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Comparison of therapy with simvastatin 80 mg and 120 mg in patients with familial hypercholesterolaemia.

High-dose preparations of simvastatin and atorvastatin have recently become available to treat resistant hypercholesterolaemia aggressively, but few studies have compared these two agents. This study compared the efficacy of simvastatin 80 mg and 120 mg in 22 patients with severe familial hypercholesterolaemia over a three-month period using an open label format. Simvastatin 120 mg was reasonably well tolerated and delivered a further 8% reduction in LDL over 80 mg, giving a total reduction of 55 +/- 13%, while further decreasing triglycerides (18%) and continuing to raise HDL (13%) further than the 80 mg dose. However, transient adverse changes were noted in both lipoprotein (a) and fibrinogen and 20% of patients were unable to tolerate the higher dose. One late case of rhabdomyolysis was observed, suggesting patients on the 120 mg dose require continued regular review.

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A comparative trial of lisinopril and nifedipine in mild to moderate hypertension in general practice.

to compare lisinopril and nifedipine in the management of essential hypertension in 52 patients in general practice with respect to the obtaining of target diastolic blood pressure and freedom from side effects. an open label, parallel randomised trial over an eight week period. lisinopril and nifedipine were found to effectively lower diastolic blood pressure with the latter having a significantly higher level of withdrawals and clinical side effects. lisinopril is equivalent to nifedipine in its hypertensive effect and has a better side effect profile.

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Five day and ten day triple therapy (amoxicillin, furazolidone and metronidazole) in the treatment of duodenal ulcer.

This investigation aimed to compare bacterial eradication and healing in patients with active duodenal ulcer treated with a combination of furazolidone 600 mg/day and metronidazole 750 mg/day and amoxicillin 1.5 and g/day for 5 (TT5) or 10 (TT10) days. Fifty four (TT5 = 28 and TT10 = 26) patients were included in the study. Ulcer healing was observed in 77.8% of TT5 Group and in 75% of TT10 Group at week 4. H pylori eradication was observed in 51.9% and 65% respectively (p > 0.05). When all patients were grouped, a significantly healing rate was observed in those eradicated as compared to those not eradicated (p = 0.03). We concluded that extending the treatment to 10 days did not significantly influence the results of ulcer healing and eradication of Helicobacter pylori.

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Intentional early delivery versus expectant management for preterm premature rupture of membranes at 28-32 weeks' gestation: A multicentre randomized controlled trial (MICADO STUDY).

Preterm premature rupture of fetal membranes (PPROM) exposes the fetus to preterm birth, and optimal timing for delivery is controversial. The aim of this study was to compare intentional early delivery ("active management") with expectant management in very preterm birth (28-32 weeks). We conducted a prospective randomized controlled trial with intent-to-treat analysis, at 19 tertiary-care hospitals in France and 1 in Geneva, Switzerland. Inclusion criteria were women age ≥18 years, PPROM at 28^0/7 to 31^6/7 weeks' gestation, singleton pregnancy. Exclusion criteria were maternal/fetal indications for immediate delivery. All participants received prophylactic antibiotics (amoxicillin + gentamicin) and two doses of corticosteroids. Women in expectant management delivered at 34 weeks, sooner if medically indicated. Women in active management delivered 24 h after the second steroid dose. The primary outcome measure was a composite of neonatal death/severe adverse events: periventricular leukomalacia, intraventricular hemorrhage, sepsis, oxygen requirement at 36 weeks, and necrotizing enterocolitis. The secondary outcome was clinical chorioamnionitis. The trial was stopped prematurely, due to recruitment difficulties. Of 360 women assessed, 139 (40% of calculated sample size) were randomized: 70 to expectant management, 69 to active management. Mean gestational age at PPROM was similar in both groups (30 ± 1.3 vs. 30.2 ± 1.2 weeks, respectively). There were 35 cases of medical/suspected complications requiring delivery in expectant management vs. 4 in active management. Mean latency between PPROM and delivery was 11.7 ± 9.8 vs. 2.8 ± 0.6 days, respectively; P < 0.0001 (median 8.4 (1.8-44.2) vs. 2.7 (1.9-4.3)). There were more caesarean deliveries in active than expectant management (80% vs. 60%, respectively; P < 0.01). There were 2 chorioamnionitis cases, both in expectant management. One baby died in expectant management; 2 in active management (one with heart defect). There was no significant difference in sepsis rates. The combined neonatal death/severe adverse events measure was 12.9% for expectant management and 13.0% for active management (OR 0.98; 95% CI: 0.33-2.93, P = 0.97). For PPROM at 28-32 weeks, and with antenatal antibiotic and steroid therapy, there were no observed differences in neonatal health when comparing expectant management to early delivery. As expected, expectant management resulted in higher gestational age and birth weight. However, our study was underpowered to draw firm and reliable conclusions.

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Rapid corticosteroid taper versus standard of care for immune checkpoint inhibitor induced nephritis: a single-center retrospective cohort study.

Current guidelines for treatment of immune checkpoint inhibitor (ICI)-induced nephritis are not evidence based and may lead to excess corticosteroid exposure. We aimed to compare a rapid corticosteroid taper to standard of care. Retrospective cohort study in patients with ICI-induced nephritis comparing a rapid taper beginning with 60 mg/day prednisone and tapered to 10 mg within 3 weeks to a historical control group that began 60 mg/day tapered to 10 mg within 6 weeks (standard of care). Renal recovery was defined as creatinine returning to within 1.5-fold baseline. The log-rank test compared the differences in time to renal recovery between the groups. We report rates of renal recovery at 30, 60 and 90 days, and timing and outcomes of ICI rechallenge. Thirteen patients received rapid corticosteroid taper and 14 patients received standard of care. Baseline characteristics were similar between groups. The median time to ≤10 mg/day prednisone was 20 days (IQR 15-25) in the rapid-taper group compared with 38 days (IQR 30-58) in the standard-of-care group. There was no significant difference in the time to renal recovery between the groups, though numerically higher numbers of patients recovered by 30 days, 11 (85%) in the rapid-taper arm versus 6 (46%) in the standard of care arm. Exposure to other nephritis-causing medications (proton pump inhibitor or trimethoprim-sulfamethoxazole) during the corticosteroid taper was more common in the standard of care group, 9 (64%) versus rapid-taper group, 2 (15%), and was associated with longer time to renal recovery, 20 days (IQR 14-101) versus 13 days (IQR 7-34) in those that discontinued nephritis-causing medications. Fifteen (56%) of patients were rechallenged with ICIs, and only two (13%) developed recurrent nephritis. Patients with ICI-induced nephritis have excellent kidney outcomes when treated with corticosteroids that are tapered over 3 weeks.

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Prophylaxis in gynaecological surgery: a prospective randomized comparison between single dose prophylaxis with amoxycillin/clavulanate and the combination of cefuroxime and metronidazole.

A prospective randomized comparison of a single pre-operative dose of 2.2 g amoxycillin/clavulanate versus the combination of 1.5 g cefuroxime plus 0.5 g metronidazole was conducted in 467 women, who underwent gynaecological surgery. The incidence of febrile morbidity, urinary tract infection, wound infection and the use of post-operative antimicrobial agents was similar in the two groups. Amoxycillin/clavulanate is as effective as a combination of cefuroxime and metronidazole and less expensive.

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A placebo-controlled clinical trial of regular monotherapy with short-acting and long-acting beta(2)-agonists in allergic asthmatic patients.

Some recent studies suggest that regular beta(2)-agonist use may result in inadequate control of asthma. It has been hypothesized that this occurs particularly in allergic asthmatic patients exposed to relevant allergens. Moreover, it is still unclear whether this occurs during the use of both short-acting and long-acting beta(2)-agonists. Asthmatic patients (n = 145) allergic to house dust mite (HDM) were randomly allocated to monotherapy with a short-acting beta(2)-agonist (SA; n = 48), a long-acting beta(2)-agonist (LA; n = 50), or placebo (n = 47), double blind, double dummy. The study covered three periods: (1) a 4-week run-in period, in which no changes took place; followed by (2) cessation of treatment with asthma medication including inhaled corticosteroids, introduction of allergen avoidance measures (active/placebo treatment) to lower HDM exposure in the active group, and an 8-week washout period to adjust patients to these changes; followed by (3) a 12-week study medication period. At the start of the 12-week medication period, and every 4 weeks thereafter, spirometric measurements (FEV(1) and provocative concentration of histamine causing a 20% fall in FEV(1) [PC(20)]) were performed. Peak flow and asthma symptoms were recorded daily. Additionally, at the start and every 6 weeks thereafter, dust samples were collected from mattresses and living room and bedroom floors to assess HDM (der p 1) concentrations. Effects on FEV(1), PC(20), peak flow, and asthma symptoms were analyzed with repeated-measurement analysis and corrected for the exposure to HDM allergens. There were no significant differences among the three medication groups after 12 weeks for FEV(1). However, a significant decrease in mean FEV(1) percent predicted (95% confidence interval [CI]) was observed within the SA group: - 6.6 (- 10.4 to - 2.8) (p = 0.0002). A decrease in geometric mean PC(20) (95% CI) of - 1.2 (- 1.96 to - 0.44) doubling concentration was observed within the SA group (p = 0.05). No significant changes in FEV(1) and PC(20) were observed > 12 weeks within the LA group or the placebo group. There were neither changes in peak flow and asthma symptom scores among the three medication groups nor within the groups. Moreover, none of the parameters showed interactive effects with allergen exposure. There were no significant differences among the three medication groups for FEV(1) and PC(20). The within-treatment group comparison showed a significant small decline in FEV(1) for the SA group (but not for the LA group), which could indicate that monotherapy with SAs might have negative effects on FEV(1). This was not seen during regular use of LAS: No clear pathophysiologic mechanism can explain these findings at the moment. Relatively high or low exposure to allergens did not alter these findings.

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Efficacy of the Natural Clay, Calcium Aluminosilicate Anti-Diarrheal, in Reducing Medullary Thyroid Cancer-Related Diarrhea and Its Effects on Quality of Life: A Pilot Study.

Medullary thyroid cancer (MTC)-related diarrhea can be debilitating, reduces quality of life (QOL), and may be the only indication for initiating systemic therapy. Conventional antidiarrheal drugs are not always helpful and may have side effects. Calcium aluminosilicate antidiarrheal (CASAD), a natural calcium montmorrilonite clay, safely adsorbs toxins and inflammatory proteins associated with diarrhea. It was hypothesized that CASAD would reduce the severity of diarrhea and improve QOL in MTC patients. This was a prospective pilot trial (NCT01739634) of MTC patients not on systemic therapy with self-reported diarrhea of three or more bowel movements (BMs) per day for a week or more. The study design included a one-week run-in period followed by one week of CASAD ± a two-week optional continuation period. The primary endpoint was efficacy of one week of CASAD treatment in decreasing the number of BMs per day by ≥20% when compared with the baseline run-in period. Secondary objectives included tolerability and safety and the impact on QOL using the MD Anderson Symptom Inventory-Thyroid questionnaire (MDASI-THY). Ten MTC patients (median age = 52 years, 70% female, 80% white) were enrolled. All had distant metastases, and median calcitonin was 5088 ng/mL (range 1817-42,007 ng/mL). Ninety percent had received prior antidiarrheals, and 40% of these had used two or more drugs, including tincture of opium (30%), loperamide (50%), diphenoxylate/atropine (20%), colestipol (10%), or cholestyramine (10%). Of seven evaluable patients, four (56%) had ≥20% reduction in BMs per day. Six out of seven patients discontinued their prior antidiarrheals. Best response ranged from 7% to 99% reduction in mean BMs/day from baseline. Five out of seven patients considered CASAD a success, and they opted for the two-week continuation period. Improvements in diarrhea and all six interference items assessed by MDASI-THY were noted at weeks 1 and 3. Total interference score was significantly improved at three weeks compared with baseline (p = 0.05). An oral levothyroxine absorption test was performed in one patient; malabsorption of levothyroxine was not observed. Adverse events included flatulence (40%), bloating (10%), heartburn (10%), and constipation (10%). CASAD is a promising strategy for treatment of MTC-related diarrhea. In this small pilot study, improvements in frequency and quality of diarrhea as well as QOL were noted. Further studies in this population are warranted.

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Subcutaneous Sarilumab in hospitalised patients with moderate-severe COVID-19 infection compared to the standard of care (SARCOVID): a structured summary of a study protocol for a randomised controlled trial.

The main aim of the study is to evaluate the efficacy of a single dose of sarilumab, in subcutaneous administration, in hospitalised patients with moderate to early severe COVID-19 infection compared to the current standard of care, to prevent progression to systemic hyperinflammatory status. Our hypothesis is that use of subcutaneous sarilumab in early stages (window of opportunity) of COVID-19 moderate-severe pneumonia can prevent higher oxygenation requirements through non-invasive and invasive mechanical ventilation and decrease in-hospital stays, as well as death rate. The secondary objectives of the study are to evaluate the safety of sarilumab through hospitalisation and up to day 14 after discharge, compared to the control arm as assessed by incidence of serious and non serious adverse events (SAEs). In addition, as an exploratory objective, to compare the baseline clinical and biological parameters, including serum IL-6 levels, of the intervention population against controls of the same pandemic outbreak (using a propensity score) to search for markers that identify the best candidates for the treatment with subcutaneous IL-6R inhibitors and to attempt an approximation in the temporal frame of the "window of opportunity" TRIAL DESIGN: SARCOVID is an investigator-initiated single center randomised proof of concept study. Patients treated at the Hospital Universitario La Princesa, Madrid, Spain requiring hospitalisation will be consecutively recruited, meeting all inclusion criteria and none of the exclusion criteria Inclusion criteria a. Age >18, <80 years old b. COVID-19 infection documented by a positive RT-PCR test or, in absence of a RT-PCR positive test, case definition of COVID 19 infection/pneumonia as per local protocol and the presence of a positive serologic test (IgM/IgA by ELISA) c. Documented interstitial pneumonia requiring admission and at least two of the following parameters: 1) Fever ≥ 37.8°C (tympanic) 2) IL-6 in serum ≥ 25 pg/mL (in the absence of a previous dose of prednisone or equivalent> 1 mg / kg) or PCR> 5mg/dL 3) Lymphocytes <600 cells/mm³ 4) Ferritin> 300 μg/L that doubles in 24 hours 5) Ferritin> 600 μg/L in the first determination and LDH> 250 U/L 6) D-dimer (> 1 mg/L) d. Informed verbal consent or requested under urgent conditions, documented in the electronic medical record. Exclusion criteria a. Patients who require mechanical ventilation at the time of inclusion. b. AST / ALT values > 5 folds the ULN. c. Absolute neutrophil count below 500 cells/mm³ d. Absolute platelet count below 50,000 cells/mm³ e. Documented sepsis or high suspicion of superimposed infection by pathogens other than COVID-19. f. Presence of comorbidities that can likely lead to an unfavourable result according to clinical judgment. g. Complicated diverticulitis or intestinal perforation. h. Current skin infection (eg, uncontrolled dermopiodermitis). i. Immunosuppressive anti-rejection therapy. j. Pregnancy or lactation. k. Previous treatment with tocilizumab or sarilumab. l. Patients participating in another clinical trial for SARS-CoV-2 infection. m. Patients with known hypersensitivity or contraindication to sarilumab or excipients. The intervention group, sarilumab plus standard of care, will receive 400 mg single dose treatment with Sarilumab (Kevzara), 2 subcutaneous injections 200mg each in a pre-filled syringe. Treatment with drugs or procedures in routine clinical practice that the clinician responsible for the patient deems necessary is allowed. The control group will receive drugs or procedures in routine clinical practice according to the best standard of care as per local protocol. Primary Outcome Measures 1. Mean change in clinical status assessment using the 7-point ordinal scale at day 7 after randomisation compared to baseline (Score ranges 1-7) 1. Death; 2. Hospitalised, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalised, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalised, requiring supplemental oxygen; 5. Hospitalised, not requiring supplemental oxygen - but in need of ongoing medical care (COVID-19 related or otherwise) 6. Hospitalised, not requiring supplemental oxygen - no longer requires ongoing medical care (independent) 7. Not hospitalised 2. Duration of hospitalisation: Days from the date of enrolment to the date of discharge 3. Number of deaths at the end of study RANDOMISATION: Randomisation to treatment arms sarilumab plus standard of care or standard of care in a 2:1 ratio will be performed by the Clinical Research and Clinical Trials Unit (CRCTU) at the Hospital using a table of random numbers, an internet-based randomisation tool. After checking that all inclusion criteria are met and none of the exclusion criteria, CRCTU will communicate the recruiting investigator the assigned treatment. This study is unblinded. 30 patients treated by COVID-19 infection who require hospitalisation: 20 will receive sarilumab plus Standard of Care and 10 will receive Standard of Care. The Protocol version number is 2, as of 6^th April 2020, with amendment 1, as of 7^th May 2020. The recruitment is ongoing. Recruitment started on April 13^th 2020 and is anticipated to be completed by November 2020. This trial was first registered in the European Union Clinical Trials Register on 4 April 2020, EudraCT Number 2020-001634-36 . Then, posted on ClinicalTrials.gov on 22 April 2020, Identifier: NCT04357808 . The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the International Council Harmonization guidelines: https://www.ich.org/page/efficacy-guidelines .

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Survival of pediatric Hodgkin lymphoma patients treated with doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) at a single institution.

Adriamycin, bleomycin, vinblastine, dacarbazine (ABVD), the de facto standard of care in adult-onset Hodgkin lymphoma (HL), has not been directly compared to doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC), a pediatric-aimed regimen designed to reduce late effects. We aimed to describe the single-institution experience of using both regimens in patients with pediatric HL. This retrospective cohort study evaluated a total of 224 patients diagnosed with HL between 1999 and 2018 at Children's Hospital Los Angeles (CHLA), of which 93 patients were eligible having received ABVD (n = 46) or ABVE-PC (n = 47) chemotherapy as their initial treatment. Descriptive analyses were performed using the Student's t-test or Fisher's exact test. Survival analysis used the Kaplan-Meier method. Events included death, relapse, and secondary malignancy. We also describe the use of radiation therapy, pulmonary toxicity, and cardiomyopathy determined by shortening fraction <29%. Analyses followed an intention-to-treat principle. There was no difference in baseline characteristics between the patients receiving ABVE-PC or ABVD in regard for stage, risk group, or prognostic variables, such as the presence or absence of "B" symptoms, bulky disease, and extra-nodal involvement. A greater proportion of patients treated with ABVE-PC received consolidating external beam radiation treatment (XRT) either by randomization or by response compared to ABVD (59.6% vs. 32.6%, respectively, p = .01). While not statistically significant, response to therapy, assessed by positron emission tomography/computerized tomography (PET/CT) where available, mirrored the use for radiation (rapid response 58.3% vs. 90.0%, n = 34, p = .11). The median dose of anthracycline (doxorubicin) was the same in patients receiving ABVE-PC versus ABVD (200 vs. 200 mg/m² , interquartile range 200-250 vs. 200-300 mg/m² , p = .002). There was no difference in event-free survival (p = .63) or overall survival (p = .37) with a median follow-up length of 3.9 years. ABVD and ABVE-PC achieved similar survival outcomes in our single-institution cohort.

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Gabapentin in the treatment of hemifacial spasm.

To evaluate the efficacy of gabapentin in the treatment of hemifacial spasm. Twenty-three patients with hemifacial spasm not suitable for surgery or therapy with botulinum toxin were treated with gabapentin. The main efficacy parameter was the percentage of spasm reduction. A clinically significant reduction of spasms was obtained by 16 patients. Gabapentin was effective and safe in reducing hemifacial spasm in 16 out 23 (69.6%) patients.

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Beta blockers in ischemic heart disease.

Many trials have reported that beta blockers increase survival after myocardial infarction; these trials are reviewed. The timolol trial was randomized and showed that mortality was reduced for all patients randomized to beta blockers. Similar findings have been found in both the metoprolol trial in Göteburg and the Beta-Blocker Heart Attack Trial in the U.S. Chronic beta-blockade therapy appears to reduce mortality in patients who survive acute myocardial infarction. The mechanism is as yet unknown.

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Administration of citalopram before ECT: seizure duration and hormone responses.

From theoretical and clinical perspectives, it is important to know if selected serotonin-reuptake inhibitors (SSRIs), often administered concurrently with electroconvulsive therapy (ECT), modify seizure duration. In a study with a double-blind, cross-over design, the authors evaluated the effect of citalopram, the most selective SSRI available, on the length of electrically induced seizures and on hormone secretion during ECT. Ten depressed women were given either 20 mg citalopram or placebo orally 2 hours before the third and fourth ECT sessions. Seizure duration was assessed by the cuff technique and from electroencephalographic recordings, whereas blood for prolactin, thyrotropin, and cortisol assessment was sampled before ECT and 5, 10, 20, 30, 40, and 60 minutes after ECT. No adverse effects after the administration of citalopram were recorded. The length of seizures was not statistically different in the citalopram (29.3+/-8.4 seconds) and placebo sessions (28.2+/-9.4 seconds). Neither pre-ECT plasma hormone levels measured 2 hours after citalopram or placebo administration nor the patterns of ECT-induced hormone secretions differed between the two drug and placebo conditions. The lack of effect of citalopram on hormones in this study may be a result of possible deficiencies of the monoaminergic (i.e., serotoninergic) systems in depression. Although safety and efficacy issues were not fully addressed by coadministering citalopram for the long term and throughout the course of ECT, these findings support the view that challenges the typical clinical practice of discontinuing SSRIs before ECT.

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Feline urinary tract pathogens: prevalence of bacterial species and antimicrobial resistance over a 10-year period.

The purpose of this retrospective study was to identify bacterial species in cats with bacterial urinary tract infections (UTIs) and to investigate their antimicrobial susceptibilities over a 10-year period. Three hundred and thirty cultures from 280 cats were included in the study. The mean age of affected cats was 9.9 years; female cats with bacterial UTIs were significantly older than male cats with UTIs. The most common pathogen identified was Escherichia coli (42.3 per cent), followed by Streptococcus species (19.3 per cent), Staphylococcus species (15.6 per cent), Enterococcus species (6.6 per cent) and Micrococcaceae (5.8 per cent). Forty specimens (12.1 per cent) yielded growth of more than one isolate. Streptococcus and Enterococcus isolates were resistant to a significantly higher number of antimicrobial agents than E coli and Staphylococcus species isolates. Applying the formula to select rational antimicrobial therapy, bacterial isolates were most likely to be susceptible to nitrofurantoin, amoxicillin clavulanic acid, enrofloxacin and gentamicin. The antimicrobial impact factor for nitrofurantoin increased significantly over the 10-year period, whereas there was no significant change in antimicrobial impact factors for doxycycline, trimethoprim-sulfamethoxazole, gentamicin, enrofloxacin, cephalothin and amoxicillin clavulanic acid. The detected changes in in vitro antimicrobial efficacy could help to develop hospital-specific guidelines for antimicrobial use to prevent the further development of resistance in feline uropathogens.

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The difference between clopidogrel responsiveness and posttreatment platelet reactivity.

Aggregation is the most common measure of platelet reactivity. The relative inhibition of platelet aggregation between pretreatment and posttreatment is the most common estimate of clopidogrel responsiveness. However, patients responsive to clopidogrel may remain with highly reactive platelets and thus have increased thrombotic risk. Platelet reactivity was determined by ADP-induced aggregation (%) in 62 patients undergoing elective coronary stenting at pretreatment and 5 days postprocedure. All patients were on aspirin (325 mg) and received 300 mg of clopidogrel immediately poststenting and 75 mg qd. Pretreatment reactivity was divided into tertiles. Based on clopidogrel drug responsiveness, nonresponders were defined as <10% relative inhibition of pretreatment aggregation, semiresponders as 10-30%, and responders as >30%. We determined the relation between clopidogrel responsiveness and platelet reactivity. Pretreatment reactivity tertiles by 5 microM ADP were: low (47+/-9%), moderate (64+/-4%), and high (78+/-6%). Eight patients were nonresponders, 18 were semiresponders, and 36 were responders. Clopidogrel responsiveness directly correlated with pretreatment reactivity, 86% of responders had moderate or high pretreatment reactivity, whereas 75% of nonresponders had low pretreatment reactivity. Despite being more responsive, 16% of patients with high pretreatment reactivity and 17% with moderate pretreatment reactivity remained with moderate posttreatment reactivity. Measuring clopidogrel responsiveness may overestimate the risk of stent thrombosis in nonresponders with low pretreatment reactivity and underestimate risk in those responders who remain with high posttreatment platelet reactivity. Posttreatment platelet reactivity is a better measure of thrombotic risk than responsiveness to clopidogrel.

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Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events.

Epidemiological evidence has suggested a link between beta(2)-agonists and increased asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta(2)-agonists are safe. The aim of this review is to assess the risk of fatal and non-fatal serious adverse events in trials that randomised patients with chronic asthma to regular salmeterol with inhaled corticosteroids versus the same dose of inhaled corticosteroids alone. Trials were identified using the Cochrane Airways Group Specialised Register of trials. Web sites of clinical trial registers were checked for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to salmeterol were also checked. The date of the most recent search was October 2008. Controlled parallel design clinical trials on patients of any age and severity of asthma were included if they randomised patients to treatment with regular salmeterol and inhaled corticosteroids (in separate or combined inhalers), and were of at least 12 weeks duration. Two authors independently selected trials for inclusion in the review. Outcome data were independently extracted by two authors. Unpublished data on mortality and serious adverse events were obtained from the sponsors, and from FDA submissions. The review included 30 studies (10,873 participants) in adults and adolescents, and three studies (1,173 participants) in children. The overall risk of bias was low and data on serious adverse events were obtained from all studies.Six deaths occurred in 5,710 adults on regular salmeterol with inhaled corticosteroids, and five deaths in 5,163 adults on regular inhaled corticosteroids at the same dose. The difference was not statistically significant (Peto OR 1.05; 95% CI 0.32 to 3.47) and the absolute difference between groups in risk of death of any cause was 0.00005 (95% CI -0.002 to 0.002). No deaths were reported in 1,173 children, and no deaths were reported to be asthma-related.Non-fatal serious adverse events of any cause were reported in 134 adults on regular salmeterol with inhaled corticosteroids, compared to 103 adults on regular inhaled corticosteroids; again this was not a significant increase (Peto OR 1.17; 95% CI 0.90 to 1.52). The absolute difference in the risk of non-fatal serious adverse events was 0.003 (95% CI -0.002 to 0.009).There were three of 586 children with serious adverse events on regular salmeterol with inhaled corticosteroids, compared to four out of 587 on regular inhaled corticosteroids: there was no significant difference between treatments (Peto OR 0.75; 95% CI 0.17 to 3.31).Asthma-related serious adverse events were reported in 23 and 21 adults in each group respectively, a non-significant difference (Peto OR 0.95; 95% CI 0.52 to 1.73), and only one event was reported in children. No significant differences have been found in fatal or non-fatal serious adverse events in trials in which regular salmeterol has been randomly allocated with inhaled corticosteroids, in comparison to inhaled corticosteroids at the same dose. Although 10,873 adults and 1,173 children have been included in trials, the number of patients suffering adverse events is too small, and the results are too imprecise to confidently rule out a relative increase in all-cause mortality or non-fatal adverse events. It is therefore not possible to determine whether the increase in all-cause non-fatal serious adverse events reported in the previous meta-analysis on regular salmeterol alone is abolished by the additional use of regular inhaled corticosteroids. The absolute difference between groups in the risk of serious adverse events was small. There were no asthma-related deaths and few asthma-related serious adverse events. Clinical decisions and information for patients regarding regular use of salmeterol have to take into account the balance between known symptomatic benefits of salmeterol and the degree of uncertainty and concern associated with its potential harmful effects.

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How can we optimise inhaled beta2 agonist dose as 'reliever' medicine for wheezy pre-school children? Study protocol for a randomised controlled trial.

Asthma is a common problem in children and, if inadequately controlled, may seriously diminish their quality of life. Inhaled short-acting beta2 agonists such as salbutamol are usually prescribed as 'reliever' medication to help control day-to-day symptoms such as wheeze. As with many medications currently prescribed for younger children (defined as those aged 2 years 6 months to 6 years 11 months), there has been no pre-licensing age-specific pharmacological testing; consequently, the doses currently prescribed (200-1000 μg) may be ineffective or likely to induce unnecessary side effects. We plan to use the interrupter technique to measure airway resistance in this age group, allowing us for the first time to correlate inhaled salbutamol dose with changes in clinical response. We will measure urinary salbutamol levels 30 min after dosing as an estimate of salbutamol doses in the lungs, and also look for genetic polymorphisms linked to poor responses to inhaled salbutamol. This is a phase IV, randomised, controlled, observer-blinded, single-centre trial with four parallel groups (based on a sparse sampling approach) and a primary endpoint of the immediate bronchodilator response to salbutamol so that we can determine the most appropriate dose for an individual younger child. Simple randomisation will be used with a 1:1:1:1 allocation. The proposed research will exploit simple, non-invasive and inexpensive tests that can mostly be performed in an outpatient setting in order to help develop the evidence for the correct dose of salbutamol in younger children with recurrent wheeze who have been prescribed salbutamol by their doctor. EudraCT2014-001978-33, ISRCTN15513131. Registered on 8 April 2015.

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Intensive therapy with peripheral blood progenitor cell transplantation in 60 patients with poor-prognosis follicular lymphoma.

Intensive therapy, mainly with purged autologous bone marrow transplantation (ABMT), has been proposed in recent years as consolidation treatment in young patients with follicular lymphoma. Reported experience with transplantation of peripheral blood progenitor cells (PBPC) is, so far, limited. The feasibility and the therapeutic efficacy of intensive therapy followed by unpurged autologous PBPC reinfusion were evaluated in 60 patients with poor-prognosis follicular lymphoma. Twelve patients were in first partial remission (PR), 34 were in second partial or complete remission (CR), and 14 were in subsequent progression. At the time of the procedure, 39 patients (65%) had persistent bone marrow involvement, 49 patients (82%) were in PR, and 16 patients had presented with a histologic transformation (HT). PBPC were collected after chemotherapy followed by granulocyte (G) colony-stimulating factor (CSF) or granulocyte-macrophage (GM)-CSF in 50 patients. Conditioning regimens included high-dose chemotherapy alone (14 patients); mainly the BCNU, etoposide, aracytine, melphalan [BEAM] regimen), or cyclophosphamide with or without etoposide plus total body irradiation (46 patients). The median time to reach a neutrophil count greater than 0.5 x 10(9)/L was 13 days. There were five treatment-related deaths, with four being associated with a delayed engraftment and all occurring in patients in third or subsequent progression. At a median follow-up of 21 months, 48 patients were still alive, 18 relapsed, and seven died of lymphomas progression. Estimated 2-year overall survival (OS) and failure-free survival (FFS) rates were 86% and 53%, respectively, without or plateau. Patients treated in PR1 or PR2/CR2 had a significantly longer rate of OS and FFS than those treated in subsequent progression (P = .002 and P = .001, respectively), whereas age, response to salvage treatment, presence or absence of residual bone marrow involvement, or conditioning regimen had no influence on outcome. Patients with HT tended to have a worse FFS rate (P = .04) without an OS difference. Along with an unusual rate of engraftment failure, the poor FFS observed in heavily pretreated patients suggests that intensive therapy should be performed early in the course of the disease. Given the high percentage of patients intensified in PR with residual bone marrow involvement, our results are comparable with those achieved with ABMT published to date. Prospective trials are warranted to compare this strategy with standard therapy in patients with relapsing or PR follicular lymphoma.

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Hydrochlorothiazide and triamterene with sustained-release oxprenolol in the treatment of hypertension.

A single-blind, three-way Latin square crossover study without wash-out periods was performed in a general practice. Thirty moderately hypertensive patients were studied to compare the antihypertensive effect of 160 mg sustained-release oxprenolol once daily, 25 mg hydrochlorothiazide/50 mg triamterene once daily or a combination of the two preparations once daily, each treatment being given for 1 month. Blood pressure control was significantly better with the combination than with either agent used separately. Pulse rates, as expected, were lower when sustained-release oxprenolol was taken either alone or in the combination. Adverse events led to withdrawal in 1 patient only. Otherwise, all treatments were well tolerated and compliance was excellent. Renal function tests indicated a slight increase in creatinine, urate and urea levels after the treatments which included hydrochlorothiazide compared with oxprenolol alone, although the results were of no clinical significance.

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Anticholinergic vs Long-Acting β-Agonist in Combination With Inhaled Corticosteroids in Black Adults With Asthma: The BELT Randomized Clinical Trial.

The efficacy and safety of long-acting β-agonists (LABAs) have been questioned. Black populations may be disproportionately affected by LABA risks. To compare the effectiveness and safety of tiotropium vs LABAs, when used with inhaled corticosteroids (ICS) in black adults with asthma and to determine whether allelic variation at the Arg16Gly locus of the β2-adrenergic receptor (ADRB2) geneis associated with treatment response. A multisite (n = 20), open-label, parallel-group, pragmatic randomized clinical trial conducted from March 2011 through July 2013, enrolling black adults with moderate to severe asthma in the United States. Patients eligible for, or receiving, step 3 or step 4 combination therapy per National Heart, Lung, and Blood Institute guidelines, received ICS plus either once-daily tiotropium (n = 532) or twice-daily LABAs (n = 538,) and were followed up for up to 18 months. Patients underwent genotyping, attended study visits at baseline, 1, 6, 12, and 18 months, and completed monthly questionnaires. The primary outcome was time to asthma exacerbation, defined as a worsening asthma event requiring oral or parenteral corticosteroids. Secondary outcomes included patient-reported outcomes (Asthma Quality of Life Questionnaire, Asthma Control Questionnaire [ACQ], Asthma Symptom Utility Index, and Asthma Symptom-Free Days questionnaire), spirometry (FEV1), rescue medication use, asthma deteriorations, and adverse events. There was no difference between LABA + ICS vs tiotropium + ICS in time to first exacerbation (mean No. of exacerbations/person-year, 0.42 vs 0.37 (rate ratio, 0.90 [95% CI, 0.73 to 1.11], log-rank P = .31). There was no difference in change in FEV1 at 12 months (0.003 L for LABA + ICS vs -0.018 L for tiotropium + ICS; between-group difference, 0.020 [95% CI, -0.021 to 0.061], P = .33) and at 18 months (-0.053 L vs -0.078 L; between-group difference, 0.025 [95% CI, -0.045 to 0.095], P = .49). There were no differences in ACQ score at 18 months (change in score from baseline, -0.68 for LABA + ICS vs -0.72 for tiotropium + ICS; between-group difference, 0.04 [95% CI, -0.18 to 0.27], P = .70). There were no differences in other patient-reported outcomes. Arg16Gly ADRB2 alleles were not associated with differences in the effects of tiotropium + ICS vs LABA + ICS (hazard ratio for time to first exacerbation, 0.84 [95% CI, 0.47 to 1.51] for Arg/Arg vs 0.85 [95% CI, 0.63 to 1.15] for Arg/Gly or Gly/Gly, P = .97). Among black adults with asthma treated with ICS, adding a LABA did not improve time to asthma exacerbation compared with adding tiotropium. These findings were not affected by polymorphisms at the Arg16Gly locus of ADRB2. These findings do not support the superiority of LABA + ICS compared with tiotropium + ICS for black patients with asthma. ClinicalTrials.gov identifier: NCT01290874.

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Outpatient treatment of COVID-19 with steroids in the phase of mild pneumonia without the need for admission as an opportunity to modify the course of the disease: A structured summary of a randomised controlled trial.

The aim of this study is to explore the effectiveness and safety of oral corticosteroids (prednisone) in the treatment of early stage SARS-Cov-2 pneumonia in patients who do not yet meet hospital admission criteria. Randomized clinical trial, controlled, open, parallel group, to evaluate the effectiveness of steroids in adult patients with confirmed COVID-19, with incipient pulmonary involvement, without hospital admission criteria. Patients will be stratified by the presence or not of radiological data on pneumonia. We will include patients with early stage SARS-Cov-2 pneumonia who do not meet hospital admission criteria from the reference hospital, the Hospital Universitario de Burgos, in the region of Castilla y León, Spain. Patients will be followed-up by specialist physicians and Primary Health Care professionals. - Men and women. - Age between 18 and 75 years old. - Diagnosed SARS-CoV-2 infection, by PCR and/or IgM+ antibody test and/or antigen test. - Clinical diagnosis of lung involvement: (respiratory symptoms +/- pathological auscultation +/- O2 desaturation) - Chest X-ray with mild-moderate alterations or normal. - Patients who give their verbal informed consent in front of witnesses, which will be reflected in the patients' medical records. - Oxygen desaturation below 93% or P0₂ < 62. - Moderate-severe dyspnea or significant respiratory or general deterioration that makes admission advisable. - Chest X-ray with multifocal infiltrates. - Insulin-dependent diabetes with poor control or glycaemia in the emergency room test greater than 300 mg/ml (fasting or not). - Other significant comorbidities: Severe renal failure (creatinine clearance < 30 mL/min); cirrhosis or chronic liver disease, poorly controlled hypertension. - Heart rhythm disturbances (including prolonged QT). - Severe immunosuppression (HIV infection, long-term use of immunosuppressive agents); cancer. - Pregnant or breast-feeding women. - Patients under use of glucocorticoids for other diseases. - History of allergy or intolerance to any of the drugs in the study (prednisone, azithromycin or hydroxychloroquine). - Patients who took one or more of the study drugs in the 7 days prior to study inclusion. - Patients taking non-suppressible drugs with risk of QT prolongation or significant interactions. - Patients unwilling or unable to participate until study completion. - Participation in another study. Eligible patients will be randomized to receive standard outpatient treatment only (group 1) or standard outpatient treatment plus prednisone (group 2). - Group 1: paracetamol 1 g/8 h (on demand) + hydroxychloroquine 400 mg/12h the first day, 200 mg/12 h for 4 days + azithromycin 500 mg/24h for 5 days. - Group 2: paracetamol 1 g/8 h (on demand) + hydroxychloroquine 400 mg/12h the first day, 200 mg/12 h for 4 days + azithromycin 500 mg/24h for 5 days + prednisone 60 mg / 24 h for 3 days, 30 mg / 24 h for 3 days and 15 mg / 24 h for 3 days. If the patient requires ambulatory observation, according to the protocol established in this respect in the Emergency Department, meets all the criteria for inclusion and none for exclusion, data will be taken by the person responsible on the data collection sheet. The main result is admission after 30 days. Secondary outcomes are 30-day ICU admission and hospital stay. The safety variable will be the occurrence of clinical symptoms or delirium related to the steroids. Also, the possible decompensations of diabetes will be measured. All tests will be on an intention-to-treat basis. Treatment will be assigned according to stratified randomization by the presence or absence of radiological data of lung involvement (previously performed by random sequence 1:1 generated with Epidat and kept hidden by opaque, sealed envelopes, which will only be opened after inclusion and basal measurement). Participants, caregivers and personnel responsible for outcomes measurement will not be blinded to group assignment, once the patient is included and the basal measurement performed, as per protocol design. The percentage of patients with incipient lung involvement is unknown, but given that pulmonary involvement already exists it is estimated to be around 20%. We consider that the intervention could reduce this percentage to 5%, so the necessary sample size would be 200 subjects (100 per group), with a power of 80% and an estimated loss percentage of 10%. The protocol with code TAC-COVID-19, version 2.0 on date: April 16, 2020 is approved by the Spanish Drug Agency (AEMPS) and the local Ethics Committee. The trial is in the recruitment phase. Recruitment began 19 April, 2020 and is anticipated to be complete by April 2021. The trial was registered under the title "OUTPATIENT TREATMENT OF EARLY PULMONARY COVID19 WITH CORTICOSTEROIDS AS AN OPPORTUNITY TO MODIFY THE COURSE OF THE DISEASE" with EudraCT number 2020-001622-64 , registered on 3 April 2020. The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

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Inspiratory muscle training during treatment with corticosteroids in humans.

In a previous study performed by us, functional alterations in the inspiratory muscles were evaluated in patients receiving corticosteroids for diseases other than respiratory. We have shown that patients who received high-dose steroids for several weeks developed inspiratory muscle weakness that was reversible following withdrawal of the drug treatment. The present study was designed to evaluate the ability of specific inspiratory muscle training (SIMT) to prevent the effects of a therapeutic dosage of corticosteroids on inspiratory muscle function in patients receiving the drug for diseases other than pulmonary, with no underlying respiratory or muscular disease. Twelve patients, 5 men and 7 women, with ages ranging from 19 to 41 years, who received corticosteroids for diseases other than respiratory were recruited into two groups: 6 patients were assigned to the control group and got sham training and 6 patients received SIMT while receiving corticosteroids in a single-blind group-comparative trial. In both groups, there was no difference between the post-treatment and pretreatment values as regard to the FEV1/FVC relationship. However, in the control group but not in the training group, there was a small but significant decrease, from 99.2 +/- 3.0 to 94.3 +/- 2.8 (mean +/- SEM, p < 0.01) in FEV1 (percent of predicted normal values) and from 103.5 +/- 4.0 to 88.7 +/- 3.1 (p < 0.001) in the FVC, following treatment. All subjects had normal inspiratory muscle strength, as expressed by the maximal inspiratory mouth pressure (PImax) at residual volume, and inspiratory muscle endurance as expressed by the relationship between peak pressure and the PImax before treatment. Following administration of corticosteroids, there was a gradual decrease in both inspiratory muscle strength (from 117.5 +/- 9.4 to 80.5 +/- 3.3 cm H2O, p < 0.005) and endurance (from 82.7 +/- 2.6 to 40.2 +/- 1.7%, p < 0.001) in the control group. On the contrary, despite corticosteroid therapy, there were no significant changes in the inspiratory muscle function in the patients whose inspiratory muscles were specifically trained. We conclude that corticosteroids have a significant deteriorating effect on respiratory muscle function in humans. This weakness is preventable by using SIMT during corticosteroid treatment.

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Failure of remission induction by glucocorticoids alone or in combination with immunosuppressive agents in IgG4-related disease: a prospective study of 215 patients.

The aim of this study was to assess the outcomes of remission induction in patients with IgG4-related disease (IgG4-RD) in our cohort, and to investigate the characteristics, prognosis, and risk factors in the patients failed of remission induction. We prospectively enrolled 215 newly diagnosed patients with IgG4-RD, who were initially treated with glucocorticoid (GC) alone or in combination with immunosuppressive agents (IM), and had at least 6 months of follow up. The therapeutic goals of remission induction were defined as fulfilling each of the following after the 6-month remission induction stage: (1) ≥ 50% decline in the IgG4-RD responder index (RI); (2) GC tapered to maintenance dose; and (3) no relapse during GC tapering. The patients not achieving the therapeutic goals were considered to have failed of remission induction. There were 26 patients in our cohort who failed of remission induction, including 16 (20.8%) on GC monotherapy, and 10 (7.2%) on combination therapy comprising GC and IM. The lacrimal gland and lung were most common sites of remission induction failure. Among the patients who relapsed during remission induction stage, 52.9% had secondary relapse during follow-up. Eosinophilia, higher baseline RI, more than five organs involved and dacryoadenitis were risk factors for remission induction failure with GC monotherapy, and the incidence of remission induction failure was 71.4% in the patients with more than three risk factors. After 6-month treatment, the patients who failed of remission induction had significantly higher erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and IgG4. In our cohort, 20.8% of patients failed of remission induction with GC monotherapy, while 7.2% of patients failed of remission induction with combination therapy comprising GC and IM.

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[Exercise performance after long-term administration of enalapril or metoprolol. A randomized double-blind study of hypertensive leisure-time sportsmen].

A randomized double-blind trial was conducted in 36 leisure-time sportsmen (mean age 40.1 +/- 5.4 years) with mild or moderate essential hypertension (WHO groups I or II) to find out whether an 8-week antihypertensive treatment with daily 10-20 mg enalapril or 100-200 mg metoprolol changed their exercise performance. This was measured by bicycle spiroergometry together with determination of lactate levels, before and at the end of the treatment period. Maximal oxygen uptake rose by 1.86 ml/kg.min during enalapril administration and by 1.06 ml/kg.min at the individual anaerobic threshold. But under metoprolol these parameters fell by 6.57 ml/kg.min and 4.61 ml/kg.min, respectively. After treatment with these two drugs 3 and 15 patients, respectively, had the sensation of greater exercise performance at identical exercise levels. The differences in exercise between the two drugs using the stated three primary criteria were statistically significant. The Watt-time product decreased in only one of the patients of the enalapril group, but in 17 of the metoprolol group. Only metoprolol significantly reduced exercise heart rate. Both drugs caused a similar fall in systolic blood pressure during exercise.

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Angiotensin II receptor antagonists role in arterial hypertension.

Angiotensin II receptor blockers represent a class of effective and well tolerated orally active antihypertensive drugs. Activation of AT(1) receptors leads to vasoconstriction, stimulation of the release of catecholamines and antidiuretic hormone and promote growth of vascular and cardiac muscle. AT(1) receptor blockers antagonise all those effects. Losartan was the first drug of this class marketed, shortly followed by valsartan, irbesartan, telmisartan, candesartan, eprosartan and others on current investigation. All these drugs have the common properties of blockading the AT(1) receptor thereby relaxing vascular smooth muscle, increase salt excretion, decrease cellular hypertrophy and induce antihypertensive effect without modifying heart rate or cardiac output. Most of the AT(1) receptor blockers in use controlled blood pressure during the 24 h with a once-daily dose, without evidence of producing tolerance to the antihypertensive effect and being with low incidence of side effects even at long term use. Monotherapy in mild-to-moderate hypertension controls blood pressure in 40 to 50% of these patients; when a low dose of thiazide diuretic is added, 60-70% of patients are controlled. The efficacy is similar to angiotensin-converting enzyme (ACE) inhibitors, diuretics, calcium antagonists and beta-blocking agents. AT(1) receptor blockers are specially indicated in patients with hypertension who are being treated with ACE inhibitors and developed side effects such as, cough or angioedema. The final position in the antihypertensive therapy in this special population and other clinical situations, such as left ventricular hypertrophy, heart failure, diabetes mellitus and renal disease, has to be determined in large prospective clinical trials, some of which are now being conducted and seem promising.

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Dopamine transporter polymorphisms are associated with short-term response to smoking cessation treatment.

To examine the association between polymorphisms in the dopamine transporter gene (SLC6A3, DAT1) and treatment outcome in smokers attempting to quit using either nicotine replacement therapy or bupropion. The sample consisted of 583 smokers recruited from a smoking cessation clinic, and followed throughout the 4 weeks of post-cessation treatment with behavioural support and either nicotine replacement therapy or bupropion. At 1 week after smoking cessation, the 3' untranslated region (3'UTR) variable number of tandem repeats (VNTRs) and the 30-bp intron 8 VNTR DAT1 genotypes were associated with the ability to stop smoking (3'UTR VNTR, odds ratio=2.0, 95% confidence interval=1.2-3.5, novel intron 8 VNTR, odds ratio=1.8, 95% confidence interval=1.0-2.9), controlling for potential confounders. The results were weaker and no longer significant at a 4-week follow-up. We find evidence, although modest, of a medium-sized effect of DAT1 genotype on the ability to stop smoking early in a smoking cessation attempt. If the effect is real, and is strongest in the very early stages of smoking cessation, this suggests that the primary utility of DAT1 screening in this field will be in the identification of those most at risk of early relapse after quitting.

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Dopaminergic activity in Tourette syndrome and obsessive-compulsive disorder.

Tourette syndrome (TS) and obsessive-compulsive disorder (OCD) both are neuropsychiatric disorders associated with abnormalities in dopamine neurotransmission. Aims of this study were to quantify striatal D2/3 receptor availability in TS and OCD, and to examine dopamine release and symptom severity changes in both disorders following amphetamine challenge. Changes in [(11)C]raclopride binding potential (BP(ND)) were assessed using positron emission tomography before and after administration of d-amphetamine (0.3 mg kg(-1)) in 12 TS patients without comorbid OCD, 12 OCD patients without comorbid tics, and 12 healthy controls. Main outcome measures were baseline striatal D2/3 receptor BP(ND) and change in BP(ND) following amphetamine as a measure of dopamine release. Voxel-based analysis revealed significantly decreased baseline [(11)C]raclopride BP(ND) in bilateral putamen of both patient groups vs. healthy controls, differences being more pronounced in the TS than in the OCD group. Changes in BP(ND) following amphetamine were not significantly different between groups. Following amphetamine administration, tic severity increased in the TS group, which correlated with BP(ND) changes in right ventral striatum. Symptom severity in the OCD group did not change significantly following amphetamine challenge and was not associated with changes in BP(ND). This study provides evidence for decreased striatal D2/3 receptor availability in TS and OCD, presumably reflecting higher endogenous dopamine levels in both disorders. In addition, it provides the first direct evidence that ventral striatal dopamine release is related to the pathophysiology of tics.

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Potential role of statins in the treatment of heart failure.

Based on the findings of retrospective studies, there has been growing interest in the potential therapeutic benefits of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy in patients with heart failure. The first published prospective randomized study of statins in heart failure patients did not demonstrate improved clinical outcomes (death and nonfatal myocardial infarction or stroke) after treatment with 10 mg daily of rosuvastatin when compared with placebo. However, use of rosuvastatin was associated with a reduced risk of hospitalization when compared with placebo and was well tolerated. Until further information becomes available, routine use of statins is not recommended in the heart failure population.

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Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial.

In controlled clinical trials there are usually several prognostic factors known or thought to influence the patient's ability to respond to treatment. Therefore, the method of sequential treatment assignment needs to be designed so that treatment balance is simultaneously achieved across all such patients factor. Traditional methods of restricted randomization such as "permuted blocks within strata" prove inadequate once the number of strata, or combinations of factor levels, approaches the sample size. A new general procedure for treatment assignment is described which concentrates on minimizing imbalance in the distributions of treatment numbers within the levels of each individual prognostic factor. The improved treatment balance obtained by this approach is explored using simulation for a simple model of a clinical trial. Further discussion centers on the selection, predictability and practicability of such a procedure.

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Association between platelet reactivity and circulating platelet-derived microvesicles in patients with acute coronary syndrome.

High on-treatment platelet reactivity (HPR) to clopidogrel has been shown to increase the risk of cardiovascular events. Platelet-derived microvesicles (PMVs) may be prothrombotic and contribute to the risk of recurrent events observed in patients with HPR. However, PMVs may also serve as biomarkers and be used to assess platelet function. We investigated the association between platelet responses to clopidogrel (measured by whole blood impedance aggregometry) and circulating PMVs in patients with acute coronary syndrome (ACS). Blood samples were obtained at discharge from 200 patients with ACS who had undergone percutaneous coronary intervention (PCI). All patients were loaded with aspirin and clopidogrel before PCI. ADP-induced whole blood impedance aggregometry and measurement of PMVs were performed. Cut-off values for HPR and other reactivity (i.e. normal on-treatment reactivity, NPR and low on-treatment reactivity, LPR) to clopidogrel were set according to data from large prospective studies. We measured PMVs as phosphatidylserine and CD42a positive vesicles, together with CD62P or CD40L, using flow cytometry. ADP-induced platelet aggregation revealed that approximately 20% of patients had HPR. Levels of PMVs were almost two-fold higher in the HPR group compared with patients without HPR (for both CD42a- and CD62P-positive PMVs, p < 0.01). Furthermore, patients with LPR to clopidogrel had significantly fewer PMVs exposing CD62P than patients with HPR or those with NPR to clopidogrel. Patients with HPR during clopidogrel treatment have elevated levels of circulating PMVs, indicating ongoing platelet activation despite clopidogrel treatment. Moreover, in patients with LPR to clopidogrel, circulating PMV numbers are decreased. Taken together, our data suggest that PMVs are potential biomarkers of antiplatelet responses to clopidogrel. If PMVs also have prognostic value after, ACS should be tested in future studies.

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Effects of short-term salbutamol ingestion during a Wingate test.

The effects of a chronic salbutamol intake (SAL, 12 mg/d during 3 weeks) on changes in body composition, metabolic indices and performance during a 30-second Wingate test were determined in 8 strength-trained male athletes (T) and 7 sedentary male (UT) subjects, according to a double-blind, randomized, cross-over protocol. Blood samples were collected both at rest, at the end of the test, and during passive recovery (5 min, 10 min, 15 min) for leptin (at rest), and blood lactate measurements. No significant changes in lean body mass, fat mass, and leptin were observed with SAL treatment in either group during the trial. Peak power was significantly increased (p < 0.05) after SAL intake in all subjects (T: 11.9 %; UT: 8.3 %) with a decrease in time to peak power with SAL compared to placebo (PLA) (p < 0.05). There was no change in total work performed and in fatigue indices with SAL compared to PLA. Blood lactate was significantly increased after SAL vs. PLA during the recovery (p < 0.05) in all subjects. The data demonstrate that the chronic administration of therapeutic levels of salbutamol increases maximal anaerobic power in man, irrespective of the subjects' training status. This study also rules out any implication of an anabolic effect in this improvement in performance during supramaximal exercise. Further studies are necessary to clarify the mechanisms involved.

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Laryngeal contact granuloma.

To report outcomes of treatment for laryngeal contact granuloma. Prospective treatment of 21 patients with laryngeal contact granulomas using proton-pump inhibitor (PPI) medication. Patients were diagnosed and followed by office endoscopy and patient interview. Three patients did not tolerate PPI medication and were managed by treatment with type 2 histamine (H2) blockers. The lesion completely resolved in 14 of the 18 patients maintained on PPI medication, and significantly regressed in the other 4. Residual granulomas were surgically excised in one patient. Lesions resolved in two patients following injection of botulinum toxin into one thyroarytenoid muscle. One patient had a residual lesion, but symptoms were controlled by medication, and he declined treatment with botulinum toxin. Of the three patients treated with H2-blocker medication, the lesion resolved in only one. PPI medication is effective in the treatment of laryngeal contact granuloma, even in the absence of identifiable symptoms of gastroesophageal reflux.

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The chemotherapy of granulosa cell tumors of the ovary: experience of the Wisconsin Clinical Cancer Center.

We reviewed the clinical records of 32 patients with granulosa cell tumor of the ovary treated at the Wisconsin Clinical Cancer Center (WCCC) between 1970 and 1982. Eleven of these patients were treated with one or more chemotherapeutic regimens, yielding a total of 22 treatment trials. Objective response was observed in 7 of 17 evaluable treatment trials (41%). The response to chemotherapy could not be assessed in five treatment trials due to the concomitant administration of radiotherapy. We conclude that granulosa cell tumor of the ovary is responsive to chemotherapy. However, the optimal chemotherapeutic regimen for this rare neoplasm remains to be established on the basis of prospective clinical trials.

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Pegylated liposomal doxorubicin, rituximab, cyclophosphamide, vincristine, and prednisone in AIDS-related lymphoma: AIDS Malignancy Consortium Study 047.

Infusional chemotherapy is efficacious in patients with AIDS-related lymphoma, but it may be difficult to administer. We studied standard agents with rituximab plus pegylated liposomal doxorubicin (DR-COP) in an attempt to provide a more practical approach to therapy while ascertaining rates of response, potential infectious complications, and prognostic role of biologic markers. We conducted a prospective, multi-institutional phase II trial, employing (day 1) pegylated liposomal doxorubicin 40 mg/m(2), rituximab 375 mg/m(2), cyclophosphamide 750 mg/m(2), vincristine 1.4 mg/m(2) (not > 2 mg), and prednisone 100 mg orally on days 1 through 5, with concomitant antiretroviral therapy. In 40 evaluable patients, median CD4 cells was 114/μL (range, 5 to 1,026/μL), and median HIV-1 viral load (VL) was 25,000 copies/mL. High or intermediate/high age-adjusted International Prognostic Index was present in 28%. Overall response was 67.5%, with complete remission in 47.5% (95% CI, 31.5 to 63.9). Of 19 complete responders, 84% had extranodal disease, 47% had CD4 < 100/μL, and 47% had VL > 50,000 copies/mL; one relapsed. With 25.5-month median follow-up, 62% (95% CI, 44 to 75) of patients remain alive. Sixteen patients (40%) experienced 22 infections, with grade 4 in only two (5%). No patient died as a result of infection during treatment; one had opportunistic infection. Profound immunodeficiency and high HIV-1 viral load do not preclude attainment of complete response after DR-COP with highly active antiretroviral therapy. The regimen is tolerable, and use of rituximab was not associated with death as a result of infection during treatment. This approach may be useful in patients in whom the more intensive infusional regimens are impractical.

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Short- and long-term efficacy of aspirin and clopidogrel for thromboprophylaxis for mechanical heart valves: an in vivo study in swine.

In the interest of exploring alternatives to warfarin, we tested the hypothesis that clopidogrel combined with aspirin is effective for thromboprophylaxis of mechanical valves using a swine model. Adult swine underwent heterotopic implantation of a modified bileaflet mechanical valved conduit bypassing the ligated, native descending thoracic aorta. Animals were randomized to no anticoagulation (n = 7), 175 U/kg dalteparin administered subcutaneously twice daily (n = 9), 325 mg of aspirin (n = 6), 75 mg of clopidogrel (n = 6), or 325 mg of aspirin and 75 mg of clopidogrel daily (n = 6) and survived for 30 days. Additionally, 11 animals were randomized to no anticoagulation (n = 5) or 325 mg of oral aspirin and 75 mg of clopidogrel daily (n = 6) and survived for 150 days. At 30 days, we observed 216 +/- 270 mg of thrombus for the no anticoagulation group, 53 +/- 91 mg for the dalteparin group, 33 +/- 23 mg for the aspirin group, 25 +/- 10 mg for the clopidogrel group, and 17 +/- 9 mg for the combined aspirin and clopidogrel group, respectively (P < .01 for clopidogrel and aspirin vs no anticoagulation). At 150 days, we observed 223 +/- 200 mg of thrombus for the no anticoagulation group and 4 +/- 4 mg for the aspirin and clopidogrel group (P = .02). Mean platelet deposition on the valve was 4.1 x 10(9) +/- 3.6 x 10(9) for the no anticoagulation and 6.81 x 10(7) +/- 1.4 x 10(8) for the combined aspirin and clopidogrel groups, respectively (P = .03). No major hemorrhagic events were observed. Effective short- and long-term thromboprophylaxis of mechanical valves can be achieved by using dual-antiplatelet therapy in this porcine model. Prospective human trials should be conducted with combination aspirin and clopidogrel as an alternative to warfarin in patients with bileaflet mechanical aortic valves.

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Usefulness of repeated recombinant human thyrotropin-stimulated thyroglobulin test in the post-surgical follow-up of very low-risk patients with differentiated thyroid carcinoma.

The European Thyroid Association (ETA) and the American Thyroid Association (ATA) guidelines identify subgroups of patients affected by thyroid carcinoma in whom, due to a low risk of recurrence, radioiodine ablation is not indicated. These patients are referred to as "very low-risk" according to the ETA consensus and "low-risk" patients according to the ATA guidelines. The recommended post-surgical follow-up of these patients is based upon periodical measurements of serum thyroglobulin (Tg) on levothyroxine therapy and neck ultrasound (US). To evaluate the usefulness of recombinant human (rh)-TSH Tg test and its repetition 2-3 yr afterwards in very low-risk patients. We consecutively enrolled 32 patients with undetectable anti-Tg antibodies. Basal serum Tg levels was undetectable in all patients. Following rhTSH serum Tg remained undetectable in 23 (71.9%) patients (UP) and was >1.0 ng/ml in 9 (DP). US and whole body scan, revealed lymph node metastasis in 4/9 DP patients. A second rhTSH stimulation test (36.9±3.5 months later) was performed in all UP and in 5 DP patients without proven recurrences. All the UP and 4/5 formerly DP patients showed undetectable Tg stimulation. Our results suggest that rhTSH Tg test may be helpful in very low-risk patients, given its ability to differentiate those who may be considered "free of disease" from those who require further investigation and treatment. Repeated rhTSH Tg tests may be indicated only in patients with detectable serum Tg at prior stimulation testing.

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Carvedilol versus metoprolol in the acute phase of myocardial infarction:.

Beta-adrenergic blockers provide significant cardioprotection during acute ischemia and reperfusion. To further explore the effects of additional alpha-1-adrenoceptor blockade on autonomic modulation in acute myocardial infarction (AMI), carvedilol was compared with metoprolol in the setting of primary percutaneous coronary interventions (PCI). In a prospective study, 100 consecutive patients (61.1 +/- 11 years; 23 females) undergoing primary PCI for AMI were randomly assigned to metoprolol 200 mg/day vs carvedilol 25 mg/day. The first oral dose of study drug was administered upon hospital admission, and a 24-hour ambulatory electrocardiogram was recorded. A total of 40 recordings of patients assigned to metoprolol and 39 of patients assigned to carvedilol were eligible for analysis of heart rate turbulence. Turbulence onset (TO), turbulence slope (TS), and turbulence timing were measured after ventricular premature beats (VPBs). The mean value of the 10 preceding RR intervals (mean RR) before VPBs was also measured. There were no significant differences in mean age, gender distributions, TIMI perfusion grades, left ventricular ejection fraction, site and size of infarction, duration of ischemia, and mean 24-hour heart rate between the two groups. Though the mean RR were not significantly different (metoprolol 863.1 +/- 157 ms; carvedilol 839.6 +/- 151 ms), there was a trend toward lower values of TO in the carvedilol group (-0.015 +/- 0.016 vs -0.012 +/- 0.023%; P = NS) and significantly higher values for TS in the metoprolol group (6.96 +/- 5.8 vs 5.6 +/- 4.22; P < 0.05). Turbulence timing was similar in both groups (metoprolol 5.8 +/- 2.4 vs carvedilol 6.1 +/- 2.1). In patients undergoing direct PCI for AMI, treatment with carvedilol, in contrast to metoprolol, was associated with a higher early acceleration and a lower deceleration of heart rate after VPBs, indicating differing effects on baroreceptor response due to additional alpha-1-adrenoceptor blockade. These data offer new insights into effects of a broader antiadrenergic therapy on autonomic reflexes in the acute phase of AMI.

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ACE inhibitors in hypertension: assessment of taste and smell function in clinical trials.

Taste and smell disturbances are infrequently reported adverse effects of treatment with captopril and are even less frequently reported with other ACE inhibitors. These adverse effects have been attributed to the chemical structure of the drugs used, although this relationship is the matter of some debate. A link between the taste disturbance associated with ACE inhibitors and changes in plasma zinc concentration has also been suggested, but again the evidence for this relationship is equivocal. One problem facing research in this area has been the lack of reliable assessment techniques for the quantitative evaluation of smell and taste function. Three quantitative methods for evaluating taste and smell function are described, together with the results of a pilot study aimed at evaluating the potential ease of application of these techniques in a larger group of patients. In this double-blind, crossover pilot study, 8-week treatment with lisinopril (20-40 mg once daily) was compared with captopril (25-50 mg twice daily) in 12 hypertensive patients. The two drugs produced similar falls in lying and standing blood pressure and neither drug produced a significant alteration in smell recognition, or olfactory or taste threshold. None of the minor changes observed appeared to correlate with either plasma zinc concentrations or intra-erythrocyte zinc levels. This study provides important observations on the use of these new techniques. Based on the wide variability of results obtained, the design of further clinical studies must address and overcome the many factors (age, sex, smoking, etc.) which may confound the study of drug effects on taste and smell.

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[CHOP-bleo versus m-BACOD in the treatment of intermediate and high-grade malignant lymphomas].

Eighty-three patients with malignant lymphoma of intermediate and high histologic subtypes were randomly assigned to receive induction chemotherapy with either of two intensive regimens: CHOP-Bleo (cyclophosphamide, adriamycin, vincristine, prednisone and bleomycin) or m-BACOD (low-dose methotrexate, bleomycin adriamycin, cyclophosphamide, vincristine and dexamethasone). The median follow-up study is 5 years. The two therapies were not significantly different in regard to response rates (52 to 59%), duration of complete remission (27 months vs 24 months) and survival, but m-BACOD was significantly more toxic than CHOP-Bleo. The relative small proportion of long-term disease free-survivors with both regimens underscores the need for other therapeutic approaches.

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Four versus six courses of a dose-escalated cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen plus etoposide (megaCHOEP) and autologous stem cell transplantation: early dose intensity is crucial in treating younger patients with poor prognosis aggressive lymphoma.

Patients with aggressive lymphoma and high-risk features at the time of diagnosis are reported to have a poor prognosis with standard therapy. Attempts to improve the results achieved with the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) using second-generation or third-generation chemotherapy have failed. In the current study, the authors increased the doses and dose intensity of drugs used for the conventional first-line therapy of aggressive lymphoma and designed a Phase II randomized trial that compared four and six courses of dose-escalated CHOP plus etoposide (megaCHOEP) supported by the transplantation of peripheral blood stem cells. Eighty-four patients age < 60 years with aggressive lymphoma and elevated lactate dehydrogenase (LDH) levels were randomized to receive either 4 (Arm A) or 6 (Arm B) courses of cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (megaCHOEP). The last three treatment courses were supported by autologous peripheral blood stem cell transplantation. Although the total doses of cyclophosphamide and etoposide were comparable, the dose intensity during the first 3 treatment courses was planned to be 2.8-fold and 2.0-fold higher, respectively, for patients in Arm A. Thirty-seven patients in Arm A (90.2%) but only 18 patients in Arm B (69.2%) were able to complete therapy (P = 0.048). The complete response rate was 65.8% in Arm A and 50.0% in Arm B; the disease recurrence rates were 18.5% versus 61.5% (P = 0.011). Freedom from treatment failure at 2 years was 52.5% (95% confidence interval [95% CI], 36.9-68.2%) in Arm A and 23.1% (95% CI, 6.9-39.3%) in Arm B (P = 0.02). The overall survival rate was 70% (95% CI, 54.9-85.0%) in Arm A and 46.2% (95% CI, 27.0-65.3%) in Arm B (P = 0.037). The results of the current study demonstrate that dose intensity, in particular early dose intensity, significantly influences disease control with high-dose therapy (HDT) and autologous stem cell transplantation. These results also may explain the failure of HDT with low early dose intensity to improve the results obtained with conventional chemotherapy.

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The impact of primary antibiotic resistance on the efficacy of ranitidine bismuth citrate- vs. omeprazole-based one-week triple therapies in H. pylori eradication--a randomised controlled trial.

To compare ranitidine bismuth citrate with omeprazole as to their efficacy to eradicate H. pylori in two different treatment schedules both consisting of a combination of either of above with two antibiotics for 1 week, and to relate these treatment results to primary antibiotic resistance. 256 H. pylori positive patients with non-ulcer dyspepsia were randomised to one of the following four treatment groups: omeprazole 20 mg + clarithromycin 500 mg + amoxycillin 1000 mg (OCA); ranitidine bismuth citrate 400 mg + clarithromycin 500 mg + amoxycillin 1000 mg (RBCCA); omeprazole 20 mg + clarithromycin 500 mg + metronidazole 500 mg (OCM); ranitidine bismuth citrate 400 mg + clarithromycin 500 mg + metronidazole 500 mg (RBCCM). All drugs were given twice daily for one week. The patients were assessed for prevalence of H. pylori by CLO test, histology and culture on gastric biopsy samples obtained during upper gastrointestinal endoscopy before randomisation and 4-6 weeks after completion of therapy. Bacterial sensitivity to clarithromycin, metronidazole and amoxycillin was determined by E-test. On per-protocol analysis, overall eradication rates were 96% for RBCCA vs. 85% for OCA (p = 0.03), and 95% for RBCCM vs. 79% for OCM (p = 0.01). Amongst the 196 patients (77% of the entire study group) in whom antibiotic sensitivity testing was technically feasible, primary resistance was found in 8% for clarithromycin, in 33% for metronidazole, and in 0% for amoxycillin. Eradication of clarithromycin sensitive/resistant strains was 89%/40% for OCA (p = 0.0042) and 98%/80% for RBCCA (p = 0.0428). When strains were sensitive to both antibiotics, cure rates with OCM/RBCCM were 87%/96% respectively (p = 0.39), for strains resistant to clarithromycin only, eradication was achieved in 82% with OCM vs. 94% with RBCCM (p = 0.2), and in the case of metronidazole resistance in 85% with OCM vs. 94% with RBCCM (p = 0.09). Ranitidine bismuth citrate in combination with clarithromycin and either metronidazole or amoxycillin produced higher eradication rates than omeprazole co-administered with the same antibiotics. This appeared especially prominent in the subgroups with clarithromycin resistance without, however, reaching statistical significance. Efficacy of neither eradication regimen was influenced by metronidazole sensitivity to a significant degree.

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Plasma concentrations of clozapine and its major metabolites during combined treatment with paroxetine or sertraline.

The effect of paroxetine or sertraline on steady-state plasma concentrations of clozapine and its major metabolites was studied in 17 patients with schizophrenia or schizoaffective disorder stabilized on clozapine therapy (200-400 mg/day). In order to treat negative symptomatology or concomitant depression, 9 patients received additional paroxetine (20-40mg/day) and 8 patients sertraline (50-100 mg/day). After 3 weeks of paroxetine administration, mean plasma concentrations of clozapine and norclozapine increased significantly by 31% (p<0.01) and by 20% (p<0.05), respectively, while levels of clozapine N-oxide remained almost unchanged. The mean plasma norclozapine/clozapine and clozapine N-oxide/clozapine ratios were not modified during paroxetine treatment. No significant changes in plasma concentrations of clozapine and its major metabolites were observed after 3 weeks of combined therapy with sertraline. Clozapine coadministration with either paroxetine or sertraline was well tolerated. Our findings suggest that the metabolism of clozapine is not affected by sertraline treatment at typical therapeutic doses, while paroxetine, a potent inhibitor of CYP2D6, appears to inhibit the metabolism of clozapine, possibly by affecting pathways other than N-demethylation and N-oxidation. While sertraline may be added safely to patients on maintenance treatment with clozapine, careful clinical observation and monitoring of plasma clozapine levels may be useful whenever paroxetine is coadministered with clozapine.

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Idiopathic inflammatory orbital pseudotumor in childhood. I. Clinical characteristics.

The cases of 29 patients aged 20 years or less with orbital inflammatory pseudotumor were studied retrospectively. There was no sex predilection, although the left orbit was involved twice as often as the right. Patients typically had abrupt onset of periocular pain, early-morning swelling, chemosis, conjunctival and extraocular muscle injection, proptosis, a palpable mass, and extraocular motility disturbances. Visual acuity was usually only mildly affected at onset. Forty-five percent of patients had or subsequently developed bilateral orbital involvement in the absence of notable systemic diseases. Papilledema and iritis were seen in 35% of patients, respectively, particularly in bilateral cases. All cases responded to steroids, but bilateral disease was the most apt to become steroid dependent. Permanent functional impairments were seen most commonly in patients who had alternating recurrent bilateral disease or who underwent surgical exploration.

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Swedish trial in old patients with hypertension. A prospective multicentre study in Swedish primary health care.

The Swedish trial in old patients with hypertension was initiated by the Swedish League against Hypertension. It will be conducted as a prospective multicentre study in Swedish primary health care, and will comprise approximately 2 000 patients on active treatment and 2 000 on placebo to be studied for three years. The primary goal with this study is to investigate whether pharmacological treatment of hypertension in men and women aged 70-84 years will reduce the incidence of fatal and nonfatal cardiac and cerebrovascular disease. Before starting the main trial a pilot study comprising 400 patients will be carried out during one year to evaluate all logistical aspects of the study. This pilot study commenced in October 1985.

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[Treatment of ascites in patients with liver cirrhosis without neither hyponatremia nor renal insufficiency. Results of a randomized study comparing diuretics and punctures compensated by albumin].

Previous studies have suggested that treatment of ascites in cirrhotic patients by repeated paracenteses and albumin infusion is fast, effective and safe. In one of these studies including patients with hyponatremia or renal impairment, this treatment was associated with a reduction of duration of hospital stay in comparison with large dose diuretics. The aim of this randomized study was to compare paracentesis with albumin perfusion and low dose diuretics in cirrhotic patients with ascites, but without hyponatremia or renal impairment. Twenty-six patients (group 1) were treated with paracentesis (4 L/day) and 27 patients (group 2) were treated with spironolactone (225 to 300 mg/day), associated with furosemide (40 to 80 mg/day), when inefficient alone. Ascites and peripheric edema disappeared more rapidly in group 1 than in group 2, 8.6 +/- 9.6 vs 13.5 +/- 6.7 days (P = 0.001) and 4.1 +/- 2.6 vs 10.5 +/- 6.5 days (P = 0.001) respectively. During hospitalisation, the incidence of complications was higher in group 2 than in group 1: 56 vs 26% (P = 0.03). Hyponatremia occurred in 30% of patients in group 2 and 4% of patients in group 1 (P = 0.04). The duration of hospital stay was shorter in group 1 (15.0 +/- 10.4 days) than in group 2 (21.0 +/- 11.7 days) (P = 0.007). During follow-up, ascites reappeared in 32% of patients in group 1 and 57% of patients in group 2 (P = 0.09). At 3 months, one patient in group 1 and 2 patients in group 2 developed spontaneous peritonitis whereas survival was similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

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Carbuterol, fenoterol, orciprenaline, salbutamol and terbutaline per os in reversible obstructive chronic bronchitis.

The effects of tablets of carbuterol, orciprenaline, salbutemol, terbutaline and fenoterol at two dosages were studied using FEV1 and specific airway conductance as parameters. A placebo was used as a reference. Carbuterol and fenoterol proved to be more potent than the other sympathomimetic competitors. Fenoterol 5 mg was on the average somewhat less potent than 3 mg carbuterol. This differnce was not statistically significant for FEV1; it was significant three hours after intake for airway conductance. None of the drugs produced significant changes of the blood pressure. Carbuterol and 12 mg fenoterol caused a statistically significant increase in heart rate. ECG changes were observed in eight patients with the different beta-sympathomimetics, with the exception of 5 mg fenoterol.

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[Community-acquired urinary tract infections in 15 to 65 years old female patients in France. Susceptibility of E. coli according to history: AFORCOPI-BIO network 2003].

A multicenter study was implemented in order to determine the distribution and antibiotic susceptibility patterns of strains isolated from 15 to 65 year old female patients with community-acquired urinary tract infections. From October to December 2003, 11 French private laboratories consecutively collected 420 clinical strains with medical data. Minimal inhibitory concentrations of antibiotics on E. coli were determined using the agar dilution method in a coordinating center and interpretation followed the recommendations of the Comité de l'antibiogramme de la Société française de microbiologie. Escherichia coli was the most prevalent pathogen (80%) followed by Proteus mirabilis (4%), Klebsiella spp (2%), other Enterobacteriaceae (4%), Enterococcus spp (3%), Staphylococcus aureus (2%), Staphylococcus saprophyticus (2%), and Streptococcus agalactiae (2%). The susceptibility of E. coli strains was 61% for amoxicillin (AMX), 93% for nalidixic acid (NAL), 97% for norfloxacin (NOR) and ciprofloxacin (CIP), 77% for cotrimoxazole (SXT), 99% for fosfomycin, gentamicin and cefotaxime. The susceptibility of E. coli was lower in case of previous treatment with beta-lactam antibiotics for AMX (84 vs 95% p=0.02) and SXT (62 vs 81% p=0.02). In the same way, previous treatment with quinolones was associated with decreased susceptibility for NAL (84 vs 95% p=0.02) and SXT (62 vs 81% p=0.02). In 2003, fluoroquinolones, third generation cephalosporins, aminoglycosides, and fosfomycin kept a good activity on E. coli collected from community-acquired urinary tract infections in 15 to 65 years old female patients in France.

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Antibiotic treatment for threatened abortion during the early first trimester in women with previous spontaneous abortion.

We retrospectively examined the usefulness of antibiotic therapy for management of first-trimester threatened abortion in women with previous spontaneous abortion. From 1993 through 1999, women with first-trimester threatened abortion received antibiotic therapy. Only those with gestational age less than 9 weeks and previous spontaneous abortion were included in this analysis. Women with mild abdominal cramping received amoxicillin plus erythromycin for 1 week; those with severe abdominal pain received amoxicillin plus clindamycin for 1 week. Recurrence was documented on the basis of either lower abdominal pain or vaginal bleeding. Of the 23 women included, 15 (65%) had abnormal vaginal flora (a score above 4, Nugent's criteria). Seven of 16 women who received amoxicillin plus clindamycin and three of seven who received amoxicillin plus erythromycin had complete resolution of lower abdominal pain and vaginal bleeding without recurrence (p=1). The recurrence rate was higher, though not significantly, in women with abnormal bacterial vaginal flora (8/15 vs. 2/8, p=0.379). Twenty-two (96%) of the 23 pregnancies were carried to term, with no identifiable neonatal anomalies. These results suggest the usefulness of early antibiotic therapy in preventing pregnancy loss in women with threatened abortion early in the first trimester, and warrant further clinical trials.

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Changes in Intestinal Microbiota Following Combination Therapy with Fecal Microbial Transplantation and Antibiotics for Ulcerative Colitis.

Fecal microbiota transplantation (FMT) is a potential therapeutic approach to restore normal intestinal microbiota in patients with ulcerative colitis (UC), which is associated with dysbiosis; however, treatment efficacy remains unclear. Hence, we studied the impact of antibiotic pretreatment with amoxicillin, fosfomycin, and metronidazole (AFM therapy) and FMT versus AFM alone. AFM therapy was administered to patients for 2 weeks until 2 days before FMT. Patients' spouses or relatives were selected as donor candidates. Donor fecal samples were collected on the day of administration and transferred into the patient's colon by colonoscopy within 6 hours. Microbiome analysis was performed by 16S rRNA next-generation sequencing. Patients with mild-to-severe active UC (combination-therapy group, n = 21; AFM monotherapy group, n = 20) were included. Thirty-six patients completed this assessment (combination-therapy group, n = 17; AFM monotherapy group, n = 19). A higher clinical response was observed after combination therapy compared with AFM monotherapy at 4 weeks after treatment. After the 2-week AFM therapy, the Bacteroidetes composition was nearly abolished. The Bacteroidetes proportion recovered in clinical responders at 4 weeks after FMT was not observed in the AFM monotherapy group. Persistent antimicrobial-associated dysbiosis found in the AFM monotherapy group was reversed by FMT. The recovery rate of Bacteroidetes at 4 weeks after FMT correlated with endoscopic severity. FMT following antimicrobial bowel cleansing synergistically contributes to the recovery of the Bacteroidetes composition, which is associated with clinical response and UC severity. Thus, this therapeutic protocol may be useful for managing UC.

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Inhibition of glycine transporter-I as a novel mechanism for the treatment of depression.

Antidepressants, aiming at monoaminergic neurotransmission, exhibit delayed onset of action, limited efficacy, and poor compliance. Glutamatergic neurotransmission is involved in depression. However, it is unclear whether enhancement of the N-methyl-D-aspartate (NMDA) subtype glutamate receptor can be a treatment for depression. We studied sarcosine, a glycine transporter-I inhibitor that potentiates NMDA function, in animal models and in depressed patients. We investigated its effects in forced swim test, tail suspension test, elevated plus maze test, novelty-suppressed feeding test, and chronic unpredictable stress test in rats and conducted a 6-week randomized, double-blinded, citalopram-controlled trial in 40 patients with major depressive disorder. Clinical efficacy and side effects were assessed biweekly, with the main outcomes of Hamilton Depression Rating Scale, Global Assessment of Function, and remission rate. The time course of response and dropout rates was also compared. Sarcosine decreased immobility in the forced swim test and tail suspension test, reduced the latency to feed in the novelty-suppressed feeding test, and reversed behavioral deficits caused by chronic unpredictable stress test, which are characteristics for an antidepressant. In the clinical study, sarcosine substantially improved scores of Hamilton Depression Rating Scale, Clinical Global Impression, and Global Assessment of Function more than citalopram treatment. Sarcosine-treated patients were much more likely and quicker to remit and less likely to drop out. Sarcosine was well tolerated without significant side effects. Our preliminary findings suggest that enhancing NMDA function can improve depression-like behaviors in rodent models and in human depression. Establishment of glycine transporter-I inhibition as a novel treatment for depression waits for confirmation by further proof-of-principle studies.

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Metformin induces lipid changes on sphingolipid species and oxidized lipids in polycystic ovary syndrome women.

Metformin is one of the treatments used for PCOS pathology decreasing body weight, plasma androgen, FSH and glucose levels. Unfortunately, there is little known about metformin's effects on lipid metabolism, a crucial process in PCOS pathology. We have employed a lipidomic approach to explore alterations in the plasma lipid profile of patients with PCOS following metformin treatment. The aim is to offer new insights about the effect of metformin in PCOS patients. Plasma samples were obtained from 27 subjects prior to and following 12 weeks of metformin treatment. A detailed biochemical characterization and lipidomic profile was performed. Metformin reduces BMI, HOMA-IR, FSH and androstenedione and increases DHEA-S but no changes were found in glucose levels after treatment. Multivariate statistics revealed a specific lipidomic signature due to the effect of 12 weeks of metformin treatment in PCOS patients. This signature includes changes in sphingolipid metabolism suggesting a crosstalk between these lipid species and the androgenic metabolism and a decrease in oxidized lipids reinforcing that metformin treatment improves oxidative stress status. Our study confirms the specific effect of metformin in lipid metabolism on women with PCOS after 12 weeks of treatment.

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Thyroid hormone changes after cardiovascular surgery and clinical implications.

Alterations in serum concentrations of total triiodothyronine (TT3), total thyroxine (TT4), and thyroid-stimulating hormone (TSH) frequently occur in patients with nonthyroidal illnesses. These changes correlate with the severity of the illness and the prognosis. In this study, 44 patients undergoing a cardiovascular operation had significant declines in serum TT3 and TT4 levels during cardiopulmonary bypass and thereafter. Serum TT3 and TT4 concentrations reached their nadir at 30 minutes after the start of cardiopulmonary bypass with values (mean +/- standard error of the mean) of 0.77 +/- 0.12 nmol/L (50.4 +/- 7.6 ng/dL) and 68.2 +/- 10.2 nmol/L (5.30 +/- 0.79 micrograms/dL), respectively. The mean serum concentrations of TSH and TT4 returned to preoperative levels by the sixth day after operation, whereas TT3 levels remained low throughout the study period. The patients whose recovery was uneventful had higher serum TT3, TT4, and TSH levels than those who had complications or died. The trend toward recovery was initiated by a sharp increase in the serum TSH level and increases in serum TT3 and TT4 concentrations on the fourth day after operation. Patients with complications either did not show these changes or had only a transient increase in TT3 and TT4 levels. All of the patients had a normal serum free T4 level before anesthesia. Those with an uneventful recovery had a higher serum free T4 level on the sixth day after operation than those with complications. Two patients in the latter group had serum free T4 levels less than normal at that time.(ABSTRACT TRUNCATED AT 250 WORDS)

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Prompt Response to Prednisone Predicts Benign Course in MuSK-MG.

The difficult course of patients with myasthenia gravis (MG) with anti-muscle-specific tyrosine kinase antibodies (MuSK) has been emphasized. However, no clear information is available on patients who have a benign course. This study was aimed at comparing patients with favorable (minimal manifestations [MM] or better) and unfavorable outcomes to determine whether excellent response to corticosteroid (CS) treatment within 3 months (good response-3 months) has any predictive effect on the prognosis. Forty-six percent of 46 patients had a favorable outcome at year 3 and 54% at final follow-up. The major finding of this study was its high predictive value with good response-3 months. Those with good response-3 months had significantly more favorable outcome as compared to those without at year 3. The positive predictive value of good response-3 months was high (89% at year 3 and 84% at final follow-up). The negative predictive value diminished from 85% at year 3 to 67% at final follow-up due to increasing number of patients improving in the long run. Overall, 33% of the patients had a benign course with good response-3 months and no major exacerbations until the end of follow-up. Excellent response to CSs within 3 months appears to predict a favorable outcome in MuSK-MG.

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Clopidogrel treatment may associate with worsening of endothelial function and development of new digital ulcers in patients with systemic sclerosis: results from an open label, proof of concept study.

Activated platelets release serotonin that binds 5-HT2B receptor on fibroblasts leading to fibroblast activation. Clopidogrel, an inhibitor of ADP-dependent platelet activation prevents fibrosis in animal models of systemic sclerosis (SSc). We aimed at assessing whether i) ADP-dependent platelet activation is increased in patients with SSc compared to healthy subjects and patients with rheumatoid arthritis (RA) and ii) whether clopidogrel can effectively suppress ADP-dependent activation, reduce circulating serotonin levels and hence, favorably affect fibrosis or vasculopathy in patients with systemic sclerosis. Thirteen patients with SSc were recruited. Platelet activation was assessed by aggregometry prior to and following 14 days of clopidogrel treatment. At the same time points serotonin and soluble vascular cell adhesion molecule 1 (s-VCAM1), a marker of endothelial dysfunction, were measured. ADP-dependent platelet activation was similar between patients with SSc (n = 13), patients with RA (n = 28) and healthy subjects (n = 22) (mean ± SEM AU*min: 392.1 ± 58.4, 535.5 ± 61.33 and 570.9 ± 42.9 in patients with SSc, patients with RA and healthy subjects respectively, p = 0.14). Clopidogrel treatment significantly reduced platelet activation in patients with SSc (mean ± SEM AU*min: 392.1 ± 58.4 vs 163.8 ± 51.7, p = 0.014). Clopidogrel treatment did not affect serotonin levels but led to a significant increase in s-VCAM1 (p = 0.03). Three patients developed new digital ulcers during the study. The potential association of the study drug with the development of new digital ulcers led to early termination of the study. Clopidogrel may worsen markers of endothelial function and associate with development of new digital ulcers in patients with SSc. ISRCTN63206606 . Registered 02/Dec/2014.

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Imaging blood-brain barrier dysfunction as a biomarker for epileptogenesis.

A biomarker that will enable the identification of patients at high-risk for developing post-injury epilepsy is critically required. Microvascular pathology and related blood-brain barrier dysfunction and neuroinflammation were shown to be associated with epileptogenesis after injury. Here we used prospective, longitudinal magnetic resonance imaging to quantitatively follow blood-brain barrier pathology in rats following status epilepticus, late electrocorticography to identify epileptic animals and post-mortem immunohistochemistry to confirm blood-brain barrier dysfunction and neuroinflammation. Finally, to test the pharmacodynamic relevance of the proposed biomarker, two anti-epileptogenic interventions were used; isoflurane anaesthesia and losartan. Our results show that early blood-brain barrier pathology in the piriform network is a sensitive and specific predictor (area under the curve of 0.96, P < 0.0001) for epilepsy, while diffused pathology is associated with a lower risk. Early treatments with either isoflurane anaesthesia or losartan prevented early microvascular damage and late epilepsy. We suggest quantitative assessment of blood-brain barrier pathology as a clinically relevant predictive, diagnostic and pharmaco!dynamics biomarker for acquired epilepsy.

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Locally deposited but not inhaled frusemide reduces nasal potential difference in healthy subjects.

Previous publications suggest that prolonged inhalation of frusemide (F) does not cause a fall in the nasal transepithelial potential difference (PD) whereas locally deposited F does. In an attempt to reconcile these observations, we have measured the effect of inhalation through the nose and local deposition of F, amiloride (A), bumetanide (B) and salbutamol (S) on nasal PD in 7 healthy male volunteers in a randomised, double blind study. Solutions of drugs ranging from 10(-6) M to 10(-3) M (3 x 10(-8) M to 3 x 10(-5) M for B) in phosphate buffered saline 0.5 ml (PBS) were sequentially deposited in both nostrils, and nasal PD was measured 5 min after each dose. In 10 further volunteers, 10(-2) M solutions of A, F and S (3 x 10(-4) M for B) 5 ml were nebulised through the nose for 15 min, when nasal PD was measured. Resting PD was similar in the left and right nostrils averaging -17.1 mV (lumen negative). Placebo, inhaled of deposited B and S, and inhaled F did not change nasal PD. Topically deposited F significantly lowered PDmax in a dose-dependent manner [10(-4) M, -12% from baseline; 10(-3) M, -24%] as did the more potent A [10(-5) M, -19%; 10(-4) M, -31%; 10(-3) M, -47%]. Nebulised A (10(-2) M) had the same effect on nasal PD as deposited A (10(-4) M). The effects of locally deposited F and A (10(-3) M) on nasal PD were additive.(ABSTRACT TRUNCATED AT 250 WORDS)

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Glucose intolerance during diuretic therapy in elderly hypertensive patients. A second report from the European Working Party on high blood pressure in the elderly (EWPHE).

Five hundred and seven elderly hypertensive patients were followed for 1 year, 371 for 2 years and 270 for 3 years in a double-blind, randomized, controlled trial in which they received either placebo or 25-50 mg hydrochlorothiazide and 50-100 mg of triamterene daily. One third of the active treatment group also received 250 mg to 2 g methyldopa daily. After 1 year the active treatment group had an average increase in fasting blood sugar of 2.5 mg/dl compared with an average fall of 1.4 mg/dl in the placebo group (P = 0.01). The increase in blood sugar 1 hour and 2 hours after 50 g oral glucose tended to be greater in the actively treated group but these increases did not achieve statistical significance. The effects of diuretic treatment were established after one year and did not increase further over the next 2 years. Overall there was an increase in fasting blood sugar of 5 mg/dl in the active treatment group which occurred mainly in the first year. The hyperglycaemic effect of diuretics appeared to be partly or wholly related to potassium loss since, in both groups, impairment of glucose tolerance was most marked in those in whom serum potassium decreased. The measures of blood sugar were also positively related to systolic pressure before and after treatment.

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Placebo-controlled, comparative study of the efficacy and safety of triamcinolone acetonide inhalation aerosol with the non-CFC propellant HFA-134a in patients with asthma. Azmacort HFA Clinical Study Group.

Triamcinolone acetonide (TAA) inhalation aerosol (Azmacort Inhalation Aerosol), a well-established corticosteroid treatment for bronchial asthma, utilizes the chlorofluorocarbon (CFC) propellant P-12, which will be phased out because of environmental concerns. Two TAA aerosol formulations have been developed using a non-chlorofluorocarbon propellant, HFA-134a (Azmacort HFA Inhalation Aerosol delivering TAA 75 microg/puff or 225 microg/puff). This study compared the efficacy and safety of the new 225 microg/puff formulation (TAA-HFA 225) to the marketed TAA inhalation aerosol (TAA-CFC) and to placebo in adult patients with moderate-to-severe persistent asthma. After a 5-day to 21-day baseline period during which all patients received TAA-CFC 150 microg/day, 538 patients were randomized to one of the following treatment schedules: TAA-HFA 450, 900, or 1800 microg/day; TAA-CFC 450 or 900 microg/day; or placebo for 12 weeks. All active treatment groups showed statistically significant improvement compared with placebo in pulmonary function (FEV1, FEF25-75%, morning and evening PEF), use of rescue albuterol, and asthma symptom scores. Improvements in all variables occurred within 1 week of treatment. The TAA-HFA 225 exhibited similar safety and efficacy profiles to the two equivalent doses of TAA-CFC studied. Our findings indicate that TAA-HFA is a safe and effective replacement for the currently marketed CFC-containing product. The higher strength 225 microg/puff formulation provides effective control of asthma with fewer inhalations.

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CT visual quantitative evaluation of hypertensive patients with coronavirus disease (COVID-19): Potential influence of angiotensin converting enzyme inhibitors / angiotensin receptor blockers on severity of lung involvement.

There is not enough data on the effect of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) on lung involvement in patients with COVID-19 pneumonia and hypertension (HT). Our aim was to compare the lung involvement of the HT patients hospitalized for COVID-19 using ACEIs/ARBs with the patients taking other anti-HT medications. : Patients who have a diagnosis of HT among the patients treated for laboratory-confirmed COVID-19 between 31 March 2020 and 28 May 2020 were included in the study. One hundred and twenty-four patients were divided into two as ACEIs/ARBs group (n = 75) and non-ACEIs/ARBs group (n = 49) according to the anti-HT drug used. The chest CT involvement areas of these two groups were evaluated quantitatively by two observers including all lobes, and total severity score (TSS) was calculated. These TSS values were compared between drug groups and clinical groups. In clinical classification; there were 4 (%3.2) asymptomatic, 5 (4.0%) mild type, 92 (74.1%) common type, 14 (11.3%) severe type, 9 (7.3%) critical type patients. ACEI/ARB group's TSS (mean±SD, 7.74 ± 3.54) was statistically higher than other anti-HT medication group (mean±SD, 4.40 ± 1.89) (<i>p</i> < .001). Likewise, severe-critical clinical type's TSS (mean±SD, 9.17 ± 3.44) was statistically higher than common type (mean±SD, 5.76 ± 3.07) (<i>p</i> < .001). Excellent agreement was established between the two blinded observers in the TSS measurements. Quantitative evaluation of CT and TSS score can give an idea about the clinical classification of the patient. TSS is higher in ACEI/ARB group than non-ACEIs/ARBs group.

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Randomized evaluation of ticagrelor monotherapy after 3-month dual-antiplatelet therapy in patients with acute coronary syndrome treated with new-generation sirolimus-eluting stents: TICO trial rationale and design.

Ticagrelor monotherapy after short-term dual-antiplatelet therapy (DAPT) may optimize ischemic and bleeding risks, particularly for acute coronary syndrome (ACS) patients, because its strategy is less potent than ticagrelor-based DAPT but more potent than aspirin or clopidogrel monotherapy. The TICO randomized open-label trial will evaluate whether ticagrelor monotherapy following 3-month DAPT is superior to 12-month ticagrelor-based DAPT in terms of net adverse clinical events (NACE) including efficacy and safety in ACS patients treated with ultrathin bioresorbable polymer sirolimus-eluting stents (BP-SES). Patients undergoing BP-SES implantation for ACS treatment will be randomized in a 1:1 fashion to the (1) ticagrelor monotherapy group after 3-month DAPT; or the (2) 12-month DAPT group. The primary endpoint is NACE within 12 months of percutaneous coronary intervention, which includes major adverse cardiac and cerebrovascular events (MACCE) plus major bleeding as defined by Thrombolysis in Myocardial Infarction. MACCE includes the composite of all-cause death, myocardial infarction, stent thrombosis, stroke, and target vessel revascularization. Secondary endpoints included each component of the primary endpoint. The TICO trial is an ongoing trial evaluating the efficacy and safety of ticagrelor monotherapy following 3-month DAPT exclusively in ACS patients treated with uniform BP-SES. It may provide novel insights regarding the need for adjusted use of DAPT for rebalancing risk-benefit in current practice and changing from the conventional concept of aspirin maintenance to a ticagrelor-based regimen in the management of ACS.

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Efficacy of antibiotic prophylaxis on postoperative inflammatory complications in Chinese patients having impacted mandibular third molars removed: a split-mouth, double-blind, self-controlled, clinical trial.

We investigated the effect of antibiotic prophylaxis on postoperative inflammatory complications after operations for impacted mandibular third molars in Chinese patients. A total of 207 patients had their bilateral third molars removed in a split-mouth, double-blind, self-controlled, clinical trial in two visits. For one side amoxicillin (or clindamycin) was given (antibiotic group) from one hour before operation until 3 days postoperatively. For the other side a placebo was given (placebo group) at the same time. The outcome, including alveolar osteitis, surgical wound infection, prebuccal infection, and infection of the anterior isthmus of fauces, was assessed 2 and 10 days postoperatively. A total of 192 patients completed the study, and there was no difference between the groups in the incidence of inflammatory complications. In the treatment group, there were 4 cases of alveolar osteitis (2%), 2 infections of the wound (1%), and 14 other reactions (gastrointestinal (n=4), bleeding (n=2), ulcer (n=2), and fever (n=6)). In the placebo group, there were 6 cases of alveolar osteitis (3%), 2 wound infections (1%), and 22 other reactions (bleeding (n=6), ulcer (n=2) and fever (n=14)). There was no significant difference in the extraction time and postoperative reactions, except the pain score on day 10 (p=0.005). Prophylactic amoxicillin (or clindamycin) is not effective for the prevention or reduction of postoperative inflammatory complications after the removal of impacted mandibular third molars in Chinese patients.

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Omeprazole versus ranitidine: short-term triple-therapy in patients with Helicobacter pylori-positive duodenal ulcers.

To compare the results of two short triple-therapy regimens, different only in the antisecretory drugs used, in patients with active duodenal ulcer and Helicobacter pylori infection. All patients received a combination of clarithromycin 250 mg b.d. and tinidazole 500 mg b.d. for 1 week, in addition to an antisecretory drug: omeprazole 20 mg (50 patients) or ranitidine 300 mg (50 patients) twice daily for 1 week, followed by a single daily dose for a further 3 weeks. Upper gastrointestinal endoscopy, with rapid urease test and histological examination of antral and corpus biopsies, was performed prior to the treatment and at least 2 months after the discontinuation of the antisecretory therapy. Duodenal ulcer healing was documented in all patients at the endoscopic examination after therapy. H. pylori eradication was achieved in 46 of 50 patients (92%, 95% CI = 85-99%) in the omeprazole group and in 43 of 50 patients (86%, 95% CI = 76-96%) in the ranitidine group: the difference is not significant. Omeprazole or ranitidine, in combination with clarithromycin and tinidazole, are equally effective in the eradication of H. pylori infection and healing of duodenal ulcers.

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The effects of zolpidem and zopiclone on daytime sleepiness and psychomotor performance.

Zolpidem (ZLP), which has selective affinity to the BZ1 (omega 1) receptor and a short half-life, is a novel hypnotic. The objective of this study is to compare the residual effects of standard clinical doses of ZLP and zopiclone (ZPC), a short-acting hypnotic marginally selective for the BZ1 (omega 1) receptor, given in a single dose on daytime sleepiness and psychomotor function. This study was carried out as a double-blind cross-over study with 10 mg ZLP, 7.5 mg ZPC and a placebo in 12 healthy male adults. In the multiple sleep latency test, sleep latency was not reduced but increased by ZLP and ZPC as well as the placebo when drug plasma levels had nearly reached the peak. Subjects administered ZLP were significantly more feeble, lethargic and antagonistic in mood rating scales than those administered ZPC. The incidence of severe behavioral side effects was higher in the case of ZLP than in the case of ZPC over the same period. Sleep latency the next morning was significantly shorter in the case of ZPC than in the case of ZLP or the placebo. The tapping test performed at the same time demonstrated that the number of taps was significantly less in the case of ZPC than in the case of ZLP or the placebo. The results of the present study suggest that ZLP acts more rapidly than ZPC. On the other hand, ZLP has less residual effect on sleepiness and psychomotor function the next morning.

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Micellar liquid chromatography: a worthy technique for the determination of beta-antagonists in urine samples.

Several beta-antagonists (acebutolol, atenolol, celiprolol, labetalol, metoprolol, nadolol, propranolol) were determined in urine samples with fluorometric detection after direct injection, in less than 15 min, with a micellar mobile phase of 0.1 M sodium dodecyl sulfate (SDS), 15% propanol, and 1% triethylamine at pH 3. The limits of detection (38 criterion) were usually between 3 and 30 ng/mL. The addition of propanol and triethylamine and the reduction of the pH of the mobile phase improved the efficiency of the chromatographic peaks that was rather low in pure micellar eluents. The selection of the composition of the mobile phase was easily performed through the use of an interpretive procedure which considered the retention times and peak shapes of the beta-antagonists in six chromatograms, obtained at varying concentrations of SDS (0.05-0.15 M) and propanol (5-15% v/v). The chromatograms of urine samples from healthy volunteers, which were administered atenolol, metoprolol, and propranolol, showed only one peak for the former drug and several peaks for the other two. These peaks corresponded to the parent drug and metabolites, which indicated the partial and the extensive degradation of metoprolol and propranolol, respectively.

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Effect of paraoxonase-1 polymorphism on clinical outcomes in patients treated with clopidogrel after an acute myocardial infarction.

Paraoxonase-1 (PON1) Q192R polymorphism was recently suggested to determine per se clopidogrel response on major cardiovascular events (MACEs). We assessed the impact of PON1, CYP2C19, and ABCB1 polymorphisms on MACE in clopidogrel-treated acute myocardial infarction (AMI) patients (N = 2,210), including those undergoing percutaneous coronary intervention (PCI) (n = 1,538). PON1 polymorphism was not associated with increased risk of in-hospital death and MACEs at 1 year (adjusted hazard ratio (HR) 1.03, 95% confidence interval (CI) 0.66-1.61 and adjusted HR 0.77, 95% CI 0.42-1.41 for QQ versus RR in all and PCI patients, respectively). The presence of two CYP2C19 loss-of-function (LOF) alleles was associated with the risk of in-hospital death and MACEs at 1 year in the overall population (adjusted odds ratio (OR) 3.67, 95% CI 1.05-12.80 and adjusted HR 1.96, 95% CI 1.08-3.54) and in PCI patients (adjusted OR 6.87, 95% CI 2.52-18.72 and adjusted HR 3.06, 95% CI 1.47-6.41). Unlike CYP2C19 polymorphism, PON1 (Q192R) polymorphism is not a major pharmacogenetic contributor of clinical response to clopidogrel in AMI patients.

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Pharmacokinetics and pharmacodynamics of torasemide and furosemide in patients with diuretic resistant ascites.

To evaluate the pharmacokinetics and pharmacodynamics of furosemide and torasemide in patients with cirrhosis and diuretic resistant ascites. Eighteen patients were randomly allocated to receive intravenous torasemide (40 mg) or furosemide (80 mg). The renal response to these drugs was assessed in baseline conditions and in the 24 h following drug administration together with plasma and urinary concentrations of furosemide, torasemide and its metabolites. Torasemide induced significantly greater diuretic and natriuretic effects than furosemide in the first hour after drug administration. No other significant differences between the two drugs were observed with respect to the renal response to these drugs. Torasemide reached a lower maximum plasma concentration than furosemide, but the former drug had a longer apparent terminal half-life and lower renal and non-renal clearances. Comparing these results with those previously reported in healthy subjects, both drugs showed a reduced elimination rate through renal and non-renal routes, and a larger distribution to body fluids. As a consequence, the half-life of both drugs was longer than in healthy subjects. Urinary excretion of pharmacologically active species, however, was quantitatively unchanged after torasemide administration, whereas it was reduced after furosemide. Finally, the natriuretic potency of both drugs was markedly reduced in these patients. The pharmacokinetics and pharmacodynamics of torasemide and furosemide are markedly altered in patients with diuretic resistant ascites.

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A randomized controlled trial of celecoxib to prevent recurrence of nonmuscle-invasive bladder cancer.

Significant morbidity and expense result from frequent recurrences of nonmuscle-invasive bladder cancer (NMIBC) after standard treatment, and carcinoma in situ (Tis) is a poor prognostic factor. Predicated on observational and preclinical data strongly supporting cyclooxygenase-2 (COX-2) in the pathogenesis, and the activity of COX-2 inhibitors, in bladder cancer, we conducted a randomized, double-blind, placebo-controlled trial to determine whether celecoxib could reduce the time-to-recurrence (TTR) in NMIBC patients at high risk for recurrence. A total of 146 patients were randomized to celecoxib (200 mg) or placebo orally twice daily for at least 12 months. The average treatment duration was 1.25 years. Primary intent-to-treat analysis revealed celecoxib did not statistically significantly prolong TTR compared with placebo (P = 0.17, log rank) with a median follow-up of 2.49 years. The recurrence-free rate at 12 months with celecoxib was 88% (95% CI: 0.81-0.96) versus 78% (95% CI: 0.69-0.89) with placebo. After controlling for covariates with Cox regression analysis, recurrence rates did not differ between the two study arms (HR = 0.69; 95% CI: 0.37-1.29). However, celecoxib had a marginally significant effect on reducing metachronous recurrences (vs. placebo) with HR of 0.56 (95% CI: 0.3-1.06; P = 0.075). Celecoxib was well tolerated, with similar adverse events and quality-of-life in both arms. Our clinical trial results do not show a clinical benefit for celecoxib in preventing NMIBC recurrence but further investigation of COX-2 inhibitors in this setting is warranted.

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Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia.

The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10^-8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.

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Feasibility and safety of a reduced duration of therapy of colony-stimulating factor in a dose-dense regimen.

The risk of febrile neutropenia (FN) in cancer patients receiving chemotherapy is mainly due to the type of chemotherapy regimen and the presence of specific risk factors in patients. The recent trend of using a dose-dense treatment schedule has enhanced the risk of FN. In the present prospective study, we evaluated the feasibility of a reduction of duration of therapy with colony-stimulating factor (G-CSF) in a dose-dense regimen. Between June 2002 and December 2011, 107 patients with a new diagnosis of non-Hodgkin lymphoma (NHL) receiving dose-dense chemotherapy, every 14 days, were included in the study. The primary endpoint was defined as the completion of planned chemotherapy cycles as scheduled. Secondary endpoints were median number of administered G-CSF doses (vials), incidence of FN, hospitalization and toxicity. The planned chemotherapy cycles (primary endpoint) were completed by 84.1 % of patients. The median number of G-CSF (lenograstim) doses administered for each patient was 24 (range 10-35), which corresponds to a median of five vials (range 0-10) for each cycle. Grades 3-4 toxicities, related to G-CSF administration, included neutropenia and thrombocytopenia (14.0 and 1.9 %, respectively). No grades 3-4 bone pain was detected. The incidence of FN and hospitalization was 9.3 % (10/107) and 4.5 % (5/107), respectively. Reduced dosage of G-CSF allows dose-dense chemotherapy scheduling, limits exposure to G-CSF and also represents an opportunity for cost savings.

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The use of dopamine for the prevention of the renal side effects of indomethacin in premature infants with patent ductus arteriosus.

To determine if dopamine would prevent the renal side effects of indomethacin, fifteen preterm infants were randomized into two groups: seven received indomethacin alone, and eight received indomethacin together with low dose dopamine infusion. Infants who received indomethacin together with dopamine had significantly higher UV (p less than 0.005), CNa (p less than 0.005), Cosm (p less than 0.005) and FENA (p less than 0.005) than those of infants who received indomethacin alone. There was, however, no significant difference in Ccr and FNa between the groups. These data indicate that dopamine overcomes indomethacins renal side effects of tubular origin, but it cannot prevent the renal vasoconstrictive action of vasoconstrictor hormones following the inhibition of prostaglandin synthesis by indomethacin. Considering that RBF and GFR turn to normal approximately 12 hours after the last dose of indomethacin, and that with the use of dopamine systemic blood pressure and peripheral circulation can also be normalized and to some extent myocardiac contractility improved, low doses of dopamine can be used instead of furosemide in the sick preterm infant with PDA when indomethacin therapy is indicated.

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The Efficacy of 24-Month Metformin for Improving Menses, Hormones, and Metabolic Profiles in Polycystic Ovary Syndrome.

The long-term effects of metformin in women with polycystic ovarian syndrome (PCOS) are inadequately studied. The effects of metformin on women with PCOS during 24 months with respect to menses, hormones, and metabolic profiles are assessed. Prospective cohort. A reproductive endocrinology clinic in a university-affiliated medical center. One hundred nineteen women with PCOS, defined by the Rotterdam criteria, were enrolled. Metformin was given daily for 24 months. The primary outcome was the proportion of patients with regular menstruation during treatment. Changes in anthropometric, hormonal, and metabolic parameters were also assessed. Analyses were performed using segmented regression analysis with a generalized estimating equation methodology. Outcomes are expressed as magnitude of change from the baseline. Both overweight (OW) and normal-weight (NW) women with PCOS had increased menstrual frequency and decreased body mass index (BMI), testosterone, and luteinizing hormone levels in the first 6 months. Further stratification showed that NW women exhibiting elevated testosterone at baseline had the largest magnitude of improvement at 6 months [odds ratio (OR), 7.21; 95% confidence interval (CI), 2.35 to 22.17], whereas OW patients with normal testosterone were most likely to achieve normal menses at 12 months (OR, 0.63; 95% CI, 0.47 to 0.77). Metformin was associated with improvements in the menstrual cycle and most hormonal profiles in OW and NW women with PCOS during 24 months of treatment. Most parameters reached maximal response and steady-state after 6 months. Phenotypic differences in baseline BMI and testosterone level can be used as patient selection criteria or treatment prognostics.

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Gastroesophageal reflux in the patients with asthma.

Thirty one patients with asthma (mean age was 44.4 10.7; range 18-63) were investigated for gastroesophageal reflux (GER). The patients were separated into two groups according to presence of reflux and/or nocturnal symptoms. 13 patients had one of the reflux and/or nocturnal asthma symptoms (Group 1), whereas 18 patients had none of them (Group 2). To assess GER patients underwent to scintigraphy with Tc99m. GER was determined 4 of 13 patients in group 1 (30,7 %) and 1 of 18 patients in group 2 (5,5 %). There was significant difference between the group 1 and group 2 in that respect (p < 0,001). The patients with established GER (5 patients) were given Omeprazole (a proton pomp inhibitor) 40 mg daily for 4 weeks following a 2 week placebo period. The patients recorded their daily and nocturnal symptoms of asthma, additional salbutamol use, morning and evening peak expiratory flow rates (PEFR) measurements in a daily chart during placebo and omeprazole treatment without changing their antiasthma treatment. Their PEFR, FEV1 values, daily and nocturnal symptoms and additional beta agonist use did not changed after omeprazole treatment except one. But their reflux symptoms (heartburn and regurgitation) were improved. As a consequence, we suggested that asthmatics which have some complaints of reflux should be searched for GER. Not the respiratory functions but GER symptoms can be improved w

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Brain glucose metabolism in diffuse large B-cell lymphoma patients as assessed with FDG-PET: impact on outcome and chemotherapy effects.

There is a lack of data on the effect of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy on brain glucose metabolism of diffuse large B-cell lymphoma (DLBCL) patients, as measured by 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET). Moreover, the prognostic value of brain glucose metabolism measurements is currently unknown. To investigate the use of FDG-PET for measurement of brain glucose metabolism in R-CHOP-treated DLBCL patients, and to assess its prognostic value. This retrospective study included DLBCL patients who underwent FDG-PET including the brain. FDG-PET metabolic volume products (MVPs) of the entire brain, cerebral cortex, basal ganglia, and cerebellum were measured, before and after R-CHOP therapy. Whole-body total lesion glycolysis (TLG) was also measured. Thirty-eight patients were included, of whom 18 had an appropriate end-of-treatment FDG-PET scan. There were no significant differences (P > 0.199) between pre- and post-treatment brain glucose metabolism metrics. Low basal ganglia MVP was associated with a significantly worse progression-free survival (PFS) and overall survival (OS) (P = 0.020 and P = 0.032), and low cerebellar MVP was associated with a significantly worse OS (P = 0.034). There were non-significant very weak correlations between pretreatment brain glucose metabolism metrics and TLG. In the multivariate Cox regression, only the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) remained an independent predictor of PFS (hazard ratio 3.787, P = 0.007) and OS (hazard ratio 2.903, P = 0.0345). Brain glucose metabolism was not affected by R-CHOP therapy. Low pretreatment brain glucose metabolism was associated with a worse outcome, but did not surpass the predictive value of the NCCN-IPI.

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Early versus late intensification for patients with high-risk Hodgkin lymphoma-3 cycles of intensive chemotherapy plus low-dose lymph node radiation therapy versus 4 cycles of combined doxorubicin, bleomycin, vinblastine, and dacarbazine plus myeloablative chemotherapy with autologous stem cell transplantation: five-year results of a randomized trial on behalf of the GOELAMS Group.

The 5-year freedom from treatment failure (FFTF) rate, with treatment failure defined as the lack of post-treatment complete remission (CR), recurrence, or death, ranges from 60% to 70% after 6 to 8 cycles of combined doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), which is the reference treatment for patients with advanced Hodgkin lymphoma (HL). In this randomized, phase 2 study, the authors tested 2 intensive chemotherapy regimens in 158 patients with clinical stage (CS) IIB through IV HL accompanied by high-risk factors who were recruited between May 1997 and December 2004. High-risk CS IIB, III, and IV were defined by the presence of > or =5 involved lymphoid areas, and/or a mediastinal mass ratio > or =0.45, and/or > or =2 extra lymph node sites affected by the disease (for CS IV). In Arm V, 82 patients received 3 courses of combined vindesine (5 mg/m(2)), doxorubicin (99 mg/m(2)), carmustine (140 mg/m(2)), etoposide (600 mg/m(2)), and methylprednisolone (600 mg/m(2)) (VABEM) followed by low-dose lymph node irradiation. In Arm A, 76 patients received 4 cycles of ABVD followed by myeloablative combined carmustine (300 mg/m(2)), etoposide (800 mg/m(2)), cytarabine (1600 mg/m(2)), and melphalan (140 mg/m(2)) and underwent autologous stem cell transplantation. After 3 cycles of VABEM, the CR rate was 89% versus 60% after 4 cycles of ABVD. However, after the completion of treatment, the CR rates for Arms V and A were similar (89% and 88%, respectively). The 5-year FFTF rates for Arms V and A also were similar (79% and 75%, respectively) along with the 5-year overall survival rates (87% and 86%, respectively). Early intensification (Arm V) and late intensification (Arm A) were equally effective for treating patients with high-risk/advanced HL.

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Pharmacokinetics of prednisolone in man during acute and chronic exposure to high altitude.

The exposure to high altitude (H) produces several physiologic alterations which may induce changes in the pharmacokinetics of drugs. This hypothesis has been confirmed in previous studies which suggest that drugs which are highly bound to plasma proteins are most likely to exhibit altered pharmacokinetics. To further elucidate the influence of H on pharmacokinetics, prednisolone was selected, since it is highly bound to plasma proteins, renally excreted and poorly bound to red blood cells. Prednisolone (80 mg) was given orally to three groups of young healthy volunteers. One group was residing at sea level (L): the same volunteers were studied again after 15 hours of exposure to high altitude (3600 m, HA group), and volunteers living at H for at least six months (group HC). There were no statistically significant differences in the pharmacokinetic parameters calculated from plasma data in the three situations studied. When calculated from whole blood data, however, AUC and Cmax were increased and both volume of distribution and clearance diminished after exposure to H, either acute or chronically. Binding to proteins increased significantly after H exposure from 57% in group L to 75% and 94% in group H and HC, respectively. Binding to erythrocytes also increased with H exposure from 43.7% in group L to 50.6% and 61.6% in group HA and HC, respectively. The prednisolone/prednisone ratio in urine was 11.1 in group L, 7.3 in group HA and 45.6 in group HC. Since prednisone has very little intrinsic glucocorticoid activity and has to be converted to prednisolone for therapeutic effect, the alteration of the prednisolone/prednisone ratio, as a result of high altitude exposure could be clinically relevant. Additional experiments are desirable to further evaluate this observation.

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[Idiopathic thrombocytopenic purpura in children. Apropos of 98 cases].

The authors report a retrospective study of 98 cases of idiopathic thrombocytopenic purpura in children. The sex ratio was 1/1 and the mean age 5 years. A history of viral infection preceded the purpura in 45% of the cases. Sudden onset was observed in 81%. The platelet count was less than 20,000 mm3 in 78.5%. A follow-up was obtained in 79 patients: 76% had an acute disease. A spontaneous remission occurred in 88.6% of the cases, most of them in the first six months (49 cases/68), and in 10 cases/68 between 7 and 11 months after onset. Six patients presented one or two relapses prior to recovery. The illness became chronic in 11% of the patients despite prednisone therapy. Four patients were treated by splenectomy, in 3 cases with success. Two children died, one girl from cerebral haemorrhage and one boy from septicemia.

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Atorvastatin inhibits oxidative stress via adiponectin-mediated NADPH oxidase down-regulation in hypercholesterolemic patients.

Interventional treatment with atorvastatin lowered the circulating levels of the catalytic core of NADPH oxidase, namely sgp91(phox), but the underlying mechanism is still undefined. To test the hypothesis that the inhibitory effect on oxidative stress, induced by Atorvastatin, could be mediated by adiponectin. We compared 36 patients with polygenic hypercholesterolemia and 18 healthy subjects. Patients were randomized to either a low-fat diet (Group A) or low-fat diet plus atorvastatin 10 mg/day (Group B) for 30 days. Lower serum adiponectin levels and higher lipid profile, gp91(phox) serum levels, urinary isoprostanes, platelet oxygen free radicals, characterized patients. After 30 days of treatment, group B showed higher levels of adiponectin which is inversely correlated to reduced levels of sgp91(phox), urinary isoprostanes and platelet oxygen free radicals (p<0.001). In in vitro model, adiponectin dosages between 5 and 10 ng/ml inhibited p47(phox) translocation to gp91(phox) and soluble gp91(phox) cleavage indicating its ability in inhibiting the assembly of NADPH oxidase subunits on cell membrane and in turn the enzymatic system activation. This study provides the first evidence that in patients higher APN serum levels are associated with gp91(phox) down-regulation. APN-mediated gp91(phox) reduction could be one of the mechanisms involved in atorvastatin's antioxidant effect.

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[Study of the effect of salbutamol inhalation on the function of small airways in patients with chronic bronchitis without ventilatory disorders using simple spirographic tests].

In 68 males with chronic bronchitis and normal standard spirometric parameters and in 30 healthy males the following were assessed: VC, FEV1, V50 and V75 before and after Salbutamol inhalations. In chronic bronchitis Salbutamol slightly decreased FEV1 values. Significant improvement of V50 and V75 was seen after Salbutamol inhalations in chronic bronchitis. This was observed more promeinently in comparison with the control group. Significant increase of V50 and V75 was seen in 14% of chronic bronchitics. The improvement in pattency of small airways following administration of bronchodilators can be an index for early identification of patients with chronic bronchitis, although this needs to be verified in prospective spirographic studies.

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Risk of adverse outcomes in Taiwan associated with concomitant use of clopidogrel and proton pump inhibitors in patients who received percutaneous coronary intervention.

Recent studies have suggested that proton pump inhibitors (PPIs) might reduce the inhibitory effect of clopidogrel on platelet aggregation, possibly through inhibition of the hepatic cytochrome P450 2C19 (CYP2C19) isoenzyme. The prevalence of CYP2C19 loss-of-function alleles is much greater among East Asians than among other populations. Thus, potential drug interactions might be more apparent. Therefore, we conducted a nationwide, population-based study using the Taiwan National Health Insurance database. We identified 3,278 patients (mean age 65.9 +/- 11.9 years, 71.9% men) with coronary artery disease who had taken clopidogrel after percutaneous coronary intervention from the 1 million sampling cohort data set since January 1, 2002. Of the 3,278 patients, 572 had received concomitant PPIs for underlying gastrointestinal disease and 2,706 had not used PPIs. To the end of 2007, 1,410 patients had been rehospitalized, 970 patients had undergone revascularization, and 499 patients had died. According to the Kaplan-Meier analysis, the incidence of rehospitalization (p = 0.001) and mortality (p <0.001) was significantly greater for the patients with concomitant PPI use than for those without concomitant PPI use. However, the incidence of revascularization was similar in the 2 groups. Multivariate analyses showed that concomitant PPI use was associated with an increased risk of rehospitalization (hazard ratio 1.23, 95% confidence interval 1.07 to 1.41, p = 0.003) and mortality (hazard ratio 1.65, 95% confidence interval 1.35 to 2.01, p <0.001). In conclusion, the concomitant use of clopidogrel and PPIs should be done with care to avoid adverse outcome in East Asians patients who have undergone percutaneous coronary intervention.

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Forms of atypical depression and their response to antidepressant drugs.

Three definitions of atypical depression are evaluated with respect to the effects of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) on the basis of pooled data from several double-blind studies. Those three definitions of atypical depression are depression with associated panic, depression secondary to a diagnosis of anxiety, and depression with reversed vegetative change. In none of these forms was a drug difference observed. However, when gender was taken into account, MAOIs were superior to TCAs in depressed women with panic attacks, whereas TCAs were superior to MAOIs in depressed men with panic attacks.

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Association of Chlamydia pneumoniae antibody with the cholesterol-lowering effect of statins.

To investigate the association between Chlamydia pneumoniae (C. pneumoniae) infection and atherosclerosis, we compared the effect of lipid-lowering drugs on carotid intima-media thickness (IMT) between patients who were positive and negative for C. pneumoniae antibodies. A total of 165 asymptomatic hypercholesterolemic patients were randomized to probucol (500 mg per day, n = 82) or pravastatin (10 mg per day, n = 83) and followed for 2 years. The 2-year change of IMT in the common carotid artery was the primary endpoint, while mean IMT change and major cardiovascular events were secondary endpoints. C. pneumoniae antibodies (IgA and IgG) were measured by enzyme-linked immunosorbent assay. The 50 patients without C. pneumoniae antibodies showed significant reduction of IMT progression (-19%), while no significant change of IMT was noted in the 115 antibody-positive patients (-6%). Significant inverse associations were found between the reduction of IMT progression and the C. pneumoniae IgA- and IgG-antibody index (P < 0.01 and 0.01, respectively). No significant differences in the reduction of serum total-cholesterol and LDL-cholesterol were found between antibody-positive and -negative patients. There was no significant difference of efficacy between probucol and pravastatin. These observations suggest that C. pneumoniae infection reduces the effect of lipid-lowering therapy on carotid atherosclerosis and that this organism may play a role in the progression of atherosclerosis.

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A review of carvedilol arrhythmia data in clinical trials.

beta-Blockers are currently being evaluated more intensively to define their role in clinical use as antiarrhythmic agents. beta-Adrenergic blockade has been studied in relation to atrial fibrillation, ventricular arrhythmias, and sudden death; however, it is apparent from a number of studies that not all beta-blockers are equally effective. Randomized clinical trial data, both in heart failure and post-myocardial infarction (MI) patients, have shown differences in mortality benefits in addition to a variable effect on arrhythmias and sudden death. Carvedilol, a third-generation beta-blocker with proven clinical benefit in the management of heart failure and post-MI patients, has properties that may make it an effective antiarrhythmic agent. This paper reviews the current clinical arrhythmia data available for carvedilol from large-scale clinical trials and small studies. The trial evidence demonstrates that carvedilol therapy can be an effective adjunctive rate-control therapy in patients with atrial fibrillation, prevent mortality in patients with heart failure or post-MI with left ventricular dysfunction, with or without atrial fibrillation, and reduce its onset and the incidence of ventricular arrhythmia and sudden death.

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Surgery for recurrent goiter: complication rate and role of the thyroid-stimulating hormone-suppressive therapy after the first operation.

This report examines outcomes in our series of patients who underwent surgery for recurrent goiter to assess the efficacy of thyroid-stimulating hormone (TSH)-suppressive therapy after the first less than total thyroidectomy. A further outcome was to understand whether redo surgery was burdened with a higher rate of complications. We evaluated 214 patients undergoing a completion thyroidectomy for recurrent goiter who had received, as their first surgery, a bilateral subtotal thyroidectomy. After the first operation, 84 patients were given TSH-suppressive therapy with levothyroxine, 32 were treated with antithyroid drugs, and 92 did not receive any suppressive treatment but only a substitutive therapy. The 84 patients who received levothyroxine at a suppressive dosage (group A) were compared with 92 patients who did not receive levothyroxine or received it only at substitutive dosage (group B). We further compared the complication rate of a similar group of 175 patients who had undergone a primary thyroidectomy. The average age at intervention for relapse in group A patients was significantly lower than that of group B patients: 54.18 vs 60.8 years (p < 0.001). The average interval between the first intervention and the intervention for relapse was significantly shorter in group A than in group B: 24 vs 27 years (p = 0.03). After the operation, temporary hypoparathyroidism occurred in 37.7 % of patients and definitive hypoparathyroidism in 7.2 %. Our results clearly show that the interval between the two surgical interventions was significantly reduced in patients undergoing TSH-suppressive therapy with levothyroxine. The incidence of hypoparathyroidism dramatically increased.

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Allopurinol for the treatment of aggressive behaviour in patients with dementia.

Aggressive behaviour is commonly observed in patients with dementia, and current pharmacological treatments are still deficient in terms of efficacy and tolerability. Allopurinol is an inhibitor of the enzyme xanthine oxidase, with previously suggested anti-aggressive effects. After successful treatment of aggression in two patients, we performed a case-series study with allopurinol 300 mg a day orally for 6 weeks (increasing 300 mg every 2 weeks if the response was less than 50%) in six patients with dementia associated with prominent aggressive behaviour who failed to respond to two previous treatment strategies. Five patients were considerably responsive to allopurinol (four with 300 mg within 2 weeks and one with 600 mg), apparently without side-effects, which is in accordance with its well-established safety and tolerability profile. The observed therapeutic effect of allopurinol might be due to the inhibition of the enzyme xanthine oxidase, possibly decreasing production of oxygen-free radicals or promoting the accumulation of purines. Controlled studies are warranted to confirm these preliminary observations.

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Risedronate and ergocalciferol prevent hip fracture in elderly men with Parkinson disease.

There is a high incidence of hip fractures in patients with Parkinson disease (PD). Bone mineral density (BMD) is decreased in patients with PD, correlating with the immobilization-induced bone resorption and hypovitaminosis D with compensatory hyperparathyroidism. To evaluate the effectiveness of risedronate, an inhibitor of bone resorption, on osteoporosis and the risk of hip fractures in elderly men with PD. This was a 2-year, randomized, double-blind, placebo-controlled trial. In a prospective study of patients with PD, 121 patients received a daily dose of 2.5 mg risedronate and vitamin D2 1,000 IU for 2 years, and the remaining 121 received placebo and vitamin D2 1,000 IU. Incidence of hip fractures was compared between the two groups. Nine patients sustained hip fractures in the placebo group, and three hip fractures occurred in the risedronate group. The relative risk of a hip fracture in the risedronate group vs the placebo group was 0.33 (95% CI, 0.09 to 1.20). BMD increased by 2.2% in the risedronate group and decreased by 2.9% in the placebo group (p < 0.0001). Urinary deoxypyridinoline, a bone resorption marker, decreased by 46.7% in the risedronate group and by 33.0% in the placebo group. Treatment with risedronate and vitamin D2 increases bone mineral density in elderly men with Parkinson disease and reduces the risk of hip fractures.

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Antithrombotic strategies in elderly patients with atrial fibrillation revascularized with drug-eluting stents: PACO-PCI (EPIC-15) registry.

We sought to investigate the antithrombotic regimens applied and their prognostic effects in patients over 75 years old with atrial fibrillation (AF) after revascularization with drug-eluting stents (DES). Retrospective registry in 20 centers including patients over 75 years with AF treated with DES. A primary endpoint of MACCE and a co-primary endpoint of major bleeding by ISTH criteria were considered at 12 months. A total of 1249 patients (81.1 ± 4.2 years, 33.1% women, 66.6% ACS, 30.6% complex PCI) were included. Triple antithrombotic therapy (TAT) was prescribed in 81.7% and dual antithrombotic therapy (DAT) in 18.3%. TAT was based on direct oral anticoagulants (DOAC) in 48.4% and maintained for only 1 month in 52.2%, and DAT included DOAC in 70.6%. Primary endpoint of MACCE was met in 9.6% and primary endpoint of major bleeding in 9.4%. TAT was significantly associated with more bleeding (10.2% vs. 6.1%, p = 0.04) but less MACCE (8.7% vs. 13.6%, p = 0.02) than DAT and the use of DOAC was significantly associated to less bleeding (8% vs. 11.1%, p = 0.03) and similar MACCE (9.8% vs. 9.4%, p = 0.8). TAT over 1 month or with VKA was associated with more major bleeding but comparable MACCE rates. Despite advanced age TAT prevails, but duration over 1 month or the use of other agent than Apixaban are associated with increased bleeding without additional MACCE prevention. DAT reduces bleeding but with a trade-off in terms of ischemic events. DOAC use was significantly associated to less bleeding and similar MACCE rates.

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Responsiveness to diving reflex after acute myocardial infarction. Influence of early beta-adrenoceptor blocker therapy.

We studied the influence of beta-adrenoceptor blockade on heart rate responses to facial immersion in ice-cooled water after acute myocardial infarction. Forty patients with acute myocardial infarction were randomized to the double-blind therapy with metoprolol 200 mg daily or matching placebo. Therapy was started as soon as possible after admission to hospital and continued for 15 days. After this initial period all patients were treated with beta-blockade during the subsequent 6 months. Repeated investigations of heart rate responses to facial immersion in ice-cooled water and 24-hour ECG-recordings were performed on day 15 (while patients were on study therapy), after 6 weeks, 3 and 6 months. Throughout the 6-month period, facial immersion elicited significant heart rate reductions in both treatment groups. No differences were found between the two groups or between different examinations during follow-up. There was no correlation between heart rate response to facial immersion and frequency of ventricular arrhythmia on a 24-hour monitoring. In conclusion, acute administration of metoprolol in myocardial infarction does not influence the bradycardial response to facial immersion either in the early postinfarction phase or during 6 months' follow-up. There is no relation between bradycardial response to face immersion and frequency of ventricular arrhythmias.

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Plasmapheresis and antineoplastic treatment in CNS paraneoplastic syndromes with antineuronal autoantibodies.

We retrospectively evaluated the effect of plasmapheresis (PE) in seven patients with paraneoplastic encephalomyelitis (PEM), small-cell lung carcinoma, and anti-Hu antibodies, and four patients with paraneoplastic cerebellar degeneration (PCD), ovarian or breast cancer, and anti-Yo antibodies. In addition to PE, patients received prednisone (nine), cyclophosphamide (eight), or treatment of the tumor (five). All but one patient were severely disabled by the time PE began. The clinical outcome was compared with that of five patients (PEM, four; PCD, one) who only had treatment of the tumor. Only one of these five patients had a severe neurologic deficit at the onset of the antineoplastic treatment. No patient improved. Two patients treated with PE and antineoplastic therapy and three who only received treatment of the tumor remained stable for at least 6 months. Four of the five patients with a stable course started the treatment when the neurologic deficit was not severe. We conclude that the efficacy of PE with other immunosuppressive therapies in the stabilization of the neurologic deficit is uncertain.

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Efficacy of Ibuprofen and ibuprofen/acetaminophen on postoperative pain in symptomatic patients with a pulpal diagnosis of necrosis.

The purpose of this prospective, randomized, double-blind study was to determine ibuprofen versus ibuprofen/acetaminophen use for postoperative endodontic pain in symptomatic patients with a pulpal diagnosis of necrosis and an associated periapical radiolucency who were experiencing moderate to severe preoperative pain. We also recorded escape medication use. Seventy-one adult patients presenting for emergency endodontic treatment with a symptomatic maxillary or mandibular tooth with a pulpal diagnosis of necrosis, periapical radiolucent area, and moderate to severe pain participated in this study. The patients were randomly divided into 2 groups by random assignment and numeric coding. An emergency debridement of the tooth was completed with hand and rotary instrumentation. At the end of the appointment, the patients randomly received capsules of either 600 mg ibuprofen or 600 mg ibuprofen combined with 1000 mg acetaminophen (blinded to both operator and patient). Patients also received a 6-day diary to be completed after anesthesia wore off and every morning for 5 days. Patients were asked to record pain, symptoms, and the number of capsules taken. Patients received escape medication (Vicodin) if the study medication did not control their pain. Postoperative data were analyzed by randomization test and step-down Bonferroni method of Holm. There were decreases in pain levels and analgesic use over time for the ibuprofen and ibuprofen/acetaminophen groups. There was no statistically significant difference between the 2 groups for analgesic use or escape medication use. Approximately 20% of patients in both groups required escape medication to control pain.

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Safety and pharmacokinetics of the CIME combination of drugs and their metabolites after a single oral dosing in healthy volunteers.

This phase I, pilot clinical study was designed to evaluate the safety and the pharmacokinetic (PK) profiles of the CIME (Metabolic Identity Card) combination of ten drugs, with a view to its use as a phenotyping cocktail. Ten healthy Caucasian subjects were orally dosed with the CIME combination (caffeine-CYP1A2, repaglinide-CYP2C8, tolbutamide-CYP2C9, omeprazole-CYP2C19, dextromethorphan-CYP2D6, midazolam-CYP3A, acetaminophen-UGT1A1, 6&9 and 2B15, digoxin-P-gp, rosuvastatin-OATP1B1&3 and memantine-active renal transport). Blood was collected over 3 days and on day 7. CIME probes and relevant metabolites were assayed by LC-MS/MS and PK parameters were calculated. Main results were: (1) good safety with reversible mild or moderate adverse effects, (2) an analytical method able to quantify simultaneously the 10 probes and the major metabolites, (3) calculation of PK parameters for all probes in general agreed with published values, and (4) identification of the low CYP2D6 metabolizer. This pilot study showed that the CIME combination was well tolerated and that its pharmacokinetics could be accurately measured in healthy volunteers. This combination can now confidently be checked for sensitivity and specificity and for lack of interaction to be validated as a phenotyping cocktail.

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Antihypertensive drugs and lip cancer in non-Hispanic whites.

In screening pharmaceuticals for possible carcinogenic effects we noted an association between lip cancer risk and the photosensitizing antihypertensive drugs hydrochlorothiazide and nifedipine. In this study, we further characterized the risk of lip cancer associated with these and other commonly used antihypertensive drugs. In a comprehensive medical care program, we evaluated prescriptions dispensed and cancer occurrence from August 1, 1994, to February 29, 2008. We identified 712 patients with lip cancer (cases) and 22,904 comparison individuals (controls) matched for age, sex, and cohort year of entry in the susceptible group, non-Hispanic whites. We determined use, at least 2 years before diagnosis or control index date, of the commonly prescribed diuretics hydrochlorothiazide and hydrochlorothiazide combined with triamterene, the angiotensin-converting enzyme inhibitor lisinopril, the calcium channel blocker nifedipine, and the β-adrenergic blocker atenolol, the only nonphotosensitizer agent studied. We analyzed the use of each drug exclusively and regardless of use of the others, and focused on duration of use. Conditional logistic regression was used for analysis of matched case-control sets, with control for cigarette smoking. At least a 5-year supply of a drug yielded the following odds ratios (95% CIs), respectively, compared with no use: hydrochlorothiazide, 4.22 (2.82-6.31); hydrochlorothiazide-triamterene, 2.82 (1.74-4.55); lisinopril, 1.42 (0.95-2.13); nifedipine, 2.50 (1.29-4.84); and atenolol, 1.93 (1.29-2.91). When the other drugs were excluded, the odds ratio for atenolol was reduced to 0.54 (0.07-4.08). These data support an increased risk of lip cancer in non-Hispanic whites receiving treatment for hypertension with long-term use of photosensitizing drugs.

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Inhaled steroid therapy and hospitalization for bronchial asthma: trend in Tokushima University Hospital.

With the recognition that airway inflammation is present even in patients with mild bronchial asthma, therapy with inhaled corticosteroids is now indicated in various stages of patients. In the present article, we retrospectively examined the prescriptions for inhaled corticosteroids and other drugs for the treatment of outpatients with bronchial asthma at Tokushima University Hospital. We also analyzed asthma control in these patients, in terms of the incidence of emergency consultations and hospitalizations due to asthma exacerbations. To analyze the recent trend, the patients observed from 1998 to 2000 (recent years) were included, and for control purpose, those in 1990 and 1991 (earlier years) were also included. The percentage of patients treated with inhaled corticosteroids remarkably increased in recent years (mean; 81.3%) compared to earlier years (mean; 23.5%). In contrast, the usage of oral corticosteroids, oral xanthine derivatives, beta-adrenergic receptor agonists and anti-allergic agents tended to decrease in the 10 years period. After the introduction in 1995, considerable patients up to 25% have been treated with anti-leukotrienes. Emergency consultations decreased in recent years (mean; 0.18/patient/year) compared to earlier years (mean; 0.79/patient/year). Emergency hospitalizations also decreased in recent years (mean; 0.043/patient/year) compared to earlier years (mean; 0.23/patient/ year). In the present study, spread of inhaled corticosteroid therapy and decline in incidence of emergency consultation and hospitalization were simultaneously observed at Tokushima University Hospital, and the former has, at least in part, a contribution to the latter.

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[Treatment with sulindac of adenomatous polyps in familial polyposis].

The effect of sulindac, a nonsteroid antiinflammatory drug, has been reported to cause both regression and suppression of colon polyps in patients with familial adenomatous polyposis and Gardner's syndrome. We report our experience with seven patients with diffuse colonic polyposis treated with sulindac. Seven patients with familiar adenomatous polyposis, four men and three women (mean age, 30 years; range 16 to 41 years) were included in this study. Two patients that underwent prior colectoctomy with ileorectal anastomosis and had polyps in the rectum were also included. The polyps ranged in size from 0.2 to 2.5 cm; most of them were less than 1 cm. Sulindac was given 150 mg. twice a day. Further colonoscopic examination was done at 6-month intervals during follow-up in all patients. A disappearance or a marked reduction in the number and size of polyps was observed in all patients after 24 months of treatment with sulindac. The drug was well tolerated and no side effects were observed during treatment. The authors conclude that sulindac is effective in inducing the regression of rectal polyps in familial, adenomatous polyposis.

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The Importance of Acinetobacter Species in the Hospital Environment.

<i>Acinetobacter</i> species is associated with health care associated infections especially in patients on respiratory therapy equipment and indwelling catheters. They are becoming increasingly drug resistant. The knowledge of the prevalence and pattern of antimicrobial susceptibility pattern of Acinetobacter spp. is important. The study is undertaken to estimate the prevalence rate, risk factors and antimicrobial resistance pattern of isolates. in <i>Acinetobacter</i> spp. from various clinical samples. The isolates of <i>Acinetobacter</i> species obtained from various clinical specimen. Specimens were processed by standard microbiological techniques. Antimicrobial sensitivity tests of the <i>Acinetobacter</i> isolates were done by modified Kirby-Bauer disc diffusion method. Out of 622 isolates, 399 isolates were from inpatients (62,18%) and 223 were from outpatients (37,82%). More than 90% of isolates displayed resistance to ampicillin, amoxicillin-clavulanic acid, ceftazidime, caftriaxon and amikacin. Resistance to gentamicin, co-trimoxazole and ciprofloxacin were also common. Least resistance was seen to piperacillin-tazobactam and imipenem. A total of 125 Acinetobacter isolates were analyzed, out of which 78.4 % were multi-drug resistant (MDR). Of these MDR isolates, 17.24% were pan-resistant. <i>A. baumannii</i> was the most common species responsible for wound infection (84,8%), pneumonia(96,15%), abscess (72.7%), urinary tract infection (85,7%) and septicemia(89,5%). Multi-drug resistant <i>Acinetobacter</i> has emerged as an important nosocomial pathogen. Antibiotic susceptibility testing is critical in the treatment of infections caused by <i>Acinetobacter.</i> Continued surveillance of prevalent organisms in ICUs, combined with preventive measures remains absolutely essential in efforts to prevent or limit the spread of <i>Acinetobacter</i> infection.

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High-dose bolus tirofiban versus low-dose bolus in patients with acute coronary syndrome undergoing percutaneous coronary intervention.

Aim of the present study was to determine effects of high-dose versus low-dose intravenous (IV) bolus tirofiban on angiographic measures, ST resolution, enzymatic infarct size, and clinical outcomes in patients with acute coronary syndrome (ACS) who were undergoing percutaneous coronary intervention (PCI) and received current pharmacoinvasive therapy. Acute coronary syndrome patients (n=271, 85.6% male; mean age: 57.9±12.6 years) from between 2009 and 2015 who received IV tirofiban therapy following PCI were retrospectively analyzed. All patients had received maintenance tirofiban infusion (0.15 µg/kg/min) after bolus dose and 600 mg clopidogrel. Percentage of patients undergoing drug eluting stent implantation procedure was 33.5%. Tirofiban was administered to all patients in bailout situation or for thrombotic complication after PCI. High-dose IV bolus group (25 µg/kg; n=140) was associated with greater ST segment resolution (66% vs. 50%, p=0.013) and reduced peak troponin release [12.4 ng/dL (range: 6.5-21.5 ng/dL) vs. 16.4 ng/dL (range: 10.1-27.4 ng/dL), p=0.001] compared with low-dose bolus group (10 µg/kg, n=131). Cardiovascular event rates were similar between groups at in-hospital, 1-month, and 6-month follow-up (p=1.000, 1.000, and 0.287, respectively). Percentage of patients with post-procedural Thrombolysis in Myocardial Infarction (TIMI) grade III flow, major, and minor bleeding were similar (p=0.085, 1.000, and 0.965, respectively). Use of high-dose IV bolus tirofiban in addition to aspirin and high-dose clopidogrel improves ST segment resolution, reduces infarct size, and does not increase bleeding events in patients with ACS undergoing PCI compared with low-dose bolus. Angiographic measures and clinical endpoints were similar between groups.

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Disposition of carvedilol enantiomers in patients with liver cirrhosis: evidence for disappearance of stereoselective first-pass extraction.

The racemic drug carvedilol exerts its antihypertensive action through vasodilation and nonselective beta-blockade. The R(+)-enantiomer has twice (31.1%) the absolute bioavailability than the S(-) form (15.1%). The pharmacokinetics of the enantiomers were investigated after intravenous (i.v.) (12.5 mg in 1 h) and p.o. (25 mg) administration of racemic carvedilol in six patients with cirrhosis of the liver according to a randomized crossover design. Although the difference between areas under the curve of R(+) and S(-) were of borderline significance after i.v. administration but significant after oral administration, no difference existed between the absolute bioavailabilities of R(+) (83.7%) and S(-) (71.3%). The enantiomer ratio is similar after i.v. (1.3) and p.o. administration (1.6). In contrast to healthy subjects, the apparent volume of distribution of S(-) is about 90% greater than that of R(+) in patients. The renal excretion of carvedilol and of one of its major metabolites, carvedilol glucuronide, also exhibited stereoselective behavior, but in opposite directions. In patients with liver cirrhosis, stereoselective metabolism of carvedilol is still operative. However, probably because of portocaval shunts, the hepatic first-pass extraction is markedly reduced, eliminating the difference in bioavailability between the two enantiomers.

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Effects of oral Akkermansia muciniphila supplementation in healthy dogs following antimicrobial administration.

OBJECTIVE To measure effects of oral Akkermansia muciniphila administration on systemic markers of gastrointestinal permeability and epithelial damage following antimicrobial administration in dogs. ANIMALS 8 healthy adult dogs. PROCEDURES Dogs were randomly assigned to receive either A muciniphila (10⁹ cells/kg; n = 4) or vehicle (PBS solution; 4) for 6 days following metronidazole administration (12.5 mg/kg, PO, q 12 h for 7 d). After a 20-day washout period, the same dogs received the alternate treatment. After another washout period, experiments were repeated with amoxicillin-clavulanate (13.5 mg/kg, PO, q 12 h) instead of metronidazole. Fecal consistency was scored, a quantitative real-time PCR assay for A muciniphila in feces was performed, and plasma concentrations of cytokeratin-18, lipopolysaccharide, and glucagon-like peptides were measured by ELISA before (T0) and after (T1) antimicrobial administration and after administration of A muciniphila or vehicle (T2). RESULTS A muciniphila was detected in feces in 7 of 8 dogs after A muciniphila treatment at T2 (3/4 experiments) but not at T0 or T1. After metronidazole administration, mean change in plasma cytokeratin-18 concentration from T1 to T2 was significantly lower with vehicle than with A muciniphila treatment (-0.27 vs 2.4 ng/mL). Mean cytokeratin-18 concentration was lower at T1 than at T0 with amoxicillin-clavulanate. No other significant biomarker concentration changes were detected. Probiotic administration was not associated with changes in fecal scores. No adverse effects were attributed to A muciniphila treatment. CONCLUSIONS AND CLINICAL RELEVANCE Detection of A muciniphila in feces suggested successful gastrointestinal transit following oral supplementation in dogs. Plasma cytokeratin-18 alterations suggested an effect on gastrointestinal epithelium. Further study is needed to investigate effects in dogs with naturally occurring gastrointestinal disease.

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Efficacy and safety of tacrolimus in Osserman grade III and Osserman grade IV Myasthenia Gravis.

A retrospective observational cohort study was conducted to evaluate the efficacy and safety of tacrolimus in Osserman grade III and Osserman grade IV myasthenia gravis (MG) patients. MG patients admitted to the First Affiliated Hospital of Guangzhou University of Chinese Medicine between June 2011 and January 2017 with grade III and grade IV according to the modified Osserman scale were recruited and received a telephone follow-up in September 2017. Patients treated with tacrolimus plus prednisone were compared with those treated without tacrolimus. The efficacy of tacrolimus was assessed using MG-activities of daily living (MG-ADL) score, Osserman classification, Myasthenia Gravis Foundation of America (MGFA) post intervention status (PIS), the number of hospitalizations, the number of myasthenic crises and deaths. The adverse drug effects of tacrolimus were monitored. A total of 124 patients were included. The tacrolimus group had a significantly lower MG-ADL score than the control group at follow-up (1.90 ± 2.27vs 2.97 ± 2.78, p = 0.029). The difference of MG-ADL score between baseline and after follow-up was significantly greater in the tacrolimus group than the control group (-7.20 ± 2.95 vs -5.52 ± 2.91, p =  0.003). Fewer patients were hospitalized in the tacrolimus group (p =  0.011). The Osserman classification, MGFA PIS, the number of myasthenic crises and deaths did not differ significantly between the two groups. Nineteen patients in the tacrolimus group had adverse drug reactions, but no severe adverse effects appeared. Our study suggested that tacrolimus could be an effective and safe treatment for Osserman grade III and Osserman grade IV MG patients.

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Modified BFM protocol for childhood acute lymphoblastic leukemia: a retrospective analysis.

Childhood acute lymphoblastic leukemia (ALL) has a 5-year disease-free survival (DFS) of more than 70%. This fact is not reflected in developing countries due to the lack of proper supportive care. A modified version of the standard Berlin-Frankfurt-Munich (BFM) protocol for pediatric ALL was developed to achieve balance between toxicity and favorable response rates. Modification included a dose reduction of asparaginase and methotrexate during the consolidation and reinduction phase. Forty-two patients younger than 15 years of age were put on the modified BFM protocol between November 1990 and November 1993. Thirty-nine patients were 2-10 years of age and 3 were older than 10 years. Male to female ratio was 3.2:1. 71.4% had L1 and 28.6% had L2 morphology. Univariate analysis factors revealed central nervous system (CNS) involvement and late complete remission (CR) during induction as poor prognostic factors. In multivariate analysis, CNS disease (P < 0.0083) was the only prognostic variable for prolonged DFS. All patients went into CR. Eleven patients have relapsed. Life table analysis of these patients shows a 59.4% probability of overall survival (OS) and a 52.5% probability of DFS at 48 months.

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Clinical performance of fluticasone propionate nasal drops.

The efficacy and safety of fluticasone propionate (FP) nasal drops were investigated in two multicentre, randomized, placebo-controlled trials. Patients received FP 400 microg once or twice daily for 12 weeks and then FP 400 microg once daily for a further 12 weeks. FP 400 microg significantly reduced polyp size and improved peak nasal inspiratory flow, rhinitis symptoms and sense of smell when administered twice daily. Significant reductions in polyp size were not achieved with once daily administration, but clinical benefits were observed for peak nasal inspiratory flow. Both dosing regimens were well tolerated, with an overall incidence of adverse events which was similar to placebo.

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