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Marked increase in gastric acid secretory capacity after omeprazole treatment.

In contrast with the histamine2 (H2) blockers, proton pump inhibitors have not been shown to give rebound hypersecretion of acid. Taking into consideration the hyperplasia of the enterochromaffin-like (ECL) cell provoked by hypergastrinaemia secondary to profound acid inhibition and the central role of histamine from ECL cells in the regulation of acid secretion, the lack of any rebound acid hypersecretion after treatment with proton pump inhibitors has been questioned. To reassess the effect of treatment with omeprazole on post-treatment acid secretion. Basal and pentagastrin stimulated acid secretion were determined in nine patients with reflux oesophagitis before and 14 days after termination of a 90 day treatment period with the proton pump inhibitor omeprazole (40 mg daily). Basal gastrin release were determined before and during omeprazole treatment. Furthermore, biopsy samples from the oxyntic mucosa were taken before and at the end of the treatment period for chemical (histamine and chromogranin A (CgA)) evaluation of the ECL cell mass. A substantial increase in meal stimulated gastrin release during omeprazole treatment resulted in an increased ECL cell mass. Furthermore, CgA in serum increased during omeprazole treatment suggesting that serum CgA may be used as a test to evaluate ECL cell hyperplasia. A significant increase in basal and a marked (50%) and significant increase in pentagastrin stimulated acid secretion were found after treatment with omeprazole. Increased acid secretion after a conventional treatment period with a proton pump inhibitor is probably due to ECL cell hyperplasia and may have negative consequences for acid related diseases.

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Effects of antisecretory agents on angiogenesis during healing of gastric ulcers.

We studied the effects of a proton pump inhibitor (PPI) and an H2-receptor antagonist (H2-blocker) on angiogenesis during gastric ulcer healing, by examining stromal cell-derived factor (SDF-1) and CXC chemokine receptor 4 (CXCR4) expression in the gastric mucosa. Patients with gastric ulcers were allocated to an untreated control group, consisting of patients with active ulcers (GA), healing ulcers (GH), and ulcer scars (GS) or a PPI group (P; given rabeprazole at 20 mg/day), or an H2-blocker group (H; given nizatidine at 800 mg/day). Frozen sections of biopsy specimens were examined by reverse transcription-polymerase chain reaction (RT-PCR) to analyze SDF-1 and CXCR4 mRNA. CXCR4 mRNA levels were elevated in the control (GH and GS patients) group and the H2-blocker group. CXCR4 was significantly elevated in the P-GA subgroup of the PPI group (P<0.01), but its level decreased with time. In the PPI group, CXCR4 levels were increased in the early phase of ulcer healing and returned to a level similar to that in the control group during the scar phase. These results suggest that PPIs increase the expression of CXCR4 mRNA and thus promote vessel regeneration and maturation, facilitating ulcer healing.

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Furosemide-induced disturbances of renal function in patients undergoing TURP.

Furosemide remains the drug of choice for patients with the transurethral resection syndrome. Furosemide is often used intraoperatively to treat patients suspected of having excessive irrigant absorption. To examine the efficacy of such therapy, a randomized study was performed in which furosemide was administered to patients undergoing routine transurethral resection of the prostate (TURP) to determine the effect of furosemide on electrolyte and fluid volume conservation in these patients. Seven patients treated with furosemide on completion of TURP had a statistically significant delayed drop in serum sodium values after normal initial values (139 mEq/L to 134 mEq/L). Seven untreated control patients did not have a similar drop in sodium values, and the difference between groups was significant. We suggest that furosemide be used with caution in patients undergoing routine TURP, and when given it should be accompanied by the infusion of an isotonic balanced salt solution.

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The natural course of Hashimoto's thyroiditis in children and adolescents.

Hashimoto's thyroiditis (HT) is the most common cause of thyroid disease in children and adolescents, but little is known about the long-term follow-up of HT. The aim of this study was to analyze the clinical and laboratory characteristics and to observe the natural course of HT in children and adolescents. We retrospectively reviewed 153 patients with HT diagnosed before 18 years of age. Subjects were grouped into euthyroid, subclinical hypothyroidism, overt hypothyroidism, and hyperthyroidism on the basis of the thyroid function test. Of the 153 subjects, 133 were followed up (range 6∼181 months) at our clinic every 6 months for evaluation of goiter size, thyroid function, thyroid peroxidase antibodies (TPO Ab), and thyroglobulin antibodies (TG Ab) serum concentration. Thyroid function tests at the time of presentation revealed euthyroid in 72 patients (47.1%), subclinical hypothyroidism in 48 (31.4%), overt hypothyroidism in 22 (14.4%), and hyperthyroidism in 11 (7.2%). Serum TPO Ab and TG Ab significantly decreased in the subclinical hypothyroidism group with levothyroxine treatment. Also, there was a significant decrease in the mean serum TG Ab levels among the overt hypothyroid patients during the follow-up period, although TPO Ab levels were not significantly different when compared to their baseline TPO Ab levels. Most children with HT were euthryoid and remained euthyroid during follow-up. However, thyroid function should still be monitored periodically for early detection and treatment of overt hypothyroidism. Our data also showed that levothyroxine treatment may have beneficial effects on the thyroid antibody titers.

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Expression of glucocorticoid receptor isoforms and associations with serine/arginine-rich protein 30c and 40 in patients with systemic lupus erythematosus.

To investigate the expression of glucocorticoid receptor (GR) isoforms in patients with systemic lupus erythematosus (SLE), confirm the main GR isoforms involving in glucocorticoids (GC) resistance, and explore the associations of GR isoforms with serine/arginine-rich protein (SRp) 30c and SRp40. Seventy patients with SLE and thirty-eight age- and sex-matched controls were recruited. All patients received prednisone (0.5-1 mg/kg/d) as their routine therapy. According to the therapeutic effect, patients were divided into glucocorticoid-resistant (GCR) and glucocorticoid-sensitive (GCS) groups. Transcript levels of GRα, GRβ, GRγ, GR-P, SRp30c and SRp40 in peripheral blood mononuclear cells (PBMCs) were determined by real-time PCR. GRα and GRβ proteins were detected by western blotting. Trial registration number is ChiCTR-RCH-12002808. Four GR transcripts in SLE patients showed the following trend: GRα (51.85%) > GR-P (23.78%) > GRγ (13.08%) >GRβ (0.03%). GR-P transcript and ratio of GRα/GR-P in SLE patients were significantly higher than that in controls (p<0.05). GRα transcript and protein as well as SRp40 transcript in GCS group were significantly higher than that in the GCR group before GC treatment (p<0.05). In the GCS group, GRα transcript and SRp40 transcript were significantly higher after GC treatment than that before GC treatment (p<0.05). In the GCR group, GR-P transcript was significantly higher after GC treatment than that before GC treatment (p<0.05). Positive correlation between SRp40 and GRα transcript was found (p<0.05). Additionally, SLE Disease Activity Index scores were significantly negatively correlated with GRα transcript and protein expression (p<0.05). Our data demonstrated that the decreased expression of GRα might be the evidence of high disease activity and help to predict GC resistance. GR-P isoform might be implicated in the development of resistance. Additionally, the preliminary finding suggested that SRp40 might be associated with GRα transcripts in SLE patients.

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Triamcinolone acetonide and fluticasone propionate aqueous nasal sprays significantly improve nasal airflow in patients with seasonal allergic rhinitis.

Domiciliary measurement of nasal peak inspiratory flow rate (nPIFR) provides a simple, noninvasive, objective assessment of nasal patency and may be useful for determining the effectiveness of therapeutic interventions. This randomized, parallel-group, investigator-blind study compared the effects of triamcinolone acetonide aqueous nasal spray (TAA AQ), 220 microg everyday (n = 19), and fluticasone propionate (FP AQ), 200 microg everyday (n = 20), for 21 days on nasal airflow in patients with seasonal allergic rhinitis (SAR), using domiciliary nPIFR. Patients had a > or = 2-year history of springtime SAR and positive epicutaneous or intradermal test to grass, tree pollen, or outdoor molds. nPIFR was measured three times each morning (before dosing) and at bedtime using an In-Check nPIF meter. All measurements were recorded on diary cards, and the best of the three measurements was used for data analysis. There were no significant demographic differences between treatment groups at baseline. Baseline nPIFR (+/- SE) was 106.5 L/minute (+/- 51.2) and 97.7 L/minute (+/- 45.0) in the TAA AQ and FP AQ groups, respectively (p = 0.5733). Model-based estimation of mean change from baseline with TAA AQ and FP AQ at the end of the study were 21.72 (+/- 6.04) and 16.48 (+/- 5.73), respectively. Both treatment groups showed an approximately 20% improvement in nPIFR versus baseline (p = 0.0002 and p = 0.0069 for TAA AQ and FP AQ, respectively), with no statistical difference between treatments. Weekly mean nPIFR scores indicated progressive improvement in nasal airflow with both treatments. Both TAA AQ and FP AQ were effective for improving nasal airflow as indicated by increases in nPIFR in patients with SAR.

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Comparison of amlodipine and quinapril on ambulatory blood pressure and platelet function in hypertension.

The effect of calcium channel blocker (CCB), amlodipine (5-10 mg/day) and angiotensin-converting enzyme (ACE) inhibitor, quinapril (10-40 mg/day) on ambulatory blood pressure (ABP), rheological and platelet function in hypertension were compared in this randomised double-blind placebo-controlled cross-over study. This study was preceded by 4 weeks placebo run-in period and the total duration of the study was 28 weeks. Casual and 24 h ABP, plasma renin activity (PRA) and plasma aldosterone (PA) concentration as well as metabolic and platelet function were determined before and at the end of each drug therapy. A total of 27 patients completed this study. Casual BP was significantly reduced after amlodipine or quinapril treatment, but there was no change in heart rate. Regarding the 24 h ABP, amlodipine produced a fall from 145 +/- 8/94 +/- 7 to 130 +/- 13/85 +/- 10 mm Hg (P < 0.001 for both SBP and DBP). Quinapril also caused a reduction from 144 +/- 10/94 +/- 7 to 134 +/- 12/88 +/- 8 mm Hg (P < 0.001 for both SBP and DBP). Neither amlodipine nor quinapril produce any significant change in heart rate. The level of 6-keto-prostaglandin Fl alpha (6-Keto-PGFl alpha) was increased from 36.8 +/- 4.4 to 45.1 +/- 2.5 pg/ml (P < 0.05) and no significant change of thromboxane B2(TXB2) was noted after amlodipine treatment. PRA was increased from 1.24 +/- 0.31 to 1.62 +/- 0.41 ng/ml/h (P < 0.05) after quinapril treatment. Other biochemical parameters were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

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Anti-Xa Levels in Morbidly Obese Patients Using Apixaban or Rivaroxaban, Before and After Bariatric Surgery.

Despite limited evidence about the efficacy and safety of anticoagulation in patients post bariatric surgery, both vitamin K antagonists (VKA) and direct-acting oral anticoagulants (DOACs) are commonly prescribed. To evaluate plasma anti-Xa levels of DOACs in morbidly obese (MO) patients before and after a Roux-en-Y gastric bypass (RYGB) procedure. Retrospective, cross-sectional, and longitudinal study of anti-Xa activity of apixaban or rivaroxaban in MO patients (N = 41). Preoperative analysis of plasma anti-Xa levels were within the normal range in patients using apixaban (n = 29; body mass index [BMI] 44.5 ± 5.1 kg/m²) as well as those using rivaroxaban (n = 12; BMI 42.6 ± 5.9 kg/m²). Postoperative anti-Xa levels of apixaban were all within the therapeutic range, whereas anti-Xa levels of rivaroxaban were subtherapeutic in nine out of 14 (64%) patients. Perioperative longitudinal follow-up in patients using apixaban (n = 18) showed no significant change in anti-Xa levels after RYGB. Plasma anti-Xa levels of apixaban in MO patients remained within the therapeutic range up to a body weight of 144 kg. In patients using rivaroxaban, no statistically significant relation between anti-Xa levels and bodyweight was found. After RYGB, plasma anti-Xa levels of apixaban were unaffected, whereas plasma anti-Xa levels of rivaroxaban tended to become subtherapeutic.

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Short course acid suppressive treatment for patients with functional dyspepsia: results depend on Helicobacter pylori status. The Frosch Study Group.

Treatment of functional dyspepsia with acid inhibitors is controversial and it is not known if the presence of Helicobacter pylori infection influences the response. After a complete diagnostic workup, 792 patients with functional dyspepsia unresponsive to one week of low dose antacid treatment were randomised to two weeks of treatment with placebo, ranitidine 150 mg, omeprazole 10 mg, or omeprazole 20 mg daily. Individual dyspeptic and other abdominal symptoms were evaluated before and after treatment according to H pylori status. The proportions of patients considered to be in remission (intention to treat) at the end of treatment with placebo, ranitidine 150 mg, omeprazole 10 mg, and omeprazole 20 mg were, respectively, 42%, 50%, 48%, and 59% in the H pylori positive group and 66%, 73%, 64%, and 71% in the H pylori negative group. In H pylori positive patients, the therapeutic gain over placebo was significant for omeprazole 20 mg (17.6%, 95% confidence intervals (CI) 4.2-31.0; p<0.014 using the Bonferroni-adjusted p level of 0.017) but not for omeprazole 10 mg (6.8%, 95% CI -6.7-20.4) or ranitidine 150 mg (8.9%, 95% CI -4.2-21. 9). There was no significant therapeutic gain from active treatment over placebo in H pylori negative patients. Complete disappearance of symptoms and improvement in quality of life also occurred most frequently with omeprazole 20 mg and was significant in both H pylori positive and H pylori negative groups. The six month relapse rate of symptoms requiring treatment was low (<20%) in all groups. Omeprazole 20 mg per day had a small but significant favourable effect on outcome in H pylori positive patients. The differential response in these patients may be explained by an enhanced antisecretory response in the presence of H pylori. The effect of weaker acid inhibition was unsatisfactory.

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Utility of transfer factor to detect different bronchodilator responses in patients with chronic obstructive pulmonary disease.

Previous studies have described that there are different types of disease in patients with established chronic obstructive pulmonary disease (COPD) with different clinical course and functional responses. The aim of this study was to evaluate if the presence of low transfer factor (LTF) values can predict the effectiveness of bronchodilator therapy, and to assess whether this group has different risk factors that may be related with the responses. Eighty patients with COPD were evaluated on three occasions. Initial assessment included a standard respiratory questionnaire, blood analysis, skin prick test and baseline lung function, all performed on the first visit. Bronchodilator response was evaluated after low (0.2 mg) and high (1 mg) doses of salbutamol, and after 2 weeks of oral prednisone. In patients with normal TLCO/VA % (NTF), a higher proportion of subjects with previous history of atopy was the only statistically significant difference compared to those with LTF (odds ratio 4.33; 95% confidence interval 1.06-25.15). Although the mean response in forced expiratory volume in 1 s (FEV1) to treatment was analogous in both groups, when bronchodilation was expressed as percent of predicted, there was a clear trend to a lower response in patients with LTF (0.2 mg salbutamol: 6.99 +/- 5.64 vs. 8.94 +/- 6. 61, p = 0.15; 1 mg salbutamol: 10.18 +/- 6.37 vs. 13.45 +/- 7.90, p < 0.05; oral prednisone: 5.51 +/- 6.94 vs. 8.74 +/- 10.81, p = 0.06). The percentage of patients who had >12% improvement from that predicted in FEV1 was also lower in this group (42 vs. 72%; p < 0. 05). Moreover, TLCO/VA% was significantly lower in those subjects with a negative bronchodilator trial with salbutamol (68 +/- 25 vs. 81 +/- 26; p < 0.05) and prednisone (69 +/- 26 vs. 90 +/- 22; p < 0. 01). In patients with LTF and NTF, airway responsiveness was only significantly related with basal airflow limitation (LTF, r = 0.44; NTF, r = 0.38). All other interaction terms were not statistically significant. These results indicate that in patiens with similar serverity of COPD, the presence of LTF indicates a decreased probability of a positive bronchodilator response, probably reflecting different pathological lesions. We suggest that transfer factor should be taken into consideration when bronchial response is evaluated in large clinical trials.

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The effect of somatostatin versus corticosteroid in the treatment of Graves' ophthalmopathy.

Uncontrolled study has demonstrated the usefulness of somatostatin in the treatment of mild Graves' ophthalmopathy (GO). We performed a prospective study to evaluate the usefulness of somatostatin as compared to corticosteroid in the treatment of moderately severe GO. All patients were rendered euthyroid and observed for 3 months to exclude spontaneous improvement without active treatment. They were randomized to receive either somatostatin (SS, octreotide 200 micrograms q8h subcutaneously, n = 8) or corticosteroid (CS, prednisone 1 mg/kg/day in decreasing doses, n = 10). Assessments of soft tissue inflammation, exophthalmos, palpebral aperture, intraocular pressure, diplopia, cornea, and visual acuity were made every 4 weeks for 3 months. MRI of the orbit was performed before and after treatment. Both SS and CS therapy decreased the palpebral aperture and activity score after 3 months (p < 0.05), but those treated with CS had a lower activity score after treatment when compared to SS [2.5 (1-7) v.s. 3.5 (0-4), median (range), p < 0.05]. Only CS, but not SS, was able to reduce intraocular pressure and muscle size as documented by MRI, but no significant reduction in proptosis was observed in either group. Also, patients' self-assessments of the eye changes after treatment were similar between the two groups. Both groups showed significant elevation of urinary glycosaminoglycan (GAG) excretion before therapy (SS 24.6 +/- 10.8; CS 27.8 +/- 11.4 mg/24 h), which was reduced after treatment (SS 12.5 +/- 7.3; CS 10.8 +/- 6.3 mg/24 h, p < 0.05). However, no significant correlation could be observed between the degree of GAG reduction and the clinical outcome of the patients. In conclusion, the long acting SS octreotide was effective in reducing soft tissue inflammation and providing symptomatic relief in GO but not as effective as corticosteroid in reducing muscle size. In view of the minimal side-effects and similar efficacy as compared to corticosteroid in patients with minimal extraocular muscle enlargement, it is suggested that a trial of SS may be considered in selected patients with GO.

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[Effect of clopidogrel combined with calcium-channel blocker on coronary artery disease in elderly patients: a propensity score-based retrospective cohort study].

To compare the effects of clopidogrel combined with dihydropyridine calcium-channel blockers (CCBs) or non-dihydropyridine CCBs on coronary artery disease (CAD) in elderly patients. The study cohort was defined as all patients ≥60 years old hospitalized for CAD with the prescription of clopidogrel between January 2001 and February 2011. The primary endpoint was death of all causes, and the secondary endpoints were nonfatal myocardial infarction (MI), hospitalization for unstable angina, stroke, transient ischemic attack, or repeat revascularization (PCI or coronary artery bypass graft). A total of 1021 patients were enrolled, among whom 402 patients were prescribed with clopidogrel and 619 with clopidogrel combined with CCB (dihydropyridine in 547 and non-dihydropyridine in 72). In clopidogrel group and clopidogrel with CCB group, the incidence density of death was 50.55 per thousand and 42.02 per thousand, respectively. The crude RR was 0.83 (95%CI: 0.55-1.26), and the multivariable-adjusted RR was 0.47 (95%CI: 0.14-1.6), showing no statistical significance in the rate of deaths of call causes between the two groups (P>0.05); the incidence density of composite thromboembolic events showed no significant difference between the two groups, either (P>0.05). After weighting of the propensity score, the patients with clopidogrel coadministered with non-dihydropyridine CCB showed a significant increase in composite thromboembolic events than those taking dihydropyridine CCB, with a SMRW-adjusted OR of 1.97 (95%: 1.2-3.23, P=0.007). No significant difference was observed in death or composite thromboembolic events between Pgp-inhibiting CCBs and non-Pgp-inhibiting CCBs. Compared with clopidogrel without CCB, clopidogrel with CCB does not increase the mortality or composite thromboembolic events in elderly CAD patients, but clopidogrel combined with non-dihydropyridine CCB is associated with significantly increased composite thromboembolic events in comparison with dihydropyridine CCB.

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[Rapidly progressing glomerulonephritis. Spontaneous course and differential therapy with special reference to the infection-associated form].

Since 1971 we observed 31 patients with histologically proven rapidly progressive (crescentic) glomerulonephritis. At the onset of therapy 16 patients presented with end stage renal failure, the others with impaired renal function. 21 patients received combined immunosuppressive therapy, consisting of prednisone, cyclophosphamide and azathioprine. 8 patients were treated with membrane plasmapheresis, additionally. 10 patients received no specific therapy. After 5 years 13 patients were on hemodialysis, 4 had impaired renal function and 10 patients were dead. Two patients died due to the progression of underlying diseases, the others were lost following infectious diseases. There was no additional positive effect in the group treated with membrane plasma separation compared with patients treated only immunosuppressive. Only in 4 patients without specific therapy normalization of renal function occurred. In these patients RPGN appeared after an infectious disease. We conclude that an infectious disease associated RPGN is an own entity of glomerulonephritis that has a very good prognosis and needs only antibiotic therapy.

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Effects of clonidine on alprazolam discontinuation in panic patients: a pilot study.

Effects of adjunctive clonidine (0.15 to 0.7 mg/day) on symptoms experienced during and for 4 weeks after gradual alprazolam discontinuation were observed in panic disorder patients after 6 weeks of successful treatment. Twelve of 14 entered patients were considered to have had a sufficient period of discontinuation (2 weeks) and clonidine administration (1 week) for effects to be assessed adequately. Nine of these 12 patients reached zero dose of alprazolam in 3 to 4 weeks. However, 10 of 12 patients experienced new withdrawal symptoms and 11 of 12 experienced recurrent panic attacks during tapering. Although a greater proportion of patients were successfully discontinued in a shorter time than in a previous nonclonidine trial, clonidine did not appear to have a specific effect on relapse or withdrawal. A placebo-controlled trial is needed to discriminate between possible contributions of clonidine and other factors (e.g., physician attitude, placebo effect of pill taking) to this improved outcome.

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The antibiotic susceptibility patterns of uropathogens among children with urinary tract infection in Shiraz.

Urinary tract infection (UTI) is one of the most common bacterial infections in pediatrics. Delay in diagnosis and treatment can cause significant morbidity. The physicians knowledge regarding the symptoms, microorganisms that caused UTI, and effective antibiotics in a geographical area can help them to select the appropriate antibiotics. This study was performed to determine the prevalence of bacteria that cause UTI and their susceptibility to common antibiotics as well as the common symptoms and associated factors in children of Shiraz, Southern Iran.This cross sectional study was performed among 202 children with UTI, aged 2 months to 18 years old, between August and November 2014 in pediatric medical centers of Shiraz University of Medical Sciences. Urine samples were collected using urinary catheter or suprapubic in children < 2 years and mid-stream in children over 2 years, respectively. The type of micro-organisms causing UTI was determined and evaluation of antibiotic susceptibility for each organism was assayed by the Kirby Bauer method using antibiogram test. Patient's information was collected through checking the medical documents and interview with parents.Our results showed that the frequency of UTI was significantly higher in girls (70.3%) than in boys. The most commonly discovered pathogens were Escherichia coli (E coli) (51.5%), followed by Klebsiella spp. (16.8%), and Enterococcus spp. (9.9%). Overall susceptibility test showed the highest resistance to ampicillin (81.2%) and cotrimoxazole (79.2%), and the highest sensitivity to imipenem (90.1%) and Gentamicin (65.3%). Gram negative and positive bacteria showed the highest antibiotic resistance to amoxicillin (83.8%) and clindamycin (100%), respectively. In addition, production of extended spectrum beta lactamase (ESBL) was 69.2% and 30.8% in E coli and Kelebsiella respectively.The efficacy of third generation of the cephalosporins was reduced because of the high rate of production of ESBL and drug resistance. These results inform the physician as to which antibiotics are appropriate to prescribe for the patient, as well as urine culture reports and following the patient's clinical response so that high antimicrobial resistance is not developed at the community level.

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How does previous corticosteroid treatment affect the biopsy findings in giant cell (temporal) arteritis?

To determine the effect of previous corticosteroid treatment on the results of temporal artery biopsy. Consecutive case series. Tertiary care center. A consecutive cohort of 535 patients who had temporal artery biopsies at Mayo Clinic, Rochester, Minnesota, between 1 January 1988 and 31 December 1991. The dose and duration of corticosteroid treatment received before temporal artery biopsy and detailed clinical and laboratory data were obtained from the patients' medical records. All temporal artery biopsy slides were re-evaluated by a pathologist blinded to clinical data, previous corticosteroid treatment information, and the original pathologic diagnosis. Biopsy specimens were classified as negative for arteritis, positive for typical temporal arteritis, or positive for atypical temporal arteritis. Biopsy results were positive for 31% of patients (89 of 286) who did not receive corticosteroids before biopsy and for 35% of those (86 of 249) who did receive corticosteroids before biopsy (P = 0.4; 95% confidence interval for the difference, -4.7% to 11.5%). Patients who received corticosteroids before biopsy tended to have clinical features more suggestive of arteritis. A multiple logistic regression analysis model, controlling for these differences in clinical and laboratory features, showed that the biopsy positivity rate was unrelated to previous corticosteroid treatment. Although these results do not prove that histologic features are unaffected by corticosteroids, they show that, in this large, consecutive sample, the positivity rates of temporal artery biopsy were similar in untreated and corticosteroid-treated patients. Temporal artery biopsy may show arteritis even after more than 14 days of corticosteroid therapy in the presence of clinical indications of active disease.

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[A new principle in long-term treatment of essential hypertension: angiotensin-converting enzyme inhibition (author's transl)].

The blood pressure lowering effect of the orally effective converting-enzyme-inhibitor captopril (SQ 14.225) was investigated in a double-blind study in 20 patients with moderate essential hypertension. During treatment with captopril alone (150 mg t.i.c.) blood pressure dropped from an average of 167/111 to 148/99 mm Hg lying and from 164/113 to 143/99 mm Hg upright whereby 4 patients showed normalisation of their blood pressure (less than 145/95 mm Hg). There was no significant change of pulse frequency. Addition of hydrochlorothiazide led to return to normal of blood pressure in all patients. Even after 6 months of treatment tolerance had not developed. The antihypertensive effect of captopril alone paralleled the one of hydrochlorothiazide and there were no side effects. Activity of the converting enzyme in serum as well as plasma concentrations of angiotensin II and aldosterone were clearly lowered by captopril whereas plasma renin activity increased significantly. Renal sodium and water excretion and glomerular filtration rate were not influenced.

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The effects of salbutamol aerosol on lung function in patients with pulmonary emphysema.

The effects of inhaling 400 micrograms of salbutamol were compared with identical placebo inhaler in a double blind cross-over study of 20 patients with radiological evidence of pulmonary emphysema. There was a small but significant rise in the forced expiratory volume in one second (FEV1), but there was a much greater increase in vital capacity (VC), which was accompanied by a reduction in residual volume. Symptomatic improvement after salbutamol was reported by 14 of the patients and VC increased significantly in this group; there was no significant increase in VC in patients who did not prefer the active inhaler. There was no consistent change in the FEV1/VC ratio after salbutamol administration and this ratio is misleading as an indicator of bronchodilator responsiveness in patients with emphysema. Salbutamol is thus a valuable addition to treatment in patients with pulmonary emphysema and the response to treatment is best judged by measuring the improvement in VC.

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A placebo controlled trial of bupropion for smoking cessation in schizophrenia.

Schizophrenic patients have high rates of cigarette smoking compared with the general population. We compared sustained-release (SR) bupropion with placebo for smoking cessation in patients with schizophrenic disorders. We also examined how antipsychotic class predicts smoking cessation outcomes with bupropion. Thirty-two subjects meeting DSM-IV criteria for schizophrenia or schizoaffective disorder and nicotine dependence were randomized to bupropion SR (BUP, 300 mg/day) or placebo (PLA). Outcomes included treatment retention, smoking abstinence rates, expired breath carbon monoxide (CO) levels, psychotic symptoms, and medication side effects. Bupropion significantly increased trial endpoint 7-day point prevalence smoking abstinence rates compared with placebo [BUP, 8/16 (50.0%), PLA, 2/16 (12.5%); chi(2) = 5.24, df = 1, p <.05], and reduced CO levels during the trial [Medication x Time interaction; Z = 3.09, p <.01]. Positive schizophrenia symptoms were not altered by BUP, but negative symptoms were significantly reduced. Atypical antipsychotic drug treatment enhanced smoking cessation responses to BUP. Major side effects were dry mouth, gastrointestinal symptoms, headache, and insomnia. Our results suggest that 1) BUP enhances smoking abstinence rates compared with PLA in nicotine-dependent schizophrenic smokers; 2) BUP is well-tolerated and safe for use in these patients; and 3) atypical antipsychotics may enhance smoking cessation outcomes with BUP.

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Switching from high-dose clopidogrel to prasugrel in ACS patients undergoing PCI: a single-center experience.

Prasugrel has been shown to be superior to clopidogrel in the setting of ACS patients undergoing coronary angioplasty. However, few data have been reported so far on those patients who switch from clopidogrel to prasugrel after coronary angioplasty. Aim of the current study was to evaluate the safety of prasugrel loading dose administration in ACS patients undergoing PCI and pretreated with high-dose clopidogrel. From May 2010 to December 2011 150 ACS patients undergoing coronary angioplasty and pretreated with high-dose clopidogrel, were switched to prasugrel loading dose soon after the procedure. They were matched (ratio 1:2) according to sex and age with a group of 300 ACS patients undergoing angioplasty and treated with high-dose clopidogrel only from May 2010 to December 2011. All demographic clinical and angiographic were collected. Primary endpoint was the rate of major bleeding complications (according to ACUITY trial definition) at 30-day follow-up. Secondary endpoints were: TIMI major and minor bleeding, definite stent thrombosis, major adverse cardiac events (MACE) and Net adverse cardiac events (NACE) at 30-day followup. The two groups of patients showed similar baseline demographic, and clinical characteristics. Most of the patients had unstable angina or non-ST segment elevation myocardial infarction. Almost (about 95 %) all patients underwent radial approach. No difference was observed in major bleeding complications according to both ACUITY (2.0 vs 2.0 %) and TIMI Major (0.7 vs 1.3 %) definition. No difference between the two groups was observed in terms of in-stent thrombosis, MACE and NACE at 30-day follow-up. Our observational study showed that switching to prasugrel with loading dose soon after angioplasty among ACS patients who were pretreated with clopidogrel seems to be well tolerated without overt evidence of heightened major bleeding. Future large randomized trials are certainly needed to confirm these findings.

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Effect of atorvastatin on progression of sensorineural hearing loss and tinnitus in the elderly: results of a prospective, randomized, double-blind clinical trial.

To test whether the 3-hydroxy-3-methylglutaryl- coenzyme A reductase inhibitor atorvastatin can slow down the progression of presbycusis. Fifty patients 60- to 75-years-old with presbycusis and moderately elevated serum cholesterol. In a double-blind design, patients were randomly assigned to treatment with either atorvastatin (40 mg/d orally) or placebo. Pure-tone audiometry and tinnitus evaluation at enrolment and after 7 and 13 months. Development of hearing thresholds after 7 and 13 months showed no significant differences between the groups. Tinnitus score continuously improved in the atorvastatin group (34.8 at 7 and 27.6 at 13 mo), whereas it slightly deteriorated in the placebo group (24.8 at 7 and 26.8 at 13 mo). The effect on tinnitus was a tendency without statistic significance (p = 0.0833). Atorvastatin had no effect on the development of hearing thresholds, but resulted in a trend toward a relief of tinnitus.

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Large early variation of residual platelet reactivity in Acute Coronary Syndrome patients treated with clopidogrel: results from Assessing Platelet Activity in Coronary Heart Disease (APACHE).

There is a large inter-individual variation in response to clopidogrel treatment and previous studies have indicated higher risk of thrombotic events in patients with high residual platelet reactivity (HRPR), but the optimal time-point for testing is not established. The aim of this study was to investigate the optimal time-point for aggregometry testing and the risk of major adverse cardiac events associated with HRPR. We included 125 patients with ACS (73 with STEMI, and 71 received abciximab). The prevalence of HRPR varied substantially over time. The rate of HRPR in patients treated and not treated with abciximab were 43% vs 67% (p=0.01) before, 2% vs 23% (p=0.001) 6-8h after, 8% vs 9% (p=0.749) 3days after, and 23% vs 12% (p=0.138) 7-9 days after loading dose of clopidogrel. We found HRPR in 18% of the patients but only four ischemic events during 6months follow-up, with no significant difference between HRPR patients compared to the rest of the population. There were 3 TIMI major bleedings, all of which occurred in the low residual platelet reactivity (LRPR) group. There is a large variation in platelet reactivity over time, also depending on adjunctive therapy, which has a large impact on optimal time-point for assessment. We found HRPR in almost 1 in 5 patients, but very few MACE, and not significantly higher in HRPR patients. In a contemporary ACS population, with low risk for stent thrombosis, the predictive value of HRPR for ischemic events will probably be low.

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Aerosolized furosemide in wheezy infants: a negative report.

We investigated the effects of 10 mg aerosolized furosemide on clinical score in 28 acutely wheezing infants (Part A) and in a second group of 20 intermittently wheezing babies on airway resistance and functional residual capacity during a symptomfree period (Part B), using a double-blind, placebo-controlled design. In both parts of the study no therapeutic effects were observed during and following aerosol inhalation of 10 mg furosemide.

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Methylphenidate use in males with Duchenne muscular dystrophy and a comorbid attention-deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD) is a common comorbidity in Duchenne muscular dystrophy (DMD). Until now, treatment with methylphenidate (MPH) has never been systematically assessed and described in this population. Our aim was to evaluate the effectiveness and safety of short acting MPH for learning problems in males with DMD and ADHD. Neuropsychological (cognition and behavior) and medical data of a sample of ten males (mean age = 8.1 years, range 6.3-9.8) with DMD and an ADHD diagnosis was retrospectively analyzed at baseline (T0; without MPH), short-term follow-up (T1; with MPH; mean interval T0-T1 = 8.3 months, range 4.3-15.6), and long-term follow-up (T2; mean interval T1-T2 = 23.1 months, range 2.6-77.7). An initial MPH dose of 5 mg/day was given on school mornings, with an increase of 2.5-5 mg/week depending on individual tolerance and treatment response, until a sufficiently effective dose was reached (range 0.2-0.6 mg/kg/day). At T1, results demonstrated an improvement in attention (i.e. concentration, impulsivity, and distractibility) in four patients. Suboptimal effects were reported in four patients, and no effects in two patients. At T2, seven patients showed considerable improvement in attention. No major side effects were reported. Overall, our data show that short acting MPH can be clinically effective for learning problems in males with DMD and ADHD, with regular cardiac follow-up, and close monitoring of side effects and neuropsychological effects. Furthermore, this underscores the importance of the use of validated cognitive and behavioral measurement tools with adequate sensitivity to objectively evaluate the effect of MPH.

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[Aortic root dilatation rate in pediatric patients with Marfan syndrome treated with losartan].

Medical therapy with angiotensin II receptor blockers/angiotensin-converting enzyme inhibitors and/or beta-blockers was reported to reduce aortic root dilatation rates in pediatric patients with Marfan syndrome. No data are available in the literature on losartan effects after 3 years of therapy. The aim of our study was to establish whether losartan reduces aortic root dilatation rates in pediatric patients with Marfan syndrome in the mid and long term. This is a retrospective analysis of 38 pediatric patients with Marfan syndrome followed at the Marfan Clinic of S. Orsola-Malpighi Hospital of the University of Bologna (Italy). Aortic diameters were measured at sinuses of Valsalva and proximal ascending aorta with transthoracic echocardiography. After a mean follow-up of 4.5 ± 2.5 years (range 2-9 years), aortic root z score at sinuses of Valsalva and proximal ascending aorta remained stable. The average annual rate of change in aortic root z score was -0.1 ± 0.4 and 0 ± 0.3 at sinuses of Valsalva and proximal ascending aorta, respectively. The mean dose of losartan was 0.7 ± 0.3 mg/kg/day. Three patients were non-responders, probably because of late beginning or low dose of therapy. Eight patients underwent cardiac surgery (aortic root surgery in 5 and mitral valve repair in 3), all of them started losartan later in life. Despite the retrospective design of the study and the small sample size, a beneficial effect of losartan therapy was observed in pediatric patients with Marfan syndrome in the mid and long term. Late beginning or low doses of losartan can turn off the effects of therapy.

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Hemodynamic comparison of twice daily metoprolol tartrate with once daily metoprolol succinate in congestive heart failure.

To compare the hemodynamic effects of twice daily metoprolol tartrate (MT) and once daily metoprolol succinate (MS) in congestive heart failure patients. Adverse hemodynamic effects with MT demonstrated during initiation persist with drug readministration during chronic therapy. Patients were randomly assigned to 6.25 mg MT or 25 mg MS orally and the dose was gradually increased to a target of 50 mg twice a day or 100 mg once a day, respectively. Hemodynamic measurements were obtained at baseline and after three months of therapy--both before and after drug readministration. Long term metoprolol therapy produced significant functional, exercise and hemodynamic benefits with no difference in response between either metoprolol preparation in the 27 patients (MT [14], MS [13]). When full dose metoprolol was readministered during chronic therapy, there were parallel adverse hemodynamic effects in both drug groups. Cardiac index decreased by 0.6 liters/min/m2 (p < 0.0001) with MT and by 0.5 liters/min/m2 (p < 0.0001) with MS. Systematic vascular resistance increased by 253 dyne-sec-cm(-5) (p < 0.001) with MT and by 267 dyne-sec-cm(-5) (p < 0.0005) with MS. Stroke volume index decreased by 7.0 ml/m2 (p < 0.0005) with MT and by 6.5 ml/m2 (p < 0.0001) with MS, while SWI decreased by 6.2 g-m/m2 (p < 0.0005) with MT and by 6.0 g-m/m2 (p < 0.001) with MS. Metoprolol tartrate and MS produce similar hemodynamic and clinical effects acutely and chronically despite the fourfold greater starting dose of MS used in this study. A more rapid initiation with readily available starting doses of MS may offer distinct advantages compared with MT in treating chronic heart failure patients with beta-adrenergic blocking agents.

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Serotonergic antidepressants and their efficacy in obsessive compulsive disorder.

Since 1985, major advances have been made in the pharmacologic treatment of obsessive compulsive disorder. Clomipramine is undoubtedly effective. Other selective serotonin reuptake inhibitors, such as fluvoxamine and sertraline, seem effective as well. Fluoxetine's efficacy has been principally based on convincing open-label studies and clinical practice. No large controlled studies have been published. A preliminary analysis of a double-blind trial in which 51 obsessive compulsive disorder patients were randomly assigned to either placebo or three fixed doses of fluoxetine reveals that the drug is decisively helpful. Unexpectedly, the 20-mg/day dose was as effective as the 40- or 60-mg/day dose. Although these findings further advance our understanding of short-term pharmacologic treatments, few data are available regarding maintenance doses, relapse, and efficacy of adjunctive treatments.

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Effect of CGP 17/582, a selective beta-adrenoceptor antagonist, on the haemodynamic and hypokalaemic response to adrenaline.

1. CGP 17/582B is a new beta-adrenoceptor antagonist which on experimental studies appears to combine selective beta 1-adrenoceptor blockade with partial agonist activity (ISA). Assessing beta-adrenoceptor selectivity and the degree of partial agonist activity in vivo can be difficult. 2. In a double-blind placebo controlled crossover study we have compared the effect of oral pretreatment for 7 days with CGP (100 mg twice daily), with propranolol (non-selective beta-adrenoceptor blocker with no ISA) and metoprolol (selective beta-adrenoceptor blocker with no ISA) on resting heart rate and heart rate response to submaximal exercise on a bicycle ergometer to assess the degree of beta-adrenoceptor blockade and also the changes in blood pressure, heart rate and potassium during the intravenous infusion of (-)-adrenaline to determine the degree of beta 2-adrenoceptor blockade. 3. Subjects underwent submaximal exercise testing on the second and fifth day of each treatment period and on the seventh day received a 2 h infusion of (-)-adrenaline (0.06 microgram kg-1 min-1). Heart rate, blood pressure, plasma potassium and catecholamines were measured throughout the study period. 4. All three active treatments significantly reduced exercise induced tachycardia. The (-)-adrenaline infusion significantly reduced plasma noradrenaline levels following propranolol and metoprolol and to a lesser extent with placebo but were unaltered on CGP. Baseline heart rate was unaltered by CGP but was significantly reduced by metoprolol and propranolol. Adrenaline significantly reduced plasma potassium levels following placebo and CGP pretreatment but plasma potassium was unaltered by adrenaline with metoprolol and propranolol pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)

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Treatment with lansoprazole also induces hypertrophy of the parietal cells of the stomach.

The aim of the present study was to investigate whether not only omeprazole but also lansoprazole leads to hypertrophy of the parietal cells of the gastric mucosa. We investigated the gastric mucosa of 295 patients with gastro-esophageal reflux disease prior to therapy, after 8 weeks of treatment with 30 mg lansoprazole/day, and after 6 and 12 months of long-term treatment with 15 or 30 mg lansoprazole, or 20 mg omeprazole/day. In a small group of 48 patients, a follow-up examination was carried out 3 months after termination of the study. Following acute treatment with 30 mg lansoprazole/day, 84% of the patients revealed parietal cell hypertrophy, while under long-term treatment this figure rose to 89%. The grade of the parietal cell hypertrophy increased continuously under long-term treatment. With regard to the incidence and grading of parietal cell hypertrophy, no significant differences were found among the three groups receiving long-term treatment. Three months after termination of treatment with these proton-pump inhibitors, the hypertrophy of the parietal cells had largely disappeared again. This study shows that hypertrophy of the parietal cells in the gastric mucosa occurs not only under treatment with omeprazole, but also under therapy with lansoprazole, and is reversible when the proton pump inhibitors are discontinued.

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Effect of Corticosteroid Therapy in Patients With Cardiac Sarcoidosis on Frequency of Venous Thromboembolism.

Sarcoidosis is a multisystem inflammatory condition with occasional cardiac involvement (CS), which may be associated with risk of venous thromboembolism (VTE). As data on VTE in CS are sparse and corticosteroid therapy has not been previously examined, we aim to determine the association between CS, corticosteroid treatment for CS, and VTE. Patients referred to our institution with concern for sarcoidosis and underwent a positron emission tomography (PET) scan were retrospectively assessed. Chi-squared and multivariate regression analyses were conducted to determine the association between a diagnosis of sarcoidosis, CS, corticosteroid use, and VTE events. Six hundred and forty nine patients were split into 3 categories: 235 with no sarcoidosis (NS), 91 with extra-cardiac sarcoidosis only (ECS), and 323 with CS (isolated CS and/or CS with extra cardiac sarcoid). Thirty nine CS, 7 ECS, and 9 NS patients developed PE while 44 CS, 3 ECS, and 18 NS patients developed DVT. On multivariate regression, neither CS nor ECS was an independent risk factor for VTE (p >0.05) but corticosteroid use was independently associated with VTE (HR 3.06, p = 0.007 for PE, HR 6.21, p <0.0001 for DVT). On logistic regression analysis, corticosteroid dose was found to be independently associated with both PE (p = 0.001) and DVT (p = 0.007). Optimal threshold for defining VTE risk with corticosteroid therapy was a prednisone-equivalent dose of 17.5 mg. In conclusion, contrary to previous studies, this current study found that neither sarcoidosis nor CS is an independent risk factor for VTE. Rather, corticosteroid therapy was associated with an increased risk of VTE.

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Acute change in anterior cingulate cortex GABA, but not glutamine/glutamate, mediates antidepressant response to citalopram.

Little is known about the acute effects of antidepressant treatments on brain glutamate and gamma-amino-butyric acid (GABA) levels, and their association with clinical response. Using proton magnetic resonance spectroscopy (¹H-MRS) we examined longitudinally the effects of citalopram on glutamine/glutamate ratios and GABA levels in the pregenual anterior cingulate cortex (pgACC) of individuals with major depressive disorder (MDD). We acquired ¹H-MRS scans at baseline and at days 3, 7, and 42 of citalopram treatment in nineteen unmedicated individuals with MDD. Ten age- and sex-matched non-depressed comparison individuals were scanned once. The association between 1) baseline metabolites and 2) change in metabolites from baseline to each time point and clinical response (change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 42) was assessed by longitudinal regression analysis using generalized estimating equations. Contrary to our hypotheses, no significant associations emerged between glutamate metabolites and clinical response; however, greater increases (or smaller decreases) in pgACC GABA levels from baseline to days 3 and 7 of citalopram treatment were significantly associated with clinical response. These findings suggest that an acute change in GABA levels in pgACC predicts, and possibly mediates, later clinical response to citalopram treatment in individuals with MDD.

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A prospective study on ultrasound-guided compression therapy or thrombin injection for treatment of iatrogenic false aneurysms in patients receiving full-dose anti-platelet therapy.

False aneurysms (FA) develop at the puncture site in up to 6% of percutaneous cardiovascular procedures. Previous management included surgery or manual compression. Recently, selective injection of thrombin has been proposed as an alternative. However, there has been no direct comparison of thrombin injection to manual compression. To study the effectiveness of manual compression compared to that of thrombin injection in patients with false aneurysms on full-dose aspirin and clopidogrel. METHODS AND PROTOCOL: All patients with a clinically suspected FA after percutaneous invasive procedures were recruited for the study. The patients were examined with color ultrasound (7.5 MHz transducer). The minimum and maximum diameters of the false aneurysm and the distance between the surface and the false aneurysm were measured online. Under local anesthesia, manual compression was applied under sonographic guidance in all patients. If compression stopped flow into the false aneurysm, manual compression was applied for a maximum of 40 min followed by compression bandage for a minimum of 12 hours. If compression failed, thrombin was injected under ultrasound guidance. Thirty-six patients had a FA. Their age ranged from 58 to 90 years (mean 71+/-9 years). All patients were taking aspirin (median dose 100 mg per day) and clopidogrel (median dose 75 mg per day). Additionally, 24 patients had received subcutaneous heparin (7500 to 12 500 units) or enoxaprin (0.4-1.0 ml) 3 to 12 hours before treatment. The mean width of the false aneurysm was 22.1+/-3 mm, mean length 33.6+/-35.4 mm, and mean depth 19.5+/-8.2 mm. In six patients (17%), ultrasound-guided manual compression was tolerated, succeeding after 5 to 31 minutes. Thirty patients received thrombin injections (100-1800 units, mean 880+/-470 units, median 800 units). Complete thrombosis occurred in 28 patients (93%). Surgery was performed in the other two patients. The thrombin injection was not associated with any complications. In particular, there were no peripheral vascular complications. In patients with FA taking aspirin and clopidogrel, selective thrombin injection is more effective than manual compression.

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[Can we prevent the progression of aortic valve sclerosis and stenosis? The need for a prospective, randomized trial].

Cardiologists long assumed that aortic valve sclerosis/stenosis is a wear-and-tear, degenerative process; recent studies suggested that lipoproteins can play a key role in the development of both sclerosis/stenosis in the aortic valve. Thus, sclerosis/stenosis cannot be considered as a simple degenerative process, but on the contrary it is complex and involves multiple pathogenetic mechanisms. Experimental, clinical and epidemiological data support the link between aortic valvulopathy and atherosclerosis: both are caused by inflammation, lipid deposition, and accumulation of extracellular bone matrix protein. In non-randomized clinical studies, hydroxy-methylglutaryl-coenzyme A reductase inhibitors minimized the progression of aortic valvulopathy. The major pharmacological effect, supposed to underlie the inferred (but still unproven) impact of statins on aortic sclerosis/stenosis is plasma cholesterol reduction. Lately, retrospective clinical studies supported this hypothesis and suggested a key role for statins in delaying the progression of aortic valvulopathy. However, the potential favorable effects of statins require confirmation. Prospective trials in Canada and Europe are now ongoing (ASTRONOMER--Aortic Stenosis Progression Observation Measuring Effects of Rosuvastatin; SEAS--Simvastatin and the Ezetimibe in Aortic Stenosis) and will address the use of cholesterol-lowering drugs in reducing the progression of aortic valve stenosis and in improving clinical outcomes.

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Antihypertensive drugs and glucose metabolism: comparison between a diuretic, a beta-blocker and felodipine, a new calcium antagonist in subjects with arterial hypertension and diabetes.

Felodipine, a new antihypertensive calcium antagonist, was compared with metoprolol, a beta-blocker, and hydrochlorothiazide, a diuretic, with respect to glucose tolerance in a randomized double-blind cross-over study consisting of 11 patients, of age range 50-70 years, who had developed diabetes during antihypertensive treatment. Each treatment period lasted for 10 weeks. The blood pressure was similar irrespective of treatment. Serum glucose levels during the oral glucose tolerance test were significantly lower when the patients were treated with felodipine than when they were taking hydrochlorothiazide. Serum insulin levels appeared to decrease at an earlier stage of the test when the patients were treated with felodipine, the calcium antagonist, than with the other two antihypertensive substances, which suggests that glucose tolerance is impaired to a lesser extent during treatment with the calcium antagonist. Glucose tolerance was never completely normalized with any of the drugs tested.

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Evaluation of medication compliance in patients on antidepressants at an outpatient tertiary cancer center setting.

The purpose is to evaluate antidepressant compliance in a cancer population at a tertiary cancer center and to determine if there are covariates of importance in predicting the level of compliance in the study population. Patients who received at least three prescriptions covering parts of each month for a continuous 6-month period with at least one of the months being in 2006 from a tertiary cancer center were identified as the prevalent population of interest for this retrospective study. Data collected included demographics, cancer and co-morbid diagnoses, and compliance to antidepressant medication using medication possession ratio (MPR) by patient, medication class, and individual agents. Analysis was conducted using descriptive statistics, analysis of variance, and logistic regression (using MPR ≥ 80 as cutoff). The study population included 297 patients with demographics showing 69% female, 71% Caucasian, a mean age of 52.94 (SD: 12.42), and an average 403 days of follow-up. The MPR for the total study population was 0.87 with 78% of the population having an MPR of ≥ 80% and 22% having an MPR of less than 80%. While there was no significant difference in MPR by different pharmaceutical classes, there were significant differences in the MPR by specific agents (p = 0.02), with nortriptyline having the lowest MPR of 0.79 and doxepin, fluoxetine, mirtazapine, and venlafaxine all having MPR over 0.90. There was also a trend toward a difference in MPR between Caucasians versus non-Caucasians, p = 0.055. There appears to be relatively good compliance to antidepressant medications in the study population.

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The effectiveness of inositol and metformin on infertile polycystic ovary syndrome women with resistant to letrozole.

The purpose is a comparison of effectiveness of myo-inositol and metformin in infertile women with polycystic ovary syndrome (PCOS) treated with letrozole. This study is a randomized single-blind controlled clinical trial undertaken in 150 infertile PCOS women. For all patients, letrozole is prescribed at a dose of 7.5 mg per day from the third day of menstruation for 5 days. Patients who did not ovulate were included and divided into three pretreatment groups: group I(control group), 200 µg of folic acid (as a placebo); group II, 1500 mg of metformin daily plus 200 µg of folic acid, and group III, inositol 2 g plus 200 µg of folic acid received twice daily for 3 months. In the last cycle, 7.5 mg letrozole was prescribed for the induction of ovulation. Primary outcomes were ovary function and pregnancy. The ovarian function was not significantly different in those groups, whereas the ovarian function of inositol + folic acid group in normal BMI found significantly higher than other BMI spectra. In addition, the ovarian function is significantly higher in the inositol + folic acid group by increasing the infertility duration. The incidence of pregnancy is lower in letrozole + folic acid + inositol group than the other groups; however, it is not significant. The addition of inositol and metformin to the treatment of infertile PCOS women with letrozole resistance improves the ovarian function; however, it is not significant. Of note, inositol was more effective than metformin in patients with normal BMI. IRCT2017070234845N1.

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Chronic histiocytic intervillositis (CHI): current treatments and perinatal outcomes, a systematic review and a meta-analysis.

Chronic histiocytic intervillositis (CHI) is a rare placental lesion with a high recurrence rate and poor perinatal outcomes. There are currently limited guidelines regarding the diagnosis of this condition in the index pregnancy and treatment where recurrence is suspected. The primary objective of this systematic review and meta-analysis was to determine the perinatal outcomes of pregnancies affected by chronic histiocytic intervillositis and to what extent they can be improved with treatment. The secondary objective was to assess the relationship between CHI lesion severity and pregnancy loss. A systematic search of Ovid Embase, Web of Science, Science Direct, PubMed, Ovid Medline, Google Scholar and CINAHL was carried out. Case reports, cohort, case-control and randomised controlled trials (RCT) detailing the perinatal outcomes of CHI pregnancies, both treated and untreated, were included. No RCTs were identified. However, in a review population of 659 pregnancies, with additional 7 in case reports, CHI treatments included aspirin, prednisone, prednisolone, low molecular weight heparin (LMWH), hydroxychloroquine and adalimumab. A descriptive synthesis of data found mixed results for treatments in relation to live birth, miscarriage and fetal growth restriction outcomes. Furthermore, quantitative synthesis of 38 pregnancies revealed a non-significant improvement in live birth rate with CHI targeted treatment (OR 1.79 [95% CI 0.33-9.61] (p=0.50), while meta-analysis of CHI severity in line with pregnancy loss, in a sample of 231 pregnancies, revealed lower odds of pregnancy loss with less severe lesions (OR: 0.17 [0.03-0.80], p=0.03). This systematic review and meta-analysis reinforce notions surrounding the insufficient evidence for CHI treatment. It also strengthens previous hypotheses detailing the positive association between CHI lesion severity and odds of pregnancy loss. Aspirin, LMWH, prednisolone, hydroxychloroquine and adalimumab are candidates with varying levels of weak to moderate evidence supporting their use. Further prospective research is required to obtain robust evidence pertaining to treatment safety and efficacy and optimal drug regimes. [website], identifier CRD42021237604.

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Impact of early (3 months) dual antiplatelet treatment interruption prior to renal transplantation in patients with second-generation DES on perioperative stent thrombosis and MACEs.

Early cessation of dual antiplatelet therapy (DAPT) is related to stent thrombosis (ST). The use of second-generation everolimus- and zotarolimus-eluting stents is associated with low restenosis rates and short duration of clopidogrel usage. Non-cardiac surgery in recently stent-implanted patients is associated with major adverse cardiac events (MACEs). Chronic renal failure patients awaiting renal transplantation may also undergo coronary stent implantation prior to surgery. Here we aimed to investigate the safety of early (3 months) DAPT interruption in second-generation drug-eluting stent (DES)-implanted renal transplant recipients. In total, 106 previously stent-implanted chronic renal failure patients who underwent renal transplantation were retrospectively enrolled. Three groups were formed according to stent type and the duration of DAPT: early-interruption (3 months from DES implantation), lateinterruption (3-12 months from DES implantation), and bare-metal stent (BMS; at least 1 month from BMS implantation) groups. Comparison among BMS, DES-early and DES-late groups indicated no difference in ST, myocardial infarction, death, and MACEs. In addition, no difference was observed in ST (p=0.998), myocardial infarction (p=0.998), death (p=0.999), and MACEs (p=0.998) between DES-early and DES-late groups. Early (3 months) interruption of antiplatelet treatment with second-generation stents before renal transplantation seems to be safe and does not lead to increase in the occurrence of ST and MACEs.

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Outcomes after implementation of a multimodal standard care pathway for laparoscopic colorectal surgery.

The aim of the study was to assess which aspects of an enhanced recovery programme are associated with better outcomes following laparoscopic colorectal surgery. A database of laparoscopic colorectal procedures performed in 2011 was reviewed. Elements of the enhanced recovery programme and compliance were evaluated for short-term (30-day) outcomes. Individual elements included gabapentin, celecoxib, intrathecal analgesia, diet, postoperative fluids, and paracetamol/non-steroidal anti-inflammatory drug pain management. Five hundred and forty-one consecutive procedures were included. Compliance with the enhanced recovery programme elements ranged from 82.4 to 99.3 per cent. Median length of hospital stay was 3 (i.q.r. 2-5) days, with 25.9 per cent of patients discharged within 48 h. Patients without complications had a median length of stay of 3 (i.q.r. 2-4) days if compliant and 3 (3-5) days if not (P < 0.001). Low oral opiate intake (oral morphine equivalent of less than 30 mg) (odds ratio (OR) 1.97, 95 per cent confidence interval 1.29 to 3.03; P = 0.002), full compliance (OR 2.36, 1.42 to 3.90; P < 0.001) and high surgeon volume (more than 100 cases per year) (OR 1.50, 1.19 to 1.89; P < 0.001) were associated with discharge within 48 h. Compliance with the elements of oral intake and fluid management in the first 48 h was associated with a reduced rate of complications (8.1 versus 19.6 per cent; P = 0.001). Median oral opiate intake was 37.5 (i.q.r. 0-105) mg in 48 h, with 26.2 per cent of patients receiving no opiates. Compliance with an enhanced recovery pathway was associated with less opiate use, fewer complications and a shorter hospital stay.

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Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men.

Selective serotonin reuptake inhibitors (SSRIs) are a widely used class of antidepressants that block the serotonin transporter. Osteoblasts and osteocytes express functional serotonin transporters; serotonin transporter gene disruption in mice results in osteopenia; and SSRI use has been associated with increased risk of hip fracture. To determine whether SSRI use is associated with lower bone mineral density (BMD) in older men and to compare the results for SSRIs with those of other antidepressants, we performed a cross-sectional analysis of data from 5995 men 65 years and older participating in the prospective cohort Osteoporotic Fractures in Men Study. Main outcome measures included medication use; BMD at the femoral neck, greater trochanter, and lumbar spine measured by dual-energy x-ray absorptiometry; and potential covariates. In adjusted analyses, mean BMD among SSRI users (n=160) was 3.9% lower at the total hip and 5.9% lower at the lumbar spine compared with BMD in men reporting no antidepressant use (n=5708 [P=.002 for total hip; P<.001 for lumbar spine]). There was no significant difference among users of trazodone hydrochloride (n=52) or tricyclic antidepressants (n=99) compared with nonusers. Adjusting for variables that could be associated with BMD and/or SSRI use did not significantly alter these results. The observed difference in BMD for SSRIs is similar to that seen with glucocorticoids. In this population of men, BMD was lower among those reporting current SSRI use, but not among users of other antidepressants. Further research is needed to confirm this finding in light of widespread SSRI use and potentially important clinical implications.

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Cognitive sequelae of treatment in childhood acute lymphoblastic leukemia: cranial radiation requires an accomplice.

We evaluated cognitive sequelae of treatment for childhood acute lymphoblastic leukemia (ALL). CNS therapy consisted of cranial irradiation (CRT) or no radiation. Children were also randomized to single intravenous high-dose methotrexate (HD-MTX) or conventional-dose methotrexate (CD-MTX) during induction, and all patients received intrathecal (IT) and systemic continuation chemotherapy. Sixty-six patients treated for ALL on Dana-Farber Cancer Institute protocol 87-01 were evaluated by standardized cognitive and achievement tests. These children had been assigned at diagnosis to a standard-risk (SR) or high-risk (HR) group and received no CRT or 18 Gy CRT, respectively. All patients were randomized to receive MTX during remission induction, either as CD-MTX (40 mg/m2) or HD-MTX (4 g/m2) with leucovorin rescue. There was no difference in cognitive outcomes between radiated and unirradiated patients (P > .4). However, the HD-MTX/CRT combination was associated with decreased intelligence quotient (IQ estimate, 9.3 points) for girls only (P < .08). A specific deficit in verbal coding and memory was documented for all patients (P < .0001). We conclude the following: (1) 18 Gy CRT per se was not an independent toxic agent for cognitive outcome; (2) HD-MTX during induction was associated with IQ decline in girls, but only when it was followed by CRT; and (3) impairment of verbal memory and coding was a consistent finding that was independent of CRT, which implicates some component of chemotherapy, possibly prednisone, as a CNS toxin.

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Improving outcomes for patients hospitalized with gout: a systematic review.

Hospital admissions for gout flares have increased dramatically in recent years, despite widely available, effective medications for the treatment and prevention of flares. We conducted a systematic review to evaluate the effectiveness and implementation of interventions in patients hospitalized for gout flares. A search was conducted in MEDLINE, Embase and the Cochrane library, from database inception to 8 April 2021, using the terms 'gout' and 'hospital' and their synonyms. Studies were included if they evaluated the effectiveness and/or implementation of interventions during hospital admissions or emergency department attendances for gout flares. Risk of bias assessments were performed for included studies. Nineteen articles were included. Most studies were small, retrospective analyses performed in single centres, with concerns for bias. Eleven studies (including five randomized controlled trials) reported improved patient outcomes following pharmacological interventions with known efficacy in gout, including allopurinol, prednisolone, NSAIDs and anakinra. Eight studies reported improved outcomes associated with non-pharmacological interventions: inpatient rheumatology consultation and a hospital gout management protocol. No studies to date have prospectively evaluated strategies designed to prevent re-admissions of patients hospitalized for gout flares. There is an urgent need for high-quality, prospective studies of strategies for improving uptake of urate-lowering therapies in hospitalized patients, incorporating prophylaxis against flares and treat-to-target optimization of serum urate levels. Such studies are essential if the epidemic of hospital admissions from this treatable condition is to be countered.

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Randomised, placebo controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients.

To determine the ability of montelukast, a leukotriene receptor antagonist, to allow tapering of inhaled corticosteroids in clinically stable asthmatic patients. Double blind, randomised, placebo controlled, parallel group study. After a single blind placebo run in period, during which (at most) two inhaled corticosteroids dose decreases occurred, qualifying, clinically stable patients were allocated randomly to receive montelukast (10 mg tablet) or matching placebo once daily at bedtime for up to 12 weeks. 23 academic asthma centres in United States, Canada, and Europe. 226 clinically stable patients with chronic asthma receiving high doses of inhaled corticosteroids (113 randomised to montelukast and 113 to placebo). Every 2 weeks, the inhaled corticosteroids dose was tapered, maintained, or increased (rescue) based on a standardised clinical score. Last tolerated dose of inhaled corticosteroids. Compared with placebo, montelukast allowed significant (P=0. 046) reduction in the inhaled corticosteroid dose (montelukast 47% v placebo 30%; least square mean difference 17.6%, 95% confidence interval 0.3 to 34.8). Fewer patients on montelukast (18 (16%) v 34 (30%) placebo, P=0.01) required discontinuation because of failed rescue. Montelukast reduces the need for inhaled corticosteroids among patients requiring moderate to high doses of corticosteroid to maintain asthma control.

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Comparison of tremor responses to orally administered albuterol and terbutaline.

This study was designed to compare the initial tremor response to 4.0 mg albuterol and 5.0 mg terbutaline orally administered and to study the question of tachyphylaxis by rechallenge after 3 wk of maintenance dosing. Twenty fasting patients with severe COPD in whom orally administered sympathomimetics were withheld for 2 wk were challenged with single doses of each drug in a crossover, randomized fashion 1 wk apart. Then after a further 3 wk of dosing 3 times a day of the second medication (10 patients received each medication), they were challenged once more 16 h after the last dose. Rest and postural tremor were measured at zero and 2 h using an accelerometer affixed to the finger, and measurements of subjective tremor, tremor power spectrum, plasma cyclic AMP and lactate, and forced vital capacity were also made. Postural tremor increased from 25.05 to 36.20 relative units for albuterol, an increase of 11.15 units, and from 24.90 to 57.70 units for terbutaline, an increase of 32.80 units (difference significant at p = 0.01). Plasma cyclic AMP (p less than 0.01) and lactate (p = 0.05) increases were also less for albuterol, and the FEV1 and FVC responses, though about one third less, did not differ significantly. After 3 wk, mean baseline tremor for both drugs was elevated even 16 h after the last 3 times a day dosing (38.00 and 33.10) for albuterol and terbutaline (difference, NS), and responses were much less to the single tablet (3.40 and 9.10, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

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Topical Clonazepam Solution for the Management of Burning Mouth Syndrome: A Retrospective Study.

To evaluate and compare the effectiveness of two concentrations of topical clonazepam solution in improving symptoms of burning mouth syndrome (BMS). A retrospective chart review was conducted of patients diagnosed with BMS and managed with topical clonazepam solution between 2008 and 2015. A 0.5-mg/mL solution was prescribed until 2012, when this was changed to a 0.1 mg/mL solution. Patients were instructed to swish with 5 mL for 5 minutes and spit two to four times daily. The efficacies of the two concentrations were compared using patient-reported outcome measures at the first follow-up, including the reported percentage of improvement in burning symptoms and the change in burning severity from baseline ranked on an 11-point numeric rating scale (NRS). Response to treatment was compared between the two concentrations using Wilcoxon rank sum test. A total of 57 subjects were included, 32 in the 0.1-mg/mL cohort and 25 in the 0.5-mg/mL cohort, and evaluated at a median follow-up of 7 weeks. The median overall percentage improvement was 32.5% in the 0.1-mg/mL cohort and 75% in the 0.5-mg/mL cohort. The median reduction in NRS score was 0.5 points in the 0.1-mg/mL cohort and 6 points in the 0.5-mg/mL cohort. The use of either outcome measure revealed that the response to treatment with the 0.5-mg/mL solution was superior to that of the 0.1 mg/mL solution (P < .01). These findings suggest that a 0.5-mg/mL topical clonazepam solution is effective in the management of BMS. Future randomized clinical trials are warranted.

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Usefulness of antiparkinsonian drugs during neuroleptic treatment and the effect of clonazepam on akathisia and parkinsonism occurred after antiparkinsonian drug withdrawal: a double-blind study.

Antiparkinsonian drugs used for 117 chronic schizophrenic patients receiving long-term neuroleptic treatment were withdrawn. Seventy-eight (66.7%) of the 117 patients were without akathisia and/or parkinsonism at least for 6 weeks after the antiparkinsonian drug withdrawal. A double-blind study of clonazepam was carried out for 22 patients and clonazepam was effective on 8 patients (100%) with akathisia and on 3 patients (75%) with parkinsonism. The authors conclude that these data support the need for discontinuous use of antiparkinsonian medication during the long-term neuroleptic therapy of chronic schizophrenic patients and the effectiveness of clonazepam in managing antiparkinsonian drug withdrawal-induced akathisia and parkinsonism.

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A prospective, randomized controlled study comparing lidocaine and tramadol in periprostatic nerve blockage for transrectal ultrasound-guided prostate biopsy.

To assess the efficacy of tramadol and lidocaine in reducing pain using the periprostatic nerve block technique with a spinal needle, guided by transrectal ultrasound (TRUS) before the biopsy application. Of the 112 eligible candidates who were asked to participate in the study, 90 agreed and provided informed consent. These 90 men were randomized into 3 groups. Group 1 (n = 30) received lidocaine, group 2 (n = 29) received tramadol, and group 3 (n = 31) received saline solution. Within 10 minutes of biopsy procedure completion, the patients were presented with visual pain scales and asked to rate the pain. The patients also asked whether they would be to return for this procedure if it became medically necessary. The postprocedural mean pain scores of lidocaine, tramadol, and placebo groups were found to be 1.73, 2.89, and 4.32, respectively. The mean pain scores were significantly lower in both the lidocaine and the tramadol groups compared with the placebo group (P <.001). In addition, statistically significant differences were found among the 3 groups regarding how willing they would be to return for the procedure if necessary. In this study, we showed that the local anesthetic effect of tramadol in decreasing pain in periprostatic nerve block during TRUS-guided biopsy. The use of tramadol for pain relief in transrectal ultrasound-guided prostate biopsy is a practical, effective, and comfortable method compared with the results of the control group.

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Treatment of bifurcation lesions using dedicated bifurcation stents versus classic bare-metal stents. Randomized, controlled trial with 12-month angiographic follow up.

The aim of this study was to compare the use of classic bare- metal stents with dedicated bifurcation bare-metal stents in patients who were not eligible for drug-eluting stents (DES) implantation. Sixty patients with bifurcation stenosis were randomly assigned to received either a dedicated bifurcation or a bare-metal stent (n = 30) or classic bare-metal stent (n = 30) with stenting of the parent vessel and angioplasty/or provisional stenting of the side branch. Fifty-nine patients underwent 12-month clinical and angiographic follow up unless this was performed earlier due to symptoms. Dual antiplatelet treatment was administered for 1 month. Acute success as well as the long-term clinical and angiographic outcome have been assessed in both groups. Baseline demographic, angiographic and procedure-related characteristics were well balanced in both groups. The use of dedicated stents was associated either with reduced procedure or fluoroscopy time (34 +/- 9 minutes vs. 46 +/- 20 minutes; p = 0.004 and 9 +/- 6 minutes vs. 15 +/- 9 minutes; p = 0.003, respectively) and lesser contrast volume (168 +/- 86 milliliters vs. 199 +/- 103 ml; p = 0.02). At the 12-month follow up, no statistically significant difference was found between both groups regarding major adverse cardiovascular events (MACE) (13.7 vs. 13.3%; p = 0.9). In our study we failed to demonstrate the superiority of a dedicated stent versus classic a bare-metal stent for the treatment of bifurcation lesions regarding MACE in patients who were not eligible for DES implantation. However, the use of dedicated stents may be preferable due to reduced procedure and fluoroscopy time and lesser contrast volume.

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HMG-CoA reductase inhibitors deplete circulating classical and non-classical monocytes following human heart transplantation.

Monocytes mediate immune responses following solid organ transplantation via cytokine secretion and differentiation to macrophage/dendritic cell lineages. To date, the pleiotropic immunomodulatory effect of statins on human monocytes following human heart transplantation has yet to be elucidated. This study was designed to assess the effects of statin administration on the monocyte repertoire. 108 patients were recruited into the study. Clinical data were collected from patients' notes. Peripheral blood immunophenotype was determined via flow cytometry (using CD11c, CD14, CD16, CD49d, CD64, CD80 and CD195). There were fewer circulating classical (p=0.0001) and non-classical (p=0.0013) monocytes in patients treated with a statin. CD64 expression was down-regulated (p=0.011 and p=0.049) whereas CD49d expression was up-regulated (p=0.004 and p=0.022) on classical and non-classical monocytes in this group. Patients receiving Atorvastatin had fewer circulating classical monocytes (p=0.001) compared to patients administered Pravastatin. Patients receiving Pravastatin had fewer circulating non-classical monocytes (p=0.029) compared to patients administered Atorvastatin. Statin administration alters the circulating monocyte repertoire following heart transplantation, including population size, FcgammaRI and VLA-4 adhesion molecule expression. Furthermore, different statin treatments are associated with a selective depletion of macrophage or DC (re)generating monocytes.

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Efficacy of loratadine-montelukast on nasal congestion in patients with seasonal allergic rhinitis in an environmental exposure unit.

Nasal congestion is considered to be one of the most bothersome symptoms of allergic rhinitis (AR) and often the most difficult to treat. Oral therapies providing safe, effective, and reliable relief of AR symptoms, including nasal congestion, are limited. To evaluate the efficacy of a single dose of loratadine-montelukast (10 mg/10 mg) vs placebo and phenylephrine (10 mg) in relieving nasal congestion over 6 hours after ragweed pollen exposure in the environmental exposure unit at the Kingston General Hospital. After a screening visit and up to 6 priming visits, patients who met minimum symptom requirements during ragweed pollen exposure were randomized to receive loratadine-montelukast, phenylephrine, or placebo. Patients evaluated nasal congestion and other symptoms of AR and measured peak nasal inspiratory flow before dosing and at 20-minute intervals during the subsequent 8 hours of pollen exposure. During the first 6 hours after treatment (primary end point), loratadine-montelukast treatment resulted in greater improvement in the mean nasal congestion score vs placebo (P = .007) and phenylephrine (P < .001). Loratadine-montelukast was more effective than placebo (P < or = .02) and phenylephrine (P < or = .002) in relieving total symptoms, nasal symptoms, and nonnasal symptoms and in improving peak nasal inspiratory flow. There were no statistically significant differences between phenylephrine and placebo for any measures. Fewer patients in the loratadine-montelukast group (3.9%) reported adverse events than in the phenylephrine (7.9%) and placebo (7.1%) groups; most adverse events were mild or moderate. Loratadine-montelukast was more effective than placebo and phenylephrine in relieving nasal congestion and other nasal and nonnasal symptoms resulting from ragweed pollen exposure. There was no statistically significant difference between phenylephrine and placebo.

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Main results of the losartan versus amlodipine (LOA) study on drug tolerability and psychological general well-being. LOA Study Group.

To compare two losartan regimens (with and without hydrochlorothiazide) and amlodipine in treating mild-to-moderate hypertension regarding their blood-pressure-lowering effect, drug tolerability and quality of life. A 12-week, randomized, double-blind, parallel-group, multi-centre study. After 4 weeks of placebo, patients with a diastolic blood pressure (DBP) in the range 95-115 mmHg were allocated randomly to be administered 50 mg losartan (increased to 100 mg if the DBP was 90 mmHg or more after 6 weeks), 50 mg losartan (plus 12.5 mg hydrochlorothiazide under the above conditions), or 5 mg amlodipine (increased to 10 mg under the above condition). The tolerability of the treatment and the quality of life were evaluated by spontaneous reporting, active questioning and the Psychological General Well-Being (PGWB) index. In total 898 hypertensives, mainly referred from primary health care (mean age 57.8 years) of whom 52% were men. Administration of 50 mg losartan (plus 12.5 hydrochlorothiazide if necessary) and of 5 mg amlodipine (or 10 mg if necessary) lowered the blood pressure as well as or better than did 50 mg losartan (or 100 mg if necessary). The incidence of 'any discomfort' and 'swollen ankles' increased with amlodipine but not with losartan treatment. The opposite was found for 'dizziness upon standing'. The incidence of drug-related adverse events and the number of patients withdrawn from therapy were higher with amlodipine than they were with losartan treatment. The PGWB index at week 12 indicated that improvements from baseline had occurred in some domains for the losartan groups whereas it remained unchanged for the amlodipine group. Both losartan and amlodipine were effective in lowering the blood pressure and were tolerated well. Administration of 50 mg losartan (plus 12.5 mg hydrochlorothiazide if necessary) and of 5 mg amlodipine (or 10 mg if necessary) lowered the blood pressure equally well or better than did 50 mg losartan (or 100 mg if necessary). Drug-related adverse effects and withdrawal from the study were more common for the amlodipine group. The clinical significance of the improvements in the PGWB index with losartan needs to be studied further.

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Amlodipine--does the effect-time profile directly reflect the concentration-time profile throughout a 24-hour period?

Two studies were undertaken to investigate correlations between the time profile of plasma drug concentration and the time profile of hypotensive activity for the dihydropyridine calcium antagonist, amlodipine. The first study compared the concentration- and effect-time profiles for amlodipine and felodipine ER (extended release), and the second study characterized the concentration-effect relationship in hypertensive patients. The inter- and intra-subject variabilities in the disposition characteristics of amlodipine were less than for felodipine and there was correspondingly less variability in plasma drug concentrations; trough-to-peak ratios were calculated as 67 +/- 8% for amlodipine and 36 +/- 13% for felodipine ER. The characteristics of the plasma-concentration profiles appeared to be reflected in the profiles of hypotensive response such that, although the peak effect with felodipine ER was greater, there was less variability with amlodipine and the trough effect with amlodipine was consistently superior. Examination of the relationship between the plasma concentrations of amlodipine and the antihypertensive effect revealed that, although there was a temporal discrepancy between the two profiles, the two could be correlated using a linear-effect model. Results of this analysis indicated that the kinetic-dynamic model was most appropriately fitted simultaneously to the acute and steady-state data. Thus, the low inter- and intra-subject variabilities in the disposition characteristics of amlodipine are translated into a consistent and smoothly sustained 24-h antihypertensive response.

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Shared and drug-specific effects of atomoxetine and methylphenidate on inhibitory brain dysfunction in medication-naive ADHD boys.

The stimulant methylphenidate (MPX) and the nonstimulant atomoxetine (ATX) are the most commonly prescribed medications for attention deficit hyperactivity disorder (ADHD). However, no functional magnetic resonance imaging (fMRI) study has as yet investigated the effects of ATX on inhibitory or any other brain function in ADHD patients or compared its effects with those of MPX. A randomized, double-blind, placebo-controlled, crossover pharmacological design was used to compare the neurofunctional effects of single doses of MPX, ATX, and placebo during a stop task, combined with fMRI within 19 medication-naive ADHD boys, and their potential normalization effects relative to 29 age-matched healthy boys. Compared with controls, ADHD boys under placebo showed bilateral ventrolateral prefrontal, middle temporal, and cerebellar underactivation. Within patients, MPX relative to ATX and placebo significantly upregulated right ventrolateral prefrontal activation, which correlated with enhanced inhibitory capacity. Relative to controls, both drugs significantly normalized the left ventrolateral prefrontal underactivation observed under placebo, while MPX had a drug-specific effect of normalizing right ventrolateral prefrontal and cerebellar underactivation observed under both placebo and ATX. The findings show shared and drug-specific effects of MPX and ATX on performance and brain activation during inhibitory control in ADHD patients with superior upregulation and normalization effects of MPX.

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Bacterial spectrum and antibiotic resistance of urinary tract infections in patients treated for upper urinary tract calculi: a multicenter analysis.

The purpose of this study is to collect information on the bacterial resistance to antibiotics of bacteria isolated from urine cultures of patients treated for upper urinary tract calculi. Data of patients with urinary tract infection and urolithiasis were retrospectively reviewed to collect information on age, gender, stone size, location, hydronephrosis, procedure of stone removal and antibiotic treatment, identification and susceptibility of pathogens, symptoms, and infectious complications. A total of 912 patients from 11 centers in 7 countries (Bulgaria, Greece, Italy, North Macedonia, Spain, and Turkey) were studied. Mean age was 54 ± 16 years and M/F ratio 322/590. Out of 946 microbial isolates, the most common were E. coli, Gram-positive, KES group (Klebsiella, Enterobacter, Serratia), Proteus spp., and P. aeruginosa. Carbapenems, piperacillin/tazobactam and amikacin showed low resistance rates to E. coli (2.5%, 7%, and 3.6%) and Proteus spp. (7.7%, 16%, and 7.4%), but higher rates were observed with Klebsiella spp., P. aeruginosa, and Gram-positive. Fosfomycin had resistance rates less than 10% to E. coli, 23% to KES group, and 19% to Gram-positive. Amoxicillin/clavulanate, cephalosporins, quinolones, and TMP/SMX showed high resistance rates to most bacterial strains. High rates of antibiotic resistance were observed in patients candidate to stone treatment from South-Eastern Europe. The empirical use of antibiotics with low resistance rates should be reserved to the most serious cases to avoid the increase of multidrug resistant bacteria. Basing on our results, carbapenems, piperacillin/tazobactam, and amikacin may be a possible option for empiric treatment of urinary stone patients showing systemic symptoms.

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Single nucleotide variation in the TP53 3' untranslated region in diffuse large B-cell lymphoma treated with rituximab-CHOP: a report from the International DLBCL Rituximab-CHOP Consortium Program.

We identified multiple single nucleotide variants (SNVs) in the TP53 3' untranslated region (3'UTR) in tumor specimens from 244 patients with diffuse large B-cell lymphoma (DLBCL). Patients carrying a wild-type TP53 coding sequence (CDS) and 1 or more 3'UTR SNVs had a better 5-year survival rate than patients carrying a wild-type CDS and the reference 3'UTR, yet there is no statistically significance difference in overall survival (OS). In contrast, 3'UTR variation predicted poorer OS for patients with a mutant TP53 CDS. We then sequenced TP53 3'UTR in 247 additional DLBCL patients as a validation set. Altogether, we identified 187 novel SNVs; 36 occurred at least twice. Most of the newly identified 3'UTR SNVs were located at sites that are complementary to seed sequences of microRNAs (miRNAs) that are predicted or experimentally known to target TP53. Three SNVs disrupt the seed match between miR-125b and the TP53 3'UTR, thereby impeding suppression of p53 by this miRNA. In addition, a germline SNV (rs78378222) located in the TP53 polyadenylation signal resulted in downregulation of both p53 messenger RNA and protein levels and reduction of cellular apoptosis. This study is the first to demonstrate the prognostic value of the TP53 3'UTR in cancer.

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Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma.

Racemic albuterol is an equal mixture of (R)-albuterol (levalbuterol), which is responsible for the bronchodilator effect, and (S)-albuterol, which provides no benefit and may be detrimental. We sought to compare 2 doses of a single enantiomer, levalbuterol (0.63 mg and 1.25 mg), and equivalent amounts of levalbuterol administered as racemic albuterol with placebo in patients with moderate-to-severe asthma. This was a randomized, double-blind, parallel-group trial. Three hundred sixty-two patients 12 years of age or older were treated with study drug administered by means of nebulization 3 times daily for 28 days. The primary endpoint was peak change in FEV1 after 4 weeks. The change in peak FEV1 response to the first dose in the combined levalbuterol group was significantly greater compared with the combined racemic albuterol group (0.92 and 0.82 L, respectively; P =.03), with similar but nonsignificant results after 4 weeks (0.84 and 0.74 L, respectively). Improvement in FEV1 was similar for levalbuterol 0.63 mg and racemic albuterol 2.5 mg and greatest for levalbuterol 1.25 mg. Racemic albuterol 1.25 mg demonstrated the weakest bronchodilator effect, particularly after chronic dosing. The greatest increase in FEV1 was seen after levalbuterol 1.25 mg, especially in subjects with severe asthma. All active treatments were well tolerated, and beta-adrenergic side effects after administration of levalbuterol 0.63 mg were reduced relative to levalbuterol 1.25 mg or racemic albuterol 2.5 mg. At week 4, the predose FEV1 value was greatest in patients who received levalbuterol or placebo when compared with those who received racemic albuterol. The difference was more evident and was statistically significant in patients who were not receiving inhaled corticosteroids. Levalbuterol appears to provide a better therapeutic index than the standard dose of racemic albuterol. These results support the concept that (S)-albuterol may have detrimental effects on pulmonary function.

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Elevation of maternal alpha-fetoprotein in systemic lupus erythematosus: a controlled study.

To determine if maternal alpha fetoprotein (AFP) is elevated in lupus pregnancy and, if so, whether it is associated with treatment or outcome. Maternal serum AFP values were obtained once during Weeks 16.3 to 31.7 in 54 pregnancies followed prospectively. AFP was measured by the Maryland State Health Department, who reported the AFP level and a corrected value, multiple of the median (AFP MOM), adjusted for weight, gestational age, and insulin dependent diabetes. Controls were 1001 consecutive samples measured by the same laboratory. AFP MOM was higher in lupus pregnancies (1.425 +/- 0.73 vs 1.169 +/- 0.50, p = 0.001), as were the unadjusted AFP levels (lupus 68.26 +/- 42.2, control 52.49 +/- 27.25, p = 0.001). Of lupus pregnancies 7.4 vs 2.6% of control pregnancies had an abnormal AFP MOM (p = 0.06). The 4 patients with abnormal AFP-MOM, using the 2.3 cutoff, were taking more prednisone (27.25 +/- 18.54 mg vs 10.85 +/- 12.29 mg, p = 0.02), were more likely to have delivered preterm (31.50 +/- 36.31 weeks, p = 0.02), and were more likely to have a high anticardiolipin (aCL) antibody during the pregnancy (p = 0.03). AFP is higher in lupus than in control pregnancies, without any increase in neural tube or other birth defects. An abnormal maternal serum AFP level is associated with higher prednisone dose, preterm delivery and aCL. Patients and obstetricians need to be aware that an elevated maternal AFP in lupus pregnancy is not necessarily due to a birth defect, and may be predictive of preterm delivery.

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The effects of modafinil, caffeine, and dextroamphetamine on judgments of simple versus complex emotional expressions following sleep deprivation.

Cognitive abilities such as vigilance, attention, memory, and executive functioning can be degraded significantly following extended periods of wakefulness. Although much evidence suggests that sleep-loss induced deficits in alertness and vigilance can be reversed or mitigated by stimulants such as caffeine, it is not clear how these compounds may affect other higher level cognitive processes such as emotional perception and judgment. Following 47 h of sleep deprivation, the study examined the effect of three stimulant medications (modafinil 400 mg, dextroamphetamine 20 mg, caffeine 600 mg) or placebo on the ability of 54 healthy participants to discriminate and label simple emotional expressions versus complex affect blends (created by morphing photographs of two different affective facial expressions). For simple affective faces, neither sleep loss nor stimulant medications made any difference on the accuracy of judgments. In contrast, for complex emotion blends, all three stimulant medications significantly improved the ability to discriminate subtle aspects of emotion correctly relative to placebo, but did not differ from one another. These findings suggest that all three stimulant medications are effective at restoring some aspects of subtle affective perception.

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A phase II study of sequential combination chemotherapy with cyclophosphamide, prednisone, and 2-chlorodeoxyadenosine in previously untreated patients with chronic lymphocytic leukemia.

In an earlier study of previously untreated patients with chronic lymphocytic leukemia (CLL), we used a concomitant combination of chlorambucil and 2-chlorodeoxyadenosine and reported overall (OR) and complete (CR) remission rates of 80% and 20%, respectively. After a median follow-up of 5 years, more than 80% of the responders have had a relapse. In the current phase II study of 27 previously untreated patients with CLL, we used a sequential combination of six cycles of intravenous cyclophosphamide (1 g/m2) plus oral prednisone (100 mg/m2 per day for 5 days) followed by two to six cycles of 2-chlorodeoxyadenosine (5 mg/m2 per day for 5 days). The OR and CR rates were 96% and 33%, respectively. After a median follow-up of 29 months, 35% of the responders have had a relapse. Progression-free survival was significantly better in CR patients than in those with partial remission. However, minimal residual disease was phenotypically detected in four of the nine CR patients. Despite the fact that the current OR and CR rates are superior to those seen in a historical cohort treated with a concomitant schedule, a longer follow-up period is needed to assess the durability of these remissions, and a controlled trial is necessary to estimate the impact on overall survival and toxicity.

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[Benefits of ipratropium bromide in the management of asthmatic crises in the emergency department].

To determine if the addition of ipratropium bromide in the emergency department (ED) for the treatment of childhood asthma reduces rates of hospitalization and relapses for moderate and severe exacerbations. Patients were given an oral corticosteroid treatment (2 mg/kg) and received every 20 minutes either three nebulizations with albuterol (0.15 mg/kg) and ipratropium bromide (250 micrograms) or six nebulizations with albuterol alone (control group). The primary end point was the need for hospitalization, additional nebulizations or a relapse during the following week. Secondary end point included the effect of age. One hundred and forty three children, two to 15 years old, were randomized to ipratropium or control groups and 121 were evaluated on day seven. As a whole, the control group was less often hospitalized or in relapse than those treated with three nebulizations of albuterol and ipratropium (17.5% vs 37.9%, p < 0.02). The ipratropium group reached the same result after three additional albuterol nebulizations. The benefit of anticholinergic therapy was observed for children less than six years of age who had a similar rate of success (73.5 vs 75.7%). The association of ipratropium bromide to the first three doses of the albuterol protocol for acute asthma did not act as well as six nebulizations of albuterol alone. The effect was age dependent and two to six years old children needed more attention. Nevertheless the hospitalization rate did not support the use of ipratropium compared with repeated albuterol nebulizations.

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The inhibitory effect of nebulized albuterol on the early and late asthmatic reactions and increase in airway responsiveness provoked by inhaled allergen in asthma.

It is widely held that inhaled beta 2-adrenoceptor agonists inhibit the early asthmatic response (EAR) but not the late response (LAR) or attendant increase in bronchial responsiveness. In this study of 10 atopic asthmatic subjects, we have investigated the effects of a high dose of nebulized albuterol (2.5 mg) on the allergen-provoked EAR, LAR, and increase in histamine responsiveness. In a randomized blinded fashion, study subjects inhaled the following combinations: albuterol followed 10 min later by allergen, placebo followed by allergen, albuterol followed by saline (albuterol, placebo, and control study periods, respectively). Airway caliber was measured as FEV1 and followed at regular intervals for 7.5 h postallergen. Bronchial responsiveness to histamine was measured and recorded as the PC20 value before and at 1.5, 3.5, 5.5, and 7.5 h after allergen or control challenge. During the placebo study period, allergen challenge caused mean 29.6 +/- 6.4 and 24.4 +/- 6.4% falls in FEV1 at 20 min and 7.5 h, respectively (both p less than 0.05), and a progressive decrease in PC20 amounting to a geometric mean of 1.9 doubling dilutions at 7.5 h (p less than 0.05). Albuterol followed by allergen resulted in a 13.1 +/- 2.2% increase in FEV1 prior to allergen followed by abolition of the EAR and inhibition of the LAR with only a 9.2 +/- 3.5% fall in FEV1 at 7.5 h, significantly different from that of placebo at 7.5 h (p = 0.048). Similarly, PC20 histamine fell by only 0.64 doubling dilutions at 7.5 h, not significantly different from baseline values but different from placebo values (p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

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Effects of vitamin D supplementation in atorvastatin-treated patients: a new drug interaction with an unexpected consequence.

The objective of this study was to determine vitamin D supplementation effects on concentrations of atorvastatin and cholesterol in patients. Sixteen patients (8 men, 8 women; 10 Caucasians, 4 African Americans, 1 Hispanic, 1 Asian), aged 63 +/- 11 years (mean +/- SD, weight 92 +/- 31 kg) on atorvastatin (45 +/- 33 mg/day) were studied with and without supplemental vitamin D (800 IU/day for 6 weeks). Levels of vitamin D (1,25-dihydroxy(OH) and 25 OH-metabolites), atorvastatin (parent, OH-acid metabolites, lactone, and lactone metabolites), and cholesterol (total, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol) were determined at 0.5, 3, and 10 h after dosing. Vitamin D supplementation increased vitamin D-25-OH metabolites (P < 0.0001) without increased 1,25-dihydroxy vitamin D. Atorvastatin and active metabolite concentrations (P < 0.001) as well as LDL-cholesterol and total-cholesterol levels (97 +/- 28 mg/dl vs. 83 +/- 30 and 169 +/- 35 mg/dl vs. 157 +/- 37, P < 0.005) were lower during vitamin D supplementation. The conclusion of the study is that vitamin D supplementation lowers atorvastatin and active metabolite concentrations yet has synergistic effects on cholesterol concentrations.

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A controlled trial of colchicine to reduce the elastase load in the lungs of cigarette smokers with chronic obstructive pulmonary disease.

Current data suggest that emphysema in smokers is caused at least in part by the unrestrained action of neutrophil elastase on pulmonary tissues. Since colchicine reduces the secretion of enzymes from stimulated neutrophils, we designed a clinical trial to determine if colchicine could reduce the elastase load in the lungs or several putative indicators of elastin destruction. We carried out a prospective, double-blind, randomized, and placebo-controlled clinical trial. Outpatients seeking treatment for chronic obstructive pulmonary disease at the University of Texas Health Center at Tyler who met specific criteria were recruited into the study. A group of 46 cigarette smokers between 45 and 75 yr of age with chronic obstructive pulmonary disease (COPD) were studied. Colchicine or placebo was given orally in disguised capsules, 0.6 mg three times per day. Volunteers were placed on a baseline bronchodilator regimen of Theodur orally and albuterol by inhalation. Blood, urine, and bronchoalveolar lavage fluids were obtained after 1 wk of stabilization. The patients were then randomized and treated for 14 days with colchicine, and the measurements were repeated. Modifications in plasma elastin peptides and neutrophil elastase-generated fibrinopeptide A, urinary desmosines, and bronchoalveolar lavage fluid neutrophils or neutrophil elastase were the indicators of success or failure of the treatment. Pre- and posttreatment measurements in each patient and the difference between colchicine-treated and placebo-treated groups were compared. There were no statistically significant differences in either of the two types of analyses in any of the variables. We conclude that variables related to elastase load in the lungs were not modified by colchicine treatment. If a drug can be identified that is successful in modifying one of these variables, it would then have to be tested in a large-scale clinical trial in which the rate of decline in the FEV1.0 or mortality would be measured. The data presented here may provide useful information about the variability of key measurements of elastase load in the lungs and the breakdown of elastin and may aid investigators in designing similar trials in the future.

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Effect of bupropion on immunodensity of putative imidazoline receptors on platelets of depressed patients.

A substantial number of studies have demonstrated increased imidazoline receptors (I1 binding sites) on platelets of depressed patients and downregulation following antidepressant treatments. Herein, imidazoline receptor binding protein (IRBP) antiserum was used to quantify imidazoline receptors on platelets of depressed patients before and after treatment with the atypical aminoketone antidepressant, bupropion. Western blots revealed an increase in IRBP-immunodensity (p = 0.01, two-tailed) in a 33 kDa protein band in untreated depressed patients (n = 21) as compared with controls (n = 17). This band has been positively correlated with I1 binding sites on platelets. Following 6 weeks' treatment with bupropion, IRBP-immunodensity was downregulated in depressed patients (p = 0.03, paired t-test); predominantly in responders (p = 0.005). Patients non-responsive to bupropion (n = 5) were significantly different from responders (p = 0.05) by exhibiting no elevation in IRBP-immunodensity at pre-treatment and no downregulation of the 33 kDa band after treatment. IRBP-immunodensity was negatively correlated (r = -0.79, p = 0.01) with plasma concentrations of bupropion and its metabolites at week-4 of BUP treatment. Thus, a 33-kDa IRBP on platelet plasma membranes is elevated in depression and normalized in responders to bupropion.

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A comparison of heart rate changes associated with levalbuterol and racemic albuterol in pediatric cardiology patients.

To our knowledge, no data exist regarding the effect of levalbuterol and racemic albuterol on heart rate in pediatric cardiology patients. To compare heart rate change in pediatric cardiology patients receiving levalbuterol and/or racemic albuterol. The secondary objective was to identify characteristics associated with heart rate changes observed with these drugs. A review of electronic medical records at a pediatric academic hospital was conducted to determine the equivalence of heart rate change in patients receiving levalbuterol or racemic albuterol. Patients receiving at least 3 doses of levalbuterol and/or racemic albuterol during the study period were included if they were younger than 18 years and had a diagnosis of congenital heart disease (CHD), cardiomyopathy, or supraventricular tachycardia. Patients were excluded if they received a β-blocker or continuous racemic albuterol or did not have documented pre- and postdose heart rates. One hundred ninety-two patients were included. One hundred forty-two received racemic albuterol, 40 received levalbuterol, and 10 received both racemic albuterol and levalbuterol. The mean increase in heart rate for patients receiving racemic albuterol and levalbuterol was 6.8 beats/min and 6.2 beats/min, respectively (p = 0.01). In patients with CHD, the racemic albuterol group experienced a mean heart rate increase of 6.6 beats/min compared to 6.3 beats/min in the levalbuterol group (p = 0.01). Equivalence was also determined in patients without surgical intervention and patients receiving concomitant cardiac and respiratory medications. Equivalence was not established in other analyzed subgroups secondary to insufficient sample sizes. Racemic albuterol and levalbuterol were associated with increased heart rate in pediatric cardiology patients. This increase was found to be equivalent.

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A multicenter comparison of carvedilol with hydrochlorothiazide in the treatment of mild-to-moderate essential hypertension.

The efficacy and safety of carvedilol, a beta-blocker with vasodilatory properties, were compared with that of hydrochlorothiazide (HCTZ) both at a once-daily dose of 25-50 mg in a double-blind, randomized, parallel-group, multicenter study. Following a single-blind placebo phase of 3-6 weeks, 201 eligible patients (aged 27-88 years) were randomized to receive 8 weeks of treatment with either carvedilol or HCTZ, 25 mg doubling to 50 mg at week 4 if the respone was inadequate. Sitting and standing blood pressure and heart rate were recorded 2 h after the first dose and 24 h postdose at weeks 4 and 8. The analysis included 179 patients (11 having withdrawn, including 5 for adverse events, and 11 excluded for protocol violations). There were no statistically or clinically significant differences between treatment groups. Eighty-six percent of patients in the carvedilol group and 88% in the HCTZ group had an 8-week sitting diastolic blood pressure less than or equal to 90 mm Hg or decreased by greater than or equal to 10 mm Hg. Safety profiles were similar for both agents, with a tendency to lower uric acid and total cholesterol levels with carvedilol. Carvedilol and HCTZ at doses compared in this study have similar efficacy and tolerability, with laboratory evidence to suggest a more favorable metabolic profile for carvedilol.

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Comparison of patient-reported outcomes during treatment with adjustable- and fixed-dose budesonide/formoterol pressurized metered-dose inhaler versus fixed-dose fluticasone propionate/salmeterol dry powder inhaler in patients with asthma.

Assessment of patient-reported outcomes is important in evaluating the impact of asthma treatment. This study was conducted to compare effects of adjustable- and fixed-dose budesonide/formoterol pressurized metered-dose inhaler with fixed-dose fluticasone propionate/salmeterol dry powder inhaler regimens on patient-reported outcomes in patients aged > or =18 years with moderate to severe asthma. In this phase III, randomized, open-label study, 1225 patients were randomized 2:1 to fixed-dose budesonide/formoterol 160/4.5 microg x 2 inhalations (320/9 mug) twice daily or fixed-dose fluticasone propionate/salmeterol 250/50 microg twice daily for 1 month. In the subsequent 6 months, patients receiving fixed-dose fluticasone propionate/salmeterol continued therapy, whereas those receiving fixed-dose budesonide/formoterol were randomized 1:1 to fixed-dose or adjustable-dose budesonide/formoterol (adjustable from 320/9 microg twice daily to 320/9 microg once daily or 640/18 microg twice daily). Mean improvements from baseline to end of treatment in the Asthma Quality of Life Questionnaire (standardized) overall and individual domain scores and the Asthma Control Questionnaire score were clinically important (> or =0.5 points) for all treatments. Patients in both budesonide/formoterol groups reported greater treatment satisfaction on the Asthma Treatment Satisfaction Measure questionnaire than patients in the fluticasone propionate/salmeterol dry powder inhaler group for the attributes of timely relief of symptoms (p < or = .037) and feel medication working (p < or = .020). Onset of Effect Questionnaire scores showed a greater percentage of patients perceiving onset of effect with budesonide/formoterol regimens versus fixed-dose fluticasone propionate/salmeterol (p < or = .002). Treatment regimens did not differ regarding improvements in asthma-specific quality of life and asthma control. Questions related to perceived rate of onset and feeling medication working in the Asthma Treatment Satisfaction Measure and Onset of Effect Questionnaire generally elicited somewhat more favorable responses with budesonide/formoterol pressurized metered-dose inhaler regimens versus fixed-dose fluticasone propionate/salmeterol dry powder inhaler.

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Comparison of tramadol with morphine for post-operative pain following abdominal surgery.

In a multi-centre, double-blind, randomized study involving 523 patients, the analgesic efficacy of tramadol was compared to that of morphine given in repeated intravenous boluses as required to control post-operative pain following abdominal surgery over 24 h. Intravenous administration of the study analgesic started as soon as the patient reported pain. Patients received an initial dose (either tramadol 100 mg or morphine 5 mg) and, if necessary, repeat doses of tramadol 50 mg or morphine 5 mg could be given on demand over the first 90 min. Further doses up to a total of tramadol 400 mg or morphine 40 mg could then be given after 90 min up to 24 h after the first dose of study medication. The primary efficacy parameter was the responder rate (no or slight pain) within the first 90 min of treatment. Whilst responder rates reached 72.6% with tramadol and 81.2% with morphine, the treatments were statistically equivalent and the observed difference in the responder rates between the groups was within the predefined range of +/- 10%. Mean cumulative doses received by treatment responders amounted to 188.2 mg within the first 1.5 h and 157.1 mg during the subsequent 22.5 h in the tramadol group and 13.9 and 18.4 mg, respectively, in the morphine group. A high incidence of gastrointestinal adverse events were observed with both treatments mostly consisting of mild nausea, dry mouth, vomiting, dyspepsia and hiccups.

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Is Helicobacter pylori eradication associated with gastroesophageal reflux disease?

A recent report has suggested an association between Helicobacter pylori eradication and the development of gastroesophageal reflux disease (GERD). We therefore assessed the incidence of GERD among comparable patients having undergone successful versus failed H. pylori eradication in a controlled trial. We also compared the H. pylori strains in the subjects that developed GERD to those that did not. Patients with a history of proven duodenal ulcer and H. pylori infection were randomised into a H. pylori eradication study. Patients subsequently underwent gastroscopy with gastric biopsies every 3 months for 1 yr. At each visit, the presence of GERD symptoms and endoscopic esophagitis were noted, and the incidence of these variables among patients in whom H. pylori eradication was successful was compared to those in whom it was not. In a subgroup, the presence of the cagA, cagE, and vacA genotypes and of cagA antibodies were determined. Of 98 patients randomized into this study, 11 dropped out before determination of H. pylori eradication, leaving 87 patients with analyzable results. H. pylori eradication was successful in 63 (72%). By the end of the follow-up period, patients with GERD symptoms or endoscopic esophagitis were more prevalent in the successful than in the failed eradication group (37% [95% CI: 25-50%] vs 13% [95% CI: 3-32%], p = 0.04, 95% CI for the difference: 6-42%), as were patients with GERD symptoms alone (29% [95% CI: 18-41%] vs 8% [95% CI: 1-27%], p = 0.04, 95% CI for the difference: 4-36%) or esophagitis alone (21% [95% CI: 12-33%] vs 4% [95% CI: 0-21%], p = 0.10, 95% CI for the difference: 4-29%, respectively). Multivariate analysis revealed no significant association between the incidence of symptoms or esophagitis and age, gender, Quetelet index, caffeine or alcohol intake, smoking, weight change, or the presence of a hiatus hernia. There were also no differences in the prevalence of H. pylori genotypes from patients who developed GERD as compared to those who did not. In this patient population, the incidence of new GERD-type symptoms or endoscopic esophagitis was greater in patients in whom successful eradication was achieved. This difference does not appear to be attributable to weight gain, habits, or specific H. pylori strains.

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A pragmatic 12-week, randomized trial of duloxetine versus generic selective serotonin-reuptake inhibitors in the treatment of adult outpatients in a moderate-to-severe depressive episode.

Some evidence suggests that medications that modulate both serotonin and norepinephrine may be more effective than selective serotonin-reuptake inhibitors (SSRIs) in severe major depressive disorder (MDD). This prospective pragmatic trial tests this hypothesis. Patients with severe MDD were randomly assigned to either duloxetine (a serotonin and norepinephrine-reuptake inhibitor) or physicians' choice of four generic SSRIs. Nonblinded, flexibly dosed treatment was used to mimic clinical practice. To address potential investigator bias, the patient-reported Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) was used as the primary efficacy outcome measure. A total of 750 outpatients (19.2%, African descent; 14.8%, Hispanic) were randomized. The primary outcome, remission at week 12 by QIDS-SR, was numerically greater for duloxetine compared with SSRIs (36 vs. 32%), but this difference was not statistically significant. Mean changes in secondary outcomes were significantly superior in favor of duloxetine for the Hamilton Depression Scale-17 item, the Brief Pain Inventory, and the Sheehan Disability Scale. Remission superiority on the QIDS-SR was not achieved. Significantly greater benefit for duloxetine compared with SSRIs was demonstrated on measures of pain and functioning. Study demographics suggest a more generalizable racial and ethnic population than is typical in randomized clinical trials.

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Favourable outcomes for high-risk diffuse large B-cell lymphoma (IPI 3-5) treated with front-line R-CODOX-M/R-IVAC chemotherapy: results of a phase 2 UK NCRI trial.

Outcomes for patients with high-risk diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP chemotherapy are suboptimal but, to date, no alternative regimen has been shown to improve survival rates. This phase 2 trial aimed to assess the efficacy of a Burkitt-like approach for high-risk DLBCL using the dose-intense R-CODOX-M/R-IVAC regimen. Eligible patients were aged 18-65 years with stage II-IV untreated DLBCL and an International Prognostic Index (IPI) score of 3-5. Patients received alternating cycles of CODOX-M (cyclophosphamide, vincristine, doxorubicin and high-dose methotrexate) alternating with IVAC chemotherapy (ifosfamide, etoposide and high-dose cytarabine) plus eight doses of rituximab. Response was assessed by computed tomography after completing all four cycles of chemotherapy. The primary end point was 2-year progression-free survival (PFS). A total of 111 eligible patients were registered; median age was 50 years, IPI score was 3 (60.4%) or 4/5 (39.6%), 54% had a performance status ≥2 and 9% had central nervous system involvement. A total of 85 patients (76.6%) completed all four cycles of chemotherapy. There were five treatment-related deaths (4.3%), all in patients with performance status of 3 and aged >50 years. Two-year PFS for the whole cohort was 67.9% [90% confidence interval (CI) 59.9-74.6] and 2-year overall survival was 76.0% (90% CI 68.5-82.0). The ability to tolerate and complete treatment was lower in patients with performance status ≥2 who were aged >50 years, where 2-year PFS was 43.5% (90% CI 27.9-58.0). This trial demonstrates that R-CODOX-M/R-IVAC is a feasible and effective regimen for the treatment of younger and/or fit patients with high-risk DLBCL. These encouraging survival rates demonstrate that this regimen warrants further investigation against standard of care. ClinicalTrials.gov (NCT00974792) and EudraCT (2005-003479-19).

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Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome.

To determine the clinical, hormonal, and biochemical effects of 4-6 months of metformin therapy in obese patients with polycystic ovary syndrome (PCOS). Prospective study. The Gynecological Endocrine Unit of University Central Hospital, Oulu, Finland. Twenty obese patients with PCOS. Patients were treated with 0.5 g of metformin three times daily for 4-6 months. Clinical symptoms, menstrual pattern, and hirsutism, as well as serum concentrations of sex steroids, sex hormone-binding globulin (SHBG), gonadotropins, and lipids were assessed during the treatment. Eleven women (68.8% of the women with menstrual disturbances) experienced more regular cycles during therapy. No changes in hirsutism, body mass index, or blood pressure occurred. The mean testosterone level was decreased significantly after 2 months of treatment but returned to the starting level by 4-6 months. Free testosterone levels decreased significantly during the treatment. There was no significant change in the levels of other sex steroids or lipids measured at 4-6 months of treatment. Metformin therapy is well tolerated by the majority of patients and may be clinically useful, especially in obese patients with PCOS and menstrual disturbances.

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Effects of aspirin, clopidogrel and dipyridamole administered singly and in combination on platelet and leucocyte function in normal volunteers and patients with prior ischaemic stroke.

The aim of this study was to assess whether triple antiplatelet therapy is superior to dual and mono therapy in attenuating platelet and leucocyte function. Aspirin (A), clopidogrel (C), and dipyridamole (D) were administered singly and in various combinations (A, C, D, AC, AD, CD, ACD), each for two weeks (without washout) to 11 healthy subjects and to 11 patients with previous ischaemic stroke in two randomised multiway crossover trials. At the end of each two-week period platelet aggregation, platelet-leucocyte conjugate formation and leucocyte activation were measured ex vivo blinded to treatment. Platelets were stimulated with collagen; additional measurements were made with adenosine diphosphate (ADP), platelet activating factor (PAF), adrenaline and the combination of, ADP, PAF and adrenaline. Results show that in the presence of collagen, ACD was superior to all antagonists or combinations, except AC, in reducing aggregation, platelet-leucocyte conjugate formation, and monocyte activation (all p<0.05). ACD was also more potent than other treatments, except AC, in inhibiting the aggregation and platelet-monocyte conjugate formation induced by the combination of ADP, PAF and adrenaline. The effects were similar in both volunteers and stroke patients. No serious adverse events or major bleeding events occurred. Triple antiplatelet therapy did not appear to be more effective than combined aspirin and clopidogrel in moderating platelet and leucocyte function. Any additional clinical benefit provided by dipyridamole may be through other mechanisms of action.

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Bronchoscopic intratumoral injection of tranexamic acid to prevent excessive bleeding during multiple forceps biopsies of lesions with a high risk of bleeding: a prospective case series.

Significant bleeding may occur following endobronchial forceps biopsy or brushing of necrotic or hypervascular tumors in the airways. In some cases, methods such as endobronchial instillation of iced saline lavage and epinephrine may fail to control bleeding. The present study evaluated the efficacy and safety of a new bronchoscopic technique using intratumoral injection of tranexamic acid (IIT) for control of bleeding during forceps biopsy in patients with endobronchial tumors with a high risk of bleeding. The study was a prospective case series carried out in a single center. Bronchoscopic IIT was performed in those patients who had endoscopically visible tumoral lesions with persistent active bleeding following the first attempt at bronchoscopic sampling. Tranexamic acid (TEA) was injected through a 22-gauge Wang cytology needle into the lesion in nominal doses of 250-500 mg. After 2-3 minutes, multiple forceps biopsy specimens were obtained from the lesion. Of the 57 consecutive patients included in the study, 20 patients (35.1%) underwent bronchoscopic IIT. The first attempt in 18 patients was endobronchial forceps biopsy (EBB), and because of a high risk of bleeding, the first attempt for the remaining two patients, who were on continuous dual antiplatelet therapy (aspirin and clopidogrel), employed endobronchial needle aspiration (EBNA) as a precautionary measure. Following IIT, subsequent specimens were obtained using EBB in all patients. Multiple forceps biopsy specimens (3-10) were obtained from the lesions (8 necrotic and 12 hypervascular) without incurring active bleeding. The following histopathologic diagnoses were made: squamous cell carcinoma (n = 14), adenocarcinoma (n = 2), small-cell lung cancer (n = 3), and malignant mesenchymal tumor (n = 1). No side effects of TEA were observed. Bronchoscopic IIT is a useful and safe technique for controlling significant bleeding from a forceps biopsy procedure and can be considered as a pre-biopsy injection for lesions with a high risk of bleeding. ISRCTN23323895.

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Randomized phase II study of a combination of cisplatin (DDP), 5-fluorouracil (5-FU), and allopurinol (HPP) versus 5-FU in advanced colorectal carcinoma. An EORTC Gastrointestinal Tract Cancer Cooperative Group study.

In order to improve the therapeutic index of fluorouracil (5-FU), it has been combined with cisplatin (DDP) as synergistic agent and with allopurinol (HPP) as toxicity modulator. Patients with measurable colorectal carcinoma, previously untreated by chemotherapy, were randomized to receive either 5-FU alone 500 mg/m2 push iv days 1-5 or HPP 3 x 300 mg po, days 1-5, 5-FU 800 mg/m2 push iv, days 3-5 and DDP 50 mg/m2 d6. Treatment was repeated every 4 weeks. Of 104 patients randomized, 82 were evaluable for response and survival. Six partial responses were seen in each treatment group (15%) and the median survival time was 7 months. Hematologic toxicities were comparable in both treatment groups, with a mean nadir white blood cell count of 3500/ vs. 3800/mm3 and a mean nadir platelet count of 148,000/ vs, 203,000/mm3 for HPP-5-FU-DDP and 5-FU, respectively. This study suggests that the addition of both HPP and DDP does not improve the activity of 5-FU.

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[Clinical observation on 112 cases with non-Hodgkin's lymphoma treated by Chinese herbs combined with chemotherapy].

To seek for the effective therapeutical method in treating non-Hodgkin's lymphoma (NHL). One hundred and sixty seven patients with non-Hodgkin's lymphoma were randomly divided into two groups, the treatment group, which consisted of 112 cases using Chinese herbs combined with chemotherapy and 55 cases of control group were treated by chemotherapy only. The effective rate (CR + PR) in the combined group was 91.96% and survival rates of 1-, 3- and 5-year were 85.7%, 54.5% and 29.5% respectively, and median survival time was 554 days. In control group the effective rate was 72.73% and 1-, 3- and 5-year survival rates were 76.4%, 38.2% and 18.2% respectively, and the median survival time was 465 days. The difference of effective rates or 3-year survival rates between two groups was significant (P < 0.05). In the combined group the activity of NK cell, OKT3, OKT4 and ratio of OKT4/OKT8 were obviously raised after treatment (P < 0.01). And the level of platelet adhesion rate and the blood viscosity markedly decreased (P < 0.01), but in the control group the values of these indexes did not distinctly change. Chinese herbs could enhance the immunologic function and improve the viscosity of blood of the patients with NHL. The side effect in the combination therapy group was less and milder than that in the chemotherapy group. These showed that Chinese herbs combined with chemotherapy was a safe and effective method for treating NHL and deserve to be recommended.

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Pharmacologic treatment of rapid ejaculation: levels of evidence-based review.

Rapid (premature) ejaculation (RE) is defined as persistent or recurrent ejaculation with minimal sexual stimulation before, upon, or shortly after penetration and before it is wished by the man or his partner. RE is the most frequently encountered sexual complaint of men and couples. Estimates suggest that as many as one third of all sexually active men suffer from RE. RE has been treated with various modalities. These include behavioral therapy, topical applications, oral pharmacotherapy and intracavernosal vasoactive drug injection. The success rates of these modalities are variable, however, to date an approved treatment does not exist. In this article, we review the evidence surrounding the pharmacological management of RE. The search included (i) a MEDLINE search from 1980 through August 2005 limited to English-language medical literature; (ii) relevant abstracts from 2003, 2004, and 2005; and (iii) a pipeline search for therapeutics in development. The review does not include behavioral therapy. The distinct feature of this review is that the level of evidence supporting each treatment will be discussed in details. Results showed that there is consistent evidence which supports the daily use of paroxetine, clomipramine, sertraline and fluoxetine for the treatment of RE. There is no strong evidence suggesting the use of these previous drugs on an as-needed basis. There is strong evidence to suggest the use of dapoxetine on an as-needed in RE. Available evidence indicates that topical anesthetic agents such as prilocaine-lidocaine and SS-cream appears to be effective in treatment of RE. There is no strong evidence to suggest that PDEI5 could prolong IELT in RE when used on-demand. In conclusion, based on literature data, although some drugs may be effective in treatment of RE, more extended multi-center prospective double-blind, placebo-controlled stopwatch studies on the benefits of SSRIs, SNRIs and PDEI5 in RE are required.

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Determine the effectiveness of lipid-lowering therapy in patients with chronic obstructive pulmonary disease combined with coronary heart disease.

In complex treatment of chronic obstructive pulmonary disease (COPD) combined with ischemic heart disease (IHD) more and more attention is drawn to pleiotropic effect of statins. The aim of our researches became determining the effectivity of utilization of rosuvastatin (CRESTOR®, IPR PHARMACEUTICALS, Inc.) in complex treatment of COPD combined with IHD. Basing on pulmonology department of Poltava regional clinical hospital, 30 patients with COPD combined with IHD have been examined (stable effort angina FC II) aged from 51 to 67 y.o. (average age was 57,03 ± 3,51). The patients were divided into two age compatible groups. Patients of the main group (n = 15) underwent regular COPD and IHD treatment, addind 20 mg of rosuvastatin per night. The observed group (n = 15) didn't receive rosuvastatin. The examination of patients was held before and half year of treatment, included the estimation of respiratory symptoms of the disease, the degree of intensity of dyspnea (Medical Research Council Dyspnea Scale). The tolerance to physical exercise was studied with 6 minute walking test. The cholesterine level, HDL, LDL, function of ventilation have been tested as well. The average frequency of aggravations during the year was estimated through retrospective examination of anamnesis. After the treatment the improvement of clinical state has been noticed at both groups due to decrease of intensity of respiratory symptoms of the disease, such as cough, amount of expectoration, dyspnea and also increase of tolerance to physical exercise and improvement of laboratory-instrumental indexes. Though the patients of the main group were noticed to have significantly less amount of expectoration and cough. The distance covered in 6 minutes was positively longer (р < 0,05). It has to be noted that the patients of the main group had positive decrease of wheezing after treatment, due to increase of FEV1, GI (р < 0,01). The retrospective studying of the anamnesis revealed that the frequency of arrogations during the year was 1-2 times a year (1,6 ± 0,48). Including rosuvastatin into the treatment scheme allows to decrease and stabilize the main clinical symptoms of this constellation of diseases, improving the quality of life, reduce the frequency of exacerbations.

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Is intravenous glucocorticoid therapy better than an oral regimen for asymptomatic cardiac rejection? A randomized trial.

This study assessed whether treatment with oral prednisone (bolus plus tapered doses) is comparable to intravenous methylprednisolone sodium succinate (Solu-Medrol) therapy in patients with asymptomatic moderate cardiac allograft rejection episodes without hemodynamic compromise. Intravenous Solu-Medrol therapy is frequently administered for moderate rejection episodes after heart transplantation but has not previously been compared with an oral prednisone therapy for asymptomatic cardiac rejection in a randomized trial. Compared with oral prednisone therapy, the administration of intravenous Solu-Medrol is more costly and resource intensive, and it can require loss of work time for patients and the family members who accompany them to treatment. Forty-one heart transplant patients with 43 episodes of asymptomatic moderate cardiac rejection were randomized to receive 3 days of 1,000 mg of intravenous Solu-Medrol (20 episodes) or prednisone as a bolus dose of 100 mg orally for 3 days, tapering to the previous maintenance dosage over 14 days (23 episodes). Follow-up endomyocardial biopsies were performed at 2 and 4 weeks. Infectious complications were monitored and the cost of the two forms of therapy was assessed. Resolution of moderate rejection occurred within 4 weeks in 19 (95%) of 20 patients treated with intravenous steroids and in 21 (91%) of 23 patients treated with oral prednisone. No significant difference in infectious complications occurred between the two groups in the ensuing 3 months after therapy. The cost of the oral prednisone therapy was $6.30 compared with the cost of $180 to $966 for administration of intravenous Solu-Medrol. Oral prednisone (bolus plus tapered doses) appears to be as effective and to have similar infectious complication rates as intravenous Solu-Medrol for the treatment of asymptomatic cardiac rejection. The convenience and lower cost of oral prednisone therapy may warrant its routine use for this type of cardiac rejection.

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Reduced Doses of Direct Oral Anticoagulants in Ischemic Stroke Patients with Nonvalvular Atrial Fibrillation.

The choice of standard or reduced doses of direct oral anticoagulants (DOACs) depends on patients' age, body weight, and renal function based on package instructions. Our aim was to conduct a simulation of DOAC dose using patients' data obtained on admission. This retrospective study included 314 ischemic stroke patients with nonvalvular atrial fibrillation admitted to our hospital between September 2014 and February 2018. Data on age, body weight, creatinine, and creatinine clearance were collected for each subject, and simulation was conducted for the dose of each DOAC. The mean age of 314 subjects was 77.2 years; those aged 75 years or older accounted for 61.5% (193 patients). It was suggested that a standard dose of rivaroxaban could be used in 67.5% of patients and that of apixaban in 65.9%. By contrast, a standard dose of dabigatran could be used in only 16.9% of patients and that of edoxaban in only 32.5%. The simulation analysis for patients aged 75 years or older showed that a standard dose of rivaroxaban could be used in 54.9% of patients and that of apixaban in 44.6%, while that of edoxaban could be used in only 19.7% of patients. When DOACs are prescribed for secondary prevention of cerebral infarction in patients with nonvalvular atrial fibrillation, the rate of standard or reduced dose varies depending on the kind of DOAC. Further analysis is required to clarify whether a standard dose of one DOAC or reduced dose of another DOAC yields the best result for each patient.

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Amoxicillin-clavulanic acid therapy may be associated with severe side effects -- review of the literature.

There is a growing body of evidence that amoxicillin-clavulanic acid may induce severe adverse effects in patients. A medline search of case reports and reviews on amoxicillin-clavulanic acid induced adverse effects was performed. The criteria of a consensus conference on the reporting of drug-induced liver disease were applied. Amoxicillin-clavulanic acid has been associated with drug-induced cholestatic hepatitis in 208 reported patients. In 153 evaluable patients there were 106 males and 47 females with a mean age of 60 years (1-90). Liver associated co-morbidity and co-medication does not play a major part in the development of disease. In most instances respiratory tract infection and sinusitis were treated by amoxicillin-clavulanic acid with a mean treatment duration of 13.9 days and a reaction time until first onset of jaundice of 25.2 days average. Infection and cholestasis from other reason were ruled out in most patients. Liver injury was classified according to laboratory parameters to be hepatocellular in 35 patients, cholestatic in 24 patients and mixed in 83 patients. Normalization of liver enzymes was observed 11.5 weeks after onset of drug administration (average); three of 153 patients did not survive the adverse event. Amoxicillin-clavulanic acid which is marketed for treatment of respiratory infections and sinusitis/otitis may in some cases induce severe adverse effects and death in patients of different age, especially if they are on multidrug regimens. In consideration of this fact many authors recommend to reflect carefully, whether amoxicillin-clavulanic acid is necessary in treatment of patients with localized or uncomplicated infections. If amoxicillin-clavulanic acid is prescribed, transaminase, alkaline phosphatase and bilirubin tests should be obtained within the first two weeks and after four to five weeks after beginning of treatment to recognize early enough undesired hepatic side effects.

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[Waldenström macroglobulinemia. Experience in 31 patients].

Waldenström macroglobulinemia (WM) is an uncommon indolent B-cell lymphoma, due to the proliferation of lymphoplasmacytic cells, and secretion of a monoclonal IgM protein. To evaluate the clinical characteristics, management and results of treatment of patients with WM at a public hospital in Chile. Review of medical records of 31 patients aged 43 to 85 years (16 males) with WM diagnosed between 2002 and 2017. Clinical features and survival were recorded. All patients had bone marrow compromise, and 31%, extranodal involvement. According to the International Prognostic Score System for WM (IPSSWM) 16, 58 and 26% were at low, intermediate and high risk, respectively. Twenty-five patients (81%) were treated, 32% with plasmapheresis and 36% with rituximab. Four cases (16%) achieved complete remission. Median follow up was 35 months (range 6-159). Estimated overall survival (OS) at 5 and 10 years was 74% and 53%, respectively. According to IPSSWM, the estimated five-year OS was 80, 92 and 39%, for low, intermediate and high-risk patients, respectively. OS was similar to that reported abroad, except for low risk patients, probably due to the low number of cases and short follow up. An improved survival should be expected with the routine use of immunochemotherapy.

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Double-blind, randomized, multicentre comparison of the effects of amlodipine and perindopril on 24 h therapeutic coverage and beyond in patients with mild to moderate hypertension. General Physicians Investigators' Group.

To compare the therapeutic coverage and safety of amlodipine and perindopril in patients with mild to moderate hypertension (diastolic blood pressure > or = 90 mmHg and < or = 109 mmHg). A double-blind, randomized, parallel-group, multicentre study. Following a 2-week placebo wash-out period, the patients were randomly allocated to treatment with either amlodipine at 5-10 mg once a day or perindopril at 4-8 mg once a day, for 60 days. Trough: peak ratios were calculated by two different methods (global and individualized approaches) from 24 h ambulatory blood pressure recordings made after the placebo period and after the active treatment period. Residual lowering of blood pressure after single-blind, single-dose omission was also investigated with further 24 h ambulatory blood pressure monitoring. Safety assessments were made throughout the study. The placebo-adjusted, global, diastolic blood pressure trough: peak ratio was 0.80 in the amlodipine group (n = 47) and 0.81 in the perindopril group (n = 49) in an intent-to-treat analysis. The corresponding global systolic blood pressure trough: peak ratio was 0.83 for amlodipine and 0.68 for perindopril. Individual trough: peak ratios were non-normally distributed. Mean (+/- SD) individual trough: peak ratios (intent-to-treat analysis) for diatolic blood pressure were 0.50 +/- 0.69 for amlodipine (median 0.42) and 0.15 +/- 3.27 for perindopril (median 0.33). In the per protocol analysis, the corresponding values were 0.50 +/- 0.72 (median 0.34) for amlodipine and 0.01 +/- 3.90 for perindopril (median 0.21). Both treatments produced comparable decreases in clinic systolic and diastolic blood pressure between days 0 and 60. Forty-eight hours after the last dose, both systolic and diastolic blood pressure were lower in amlodipine-treated patients than perindopril-treated patients. Amlodipine and perindopril were generally well tolerated. The most frequently reported adverse event was leg oedema in amlodipine-treated patients (19.1%), and coughing in perindopril-treated patients (14.3%). These results showed no statistically significant difference in trough: peak ratios between amlodipine and perindopril. However, the ambulatory blood pressure trough: peak ratios showed very large variations. Determination of trough: peak ratios by the conventional approach or by an individual approach can yield disparate values. After omitting one dose, a condition imitating noncompliance, blood pressure was more effectively controlled with amlodipine than with perindopril.

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Effects of tirofiban plus clopidogrel versus clopidogrel plus provisional abciximab on biomarkers of myocardial necrosis in patients with non-ST-elevation acute coronary syndromes treated with early aggressive approach. Results of the CLOpidogrel, upstream TIrofiban, in cath Lab Downstream Abciximab (CLOTILDA) study.

In non-ST-elevation acute coronary syndromes (NSTE-ACS), a strong correlation between adverse clinical events and peak values of myocardial necrosis markers has been found. In this study, we evaluated whether the adjunctive treatment with upstream tirofiban reduces the peak levels of cardiac troponin I and creatine kinase-MB (CK-MB) fraction in patients with NSTE-ACS undergoing early invasive strategy and pretreated with aspirin, heparin, and clopidogrel. A total of 300 patients were randomized to receive tirofiban (group 1) or not (group 2). Serial marker samples were collected before and after coronary angiography in all cases and after percutaneous coronary intervention (PCI) when performed. Between the 2 groups, no differences were observed in clinical and angiographic findings. Percutaneous coronary intervention was globally performed in 198 patients (66%). Of 99 group 2 patients, 26 (26%) received abciximab just before PCI. No significant differences between the 2 groups were observed with regard to cardiac troponin I and CK-MB values at admission and at 6, 12, and 24 hours thereafter; peak values before coronary angiography; and peak values of index event. In addition, the cumulative biomarkers release of the index event was similar between the 2 groups. Major bleeding rate was 2% in group 1 and 1% in group 2 (P = not significant). Composite incidence of death, myocardial infarction, or rehospitalization for ACS at 30 days was 9% in group 1 and 10% in group 2. In patients with NSTE-ACS undergoing early invasive strategy, the adjunctive administration of upstream tirofiban did not reduce the peak values and the cumulative release of myocardial necrosis markers, compared with aspirin, heparin, and clopidogrel given on admission and associated with selective use of abciximab just before PCI.

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Efficacy and safety of Levofloxacin, Clarithromycin and Esomeprazol as first line triple therapy for Helicobacter pylori eradication in Middle East. Prospective, randomized, blind, comparative, multicenter study.

Antibiotic resistance and poor compliance are the main causes of Helicobacter pylori (H. pylori ) eradication failure. This study evaluated the eradication rate, tolerability, and compliance of Levofloxacin, Clarithromycin and Esomeprazol combined triple therapy for H. pylori eradication. Four hundred-fifty patients from 3 centres who were diagnosed to have Helicobacter pylori infection by (13)C-urea breath test were randomized into 3 equal groups; group 1 (CAE) received Clarithromycin 500mg twice daily, Amoxicillin 1000mg twice daily, plus Esomeprazol 20mg twice daily for 7 days, group 2 (LAE) received Levofloxacin 500mg once daily, Amoxicillin 1000mg twice daily, plus Esomeprazol 20mg twice daily for 7 days, group 3 (CLE) received Levofloxacin 500mg once daily, Clarithromycin 500mg twice daily, plus Esomeprazol 20mg twice daily for 7 days. 436 patients were re-evaluated by (13)C-urea breath test after 6weeks from completion of treatment. H. pylori eradication (intention to treat) was successful in 136/150 (90.6%) with CLE, 127/150 (84.7%) with LAE and 118/150 (78.6%) with CAE. There was a significant difference (p<0.001) regarding treatment success between CLE and LAE when compared with CAE. There was no difference among the treatment groups with regard to the incidence and severity of adverse events reported. The combined Levofloxacin, and Clarithromycin and Esomeprazol based regimen as first line triple therapy for H. pylori eradication can give more significant eradication rate with same safety when compared with classic triple therapy.

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Coronary vasomotor dysfunction in the cardiac allograft: impact of different immunosuppressive regimens.

Immunosuppression may have an important impact on early graft coronary endothelial injury. We investigated functional and morphologic coronary alterations, myocardial expression, and cardiac release of possible mediators of allograft vasculopathy within 6 months after cardiac transplantation with respect to different immunosuppressive regimens. Epicardial and microvascular endothelium-dependent and endothelium-independent vasomotor function and epicardial intimal thickening were measured in 8 transplant recipients treated with cyclosporin A (CyA), azathioprine, and prednisone (group 1), 9 transplant recipients treated with tacrolimus (TKL), azathioprine, and prednisone (group 2), and 14 patients treated with TKL, mycophenolate mofetil (MMF), and prednisone (group 3). The gene expressions of inducible and endothelial nitric oxide synthase (iNOS and eNOS), endothelin-1, prostacyclinsynthase, and thromboxansynthase were analyzed in endomyocardial biopsy specimens using semiquantitative reverse transcription polymerase chain reaction. Transcardiac cytokine release, endothelin-1, and nitrate-release were determined from plasma samples. Epicardial endothelial dysfunction (vasoconstriction to acetylcholine > 10%) and microvascular smooth muscle cell dysfunction (flow velocity increase to adenosine and nifedipine < 2.0) were enhanced in heart transplant recipients immunosuppressed with TKL, azathioprine, and prednisone. The prevalence of epicardial dysfunction was 78% in group 2 versus 44% and 46% in group 1 and 3 (p < 0.05), respectively. The prevalence of microvascular dysfunction was 56% in group 2 versus 13% and 7% in group 1 and 3 (p < 0.02), respectively. Coronary vasomotor dysfunction was associated with increased myocardial iNOS expression (p < 0.05), decreased eNOS expression (p < 0.05), and enhanced cardiac immunoreactive interleukin-6 (p < 0.01). Coronary intimal thickening was not different between the groups. The combination of TKL and MMF appears to be superior to TKL and azathioprine (and comparable to CyA and azathioprine) concerning preservation of early coronary vasomotor function, eNOS expression, iNOS suppression as well as cardiac interleukin-6 release. This may have an important impact on subsequent development of transplant coronary atherosclerosis.

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Treatment of corticosteroid-responsive autoimmune inner ear disease with methotrexate: a randomized controlled trial.

A number of therapies have been proposed for the long-term management of corticosteroid-responsive, rapidly progressive, bilateral sensorineural hearing loss (autoimmune inner ear disease [AIED]). Methotrexate has emerged as the benchmark agent but has not been rigorously evaluated for hearing improvement in patients with AIED. To assess the efficacy of long-term methotrexate in maintaining hearing improvements achieved with glucocorticoid (prednisone) therapy in patients with AIED. A randomized, double-blind, placebo-controlled trial conducted from February 3, 1998, to November 5, 2001, of 67 patients with rapidly progressive, bilateral sensorineural hearing loss at 10 tertiary care centers in the United States. Randomization to either oral methotrexate (15 to 20 mg/wk; n = 33) or placebo (n = 34), in combination with an 18-week prednisone taper. Follow-up examinations, including audiometric evaluation, were performed at 4, 8, 12, 24, 36, 48, and 52 weeks, or until hearing loss was documented. Maintenance of hearing improvement achieved from prednisone treatment. Sixty-seven patients (57.8%) enrolled in the prednisone challenge experienced hearing improvement. Twenty-five patients (37%) experienced hearing improvements in both ears. Of the individuals who reached study end points, 24 (80%) of 30 end points were because of measured hearing loss in the methotrexate group and 29 (93.5%) of 31 end points were because of measured hearing loss in the placebo group (P =.15). Methotrexate was no more effective than placebo in maintaining the hearing improvement achieved with prednisone treatment (hazard ratio, 1.31; 95% confidence interval, 0.79-2.17; P =.30). Methotrexate does not appear to be effective in maintaining the hearing improvement achieved with prednisone therapy in patients with AIED.

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Doxorubicin-Based Chemotherapy and Radiation Therapy Produces Favorable Outcomes in Limited-Stage Plasmablastic Lymphoma: A Single-Institution Review.

Plasmablastic lymphoma (PBL) is an aggressive variant of diffuse large B-cell lymphoma. We sought to assess the treatment outcomes after combined-modality therapy for early-stage PBL. We retrospectively reviewed the outcomes of 10 consecutive patients diagnosed with stage I-II PBL from February 2001 to December 2013 at a single institution. The baseline clinical characteristics, treatment modalities, overall outcomes, and treatment-related toxicity were assessed. The median age at diagnosis was 50.5 years. All patients had extranodal disease; 2 were positive for human immunodeficiency virus. Seven patients received hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone)-based chemotherapy, 2 received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), and 1 received dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin). Radiotherapy (RT) was administered after a complete response to chemotherapy in 7 patients and a partial response in 1 patient. At a median follow-up period of 42 months, the estimated 2-year progression-free and overall survival rates were 90% and 100%, respectively. PBL can be successfully treated with aggressive chemotherapy followed by RT. The treatment was well tolerated and can result in long-term survival for patients with limited-stage disease.

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Safety and effectiveness of apixaban compared with warfarin among clinically-relevant subgroups of venous thromboembolism patients in the United States Medicare population.

The AMPLIFY trial found significantly lower major bleeding (MB) and similar recurrent venous thromboembolism (VTE) risks associated with apixaban vs warfarin among patients with VTE. To compare MB, clinically-relevant non-major (CRNM) bleeding, and recurrent VTE risks among clinically-relevant subgroups of newly diagnosed elderly patients with VTE prescribed apixaban vs warfarin. US Medicare patients prescribed apixaban or warfarin within 30 days post-VTE encounter were identified. Propensity score matching (PSM) was used to control for patient characteristics. Cox models were used to assess MB, CRNM bleeding, and recurrent VTE. Subgroup analyses were conducted for index VTE encounter type, index VTE diagnosis type, index VTE etiology, sex, and frailty. Post-PSM, 11,363 matched pairs of patients prescribed apixaban or warfarin were identified. Apixaban had lower MB (Hazard Ratio [HR]:0.76; 95% CI:0.64-0.91) and similar recurrent VTE risks (HR:1.04; 95% CI:0.75-1.43) vs warfarin. No significant interactions were observed between treatment and index VTE encounter type, index VTE diagnosis type, or sex for risk of MB, CRNM bleeding, or recurrent VTE. Significant interactions: frail patients prescribed apixaban had a 15% lower, while non-frail patients prescribed apixaban had 32% lower CRNM bleeding risk vs those prescribed warfarin. Patients with provoked VTE prescribed apixaban trended toward a higher, while those with unprovoked VTE trended toward a lower risk of recurrent VTE vs patients prescribed warfarin. Apixaban was associated with significantly lower risks of MB and CRNM bleeding, and similar risk of recurrent VTE as compared with warfarin across the overall population and most subgroups.

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Subepithelial collagen deposition, profibrogenic cytokine gene expression, and changes after prolonged fluticasone propionate treatment in adult eosinophilic esophagitis: a prospective study.

Recent research shows that both pediatric and adult patients with eosinophilic esophagitis (EoE) experience esophageal remodeling marked by increased collagen deposition in which TGF-β plays an important role. However, limited data are available on the intensity and reversibility of fibrous remodeling in adults with EoE. We sought to analyze differences in collagen deposition in the lamina propria (LP) and profibrogenic cytokine gene expression along with other changes induced by prolonged treatment with fluticasone propionate in adults with EoE. Ten adults given consecutive diagnoses of EoE were studied prospectively. Deep esophageal biopsy specimens were obtained before and after 1 year of treatment with fluticasone propionate. Collagen deposition in the LP was assessed in tissue sections with the aid of the Masson trichrome technique. IL5, TGFB1, fibroblast growth factor 9 (FGF9), and CCL18 gene expression was quantified through real-time PCR. EoE results were compared among samples from 10 adult patients with gastroesophageal reflux disease and 10 control subjects with healthy esophagi. Patients with EoE showed a significant increase in subepithelial collagen deposition; this correlated positively with eosinophil density in the LP and the patient's age. Prolonged steroid treatment induced a nonsignificant reduction in subepithelial fibrosis, which remained significantly higher than in control subjects. Profibrogenic cytokine gene expression also increased in patients with EoE, with IL5 (P < .001), FGF9 (P = .005), and CCL18 (P = .008) all significantly upregulated. After 1 year of treatment, a reduction was observed in gene expression; for CCL18 expression, this decrease was statistically significant (P < .001). Esophageal remodeling is associated with upregulated gene expression of profibrogenic cytokines in adults with EoE. Prolonged treatment with fluticasone propionate leads to a nonsignificant reduction in subepithelial collagen deposition accompanied by downregulation of profibrogenic cytokine gene expression, with that of CCL18 being especially significant.

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Awake Sedation With Propofol Attenuates Intraoperative Stress of Carotid Endarterectomy in Regional Anesthesia.

Carotid endarterectomy in regional anesthesia is often associated with increased perioperative stress. We assumed that carotid endarterectomy performed under awake sedation with propofol is more beneficial to prevent such stress than alprazolam premedication only. A total of 47 consecutive patients with significant carotid artery stenosis were enrolled into this investigation and followed up for 5 years to explore vascular complications. All operations were performed under regional anesthesia. As premedication, all patients took 0.5 mg of alprazolam 30 minutes before the procedure. After randomization, 22 patients had awake sedation with target controlled propofol infusion, and the other 25 had only premedication. Cortisol plasma levels were serially analyzed: before surgery (T₁), before (T₂) and after release of carotid clamp (T₃), and at 2 (T₄) and 24 postoperative hours (T₅). Alprazolam levels were also measured before and after the surgery. The plasma concentration of cortisol was significantly lower in the propofol sedation group at T₂ (P < 0.001), T₃ (P = 0.001), and T₄ (P < 0.001) than in the alprazolam-only group. Alprazolam levels did not correlate with cortisol levels at any time point. A significant positive correlation was found between the clamp time and plasma cortisol level at T₃ (P = 0.018), similarly between the degree of contralateral carotid stenosis and plasma cortisol level at T₃ (P = 0.03). Plasma cortisol concentration 2 hours after the operation (T₄) proved to be an independent predictor of carotid restenosis during the 5-year follow-up (odds ratio: 1.67, 95% confidence interval: 1.02-2.73, P = 0.04). An additional intraoperative propofol sedation provides better stress relief than alprazolam-only premedication during awake carotid endarterectomy.

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A 21-day double-blind study of the effect of adding sustained-release theophylline (Nuelin SA) to inhaled salbutamol in patients with asthma.

The effect of adding sustained-release theophylline tablets (Nuelin SA) in a dose of 350 and 700 mg daily to regular treatment with inhaled salbutamol was assessed in a double-blind cross-over study in 19 patients with reversible airways obstruction. In this combination, oral theophylline, even in the relatively low dose of 350 mg a day, produced a significant additional improvement in lung function. Subjectively, patients showed a preference for the combination of theophylline and inhaled salbutamol compared with the beta-stimulant alone.

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Hemorrhage associated with ventriculoperitoneal shunt placement in aneurysmal subarachnoid hemorrhage patients on a regimen of dual antiplatelet therapy: a retrospective analysis.

Intracranial stenting and flow diversion require the use of dual antiplatelet therapy (DAPT) to prevent in-stent thrombosis. DAPT may significantly increase the risk of hemorrhagic complications in patients who require subsequent surgical interventions. In this study, the authors sought to investigate whether DAPT is a risk factor for hemorrhagic complications associated with ventriculoperitoneal (VP) shunt placement in patients with aneurysmal subarachnoid hemorrhage (aSAH). Moreover, the authors sought to compare VP shunt complication rates with respect to the shunt's location from the initial external ventricular drain (EVD) site. Patients with aSAH who presented to the authors' institution from July 2009 through November 2016 and required VP shunt placement for persistent hydrocephalus were included. The rates of hemorrhagic complications associated with VP shunt placement were compared between patients who were on a regimen of DAPT (aspirin and clopidogrel) for use of a stent or flow diverter, and patients who underwent microsurgical clipping or coiling only and were not on DAPT using a backward stepwise multivariate analysis. Rates of radiographic hemorrhage and infection-related VP shunt revision were compared between patients who underwent VP shunt placement along the same track and those who underwent VP shunt placement at a different site (contralateral or posterior) from the initial EVD. A total of 443 patients were admitted for the management of aSAH. Eighty of these patients eventually required VP shunt placement. Thirty-two patients (40%) had been treated with stent-assisted coiling or flow diverters and required DAPT, whereas 48 patients (60%) had been treated with coiling without stents or surgical clipping and were not on DAPT at the time of VP shunt placement. A total of 8 cases (10%) of new hemorrhage were observed along the intracranial proximal catheter of the VP shunt. Seven of these hemorrhages were observed in patients on DAPT, and 1 occurred in a patient not on DAPT. After multivariate analysis, only DAPT was significantly associated with hemorrhage (OR 31.23, 95% CI 2.98-327.32; p = 0.0001). One patient (3%) on DAPT who experienced hemorrhage required shunt revision for hemorrhage-associated proximal catheter blockage. The remaining 7 hemorrhages were clinically insignificant. The difference in rates of hemorrhage between shunt placement along the same track and placement at a different site of 0.07 was not significant (6/47 vs 2/32, p = 0.46). The difference in infection-related VP shunt revision rate was not significantly different (1/47 vs 3/32, p = 0.2978). This clinical series confirms that, in patients with ruptured aneurysms who are candidates for stent-assisted coiling or flow diversion, the risk of clinically significant VP shunt-associated hemorrhage with DAPT is low. In an era of evolving endovascular therapeutics, stenting or flow diversion is a viable option in select aSAH patients.

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Fluoxetine versus moclobemide: cross-comparison between the time courses of improvement.

Competitive statistical methods were used in a meta-analysis of the data of 440 fluoxetine-treated and 437 moclobemide-treated patients in order to address the issue of the timing of recovery from depression, and to elucidate potential differences in the onset of action between the two different classes of antidepressants. In spite of large biochemical and pharmacological differences, fluoxetine and moclobemide turned out to be virtually identical with regard to the overall efficacy, proportions and time characteristics of premature withdrawal, and most notably, the time course of recovery. The onset of improvement occurred in the majority of cases within the first two weeks of treatment and was highly predictive for the outcome after six weeks. The analyses yielded no indication of a delayed onset of action of antidepressants. Given the apparent nonspecificity of antidepressants, together with their relatively modest response rates, future research will need consider whether mechanisms different from those related to the monoaminergic systems may be involved in the pathogenesis of depression.

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Time-dependent effect of statins on platelet function in hypercholesterolaemia.

Reduction of platelet activity induced by statins has been described as a positive effect exerted by such molecules on vascular thrombotic events. However, the relations among cholesterol (LDL-C) reduction, the timing of the antiplatelet effect, the involved mechanisms and the doses of each statin able to reduce platelet function are not actually well known. The aim of our study was to evaluate the impact of simvastatin (20 mg day-1), atorvastatin (10 mg day-1), fluvastatin (40 mg day-1) and pravastatin (40 mg day-1) on platelet function in hypercholesterolaemic subjects with relation to (LDL-C), oxidized-LDL (ox-LDL) and antiport mechanism modifications. Sixteen subjects were assigned to each treatment (40 males, 24 females, mean age 48.7 +/- 13.4, LDL-C 5.13 +/- 0,23 mmol L-1) and evaluated for platelet surface P-selectin (P-sel), lipid profile, ox-LDL, platelet-associated ox-LDL (Pox-LDL), platelet cholesterol content, antiport mechanisms, and intracellular and systemic NO synthase every 7 days for one month. Our data show a strong relation between enhanced P-sel and Pox-LDL (r = 0.68, P < 0.01). Simvastatin, atorvastatin, fluvastatin and pravastatin reduce platelet activity after 1, 2, 3 and 4 weeks of treatment, respectively (P < 0.001, P < 0.001, P < 0.01, P < 0.05). Pox-LDL are modulated early by simvastatin, atorvastatin and fluvastatin Pox-LDL (r = 0.66, 0.65 and 0.52; P < 0.001, 0.001 and 0.01, respectively) whereas LDL-C and ox-LDL reductions associated to modifications of antiport activity act later. Moreover, they are the most relevant finding in pravastatin-related subjects. Our data suggest a different impact of several statins on platelet function, which is initially related to interference with Pox-LDL rather than LDL-C reduction.

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Ticagrelor or clopidogrel dual antiplatelet therapy following a pharmacoinvasive strategy in ST-segment elevation myocardial infarction.

To describe and evaluate outcomes in STEMI patients sustained on clopidogrel compared to those switched to ticagrelor following fibrinolysis. World-wide, many STEMI patients cannot achieve timely PCI and therefore require fibrinolysis. Although comparable 30-day and 1-year safety was shown with clopidogrel or ticagrelor in the TREAT study, there is paucity of long-term outcomes in pharmacoinvasive treated STEMI. We conducted an observational cohort study evaluating consecutive pharmacoinvasive STEMI patients treated in a network, comparing those switched to ticagrelor to those sustained on clopidogrel. The primary efficacy composite was one-year all-cause death, recurrent myocardial infarction, and stroke with major bleeding and intracranial hemorrhage (ICH) as the safety outcomes. Multivariable Cox regression model was used to examine the association between P2Y12 inhibitor and outcomes with inverse probability weighting. Of 1426 pharmacoinvasive STEMI patients, 28% (n = 396) were converted to ticagrelor at a mean of 9.9 h after fibrinolysis with comparable GRACE Risk Scores (median; 158 vs 157, p0.352). The primary composite occurred in 3.5% of ticagrelor and 7.0% of clopidogrel treated patients (p0.014). Following adjustment, ticagrelor was associated with a 54% lower composite outcome (adjusted HR 0.46, 95% confidence interval 0.26-0.84). Major bleeding 6.3% vs 6.1% (NS) and ICH 0.0% vs 0.2% (NS) were similar. In a prospective STEMI cohort, switching to ticagrelor compared with sustaining clopidogrel following fibrinolysis pharmacoinvasive reperfusion reduced recurrent ischemic events at 1-year with no differences in major bleeding or ICH. Aligned with randomized data, these findings provide support to switch pharmaco-invasively treated STEMI patients.

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Fibrotic idiopathic interstitial pneumonias: mortality is linked to a decline in gas transfer.

Baseline clinical and physiological features and changes in these parameters over time are known predictors of survival in patients with fibrotic idiopathic interstitial pneumonia (IIP). Pulmonary hypertension is common in advanced fibrotic IIP, and has a negative impact on survival. Serial pulmonary function profiles, indicative of increasing vascular impairment in patients with IIP, and in particular, selective reductions in gas transfer, have not been studied previously. Predictors of event-free survival time were investigated in a cohort of Dutch patients with IPF and fibrotic non-specific interstitial pneumonia (n = 117). Pulmonary function test data were prospectively collected from November 1993 to December 2005. Multivariate Cox regression models were developed to identify the prognostic relevance to survival of variables related to baseline demographics, histopathology, pulmonary function and the 6- and 12-month changes in pulmonary function parameters. Different survival patterns were observed for patients with different histopathological diagnoses. At baseline, FVC was the most important prognostic factor. At the 6-month follow up, change in transfer coefficient (K(CO), DL(CO)/V(A)), and at the 12-month follow up, age, baseline K(CO) and 12-month change in FVC and K(CO), were independent predictors of event-free survival. Apart from histopathology, change in K(CO) over time appeared to be the most consistent and powerful predictor of survival in these patients. The decline in K(CO) may be indicative of increasing vascular impairment, which may have a major impact on survival, in patients with fibrotic IIP.

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Study protocol for a multicentre, prospective cohort study of the association of angiotensin II type 1 receptor blockers on outcomes of coronavirus infection.

The COVID-19 epidemic grows and there are clinical trials of antivirals. There is an opportunity to complement these trials with investigation of angiotensin II type 1 receptor blockers (ARBs) because an ARB (losartan) was effective in murine influenza pneumonia. Our innovative design includes: ARBs; alignment with the WHO Ordinal Scale (primary endpoint) to align with other COVID-19 trials; joint longitudinal analysis; and predictive biomarkers (angiotensins I, 1-7, II and ACE1 and ACE2). Our hypothesis is: ARBs decrease the need for hospitalisation, severity (need for ventilation, vasopressors, extracorporeal membrane oxygenation or renal replacement therapy) or mortality of hospitalised COVID-19 infected adults. Our two-pronged multicentre pragmatic observational cohort study examines safety and effectiveness of ARBs in (1) hospitalised adult patients with COVID-19 and (2) out-patients already on or not on ARBs. The primary outcome will be evaluated by ordinal logistic regression and main secondary outcomes by both joint longitudinal modelling analyses. We will compare rates of hospitalisation of ARB-exposed versus not ARB-exposed patients. We will also determine whether continuing ARBs or not decreases the primary outcome. Based on published COVID-19 cohorts, assuming 15% of patients are ARB-exposed, a total sample size of 497 patients can detect a proportional OR of 0.5 (alpha=0.05, 80% power) comparing WHO scale of ARB-exposed versus non-ARB-exposed patients. This study has core institution approval (UBC Providence Healthcare Research Ethics Board) and site institution approvals (Health Research Ethics Board, University of Alberta; Comite d'etique de la recerche, CHU Sainte Justine (for McGill University and University of Sherbrook); Conjoint Health Research Ethics Board, University of Calgary; Queen's University Health Sciences & Affiliated Hospitals Research Ethics Board; Research Ethics Board, Sunnybrook Health Sciences Centre; Veritas Independent Research Board (for Humber River Hospital); Mount Sinai Hospital Research Ethics Board; Unity Health Toronto Research Ethics Board, St. Michael's Hospital). Results will be disseminated by peer-review publication and social media releases. NCT04510623.

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Do angiotensin-converting enzyme inhibitors reduce the risk of symptomatic radiation pneumonitis in patients with non-small cell lung cancer after definitive radiation therapy? Analysis of a single-institution database.

Preclinical studies have suggested that angiotensin-converting enzyme inhibitors (ACEIs) can mitigate radiation-induced lung injury. We sought here to investigate possible associations between ACEI use and the risk of symptomatic radiation pneumonitis (RP) among patients undergoing radiation therapy (RT) for non-small cell lung cancer (NSCLC). We retrospectively identified patients who received definitive radiation therapy for stages I to III NSCLC between 2004 and 2010 at a single tertiary cancer center. Patients must have received a radiation dose of at least 60 Gy for a single primary lung tumor and have had imaging and dosimetric data available for analysis. RP was quantified according to Common Terminology Criteria for Adverse Events, version 3.0. A Cox proportional hazard model was used to assess potential associations between ACEI use and risk of symptomatic RP. Of 413 patients analyzed, 65 were using ACEIs during RT. In univariate analysis, the rate of RP grade ≥2 seemed lower in ACEI users than in nonusers (34% vs 46%), but this apparent difference was not statistically significant (P=.06). In multivariate analysis of all patients, ACEI use was not associated with the risk of symptomatic RP (hazard ratio [HR] = 0.66; P=.07) after adjustment for sex, smoking status, mean lung dose (MLD), and concurrent carboplatin and paclitaxel chemotherapy. Subgroup analysis showed that ACEI use did have a protective effect from RP grade ≥2 among patients who received a low (≤20-Gy) MLD (P<.01) or were male (P=.04). A trend toward reduction in symptomatic RP among patients taking ACEIs during RT for NSCLC was not statistically significant on univariate or multivariate analyses, although certain subgroups may benefit from use (ie, male patients and those receiving low MLD). The evidence at this point is insufficient to establish whether the use of ACEIs does or does not reduce the risk of RP.

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Loop diuretics in the management of acute renal failure: a prospective, double-blind, placebo-controlled, randomized study.

Studies on the role of loop diuretics in patients with acute renal failure (ARF) are largely retrospective, anecdotal, and poorly controlled. We report the results of a prospective, randomized, placebo-controlled, double-blind study examining the effect of loop diuretics on renal recovery, dialysis, and death in patients with ARF. Ninety-two patients with ARF were enrolled into the study. All received intravenous dopamine, 2 micrograms/kg body weight/min throughout, 20% mannitol, 100 ml every 6 h for the first 3 days, and, in a double-blind manner, either torasemide, frusemide, or placebo, 3 mg/kg body weight i.v. every 6 h for 21 days or until renal recovery or death. Renal recovery, the need for dialysis, and death were no different in the three groups. Patients given a loop diuretic had a significant rise in urine flow rate in the first 24 h compared to placebo (P = 0.02). Based on the urine flow rate during the first post-medication day patients were divided into two groups--oliguric (< 50 ml/h) and non-oliguric (> or = 50 ml/h). Non-oliguric patients had a significantly lower mortality than oliguric patients (43% vs 69%, P = 0.01). However, they were less ill (APACHE II score 17.2 vs 20.6, P = 0.008) and had less severe renal failure at entry (creatinine clearance 14 ml/min vs 4 ml/min, P < 0.0001). The use of loop diuretics in oliguric patients with ARF can result in a diuresis. There is no evidence that these drugs can alter outcome.

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