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Patient perceptions of an inhaled asthma medication administered as an inhalation powder via the Diskus or as an inhalation aerosol via a metered-dose inhaler.

To evaluate patient preference, ease of use, and correctness of use of fluticasone propionate administered as inhalation powder via the Diskus (GlaxoSmithKline, Research Triangle Park, NC) and as inhalation aerosol administered via metered-dose inhaler (MDI). In 154 patients 12 years of age and older with asthma and a history of MDI use, the Diskus and the MDI were compared in a randomized, open-label, 7-week crossover study. In patients who had used both devices, more found the Diskus easier to use (59%) and preferred it overall (60%) compared with the MDI (P < or = 0.025). Ninety-eight percent (for the MDI) vs 91% (for the Diskus) of patients were able to correctly perform all the maneuvers necessary to use the devices correctly by either viewing a single demonstration and/or reading the instructions for use. Ninety-four percent of all patients found it easier to tell the number of residual doses with the Diskus (P < 0.001), and 59% of patients indicated that they would most likely request the Diskus from their physician (P = 0.025). Compliance was significantly better with the Diskus; 91.1% of patients used the Diskus as directed compared with 78.6% for the MDI (P = 0.013). In patients exposed to both devices, the majority preferred the Diskus and found it easier to use compared with the MDI. Ninety-one percent of patients used the Diskus correctly with minimal training, and when given a choice, most indicated they would likely request the Diskus from their physicians. Together, these data indicate a significant level of acceptance of the Diskus device in this patient population.

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Mycophenolate therapy in frequently relapsing minimal change disease that has failed cyclophosphamide therapy.

We report 4 consecutive adult patients with steroid-responsive frequently relapsing minimal change disease (MCD) who continued to experience relapse after 1 to 4 courses of cyclophosphamide therapy. Each patient then was administered mycophenolate mofetil (MMF) and prednisone in tapering doses. This therapy was followed by sustained remission and is being well tolerated. MMF is promising therapy in frequently relapsing MCD, even in those with disease that continued to relapse after cyclophosphamide therapy. A controlled clinical trial of MMF therapy in this disorder is warranted.

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Narcotic-Free Perioperative Total Knee Arthroplasty: Does the Periarticular Injection Medication Make a Difference?

Multimodal pain management strategies are critical in total knee arthroplasty (TKA). There has recently been a shift toward opioid sparing protocols, yet most publications continue to use narcotics in the perioperative period. Periarticular injections are a popular adjunct but studies regarding the optimal medications have high variability making it difficult to choose the optimal medication. The purpose of this study is to validate a perioperative, opioid-free protocol and compare two different periarticular injections without the variability in previous reports. A multimodal pain protocol was instituted that administered no narcotic medications in the perioperative period. Over 2 years, primary TKA patients were informally randomized to receive liposomal bupivacaine (LB), or a cocktail of medications (CO). A total of 189 patients were included: 101 patients in group LB and 88 patients in group CO. Postoperative opioid consumption, length of stay, and inpatient distance ambulated were compared across the two injection groups. In morphine milligram equivalents, group LB consumed a mean of 20.36 mg of oxycodone versus 23.18 mg in group CO (<i>p</i> = 0.543). For tramadol, group LB consumed 27.24 mg versus 28.69 mg in group CO (<i>p</i> = 0.714). Mean hospital stay was 1.70 days for group LB and 1.72 days for group CO (<i>p </i>= 0.811). Distance ambulated was 528.4ft for group LB and 499.8ft for group CO (<i>p</i> = 0.477). In the LB group, 50% of patients required no oxycodone, and 12% of them took neither oxycodone nor tramadol for pain. In the CO group, 40% declined oxycodone and 10% declined both oxycodone and tramadol. We successfully treated all patients without narcotic medications in the perioperative period. Although we saw trends for improvements in group LB, these were small and not clinically meaningful. It appears that both injections were effective. There is a significant cost difference and medications should be chosen based on surgeon preference and institutional needs.

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Comparison of analgesic effect of tramadol alone and a combination of tramadol and paracetamol in day-care laparoscopic surgery.

To compare the analgesic efficacy of tramadol alone (1.5 mg kg(-1)) with a tramadol (1 mg kg(-1)) and paracetamol combination in day-care laparoscopic patients. The analgesic efficacy of intravenous tramadol alone (1.5 mg kg(-1)) (group T) was compared with a combination of intravenous tramadol (1 mg kg(-1)) and oral paracetamol 1 g (group TP) in 60 day-care laparoscopic patients in a prospective randomized double-blind clinical trial in a tertiary care hospital. Intraoperative haemodynamic responses and postoperative visual analogue scores were used to assess the analgesic efficacy. Only one patient (in group T) received a single dose of rescue analgesia intraoperatively. The highest pain scores were recorded at 30 min postoperatively in both groups, and rescue analgesia was needed in eight patients in group T and in 13 patients in group TP (P = 0.08). The incidence of moderate-to-severe nausea was high in group T (P = 0.001). We conclude that reducing the dose of tramadol to 1 mg kg(-1) and combining it with paracetamol 1 g orally decreased the incidence of side effects of tramadol without reducing analgesic efficacy.

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Add-on angiotensin receptor blockade with maximized ACE inhibition.

Prolonged angiotensin-converting enzyme (ACE) inhibitor therapy leads to angiotensin I (Ang I) accumulation, which may "escape" ACE inhibition, generate Ang II, stimulate the Ang II subtype 1 (AT1) receptor, and exert deleterious renal effects in patients with chronic renal diseases. We tested the hypothesis that losartan therapy added to a background of chronic (>3 months) maximal ACE inhibitor therapy (lisinopril 40 mg q.d.) will result in additional Ang II antagonism in patients with proteinuric chronic renal failure with hypertension. Sixteen patients with proteinuric moderately advanced chronic renal failure completed a two-period, crossover, randomized controlled trial. Each period was one month with a two-week washout between periods. In one period, patients received lisinopril 40 mg q.d. along with other antihypertensive therapy, and in the other, losartan 50 mg q.d. was added to the previously mentioned regimen. Hemodynamic measurements included ambulatory blood pressure monitoring (ABP; Spacelabs 90207), glomerular filtration rate (GFR) with iothalamate clearances and cardiac outputs by acetylene helium rebreathing technique. Supine plasma renin activity and plasma aldosterone and 24-hour urine protein were measured in all patients. Twelve patients had diabetic nephropathy, and four had chronic glomerulonephritis. The mean age (+/- SD) was 53 +/- 9 years. The body mass index was 38 +/- 5.7 kg/m(2), and all except two patients were males. Seated cuff blood pressure was 156 +/- 18/88 +/- 12 mm Hg. The pulse rate was 77 +/- 11 per min, and the cardiac index was 2.9 +/- 0.5 L/min/m(2). Mean log 24-hour protein excretion/g creatinine or overall ABPs did not change. Mean placebo subtracted, losartan-attributable change in protein excretion was +1% (95% CI, -20% to 28%, P = 0.89). Similarly, the change in systolic ambulatory blood pressure (ABP) was 4.6 mm Hg (-5.7 to 14.9, P = 0.95), and diastolic ABP was 1.5 mm Hg (-4.5 to 7.6, P = 0.59). No change was seen in cardiac output. However, there was a mean 14% increase (95% CI, 3 to 26%, P = 0.017) in GFR attributable to losartan therapy. A concomitant fall in plasma renin activity by 32% was seen (95% CI, -15%, - 45%, P = 0.002). No hyperkalemia, hypotension, or acute renal failure occurred in the trial. These results were not attributable to sequence or carryover effects. Add-on losartan therapy did not improve proteinuria or ABP over one month of add on therapy. Improvement of GFR and fall in plasma renin activity suggest that renal hemodynamic and endocrine changes are more sensitive measures of AT1 receptor blockade. Whether add-on AT1 receptor blockade causes antiproteinuric effects or long-term renal protection requires larger and longer prospective, randomized controlled trials.

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[Prevention of cardiovascular complications in patients undergoing aortic-iliac reconstructions by correction of inflammation and endotoxemia].

There were presented the results of examination and treatment of 130 patients with atherosclerosis. Objective is to study the role of atorvastatin in correction of inflammation, endotoxemia and prevention of cardiovascular complications in patients with atherosclerosis undergoing aorto-iliac reconstruction. There were observed initial and postoperative activation of inflammation, endotoxemia in patients with multifocal atherosclerosis. We found that short-term therapy with atorvastatin 60 mg per day had a significant advantage over low-dose in correction of pre- and postoperative endogenous inflammation, endotoxemia and prevention of cardiac events after aorto-iliac reconstruction.

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Efficacy of metformin therapy in adolescent girls with androgen excess: relation to sex hormone-binding globulin and androgen receptor polymorphisms.

We studied the effects of the SHBG (TAAAA)(n) and androgen receptor gene [AR] (CAG)(n) allele length on endocrine-metabolic features and body composition (by dual-energy X-ray absorptiometry) before and after 1 year on metformin (850 mg/d) in 70 girls with polycystic ovary syndrome after precocious pubarche; allele lengths were assessed by polymerase chain reaction in both patients and in population control subjects (n = 107). Longer SHBG (TAAAA)(n) alleles (>8 repeats) were associated with more improvement of the lipid profile after 1 year on metformin, whereas longer AR (CAG)(n) alleles were related to more normalization of the androgen and lipid levels after therapy; longer alleles in both genes had an additive effect on the beneficial changes of SHBG, T, and lipids after metformin.

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Effects of intensive urate lowering therapy with febuxostat in comparison with allopurinol on pulse wave velocity in patients with gout and increased cardiovascular risk: the FORWARD study.

Hyperuricaemia and gout are strongly related with traditional cardiovascular risk factors and vascular damage. This study aimed to assess whether febuxostat and allopurinol could differently influence carotid-femoral pulse wave velocity (cfPWV) in patients with gout and elevated serum uric acid (SUA) levels. A multi-centre, multinational, phase IV, randomized, parallel-group, active-controlled, open-label trial with blind endpoints evaluation. One hundred and ninety-seven adults with gout and SUA levels ≥8 mg/dL were randomized to febuxostat or allopurinol in a 1:1 ratio for 36 weeks. The primary outcome was the comparison of the effects of febuxostat and allopurinol on changes in cfPWV. The mean cfPWV values at randomization and Week 36 were 8.69 and 9.00 m/s, respectively for subjects randomized to febuxostat and 9.02 and 9.05 m/s for subjects randomized to allopurinol. No statistically significant changes in cfPWV by treatment assignment were observed at any time point for any of the assessed parameters. More subjects who received febuxostat had serum urate concentrations ≤6 mg/dL following treatment (78.3% vs. 61.1% at Week 36, P = 0.0137). Treatment-emergent adverse events were reported by 51 (52.0%) patients randomized to febuxostat and 63 (62.5%) patients randomized to allopurinol. The majority of events were mild in both treatment groups and included gout flares and arthralgia. In patients with gout and elevated SUA levels the arterial stiffness remained stable both with febuxostat and allopurinol. Febuxostat was more effective and faster than allopurinol in achieving the SUA target. Both treatments were safe and well tolerated.

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Neuroactive steroids - new possibilities in the treatment of postpartum depression.

Pregnancy and postpartum period are associated with demanding physical and psychological changes that often lead to the development of psychological disorders. Depression is diagnosed in more than one in six women after childbirth. However, the prevalence of postpartum depression can be much higher because many cases are undiagnosed. In the case of severe depression, the patient is switched to pharmacological treatment, with sertraline being the most commonly used for this diagnosis. A new drug used in the treatment of postpartum depression is brexanolone, which was registered by FDA in 2019. The advantage over conventional therapy is its rapid onset of action. The structure represents the neuroactive steroid - allopregnanolone, which acts as an agonist on the &#948;-subunit of the GABA receptor and improves the symptoms of postpartum depression. In addition to the registered brexanolone, another steroidal drug, zuranolone, is available in the third phase of the clinical trial. The steroid structure was chemically altered to improve bioavailability and create an oral dosage form. Another synthetic analogue of neuroactive allopregnanolone, known as ganaxolone, did not show a significant reduction in depressive symptoms in the second phase of the clinical trial compared to placebo. Nevertheless, it has great therapeutic potential in the treatment of various types of epilepsy.

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Biotin Interference in Assays for Thyroid Hormones, Thyrotropin and Thyroglobulin.

<b><i>Background:</i></b> Biotin has been reported to interfere with several commonly used laboratory assays resulting in misleading values and possible erroneous diagnosis and treatment. This report describes a prospective study of possible biotin interference in thyroid-related laboratory assays, with a comparison of different commonly used assay platforms. <b><i>Materials and Methods:</i></b> Thirteen adult subjects (mean age 45 ± 13 years old) were administered biotin 10 mg/day for eight days. Blood specimens were collected at three time points on day 1 and on day 8 (baseline, two, and five hours after biotin ingestion). Thyrotropin (TSH), free triiodothyronine (fT3), free thyroxine (fT4), total triiodothyronine (TT3), total thyroxine (TT4), thyroxine binding globulin (TBG), and thyroglobulin (Tg) levels were analyzed with four different platforms: Abbott Architect, Roche Cobas 6000, Siemens IMMULITE 2000, and liquid chromatography with tandem mass spectrometry (LC-MS/MS). TSH, fT3, fT4, TT3, and TT4 were measured with Abbott Architect and Roche Cobas 6000. fT3, fT4, TT3, and TT4 were also measured by LC-MS/MS. Tg was measured by Siemens IMMULITE 2000. TBG was assessed with Siemens IMMULITE 2000. <b><i>Results:</i></b> Significant changes in TSH, fT4, and TT3 measurements were observed after biotin exposure when the Roche Cobas 6000 platform was used. Biotin intake resulted in a falsely lower Tg level when measurements were performed with Siemens IMMULITE 2000. At the time points examined, maximal biotin interference was observed two hours after biotin exposure both on day 1 and day 8. <b><i>Conclusions:</i></b> A daily dose of 10 mg was shown to interfere with specific assays for TSH, fT4, TT3, and Tg. Physicians must be aware of the potential risk of erroneous test results in subjects taking biotin supplements. Altered test results for TSH and Tg can be particularly problematic in patients requiring careful titration of levothyroxine therapy such as those with thyroid cancer.

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Hormonal responses to the 5-HT1A agonist buspirone in remitted endogenous depressive patients after long-term imipramine treatment.

The serotonin-1A (5-HT1A) receptor subtypes are considered as targets of a variety of antidepressant drugs. Previous studies have suggested different adaptive changes in pre- and post-synaptic 5-HT receptors in the brain after treatment with non-selective tricyclic antidepressants (TCA) and selective 5-HT re-uptake inhibitors (SSRIs). The present study aimed to investigate the adaptive effect of the TCA imipramine on the post-synaptic 5-HT1A receptor function in the hypothalamus. A longitudinal design was used in 14 patients with major depressive disorder (DSM-IV) with endogenous features (Newcastle Scale) in order to assess the functional status of post-synaptic 5-HT1A receptors before and after successful antidepressant treatment with imipramine. The effect of the 5-HT1A receptor agonist, buspirone, on ACTH, cortisol, and prolactine (PRL) plasma levels was used to assess the functional status of hypothalamic 5-HT1A receptors. A group of 15 concurrent normal subjects were used as control. Endogenous depressed patients in remission and currently receiving treatment with imipramine (mean length of treatment 145 days, SD=27) presented significantly lower buspirone responses to ACTH and cortisol than in the pre-treatment condition (Deltamax p< or =.05; AUC p<.001) and to ACTH in comparison with healthy controls (Deltamax p<.01; AUC p<.05). No significant differences were found between the post-treatment and pre-treatment PRL responses, or between patients in both conditions and controls; nevertheless, the PRL response in patients in remission and receiving treatment almost reached the values seen in controls. This study extends previous findings from our group using the SSRI citalopram as an antidepressant. Imipramine and citalopram induce similar changes in the endocrine response to buspirone in depressed patients. As the direction of change in ACTH-cortisol and PRL responses after treatment is the opposite, we cannot substantiate increases or decreases in the sensitivity of post-synaptic 5-HT1A receptors in the hypothalamus by long-term imipramine treatment and/or resolution of illness. Therefore, the hormonal changes may result from different or multiples unknown mechanisms.

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PET imaging of dopamine-D2 receptor internalization in schizophrenia.

Recent genetic, molecular and post-mortem studies suggest impaired dopamine (DA)-D2 receptor (D2R) trafficking in patients with schizophrenia (SZ). Imaging and preclinical studies have shown agonist-induced D2R internalization can be imaged with positron emission tomography (PET) using D2R radiotracers combined with psychostimulant challenge. This is feasible if radiotracer binding is measured when postchallenge DA levels have returned to baseline, following the initial competition phase between DA and radiotracer for binding to D2R. Here we used 'late-phase' imaging after challenge to test the hypothesis that impaired D2R internalization in SZ leads to blunted late-phase displacement, or a faster return to baseline, in patients compared with healthy controls (HCs). We imaged 10 patients with SZ and 9 HCs with PET and [¹¹C]raclopride at baseline and two times (3-5 and 6-10 h) following 0.5 mg kg^-1 dextroamphetamine. We measured binding potential relative to non-displaceable compartment (BP_ND) and derived percent reduction from baseline (ΔBP_ND) for each postamphetamine scan. To test the hypothesis that time course of return of striatal BP_ND to baseline differed between SZ and HCs, we implemented a linear model with ΔBP_ND as dependent variable, time after amphetamine as repeated measure and time after amphetamine and diagnostic group as fixed effects. Neither diagnostic group nor interaction of diagnostic group-by-time after amphetamine significantly affected striatal ΔBP_ND (F=1.38, P=0.26; F=0.51, P=0.61). These results show similar pattern of return of BP_ND to baseline as a function of time in patients with SZ and HC, suggesting that striatal D2R internalization as measured by our imaging paradigm is normal in patients with SZ.

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Microsatellite instability at D18S61 is associated with no regression of gastric mucosa-associated lymphoid tissue lymphoma after Helicobacter pylori eradication.

Recent studies have shown 70-80% of gastric low-grade mucosa-associated lymphoid tissue (MALT) lymphomas regressing in response to eradication of Helicobacter pylori (H. pylori). Genetic mechanism of regression of gastric MALT lymphoma after H. pylori eradication remains unclear. To clarify the issue, we evaluated microsatellite instability (MSI) at 12 microsatellite loci in 15 patients with gastric low-grade MALT lymphoma, who received eradication therapy of H. pylori. H. pylori infection was observed in all the patients. After eradication therapy of H. pylori, patients were observed for a median of 21 months (range, 6-49 months). Eradication was achieved in all the patients. Nine of the 15 (60%) patients showed complete regression (CR), 3 (20%) partial regression (PR), and 3 (20%) no change (NC). MSI was detected in 3 of the 15 (20%) patients with low-grade MALT lymphoma. Compared with response to eradication therapy of H. pylori, MSI was detected in 1 of the 12 (8%) CR and PR patients, and in 2 of the 3 (67%) NC patients. Especially, MSI at D18S61 was detected in 2 of the 3 (67%) NC patients but in none of the 12 CR and PR patients. There was a significant difference between frequency of MSI at D18S61 in NC patients and that in CR and PR patients (p<0.05). These data suggest that MSI at D18S61 may be associated with lack of regression of gastric MALT lymphoma after H. pylori eradication.

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One-week triple regime therapy consisting of pantoprazole, amoxicillin and clarithromycin for cure of Helicobacter pylori-associated upper gastrointestinal diseases.

This study was designed to determine the efficacy and safety of 1-week triple therapy regime consisting of pantoprazole, amoxicillin and clarithromycin in the cure of Helicobacter pylori infection leading to duodenal ulcer disease and/or gastritis. Sixty-one patients (47 males, 14 females with a mean age of 34 years) belonging to different ethnic groups suffering from H. pylori-associated duodenal ulcer and/or gastritis for an average of 2.46 years were recruited. Having satisfied primary selection criteria, patients received pantoprazole 40 mg b.i.d., clarithromycin 500 mg b.i.d. and amoxicillin 1,000 mg b.i.d. for 7 days. All medications were stopped there after H. pylori eradication was determined 4-6 weeks after treatment by a repeat endoscopy, a rapid urease test, H. pylori culture and histology assessment as indicators of cure. All three tests must be negative to consider the infection to have been successfully eradicated. Fifty-seven patients completed the efficacy analysis per protocol. Dramatic symptomatic improvement was noted in most patients immediately after stopping treatment and it was sustained at 6 weeks. At the end of the study, the healing rate of duodenal ulcers (complete re-epithelialization) following 1-week treatment only, as indicated above, and without any maintenance therapy was 66.7%, that of gastritis was 55.7%, and that of erosions was 64.3%. The overall eradication rate for H. pylori, however, was 93% (95% CI 83.0-98.1%). Furthermore, histologic evaluation revealed a remarkable resolution in the activity of gastritis in all the patients who had successful eradication of the infection.

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Selective AT1 receptor antagonism enhances sympathetically mediated vasoconstriction in man.

The vasoconstrictive action of angiotensin II (AII) is partly, sympathetically mediated and angiotensin-converting enzyme (ACE) inhibitors appear to exert a sympatholytic effect. We examine the effect of an orally administered, selective AT(1) receptor antagonist (losartan 50 mg) on sympathetically mediated vasoconstriction in healthy volunteers in an observer blind crossover study. Seven healthy, normotensive volunteers (21-32 years), were studied on two occasions at the end of each 6-week treatment period (losartan or placebo). Forearm blood flow (FABF) (ml/dl forearm/min) was measured by venous occlusion plethysmography during the application of lower body negative pressure (LBNP) (-20 cm H(2)O) and at the end of each incremental infusion of norepinephrine (60, 120, and 240 pmol/min). Comparison of blood flow changes was by repeated measures analysis of variance; P<0.05 was taken as statistically significant. Losartan did not alter blood pressure compared to placebo. It did significantly enhance LBNP-induced vasoconstriction in both the left arm compared to placebo (-36.6+/-3.4 vs -23.5+/-3.3%; P=0.017) and the right arm compared to placebo (-39.5+/-3.8 vs -21.0+/-3.6%; P=0.005). The FABF response to all doses of infused norepinephrine (60, 120, and 240 pmol/min) was also enhanced by losartan compared to placebo (-35.0+/-2.7 vs -18.2+/-6.0%; -43.6+/-4.3 vs -28.6+/-5.8%, and -53.9+/-3.2 vs -42.5+/-6.8%; P=0.057, respectively. Losartan enhances locally mediated sympathetic vasoconstriction in the forearm circulation of man, probably through its effect on circulating AII concentrations and we postulate that the adrenergic sympathetic constrictor action of AII is not mediated by the AT(1) receptor or is surmountable at this receptor.

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Comparison of the pharmacokinetics and pharmacodynamics of torasemide and furosemide in healthy volunteers.

The pharmacodynamic effects and the pharmacokinetic parameters of torasemide (1-isopropyl-3- ([4-(3-methyl-phenylamino)pyridine]-3-sulfonyl)urea) 20 mg and furosemide 40 mg were compared after oral and intravenous administration in 6 healthy volunteers. The plasma elimination half-life for i.v. and oral torasemide was 2.2 h and 2.8 h, its bioavailability after oral administration was 91%, about 25% of the total body clearance was due to renal excretion both after iv. or oral application. For furosemide, a plasma elimination half-life of 0.6 h for i.v. and 0.8 h for oral application was found. The bioavailability was 40%, and about 62% of the drug was excreted via the kidney. Both drugs produced a similar diuretic and natriuretic effect. However, torasemide showed an increased duration of action compared to furosemide and a higher relation between urinary Na and K excretion, both after i.v. and oral administration, suggesting less loss of potassium after To. Both agents were well tolerated.

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Increased risk of paclitaxel-induced peripheral neuropathy in patients using clopidogrel: a retrospective pilot study.

Paclitaxel-induced peripheral neuropathy (PIPN) is one of the serious adverse events associated with paclitaxel-based cancer treatments. A recent case study showed that the antiplatelet agent clopidogrel inhibits paclitaxel metabolism via cytochrome P450 (CYP) 2C8, resulting in severe PIPN. The aim of this study was to determine the impact of clopidogrel as a risk factor for the development of PIPN, using a retrospective cohort study. Data from paclitaxel-treated patients with or without clopidogrel and low-dose aspirin treatment were retrieved from medical charts. A total of 161 adult patients were included in this study: 135 were controls, 9 were clopidogrel-treated and 17 were aspirin-treated. The clopidogrel group had a greater proportion of males and a higher rate of comorbidities, such as diabetes mellitus and dyslipidemia, than the control group. However, patient characteristics were similar between the clopidogrel and aspirin groups. Severe PIPN was diagnosed in 3 (2.2%) and 2 (22.2%) patients in the control and clopidogrel groups, respectively (odds ratio: 12.0; p = 0.031). No patients in the aspirin group presented with severe neuropathy. These pilot data suggest that concomitant treatment with clopidogrel leads to a greater risk of PIPN. The avoidance of concomitant clopidogrel use may be effective in reducing clopidogrel-associated PIPN.

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Dose-intensive melphalan with stem cell support (MEL100) is superior to standard treatment in elderly myeloma patients.

A clinical relationship between dose-intensity of melphalan and response rate has been demonstrated in multiple myeloma. Promising results have been reported after 200 mg/m(2) melphalan, especially in younger patients. It is uncertain whether 100 mg/m(2) melphalan (MEL100) can offer similar results in older patients. To address this issue, patients were treated with 2 or 3 MEL100 courses followed by stem cell support. Seventy-one patients (median age, 64 years) entered the protocol at diagnosis. Their clinical outcome was compared with that of 71 pair mates (median age, 64 years) selected from patients treated at diagnosis with oral melphalan and prednisone (MP) and matched for age and beta2-microglobulin. Complete remission was 47% after MEL100 and 5% after MP. Median event-free survival was 34 months in the MEL100 group and 17.7 months in the MP group (P <.001). Median overall survival was 56+ months for MEL100 and 48 months for MP (P <.01). In a multivariate analysis, beta2-microglobulin levels and MEL100 were independent risk factors associated with outcome: superior event-free and overall survival were observed in patients presenting low beta2-microglobulin levels at diagnosis and receiving MEL100 as induction regimen. In conclusion, MEL100 was superior to MP in terms of complete remission rate, event-free survival, and overall survival.

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Longitudinal Neurocognitive Effects of Combined Electroconvulsive Therapy (ECT) and Pharmacotherapy in Major Depressive Disorder in Older Adults: Phase 2 of the PRIDE Study.

There is limited information regarding neurocognitive outcomes of right unilateral ultrabrief pulse width electroconvulsive therapy (RUL-UB ECT) combined with pharmacotherapy in older adults with major depressive disorder. We report longitudinal neurocognitive outcomes from Phase 2 of the Prolonging Remission in Depressed Elderly (PRIDE) study. After achieving remission with RUL-UB ECT and venlafaxine, older adults (≥60 years old) were randomized to receive symptom-titrated, algorithm-based longitudinal ECT (STABLE) plus pharmacotherapy (venlafaxine and lithium) or pharmacotherapy-only. A comprehensive neuropsychological battery was administered at baseline and throughout the 6-month treatment period. Statistical significance was defined as a p-value of less than 0.05 (two-sided test). With the exception of processing speed, there was statistically significant improvement across most neurocognitive measures from baseline to 6-month follow-up. There were no significant differences between the two treatment groups at 6 months on measures of psychomotor processing speed, autobiographical memory consistency, short-term and long-term verbal memory, phonemic fluency, inhibition, and complex visual scanning and cognitive flexibility. To our knowledge, this is the first report of neurocognitive outcomes over a 6-month period of an acute course of RUL-UB ECT followed by one of 2 strategies to prolong remission in older adults with major depression. Neurocognitive outcome did not differ between STABLE plus pharmacotherapy versus pharmacotherapy alone over the 6-month continuation treatment phase. These findings support the safety of RUL-UB ECT in combination with pharmacotherapy in the prolonging of remission in late-life depression.

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Antibacterial resistance and the success of tailored triple therapy in Helicobacter pylori strains isolated from Slovenian children.

Primary Helicobacter pylori (H. pylori) infection occurs predominantly in childhood. Antimicrobial resistance is the leading cause for H. pylori eradication failure. The aims of this study were (i) to establish for the first time the antimicrobial resistance of H. pylori strains in infected Slovenian children not previously treated for H. pylori infection and (ii) to evaluate the effectiveness of tailored triple therapy, assuming that eradication rate with tailored triple therapy will be >90%. Data on all treatment-naive children 1-18 years old and treated for H. pylori infection according to susceptibility testing were retrospectively analyzed. All relevant clinical information and demographical information were retrospectively collected from the hospital information systems and/or patients' medical documentation. The inclusion criteria were met by 107 children (64.5% girls) with a median age of 12.0 years (range 2.0-17.6 years). Primary antimicrobial resistance rates of H. pylori were 1.0% to amoxicillin (AMO), 23.4% to clarithromycin (CLA), 20.2% to metronidazole (MET), 2.8% to levofloxacin (LEV), and 0.0% to tetracycline (TET). Dual resistances were detected to CLA and MET in 11.5% (n=12) of strains, to CLA and LEV in 2.8% (n=3), and to MET and LEV in 2.9% (n=3). Results of treatment success were available for 71 patients (66.2% girls). Eradication of H. pylori was evaluated using the 13C-urea breath test, monoclonal stool antigen test or in some cases with repeated upper GI endoscopy with histology and cultivation/molecular tests. Eradication was achieved in 61 of 71 (85.9%) patients. The primary resistance rates of H. pylori to CLA and MET in Slovenia are high. Our data strongly support the fact that in countries with high prevalence of resistant H. pylori strains susceptibility testing and tailored therapy is essential.

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Idarubicin, cytarabine, and pravastatin as induction therapy for untreated acute myeloid leukemia and high-risk myelodysplastic syndrome.

Previous studies suggest that idarubicin/cytarabine(ara-C)/pravastatin (IAP) is an active salvage regimen for patients with AML. We therefore investigated this regimen in patients with newly-diagnosed AML or MDS (≥10% blasts). Patients were eligible if the anticipated treatment-related mortality (TRM) was <10%. Patients received pravastatin (1,280 mg/day po; days 1-8), cytarabine (1.5 g/m(2) /day; days 4-7), and idarubicin (12 mg/m(2) /day, days 4-6). Up to 3 cycles of consolidation with a shortened course was permitted. The primary endpoints were "good CR" rate (CR on day 35 without minimal residual disease) and TRM in the first 28 days. The study was to stop if after each cohort of 5 patients (a) the Bayesian posterior probability was < 5% that the true "good CR rate" was ≥ 70% or (b) the posterior probability was >25% that the TRM rate was ≥5%. Twenty-four patients were included. Conventional CR was achieved in 15 (63%) patients but only 12 (50%) achieved "good CR". 4 of 12 (33%) patients with "good CR" relapsed at median of 16 weeks (10.5-19). Five (21%) patients had refractory disease. Survival probability at 1 year was 72% (48.7-64). Two (8.3%) patients died within 28 days from multiorgan failure. The most common grade 3-4 adverse effects were febrile neutropenia (75%) and diarrhea (25%). Based on the stopping rules accrual ceased after entry of these 24 patients. IAP did not meet the predefined efficacy criteria for success. Therefore, we would not recommend this regimen for phase three testing in this patient subset.

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Additive effect of pronase on the efficacy of eradication therapy against Helicobacter pylori.

Helicobacter pylori (H. pylori) colonizes not only the surface of the surface mucous cells but also the surface mucous gel layer (SMGL). Thus, we examined the possible value of pronase, a mucolytic agent, as a potential eradication therapy. One hundred and thirty-five patients were randomly assigned to two treatment groups. Sixty-eight patients received 30 mg of lansoprazole once daily, 500 mg of amoxicillin and 250 mg of metronidazole thrice daily for 2 weeks (LAM group), while the other 67 patients received the same dosage of those agents plus 18,000 tyrosine units of pronase thrice daily for 2 weeks (LAMP group). Eradication was assessed 4-6 weeks after treatment by immunohistochemical tests and cultures. We also determined the in vitro activity of pronase against H. pylori, and evaluated the synergistic effects between pronase and the other three drugs. To investigate the effect of pronase on the structure of the SMGL, surgically removed stomachs obtained from patients who had taken pronase were examined histopathologically. The cure rates for H. pylori infection in the LAMP group were significantly higher than those in the LAM group (intention to treat analysis: 94.0 vs. 76.5%, p =.0041). Pronase exhibited no antibacterial activity against H. pylori., and no in vitro synergistic effects were observed. In the patients who took pronase before surgery, the SMGL was thinner than in the patients who did not take pronase, and the structure of the SMGL was markedly disrupted. Pronase has an additive effect in curing H. pylori infection. Pronase has no apparent in vitro activity against H. pylori, but may improve the local delivery of antibiotics by virtue of its removal and disruption of the SMGL.

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A 10-years retrospective study on Severe Cutaneous Adverse Reactions (SCARs) in a tertiary hospital in Penang, Malaysia.

Severe cutaneous adverse drug reactions (SCARs) are not uncommon and potentially lifethreatening. Our objective is to study the patient characteristics, the pattern of implicated drugs and treatment outcome among patients with SCARs. A 10-year retrospective analysis of SCARs cases in Penang General Hospital was carried out from January 2006 to December 2015. Data collection is based on the Malaysian Adverse Drug Reactions Advisory Committee registry and dermatology clinic records. A total of 189 cases of SCARs were encountered (F:M ratio; 1.2:1.0; mean age of 45 year). The commonest manifestation was Stevens-Johnson Syndrome [SJS] (55.0%), followed by toxic epidermal necrolysis [TEN] (23.8%), drug rash with eosinophilia and systemic symptoms [DRESS] (12.7%), acute generalised exanthematous pustulosis [AGEP] (4.8%), SJS/TEN overlap syndrome (2.6%) and generalised bullous fixed drug eruptions [GBFDE] (1.1%). Mean time to onset for TEN/SJS/Overlap syndrome was 10.5±13 days; AGEP, three days; GBFDE, 2.5±0.7 days, and DRESS, 29.4±5.7 days. The most common drugs implicated were antibiotics (33.3%), followed by allopurinol (18.9%) and anticonvulsant (18.4%). Out of 154 cases of SJS/TEN/overlap syndrome, allopurinol was the commonest causative agents (20.1%). In DRESS, allopurinol accounts for 45.8% of the cases. The mortality rate in SJS, TEN and DRESS were 1.9%, 13.3% and 12.5% respectively. No mortality was observed in AGEP and GBFDE. The commonest manifestations of SCARs in our setting were SJS, TEN and DRESS. Allopurinol was the most common culprit. Thus, judicious allopurinol use is advocated and pre-emptive genetic screening for HLAB *5801 should be considered.

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Small for gestational age is a risk factor for the development of delayed thyrotropin elevation in infants weighing less than 2000 g.

Delayed thyrotropin (TSH) elevation (dTSHe) is common in low birthweight infants. We aimed to clarify the risk factors for the development of dTSHe in infants weighing <2000 g at birth. According to Japanese guidelines, infants with birthweight <2000 g underwent second capillary TSH screening within 30 days, either at 1 month of age; or when weight reached 2.5 kg; or at discharge. dTSHe was defined as TSH >20 mIU/L by venous sampling following a normal result (<15 mIU/L) at first screening aged 4-6 days. For each infant who developed dTHSe three babies without dTSHe were selected and matched for gestational age and birth year. Small for gestational age (SGA) was defined as a birthweight <10th percentile for the gestational age and sex. A multivariate analysis was performed to identify risk factors for the development of dTSHe. Among the 911 study infants, 17 infants (1.9%) had dTSHe. The median (range) birthweight in the dTSHe group (796 [388-1912] g) was significantly smaller than the comparison group (961 [408-1981] g) (P = 0.04). The number (%) of SGA infants was significantly higher in the dTSHe group (12 [71%]) than in the comparison group (13 [25%]) (P = 0.001). The multivariate analysis revealed that SGA was an independent risk factor for the development of dTSHe (adjusted odds ratio, 9.0; 95% confidence interval, 2.5-32.8; P = 0.001). Small for gestational age is an independent risk factor for the development of dTSHe in infants with a birthweight <2000 g. The influence of prematurity, a matching criterion for this study, on dTSHe requires additional study.

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Association of increased plasma cardiotrophin-1 with inappropriate left ventricular mass in essential hypertension.

Inappropriate left ventricular mass is present when the value of left ventricular mass exceeds individual needs to compensate hemodynamic load imposed by increased blood pressure. The goal of this study was to investigate whether plasma concentration of cardiotrophin-1, a cytokine that induces exaggerated hypertrophy in cardiomyocytes with hypertensive phenotype, is related to inappropriate left ventricular mass in patients with essential hypertension. The study was performed in 118 patients with never-treated hypertension and without prevalent cardiac disease. The left ventricular mass prediction from stroke work (systolic blood pressurexDoppler stroke volume), sex, and height (in meters(2.7)) was derived. An observed left ventricular mass/predicted left ventricular mass value >128% defined inappropriate left ventricular mass. Plasma cardiotrophin-1 was measured by an enzyme-linked immunosorbent assay. The studies were repeated in a group of 45 patients after 1 year of antihypertensive treatment. At baseline 67 and 51 patients presented with appropriate and inappropriate left ventricular mass, respectively. Plasma cardiotrophin-1 was higher (P<0.001) in patients with inappropriate mass than in patients with appropriate mass and normotensive controls. A direct correlation was found between cardiotrophin-1 and observed left ventricular mass/predicted left ventricular mass ratio (r=0.330, P<0.001) in all hypertensive patients. After treatment, plasma cardiotrophin-1 decreased and increased in patients in which inappropriate left ventricular mass regressed and persisted, respectively, despite a similar reduction of blood pressure in the 2 subgroups of patients. Albeit descriptive in nature, these results suggest the hypothesis that an excess of cardiotrophin-1 may contribute to inappropriate left ventricular growth in hypertensive patients.

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Pulse-wave analysis: clinical evaluation of a noninvasive, widely applicable method for assessing endothelial function.

Current methods for assessing vasomotor endothelial function are impractical for use in large studies. We tested the hypothesis that pulse-wave analysis (PWA) combined with provocative pharmacological testing might provide an alternative method. Radial artery waveforms were recorded and augmentation index (AIx) was calculated from derived aortic waveforms. Thirteen subjects received sublingual nitroglycerin (NTG), inhaled albuterol, or placebo. Twelve subjects received NTG, albuterol, and placebo separately during an infusion of N(G)-monomethyl-L-arginine (LNMMA) or norepinephrine. Twenty-seven hypercholesterolemic subjects and 27 controls received NTG followed by albuterol. Endothelial function was assessed by PWA and forearm blood flow in 27 subjects. Albuterol and NTG both significantly and repeatably reduced AIx (P<0.001). Only the response to albuterol was inhibited by LNMMA (-9.8+/-5.5% vs -4.7+/-2.7%; P=0.02). Baseline AIx was higher in the hypercholesterolemic subjects, who exhibited a reduced response to albuterol (P=0.02) but not to NTG when compared with matched controls. The responses to albuterol and acetylcholine were correlated (r=0.5, P=0.02). Consistent with an endothelium-dependent effect, the response to albuterol was substantially inhibited by LNMMA. Importantly, the response to albuterol was reduced in subjects with hypercholesterolemia and was correlated to that of intra-arterial acetylcholine. This methodology provides a simple, repeatable, noninvasive means of assessing endothelial function in vivo.

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Steroid sparing effect of intravenous immunoglobulin therapy in patients with pemphigus foliaceus.

Pemphigus foliaceus (PF) is a rare autoimmune cutaneous blistering disease, with only skin involvement. Systemic corticosteroids and immunosuppressive agents are the mainstay of therapy. However, some patients develop multiple side effects to systemic corticosteroids, when they are used in high doses over prolonged periods. In some patients, immunosuppressive agents are not effective or contraindicated. In such patients, alternative treatment modalities are needed. The purpose of this study is to demonstrate the use of intravenous immunoglobulin (IVIg) therapy in seven patients with severe PF, who were steroid-dependent. The following information was recorded in each patient, before and after IVIg therapy initiation: total dose and total duration of prednisone therapy, and number of relapses. In addition, the highest dose and side effects of prednisone therapy, and duration of observation were documented. After the initiation of IVIg treatment, doses of systemic corticosteroids were gradually reduced and eventually discontinued over a mean period of 2.8 months. Thereafter, IVIg was used as monotherapy. A statistically significant difference was noted between pre-IVIg therapy and after the initiation of IVIg therapy in the total dose (p = 0.005), and total duration of prednisone treatment (p = 0.02), and the number of relapses (p = 0.002). In all seven patients, IVIg produced an effective clinical response and demonstrated a steroid-sparing effect. In patients with PF, who are steroid-dependent and in whom use of conventional immunosuppressive agents is contraindicated, IVIg appears a safe and effective agent to induce and maintain a prolonged clinical remission.

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A Randomized, Double-Blind, Active- and Placebo-Controlled Efficacy and Safety Study of Arhalofenate for Reducing Flare in Patients With Gout.

Arhalofenate is a novel antiinflammatory uricosuric agent. The objective of this study was to evaluate its antiflare activity in patients with gout. This was a 12-week, randomized, double-blind, controlled phase IIb study. Eligible patients had had ≥3 flares of gout during the previous year, had discontinued urate-lowering therapy and colchicine, and had a serum uric acid (UA) level of 7.5-12 mg/dl. Patients were randomly assigned at a 2:2:2:2:1 ratio to receive 600 mg arhalofenate, 800 mg arhalofenate, 300 mg allopurinol, 300 mg allopurinol plus 0.6 mg colchicine, or placebo once a day. The primary outcome measure was the flare incidence (number of flares divided by time of exposure). The serum UA level was a secondary outcome measure. A total of 239 gout patients were randomized and took at least 1 dose of study medication. The primary outcome measure comparing flare incidence between 800 mg arhalofenate and 300 mg allopurinol was achieved, with a 46% decrease in the 800 mg arhalofenate group (0.66 versus 1.24; P = 0.0056). Treatment with 800 mg arhalofenate was also significantly better than placebo (P = 0.049) and not significantly different from treatment with 300 mg allopurinol plus 0.6 mg colchicine (P = 0.091). Mean changes in serum UA level were -12.5% with 600 mg arhalofenate and -16.5% with 800 mg arhalofenate (P = 0.001 and P = 0.0001, respectively, versus -0.9% with placebo). There were no meaningful differences in adverse events (AEs) between groups, and there were no serious AEs related to arhalofenate. Urinary calculus occurred in 1 patient receiving 300 mg allopurinol. No abnormal serum creatinine values >1.5-fold the baseline value were observed in the arhalofenate-treated groups. Arhalofenate at a dosage of 800 mg decreased gout flares significantly compared to allopurinol at a dosage of 300 mg. Arhalofenate was well tolerated and appeared safe. Arhalofenate is the first urate-lowering antiflare therapy.

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Newly initiated opioid treatment and the risk of fall-related injuries. A nationwide, register-based, case-crossover study in Sweden.

There is growing epidemiological evidence that opioids may increase the risk of unintentional injuries and it is plausible that the time of initiation is most critical in that respect. Studies on fall-related injuries remain few, limited and mostly focused on specific groups of elderly patients. The objective of this study was to assess the short-term effects of newly prescribed opioids on the risk of fall-related injuries in the general adult population. A case-crossover design was applied on national register data linking, at the individual level, fall-injury information involving adults aged 18 years and above identified in the Swedish National Inpatient Register (during the period 1 May 2006 to 31 December 2009) and dispensed drugs from the Swedish Prescribed Drug Register (n=167,257 cases with a first fall-related injury). All types of opioid substances were considered, classified according to the Anatomical Therapeutic Chemical (ATC) classification system. We investigated newly dispensed opioids 28 days preceding the injury, compared with an earlier, and equally long, control period following a 3-month washout period. Conditional logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI). The analyses were also conducted stratified by age group, by type of fall and for each period of 1 week during the 28-day period. From among the fall-injured patients, 7,450 patients (4.5%) had a new opioid dispensation within 28 days prior to the injury, of which the most frequent types were tramadol (2.0%) and codeine (1.1%). Consistently increased risks of fall-related injuries associated with a new prescription of any opioid were found and they were most pronounced among young adults, 18-29 years of age (OR, 7.17; 95% CI 5.04-10.2). The closer the dispensation date to the injury, the higher the odds: an OR of 5.14 (95% CI 4.76-5.55) during the first week of opioid treatment and 1.23 (95% CI 1.10-1.38) for the fourth week. Of the documented falls, the risk was most pronounced for falls from 'another, high level' (OR, 5.33; 95% CI 3.99-7.10). Newly prescribed opioids may trigger injurious falls. The effect lowers over time and is less pronounced with increasing age. The risk is also higher for fall from height.

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Rationale and design of the AXIOMATIC-SSP phase II trial: Antithrombotic treatment with factor XIa inhibition to Optimize Management of Acute Thromboembolic events for Secondary Stroke Prevention.

Individuals with ischemic stroke or transient ischemic attack (TIA) have a high early risk of ischemic stroke despite dual antiplatelet therapy. The risk of ischemic stroke, and associated disability, represents a significant unmet clinical need. Genetic variants resulting in reduced factor XI levels are associated with reduced risk for ischemic stroke but are not associated with increased intracranial bleeding. Milvexian is an oral small-molecule inhibitor of FXIa that binds activated factor XI with high affinity and selectivity and may reduce the risk of stroke when added to antiplatelet drugs without significant bleeding. We aimed to evaluate the dose-response relationship of milvexian in participants treated with dual antiplatelets. We began a phase II, double-blinded, randomized, placebo-controlled trial at 367 sites in 2019. Participants (N = 2366) with ischemic stroke (National Institutes of Health Stroke Scale score ≤7) or high-risk TIA (ABCD² score ≥6) were randomized to 1 of 5 doses of milvexian or placebo for 90 days. Participants also received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg for 90 days. The efficacy endpoint was the composite of ischemic stroke or incident infarct on magnetic resonance imaging. Major bleeding, defined as type 3 or 5 bleeding according to the Bleeding Academic Research Consortium, was the safety endpoint. Participant follow-up will end in 2022. The AXIOMATIC-SSP trial will evaluate the dose-response of milvexian for ischemic stroke occurrence in participants with ischemic stroke or TIA.

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[Pharmacokinetic study on aspoxicillin transfer into pulmonary and tracheal tissues].

Each of 36 patients who underwent tracheotomy for removal of malignant or benign tumors or for treatment of pneumothorax was infused with 2 g of aspoxicillin (ASPC, Doyle injection) intravenously over 1-hour period. ASPC concentrations determined at 1 postoperative time-point in tissues of the lung and trachea and in serum of each patient were analyzed pharmacokinetically to elucidate the transfer of ASPC to the thoracic tissues. The preventive effect of ASPC against postoperative infections was also investigated in 39 tracheotomy patients. 1. The analysis of ASPC concentrations in 36 patients with tracheotomy gave the following results; 1) The peak blood level (about 80 micrograms/ml) was attained at the end of infusion. The serum level then decreased with time to below about 10 micrograms/ml at 6 hours after the start of infusion, with an elimination half-life of about 1.4 hours, which was comparable to that in healthy adults. 2) Peak levels in the lung and tracheal tissues were achieved at about 30 minutes after the start of infusion, at levels of about 30 and 40 micrograms/g, respectively, which decreased to about 5 micrograms/g in both tissues at 6 hours after the start of infusion. 2. Thirty nine patients who were treated with ASPC before operation were examined for the preventive effect of ASPC against postoperative infections for 1 week after operation. No postoperative infection was noted in any patients and ASPC was found to be useful for prevention of postoperative infections. 3. No side effects or abnormal laboratory findings were noted in any patients. Based on the results of the transfer into the tissues of respiratory organs and preventive effect against postoperative infections, we have concluded that ASPC is useful for prevention of infections after thoracic operation.

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Angiotensin II receptor antagonists in heart failure: rationale and design of the evaluation of losartan in the elderly (ELITE) trial.

Angiotensin-converting enzyme inhibitors (ACE-I) have been proven to be effective in reducing morbidity and mortality in patients with heart failure or post-myocardial infarction left ventricular dysfunction. Despite evidence from several large-scale randomized trials, the use of ACE-I in patients with heart failure remains relatively low. In part, the failure to achieve more widespread use of ACE-I in patients with heart failure may be due to physician's perceptions of the side effects associated with ACE-I, such as angioedema, renal dysfunction, cough, and hypotension. Many of these side effects are thought to be due to ACE-I-induced bradykinin accumulation. It is possible to inhibit the effect of angiotensin II without increasing bradykinin levels using an angiotensin II type I blocking agent such as losartan. How effective losartan is compared with an ACE-I is uncertain, however. Some of the beneficial effects of ACE-I have been attributed to bradykinin accumulation, and therefore ACE-I might have an advantage compared with an angiotensin II type I receptor antagonist such as losartan. On the other hand, angiotensin II may be produced by non-ACE-I-dependent mechanisms, which would suggest that an angiotensin II type I receptor blocking agent would be advantageous. To determine the relative safety and efficacy of an ACE-I, which results in bradykinin accumulation and inhibitors of angiotensin II, versus an angiotensin II type I receptor blocking agent, which does not result in bradykinin accumulation, we have begun the Evaluation of Losartan In The Elderly (ELITE) trial, which will compare the safety and efficacy of captopril and losartan in elderly patients with heart failure.

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Diuresis and pulmonary function in premature infants with respiratory distress syndrome.

A prospective study of 99 premature infants with severe respiratory distress syndrome who were randomly assigned to receive diuretic treatment with either furosemide or chlorothiazide was analyzed to examine the relationship of diuretic administration and diuresis to survival and to the duration and degree of mechanical ventilatory support. Subjects were given a diuretic, usually beginning on the second or third day of life, if they had not initiated the expected spontaneous diuresis and did not show pulmonary improvement. Infants given furosemide experienced a postnatal weight loss nearly identical to that in infants who were deemed not to need a diuretic; infants given chlorothiazide lost weight more slowly and had significantly greater body weight on postnatal days 4 and 5. Four factors were independently correlated with improved survival: furosemide usage, high birth weight, low initial mean airway pressure, and the absence of intraventricular hemorrhage. Ventilator mean airway pressure on the seventh day of life and duration of mechanical ventilation were both related to diuresis. These data provide additional evidence for the importance of water homeostasis in determining the course of respiratory distress syndrome in premature infants and indicate that furosemide administration is beneficial when spontaneous diuresis does not occur. Furosemide may be particularly effective if combined with early closure of the ductus arteriosus.

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[A CHOP-21 course efficacy in therapy of diffuse large B-cell lymphosarcoma].

To examine efficacy of polychemotherapy (PCT) CHOP-21 in patients with diffuse large B-cell lymphosarcoma (DLBCL). Fifty-five DLBCL patients received first-line therapy according to CHOP-21 program in 1996-2004. The diagnosis was made by WHO criteria. Initially, 37 patients had lymph node lesions, 18--nonlymphatic lesions. Complete remissions were achieved in 49% (56.7% in nodal lesions, 33.3% in extranodal ones). Overall 5-year survival was 35%, event-free--25%, for patients with nodal lesions--36 and 32%, respectively, extranodal lesions--35 and 22%, respectively. Overall 5-year and event-free survival in patients with local lesions was 85 and 75%, generalized--25 and 20%, respectively. In patients with involvement of the gastrointestinal tract 3-year overall and event-free survival reached 50 and 45%. Event-free survival was not seen in patients with extranodal lesions of other locations in overall 3-year survival 45%. PCT program CHOP-21 was effective in DLBCL patients with local nodular lesions except cases with large-size tumors, invasion in the adjacent organs and tissues and isolated gastric lesion.

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Density of Helicobacter pylori may affect the efficacy of eradication therapy and ulcer healing in patients with active duodenal ulcers.

To evaluate the association of pre-treatment Helicobacter pylori (H. pylori) density with bacterial eradication and ulcer healing rates in patients with active duodenal ulcer. One hundred and four consecutive duodenal ulcer outpatients with H. pylori infection ascertained by gastric histopathology and (13)C-urea breath test (UBT) were enrolled in this study. H. pylori density was graded histologically according to the Sydney system (normal, mild, moderate, and marked). In each patient, lansoprazole (30 mg b.i.d.), clarithromycin (500 mg b.i.d.) and amoxicillin (1 g b.i.d.) were used for 1 week, then 30 mg lansoprazole once daily was continued for an additional 3 weeks. Follow-up endoscopy was performed at 4 weeks after completion of the therapy, and UBT was done at 4 and 8 weeks after completion of the therapy. The H. pylori eradication rates were 88.9 %/100.0 %, 94.3 %/100.0 %, and 69.7 %/85.2 %; and the ulcer healing rates were 88.9 %/100.0 %, 94.3 %/100.0 %, and 63.6 %/77.8 % (intention-to-treat/per protocol analysis) in the mild, moderate, and marked H. pylori density groups, respectively. The association of pretreatment H. pylori density with the eradication rate and ulcer healing rate was both statistically significant (P=0.013/0.006 and 0.002/<0.001, respectively; using results of intention-to-treat/per protocol analysis). Intragastric bacterial load may affect both the outcome of eradication treatment and ulcer healing in patients with active duodenal ulcer disease.

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Fluoxetine-maintained obese humans: effect on food intake and body weight.

The effects of fluoxetine on food intake, body weight, and mood of obese individuals was examined in a 16-week inpatient/outpatient study. Six male and eight female obese volunteers began the study (four male and five females completed all phases of the study). They lived in a residential laboratory during three one-week inpatient periods separated by a 5-week and an 8-week outpatient period. Following an initial 4-day placebo baseline, participants were maintained on fluoxetine (60 mg/day) for the remainder of the study. Food intake parameters (total daily energy intake, macronutrient intake, mean number of eating bouts, interbout interval), body weight, subjective effects, and task performance were measured several times during the day during inpatient periods; food intake questionnaires were completed daily during the outpatient periods. Fluoxetine significantly reduced daily energy intake derived from fat, carbohydrate, and protein by decreasing the mean number of eating bouts per day throughout the study. No other food intake parameter was affected. Body weight was significantly reduced after 7 weeks, but not after 16 weeks of daily fluoxetine administration. These results indicate that fluoxetine reduced food intake for at least 16 weeks in nondepressed obese individuals without specifically affecting carbohydrate intake. Weight that was lost during the first few weeks of daily fluoxetine administration was subsequently regained even though food intake remained reduced. Therefore, fluoxetine maintenance does not appear promising as a sole long-term therapy for obesity.

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Comparisons of long-term effects of lisinopril vs nifedipine vs conventional therapy in the treatment of mild-to-moderate hypertension in patients with chronic obstructive pulmonary disease.

Any hypertensive patient may be found to have associated lung disease. The response of high blood pressure to specific antihypertensive agents in this category is still unknown. Thus, a group of 76 consecutive patients with mild-to-moderate hypertension and chronic obstructive pulmonary disease (COPD) were selected to participate in a clinical antihypertensive trial to define the roles of lisinopril, nifedipine and conventional therapy, and their impact on the renin-antiotensin system (RAS). After a two-week placebo period, patients were randomly assigned to a regimen of one of three main treatment strategies: (A) lisinopril with or without diuretics; (B) nifedipine with or without diuretics; or (C) diuretics with or without conventional vasodilators (sorbitrate and hydralazine) or selective beta-blockers. The drug doses were titrated to a goal of less than 90 mmHg for maximal diastolic pressure, and the patients continued to receive therapy for at least one year. After one year of follow-up, only 66 patients had completed the study. All high blood pressure was significantly reduced by the three regimens (p < 0.005), but no significant difference in blood pressure control by any individual regimen was noted. Double product also showed the similar trend. Therapy A achieved the best reduction of double product among three regimens, but statis tieally insignificant. Furthermore therapy A suppressed the RAS, whereas therapies B and C might activate this system. Concomitantly, therapy A also had significant favorable effects on metabolic responses in contrast to therapy C. Therapy B revealed a neutral effect on such responses. These data indicated that these three main strategies could provide significant antihypertensive efficacy for blood pressure control in patients with hypertension and COPD. For preventive strategy, therapy A may provide more advantageous effects than therapy C. A long-term double-blind trial including more subjects is warranted to identify the true advantages of therapy A in reduction or major cardiovascular and respiratory events.

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Impact of losartan on stroke risk in hypertensive patients in primary care.

While a number of conditions and risk factors that increase stroke risk have been identified, arterial hypertension is the most consistent and powerful predictor. The angiotensin II type 1 receptor antagonist (angio-tensin receptor blocker [ARB]) losartan has been shown in the LIFE (Losartan Intervention for Endpoint Reduction in Hypertension) study to decrease stroke risk in hypertensive patients to a substantially greater extent than conventional therapy. We aimed to assess the impact of the blood pressure-lowering effect of losartan therapy on stroke risk in hypertensive patients in primary care. A total of 2977 primary-care practices throughout Germany included 22 499 consecutive unselected patients with a confirmed diagnosis of hypertension in an open-label, prospective, observational study. In addition to demographics, known risk factors for stroke were documented on standardised questionnaires. The 10-year predicted risk of first stroke was calculated according to the Framingham Stroke Risk Score at baseline and after a mean of 94 +/- 24 days of losartan (+/- hydrochlorothiazide [HCTZ]) therapy. The mean patient age was 64.1 +/- 10.6 years, and 52.4% were males. Mean systolic/diastolic blood pressure decreased from 160 +/- 15/93 +/- 9 mm Hg at baseline by -21 +/- 14/-11 +/- 9 mm Hg. Besides hypertension, 84.9% of patients had other co-morbidities, of which the most frequent were hypercholesterolaemia (53.0%), diabetes mellitus (36.1%), coronary heart disease (31.1%) and left ventricular hypertrophy (24.2%). The average predicted 10-year stroke risk was 28.0 +/- 21.9% at baseline, and 22.1 +/- 19.5% at study end (relative risk reduction 24 +/- 16%, p<0.05). In subgroups of patients with diabetes or nephropathy, similar effects were noted. Drug-related adverse events were reported in 18 patients; all of these were non-serious. Because of the high prevalence of co-morbidities and risk factors, the hypertensive patient population observed in this study presented with a high 10-year stroke risk. Treatment with losartan (+/- HCTZ) was well tolerated and led to a substantial decrease in blood pressure and associated stroke risk.

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Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports.

Clinical trial data provide an approach to the investigation of the effects of psychopharmacological agents, and psychiatric disorders themselves, on seizure threshold. We accessed public domain data from Food and Drug Administration (FDA) Phase II and III clinical trials as Summary Basis of Approval (SBA) reports that noted seizure incidence in trials of psychotropic drugs approved in the United States between 1985 and 2004, involving a total of 75,873 patients. We compared seizure incidence among active drug and placebo groups in psychopharmacological clinical trials and the published rates of unprovoked seizures in the general population. Increased seizure incidence was observed with antipsychotics that was accounted for by clozapine and olanzapine, and with drugs indicated for the treatment of OCD that was accounted for by clomipramine. Alprazolam, bupropion immediate release (IR) form, and quetiapine were also associated with higher seizure incidence. The incidence of seizures was significantly lower among patients assigned to antidepressants compared to placebo (standardized incidence ratio = .48; 95% CI, .36- .61). In patients assigned to placebo, seizure incidence was greater than the published incidence of unprovoked seizures in community nonpatient samples. Proconvulsant effects are associated with a subgroup of psychotropic drugs. Second-generation antidepressants other than bupropion have an apparent anticonvulsant effect. Depression, psychotic disorders, and OCD are associated with reduced seizure threshold.

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Esophageal carcinoma. The value of staging in long-term survival.

A three-stage study of 177 patients in Puerto Rico who had esophageal carcinoma is presented. Those surviving five or more years over a twenty-one-year period were located. Next, the experience at the San Juan City Hospital from 1968 to 1973 was examined. The information obtained from those two groups led to the last stage, a prospective study in which treatment was based on objective staging of the extent of the disease. Only 27% of these patients are really potentially curable upon admission to the hospital, and they should have aggressive therapy. Adequate palliation can be obtained with radiotherapy and chemotherapy in the remainder. The findings that nearly half of the five-year survivors had metastases or tumor extension and that some patients survived for prolonged periods without treatment emphasize the need for individualized treatment and research in tumor immunology.

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An analysis of which subgroups of multiple myeloma patients, divided according to b(2)-microglobulin and plasma cell labeling index, benefit from high dose vs conventional chemotherapy.

The clinical advantage of high-dose therapy (HDT) over standard treatment for multiple myeloma (MM) patients has been recently assessed. Which patient subgroups benefit most from this approach is unclear. To address this issue, the outcome of 54 patients under 55 years old treated with HDT was compared with that of 101 age-matched controls selected from 390 patients who received standard melphalan and prednisone (MP) chemotherapy in a national multi-center trial (M90 protocol). The complete response (CR) rate was 50% in the HDT group compared to 5% in the MP group. Event-free survival (EFS) was three times longer for the HDT patients (median 34.5 vs 12.2 months, p<0. 0001), though the controls enjoyed a prolonged survival after relapse, and hence there was no statistically significant difference in OS. Overall survival (OS) was analyzed in relation to to two major prognostic factors: b(2)-microglobulin (b(2)-M) and bone marrow plasma cell labeling index (LI). HDT significantly improved OS in poor prognosis patients with a high LI (>1.2%), (median 49.5 vs 32.5 months, p<0.03), whereas it did not prolong OS in poor prognosis patients with high b(2 )-M (> 3 mg/L). In conclusion, HDT has a major impact on CR and EFS, and is the treatment of choice for patients with a high LI. Alternative strategies should be adopted in poor prognosis patients with high b(2 )-M.

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Outcomes of adalimumab therapy in refractory punctate inner choroidopathy and multifocal choroiditis.

This study aims to evaluate the outcomes of adalimumab (ADA) therapy in patients with refractory punctate inner choroidopathy (PIC) and multifocal choroiditis (MFC). Demographic and clinical data, including LogMAR best-corrected visual acuity (BCVA), were retrospectively collected. Doses of prednisone, immunomodulatory therapies (IMT), and anti-vascular endothelial growth factor (VEGF) injections before and after baseline (ADA initiation) were recorded, as well as the time to clinical remission, time to first flare, and drug-associated adverse events. Seven patients (4 females, ten eyes) were included. The mean follow-up after baseline was 17.8 ± 11.1 months (range 6-33). The mean LogMAR BCVA was 0.35 ± 0.77 at 6 months before baseline and remained stable throughout 12 months after baseline (0.31 ± 0.46 at 12 months; p = 0.47). The mean dose of prednisone decreased from 17.3 ± 19.6 mg/day 6 months before baseline (range 0-60) to 2.6 ± 2.4 mg/day at the last follow-up (range 0-6, p = 0.03). The mean number of flares decreased significantly from 1.43 ± 0.79 over a 6-month period before baseline to 0.2 ± 0.45 (p = 0.02) at 6-12 months after baseline. The mean number of anti-VEGF injections was 4.17 ± 3.92 over the 12-month period before baseline, and it was 2.17 ± 3.06 (p = 0.31) during the first 12 months after baseline. No adalimumab-related adverse events were noted. Adalimumab therapy for refractory PIC/MFC enabled a significant steroid-sparing effect, decreased disease flares, and preserved vision over a mean follow-up of 17.8 months.

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Factors of importance for QRS complex recovery after acute myocardial infarction.

The regression of the ECG signs of myocardial infarction has been studied in 101 patients. A significant increase in R wave amplitude and decrease in Q wave depth on the standard ECG was observed over three months. In 21% of the patients, Q waves disappeared completely. In inferior infarction, these changes were more apparent in the lateral V leads than in the inferior limb leads. Patients with intraventricular conduction defects were excluded. Two factors associated with the Q and R wave changes have been identified. Lower heart rates appeared to facilitate the recovery of R waves, and smaller infarcts, as assessed by peak LDH, showed greater ECG recovery. This study raises the interesting possibility that modification of the heart rate may affect favourably the healing process after an acute myocardial infarction.

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Effects of cyclooxygenase inhibition on endothelial function in hypertensive patients treated with angiotensin-converting enzyme inhibitors.

Cyclooxygenase inhibition restores endothelium-dependent vasodilatation in hypertension, but it is unknown whether it restores endothelial function in hypertensive patients treated with angiotensin-converting enzyme (ACE) inhibitors. The purpose of the present study was to evaluate the effects of cyclooxygenase inhibition on endothelial function in hypertensive patients treated with ACE inhibitors. Endothelium-dependent flow-mediated dilatation (FMD) and endothelium-independent glyceryl trinitrate-induced dilatation were investigated in 10 patients treated with enalapril (ACE group), 11 patients treated with manidipine and metoprolol (non-ACE group), and 12 normotensive control subjects. After administration of 1000 mg of aspirin, FMD was investigated once again. Plasma cyclic guanosine monophosphate (cGMP) and eicosanoids were also measured during reactive hyperemia before and after aspirin administration. Flow-mediated dilatation was more impaired in the non-ACE group than in the ACE group (8.3 +/- 3.8%, 5.7 +/- 1.7%, respectively, p<0.04). Glyceryl trinitrate-induced dilatation was similar in the ACE group, the non-ACE group, and in the control subjects. In the ACE group, FMD was reduced after administration of aspirin (5.3 +/- 4.2%, p<0.05). The percent change in FMD after administration of aspirin correlated significantly with percent change in cGMP (r=0.77, p<0.03; y-intercept, -62.1%, p<0.01). After aspirin administration, levels of thromboxane B2 and 6-keto-prostaglandin(1alpha) were significantly decreased compared with those before aspirin administration in all groups. Cyclooxygenase inhibition may reduce the beneficial effect on endothelium-dependent vasodilatation induced by ACE inhibitors. The results suggested that prostacyclin in addition to nitric oxide plays a significant role in the restoration of endothelial function in hypertensive patients treated with ACE inhibitors.

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Retrospective analysis of first-line treatment for follicular lymphoma based on outcomes and medical economics.

Follicular lymphoma (FL) is the most common type of non-Hodgkin lymphoma (NHL), with indolent progression. Several treatment options are selected, based not only on disease status, quality of life (QOL), and age of patient, but also on recent increasing medical costs. We retrospectively analysed the first-line treatment of FL with regard to treatment outcomes and medical economics, and discuss the appropriate strategies for FL. Data on a total of 69 newly-diagnosed patients with FL was retrospectively collected from 2001 to 2015. The median age of the patients was 60 years and the median follow-up was 58 months. A total of 25 cases with FL were treated with R monotherapy, and 28 cases were treated with R-CHOP as first-line treatment. The factors affecting the decision of physicians to use R or R-CHOP treatment were serum level of lactate dehydrogenase (LDH) and disease stage. The first-line treatment-associated survival did not show any statistical differences between R and R-CHOP. The average hospitalization and average of all medical costs during the first-line treatment were 4.1 days (R) versus 55.7 days (R-CHOP), and JPY 1,707,693 (USD 15,324) (R) versus JPY 2,136,117 (USD 19,170) (R-CHOP), respectively. R monotherapy for patients whose diseases show low tumor burden and who are not candidates for local treatment has benefits as a first-line treatment compared to R-CHOP, based on the patients' QOL and medical economics.

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Atorvastatin and fenofibric acid differentially affect the release of adipokines in the visceral and subcutaneous cultures of adipocytes that were obtained from patients with and without mixed dyslipidemia.

In this study, we compared the effects of atorvastatin and fenofibric acid, which were administered alone or in combination, on the secretory function of human adipocytes that were obtained from the visceral and subcutaneous adipose tissues of 19 mixed dyslipidemic patients and 19 subjects with a normal lipid profile. The adipocytes were incubated in vitro in the presence of atorvastatin and/or fenofibric acid. The secretory function of the cells was determined using ELISA assays. The visceral adipocytes released significantly more adiponectin and IL-6 and less PAI-1 than those that were obtained from subcutaneous tissue. The levels and patterns of adipokine release differed between the patients with or without lipid abnormalities and between the adipocytes that were obtained from visceral or subcutaneous adipose tissue. The culture that contained hypolipidemic drugs resulted in the significant changes of the release of adipokines. The effects of atorvastatin and fenofibric acid on the hormonal function of human adipocytes may be, in part, responsible for the clinical efficacy of these drugs in the prevention and treatment of dyslipidemia-related cardiovascular and metabolic disorders. The study supports the concept that the pleiotropic effects of fenofibrate and atorvastatin may be, in part, a result of their impact on the secretory function of adipocytes.

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Obesity negatively impacts outcome in elderly female patients with aggressive B-cell lymphomas treated with R-CHOP: results from prospective trials of the German high grade non-Hodgkin's lymphoma trial group.

To study if obesity is a risk factor in elderly patients (>60 years) with aggressive B-cell lymphoma, the outcomes of 576 elderly patients treated with rituximab in the RICOVER-60 trial were analysed in a retrospective study with regard to body mass index (BMI) and gender. Of the 576 patients, 1% had low body weight (BMI < 18·5), 38% were normal weight (18·5 ≤ BMI < 25), 42% were overweight (25 ≤ BMI < 30) and 19% were obese (BMI ≥ 30). Event-free (EFS), progression-free (PFS) and overall survival (OS) according to BMI showed no significant differences for all and for male patients. EFS (P = 0·041), PFS (P = 0·038) and OS (P = 0·031) were significantly better for female non-obese patients. A multivariate analysis adjusted for International Prognostic Index risk factors confirmed these results, with the following hazard ratios (HR) for obesity (BMI ≥ 30) for EFS/PFS/OS: all patients - 1·4/1·4/1·4 (not significant); male patients - 1·2/1·2/1·0 (not significant) and female patients - 1·7 (P = 0·032)/1·9 (P = 0·022)/2·0 (P = 0·017). In conclusion, obesity is a risk factor that influences treatment outcome in elderly female patients with aggressive B-cell lymphoma treated with R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, prednisolone). The inferior outcomes in obese female patients may be due to faster rituximab clearance in obese females.

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Neopterin production in posttraumatic stress disorder before and after pharmacotherapy.

Post-traumatic stress disorder (PTSD) has been associated with decreased neopterin levels. In the present study, we evaluated whether this low neopterin levels would normalize following pharmacotherapy with sertraline in PTSD. Fourteen patients with PTSD and 14 controls were enrolled in the study. A clinical evaluation and measurements of neopterin levels before and after sertraline treatment were performed. In addition, all patients were assessed with the Clinician Administered PTSD Scale (CAPS). The mean neopterin levels were significantly lower in the patient group than control group at baseline and were negatively correlated with the duration of illness, or severity of illness. Sertraline treatment decreased the symptoms of PTSD; however this was not accompanied by a significant increase in neopterin production. In conclusion, our results reveal that the failure for neopterin to normalize through symptom alleviation suggests that either neopterin may be a trait marker of the illness, or that more sustained treatment is necessary to elevate the neopterin production.

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Bisoprolol and nifedipine retard in elderly hypertensive patients: effect on quality of life.

Subjects over the age 60 with sustained sitting diastolic pressures of 95-115 mm Hg were randomised to a regime based on bisoprolol (n = 368) or nifedipine retard (n = 379) for 24 weeks. The goal diastolic pressure was < or =90 mm Hg and to achieve this, double-blind medication could be doubled (5/10 mg bisoprolol, 40/80 mg nifedipine retard) or hydrochlorothiazide 25 mg (unblinded) could be added to the higher dose. In an intention-to-treat analysis, 309 subjects in both the bisoprolol and nifedipine retard treated group provided at least a baseline and a second quality of life assessment (82%). An excess of symptoms was observed in the nifedipine group for oedema of the legs, nocturia, constipation, racing heart and heart thumping. Fewer patients reported wheeze in the nifedipine group. For quality of life, there were no statistically significant differences between the two groups after 8 weeks. However, when analysing the results of the last available assessment (usually at 24 weeks) there were significant (P < 0.05) improvements in tension/anxiety, anger/ hostility, vigour/activity, and confusion/bewilderment, assessed by the Profile of Mood States (POMS) in patients receiving bisoprolol in comparison to those receiving nifedipine retard. The Sickness Impact Profile and objective tests of cognitive function did not differ statistically between the two groups. Quality of life was maintained at a good level on both treatments with advantages for bisoprolol in certain areas. Journal of Human Hypertension (2000) 14, 205-212.

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Daily inhaled corticosteroids or montelukast for preschoolers with asthma or recurrent wheezing: A systematic review.

Most international asthma guidelines recommend that children ≤5 years with asthma or recurrent wheezing be treated with daily low- moderate dose inhaled corticosteroids (ICS) as the preferred controller and leukotriene receptor antagonists (LTRA) as alternative therapy. There is no systematic review comparing the efficacy of ICS versus LTRA monotherapy in this age group. To compare the efficacy of daily ICS versus LTRA in preschoolers with asthma or recurrent wheezing. Randomized, prospective, controlled trials published by December 2017, with a minimum of 3-month therapy with daily ICS versus LTRA were identified. The co-primary outcomes were the number of wheezing episodes and daily symptom score. Secondary outcomes included unscheduled emergency visits, need of rescue systemic corticosteroids (SC), hospitalization for exacerbations, lung function, and adverse effects. Of 29 trials identified, six studies (n = 3204 patients, 62% males, age range: 6-54 months) met the inclusion criteria; two were at low risk of bias. Five pertained to children with asthma; one to those with recurrent wheezing. No outcomes were similarly reported in the six studies, preventing meta-analysis. Based on trials at lowest risk of bias and the largest open-labelled studies, ICS was associated with better control of symptoms and less exacerbations than LTRA. And also less need for rescue SC. Insufficient data of high quality prevented firm conclusions on other secondary outcomes. In preschoolers with asthma or recurrent wheezing, daily ICS appears more effective than daily LTRA for improving symptom control and decreasing exacerbations, particularly those requiring rescue SC, although the magnitude of benefit remains to be quantified.

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Impact of age on renal graft survival in children after the first rejection episode.

Infants are thought to be more immunoreactive and at a greater risk for developing irreversible rejection compared with older children. We investigated this by analyzing patient and graft survival rates, incidence of acute rejection, reversibility of acute rejection, development of a subsequent acute rejection, and incidence of graft loss due to rejection in 154 children (< 18 years of age) after primary renal transplantation. Most patients (n = 139) were treated with quadruple immunosuppression (antibody, azathioprine, prednisone, cyclosporine). Treatment of the first acute rejection episode (ARE) consisted of antibody and increased prednisone (68%) or increased prednisone alone (30%), and was not significantly different between the age groups. Transplants were from living donors (LRD) in 80% of cases. Patients were followed for at least 1 year (mean 58 +/- 30 months); 68% (105/154) of recipients experienced 1 or more ARE. The incidence of ARE was significantly lower in patients < 2 years of age (45%) compared with patients 2-5 (76%, P = 0.01), 6-12 (78%, P = 0.005), and 13-17 (76%, P = 0.009) years of age. There was no significant difference in the 1-, 2- and 5-year patient or graft survival rates, the development of a subsequent acute rejection, or the incidence of graft loss due to acute rejection when analyzed by age group. These data suggest that the impact of an ARE is similar for younger and older children in our population receiving predominantly LRD transplants and quadruple immuno-suppression.

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Eradication of gastric Helicobacter pylori ameliorates halitosis and tongue coating.

The influence of gastric Helicobacter pylori infection on the development of oral pathoses remains unclear. The aim of this study is to examine the influence of gastric H. pylori infection on occurrence of halitosis and coated tongue. Ninety-eight patients with dyspepsia were included in the study and their salivary samples and gastric biopsies were analyzed for the presence of H. pylori by Nested-PCR. Halitosis and coated tongue were assessed at the initial examination and 3 months after systemic eradication therapy against H. pylori. Gastric biopsies of 66 patients were positive for H. pylori. Only one saliva sample was H. pylori positive. At initial examination, halitosis was observed in 20 patients (30.3%) out of 66 who had gastric H. pylori infection and in only 3 patients (9.4%) out of 32 without H. pylori infection (p = 0.0236). Coated tongue was diagnosed in 18 (27.2%) patients with the infection compared to only 2 (6.25%) patients negative for gastric H. pylori (p = 0.0164). Patients with gastric infection were treated with the triple eradication therapy (Amoxicillin, Clarythromycin, Pantoprazol) and their gastric biopsies and oral status were examined 3 months later. Halitosis was significantly more prevalent in the group of patients with persistent H. pylori infection (42.1%) compared to only 6.4% of patients in the group where infection was successfully eradicated (p = 0.0012). Coated tongue was diagnosed in 47.4% of patients where H. pylori was still present after eradication therapy and in only 6.4% where eradication succeeded (p = 0.0003). Our findings suggest that eradication of gastric H. pylori significantly alleviates halitosis and coated tongue, the two oral conditions that may be considered as extragastric manifestations of this common chronic bacterial infection.

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Estrogen/progesterone replacement versus pravastatin and their sequential association in hypercholesterolemic postmenopausal women.

The objectives of this study were to assess serum lipid changes in response to an oral estrogen combined with progesterone (Group A) as compared with pravastatin (Group B) and to evaluate the additive effects of the sequential addition of statin to hormonal replacement therapy (HRT) and of HRT to statin. Thirty-seven of 63 hypercholesterolemic menopausal women initially submitted to a 4-month diet were randomised to oral conjugated estrogens (0.625 mg)/micronised progesterone (200 mg) or to pravastatin (40 mg). After 6 months, each group received both medications for another 6 months. Nineteen percent of women corrected their lipids below decision levels with diet alone. Low density lipoprotein-cholesterol (LDL-C) decreased by 8+/-5% with HRT and by 26+/-3% (P<0.001) with the statin. These single medications increased high density lipoprotein-cholesterol (HDL-C) by 13+/-5% (P<0.01) and 11+/-7%, respectively. Combined interventions produced cumulative LDL-C reductions of 40+/-2 and 42+/-3% (P<0.001) and additive HDL-C augmentations of 16+/-4 and 23+/-5% (P<0.01) with proportional changes in apolipoprotein (Apo)B-100 and ApoA-1. These combined effects brought the atherogenic index (C/HDL-C) for Groups A and B, respectively, from a moderate (5.18+/-0.25 and 5.87+/-0.18) to a reduced (3.35+/-0.20 and 3.52+/-0.19) risk category. Triglycerides (TG) which were increased by HRT and decreased by the statin returned to baseline during combined treatments. No changes in diet, physical activity or anthropomorphometric measurements explained the lipid modifications. In menopausal patients with elevated C not responding to diet, pravastatin was most effective to decrease LDL-C, and oral estrogen-micronised progesterone most effective to increase HDL-C. Marked reduction of the atherogenic index is achieved by sequential combinations of medications resulting from beneficial cumulative effects on both C-LDL and C-HDL.

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Risk of hospitalized depression and intentional self-harm with brand and authorized generic sertraline.

Recent suggestions of therapeutic inequivalence of brand and generic sertraline have raised concerns about disproportionately higher adverse events among generic users. To assess the impact of confounding in a comparison of the risks of worsening depression and intentional self-harm (ISH) between users of brand name sertraline and its pharmaceutically equivalent authorized generic (AG). Using a retrospective new-user cohort design, we identified patients with a diagnosis code for depression aged ≥12 years who were continuously enrolled in a Sentinel Data Partner health plan for ≥180 days before their first sertraline dispensing between June 30, 2006 and September 30, 2015. New use was defined as no evidence of sertraline dispensing in the 180 days before index date. We matched each brand name user to up to 10 AG users using propensity scores (PS) and conducted case-centered logistic regression to assess the risks of hospitalized depression and ISH. Before PS matching, brand name users were significantly less likely to be hospitalized for depression [Hazard Ratio (HR) = 0.70 (95% confidence interval (CI): 0.53-0.94)]. However, in the matched analysis, we observed no statistical difference between brand and AG users [HR = 0.84 (95% CI: 0.59-1.21)]. The risk of ISH did not significantly differ between the exposure groups in unmatched (HR = 0.99 (95% CI: 0.60-1.62) and matched analyses [HR = 0.91 (95% CI: 0.49-1.70). In depressed patients receiving brand versus AG sertraline, patient characteristics confounded the association with hospitalization. Baseline differences were ameliorated by PS matching resulting in no statistical difference between brand and AG sertraline users.

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[Biological age and the pain syndrome at diabetic polyneuropathy].

Patients with diabetic polyneuropathy were examined to study their biological age, rate of aging and pain syndrome. More rapid rate of aging was revealed in patients with diabetic polyneuropathy and pain syndrome. Using Duloxetin and Gabapentin is reliable to decrease the display of pain syndrome in diabetic polyneuropathy patients. Against the background of pain syndrome therapy the rate of aging is noticed to decrease along with the regression of pain syndrome. The medicines of Duloxetin and Gabapentin which are used during depression and epilepsy protect against aging.

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University of Wisconsin solution versus Stanford cardioplegic solution and the development of cardiac allograft vasculopathy.

University of Wisconsin (intracellular) solution has been shown to offer some distinct benefits of myocardial preservation over Stanford (extracellular) solution, including a more rapid functional recovery, improved adenosine triphosphate preservation, and a tendency for less postoperative inotropic agents. However intracellular solutions with high potassium content have been reported to cause a functional if not structural endothelial injury in laboratory experiments. Because of this information we retrospectively viewed our follow-up angiographic data for the development of the cardiac allograft vasculopathy in a consecutive series of 195 heart transplant recipients. These patients were treated in identical fashion, with the same immunosuppression regimen, except for the type of cardioplegia used--Stanford solution (group I n = 95) and University of Wisconsin solution (group II n = 100). With a mean follow-up of 24 months after transplantation, a significant difference was seen in the development of cardiac allograft vasculopathy in group II (22%) versus group I (14%, p < 0.03). Although significant differences were observed with univariate analysis with respect to donor age and ischemic time favoring group I and with multivariate statistical analysis with respect to overall rejections favoring group II, the only significant variable for the difference in the development of allograft vasculopathy was University of Wisconsin cardioplegic solution (p < 0.003). A subgroup of 30 patients previously randomized for a functional study comparing the two cardioplegic agents showed a tendency for statistical significance with a freedom from allograft vasculopathy of 93% in group I, as compared with 83% in group II, after 13 months follow-up (p = 0.09). The overall probability of being free of vasculopathy at 24 months was 86% for group I and 70% for group II. The data support the conclusion that University of Wisconsin intracellular solution is associated with an increased incidence of vasculopathy versus Stanford solution and warrants investigation for modification of this preservation agent in heart transplantation.

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[Comparative study of 1st generation versus 2d generation (CAVPE) combinations in intermediate and high-grade lymphomas].

To compare four first generation chemotherapy regimes (FGR) used by GATLA in low and intermediate grade lymphomas. Versus a second generation regimen called CAVPE. A group of 205 patients treated with FGR (79 with BACOP, 89 with COPP, 19 with CHOP, and 18 with CNOP), and 244 others treated with the combination of cyclophosphamide, doxorubicin, vincristine, prednisone and etoposide (CAVPE) were included. Two randomized phase III multicentric studies, COPP vs BACOPP and CHOP vs CNOP, as a whole group, were compared with the second generation scheme, CAVPE. All the patients with FGR received 6 monthly treatment courses, and the CAVPE patients were given 8 monthly courses. The median age was 55 years (18-85) for the FGR group and 51 years (15-79) for the CAVPE group. The stage distribution for both FGR and CAVPE groups was, respectively, as follows: II: 38 and 55 cases; III 80 and 84 cases; IV: 87 and 105 cases. No significant differences were found between both groups when comparing other characteristics of the patients, namely, sex, symptoms, mediastinal, abdominal or extranodal involvement, liver, spleen or bone-marrow infiltration, and bulky tumoural mass. The percentage of complete remission (CR) was 52% (107/205) in the patients treated with FGR, and 67% (163/244) in the CAVPE group (p < 0.001). The estimated probability of sustained first CR at 72 months was 38% for the FGR group and 54% for the CAVPE group (p = 0.0167), whereas 17% and 36%, respectively, of the evaluable patients were alive and well, with no signs of disease progression (p = 0.000). The 72-month survival was estimated in 32% and 51%, respectively, for each group (p = 0.0004). 1. CAVPE seems to offer better responses and disease-free survival in this non-selected group of low and intermediate lymphoma patients. 2. The better results in terms of CR and lower incidence of relapses attained with CAVPE with regard to FGR are probably related with a number of facts, such as the use of more aggressive drugs, higher doses, a better drug combination rationale, the inclusion of new drugs, such as etoposide, or a selection of the patients.

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Alternate day rosuvastatin, an underutilized option in statin intolerant hyperlipidemic patients: a case report and literature review.

Statin agents have proven effective in primary and secondary prevention of cardiovascular disease. Approximately 10-15 percent of patients on statin agents discontinue these agents because of myalgia. We report a patient with a remote history of a transient ischemic attack, significant hyperlipidemia and a positive family history of vascular disease and intolerance to multiple lipid lowering agents, including several statin agents. The patient was started on 5 mg rosuvastatin every other day with no adverse symptoms. The dose was increased to 20 mg rosuvastatin every other day over approximately four months resulting in a 39-percent decrease in LDL levels and a 14-percent improvement in HDL levels with excellent tolerability. The long half-life of rosuvastatin along with its high potency make it a good candidate for alternate-day administration. While few studies have evaluated the efficacy of the described alternate-day statin therapy, the failure to address significant hyperlipidemia is associated with adverse health outcomes and costs. Alternate-day statin agent use remains an underutilized option in patients intolerant of daily statin administration. While significant cost benefits also may occur with an alternate-day regimen, prospective studies are needed to confirm the long-term safety and efficacy of this mode of administration.

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[The prognostic value of the international prognostic index, the national comprehensive cancer network IPI and the age-adjusted IPI in diffuse large B cell lymphoma].

<b>Objective:</b> To explore the prognostic value of the international prognostic index (IPI), the national comprehensive cancer network IPI(NCCN-IPI)and the age-adjusted IPI (aa-IPI) in diffuse large B cell lymphoma. <b>Methods:</b> A total of 311 patients with de novo diffuse large B-cell lymphoma (DLBCL) diagnosed from 2003 to 2012 in Nanfang hospital were included. All patients were divided into CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) and R-CHOP (rituximab, CHOP) groups. Survival analysis was compared among IPI, NCCN-IPI and aa-IPI models. Discrimination of three different prognostic models was assessed using the Harrell's C statistic. <b>Results:</b> A total of 311 patients were analyzed. Among them, 128 patients were treated with CHOP regimen and other 183 patients were treated with R-CHOP regimen. In CHOP groups, both NCCN-IPI (5-year OS: 59.7% <i>vs</i> 26.8%, <i>P</i><0.001) and aa-IPI (5-year OS: 71.0% <i>vs</i> 25.0%, <i>P</i><0.001) showed better risk stratification for low-intermediate and high-intermediate group than the IPI (5-year OS: 47.6% <i>vs</i> 36.6%, <i>P</i>=0.003). However, in the patients treated with R-CHOP, NCCN-IPI showed better risk stratification in low, low-intermediate, high-intermediate groups (5-year OS: 96.0% <i>vs</i> 83.0% <i>vs</i> 66.5%, <i>P</i>=0.009). According to the Harrell's C statistic, C-index of IPI, NCCN-IPI and aa-IPI for overall survival (OS) were 0.546, 0.667, 0.698 in CHOP group and 0.611,0.654, 0.695 in R-CHOP group respectively. In patients younger than 60 years old, C-index of IPI, NCCN-IPI and aa-IPI for OS were 0.534, 0.675, 0.698 in CHOP group and 0.584, 0.648, 0.695 in R-CHOP respectively. <b>Conclusion:</b> The NCCN-IPI is more powerful than IPI and aa-IPI in DLBCL patients receiving R-CHOP. aa-IPI is a preferable model in predicting prognosis than IPI and NCCN-IPI in anthracycline-based chemotherapy without rituximab.

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Mycophenolate mofetil reduces disease activity and steroid dosage in Takayasu arteritis.

Mycophenolate mofetil (MMF) has recently been reported as a useful alternative immunosuppressive drug in autoimmune diseases including in Takayasu arteritis (TA). The aim of this study was to verify the efficacy and tolerability of MMF administration in controlling TA disease activity and allowing glucocorticosteroid reduction. Ten consecutive active TA patients followed at the Vasculitis Clinic were enrolled from January 2003 to 2006 and received oral MMF (2 g/day) for an average of 23.3 months. Disease activity assessed using the National Institutes of Health criteria, clinical features, and inflammatory laboratory findings were evaluated. Five patients had received at least one immunosuppressive drug before administration of MMF (four methotrexate, two azathioprine, and one chlorambucil) but had not achieved clinical and laboratory remission. The other five patients received MMF as their first immunosuppressive drug because of an important disease flare during steroid dose reduction. Clinical activity disappeared in all patients with MMF therapy, except in one patient who abandoned the study because of an important headache, attributed to the drug. Moreover, the MMF therapy allowed significant tapering of the prednisone dose in the rest of the nine patients (24.5 +/- 17.1 vs 5.8 +/- 7.8 mg/day; p = 0.0019). Reinforcing this finding, a significant reduction in inflammatory laboratory parameters, erythrocyte sedimentation rate (24.7 +/- 15.5 vs 12.8 +/- 10.8 mm/h; p = 0.036) and C-reactive protein (24.0 +/- 14.9 vs 11.2 +/- 10.7 mg/l; p = 0.0167), was observed. In summary, MMF therapy reduced clinical and laboratory parameters of TA disease activity, suggesting that this drug is a promising immunosuppressive drug, particularly in refractory cases and as a steroid-sparing agent.

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REP1 deficiency causes systemic dysfunction of lipid metabolism and oxidative stress in choroideremia.

Choroideremia (CHM) is an X-linked recessive chorioretinal dystrophy caused by mutations in CHM, encoding for Rab escort protein 1 (REP1). Loss of functional REP1 leads to the accumulation of unprenylated Rab proteins and defective intracellular protein trafficking, the putative cause for photoreceptor, retinal pigment epithelium (RPE), and choroidal degeneration. CHM is ubiquitously expressed, but adequate prenylation is considered to be achieved, outside the retina, through the isoform REP2. Recently, the possibility of systemic features in CHM has been debated; therefore, in this study, whole metabolomic analysis of plasma samples from 25 CHM patients versus age- and sex-matched controls was performed. Results showed plasma alterations in oxidative stress-related metabolites, coupled with alterations in tryptophan metabolism, leading to significantly raised serotonin levels. Lipid metabolism was disrupted with decreased branched fatty acids and acylcarnitines, suggestive of dysfunctional lipid oxidation, as well as imbalances of several sphingolipids and glycerophospholipids. Targeted lipidomics of the chmru848 zebrafish provided further evidence for dysfunction, with the use of fenofibrate over simvastatin circumventing the prenylation pathway to improve the lipid profile and increase survival. This study provides strong evidence for systemic manifestations of CHM and proposes potentially novel pathomechanisms and targets for therapeutic consideration.

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[Comparative studies of enoxacin and amoxicillin for acute uncomplicated cystitis in women].

120 women suffering from acute uncomplicated bacterial cystitis were treated in an open randomized study either with 1 X 400 mg enoxacin or 1 X 3 g amoxicillin per os. Analysis of midstream urine and bacteriological urine cultures were examined before, two and seven days as well as six weeks after therapy. Treatment with enoxacin resulted in 97.5% (second day), respectively 92.5% (seventh day) bacteriologically sterile urine cultures, whereas the rate of sterile urines following amoxicillin reached only 72.5% (second day), and 65% (seventh day), respectively. Side effects (gastrointestinal, allergic, cardiovascular) were noted in one case in the enoxacin group and in ten cases in the amoxicillin group. The highly active antibiotic derivatives of the 4-quinolone-group (e.g. enoxacin) administered as a single dose achieve high cure rates in carefully selected female patients with acute uncomplicated bacterial cystitis.

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A comparison of cyclophosphamide, adriamycin, 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, prednisone (CMFVP) in patients with metastatic breast cancer: a Southeastern Cancer Study Group project.

In an ongoing prospective randomized study, 113 evaluable patients have received either a three-drug combination that included cyclophosphamide, Adriamycin and 5-fluorouracil (CAF) or a five-drug combination including cyclophosphamide, methotrexate, 5-fluorouracil, vincristine and prednisone (CMFVP) given intermittently 1 week out of 4. Responses (64%), median duration of response (32 weeks), and median duration of disease control (32 weeks) achieved with CAF were superior to those achieved with CMFVP (37%, 22 weeks, 17 weeks, respectively). Morbidity secondary to CAF was significant, with nausea and vomiting, malaise, total alopecia, and granulocytopenia being the main features.

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Cyclosporine in renal transplantation: a single institutional experience.

Cyclosporine (CsA) as immunosuppression in renal transplantation was evaluated in a single institutional experience to answer several controversial questions. CsA was found to be the superior method of immunosuppression for primary cadaveric renal transplantation. Graft survival, with CsA, was improved over that with conventional immunosuppression which included an antilymphocyte preparation. CsA was found to be the immunosuppressive agent of choice in retransplantation for patients who had rejected a previous renal allograft. Also, CsA was indeed the agent of choice for immunosuppression in patients over 50 years of age seeking renal transplantation. The risks of CsA following transplantation were almost exclusively related to the associated nephrotoxicity. The nephrotoxicity, however, was easily manageable through a defined management strategy which titrates the CsA dose to renal function. CsA was also found to be more cost effective when compared to conventional immunosuppression. Morbidity was substantially decreased with CsA as fewer infectious complications and rejection episodes resulted.

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Prophylaxis of bacterial infections after bone marrow transplantation. A randomized prospective study comparing oral broad-spectrum nonabsorbable antibiotics (vancomycin-tobramycin-colistin) to absorbable antibiotics (ofloxacin-amoxicillin).

Bacterial infection is a common complication after allogeneic bone marrow transplantation. It is related to the toxic effects of the conditioning regimen on mucosal surfaces, to bone marrow aplasia and to the prolonged lymphopenia with immune deficiency that lasts for several weeks after bone marrow transplantation. We have performed a prospective randomized study comparing two methods of prophylaxis. Group I (OA) received a combination of ofloxacin 400 mg/day and amoxicillin 20 g/day; group II (VTC) received the oral nonabsorbable antibiotics vancomycin 450 mg/day, tobramycin 450 mg/day and colistin 4.5.10(6) units daily, from day -15 to 15 days after discharge from laminar air flow (LAF) rooms. All patients were nursed in LAF rooms with a strict isolation procedure and sterile water and food. They were evaluated daily for clinical symptoms, and bacterial culture samples were taken from the throat, stools and blood twice weekly. Forty-four patients were randomized, 22 entered in group I (OA) and 22 in group II (VTC). There were no differences between the two groups in age (mean 33 years, range 11-54), sex, diagnosis and mean duration of agranulocytosis (21.8 days, range 10-49). Seven patients were excluded because of the selection of a resistant bacteria, 5 were in group I (OA), and 2 were in group II (VTC). The mean duration of fever was 9.2 +/- 7.1 days in group I (OA) and 13.7 +/- 6.8 days in group II (VTC; p = 0.05). There were no significant differences between the two groups in graft-versus-host disease.(ABSTRACT TRUNCATED AT 250 WORDS)

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Impact of lymphoma treatments on spermatogenesis and sperm deoxyribonucleic acid: a multicenter prospective study from the CECOS network.

To determine consequences of lymphoma treatments on sperm characteristics and sperm DNA, and to evaluate predictors of sperm recovery. Multicenter prospective longitudinal study of patients analyzed before treatment and after 3, 6, 12, and 24 months. University hospitals. Seventy-five Hodgkin lymphoma and non-Hodgkin lymphoma patients and a control group of 257 fertile men. Semen analyses, and sperm DNA and chromatin assessments. Comparisons of sperm characteristics before and after treatment. Patients already had altered sperm characteristics before lymphoma treatment, with no identified risk factor. Sperm count, total sperm count, motility, and vitality decreased after treatment, with lowest values at 3 and 6 months. Twelve months after treatment, mean sperm count recovered to pretreatment values after doxorubicin, bleomycin, vinblastine, darcarbacine (ABVD) or ABVD+radiotherapy, but not after doxorubicin, cyclophosphamide, vincristine, prednisone (CHOP) or mechlorethamine, oncovin, procarbazine, prednisone (MOPP) chemotherapies. It was noteworthy that 7% of patients remained azoospermic at 24 months. After 24 months, Kaplan-Meier estimates showed that more than 90% of patients will recover normal sperm count after ABVD or ABVD+radiotherapy vs. 61% for CHOP chemotherapies. In multivariate analyses including diagnosis and treatment protocol, only pretreatment total sperm count was related to recovery. Compared with a control group, lymphoma patients had higher sperm chromatin alterations and DNA fragmentation before any treatment. After treatment, DNA fragmentation assessed by TUNEL assay and sperm chromatin structure assay decreased from 3 and 6 months, respectively, while remaining higher than in the control group during follow-up. Lymphoma patients had altered sperm DNA and chromatin before treatment. Lymphoma treatment had damaging effects on spermatogenesis. These data on both the recovery period according to treatment modalities and the pre- and post-treatment chromatin status of sperm are useful tools for counseling patients wishing to conceive.

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Mortality after 10 1/2 years for hypertensive participants in the Multiple Risk Factor Intervention Trial.

The Multiple Risk Factor Intervention Trial (MRFIT) is a randomized primary prevention trial that tested the effect of a multifactor intervention program on coronary heart disease (CHD) mortality in 12,866 high-risk men aged 35-57 years. Men were randomly assigned to either a special intervention (SI) program, which consisted of dietary advice for lowering blood cholesterol levels, counseling aimed at cessation for cigarette smokers, and stepped-care treatment for hypertension for those with elevated blood pressure, or to their usual sources of health care within the community (UC). Among the 12,866 randomized men, 8,012 (62%) were hypertensive at baseline. For this subgroup, mortality rates with 10.5 years of follow-up were lower for the SI than for the UC group by 15% (p = 0.19) for CHD and 11% (p = 0.13) for all causes. These results reflected more favorable outcomes for SI compared with UC hypertensive men during the 3.8 posttrial years (March 1982 through December 1985) than during the preceding 6-8 years (through February 1982). During the posttrial years, death rates were lower for SI than for UC men by 26% (p = 0.09) for CHD and 23% (p = 0.02) for all causes. For those with diastolic blood pressure equal to or more than 100 mm Hg, this posttrial trend was a continuation of a trend during the trial; therefore, with 10.5 years of follow-up, death rates were markedly lower for SI than for UC by 36% (p = 0.07) for CHD and 50% (p = 0.0001) for all causes. Similarly, for those without baseline resting electrocardiographic abnormalities, the favorable posttrial outcome for the SI group was a continuation of a trend during the trial. In contrast, for those with baseline diastolic blood pressure of 90-99 mm Hg and for those with baseline resting electrocardiographic abnormalities, the favorable posttrial mortality findings for the SI group were a reversal of unfavorable trends recorded during the trial. Two factors appear to have contributed to this more favorable mortality trend for the SI group: 1) a change in the diuretic treatment protocol for SI men about 5 years after randomization, which involved replacement of hydrochlorothiazide with chlorthalidone at a daily maximum dose of 50 mg; and 2) a favorable effect of intervention on nonfatal cardiovascular events during the trial years. In addition, delay until the full impact of beneficial effects on mortality end points from smoking cessation and cholesterol lowering could have contributed.(ABSTRACT TRUNCATED AT 400 WORDS)

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Comparison of trimethoprim-sulfamethoxazole and amoxicillin in therapy of chloramphenicol-resistant and chloramphenicol-sensitive typhoid fever.

The efficacy of orally administered trimethoprim-sulfamethoxazole was compared with that of oral amoxicillin in therapy of typhoid fever due to both epidemic chloramphenicol-resistant and endemic chloramphenicol-sensitive Salmonella typhi. Both drug regimens were effective and of comparable value in treatment of chloramphenicol-resistant infections, as measured by duration of fever (124 hr and 115 hr, respectively) and duration of bacteremia (1.0 and 0.4 days, respectively). Trimethoprim-sulfamethoxazole therapy of infections due to chloramphenicol-sensitive S. typhi resulted in more rapid lysis of fever than did amoxicillin therapy. Trimethoprim and sulfamethoxazole were not synergistic in vitro against the chloramphenicol-resistant strain of S. typhi, and the role of sulfamethoxazole in treatment of such infections appears to be minimal. Oral administration of trimethoprim-sulfamethoxazole is effective therapy of chloramphenicol-resistant, and probably of ampicillin-amoxicillin-resistant, typhoid fever.

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[Clinical investigation on the treatment of HCMV hepatitis in children].

To investigate the effective therapeutic method of human cytomegalovirus (HCMV) hepatitis in children. Twenty-five children with HCMV hepatitis were randomly assigned to a treated group (n=13) or a control group (n=12). Both groups were treated with prednisone, glucurone, luminal and Xiaoyanlidanpian. But the treated group was given ganciclovir (GCV) + intravenous immunoglobulin (IVIG) in addition. Each infant of the two groups was checked for blood routine, liver function and HCMV copy numbers on admission and before discharge. They were seen at the third, sixth and ninth month after discharge. On each visit blood specimens were collected for HCMV copy numbers (fluorescence quantitative PCR, FQ-PCR). The viral load of the treated group decreased significantly. A significant difference in viral copy numbers was found between the two groups on admission, discharge, and third, sixth and ninth month after discharge (P less than 0.001). The number of HCMV DNA copy fell to 10(3) copies/ml on discharge while that of the control group fell to the same level after the third month. The differences between the two groups in the length of hospitalization, time of initial jaundice disappearance and complete disappearance were statistically significant (P less than 0.05). The need for transfusion in the treated group was significantly less than that in the control group (chi-square=4.012, P less than 0.05). Combination of GCV with a high dosage of IVIG to treat HCMV active infection could decrease viral load remarkably; The duration of disease, severity of symptoms, degree of anemia and the need for blood transfusion were reduced. No adverse effects related to the combination of GCV with IVIG therapy were observed.

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[Treatment with venlafaxine extended release for climacteric women with depression or anxiety diagnosis. An open-label study].

The objective of this observational study was to assess under real clinical practice conditions the effectiveness and safety of venlafaxine extended release in anxiety-depressed and hormone-related symptoms in climacteric women with anxiety or depressive disorders. Observational, prospective, open-label, multicenter, 24-week study, carried out in Spain. A sample of 45 outpatients, adult women between 45 and 55 years of age, diagnosed of depressive disorder, generalized anxiety disorder or social anxiety disorder were analyzed. Venlafaxine extended release was administered for 24 weeks at doses according to the investigator's clinical criteria. Of the total of 45 patients who were included in the study, 43 (95.6%) completed it. The patients' age range was of 47 to 55 years old, median of 50 and mean of 50.82. The clinical condition evolution was assessed with the evaluation scales scores: Blatt-Kuppermann Menopausal Index, Hamilton Depression Rating Scale, Hamilton Anxiety Scale and Clinical Global Impression. During the 24-week period, a significant decrease in the different scales scores showed a clinical improvement. The results achieved show that treatment with venlafaxine extended release significantly improved the clinical condition of climacteric patients with anxiety or depressive disorder. If these results are confirmed with placebo-controlled clinical trials, they will support the utility of Venlafaxine extended release in this kind of patients.

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Adolescents' response to antidepressant treatment in a community mental health center.

This study examines antidepressant response in 52 adolescents after 6 months of treatment in a community mental health clinic. No patients were excluded based on psychiatric or medical co-morbidity. Symptomatic and functional outcome measures were administered to patients and parents. A pharmacotherapy algorithm was followed. Thirty-four patients (65%) completed the 6 month of treatment. Eighty-eight percent of patients improved, while 47% responded. These results are compared to response rates in acute research studies, in continuation studies, and in a study of depressed adults treated in a community clinic. Research to improve response rates to antidepressants in the real world is urgently needed, since it appears that rates are low and diminish with age.

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Risk predictors for hypnosedative-related complex sleep behaviors: a retrospective, cross-sectional pilot study.

To explore the risk predictors for complex sleep-related behaviors (CSBs) in subjects with a DSM-IV-diagnosed depressive disorder, anxiety disorder, adjustment disorder, somatoform disorder, or sleep disorder taking hypnosedative drugs. One hundred twenty-five subjects using hypnosedatives were enrolled from the psychiatric outpatient clinics of a medical center in Taiwan from May 2006 to July 2006. All subjects completed a questionnaire that included demographic data, current and childhood sleep habits, and CSBs after taking hypnosedatives. Complex sleep-related behaviors were defined as somnambulism with object manipulation, sleep-related eating, and other amnestic sleep-related behaviors. Demographic and clinical variables were compared in those with CSBs and those without. Then multiple logistic regression analyses were performed in order to identify significant risk predictors for CSBs. Of the 125 subjects, 19 (15.2%) reported CSBs, all of whom took zolpidem. Among a total of 67 subjects taking zolpidem, those with CSBs were significantly more likely to be younger (P = .023), to be female (P = .011), to take a higher dose of zolpidem (> 10 mg/d; P < .001), and to not go to sleep immediately after taking zolpidem (P = .047). Multiple logistic regression analyses showed that a higher dose of zolpidem (> 10 mg/d) was the only significant predictor of CSBs (OR = 13.1; 95% CI, 2.6-65.9; P = .002). This pilot study suggests that a higher dosage of zolpidem (> 10 mg/d) is the key risk predictor for CSBs.

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Comparative efficacy of low-dose versus regular-dose colchicine to prevent flares in gout patients initiated on urate-lowering therapies.

The objective of this study was to compare the prophylactic effect of regular-dose (RD, 1.2 mg/day) vs low-dose (LD, 0.6 mg/day) colchicine on gout flare when initiating urate-lowering therapy. In this retrospective cohort study, we included gout patients who were initiated on either allopurinol or febuxostat, in combination with colchicine therapy and followed them up for 3 months. We analysed the rates of gout flare and adverse events according to the dose of colchicine. We performed the inverse probability of treatment weighting (IPTW) and weighted logistic regression analysis to assess the treatment effect. Analysis of gout flares and adverse events was performed on an intention-to-treat (ITT) and per-protocol (PP) basis. Of the total of 419 patients with gout, 177 patients (42.2%) received LD colchicine, whereas 242 patients (57.8%) received RD colchicine. Lower BMI and estimated glomerular filtration rate, and higher incidence of cardiovascular disease were seen in the LD group than in the RD group. In IPTW-adjusted analysis, events of gout flare were not significantly different between the LD and RD groups [ITT: 14.3% vs 11.3%; odds ratio (OR): 1.309, 95% CI: 0.668, 2.566, P = 0.432; PP: 15.3% vs 10.0%; OR: 1.623, 95% CI: 0.765, 3.443, P = 0.207]. However, LD colchicine was associated with a lower rate of adverse events than RD colchicine [ITT: 8.2% vs 17.9%; OR: 0.410, 95% CI: 0.217, 0.777; P < 0.05; PP: 8.4% vs 17.2%; OR: 0.442, 95% CI: 0.223, 0.878; P < 0.05]. Our data suggest that LD colchicine can adequately prevent gout flare with fewer adverse events compared with RD colchicine.

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Effects of two lipid lowering therapies on immune responses in hyperlipidemic subjects.

To compare the effects of two of the most effective lipid-lowering therapies with similar LDL-cholesterol reduction capacity on the innate and adaptive immune responses through the evaluation of autoantibodies anti-oxidized LDL (anti-oxLDL Abs) and electronegative LDL [LDL(-)] levels. We performed a prospective, randomized, open label study, with parallel arms and blinded endpoints. One hundred and twelve subjects completed the study protocol and received rosuvastatin 40 mg or ezetimibe/simvastatin 10/40 mg for 12 weeks. Lipids, apolipoproteins, LDL(-), and anti-oxLDL Abs (IgG) were assayed at baseline and end of study. Main clinical and laboratory characteristics were comparable at baseline. Lipid modifications were similar in both treatment arms, however, a significant raise in anti-oxLDL Abs levels was observed in subjects treated with rosuvastatin (p=0.026 vs. baseline), but not in those receiving simvastatin/ezetimibe. (p=0.233 vs. baseline), thus suggesting modulation of adaptive immunity by a potent statin. Titers of LDL(-) were not modified by the treatments. Considering atherosclerosis as an immune disease, this study adds new information, showing that under similar LDL-cholesterol reduction, the choice of lipid-lowering therapy can differently modulate adaptive immune responses.

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The prevalence and prescribing patterns of benzodiazepines and Z-drugs in older nursing home residents in different European countries and Israel: retrospective results from the EU SHELTER study.

Benzodiazepines (BZDs) and Z-drugs have high potential for developing frequent adverse drug events in older adults (e.g., psychomotor sedation, drug-related dementia, deliria, drug dependence, etc.). Knowledge of the prevalence and patterns of the use of BZDs/Z-drugs in vulnerable older patients is important in order to prevent and reduce the burden caused by their drug-related complications. Our study focused on international comparisons of the prevalence, country-specific prescribing patterns and risk factors of regular BZD/Z-drug use in nursing home (NH) residents. This cross-sectional study retrospectively analysed data of 4156 NH residents, prospectively assessed in the Services and Health in the Elderly in Long TERm care (SHELTER) project conducted from 2009 to 2014. Residents aged 65+ in 57 NHs in 7 European countries and Israel were assessed by the InterRAI Long-Term Care Facilities instrument. Descriptive statistics and multiple logistic regression models were used to describe the country-specific prevalence, patterns and risk factors of BZD/Z-drug use. The mean age of the participants was 83.4 ± 9.4 years, 73% were female and 27.7% used BZDs/Z-drugs. The prevalence of BZD/Z-drug use differed significantly across countries, ranging from 44.1% in Israel to 14.5% in Germany. The most frequently prescribed were zopiclone (17.8%), lorazepam (17.1%) and oxazepam (16.3%). Lorazepam, oxazepam and diazepam were used in most of the countries. Brotizolam, temazepam and zolpidem showed highest prevalence in Israel (99.4% of all regular users of this medication in the sample), the Netherlands (72.6%) and France (50.0%), respectively. Residing in Israel was the most significant factor associated with the use of BZDs/Z-drugs or BZDs only (odds ratio [OR] 6.7; 95% confidence interval [CI] 4.8-9.2 and OR 9.7, 95%CI 6.5-14.5, respectively). The use of Z-drugs only was most significantly associated with residing in France (OR 21.0, 95%CI 9.0-48.9). Despite global recommendations and warnings, the preference for and extent of use of individual BZDs and Z-drugs in vulnerable NH residents differ significantly across countries. The strong association with country of residence compared to clinical and functional factors denotes that prescribing habits, social, cultural, behavioural, and regulatory factors still play an important role in the current diverse use of these medications.

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Differential effectiveness of methylphenidate and Adderall in school-age youths with attention-deficit/hyperactivity disorder.

To compare the effectiveness of a single dose of Adderall (q.d.) with that of 2 daily doses of methylphenidate (b.i.d.; MPH) as a treatment for attention-deficit/hyperactivity disorder (ADHD) in youths ranging in age from 5 to 17 years. Forty-two youths treated with MPH were compared with 42 youths treated with Adderall. Subjects were matched for age, sex, and DSM-IV diagnostic subtype. Youths were assigned to the Adderall or MPH condition by their prescribing physician. All youths were evaluated under 5 conditions, including baseline, placebo, 5 mg, 10 mg, and 15 mg. The best dose was assigned prior to breaking the medication blind and was assigned by the consensus of the psychologist and psychiatrist. Subjective ratings by both teachers and parents were examined for dosage level effects and medication type effects. Best dose was always superior to baseline and placebo conditions. No differences between MPH and Adderall were observed on either teacher or parent ratings of behavior. Both MPH and Adderall have been shown to be effective treatments for children with ADHD. Both medications appear to improve teachers' and parents' ratings of behavior. Single-dose treatments of Adderall appear to be as effective as 2 daily doses of MPH and therefore increase the possibility of managing treatment without involving the school in medication administration. In addition, youths who have previously been unsuccessfully treated with MPH because of adverse side effects or poor response may be successfully treated with Adderall.

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[The effects of inhaled bronchodilators on central inspiratory drive in patients with COPD].

To evaluate the effects of inhaled bronchodilators on the central inspiratory drive in patients with COPD. 91 patients with COPD were divided into three groups (A, B, C) randomly. Lung functions and P(0.1) were measured at baseline and 20 min and 60 min after inhalation (A: albuterol; B: iprotropium; C: albuterol + iprotropium). P(0.1) decreased after inhalation in all three groups (P < 0.05 approximately 0.001). A positive correlation between DeltaP(0.1) and DeltaFRC was found in the three groups (r = 0.4325 - 0.5230, P < 0.05 approximately 0.01). V(E)/P(0.1) increased in the three groups after inhalation (P < 0.05 approximately 0.005). There was significant improvement of V(E)/P(0.1) in group B and C as compared with that of group A (P < 0.05, P < 0.001); There was a different correlative factor with V(E)/P(0.1) in group B and C. (1) P(0.1) decreased after inhalation, It may be caused by decreased FRC. (2) V(E)/P(0.1) became appropriate after inhalation in all groups; The improvement in group B and C was superior to that of group A. There may be different mechanisms to improve V(E)/P(0.1) by different inhalators.

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[Treatment of essential hypertension with a combination of propranolol, spironolactone-thiabutazide and dihydralazine (author's transl)].

In 61 out-patients with essential hypertension, grade I or II, propranolol was administered alone in increasing doses (3 x 40 mg/d or 3 x 80 mg/d) or, if there was insufficient response, with a double or triple combination consisting additionally of spironolactone (50 mg/d)-thiabutazide (5 mg/d) and dihydralazine (3 x 25 mg/d). This treatment schedule achieved normal pressures in 51 patients, in 22 on 40 mg, in 7 on 80 mg propranolol, in 16 after the addition of the diuretic, and in 6 with the triple combination. Four patients had to be excluded from the study because they developed either marked bradycardia or anxiety states or paraesthesias after propranolol (3 x 40 mg/d). On chronic beta-adrenergic blockade the serum potassium level increased slightly, but remained within normal limits. The initial value of plasma-renin activity was highest in the group of those who responded to the propranolol treatment.

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Effect of antihypertensive treatment on retinal microvascular changes in hypertension.

Hypertension causes arteriolar narrowing and rarefaction in the retinal circulation, but the extent to which these changes are reversible by antihypertensive treatment is not well studied. We compared the effect of antihypertensive treatment with a calcium-channel-blocker-based regimen and an angiotensin-converting-enzyme-inhibitor-based regimen on the retinal microvasculature. Twenty-five patients (17 men, age range 24-71 years) with untreated hypertension were randomized to treatment with an amlodipine-based (n = 12) or lisinopril-based (n = 13) regimen in a double-blind, prospective parallel limb trial for 52 weeks. Measurements of blood pressure and the retinal microvasculature were made at baseline and at the end of the study. Both the amlodipine-based and lisinopril-based treatments reduced blood pressure to similar extents. Blood pressure reduction was associated with a reduction in arteriolar narrowing, a widening of arteriolar branch angle and an increase in arteriolar density. There were no significant differences between the two treatment regimens. Antihypertensive treatment is associated with improvement in arteriolar narrowing and rarefaction. Improved microvascular structure may contribute to the beneficial effects of antihypertensive treatment in hypertension.

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An original accelerated radiotherapy schedule in stage III to IV head and neck cancers. Results in a multicenter setting.

Accelerated radiotherapy delivery has recently been shown to be effective in overcoming repopulation during fractionated radiotherapy. The therapeutic ratio may be particularly favorable for 5-week regimens. This study reports the feasibility and results of a particular accelerated schedule in Stage III to IV head and neck carcinomas used in a multicenter setting. Seventy-four patients with Stage III (26 patients) or IV (48 patients) head and neck carcinomas were treated with a 5-week accelerated schedule (69.6 to 69.8 Gy in 41 to 40 fractions over a period of 35 to 36 days). Treatment began with 20 Gy in 10 daily fractions to initial involved sites, followed by bi-fractionated radiotherapy (2 x 1.6 Gy to 1.66 Gy/day) to a larger head and neck volume. Thirty-six (49%) patients received induction chemotherapy (median 3 cycles, range 1 to 4 cycles). Grade 3 or 4 (RTOG) confluent mucositis was observed in 57 patients (77%) and Grade 3 dysphagia in 33 patients (44%). Grade 3 or 4 (RTOG-EORTC) late complications were scored in 10.5% of cases. The 5-year actuarial locoregional control rate was 56% (95% CI: 42 to 71). The 5-year overall actuarial survival was 32% (95% CI: 18 to 46). Induction chemotherapy was not associated with a more favorable outcome. This study demonstrates the feasibility of this schedule in a multicenter setting. The oncologic results appear similar to those obtained by other accelerated regimens, while the rate of late complications seems acceptable. Five-week accelerated regimens warrant further evaluation, particularly in conjunction with concomitant chemotherapy, in the framework of prospective trials.

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Randomized clinical trial of dexketoprofen/tramadol 25 mg/75 mg in moderate-to-severe pain after total hip arthroplasty.

The aim was to evaluate the analgesic efficacy and safety of the dexketoprofen/tramadol 25 mg/75 mg fixed-dose combination vs dexketoprofen (25 mg) and tramadol (100 mg) in moderate-to-severe acute pain after total hip arthroplasty. This was a randomized, double-blind, parallel-group study in patients experiencing pain of at least moderate intensity on the day after surgery, compared with placebo at first administration to validate the pain model. The study drug was administered orally every 8 h throughout a 5 day period. Rescue medication, metamizole 500 mg, was available during the treatment period. The evaluation of efficacy was based on patient assessments of pain intensity and pain relief. The primary end point was the mean sum of the pain intensity difference values throughout the first 8 h (SPID8). Overall, 641 patients, mean age 62 (range 29-80) yr, were analysed; mean (sd) values of SPID8 were 247 (157) for dexketoprofen/tramadol, 209 (155) for dexketoprofen, 205 (146) for tramadol, and 151 (159) for placebo. The primary analysis confirmed the superiority of the combination over dexketoprofen 25 mg (P=0.019; 95% confidence interval 6.4-73) and tramadol 100 mg (P=0.012; 95% confidence interval 9.5-76). The single components were superior to placebo (P<0.05), confirming model sensitivity. Most secondary analyses supported the superiority of the combination. The incidence of adverse drug reactions was low and similar among active treatment groups. The efficacy results confirmed the superiority of dexketoprofen/tramadol over its single components, even at higher doses (tramadol), with a safety profile fully in line with that previously known for these agents in monotherapy. EudraCT 2012-004548-31 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-004548-31);ClinicalTrials.gov NCT01902134 (https://www.clinicaltrials.gov/ct2/show/NCT01902134?term=NCT01902134&rank=1).

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Comparative effect of aspirin and clopidogrel on arterial function in CHF.

By inhibiting prostaglandins, aspirin may be deleterious in congestive heart failure (CHF) and/or partially counteract the efficacy of angiotensin-converting enzyme inhibitors (ACEI). Conversely, clopidogrel has no effect on prostaglandin metabolism. The aim of this study was to prospectively investigate the effect of aspirin and clopidogrel on arterial functional properties in CHF patients treated with ACEI. Forty-five patients with stable NYHA class II-IV CHF (64.0+/-15.5 years), ejection fraction <40%, were included in this prospective double-blind study and randomized to receive aspirin 325 mg/day or clopidogrel 75 mg/day for 14 days. Reflected wave assessed by radial applanation tonometry and pulse wave velocity (PWV) were measured at day 0 and day 14. Aspirin resulted in an increase in the augmentation index of the reflected wave (Delta=+3.5+/-5.2%, p=0.005) and the height above the shoulder of the reflected wave (Delta=+1.7+/-3.1 mm Hg, p=0.023), without statistically variation in PWV. Conversely, clopidogrel had no effect on the same parameters (p=0.512, p=0.677 and 0.801, respectively). Overall, variations in the augmentation index of reflected wave significantly differed when compared aspirin with clopidogrel (p=0.0261). This study demonstrates the existence of a negative effect of aspirin 325 mg/day when compared to clopidogrel 75 mg/day on arterial functional properties in CHF patients treated with ACEI.

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Cladribine with prednisone versus chlorambucil with prednisone as first-line therapy in chronic lymphocytic leukemia: report of a prospective, randomized, multicenter trial.

The efficacy and toxicity of cladribine (2-CdA) + prednisone (P) versus chlorambucil (Chl) + P were compared in previously untreated patients with progressive or symptomatic chronic lymphocytic leukemia (CLL) in a randomized, multicenter prospective trial. Eligible patients were assigned to either 2-CdA 0.12 mg/kg per day in 2-hour infusions and P 30 mg/m(2) per day for 5 consecutive days or Chl 12 mg/m(2) per day and P 30 mg/m(2) per day for 7 consecutive days. Three courses were administered at 28-day intervals or longer if myelosuppression developed. The therapy was finished if complete response (CR) was achieved. Of 229 available patients 126 received 2-CdA+P and 103 received Chl+P as a first-line treatment. CR and overall response rates were significantly higher in the patients treated with 2-CdA+P (47% and 87%, respectively) than in the patients treated with Chl+P (12% and 57%, respectively) (P = .001). Progression-free survival was significantly longer in the 2-CdA-treated group (P = .01), but event-free survival was not statistically different. Thirteen percent of patients were refractory to 2-CdA+P and 43% to Chl+P (P = .001). Drug-induced neutropenia was more frequently observed during 2-CdA+P (23%) than Chl+P therapy (11%) (P = .02), but thrombocytopenia occurred with similar frequency in both groups (36% and 27%, respectively). Infections were seen more frequently in the 2-CdA+P-treated group (56%) than in the Chl+P-treated group (40%; P = .02). Death rates have so far been similar in patients treated with 2-CdA (20%) and with Chl (17%). The probability of overall survival calculated from Kaplan-Meier curves at 24 months was also similar for both groups (78% and 82%, respectively). (Blood. 2000;96:2723-2729)

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Pharmacokinetics of the HIV integrase inhibitor S/GSK1349572 co-administered with acid-reducing agents and multivitamins in healthy volunteers.

To evaluate the effect of pH-altering agents on S/GSK1349572 exposure in healthy subjects. S/GSK1349572 is an unboosted, once-daily, next-generation HIV integrase inhibitor. In the first study, 16 subjects received four single-dose treatments: (i) S/GSK1349572 50 mg; (ii) S/GSK1349572 50 mg with a multivitamin (MVI; One A Day Maximum); (iii) S/GSK1349572 50 mg with a liquid antacid (Maalox Advanced Maximum Strength); and (iv) S/GSK1349572 50 mg 2 h before an antacid. In the second study, 12 subjects received a single dose of S/GSK1349572 alone and on day 5 of omeprazole. All treatments were well tolerated. MVI co-administration modestly decreased S/GSK1349572 AUC by 33%. Concurrent antacid co-administration reduced S/GSK1349572 AUC by 74% and staggered antacid dosing significantly diminished this interaction, with a reduction in S/GSK1349572 AUC of 26%. Omeprazole did not significantly affect S/GSK1349572 exposure. S/GSK1349572 can be taken with proton pump inhibitors and MVIs without dose adjustment but should be administered 2 h before or 6 h after antacids.

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Reduction in albuminuria predicts diminished progression in diabetic nephropathy.

We have evaluated putative predictors of the progression in diabetic nephropathy during long-term antihypertensive treatment. Twenty hypertensive insulin-dependent diabetic patients with nephropathy were followed for three (2 to 5) years before, and for three years during antihypertensive treatment with metoprolol and furosemide. Fall rate in glomerular filtration rate (GFR) was 9.5 +/- 3.8 ml/min/year (mean +/- SD) before and 3.6 +/- 3.6 during antihypertensive treatment. Albuminuria was 1442 (150 to 7564) micrograms/min (median range) in the last year before and 880 (96 to 3310) micrograms/min in the first year during treatment. Relative change in adjusted albumin excretion (ratio of values obtained during first year of treatment/and last year before) was significantly correlated to fall rate in GFR during the three years of treatment (r = 0.46, P < 0.05) and to relative change in fall rate in GFR (fall rate during and before treatment were compared) (r = 0.47, P < 0.05). No significant correlations were found between fall rate in GFR during the three years of treatment and arterial blood pressure, albuminuria or GFR measured the last year before, the first year during treatment or the relative changes in these three variables (after-before). In conclusion, a decrease in fractional albumin excretion during conventional antihypertensive treatment predicts an attenuated fall rate in GFR in diabetic nephropathy. The finding suggests a clinical application in monitoring the efficacy of antihypertensive treatment in diabetic nephropathy.

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High prevalence of low bone turnover and occurrence of osteomalacia after kidney transplantation.

Kidney transplantation corrects most of the metabolic abnormalities that cause renal osteodystrophy. However, many transplanted patients develop osteoporosis and other bone lesions that are related, at least in part, to their immunosuppressive regimen. The precise histologic patterns of bone disease after transplantation are not well defined. In a study designed to investigate this issue, 57 adult posttransplant patients agreed to undergo bone biopsies and blood drawings. There were 32 men and 25 women, mean age 45 +/- 2 yr, who had received a kidney transplantation 5.6 +/- 0.8 yr before biopsy. History of bone pain, fractures, and avascular necrosis was found in 22, 12, and 7 patients, respectively. Serum creatinine was 1.68 +/- 0.1 mg/dl, 21% of patients were hypercalcemic, 63.2% had elevated parathyroid hormone (PTH) (>65 pg/ml), and 91.2% had normal calcitriol levels. Cancellous bone volume/tissue volume was below normal compared to age- and gender-matched control subjects in 56.1% of patients. Bone turnover (activation frequency) was low in 45.6%, normal in 28.1%, and elevated in 26.3% of patients. Bone formation rate/bone surface was low in 59.7%, normal in 35%, and elevated in 5. 3% of the patients. Erosion surface/bone surface was high in 21.1% of patients. Mineralization was prolonged in 87.5% of patients, including 9 patients with osteomalacia and 12 patients with focal osteomalacia. Cumulative and maintenance doses of prednisone and time elapsed since transplantation correlated negatively with bone volume and bone turnover (r = -0.32 to -0.59, P < 0.05 to 0.01), whereas cumulative doses of cyclosporine or azathioprine, age, gender, or serum PTH levels did not. Regression analysis identified prednisone as the main factor responsible for low bone volume and bone turnover (r = 0.54 and r = 0.43, P < 0.01). No factors were found to predict delayed mineralization. The present study shows that low bone volume, low bone turnover, and generalized or focal osteomalacia are frequent histologic features in transplanted patients. The effects of age, gender, PTH, and cyclosporine on bone volume and bone turnover are apparently overridden by the prominent effects of glucocorticoids. The prevalence of mineralization defect in the presence of normal serum levels of calcidiol and calcitriol suggests vitamin D resistance and deserves further study.

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[Clinical study of primary central nervous system lymphoma: the role of chemotherapy].

We conducted a retrospective study of 32 patients with histologically confirmed primary central nervous system lymphoma treated in our institute between 1971 and 1995 with an emphasis on the role of chemotherapy. Thirty of the 32 patients underwent tumor resection, whereas 2 patients had biopsies only. Twenty-eight patients received adjuvant therapy, 9 of whom received radiation therapy alone, 2 received chemotherapy alone, and 17 received both radiation therapy and chemotherapy. Chemotherapies performed were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone). VEMP or VENP (vincristine, cyclophosphamide, mercaptopurine [or Natulan], and prednisolone), intravenous ACNU (nimustine), and intravenous or intra-arterial MCNU (ranimustine) and CBDCA (carboplatin). Survival data were available for 30 of the 32 patients. The median survival time of this study was 12.5 months. Twenty-seven patients died from one month through 79 months after the initiation of therapy, and 3 patients were alive for 13 to 69 months. Two patients who received the combination of radiation therapy and chemotherapy survived longer than 5 years. Although radiation therapy and chemotherapy were individually both effective and prolonged the survival time, their combination was more effective. The median survival time was significantly shorter (7.0 vs 16.5 months, p < 0.05) for the patients who received radiation therapy alone than for the patients who received the combination of radiation therapy and chemotherapy. We conclude from our results and review of previous studies that it is important for the chemotherapy of primary central nervous system lymphoma 1) to apply a combination of a variety of effective drugs, similar to that for systemic malignant lymphoma, and 2) to make a sufficient amount of anti-cancer drugs penetrate the whole central nervous system, thereby satisfying the adequate dose intensity for each drug.

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Comparative Effectiveness of Smoking Cessation Medications to Attenuate Weight Gain Following Cessation.

To compare the postcessation weight gain following the use of different FDA-approved smoking cessation medications among obese smokers. A retrospective cohort study was conducted using the General Electric (GE) electronic medical record database (2006-2011). The cohort consisted of obese adult smokers newly initiating use of an FDA-approved smoking cessation medication (i.e., bupropion vs. varenicline). The outcome variable was weight change at 3, 6, or 12 months following the first prescription. Descriptive analyses and t-tests were conducted to assess the frequency distribution of sample characteristics and their association with the postcessation weight change. Multivariate linear regression models were carried out to compare the weight change among the FDA-approved smoking cessation medications and to identify predictors of weight change at 3, 6, and 12 months after assessing the model assumptions. The mean weight gain was 1.14 pounds (±17.26), 2.06 pounds (±18.46), and 3.06 pounds (±20.78) at 3-, 6-, and 12-month, respectively. Obese smokers who were prescribed varenicline had a mean weight gain of 1.18 pounds (±16.75), 2.14 pounds (±18.14), and 3.12 pounds (±20.89) for each follow up, while those who were prescribed bupropion had a mean weight gain of 0.23 pounds (±25.90), 0.22 pounds (±25.32), and 1.47 pounds (±17.50), respectively. Descriptive analysis showed that obese smokers taking bupropion had less weight gain than those taking varenicline at each follow up; however, this association was not statistically significant after accounting for all covariates. While patients using bupropion gained slightly less weight compared to those using varenicline, type of smoking cessation medication was not a significant predictor of weight change in the multivariate linear regression model.

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The influence of mTOR inhibitors on the incidence of CMV infection in high-risk donor positive-recipient negative (D+/R-) kidney transplant recipients.

Several studies and meta-analysis suggest the mTOR inhibitors are associated with reduced incidence of CMV infection after kidney transplantation, although their effects on the high-risk population have not been investigated thoroughly. This retrospective cohort study investigates the association between immunosuppression and CMV infection in D+/R- kidney transplant recipients receiving preemptive therapy. All patients received rabbit anti-thymocyte globulin, tacrolimus, prednisone and azathioprine (AZA), mycophenolate (MPA) or everolimus (EVR). Among 89 D+R-, the overall incidence of CMV infection was 76%, with no difference among the groups AZA vs MPA vs EVR (73 vs 83 vs 74%, P = 0.643). CMV infection occurred later (31 in AZA vs 31 in MPA vs 43 days in EVR group, P < 0.001) and showed a lower trend of recurrences (57% in AZA vs 79% in MPA vs 48% in EVR group, P = 0.058) in the everolimus group. There were no differences in the IgG seroconversion rate (82% in AZA vs 76% in MPA vs 72% in EVR group, P = 0.983). There were no differences in the incidence of biopsy-proven acute rejection (10% in AZA vs 8% in MPA vs 6% in EVR group, P = 0.811) and renal function at 12 months (53.6 in AZA vs 60.3 in MPA vs. 55.4 mL/min/1.73 m² in EVR group). In this cohort of high-risk CMV D+/R- kidney transplant recipients receiving rATG induction and tacrolimus, the use of mTOR inhibitors could only show a tendency towards but not a significant difference on the incidence of CMV events, when compared to antimetabolites.

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Predictors of hospitalization in children with acute asthma.

To identify predictors of long duration of bronchodilator therapy in children with acute asthma. An emergency department prospective cohort study of 278 children > or =12 months of age, with clinical and socioeconomic parameters collected at baseline and 4 hours after administration of corticosteroids. Patients were classified into short and long therapy groups, with interval from first albuterol dose to initiation of administration every 4 hours < or =12 or >12 hours, respectively. Predictors significant by univariate analysis were examined by multiple logistic regression. Five variables were associated with long therapy (n = 85) versus short therapy (n = 193): previous intensive care unit admission (odds ratio [OR] 7.2, 95% CI = 1.85, 27.7); baseline oxygen saturation < or =92% (OR 2.6, 95% CI = 0.89, 7.4), asthma score > or =6/9 (OR 2.9, 95% CI = 1.9, 4.37), oxygen saturation < or =92% (OR 6.6, 95% CI = 1.34, 32.0), and hourly albuterol dosing interval (OR 4.3, 95% CI = 0.82, 22.12) 4 hours after administration of corticosteroids. Probability of long therapy was 91.8% to 99% for > or =3 predictors, but only 40.6% to 61.8% for individual factors. A combination of 3 or more factors predicts long bronchodilator therapy and signals the need for hospitalization. Children with only one predictor can be safely treated in the emergency department or observation unit and reevaluated.

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The safety of combined thrombolysis and beta-adrenergic blockade in patients with acute myocardial infarction. A randomized study.

To assess the safety of combined intervention in acute myocardial infarction, a pilot study of thrombolysis and beta-adrenergic blockade was performed. Twenty-five subjects were randomized to therapy with intravenous (IV) metoprolol and IV streptokinase (group 1) or to IV metoprolol (group 2) alone. Two-dimensional echocardiography was performed before intervention and five days later. The mean time from onset of symptoms to intervention was 1.92 hours. No major adverse reactions related to the intervention were observed in either group. Significant improvement from baseline was observed with combined therapy on both the biplane mean ejection fraction (p less than .02) and a calculated wall motion index of regional wall motion abnormalities (p less than .002). The presumed reperfusion rate was significantly higher in group 1 (p less than .03). Intravenous metoprolol and IV streptokinase in combination was found to be safe in the acute phase of acute myocardial infarction when administered to appropriate patients without contra-indications and deserves further study.

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Risk of All-Cause Mortality in Diabetic Patients Taking β-Blockers.

To assess the relationship between use of β-blockers and all-cause mortality in patients with and without diabetes. Using data from the US National Health and Nutrition Examination Survey 1999-2010, we conducted a prospective cohort study. The study participants were followed-up from the survey participation date until December 31, 2011. We used a Cox proportional hazards model for all-cause mortality analysis. The multivariate-adjusted hazard ratios (HRs) of the participants taking β-blockers were compared with those of the participants not taking β-blockers. This study included 2840 diabetic participants and 14,684 nondiabetic participants. Compared with diabetic participants not taking a β-blocker, all-cause mortality was significantly higher in diabetic participants taking any β-blocker (HR, 1.49; 95% CI, 1.09-2.04; P=.01), taking a β₁-selective β-blocker (HR, 1.60; 95% CI, 1.13-2.24; P=.007), or taking a specific β-blocker (bisoprolol, metoprolol, and carvedilol) (HR, 1.55; 95% CI, 1.09-2.21; P=.01). In addition, all-cause mortality in diabetic participants with coronary heart disease (CHD) was significantly higher in those taking beta-blockers, compared with those not taking beta-blockers (HR, 1.64; 95% CI, 1.08-2.48; P=.02), whereas that in non-diabetic participants with CHD was significantly lower in those taking beta-blockers (HR, 0.68; 95% CI, 0.50-0.94; P=.02). A propensity score-matched Cox proportional hazards model yielded similar results. Use of β-blockers may be associated with an increased risk of mortality for patients with diabetes and among the subset who have CHD.

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Reversal of subclinical left ventricular dysfunction by antihypertensive treatment: a prospective trial of nebivolol against metoprolol.

To assess the effects of antihypertensive treatment on subclinical left ventricular dysfunction and to compare the effects of nebivolol with metoprolol. This is a prospective, randomized, parallel, active-controlled, PROBE design study (ClinicalTrials.org: NCT00942487) in 60 patients (53±9 years, 67% men) with arterial hypertension, left ventricular hypertrophy, normal ejection fraction, and no coronary heart disease, randomized to either a nebivolol-based or a metoprolol-based treatment, who had conventional and tissue Doppler echocardiography, at rest and during dobutamine stress, at baseline and after 6 months. SBP and DBP, and resting heart rate decreased by 13, 13, and 12%, respectively, on nebivolol, and by 11, 13, and 7%, respectively, on metoprolol (all, P<0.01). Mean longitudinal early diastolic velocity increased by 16% (P<0.05) on nebivolol compared with 9% (P=not significant) on metoprolol (P=not significant for intergroup differences), whereas flow propagation velocity increased by 34% on nebivolol (P<0.05) and did not change on metoprolol (P<0.01 for intergroup differences). Mean longitudinal displacement increased by 10% on nebivolol (P<0.05) and did not change on metoprolol (P<0.05 for intergroup differences), whereas ejection time increased by 5% on nebivolol (P<0.05) and did not change on metoprolol. All the other parameters of left ventricular function were not different between the two treatment arms. Patients with mild-to-moderate hypertension have a beneficial effect from 6-month antihypertensive treatment on diastolic longitudinal left ventricular function; effects are significant with nebivolol, but not with metoprolol.

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Efficacy and safety of high-dose inhaled steroids in children with asthma: a comparison of fluticasone propionate with budesonide.

To compare the efficacy and adverse effects of inhaled fluticasone propionate (FP), 400 microgram/d, with those of budesonide (BUD), 800 microgram/d, in children with moderate to severe asthma. Three hundred thirty-three children, ages 4 to 12 years, receiving inhaled corticosteroids were enrolled in a double-blind, double-dummy, randomized, parallel-group study. After a 2-week run-in phase, 166 children received FP and 167 received BUD for 20 weeks. The primary outcome variable was mean morning peak expiratory flow; the 2 treatments were to be regarded as equivalent if the 90% CI for the treatment difference was within +/- 15 L/min. Pulmonary function, height, and diary cards were assessed at each visit; and morning serum cortisol levels were determined before and after treatment. Baseline peak expiratory flow was similar, FP 236 +/- 72 (SD) L/min and BUD 229 +/- 74, increasing after treatment to 277 +/- 41 and 257 +/- 28, a difference between treatments of 12 L/min (90% CI 6-19 L/min; P =.002). Symptom control and use of rescue medication were the same. Cortisol levels after treatment were 199 nmol/L (FP) and 183 nmol/L (BUD) (treatment ratio = 1.09; 90% CI 0.98-1.21; P =.172). Linear growth was less in those receiving BUD (mean difference, 6.2 mm; 95% CI 2.9-9.6; P =.0003). FP at half the dose was superior to BUD in improving peak expiratory flow and comparable in controlling symptoms. Growth was reduced with BUD compared with FP, but there was no difference in serum cortisol suppression or hepatic or renal function.

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West syndrome: the Philippine experience.

To provide information on the current status of West syndrome (WS) in the Philippines. This is a retrospective review of WS cases from January 1997 to December 1999 from two largest referral government institutions. A questionnaire interview survey on anticonvulsant usage was also conducted among practicing child neurologists. Twelve patients diagnosed to have infantile spasms at 2-15 months were included, with a male:female ratio of 1:1. The proportion of WS cases among epileptic children under age 3 was 3.18%. The etiologies were idiopathic/cryptogenic in four (33%) and symptomatic in eight (66%). Symptomatic cases include hypoxic-ischemic encephalopathy, neonatal sepsis, bacterial meningitis, inborn error of metabolism, congenital brain anomaly and intracranial hemorrhage. Phenobarbital was the first line drug in 75% of cases. Other drugs used were valproic acid, clonazepam and pyridoxine. With a follow-up duration of 1-40 months, only three patients became seizure free and most had poor neurodevelopmental outcome. Among practicing child neurologists, the preferred ideal drug was adrenocorticotrophic hormone (ACTH) and valproic acid for idiopathic and symptomatic cases, respectively. However, in actual clinical practice valproic acid or prednisone was the initial drug used. Pyridoxine was usually added on. The proportion of WS in our patient population may not reflect the true prevalence in our country since our data came from a biased population, i.e. referral centers. A national statistics is currently not available. ACTH, which was perceived by most child neurologists as the ideal first line drug was not used primarily because it is unavailable and unaffordable. The poor seizure control and developmental outcome may be due to the treatment given or directly related to the etiology of WS.

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Assessment of ADP-induced platelet aggregation with light transmission aggregometry and multiple electrode platelet aggregometry before and after clopidogrel treatment.

The level of platelet aggregation, measured with light transmission aggregometry (LTA) in platelet rich plasma (PRP), has been shown to predict outcomes after percutaneous coronary intervention (PCI). However, measuring parameters of platelet function with LTA is time consuming and weakly standardized. Thus, a fast and standardized method to assess platelet function after clopidogrel treatment would be of great value for clinical practice. A new method, multiple electrode platelet aggregometry (MEA), to rapidly measure platelet aggregation in whole blood has recently been developed. The aim of this study was to assess parameters of platelet function with MEA and LTA before and after administration of 600 mg clopidogrel. Blood samples from 149 patients scheduled for coronary angiography were taken after clopidogrel treatment; in addition, in 60 of the patients samples were available before clopidogrel treatment. ADP-induced platelet aggregation was measured with LTA and simultaneously in whole blood with MEA on the Multiplate analyzer. Platelet aggregation measured with MEA decreased significantly after clopidogrel treatment (P < 0.0001). ADP-induced platelet aggregation assessed with MEA and LTA correlated significantly (Spearman rank correlation coefficient = 0.71; P < 0.0001). The results of MEA, a fast and standardized method to assess the platelet response to ADP prior to and after clopidogrel treatment, correlate well with LTA.

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Oral salbutamol vs fenoterol in childhood asthma.

A study to compare the effects of single oral doses of salbutamol (4 mg) and fenoterol (5 mg) was carried out in 22 asthmatic children aged 6-14 years. The patients received both drugs sequentially on two consecutive days within a week in a randomized, double-blind, crossover fashion. Peak expiratory flow rate, spirometry, flow-volume loops and whole body plethysmography were performed basally, at half-an-hour and hourly from 1 through 6 h. In 17 cases, all four pulmonary tests were performed also 8 h after drug administration. No significant difference in bronchodilator power was observed. Both drugs produced a significant increase in heart rate, which was more pronounced after fenoterol. These data suggest that, at the doses used, salbutamol may be a preferable choice.

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Adrenal function and high dose inhaled corticosteroids for asthma.

To investigate effects on adrenal function of fluticasone, a recently released inhaled steroid preparation with lower systemic bioavailability than beclomethasone dipropionate. 34 children on high doses (400-909 micrograms/m2/d) of inhaled beclomethasone dipropionate or budesonide were recruited into a double blind, crossover study investigating the effects on adrenal function of beclomethasone and fluticasone propionate, given using a standard spacer (Volumatic). The 24 hour excretion rates of total cortisol and cortisol metabolites were determined at baseline (after a two week run in), after six weeks treatment with an equal dose of beclomethasone, and after six weeks of treatment with half the dose of fluticasone, both given through a spacer device. The comparison of effects between fluticasone and beclomethasone during treatment periods, although favouring fluticasone in all measured variables, reached significance only after correction for urinary creatinine excretion (tetrahydrocortisol and 5 alpha-tetrahydrocortisol geometric means: 424 v 341 micrograms/m2/d). The baseline data showed adrenal suppression in the children taking beclomethasone (total cortisol geometric means: 975 v 1542 micrograms/d) and a dose related suppression in the children taking budesonide. Suppressed adrenal function in the children who were taking beclomethasone at baseline subsequently improved with fluticasone and beclomethasone during treatment periods. Fluticasone is less likely to suppress adrenal function than beclomethasone at therapeutically equivalent doses. The baseline data also support the claim that spacer devices should be used for the administration of high doses of inhaled topical steroids.

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Implementation of Hospital's Antibiotic Policy Decreases Antimicrobial Use in the General Pediatric Ward.

Hospitalized children are often treated with antibiotics. However, 30-75% of antibiotic treatment in pediatric hospitals is administrated incorrectly or unreasonably. Implementation of Hospital's Antibiotic Policy (HAP) should improve antibiotic consumption patterns in pediatric wards. The objective of this study was to determine the effectiveness of HAP by assessing antibiotic consumption in the General Pediatric Ward of an academic hospital in the city of Warsaw, Poland before and after this policy was introduced in the years 2012 and 2013, respectively. Antibiotic use was calculated in daily-defined doses (DDDs) per 100 patient-days and DDDs per 100 admissions. Antibiotics were ranked by the volume of DDDs and the number of antibiotics which accounted for 90% and 100% of the total volume: DU90% and DU100% (where DU stands for drug use). The total antibiotic consumption and significantly decreased after the implementation of HAP; DDDs were 2,177.5 before and 1,335.4 after implementation of HAP. The number of DDDs/100 patient-days was also lower; 36.3 vs. 24.9 before and after HAP, respectively. After implementation of HAP a decreased use of ceftriaxone and cefuroxime was observed. The most commonly used antibiotic was amoxicillin with clavulanic acid. The DU100% rates remained the same (8 antibiotics) and DU90% increased (from 3 in 2012 to 5 in 2013). We conclude that implementation of HAP resulted a decreased consumption of antibiotics in the General Pediatric Ward, despite the hardly changed number of children treated with antibiotics.

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Effect of antianginal medication on resting myocardial perfusion and pharmacologically induced hyperemia.

Patients scheduled for myocardial perfusion imaging are often taking several antianginal drugs. There is presently no consensus concerning a regimen of discontinuation before either rest or pharmacologic stress myocardial perfusion imaging. Whether antianginal treatment affects diagnostic sensitivity and specificity is not well documented. Methods and results The effect of the three most commonly used antianginal drugs (nitroglycerin, 400 microg [NTG]; metoprolol, 50 mg [MET]; and amlodipine, 5 mg [AML]) on myocardial perfusion was tested in 49 patients (age, 63 +/- 8 years; 43 men) allocated prospectively to one of the treatments (NTG, n = 25; MET, n = 14; and AML, n = 10). All patients had documented coronary artery disease and were scheduled for elective percutaneous coronary intervention. Patients were studied once on treatment and once off treatment with an interval of 1 to 3 weeks. For NTG, the measurements were performed on the same day with an interval of 1 hour. The MET and AML groups were also studied during dipyridamole-induced hyperemia (0.56 mg. kg(-1). min(-1) for 4 minutes). So that a quantitative value of myocardial perfusion in milliliters per gram per minute could be obtained, myocardial perfusion was quantified with nitrogen 13 ammonia positron emission tomography as an average of the midventricular perfusion in each of the 3 vascular territories. NTG treatment increased the overall resting perfusion (0.75 +/- 0.18 vs 0.86 +/- 0.22, P <.05), whereas resting perfusion was reduced after MET treatment (0.92 +/- 0.14 vs 0.82 +/- 0.17, P <.05). AML treatment did not alter resting perfusion (0.87 +/- 0.22 vs 0.87 +/- 0.23, P = NS). Dipyridamole-induced hyperemia was reduced after treatment with MET (2.02 +/- 0.66 vs l.57 +/- 0.52, P <.001), whereas the hyperemic response was unchanged after treatment with AML (1.54 +/- 0.49 vs 1.86 +/- 0.91, P = NS). Antianginal medication can alter both resting and hyperemic myocardial perfusion and might affect the ability to detect flow-limiting stenosis. NTG increases perfusion, MET reduces perfusion, and AML does not affect perfusion. Larger-scale trials are warranted to establish a consensus for optimal antianginal medication for patients undergoing perfusion imaging.

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