beta-lactam monotherapy and beta- lactam/macrolide combination therapy in the outpatient management of children with community-acquired pneumonia (CAP). This retrospective cohort study included children, ages 1-18 years, with CAP diagnosed between January 1, 2008 and January 31, 2010 during outpatient management in the Geisinger Health System. The primary exposure was receipt of beta-lactam monotherapy or beta-lactam/macrolide combination therapy. The primary outcome was treatment failure, defined as a follow-up visit within 14 days of diagnosis resulting in a change in antibiotic therapy. Logistic regression within a propensity score- restricted cohort was used to estimate the likelihood of treatment failure. Of 717 children in the analytical cohort, 570 (79.4%) received beta-lactam monotherapy and 147 (20.1%) received combination therapy. Of those who received combination therapy 58.2% of children were under 6 years of age. Treatment failure occurred in 55 (7.7%) children, including in 8.1% of monotherapy recipients, and 6.1% of combination therapy recipients. Treatment failure rates were highest in children 6-18 years receiving monotherapy (12.9%) and lowest in children 6-18 years receiving combination therapy (4.0%). Children 6-18 years of age who received combination therapy were less likely to fail treatment than those who received beta-lactam monotherapy (propensity-adjusted odds ratio, 0.51; 95% confidence interval, 0.28, 0.95). Children 6-18 years of age who received beta- lactam/macrolide combination therapy for CAP in the outpatient setting had lower odds of treatment failure compared with those who received beta-lactam monotherapy.

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Efficacy and safety of 1-week Helicobacter pylori eradication therapy and 7-week rebamipide treatment after endoscopic submucosal dissection of early gastric cancer in comparison with 8-week PPI standard treatment: a randomized, controlled, prospective, multicenter study.

Endoscopic submucosal dissection (ESD) has been developed for early gastric cancer (EGC). Helicobacter pylori eradication therapy has been reported to have a preventive effect against metachronous recurrence of EGC after ESD. However, the efficacy and safety of eradication therapy on ESD-induced ulcer healing are not clear. In a randomized control study, we compared the standard therapy (8-week proton pump inhibitor) and eradication therapy combined with subsequent treatment with 7-week rebamipide for healing ESD-induced ulcers. A multicenter, randomized, open-label study was conducted. In group A, patients received 20 mg of omeprazole for 56 days. In group B, patients received 40 mg of omeprazole, 1,500 mg of amoxicillin, and 800 mg of clarithromycin for 7 days, and then 300 mg of rebamipide for 49 days. The primary end point was to evaluate the scarring ratio. The scarring rate in group A was significantly higher than that in group B [85.0 % (34/40) vs. 56.8 % (21/37), P = 0.011]. The scarring rate of ulcers with an area ≥565.5 mm(2) in group A was significantly higher than that in group B [78.9 % (15/19) vs. 37.5 % (6/16), P = 0.018]. There was no significant difference between the groups in the scarring rate of smaller ulcers. No serious adverse events were observed in any of the patients in either group. H. pylori eradication therapy and 7-week rebamipide monotherapy were not superior to PPI monotherapy, but this combination therapy for smaller sized ulcers was an optimal therapeutic option for healing. Serious adverse events were not observed in either group.

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