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Evaluation of omeprazole in reflux oesophagitis.

In patients with reflux disease, pH monitoring has shown that omeprazole virtually eliminates oesophageal exposure to a pH of less than 4. Motility studies concurrent with pH monitoring have indicated that reflux continues on omeprazole, its effect on acid exposure being entirely dependent on elevation of gastric pH. Omeprazole and placebo have been compared in 64 patients with erosive or ulcerative oesophagitis; the 4-week healing rates were 81% with omeprazole, 20 mg or 40 mg daily, and 6% with placebo. The efficacies of omeprazole at doses of 20 mg and 40 mg daily, were then compared in 164 patients. At 4 weeks, oesophagitis was healed in 70% and 82% of patients for the 20 mg and 40 mg doses respectively (p = 0.05). Eight-week healing rates (79% for 20 mg and 85% for 40 mg) did not differ significantly. Symptom response was excellent for both doses. Relapse of oesophagitis was determined over 6 months for patients healed with omeprazole. Relapse was shown to occur in 88 of 107 patients by 6 months. Omeprazole is a highly effective treatment for erosive/ulcerative peptic oesophagitis, 40 mg daily being marginally superior to 20 mg. Relapse is almost inevitable within 6 months of cessation of therapy.

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Impact of Cytochrome P450 2C19*2 and *3 on Clopidogrel Loading Dose in Saudi Patients with Acute Coronary Syndrome.

Emerging evidence shows that clopidogrel is greatly affected by nonfunctioning alleles measured by P2Y12 or platelet reactivity units (PRU). Cardiac events during short in-hospital stays have been inconclusively suggested as the main causes of discrepancies. Evaluate the impact of CYP2C19 allele *2 and allele *3 on PRU and the potential clinical consequences of such interaction. To establish a rough estimation for the safe PRU limits for short inhospital stay following PCI. A short-term experimental study was conducted with 90 patients who underwent coronary angioplasty with drug eluting stents at the Prince Sultan Cardiac Center, Buraidah. All the patients received an initial loading dose of 300 mg clopidogrel, followed by 75 mg daily. Blood samples were used for DNA extraction for cytochrome P450 (CYP) and realtime polymerase chain reaction (PCR) was used for genotyping. PRU and inhibition rate were tested by Verifynow®. All in-hospital cardiac events were recorded until patients were discharged. Genotypes 1/1, 2/2, and 1/2 were expressed by 60, 28, and two patients (67, 32, and 3%), respectively. The PRU of the female patients was significantly higher than that of the male patients was (255.6 ± 68.8 and 177.7 ± 66.6, p = 0.000, respectively). There was no significant difference in PRUs (193 ± 79 and 212 ±55.4, respectively, p = 0.349), nor inhibition (17.9 ± 18.80 and 13.88 ± 11.5, p = 0.135) in wild and resistant variants, respectively. We only reported one cardiac in-thrombosis events. Genotype differences may not explain variations in the PRU of patients during short-term in-hospital stays. Although it is difficult to confirm, 117-267 units may be a safe PRU range for such patients, with emphasis on attaining higher PRU values in females.

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Amoxycillin/clavulanic acid: the effect of probenecid.

The effect of probenecid on the combination of amoxycillin/clavulanic acid has been compared with the effect on amoxycillin alone and it has been shown that probenecid, whilst producing its expected effect on amoxycillin, did not affect the clavulanic acid concentration of the combination. A possible minor role for tubular secretion of clavulanic acid is discussed.

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Is eradication sufficient to heal gastric ulcers in patients infected with Helicobacter pylori? A randomized, controlled, prospective study.

In Helicobacter pylori infection, the effect of short-term triple therapy with proton pump inhibitor plus two antibiotics on gastric ulcer healing is not well known. To compare 1-week triple therapy with 8-week proton pump inhibitor therapy on gastric ulcer healing in infected patients. We randomly assigned 120 patients with H. pylori and gastric ulcers to proton pump inhibitor plus amoxicillin and clarithromycin for 1 week (n = 61) or proton pump inhibitor alone for 8 weeks (n = 59), with endoscopic assessment of ulcer healing 8 weeks after the start of treatment. Triple therapy eradicated H. pylori in 51 patients [intention-to-treat, 84%; 95% confidence interval (CI), 75-93%]. At 8 weeks, gastric ulcers were healed in 30 patients given triple therapy (49%; 95% CI, 37-62%) and in 49 patients given proton pump inhibitor (83%; 95% CI, 73-93%, P < 0.001). Healing rates in the triple therapy and proton pump inhibitor-only groups were 89% and 100%, respectively, for ulcers of < 1.0 cm in diameter, 54% and 77% for ulcers of 1.0 to < 1.5 cm in diameter, and 5% and 77% (P < 0.001) for ulcers of > or = 1.5 cm in diameter. One-week triple therapy healed most ulcers of < 1.0 cm, but not ulcers of > or = 1.5 cm. Short-term therapy is effective for gastric ulcers of < 1.0 cm, but, for larger ulcers, follow-up therapy to suppress acid is needed.

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Long-term safety of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder: an open-label, dose-titration, 1-year study.

To evaluate the long-term safety of OROS methylphenidate in the management of attention-deficit/hyperactivity disorder (ADHD) in adults. This multicenter, open-label, dose-titration, flexible dose study enrolled adults with ADHD for 6 or 12 months of treatment with OROS methylphenidate. Dosing began at 36 mg/d, with titration in 18-mg increments every 7 days until a predefined outcome (efficacy threshold, maximum dosage of 108 mg/d, or limiting adverse event). Dose reduction occurred for prespecified reasons, and the subjects discontinued if unable to tolerate 36 mg/d. Assessments included ADHD symptoms, adverse events, vital signs, and laboratory results. A total of 550 subjects received treatment (52% were men; mean age, 39 years; range, 18-65 years), and 57% (146/258) and 44% (129/292) completed their 6 or 12 months of treatment with mean durations of 128 and 213 days, respectively. The final prescribed dosages were 36 mg/d (22.4%), 54 mg/d (25.1%), 72 mg/d (22.0%), 90 mg/d (17.1%), and 108 mg/d (13.5%). Modest increases from baseline to final visit were observed in mean systolic (2.6 mm Hg) and diastolic (1.9 mm Hg) blood pressure and pulse (4.1 beats per minute). The mean weight decreased by 2.3 kg. No clinically meaningful changes in laboratory values or electrocardiogram parameters were observed other than increased heart rate. Most common adverse events included decreased appetite (26.7%), headache (24.0%), and insomnia (20.7%). No serious adverse event was considered related to study medication. Several measures of efficacy indicated improvement during the study. OROS methylphenidate, in the flexible dosage range from 36 to 108 mg/d, was well tolerated for up to 1 year in adults with ADHD.

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[Ulcer healing through the elimination of Helicobacter pylori: is a week of therapy enough?].

To test whether one week's triple therapy with omeprazole and two antibiotics is enough to induce healing of a peptic (gastric and/or duodenal) ulcer. 112 Patients (73 males, 39 females; median age 55 [18-88] years) proven by culture or histology to have an Helicobacter (H.) pylori infection and uncomplicated peptic (gastroduodenal) ulcer. For one week they received omeprazole (20 mg once or twice daily) plus two antibiotics (clarithromycin/metronidazole, clarithromycin/tetracycline, clarithromycin/amoxycillin or amoxycillin/metronidazole) to eradicate H. pylori. No further anti-ulcer treatment was given subsequently. Healing of the ulcer and H. pylori status were checked by the urease test, culture and histology (endoscopic biopsy) 4 weeks later. The 5-week ulcer healing rate was 94.6% (95% confidence interval: 89-98%). Persisting ulcers (n = 6) were associated with either treatment with aspirin or nonsteroidal antiinflammatory drugs (n = 3), persistent H. pylori infection (n = 2) or persistent H. pylori infection plus treatment with aspirin (n = 1). The ulcer healing rate was significantly higher in patients with eradicated infection than in those with posttherapy persistence of H. pylori (97.0 vs. 76.9%; P = 0.02). There were no significant differences after 5 weeks between patients with duodenal and those with gastric ulcer (97.4 vs. 89.3%). One-week effective eradication treatment is adequate to induce healing of H. pylori-positive peptic ulcers. Anti-ulcer treatment after eradication of H. pylori should be considered only if the patient is receiving treatment with ulcerogenic drugs or continues to have symptoms.

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Predictors of duloxetine versus other treatments among veterans with diabetic peripheral neuropathic pain: a retrospective study.

This study used medical and pharmacy records from the Veterans Affairs (VA) health system to explore the predictors of duloxetine versus other treatments for patients with diabetic peripheral neuropathic pain (DPNP). The electronic medical and pharmacy records from January 2004 to December 2008 were requested from the Veterans Integrated Service Network 16 data warehouse. All select patients received either duloxetine or other treatments [tricyclic antidepressants (TCAs), venlafaxine, gabapentin, and pregabalin] over the study period, with the first dispense date of the index agent as the index date. All patients must have 1(+) prior DPNP diagnosis (ICD-9-CM: 250.6x or 357.2), but no diagnoses of prior depression (ICD-9-CM: 296.2, 296.3, 300.4, 309.1, or 311.0), fibromyalgia (ICD-9-CM: 729.1), or neuralgia (ICD-9-CM: 729.2). Logistic regression was used to examine the predictors of receiving duloxetine versus other treatments, controlling for demographics, comorbidities, prior pain level, prior use of other medications, and opioid use. The analytical sample included 2,694 patients (duloxetine cohort, n = 216; other-treatment cohort, n = 2,478). Prior uses of gabapentin (odds ratio [OR] = 13.66, 95% confidence interval [CI]: 9.70-19.24), TCAs (OR = 5.40, 95% CI: 3.73-7.82), or venlafaxine (OR = 3.67, 95% CI: 1.67-8.06) were strong predictors of duloxetine. Other comorbidities associated with duloxetine were anxiety (OR= 2.08, 95% CI: 1.40-3.08), cerebrovascular disease (OR = 1.44, 95% CI: 1.01-2.07), and substance abuse (OR = 2.11, 95% CI: 1.10-4.03). Prior opioid users were 1.47 (95% CI: 1.02-2.12) times as likely to receive duloxetine as those without prior opioid use. Patients with self-reported severe pain were 1.66 (95% CI: 1.11-2.50) times as likely to receive duloxetine as those with no pain reported. DPNP patients in the VA healthcare system with prior other treatment use, select comorbid conditions, prior substance abuse, prior opioid use, and higher pain level were more likely to receive duloxetine.

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Study of Optimal Replacement of Thyroxine in the ElDerly (SORTED): protocol for a mixed methods feasibility study to assess the clinical utility of lower dose thyroxine in elderly hypothyroid patients: study protocol for a randomized controlled trial.

The population of the UK is ageing. There is compelling evidence that thyroid stimulating hormone distribution levels increase with age. Currently, in UK clinical practice elderly hypothyroid patients are treated with levothyroxine to lower their thyroid stimulating hormone levels to a standard non-age-related range. Evidence suggests that mortality is negatively associated with thyroid stimulating hormone levels. We report the protocol of a feasibility study working towards a full-scale randomized controlled trial to test whether lower dose levothyroxine has beneficial cardiovascular outcomes in the oldest old. SORTED is a mixed methods study with three components: SORTED A: A feasibility study of a dual-center single-blinded randomized controlled trial of elderly hypothyroid patients currently treated with levothyroxine. Patients will be recruited from 20 general practices and two hospital trust endocrine units in Northumberland, Tyne and Wear. Target recruitment of 50 elderly hypothyroid patients currently treated with levothyroxine, identified in both primary and secondary care settings. Reduced dose of levothyroxine to achieve an elevated serum thyroid stimulating hormone (target range 4.1 to 8.0 mU/L) versus standard levothyroxine replacement (target range 0.4 to 4.0 mU/L). Using random permuted blocks, in a ratio of 1:1, randomization will be carried out by Newcastle Clinical Trials Unit. Study feasibility (recruitment and retention rates and medication compliance), acceptability of the trial design, assessment of mobility and falls risk, and change in cardiovascular risk factors. Qualitative study using in-depth interviews to understand patients' willingness to take part in a randomized controlled trial and participants' experience of the intervention. Retrospective cohort study of 400 treated hypothyroid patients aged 80 years or over registered in 2008 in primary care practices, studying their 4-year cardiovascular outcomes to inform the power of SORTED II. This is a study to evaluate the feasibility of conducting a randomized controlled trial in elderly hypothyroid patients in general practice and hospital settings. The results will inform the design of the definitive SORTED II trial to evaluate the effects of lower dose thyroxine in elderly hypothyroid patients. Current Controlled Trials ISRCTN16043724.

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Multiple-dose pharmacokinetics and safety of amoxicillin/clavulanate in healthy elderly subjects.

Amoxicillin/clavulanate is a widely used oral formulation of penicillin combined with a β-lactamase inhibitor. When using amoxicillin/clavulanate in the elderly, the risk of adverse drug reaction may be greater. This study aimed to evaluate the pharmacokinetics (PKs) and safety of multiple-dose amoxicillin/clavulanate administration in healthy elderly subjects and to compare the observed PK profiles with those in healthy younger adults. An open-label, one-sequence, multiple administration study was conducted in 16 healthy elderly subjects. Subjects orally received amoxicillin and clavulanate 750/187.5 twice daily for 9 days. For PK analysis, serial blood samples were collected up to 12 hours after the last administration of amoxicillin/clavulanate. The demographic and PK data of this study were compared to those of healthy young adults from a separate study with a similar design. Safety assessments including clinical laboratory tests, physical examination, vital signs, and adverse event (AE) monitoring were performed throughout the study. All AEs were mild, and no serious AEs were reported in this study. The systemic exposure of amoxicillin and clavulanate was ~ 90% and 60% higher, respectively, in the elderly subjects than in the younger subjects. However, the time required to reach maximum concentration at steady state and the elimination half-life were similar in the two age groups. Although multiple administration of amoxicillin/clavulanate 750/187.5 mg was safe and well-tolerated, the systemic exposure of amoxicillin and clavulanate was higher in elderly subjects than in younger subjects.

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Treatment of chronic stable angina with carvedilol in comparison with nifedipine s.r.

Carvedilol 25 mg b.d. was compared with nifedipine s.r. 20 mg b.d. for subchronic treatment of patients with chronic stable angina. After washout and placebo run-in, 163 patients were randomly and double-blindly allocated to one of the two treatment groups. Two symptom-limited seated bicycle exercise tests were performed on placebo in order to confirm stable baseline conditions. After 4 weeks of active treatment, a further exercise test was performed in the morning, 12 h after the preceding dose. Diary cards were kept by the patients throughout the trial in order to record angina attacks and glyceryl trinitrate consumption. Carvedilol seemed to be somewhat more effective than nifedipine s.r. for improving exercise tolerance and exercise time to onset of angina and 1 mm ST-segment depression. Although there were highly statistically significant differences vs placebo, the two treatment groups did not differ significantly. No difference between treatment with carvedilol and nifedipine s.r. was found regarding angina symptoms and glyceryl trinitrate consumption during daily life. Adverse events were less frequently reported in the carvedilol group than in the nifedipine group. Generally, however, both agents were well tolerated. Carvedilol therapy for chronic stable angina seems to be both efficacious and safe.

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Hyperbaric oxygen therapy in treatment of sudden sensorineural hearing loss: finding for the maximal therapeutic benefit of different applied pressures.

We compared the efficacy of hyperbaric oxygen (HBO2) therapy used in the treatment of sudden sensorineural hearing loss (SSNHL) as a supplementary therapy to the first-line medical treatment according to the different applied pressures used in HBO2 treatment while maintaining the same number of sessions, periodicity and exposure times. We evaluated data from 115 patients suffering from SSNHL within seven days of hearing loss: 35 patients received the standard treatment protocol (control group), and 80 individuals were treated with additional application of HBO2 therapy pressured to 2.0 ATA (H2.0; n=49) or 2.5 ATA (H2.5; n=31), respectively. Treatment success was assessed using pre- and post-treatment audiograms. We found significant differences in both HBO2 groups compared to the control group. In low frequencies the most significant differences can be seen in both H2.0 and H2.5. In spoken speech frequencies only the H2.0 group was statistically significant. In high frequencies the therapeutic benefits were the lowest. Furthermore, we found a notable difference in the therapeutic effect of HBO2 therapy according to the different applied pressure. At low frequencies, the use of 2.5 ATA pressure was more efficient. However, in the higher frequency ranges, the better hearing gains were obtained at the 2.0 ATA pressure. Our results support the possibility of optimizing treatments individually, depending on the type and frequency range of hearing impairment (shape of the audiogram) in favor of using the 2.0 ATA. This is important in terms of an individual approach to each patient as well as to minimize the burden of a patient in order to obtain the maximum therapeutic effect.

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Methylphenidate bioavailability in adults when an extended-release multiparticulate formulation is administered sprinkled on food or as an intact capsule.

To determine the single-dose bioavailability of 20-mg Metadate CD (methylphenidate HCI, USP) Extended-Release Capsules sprinkled onto 1 level tablespoon (15 mL) of applesauce relative to an intact capsule under fasted conditions in healthy adults. This was a single-center, open-label, single-dose, randomized, two-way crossover study with a 6-day washout period between doses, in healthy male and female subjects (N= 26), aged 21-40 years. Plasma concentration-time data for methylphenidate were used to calculate the pharmacokinetic parameters for each treatment. The pharmacokinetic profile for Metadate CD exhibited biphasic release characteristics with a sharp initial slope and a second rising portion. For Cmax (maximum observed concentration), AUC(0-infinity) (area under the plasma concentration curve from time 0 to infinity) and AUC(0-infinity) (area under the plasma concentration curve from time 0 to the last measurable time point), the geometric least squares mean ratios and 90% confidence intervals were within the 80% to 125% confidence interval for bioequivalence. Adverse events were similar to those reported for methylphenidate. The bioavailability of methylphenidate was not altered when Metadate CD capsules were administered by sprinkling their contents onto a small amount of applesauce.

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MACOP-B treatment for advanced stage diffuse large cell lymphoma: a multicenter Italian Study.

Seventy-one patients with advanced stage diffuse large cell lymphoma were treated with MACOP-B. Sixty-nine per cent of patients achieved a complete response (CR), 10% a partial remission, while 11% had no response and 10% died because of toxicity. The CR rate was adversely affected by immunoblastic type, poor performance status and bone marrow involvement. Two-year survival for all 71 patients was 55% and 2-year disease-free survival (DFS) for the 49 CRs was 73%. Relapses were lower (P less than 0.05) in patients achieving CR in 8 weeks or less (DFS 83% vs. 59%) and in patients without tumor bulk (DFS 87% vs. 54%). Overall toxicity was acceptable with mucositis proving to be the most frequent severe side-effect. However, treatment-related deaths were unacceptably high in patients over 59 years of age (30% vs. 7%). Thus for the elderly MACOP-B is potentially lethal and must be used cautiously. These preliminary results confirm the effectiveness of MACOP-B. The delay of response and/or the presence of tumor bulk may be important prognostic factors in identifying a subset of poor risk patients with a high incidence of relapse.

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Overdose Risk Associated with Opioid Use upon Hospital Discharge in Veterans Health Administration Surgical Patients.

To determine an association between opioid use upon hospital discharge (ongoing and newly started) in surgical patients and risks of opioid overdose and delirium for the first year. Retrospective, cohort study. Population-level study of Veterans Health Administration patients. All Veterans Health Administration patients (N = 64,391) who underwent surgery in 2011, discharged after one or more days, and without a diagnosis of opioid overdose or delirium from 90 days before admission through 30 days postdischarge (to account for additional opioid dosing in the context of chronic use). Patients' opioid use was categorized as 1) no opioids, 2) tramadol only, 3) short-acting only, 4) long-acting only, 5) short- and long-acting. We calculated unadjusted incidence rates and the incidence rate ratio (IRR) for opioid overdose and drug delirium for two time intervals: postdischarge days 0-30 and days 31-365. We then modeled outcomes of opioid overdose and delirium for postdischarge days 31-365 using a multivariable extended Cox regression model. Sensitivity analysis examined risk factors for overdose for postdischarge days 0-30. Incidence of overdose was 11-fold greater from postdischarge days 0-30 than days 31-365: 26.3 events/person-year (N = 68) vs 2.4 events/person-year (N = 476; IRR = 10.80, 95% confidence interval [CI] = 8.37-13.92). Higher-intensity opioid use was associated with increasing risk of overdose for the year after surgery, with the highest risk for the short- and long-acting group (hazard ratio = 4.84, 95% CI = 3.28-7.14). Delirium (IRR = 10.66, 95% CI = 7.96-14.29) was also associated with higher opioid intensity. Surgical patients should be treated with the lowest effective intensity of opioids and be monitored to prevent opioid-related adverse events.

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[Investigation of adjuvant treatment for difficult weaning from mechanical ventilation].

To investigate the value of drug intervention for difficult weaning from mechanical ventilation. A prospective single-blind randomized controlled trial was conducted. 120 patients with difficult weaning from mechanical ventilation encountered in Department of Critical Care Medicine of Peking University Third Hospital from January 2008 to December 2013 were included, and the patients were divided into treatment group and control group according to random number table, with 60 cases in each group. Patients received furosemide therapy in the treatment group 3 days before weaning up to 48 hours after weaning in order to control negative liquid balance. Enema was given the day before weaning to reduce abdominal pressure. On the weaning day, all of the patients received nitroglycerin and beta blocker or cedilanid to prevent or control elevation of blood pressure and heart rate in the process of weaning. All patients in treatment group received anisodamine in small dosage 2 hours before extubation. The patients in control group received conventional treatment without drug intervention. Baseline indexes of two groups were compared, including the heart rate, respiration rate (RR), mean arterial pressure (MAP), pulse blood oxygen saturation (SpO₂), blood gas, hemoglobin (HG), albumin (ALB) and creatinine (Cr). The main reasons of difficulty in weaning, sedative and analgesic drug selection, presence of abdominal discomfort before weaning, interval between sputum suction before extubation, liquid balance at the beginning of the investigation and at time of weaning, 24 hours and 48 hours after weaning, failures of spontaneous breathing test (SBT), length of mechanical ventilation,length of ICU stay, and total length of mechanical ventilation and total length of ICU stay during hospitalization. There was no statistically significant difference in the heart rate, RR, MAP, SpO₂, blood gas, HG, ALB, Cr at the beginning of the investigation between the two groups. The main reasons for difficult weaning in both groups of patients were respiratory dysfunction, cardiac insufficiency, and central nervous system dysfunction. The use of propofol combined dexmedetomidine in the treatment group was more frequent than the control group [16.7% (10/60)vs. 1.7% (1/60), χ² = 8.107, P=0.004], and there was no statistically significant difference in the use of other combinations of sedative drugs between the two groups. Abdominal discomfort before weaning was milder in treatment group as compared with control group [10.0% (6/60) vs. 25.0% (15/60), χ² = 4.675, P=0.031]. The interval between sputum suction before extubation in the treatment group was significantly longer than that of the control group [hours: 1 (1, 2) vs. 1 (1, 1), Z=-2.209, P= 0.027]. SBT failure was less frequent in treatment group compared with control group [times: 0 (0, 1) vs. 1 (1, 2), Z=-6.561, P=0.000]. Liquid balance was better in the treatment group than the control group at time of weaning, 24 hours and 48 hours after weaning [at time of weaning: -567.71(-755.95,-226.41) vs. 1 256.76 (472.48, 1 796.63), Z=-9.038, P=0.000; 24 hours after weaning: -5.03 (-530.28, 245.09) vs. 342.28 (125.36, 613.25), Z=-4.711, P=0.000; 48 hours after weaning: 115.50 (-450.26,485.00) vs. 330.00 (16.25,575.25), Z=-1.932, P=0.053]. Compared with control group, length of mechanical ventilation [days: 1.0 (1.0, 2.0) vs. 2.0 (2.0, 3.0), Z=-6.545, P=0.000], ICU stay time [days: 3.0 (3.0, 4.0) vs. 4.0 (4.0, 5.0), Z=-6.545, P=0.000], and total length of mechanical ventilation [days: 8.0 (6.0,12.0) vs. 11.0 (8.0, 15.0), Z=-4.091, P=0.000] and total length of ICU stay during hospitalization [days: 12.5 (9.2, 19.0) vs. 17.0 (12.0, 29.5), Z=-2.722, P=0.000] were all significantly shorter in the treatment group. Adjuvant drugs therapy is helpful in patients weaning from the mechanical ventilation, and can shorten length of mechanical ventilation and ICU stay time. Propofol, combined dexmedetomidine, is helpful for weaning.

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Effects of atorvastatin on red-blood cell Na(+)/Li(+) countertransport in hyperlipidemic patients with and without hypertension.

To explore the effect of short-term cholesterol-lowering treatment with atorvastatin on erythrocyte sodium-lithium countertransport (Na(+)/Li(+) CT) activity. Group A consisted of 30 patients (14 men) with mild essential hypertension (systolic blood pressure (SBP), 140-159 mm Hg and/or diastolic BP, 90-99 mm Hg) and primary hypercholesterolemia low-density lipoprotein (LDL) cholesterol >4.1 mmol/l and triglycerides (TG) <2.8 mmol/l), group B of 30 normotensive patients (16 men) with primary hypercholesterolemia, while 37 (18 men) healthy volunteers comprised the control group. After a 6-week dietary lead-in, all eligible patients were prescribed 20 mg/day of atorvastatin. Anthropometric data, blood-pressure (BP) measurements and determinations of lipid, non-lipid metabolic parameters (including homeostasis model assessment index, (HOMA-IR)) and erythrocyte Na(+)/Li(+) CT activity were collected at baseline and after 12 weeks of treatment. At baseline Na(+)/Li(+) CT activity was significantly higher in group A and B compared with the control group and correlated directly with obesity indices, systolic and diastolic BP, total cholesterol, LDL-cholesterol, TG, apolipoprotein B (apoB), HOMA-IR, uric acid and inversely with high-density lipoprotein (HDL)-cholesterol and apoA1. Systolic and diastolic BP levels, HOMA-IR and Na(+)/Li(+) CT activity were significantly decreased after atorvastatin treatment in both patient groups. The reduction in Na(+)/Li(+) CT activity correlated with baseline Na(+)/Li(+) CT activity and the changes in HOMA-IR values. Short-term treatment with atorvastatin for patients with hypercholesterolemia, and with or without essential hypertension, is associated with a significant reduction in the erythrocyte Na(+)/Li(+) CT activity, BP levels and insulin resistance independent of concomitant changes in lipid parameters.

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[Comparative study of 2 antibiotic prophylactic protocols in oncologic surgery of the pharynx and larynx].

The use of antibiotic prophylaxis in oncological pharyngeal and laryngeal surgery has reduced the risk of postoperative wound infection, which decreases morbidity and health-care costs. We report the results of a prospective randomized study in our hospital comparing the effectiveness of two antibiotic protocols, amoxicillin-clavulanate and clindamycin plus gentamicin, both given for 24 hours, in patients who underwent clean-contaminated oncological surgery of the pharynx or larynx.

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Effects of ezetimibe coadministered with simvastatin on C-reactive protein in a large cohort of hypercholesterolemic patients.

This study assessed the effect of coadministration of ezetimibe and simvastatin on high sensitivity C-reactive protein (hs-CRP) in a large subject cohort (N=1089). Data were combined from two nearly identical prospective trials. After dietary stabilization, washout period, and placebo lead-in period, patients with baseline low-density lipoprotein cholesterol (LDL-C) > or =3.75-6.50 mmol/l and triglycerides (TG) < or =4.0 mmol/l were randomized to one of the following daily treatments for 12 weeks: ezetimibe 10 mg; simvastatin monotherapy (10, 20, 40, or 80 mg); ezetimibe 10mg plus simvastatin (10, 20, 40, or 80 mg); or placebo. The primary analysis was the percent change in hs-CRP for the pooled ezetimibe plus simvastatin versus simvastatin monotherapy cohorts. Ezetimibe coadministered with simvastatin more than doubled the hs-CRP reduction compared to simvastatin monotherapy (-33.3% versus -14.3%, p<0.01). At each individual simvastatin dose level, coadministration therapy exerted significant further incremental hs-CRP reductions compared to simvastatin monotherapy. Similar hs-CRP reductions with coadministered ezetimibe and simvastatin were observed in the major subgroups examined (coronary heart disease, gender, age, baseline LDL-C, and body mass index). In this large subject cohort, ezetimibe coadministered with simvastatin significantly reduced hs-CRP, suggesting a possible additional anti-inflammatory/anti-atherosclerotic action of combination therapy compared to simvastatin monotherapy.

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Inflammation-related gene polymorphisms and colorectal adenoma.

Chronic inflammation has been reported to be a risk factor for colorectal neoplasia. The propensity to mount an inflammatory response is modified by germ line variation in cytokine and other inflammation-related genes. We hypothesized that a proinflammatory genotype would be positively associated with colorectal adenoma, a precursor of colorectal cancer. We investigated the association of colorectal adenoma with 19 single nucleotide polymorphisms in a range of important proinflammatory (IL1B, IL6, IL8, TNF, and LTA) and anti-inflammatory (IL4, IL10, and IL13) cytokines and other inflammation-related genes (PTGS2 and PPARG) in a case-control study of risk factors for colorectal polyps in which all participants (ages 18-74 years) had undergone colonoscopy or sigmoidoscopy. The study sample comprised 244 cases of colorectal adenoma and 231 polyp-free controls. Compared with being homozygous for the common allele, heterozygosity at the IL1B -31 (C>T) locus was associated with an odds ratio (OR) for colorectal adenoma of 1.8 [95% confidence interval (95% CI), 1.2-2.9]. Homozygous carriers of the IL8 -251-A allele were at 2.7-fold increased risk of adenoma (95% CI, 1.5-4.9) compared with homozygosity for the common T allele, whereas carriage of at least one IL8 -251-A allele conferred a 1.5 increased odds of disease (95% CI, 1.0-2.4). Among non-nonsteroidal anti-inflammatory drug users, there was a statistically significant association between the IL10 -819-T/T genotype and adenoma compared with the common IL10 -819-C/C genotype (OR, 3.9; 95% CI, 1.1-13.6), which was not evident among nonsteroidal anti-inflammatory drug users (OR, 0.7; 95% CI, 0.3-1.5; P(interaction) = 0.01). These exploratory data provide evidence that polymorphic variation in genes that regulate inflammation could alter risk for colorectal adenoma.

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Compartment theory in Helicobacter pylori-associated gastric carcinogenesis.

The compartment theory has not been well investigated in gastric carcinogenesis. This study was aimed at examining the compartment alterations through the Helicobacter pylori (H. pylori)-related chronic gastritis-intestinal metaplasia-carcinoma sequence, and investigating the long-term effect of bacterial eradication on the compartment changes. Gastric biopsy specimens were obtained from subjects with H. pylori-negative normal mucosa (N = 12), H. pylori-positive non-metaplastic gastritis (N = 42), H. pylori-positive intestinal metaplasia (N = 21) and intestinal-type adenocarcinoma (N = 20). The specimens were immnostained for monocloncal antibodies against the proliferating cell nuclear antigen (PCNA) for proliferating analysis. Additionally, 50 patients with H. pylori-positive gastritis were enrolled to investigate the long-term effect of bacterial eradication on the compartment changes of gastric epithelium. The mean PCNA labeling indices (L.I.) of non-metaplastic gastritis, intestinal metaplasia and adenocarcinoma were significantly higher than that of normal mucosa (31.1, 49.2 and 40.7 vs. 21.4; p < 0.01, 0.001 and 0.001, respectively). The proliferating zone was principally located in the lower compartment of normal mucosa. In patients with intestinal metaplasia, there was a full expansion (phase 1 change) of proliferating zone to the middle compartment of gastric pits (ratio of L.I. between middle and lower compartment = 1.00). The proliferating cells were evenly distributed in adenocarcinoma (complete loss of compartmentalization). Eradiation of H. pylori led to a reversion of compartment changes of gastric epithelium in patients with chronic gastritis. H. pylori-related gastric carcinogenesis is a multistep process involving progressive alterations of proliferating activity as well as loss of compartmentalization. Eradication of H. pylori reverses the changes in growth kinetics of gastric epithelium.

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Tailored Helicobacter pylori eradication based on prior intake of macrolide antibiotics allows the use of triple therapy with optimal results in an area with high clarithromycin resistance.

the previous intake of macrolide antibiotics is associated with a failure to eradicate Helicobacter pylori (H. pylori) with clarithromycin-containing regimens. However, the standard triple therapy achieves eradication rates of over 90% in patients without a previous use of macrolides in our health area. The aim of this study was to evaluate the efficacy of an H. pylori eradication strategy based on the intake of macrolides by the patient during the previous years. one hundred and sixty-nine patients with H. pylori infection were prospectively included in the study. The electronic medical record of each patient was reviewed at the time of inclusion. Depending on their previous intake of macrolides, patients were assigned to one of two eradication regimens: group A) patients without a previous intake of macrolides received an optimized triple therapy for 14 days; and group B) patients with a previous intake of macrolides received bismuth quadruple therapy for ten days. ninety-one patients (53.84%) without a previous intake of macrolides received an optimized triple therapy (group A) and 78 patients (46.15%) with a previous intake of macrolides received bismuth quadruple therapy (group B). In group A, the H. pylori eradication rates were 90.11% in the intention-to-treat and 95.35% in the per-protocol analysis. In group B, the H. pylori eradication rates were 85.89% in the intention-to-treat and 98.5% in the per-protocol analysis. The overall eradication rates obtained using this strategy were 88.16% (95% CI: 82.32-92.02%) in the intention-to-treat and 96.75% (95% CI: 92.59-98.94%) in the per-protocol analysis. an H. pylori eradication strategy based on the intake of macrolides during the previous years achieves overall eradication rates close to 90% and allows the use of standard triple therapy in more than half of the patients from a health area with a high level of clarithromycin resistance.

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Long-term reduction of peripheral resistance with celiprolol and effects on left ventricular mass.

The antihypertensive efficacy of a new beta-blocker, celiprolol, was compared with that of a well established antihypertensive drug, metoprolol. Systemic and forearm haemodynamic effects were investigated using echocardiography and two-dimensional pulsed Doppler flowmetry, respectively. Twenty hypertensive patients completed the double-blind crossover randomized study. Each 6-week active treatment period was both preceded and followed by 2 weeks of placebo treatment such that the total duration of the study was 18 weeks. Despite comparable efficacy in reducing systolic and diastolic blood pressures by approximately 10% of the basal value, the two drugs differed in their systemic and haemodynamic effects. Celiprolol significantly decreased forearm peripheral resistance and total peripheral resistance. Cardiac output remained unchanged and forearm blood flow was increased. Metoprolol reduced cardiac output through a reduction in heart rate, but stroke volume was unaltered. Neither drug significantly modified cardiac performance, as evaluated by left ventricular circumferential fibre shortening and left ventricular ejection fraction. Differences in the systemic and regional haemodynamic effects of the two drugs could account for the different blood pressure response seen in some patients. There was no observable change in left ventricular wall thickness or left ventricular mass. These results confirm previous reports which demonstrate that antihypertensive treatment with beta-blockers does not reduce left ventricular mass in patients with a left ventricle of normal size. It is generally accepted, however, that the ability of beta-blockers to reverse left ventricular hypertrophy is unrelated to the individual pharmacological characteristics of each agent.

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Carvedilol for prevention of restenosis after directional coronary atherectomy : final results of the European carvedilol atherectomy restenosis (EUROCARE) trial.

In addition to its known properties as a competitive, nonselective beta and alpha-1 receptor blocker, carvedilol directly inhibits vascular myocyte migration and proliferation and exerts antioxidant effects that are considerably greater than those of vitamin E or probucol. This provides the basis for an evaluation of carvedilol for the prevention of coronary restenosis. In a prospective, double-blind, randomized, placebo-controlled trial, 25 mg of carvedilol was given twice daily, starting 24 hours before scheduled directional coronary atherectomy and continuing for 5 months after a successful procedure. The primary end point was the minimal luminal diameter as determined during follow-up angiography 26+/-2 weeks after the procedure. Of 406 randomized patients, 377 underwent attempted atherectomy, and in 324 (88.9%), a </=50% diameter stenosis was achieved without the use of a stent. Evaluable follow-up angiography was available in 292 eligible patients (90%). No differences in minimal luminal diameter (1.99+/-0.73 mm versus 2.00+/-0.74 mm), angiographic restenosis rate (23.4% versus 23.9%), target lesion revascularization (16.2 versus 14.5), or event-free survival (79.2% versus 79.7%) between the placebo and carvedilol groups were observed at 7 months. The maximum recommended daily dose of the antioxidant and beta-blocker carvedilol failed to reduce restenosis after successful atherectomy. These findings are in contrast to those of the Multivitamins and Probucol Trial, which raises doubts regarding the validity of the interpretation that restenosis reduction by probucol was via antioxidant effects. The relationship between antioxidant agents and restenosis remains to be elucidated.

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Brief-duration rituximab/chemotherapy followed by maintenance rituximab in patients with diffuse large B-cell lymphoma who are poor candidates for R-CHOP chemotherapy: a phase II trial of the Sarah Cannon Oncology Research Consortium.

Patients with diffuse large B-cell lymphoma (DLBCL) who are very elderly or have poor performance status are difficult to treat with a full course of R-CHOP (rituximab plus cyclophosphamide/doxorubicin/vincristine/ prednisone) therapy. In this phase II trial, we treated this group of patients with a novel regimen containing 3 courses of rituximab/chemotherapy followed by maintenance rituximab. Patients with newly diagnosed stage II-IV DLBCL were eligible if they were considered poor candidates for 6-8 cycles of R-CHOP therapy. Patients who were eligible for anthracycline therapy received 3 cycles of rituximab plus cyclophosphamide/ mitoxantrone/vincristine/prednisone (CNOP); the remainder of patients received R-CVP (rituximab plus cyclophosphamide/ vincristine/prednisone). Patients without progression after completion of 3 cycles received 4 courses of maintenance rituximab (375 mg/m2 weekly x 4, repeated every 6 months) for 24 months. Between May 2003 and July 2007, 51 patients were enrolled. The median age was 78 years, and 43% of patients were > 80 years of age. Nineteen patients (37%) had Eastern Cooperative Oncology Group performance status of 2, and 72% had high-intermediate or high-risk International Prognostic Index scores. After a median follow-up of 48 months, the 2-, 3-, and 4-year progression-free survival rates are 71%, 65%, and 56%, respectively. The 2-, 3-, and 4-year overall survival rates are 72%, 67%, and 67%, respectively. Treatment was well tolerated, with few severe toxicities and no treatment-related deaths. This abbreviated course of rituximab/chemotherapy, followed by maintenance rituximab, was active and well tolerated in these very elderly patients. Brief-duration rituximab/chemotherapy as well as maintenance rituximab merit further evaluation in this setting.

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Safety and efficacy of agomelatine in children and adolescents with major depressive disorder receiving psychosocial counselling: a double-blind, randomised, controlled, phase 3 trial in nine countries.

Major depressive disorder is a severe illness that frequently manifests before the age of 18 years, often recurring later in life. Paediatric medical treatment options are scarce. The melatonin receptor agonist and 5-hydroxytryptamine_2C receptor antagonist agomelatine is used to treat adults, and could offer a new therapeutic option for paediatric patients. Therefore, we aimed to investigate the short-term antidepressant efficacy and safety of agomelatine in children and adolescents with major depressive disorder. We performed a 12 week, randomised, double-blind, parallel-group, multicentre, phase 3 trial in 46 specialist psychiatric units or centres in Bulgaria, Finland, Hungary, Poland, Romania, Russia, Serbia, South Africa, and Ukraine. Participants (aged 7-17 years) were eligible if they were unresponsive to psychosocial therapy during the 3-week run-in period (Children's Depression Rating Scale-revised [CDRS-R] score of ≥45). Ethnicity was not recorded. We investigated short-term antidepressant efficacy of agomelatine (10 mg or 25 mg per day) versus placebo with an active control (fluoxetine 10-20 mg depending on symptom severity) after 12 weeks of treatment in children (aged 7-11 years) and adolescents (12-17 years) with major depressive disorder. Patients were randomly assigned (1:1:1:1) to agomelatine 10 mg, agomelatine 25 mg, placebo, or fluoxetine via an interactive response system with permuted-block randomisation. Standardised manualised psychosocial counselling, developed for this trial, was initiated from selection and continued throughout the study, including the open-label extension. All people involved in the conduct of the clinical trial and patients were masked to treatment allocation. Study outcomes were measured using standardised interviews at each study visit. The primary endpoint was change in CDRS-R raw score from baseline to week 12. This study is registered with EudraCT, 2015-002181-23. Between Feb 23, 2016, and Jan 14, 2020, 466 individuals were assessed for eligibility and of 400 included patients, 396 (247 [62%] girls, 149 [38%] boys; mean age 13·7 years [SD 2·7]) were analysed (full analysis set). The primary objective was met; 25 mg/day agomelatine (n=94, with n=102 receiving 10 mg/day) resulted in an improvement versus placebo (n=101) in CDRS-R raw score of 4·22 (95% CI 0·63-7·82; p=0·040) at 12 weeks, with a similar effect for fluoxetine (n=99), establishing assay sensitivity. The overall effect was confirmed in adolescents (n=317), but not in children (n=79). No unexpected safety signals were observed with agomelatine, with no significant weight gain or effect on suicidal behaviours. This first study in a paediatric population supports the efficacy of 25 mg/day agomelatine, in addition to psychosocial counselling, in treating adolescent patients with major depressive disorder, with no unexpected safety signals. This medication could provide another option in the limited psychopharmaceutical repertoire for management of major depressive disorder. Servier. VIDEO ABSTRACT.

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Ambulatory blood pressure monitoring for the assessment of nicardipine as a third drug in severe essential hypertension.

The antihypertensive efficacy of sustained-release nicardipine compared to placebo as third-line therapy has been assessed by ambulatory blood pressure monitoring in severely hypertensive patients with clinically unsatisfactory blood pressure control on 50 mg hydrochlorothiazide o.d. and 75 mg captopril b.d. Forty-two patients, 31 m and 11 f, with supine diastolic blood pressure 95-115 mm Hg after a 4 week run-in period on open hydrochlorothiazide and captopril, were randomly allocated to sustained-release nicardipine 45-60 mg/d or placebo. At a visit to the clinic blood pressure and heart rate were measured 12 h after the evening dose by a trained observer unaware of the treatment. Twenty-four hour ambulatory monitoring was performed at the end of baseline and after 8 weeks of blinded medication. There was no significant change in BD at the visit or on ambulatory monitoring in the placebo treated patients. In contrast, nicardipine produced a significant reduction in both blood pressures without affecting heart rate. Nicardipine also decreased the mean 24-h blood pressure by 14/10 mm Hg in patients whose clinical hypertension had been confirmed by ambulatory blood pressure monitoring but by only 3/2 mm Hg in ambulant patients who were normotensive on two-drug therapy. One patient experienced an episode of severe symptomatic hypotension while on nicardipine. Otherwise, the numbers and percentages of patients from each group reporting adverse experiences were similar. It is concluded that nicardipine appears to be an effective antihypertensive agent when used as third line therapy with diuretics and angiotensin converting enzyme inhibitors in patients with severe hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

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Case report of successful treatment of pallid breath-holding spells with glycopyrrolate.

Breath-holding spells are a common childhood disorder that typically present before 12 months of age. Whereas most cases are benign, some patients have very severe cases associated with bradycardia that can progress from asystole to syncope and seizures. Treatment studies have implicated the use of several therapies, such as oral iron, fluoxetine, and pacemaker implantation. This is a retrospective study of patients treated with glycopyrrolate for pallid breath-holding spells. Clinical data from 4 patients referred to pediatric cardiology who saw therapeutic benefit from treatment using glycopyrrolate were reviewed to evaluate for clinical response to the drug. Two twin patients, whose symptoms began at 5 months of age, experienced a decrease in breath-holding frequency after 1 month. A patient diagnosed at 7 months of age experienced a decrease in frequency of spells. A patient diagnosed at 10 months of age reported cessation of syncope shortly after initiation of glycopyrrolate and complete resolution of breath-holding spells during prolonged treatment. This case study of 4 patients with pallid breath-holding offers evidence that glycopyrrolate may be beneficial in treating breath-holding spells and has a safer side-effect profile than pacemaker implantation.

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The Stanford experience with combined procarbazine, Alkeran and vinblastine (PAVe) and radiotherapy for locally extensive and advanced stage Hodgkin's disease.

This report describes the efficacy and toxicity of PAVe (procarbazine, Alkeran, vinblastine) and irradiation (RT) in the management of 159 patients with locally extensive or advanced stage Hodgkin's disease (HD) at Stanford University. Patients received six courses of chemotherapy alternating with RT. The extent of RT and the schedule of treatment varied according to the stage of disease. About 2/3 of patients received PAVe/RT in the setting of prospective, randomized clinical trials. The rate of complete response was 93%. With a median follow-up of seven years (range 2-17), the 15 year actuarial freedom from progression (FFP) is 78% and overall survival is 75%. Ten-year FFP by stage is: 80% for locally extensive stage II, 90% for stage IIIA and 70% for stage IIIB. Excellent and equal results were attained with PAVe/RT vs. MOP(P) (mustard, Oncovin, procarbazine with or without prednisone)/RT in the randomized combined modality studies. Progression or recurrence was documented in 30 patients and was more common in irradiated sites. PAVe was well tolerated acutely. There were no treatment related fatalities. Twenty-three (14%) patients were admitted to the hospital for neutropenic fever. Five second malignancies have occurred after PAVe/RT only: one myelodysplastic syndrome, one acute myelogenous leukemia, one non-Hodgkin's lymphoma and two solid tumors including a case of non-small cell lung cancer and an in situ carcinoma of the cervix. Three patients died from myocardial infarction several years after the completion of treatment. These mature data show that PAVe/RT is effective and well-tolerated therapy for locally extensive stage II and IIIA/B HD.(ABSTRACT TRUNCATED AT 250 WORDS)

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Effects of d-amphetamine in grouped versus isolated humans.

This study was designed to determine whether the subjective, behavioral or physiological effects of a stimulant drug in humans depend on whether subjects are tested under isolated or social conditions. Forty-two subjects were randomly assigned to either the Social (SOC) or Isolated (ISO) condition. SOC subjects participated in 4 h laboratory sessions in groups of 3 or 4, whereas ISO subjects participated in the sessions alone. All subjects participated in three sessions, during which they received capsules containing d-amphetamine (10 or 20 mg) or placebo, in mixed order under double blind conditions. Subjective, physiological and behavioral measures were obtained at regular intervals, d-amphetamine produced dose-related, prototypic stimulant effects on many measures, including self-reported mood states, behavioral indices and physiological measures. Most of these effects were unaffected by the setting in which subjects were tested (SOC vs ISO). However, body temperature was overall higher in the SOC group, and there was a trend for d-amphetamine to produce greater hyperthermic effects in the SOC group. In addition, 10 mg d-amphetamine increased heart rate in the SOC group but not in the ISO group. The results suggest that, like in laboratory animals, some of the effects of stimulants in humans are greater under aggregated conditions. However, unlike in the animal studies, this observed enhancement of the drug's effects under aggregated conditions was limited to physiological measures and did not apply to other subjective or behavioral measures.

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Variable platelet responsiveness to aspirin and clopidogrel: role of platelet function and genetic polymorphism testing.

Dual antiplatelet therapy with aspirin and clopidogrel is the standard treatment for patients with an acute coronary syndrome or percutaneous coronary intervention. However, at standard doses, many patients still experience an adverse cardiovascular event. Numerous studies have demonstrated that a laboratory assessment of platelet resistance to an antiplatelet medication is associated with adverse outcomes. The gold standard in assessing platelet function is light transmittance aggregometry. However, because of the time necessary to complete the test, the need for skilled technicians, and the associated costs, newer point-of-care tests have been developed to assess rapidly an individual's platelet responsiveness. Although numerous studies demonstrate an association with adverse outcomes and platelet resistance, currently no clinical trial results demonstrate a treatment strategy to mitigate the adverse outcomes associated with platelet resistance. Studies currently underway are evaluating treatment options for a laboratory assessment of platelet resistance, such as increasing the clopidogrel maintenance dose. Until such results are available, routine testing of platelet resistance to aspirin or clopidogrel should be used only in a research setting.

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Fifteen-year experience in Hodgkin's disease: role of combined modality treatment and splenectomy in the incidence of secondary acute leukemia.

Following irradiation alone, secondary acute leukemia is extremely uncommon; following chemotherapy alone, the risk is increased, but not as much as when continued maintenance chemotherapy or combined modality treatments are used. The risk of secondary acute nonlymphocytic leukemia (ANLL) was assessed in 552 patients with Hodgkin's disease (HD), who were diagnosed at the Hematology Institute of Bologna from 1970 through 1984 and followed-up through July, 1990. Median follow-up time was 12 years. ANLL developed in 14 of 328 patients treated with the combined modality of extended-field radiotherapy (RT) plus chemotherapy (CT). All ANLL was observed in patients who had received the mechlorethamine-vincristine-procarbazione-prednisone (MOPP) regimen. No ANLL was documented among 115 patients treated with RT alone, nor among the 109 given CT alone. Leukemia, which developed 34-184 months after diagnosis of HD, was always preceded by a preleukemic phase and was fatal (after 1-12 months) to 13 patients. The karyotype of the leukemia cells was studied in 11 of the 14 patients and was always abnormal. A Cox's Linear Logistic Model that was performed did not demonstrate that the treatment categories, age, sex, and splenectomy were prognostic factors. Because all ANLL was observed in patients who were treated with extended-field RT plus MOPP and who had undergone splenectomies at diagnosis of HD, further research with larger numbers of patients and longer follow-up should be pursued. Thus with such additional data, clinicians could come to appreciate fully the statistical significance of our interesting observations.

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Metformin for preventing gestational diabetes in women with polycystic ovarian syndrome.

To assess the effect of metformin in controlling Gestational Diabetes Mellitus (GDM) in women with Polycystic Ovarian Syndrome (PCOS). Comparative cohort study. Gynecology Clinics of Mamji Hospital, Karachi, from 2008 to 2010. Patients who had been diagnosed Polycystic Ovarian Syndrome (PCOS) with hyperinsulinemia and conceived and continued pregnancy, were divided in two groups; 50 patients received metformin throughout pregnancy and 32 did not. Development of GDM was ascertained in both groups. The patients were followed throughout pregnancy and in puerperium with OGTT as per WHO criteria. Primary outcome measure was development of gestational diabetes mellitus. Comparison of continuous variables was done using student 't' test. For categorical variables, frequency and percentages are reported while, odds ratio is also estimated for GDM during pregnancy. A total of 82 women with PCOS were included in this study, out of whom, 50 patients received metformin treatment while 32 patients did not. Pregnant women with PCOS in both groups were comparable in age, weight, parity and BMI. Mean fasting insulin levels at beginning of study entry were 17.22 ± 2.3 mIU/L and 16.93 ± 2.28 mIU/L in metformin and no metformin group respectively (p=0.589). Mean fasting blood sugar levels were 94.54 mg/dl in metformin and 99.59 mg/dl in no metformin group p < 0.001. A total of 5 (10%) patients in metformin group developed GDM while 11 (34.37% OR 4.71, p = 0.01) developed GDM in no metformin group. Patients not receiving metformin were 4.7 times likely to have GDM (OR: 4.71) compared to those who received it. The frequency of gestational diabetes, was significantly higher in patients with PCOS who had not received metformin compared to those who did.

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A multicentre study to assess long-term use of fluticasone propionate aqueous nasal spray in comparison with beclomethasone dipropionate aqueous nasal spray in the treatment of perennial rhinitis.

Two hundred and fifty-one patients, aged 16 years and over, with perennial rhinitis were recruited to this multicentre, randomized, double-blind, parallel group study. One hundred and fifty-nine patients received fluticasone propionate (200 micrograms) aqueous nasal spray (FPANS) twice daily, and 83 patients received beclomethasone dipropionate (200 micrograms) aqueous nasal spray (BDPANS) twice daily; treatment randomization being 2:1, respectively, in order to increase the number of patients in the FPANS group as FPANS was the drug under study. After 1 year of treatment, nasal blockage (p = 0.002), nasal discharge (p = 0.002) and eye watering/irritation (p = 0.048) were significantly improved in patients treated with FPANS twice daily, compared to patients treated with BDPANS twice daily. The symptom grades for nasal itching (p = 0.052) were improved in the FPANS group, but just failed to attain statistical significance at the 5% level. The symptom grades for sneezing tended to be better for the FPANS group, but the difference was not statistically significant. Assessment of changes in the findings during nasal examination (rhinoscopy) and in haematological, biochemical and urinary parameters, and measurements of plasma cortisol levels during the one year of treatment with the study drugs, showed that there were no clinically significant differences between the two treatment groups and that the study drugs were equally well tolerated. This study indicates that long-term use of FPANS provides better relief than BDPANS for most of the symptoms of perennial rhinitis.

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Effects of bile-acid-binding resin (colestimide) on blood glucose and visceral fat in Japanese patients with type 2 diabetes mellitus and hypercholesterolemia: an open-label, randomized, case-control, crossover study.

The objective was to examine the effects of colestimide on blood glucose, visceral fat, adipocytokines, and bile acid conjugate fractions in Japanese patients. This study was an open-label, randomized, case-control, crossover study of colestimide 3 g/day in 40 Japanese patients with type 2 diabetes mellitus (T2D) and hypercholesterolemia. Patients were assigned to the colestimide group in which pravastatin and colestimide were administered orally and to the statin group in which pravastatin alone was administered orally. The principal outcome measures were serum lipid levels, fasting plasma glucose level in the early morning, hemoglobin A1c (HbA(1c)), visceral fat area (VFA), and serum 1,5-anhydroglucitol (1,5-AG) level. Serum low-density lipoprotein cholesterol levels significantly decreased from 113±38 mg/dl at baseline to 90±20 mg/dl (P=.009) at week 12 of colestimide administration. HbA(1c) significantly decreased from 7.4%±0.9% at baseline to 6.9%±0.9% (P=.001) at week 12 of colestimide administration. Serum 1,5-AG levels increased from 9.4±10.1 μg/ml to 12.4±9.5 μg/ml (P=.05) at week 12 of colestimide administration. The statin group showed no significant changes in lipids and 1,5-AG. However, ΔVFA was inversely correlated with Δcholic acid, and multivariate analysis revealed that ΔVFA was a significant explanatory variable. Colestimide holds promise not only for the treatment of hypercholesterolemia but also for the possible improvement of T2D and visceral fat obesity.

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Pilot randomized trial of bupropion for adolescent methamphetamine abuse/dependence.

To perform a pilot clinical trial of bupropion for methamphetamine abuse/dependence among adolescents. Nineteen adolescents with methamphetamine abuse (n = 2) or dependence (n = 17) were randomly assigned to bupropion SR 150 mg twice daily or placebo for 8 weeks with outpatient substance abuse counseling. Bupropion was well-tolerated except for one female in the bupropion group who was hospitalized for suicidal ideation during a methamphetamine relapse. Adolescents receiving bupropion and females provided significantly fewer methamphetamine-free urine tests compared to participants receiving placebo (p = .043) and males (p = .005) respectively. Results do not support the feasibility of additional trials of bupropion for adolescent methamphetamine abuse/dependence. Future studies should investigate the influence of gender on adolescent methamphetamine abuse and treatment outcomes.

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[Safety and clinical efficiency of long-term complete blockade of renin-angiotensin-aldosterone system in patients with chronic obstructive pulmonary diseases].

To study a corrective influence of a complete blockade of renin-angiotensin-aldosterone system (RAAS) on right ventricular failure in patients with chronic obstructive pulmonary diseases (COPD). 91 COPD patients were randomised into 3 groups who received standard therapy (ST), ST + losartan, ST + losartan + aldactone. The duration of the follow-up was 24 months. A complete RAAS blockade produced a significant decline in the pressure in the pulmonary artery, improved diastolic and systolic right ventricular function. This led to decreased number of hospitalizations because of progressing right ventricular failure. Safety of therapy with ACE inhibitor and aldactone was proved by a comparison of the number of side effects in the three groups.

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Hydroxychloroquine in lupus pregnancy.

Hydroxychloroquine (HCQ) is often needed to manage disease activity in systemic lupus erythematosus (SLE) during pregnancy. The purpose of this study was to examine lupus activity and pregnancy outcomes in women with SLE treated or not treated with HCQ during pregnancy. This was a prospective study of pregnancies in women with SLE who were evaluated between 1987 and 2002. The pregnancies were divided into 3 groups: no HCQ exposure during pregnancy (163 pregnancies), continuous use of HCQ during pregnancy (56 pregnancies), or cessation of HCQ treatment either in the 3 months prior to or during the first trimester of pregnancy (38 pregnancies). The pregnancy outcomes, fetal outcomes, and lupus activity during pregnancy were compared among these groups. The rates of miscarriage, stillbirth, pregnancy loss, and congenital abnormality were not statistically different among the 3 groups. The degree of lupus activity during pregnancy, however, was significantly higher in women who stopped taking HCQ. These women had a higher degree of lupus activity, as measured by the physician's estimate of lupus activity and the SLE Disease Activity Index, as well as an increased rate of flare, during pregnancy. More serious lupus complications, such as proteinuria and thrombocytopenia, were not significantly higher in women who stopped taking HCQ. Women who continued taking HCQ were maintained on a lower average dose of prednisone during pregnancy. We recommend the continuation of HCQ treatment during pregnancy. Our findings are consistent with prior reports of the absence of fetal toxicity. Similar to studies of nonpregnant women, the cessation of HCQ treatment during pregnancy increases the degree of lupus activity.

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[Potential possibilities of using adrenergic beta blockers in chronic heart failure].

The study was undertaken to examine the efficacy of beta-adrenoblockers used in 26 patients with chronic heart failure which had been caused by coronary heart disease in 12 patients, by rheumatic heart disease in 8 patients, by dilated cardiomyopathy in 5 patients, and by chronic myocarditis in 1 patient. beta-Blockers such as oxprenolol, propranolol, and metoprolol were supplemented to the therapy of the patients with chronic heart failure who were resistant to cardiac glycosides, diuretics, and vasodilators. This resulted in functional class improvement by the New York Heart Association from 3.67 +/- 0.1 to 2.29 +/- 0.1. The authors defined the following predictors of the efficacy of beta-blockers in chronic heart failure: duration of the disease, diastolic pressure, cardiac rhythm, and left ventricular ejection fraction and discussed the mechanisms responsible for their positive effect in chronic heart failure.

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Prevalence and treatment of decreased bone density in renal transplant recipients: a randomized prospective trial of calcitriol versus alendronate.

Reduced bone mineral density (BMD) is common in long-term renal transplant recipients and results in a high incidence of fractures. The optimal therapy for these patients is not known. Baseline BMD determinations were obtained in 211 long-term adult renal transplant recipients. One hundred and seventeen patients with a reduced BMD (T score < or = -1) were randomly assigned to treatment with alendronate and calcium (n=60) versus calcitriol and calcium (n=57). Of these, 46 and 51 patients, respectively, completed 1 year of treatment. Forty-nine patients who were not eligible or did not consent to the trial were followed prospectively. Reduced baseline BMD (T score < or = -1) was present in 159 (78.7%) of patients at the lumbar spine or femur. There was no significant loss of BMD in the prospectively followed patients during 2.7 years. The average lumbar BMD increased from 0.984+/-0.149 to 1.025+/-0.143 g/cm2 (P<0.001) with alendronate and from 1.014+/-0.15 to 1.034+/-0.146 g/cm2 (P=0.002) with calcitriol. BMD at the femur increased from 0.809+/-0.092 to 0.836+/-0.107 g/cm2 (P<0.001) with alendronate and from 0.830+/-0.144 to 0.857+/-0.125 g/cm2 (P=0.023) with calcitriol. One year of treatment with alendronate or calcitriol, both with calcium supplementation, resulted in significant increases in BMD at the lumbar spine and femur, with a trend toward alendronate being more effective at the spine (P=0.082). Further studies are needed to determine whether BMDs continue to increase after 1 year and whether there is any additional benefit to combining vitamin D and alendronate. Larger studies are needed to determine whether treatment decreases fracture rates.

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Myocarditis in a patient treated with Nivolumab and PROSTVAC: a case report.

Immune checkpoint inhibitors have revolutionized treatment and improved survival in many cancers. However, since immune-related adverse events (irAEs) are potentially fatal, early recognition and prompt treatment are warranted. One of the rarest but most dramatic irAE is myocarditis, which has significant morbidity and mortality if not recognized and treated early. To report the first case of myocarditis in a patient with metastatic castration-resistant prostate cancer (mCRPC) treated with a combination of nivolumab, an anti-programmed cell death protein 1 antibody, and PROSTVAC, a vector-based therapeutic prostate cancer vaccine. A 79-year-old man with mCRPC metastatic to bone and lymph nodes and a history of atrial fibrillation presented with blurred vision and pain and stiffness in the upper back after 8 weeks on a clinical trial with nivolumab (1 mg/kg) and PROSTVAC, both given every 2 weeks. Eye exam was within normal limits, while musculoskeletal exam revealed tenderness in trapezius muscles and decreased motor strength in arms (III/V) and neck (IV/V). The rest of the physical exam was within normal limits, with the exception of an irregular heart rhythm. Laboratory tests were as follows: creatinine kinase (CK) 3200 U/L (normal: 39-308 U/L), CK-MB 65.7 mcg/L (normal: 0-7.6 mcg/L), troponin I 0.209 ng/mL (normal: 0-0.056 ng/mL). Electrocardiogram (ECG) revealed atrial fibrillation with QT prolongation (QTc 514 msec) and left anterior fascicular block, unchanged from baseline. 2D-echocardiogram showed a left ventricular ejection fraction of 65% with an enlarged left atrium, dilated right ventricle, and increased pulmonary artery pressure (45 mmHg). ProBNP was elevated at 1463 pg/mL and peaked at 3066 pg/mL one day after hydration. With a presumed diagnosis of autoimmune myositis and possible myocarditis, the patient was admitted and started on methylprednisolone 1 mg/kg/day. Cardiac MRI showed elevated native myocardial T1 values consistent with myocarditis (Fig. 1). The patient was discharged on a prednisone taper after normalization of cardiac enzymes on day 4. Treatment with PROSTVAC continued for three more months; nivolumab was discontinued. Six months later, patient is doing well, with no residual cardiac damage. Cardiovascular irAEs are relatively rare (< 1%) and have a variety of clinical presentations. Myocarditis is potentially life-threatening and can range from subclinical to fulminant. Therefore, clinical suspicion, early detection, and prompt treatment are imperative (1). The initial diagnostic workup should include cardiac enzymes, ECG, and 2D-echocardiogram. The most commonly observed ECG changes are generalized repolarization abnormalities, prolonged QT interval, and conduction abnormalities (2). An elevated troponin I in the absence of overt coronary artery disease is suggestive of myocarditis and should be evaluated further. Myocardial biopsy is the standard diagnostic procedure; however, a cardiac MRI can achieve a diagnosis when biopsy is not feasible (3). Advancements in parametric mapping techniques have allowed the use of native myocardial T1 in the detection of myocarditis, as it has superior diagnostic performance and higher sensitivity than older parameters (3). Our patient had been treated with an immune checkpoint inhibitor and a therapeutic cancer vaccine to induce effective antitumor activity through immunogenic intensification and presented with muscle stiffness and elevated CK. Although he had no new cardiovascular symptoms, cardiac enzymes were tested to rule out myocardial involvement. MRI with gadolinium confirmed the diagnosis of myocarditis. To date, none of the 1360 patients treated with PROSTVAC as a single agent have developed myocarditis, while myocarditis has been rarely reported in patients treated with nivolumab (< 1%) (1). Whether the combination of PROSTVAC and nivolumab presents an additional risk of myocarditis is unclear. To our knowledge, this is the first case of myocarditis in a patient with mCRPC receiving simultaneous treatment with an immune checkpoint inhibitor and a prostate cancer vaccine. Our experience highlights the importance of suspicion and early intervention in patients who present with cardiac abnormalities after receiving cancer immunotherapy. We propose following protocol: baseline troponin, ECG, and 2D-echocardiogram prior to treatment, then repeated troponin at 2, 4, and 12 weeks post-treatment, then monthly. If troponin becomes positive without alternative explanation, myocarditis should be ruled out with cardiac MRI or myocardial biopsy, and patient should be admitted for treatment with high-dose steroids as early intervention may minimize myocardial injury.

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Precatheterization Use of P2Y₁₂ Inhibitors in Non-ST-Elevation Myocardial Infarction Patients Undergoing Early Cardiac Catheterization and In-Hospital Coronary Artery Bypass Grafting: Insights From the National Cardiovascular Data Registry^®.

Current guidelines recommend early P2Y₁₂ inhibitor administration in non-ST-elevation myocardial infarction, but it is unclear if precatheterization use is associated with longer delays to coronary artery bypass grafting (CABG) or higher risk of post-CABG bleeding and transfusion. This study examines the patterns and outcomes of precatheterization P2Y₁₂ inhibitor use in non-ST-elevation myocardial infarction patients who undergo CABG. Retrospective analysis was done of 20 304 non-ST-elevation myocardial infarction patients in the ACTION (Acute Coronary Treatment and Intervention Outcomes Network) Registry (2009-2014) who underwent catheterization within 24 hours of admission and CABG during the index hospitalization. Using inverse probability-weighted propensity adjustment, we compared time from catheterization to CABG, post-CABG bleeding, and transfusion rates between patients who did and did not receive precatheterization P2Y₁₂ inhibitors. Among study patients, 32.9% received a precatheterization P2Y₁₂ inhibitor (of these, 2.2% were given ticagrelor and 3.7% prasugrel). Time from catheterization to CABG was longer among patients who received precatheterization P2Y₁₂ inhibitor (median 69.9 hours [25th, 75th percentiles 28.2, 115.8] versus 43.5 hours [21.0, 71.8], <i>P</i><0.0001), longer for patients treated with prasugrel (median 114.4 hours [66.5, 155.5]) or ticagrelor (90.4 hours [48.7, 124.5]) compared with clopidogrel (69.3 [27.5, 114.6], <i>P</i><0.0001). Precatheterization P2Y₁₂ inhibitor use was associated with a higher risk of post-CABG major bleeding (75.7% versus 73.4%, adjusted odds ratio 1.33, 95% confidence interval 1.22-1.45, <i>P</i><0.0001) and transfusion (47.6% versus 35.7%, adjusted odds ratio 1.51, 95% confidence interval 1.41-1.62, <i>P</i><0001); these relationships did not differ among patients treated with clopidogrel, prasugrel, or ticagrelor. Precatheterization P2Y₁₂ inhibitor use occurs commonly among non-ST-elevation myocardial infarction patients who undergo early catheterization and in-hospital CABG. Despite longer delays to surgery, the majority of pretreated patients proceed to CABG <3 days postcatheterization. Precatheterization P2Y₁₂ inhibitor use is associated with higher risks of postoperative bleeding and transfusion.

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Rituximab plus gemcitabine: a therapeutic option for elderly or frail patients with aggressive non Hodgkin's lymphoma?

The standard treatment for patients with aggressive B-cell lymphoma--particularly diffuse large-B-cell lymphoma [DLBCL)--is cyclophosphamide, doxorubicin, vincristine and prednisone [CHOP) plus rituximab, a chimeric monoclonal antibody against the CD20 antigen. However, some patients are not fit enough to tolerate CHOP or they relapse after previous therapy with CHOP. Gemcitabine as a monotherapy is active and relatively non-toxic in the treatment of NHL. We investigated the toxicity and efficacy of a combination of gemcitabine with rituximab in a small series of elderly patients with high-grade B-cell lymphoma who had either a relapse after CHOP, or were medically unfit to tolerate CHOP as a first-line therapy. Gemcitabine was given at 1000 mg/m2/week x 3, q28 days; rituximab at 325 mg/m2/week x 4 in the first cycle, and on day 1 of all subsequent cycles. Seven patients have been treated. The median number of cycles given was 4. The major toxicity was haematologic: grade 3/4 leukocytopenia occurred in 4 patients, grade 3/4 thrombocytopenia in 3 patients. There were no episodes of clinically significant bleeding. One patient developed febrile neutropenia and died in the course of treatment; another patient developed non-Q-wave myocardial infarction possibly related to hydration pre-treatment to rituximab and erythrocyte transfusion. He recovered well after symptomatic therapy. In 7 patients, 2 complete and 3 partial remissions were achieved, with an estimated median time to progression of 12 months. This series of patients shows that the combination of gemcitabine and rituximab is feasible in this population not able to undergo standard poly-chemotherapy, shows promising activity, and merits further evaluation.

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Determination of Guan-Fu Base A, a new anti-arrhythmic, in human plasma by gas chromatography and electron-capture detection.

A gas chromatographic-electron capture detection (GC-ECD) method has been developed for determining Guan-Fu Base A (GFA), an experimental anti-arrhythmic, in human plasma. The method was based on one-step liquid-liquid extraction with toluene and chemical derivatization with pentafluoropropionic anhydride followed by GC-ECD. The derivatives of GFA and metoprolol (Met, internal standard) were confirmed by gas chromatography-mass spectrometry (GC-MS) to be dipentafluoropropionyl-GFA and dipentafluoropropionyl-Met. The method was linear over the concentration ranges of 0.1-20.0 and 1.0-30.0 microg/ml with the detection limit of 0.05 microg/ml at S/N=5. The intra- and inter-assay precisions were less than 6 and 10%, and accuracy 99.70+/-3.30 and 97.60+/-5.99%, respectively. The absolute recoveries were 81.88, 77.35, 80.79 and 83.85% for GFA at concentrations of 0.5, 1.0, 5.0 and 14.0 microg/ml and 88.24% for Met at 3.0 microg/ml, respectively.

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Efficacy of Cyclophosphamide treatment for immunoglobulin G4-related disease with addition of glucocorticoids.

Aim to evaluate the efficacy and safety of glucocorticoid monotherapy vs combination therapy of cyclophosphamide (CYC) for IgG4 related disease (IgG4-RD). 102 newly diagnosed IgG4-RD patients were enrolled and assigned to 2 groups: Group I was prednisone monotherapy (0.5-1.0 mg/kg.d, tapered gradually) and Group II was glucocorticoid and CYC (50-100 mg per day). Patients were assessed at different periods. Primary end point was relapse rate; secondary end points included response, remission rate and adverse effects. 52 patients were in Group I and 50 in Group II. At 1 month, both groups achieved obvious improvement. Accumulated relapse rate during 1 year was 38.5% in Group 1, including 12 cases with clinical relapse and 8 patients manifesting only serological relapse; whereas there was 12.0% of relapse in Group 2, only 1 with clinical relapse and other 5 patients got serological relapse. The mean flare time in Group II was significantly longer than that in Group I. All relapsing patients in Group I were sensitive to immunosuppressants. Most patients involving more than 6 organs in Group I relapsed during 1 year. IgG4 levels of relapse cases were significantly higher than non-relapsing patients at baseline. Bile duct, lacrimal glands and lymph nodes were commonly relapsed organs in Group I.

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Anti-Inflammatory HDL Function, Incident Cardiovascular Events, and Mortality: A Secondary Analysis of the JUPITER Randomized Clinical Trial.

Background High-density lipoprotein (HDL) cholesterol has inverse association with cardiovascular disease. HDL possesses anti-inflammatory properties in vitro, but it is unknown whether this may be protective in individuals with inflammation. Methods and Results The functional capacity of HDL to inhibit oxidation of oxidized low-density lipoprotein (ie, the HDL inflammatory index; HII) was measured at baseline and 12 months after random allocation to rosuvastatin or placebo in a nested case-control study of the JUPITER (Justification for the Use of Statins in Prevention: An Intervention Evaluating Rosuvastatin) trial. There were 517 incident cases of cardiovascular disease and all-cause mortality compared to 517 age- and sex-matched controls. Multivariable conditional logistic regression was used to examine associations of HII with events. Median baseline HII was 0.54 (interquartile range, 0.50-0.59). Twelve months of rosuvastatin decreased HII by a mean of 5.3% (95% CI, -8.9% to -1.7%; <i>P</i>=0.005) versus 1.3% (95% CI, -6.5% to 4.0%; <i>P</i>=0.63) with placebo (<i>P</i>=0.22 for between-group difference). HII had a nonlinear relationship with incident events. Compared with the reference group (HII 0.5-1.0) with the lowest event rates, participants with baseline HII ≤0.5 had significantly increased risk of cardiovascular disease/mortality (adjusted hazard ratio, 1.53; 95% CI, 1.06-2.21; <i>P</i>=0.02). Furthermore, there was significant (<i>P</i>=0.002) interaction for HDL particle number with HII, such that having more HDL particles was associated with decreased risk only when HDL was anti-inflammatory. Conclusions In JUPITER participants recruited on the basis of chronic inflammation, HII was associated with incident cardiovascular disease/mortality, with an optimal anti-inflammatory HII range between 0.5 and 1.0. This nonlinear relationship of anti-inflammatory HDL function with risk may account in part for the HDL paradox. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00239681.

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Comparison of the angiotensin II receptor antagonist irbesartan with atenolol for treatment of hypertension.

In this multicenter, double-blind study, the antihypertensive efficacy and safety of irbesartan were compared with those of atenolol in patients with mild-to-moderate hypertension. Following a 4- to 5-week placebo lead-in period, 231 patients with seated diastolic blood pressure (SeDBP) 95-110 mmHg were randomized to irbesartan 75 mg or atenolol 50 mg once daily for 24 weeks. Doses were doubled at Week 6 for SeDBP > or = 90 mmHg. At Week 12, or anytime thereafter, doses were doubled for SeDBP > or = 90 mmHg if not done at Week 6, and hydrochlorothiazide and then nifedipine were added. Efficacy was determined by change from baseline in blood pressure and by therapeutic response rates. Safety was assessed by monitoring adverse events (AEs). Both treatments significantly lowered blood pressure from baseline. There were no significant differences between treatment groups with respect to blood pressure changes or therapeutic response. Atenolol significantly reduced seated heart rate compared with irbesartan at Week 12. The incidences of serious AEs and discontinuations due to AEs were approximately twice as high in the atenolol group compared with the irbesartan group. Thus, in comparison to atenolol, irbesartan < or = 150 mg provided at least equivalent blood pressure control while demonstrating an excellent safety and tolerability profile.

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From hydrofluoroalkane pressurized metered dose inhalers (pMDIs) and comparability with chlorofluorocarbon pMDIs.

Fluticasone propionate pressurized metered dose inhalers (pMDIs) containing the hydrofluoroalkane (HFA) propellant, HFA 134a, are being developed to replace existing chlorofluorocarbon (CFC) pMDIs. This is part of the ongoing worldwide project to limit the damage to the earth's ozone layer. The in vivo performance and dose proportionality of fluticasone propionate HFA 134a pMDIs was examined for fluticasone propionate doses of 400, 1000 and 2000 microg using the 50, 125 and 250 microg strength pMDIs, respectively. The 125 and 250 microg strength HFA 134a pMDIs were compared with corresponding fluticasone propionate CFC pMDIs. Twenty-three healthy subjects participated in this single dose, randomized, five-way, cross-over study. Serial blood samples were collected 24 h post-dose to measure fluticasone propionate plasma concentrations. Twenty-four hour urinary-free cortisol was also measured before and after dosing. A dose-proportional increase in plasma fluticasone propionate concentrations was observed with increasing dose for the HFA 134a pMDIs. This was associated with a dose-related decrease in urinary cortisol excretion. Similar or lower fluticasone propionate systemic exposure was observed with the HFA 134a pMDIs compared to the corresponding CFC inhalers. The differences in systemic exposure observed for the HFA 134a and CFC pMDIs were too small to produce a differential effect on urinary cortisol excretion. Since fluticasone propionate has negligible oral bioavailability, the systemic exposure, which arises only from pulmonary absorption, is a measure of lung deposition. There was a good correlation between the in vitro fine particle mass produced by the different strengths and types of pMDI and the systemic exposure to fluticasone propionate. Therefore, the fluticasone propionate HFA 134a pMDI is an acceptable pharmaceutical alternative to the current CFC pMDI, producing similar lung deposition and no increase in systemic exposure at microgram equivalent doses.

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Esomeprazole-based one-week triple therapy with clarithromycin and metronidazole is effective in eradicating Helicobacter pylori in the absence of antimicrobial resistance.

This study aimed to investigate the effectiveness of a one-week triple therapy with esomeprazole, clarithromycin and metronidazole for eradication of Helicobacter pylori infection in the absence of antimicrobial resistance. Patients testing positive for H. pylori susceptible to metronidazole and clarithromycin (E-test) were randomized to receive a one-week regimen with either esomeprazole 2 x 20 mg or omeprazole 2 x 20 mg in combination with clarithromycin 2 x 250 mg and metronidazole 2 x 400 mg. Follow-up endoscopy with histology and culture and/or rapid urease test was performed 4-8 weeks after the end of treatment. Eighty patients were randomized. Helicobacter pylori infection was cured in 38/39 patients of the esomeprazole group and 31/33 patients of the omeprazole group (per protocol 97.4% (95% confidence interval [CI], 86.2-99.9), 93.7% (95% CI, 79.2-99.2), P=0.59); intention-to-treat 90.4% (95% CI: 77.4-97.3), 81.6% (95% CI: 65.7-92.3), respectively. No major side effects occurred. Minor side effects occurred in eight (20%) and six (23%) patients during esomeprazole and omeprazole therapy, respectively. Post-treatment susceptibility testing revealed resistance to both metronidazole and clarithromycin in two of the three patients who failed. We conclude that esomeprazole, clarithromycin and metronidazole as one-week triple therapy is effective for eradication of H. pylori in the absence of antimicrobial resistance.

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A comparison of albuterol solution nebulized versus albuterol powder given by breath activated metered dose inhaler.

The goal of the present study was to compare the efficacy of nebulized vs powdered albuterol in patients with exacerbated bronchial asthma who required hospitalization. From January to May 1990 known asthmatics admitted with acute exacerbation were included by established criteria. Two groups were randomized. Group I for Albuterol powder 200 micrograms inhaled q 4 hours. Group II with Albuterol nebulized solution 2.5 mg inhaled q 4 hrs. Force Vital Capacity and Force Expiratory Volume in one second were measured with a pressure differential transducer upon admission, 30 minutes and 24-hours following therapies. Absolute FEV1 improvement was calculated. Statistical analysis was performed using student's T-Test and Fisher's exact Test with significance established at p > 0.01%. Fifteen patients enrolled in both groups, two patients of group I were excluded from the statistic analysis due to refusal to continue with the therapy. Both groups were comparable with respect to sex, asthma exacerbations/year, smoking history and hospital length of stay. FVC and FEV1 were comparable also. In contrast, there were significant difference when the absolute improvement were compared. The mean +/- SE for FEV1 absolute improvement at the first 30 min was 0.42 +/- 0.08 lts for the Group I versus 0.65 +/- 0.6 lts in the Group II. In the next 24 hours, Group I was 0.16 +/- 0.2 lts versus 0.30 +/- 0.7 lts in Group II (p > .01). We conclude that although the dose equivalence of both delivery systems have not been established in our study, the nebulized solution was more effective during the first 24 hours of hospitalization than the dry powder.

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Clopidogrel vs. prasugrel vs. ticagrelor in patients with acute myocardial infarction complicated by cardiogenic shock: a pooled IABP-SHOCK II and CULPRIT-SHOCK trial sub-analysis.

The aim of this pooled sub-analysis of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) and Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) trial was to compare the clinical outcome of patients with acute myocardial infarction complicated by cardiogenic shock treated either with clopidogrel or the newer, more potent ADP-receptor antagonists prasugrel or ticagrelor. For the current analysis the primary endpoint was 1-year mortality and the secondary safety endpoint was moderate or severe bleedings until hospital discharge with respect to three different ADP-receptor antagonists. 856 patients were eligible for analysis. Of these, 507 patients (59.2%) received clopidogrel, 178 patients (20.8%) prasugrel and 171 patients (20.0%) ticagrelor as acute antiplatelet therapy. The adjusted rate of mortality after 1-year did not differ significantly between prasugrel and clopidogrel (hazard ratio [HR]: 0.81, 95% confidence interval [CI] 0.60-1.09, p_adj = 0.17) or between ticagrelor and clopidogrel treated patients (HR: 0.86, 95% CI 0.65-1.15, p_adj = 0.31). In-hospital bleeding events were significantly less frequent in patients treated with ticagrelor vs. clopidogrel (HR: 0.37, 95% CI 0.20 -0.69, p_adj = 0.002) and not significantly different in patients treated with prasugrel vs. clopidogrel (HR: 0.73, 95% CI 0.43 -1.24, p_adj = 0.24). This pooled sub-analysis is the largest analysis on safety and efficacy of three oral ADP-receptor antagonists and shows that acute therapy with either clopidogrel, prasugrel or ticagrelor is no independent predictor of 1-year mortality. Treatment with ticagrelor seems independently associated with less in-hospital moderate and severe bleeding events compared to clopidogrel. This finding might be due to selection bias and should be interpreted with caution.

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Diabetes Mellitus and Metformin Are Not Associated With Breast Cancer Pathologic Complete Response.

Metformin use has been linked to pathologic complete response (pCR) following neoadjuvant chemotherapy for several malignancies. We aimed to investigate the association of diabetes mellitus (DM) and metformin use with pCR in breast cancer. All breast cancer patients who received neoadjuvant chemotherapy during June 2013-October 2016 at two academic medical centers were identified. A retrospective cohort study evaluated patients who did and did not achieve pCR. Multivariable logistic regression identified independent predictors of pCR, specifically looking at metformin use and DM. The study group included 351 breast cancer patients, with 90 (25.6%) achieving pCR after neoadjuvant chemotherapy. The rate of DM did not differ between those with and without pCR, nor did the rate of metformin use. Multivariable logistic regression identified HER2-positive tumors and smaller preoperative tumor size as predictors of pCR. The estrogen receptor (ER) positivity was associated with an absence of pCR. Importantly, neither DM nor metformin use was predictive of pCR. This study by the two institutions supports previous data of tumor-related factors known to be associated with pCR; however, the current analysis found neither DM nor metformin to be independently associated with pCR. Thus, additional prospective study is warranted prior to validating metformin as an antitumor agent.

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Ambulatory blood pressure monitoring for evaluation of long-acting beta-blockers in Taiwan.

This study attempted to evaluate the efficacy of several "long-acting" antihypertensive agents. One-hundred consecutive hypertensive subjects with normal casual blood pressure after once-daily antihypertensive monotherapy treatment were studied. They were divided into three groups: group A, metoprolol (100 mg, daily); group B, atenolol (100 mg, daily); and group C, nadolol (80 mg, daily). Ambulatory blood pressure monitoring (ABPM) was used to evaluate the efficacy of the antihypertensive agents. The overall average ambulatory blood pressures were within the normal limits for all three groups. However, there were some abnormally high blood pressure (BP) readings shown on ABPM. Patients with an abnormally high systolic blood pressure (SBP) average > 140 mmHg accounted for 16.7% of group A, 19.4% of group B and 20% of group C. Those with an abnormally high diastolic blood pressure (DBP) average > 90 mmHg accounted for 16.7%, 19.4% and 10%, respectively, of the corresponding groups. There were no significant differences in the frequency of abnormally high SBP and DBP among the three groups. These "long-acting" antihypertensive drugs did not effectively control BP throughout the entire day. The duration of antihypertensive effect is not necessarily reflected by the blood half-life of the drug. ABPM is an effective way to ascertain the efficacy of "long-acting" hypertensive agents.

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Enantioselective disposition of oral amlodipine in healthy volunteers.

Plasma concentrations of (R)- and (S)-amlodipine were measured after single oral administrations to 18 healthy volunteers of 20 mg amlodipine racemate. The contribution of the pharmacologically active (S)-enantiomer to the concentrations of total amlodipine (sum of enantiomers) was significantly higher than that of the inactive (R)-enantiomer, with mean values of 47% R to 53% S for the Cmax and 41% R to 59% S for the AUC (range between 24% R:76% S and 50% R:50% S). The oral clearance of the active (S)-form was subject to much less intersubject variation (25% CV) than that of the inactive (R)-form (52% CV). (R)-Amlodipine was more rapidly eliminated from plasma than (S)-amlodipine, with mean terminal half-lives of 34.9 h (R) and 49.6 h (S). The terminal half-lives of total amlodipine (mean 44.2 h) were strongly correlated with--and thus highly predictive for--the half-lives of the (S)-enantiomer. It is proposed that the observed enantioselectivity of oral amlodipine is due to differences in the systemic blood clearance of the enantiomers.

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Treatment with atorvastatin to the National Cholesterol Educational Program goal versus 'usual' care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study.

Atorvastatin is very effective in reducing plasma low-density lipoprotein cholesterol (LDL-C) levels. However, there is no long-term survival study that evaluated this statin. To assess the effect of atorvastatin on morbidity and mortality (total and coronary) of patients with established coronary heart disease (CHD), 1600 consecutive patients were randomised either to atorvastatin or to 'usual' medical care. The dose of atorvastatin was titrated from 10 to 80 mg/day, in order to reach the National Cholesterol Education Program (NCEP) goal of LDL-C <100 mg/dl (2.6 mmol/l). All patients were followed up for a mean period of 3 years. Primary endpoints of the study were defined as death, non-fatal myocardial infarction, unstable angina, congestive heart failure, revascularisation (coronary morbidity) and stroke. Secondary endpoints were the safety and efficacy of the hypolipidaemic drugs as well as the cost-effectiveness of atorvastatin. The mean dosage of atorvastatin was 24 mg/day. This statin reduced total chlesterol by 36%, LDL-C by 46%, triglycerides by 31%, and non-high-density lipoprotein cholesterol (non-HDL-C) by 44%, while it increased HDL-C by 7%; all these changes were significant. The NCEP LDL-C and non-HDL-C treatment goals were reached by 95% (n = 759) and 97% (n = 776), respectively, of patients on atorvastatin. Only 14% of the 'usual' care patients received any hypolipidaemic drugs throughout the study and 3% of them reached the NCEP LDL-C treatment goal. The cost per quaility-adjusted life-year gained with atorvastatin was estimated at $US 8350. During this study 196 (24.5%) CHD patients on 'usual' care had a CHD recurrent event or died vs. 96 (12%) CHD patients on atorvastatin; risk ratio (RR) 0.49, confidence interval (CI) 0.27-0.73, p < 0.0001. In detail, atorvastatin reduced, in comparison to 'usual' care, total mortality (RR 0.57, CI 0.39-0.78, p = 0.0021), coronary mortality (RR 0.53, CI 0.29-0.74, p = 0.0017), coronary morbidity (RR 0.46, CI 0.25-0.71, p < 0.0001), and stroke (RR 0.53, CI 0.30-0.82, p = 0.034). All subgroups of patients (women, those with diabetes mellitus, arterial hypertension, age 60 to 75 years, congestive heart failure, recent unstable angina or prior revascularisation) benefited from treatment with atorvastatin. Withdrawal of patients because of side-effects from the atorvastatin group was low (0.75%) and similar to that of the 'usual' care group (0.4%). Long-term treatment of CHD patients with atorvastatin to achieve NCEP lipid targets significantly reduces total and coronary mortality, coronary morbidity and stroke, in comparison to patients receiving 'usual' medical care. Treatment with atorvastatin is well tolerated and cost-effective.

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[A clinical trial of lansoprazole in the treatment of duodenal ulcer].

To evaluate the efficacy of a second generation acid pump inhibitor-lansoprazole (L) a controlled clinical trial in 72 patients of duodenal ulcer was carried out with omeprazole (O) as control. The results showed that the ulcer healing rate after 4-week treatment was 97.4% in lansoprazole group and 91.2% in omeprazole, while the effective rate was 100% and 97.1% respectively (P > 0.05). Ulcer related pain was relieved more quickly in lansoprazole group. The pain relief rate after treatment of 3 days was different significantly between the two group, being 74.3% (L) and 51.6% (O) respectively (P < 0.05). No marked side-effect was observed in lansoprazole group. It is shown that lansoprazole is effective and safe for treatment of duodenal ulcer.

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Antibiotic prophylaxis for dental implant placement?

Electronic searches without time or language restrictions were performed in PubMed, Web of Science and the Cochrane Oral Health Group trials Register. A vast manual search was done in many dental implant-related journals. Reference lists were scanned for possible additional studies. Ongoing clinical trials were also searched. Titles and abstracts of the reports identified were read independently by the three authors. Disagreements were resolved by discussion. Rejected studies were recorded with the reasons for exclusion. The inclusion criteria included clinical human studies, either randomised or not, comparing the implant failure/survival rates in any group of patients receiving antibiotic prophylaxis versus not receiving antibiotics prior to implant placement. Case reports and non-human studies were excluded. Implant failure was considered as complete loss of the implant. Data were extracted by the authors. Study risk of bias was assessed. Implant failure and post-operative infection were the outcomes measured, both dichotomous outcomes. Results were expressed using fixed or a random effect model depending on the heterogeneity calculated using an I(2) statistical test. The estimate of relative effect was expressed in risk ratio (RR) with 95% confidence interval. Number needed to treat (NNT) was calculated and sensitivity analysis was performed to detect differences among the studies considered to have high a risk of bias. Fourteen trials were included in the review and evaluated a total of 14,872 implants. Of the fourteen studies included in the review eight were randomised clinical trials, four were controlled clinical trials and two were retrospective studies. Seven studies had both patients and operators/outcome assessors blinded to the tested intervention. Nine studies had short follow-ups; six of them with a follow-up of four months, one of five months and two of six months.The antibiotic regimen was variable: seven studies did not use post-op antibiotics in all patients. Seven studies used amoxicillin as the antibiotic of choice. Ten studies had patients rinse with antimicrobial solutions as well.Among the fourteen studies, 8603 implants were placed in patients receiving antibiotics, 304 failures (3.53%) were recorded; 6269 implants were placed in patients not receiving antibiotics or receiving placebo, with 396 failures recorded (6.32%).From eight articles that provided the information about post-operative infection there were 25 occurrences of infection in 1000 patients receiving antibiotics (2.5%) and 29 episodes in 770 patients not receiving antibiotics (3.8%).Some studies involved grafting procedures and a portion of the patients (in nine studies) were smokers.The test of overall effect for implant failure rate showed that the difference between the procedures with or without antibiotic is statistically significant: RR 0.55, 95% confidence interval (CI) 0.41 to 0.75, p value 0.0002, a relative risk reduction (RRR) of 45% and the number needed to treat (NNT) of 50 (95% CI 33-100).For the post operative infection outcome, the results of the meta-analysis showed no statistically significant results; RR 0.84, 95 % confidence interval 0.49-1.44, and a p value of 0.52.The results did not differ in the sensitivity analysis when removing the high risk of bias studies. For the implant failure, the results were RR 0.37, 95% CI 0.19-0.72, p value 0.003, and for the 'post operative infection' outcome the results were RR 0.78, 95% CI 0.38-1.39. p value 0.33. The funnel plot to calculate publication bias showed asymmetry for the studies reporting implant failure, while the studies reporting post-operative infection the funnel plot did not show asymmetry. The evidence from the review suggests that a prophylactic antibiotic regimen reduces failure of dental implants placed under ordinary conditions. However, there are no apparent differences in the occurrence of post-operative infections in patients receiving or not receiving antibiotics.The results have to be interpreted with caution due to the presence of several cofounding factors in the studies.

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Pantoprazole-induced thrombocytopenia in patients with upper gastrointestinal bleeding.

Proton pump inhibitors (PPIs) are highly effective drugs for patients suffering from peptic ulcer and gastro-esophageal reflux diseases, but recent studies have indicated possible risks with the long-term use of PPIs, such as osteoporosis, fractures, increased risk of pneumonia, diarrhea, iron and vitamin B12 deficiencies. There are publications written as a case study that indicate thrombocytopenia as side effects of PPIs, but there is no study on this subject. This study aimed to investigate the development of thrombocytopenia in patients with short-term use of PPI-infusion therapy. In this study, the records of the patients were evaluated retrospectively, for the period between January 2012 and January 2013. Thirty-five patients with upper gastrointestinal bleeding were enrolled. Platelet counts were analyzed before treatment, and on the first, second and third day of treatment, respectively. All patients were treated with intravenous pantoprazole. Hemogram values of patients were analyzed before and after PPI infusion treatment. Platelet counts were found to decrease from the first day to the third day of treatment (249 714.29/µl, 197 314.29/µl, 193 941.18/µl, 183 500/µl, respectively). The platelet count decrease was statistically significant (p < 0.001). After cessation of infusion therapy, platelet counts began to rise on the fourth day. Three patients had severe thrombocytopenia on the third day of the treatment. (69 000/µl, 97 000/µl and 49 000/µl respectively). Platelet counts recovered after discontinuation of treatment. In conclusion, this study demonstrates that PPIs may cause thrombocytopenia, and this result should not be ignored. In particular, patients with PPI infusion therapy should be monitored more closely.

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Factors associated with the failure of clopidogrel dose-adjustment according to platelet reactivity monitoring to optimize P2Y12-ADP receptor blockade.

Inter-individual variability in clopidogrel responsiveness is dependent on genetic polymorphisms. We aimed to investigate the impact of 3 genetic polymorphisms involved in clopidogrel metabolism on a strategy of dose-adjustment according to platelet reactivity (PR) monitoring. [corrected] This prospective multicenter study enrolled 498 ACS patients undergoing PCI. PR was measured using the Vasodilator-Stimulated Phosphoprotein index (VASP) and a cut-off value of ≥50% defined high on-treatment platelet reactivity (HTPR). Genetic polymorphisms of cytochrome (CYP) 2C19, Paraxonase-1 (PON1) and ABCB1 were determined by allele specific PCR. Dose-adjustment was performed using up-to 3 additional loading doses (LD) of 600mg clopidogrel in order to obtain a VASP <50% in patients with HTPR following the first LD. CYP 2C19 2*polymorphism (p=0.02), but neither PON1 (p=0.8) nor ABCB1 genotype (p=0.9), was significantly associated with HTPR. The dose-adjustment strategy failed in 11% of patients. ABCB1 polymorphism was significantly associated with a failed dose-adjustment (FDA) (p=0.04). No relation was found between the other genotypes and the efficacy of LD adjustment. In multivariate analysis, BMI and ABCB1 polymorphism were the only factors significantly associated with FDA (p=0.005 and p=0.04 respectively). While CYP 2C19 2* is associated with HTPR after 600mg of clopidogrel, ABCB1 is responsible for the failure of a strategy of loading dose-adjustment according to PR monitoring. These findings may help to define a therapeutic strategy to optimize anti-platelet therapy in ACS patients undergoing PCI.

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[Relationship between regression of hypertensive left ventricular hypertrophy and improvement of coronary flow reserve].

To elucidate the relationship between regression of hypertensive left ventricular hypertrophy (LVH) and changes of coronary flow reserve (CFR). Ninety-six essential hypertensive patients with LVH were randomly divided into 3 groups: ramipril group, losartan group, and combination group. Before the treatment and 6 months after the treatment, left ventricular mass (LVM) was calculated by three-dimensional echocardiography and CFR was evaluated by transesophageal echocardiography with left anterior descending artery. CFR was calculated as the ratio of coronary flow velocity, after intravenous injection of dipyridamole (D), to rest peak velocity (R). All the indexes of the CFR were corrected by LVM. (1) The systolic blood pressure (SBP), diastolic blood pressure (DBP) and LVM were significantly decreased in ramipril group, losartan group and combination group after 6 months treatment (all P < 0.01). Diastolic flow velocity integral was used as one representative index of CFR. Compared with baseline values, the diastolic flow velocity intergral corrected by LVM (D/R DVi(C)) was significantly increased in ramipril group, losartan group and combination group (1.83 +/- 0.61 vs 1.57 +/- 0.58, P < 0.05; 1.94 +/- 0.45 vs 1.53 +/- 0.64, P < 0.01; 2.03 +/- 0.38 vs 1.49 +/- 0.34, P < 0.01). (3) The changes of D/R DVi(C) showed a positive correlation with the changes of LVM (r = 0.579, P < 0.05) and no significant correlation with the decrease of blood pressure (r = 0.288 and 0.295,both P > 0.05). Ramipril, losartan and combination of these two drugs all reduce blood pressure and LVH, and increases CFR. CFR corrected by LVM may help assess drug's effect on CFR. Improvement of CFR is associated with the regression of hypertensive LVH.

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Profile of antibiotic consumption, sensitivity and resistance in an urban area of Andhra Pradesh, India.

Antibiotics are an important category of drugs in which indiscriminate use can affect the susceptibility patterns among infectious organisms, resulting in antibiotic resistance. Data on antibiotic usage and susceptibility patterns were collected from public and private health centres in Vijayawada, Andhra Pradesh, India, through the use of questionnaires. The data collected were then coded, tabulated, computed and evaluated using statistical analysis. The consumption profile of the different categories of drugs used in public and private hospitals was as follows: nutrition and metabolism products 19.0%; gastrointestinal disorder-related drugs 18.5%; antibiotics 16.8%; anti-pyretics and anti-analgesics 20.6%. These drugs were found to be in high demand. Among the antibiotics, aminoglycosides (amikacin), quinolones (ofloxacin, ciprofloxacin), tetracyclines (doxycycline), penicillin (ampicillin) and sulphonamides (co-trimoxazole) were the most commonly prescribed drugs for antibiotic therapy. 46% of the culture laboratory reports were positive with the following organism profile: Escherichia coli (36%), Klebsiella pneumoniae (16%), Staphylococcus aureus (29%), Enterococcus faecalis (9%) and Pseudomonas aeruginosa (10%). In terms of the sensitivity profile of antibacterials, amikacin (66.9%) was the only antibiotic showing sensitivity patterns, while the majority of antibiotics, such as cotrimoxazole, nalidixic acid, amoxicillin, gentamycin and norfloxacin, had acquired a resistance rate of 55.1%-80.6%. The results of this study suggest that indiscriminate prescription and consumption of new broad-spectrum antibiotics against sensitive organisms results in the development of antimicrobial resistance. Therefore, there is an urgent need to curb the excessive use of antibiotics in local hospitals in order to control the trend of increasing antimicrobial resistance to antibiotics.

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Bupropion and venlafaxine responders differ in pretreatment regional cerebral metabolism in unipolar depression.

Pretreatment functional brain imaging was examined for never-hospitalized outpatients with unipolar depression compared with control subjects in a crossover treatment trial involving bupropion or venlafaxine monotherapy. Patients (n = 20) with unipolar depression received baseline (medication-free) fluorine-18 deoxyglucose (FDG) positron emission tomography (PET) scan and then at least 6 weeks of bupropion or venlafaxine monotherapy in a single-blind crossover trial. Age-matched healthy control subjects (n = 20) also received baseline FDG PET scans. For each medication PET data from patients compared with control subjects was analyzed as a function of treatment response (defined as moderate to marked improvement on the Clinical Global Impression Scale). Treatment response rates were similar for buproprion (32%) and venlafaxine (33%). Compared with control subjects, responders but not nonresponders, to both drugs demonstrated frontal and left temporal hypometabolism. Selectively, compared with control subjects bupropion responders (n = 6) also had cerebellar hypermetabolism, whereas venlafaxine responders (n = 7) showed bilateral temporal and basal ganglia hypometabolism. These data suggest that pretreatment frontal and left temporal hypometabolism in never-hospitalized depressed outpatients compared with control subjects is linked to positive antidepressant response and that additional alterations in regional metabolism may be linked to differential responsivity to bupropion and venlafaxine monotherapy.

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Cytomegalovirus infections in cardiac transplant patients: an experience at a clinical hospital, university of Chile.

Since cytomegalovirus (CMV) infects between 20% and 50% of heart transplant patients, we reviewed our experience in 7 cases of this infection. A prospective analysis of CMV infection was performed in heart transplant patients who received cyclosporine, azathioprine, or mycophenolate mofetil, and prednisone. An elevated creatinine de novo was managed with antibody induction. Between August 2001 and December 2005, we performed 22 heart transplants and 1 heart plus kidney transplant. Twenty-two patients were positive for CMV before transplantation. One patient died early because of graft failure. Immunosuppression included cyclosporine and prednisone (100%), azathioprine (52%), or mycophenolate (47%). Two recipients were induced with thymoglobulin and 13 with Daclizumab, while 8 did not receive any antibody. Nineteen patients received prophylaxis for CMV. Seven patients (30%) showed CMV infection, 6 of whom had received prophylaxis. Symptoms started at an average of 107 days posttransplantation in patients with prophylaxis. Three patients had gastritis, 2 pneumonia, and 1 colitis. One patient had concomitant lung aspergillosis. The two patients who received ATG developed CMV infections; 3 of the 12 with Daclizumab; and 2 who did not receive antibody. Of the CMV-infected subjects, 5 were on azathioprine and 2 on mycophenolate. All patients were treated with gancyclovir. The 1 patient with concomitant aspergillosis died. The incidence of infection by CMV was 30%. Prophylaxis seemed to delay infection. Daclizumab induction did not increase the risk for CMV.

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Effect of genetic variations on ticagrelor plasma levels and clinical outcomes.

Ticagrelor, a direct-acting P2Y12-receptor antagonist, is rapidly absorbed and partly metabolized to the major metabolite AR-C124910XX (ARC). To identify single-nucleotide polymorphisms (SNPs) associated with pharmacokinetics of ticagrelor and clinical outcomes, we performed a genome-wide association study (GWAS) in patients treated with ticagrelor in the PLATO trial. A two-stage design was used for the GWAS with discovery (discovery phase: n = 1812) and replication cohorts (replication phase: n = 1941). The steady-state area under the curve (AUCss) values, estimated by the population pharmacokinetic (PK) models, were log transformed and analysed on a genome-wide scale using linear regression. SNPs were analysed against clinical events using Cox-regression in 4990 patients. An SNP (rs113681054) in SLCO1B1 was associated with levels of ticagrelor (P = 1.1 × 10(-6)) and ARC (P = 4.6 × 10(-13)). This SNP is in linkage disequilibrium with a functional variant (rs4149056) that results in decreased OATP1B1 transporter activity. Ticagrelor levels were also associated with two independent SNPs (rs62471956, P = 7.7 × 10(-15) and rs56324128, P = 9.7 × 10(-12)) in the CYP3A4 region. Further, ARC levels were associated with rs61361928 (P = 3.0 × 10(-14)) in UGT2B7. At all loci, the effects were small. None of the identified SNPs that affected ticagrelor PK were associated with the primary composite outcome (cardiovascular death myocardial infarction, and stroke), non-CABG-related bleeds or investigator-reported dyspnoea. In patients with ACS, ticagrelor pharmacokinetics is influenced by three genetic loci (SLCO1B1, UGT2B7, and CYP3A4). However, the modest genetic effects on ticagrelor plasma levels did not translate into any detectable effect on efficacy or safety during ticagrelor treatment. NCT00391872.

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Role of diuretics in the preservation of residual renal function in patients on continuous ambulatory peritoneal dialysis.

Patients on continuous ambulatory peritoneal dialysis (CAPD) are dependent on residual renal function for solute and water clearances, and this declines with time on dialysis. Loop diuretics have been postulated to slow this decline. Sixty-one patients new to dialysis were randomly assigned to either furosemide 250 mg every day or no furosemide at the time of CAPD training and were followed prospectively. Urine volume (UV), urea clearance (C(Urea)), and creatinine clearance on cimetidine (C(Cr)) were measured at randomization at six months and at one year. Patients underwent a standard four-hour peritoneum equilibrium test, and total body water was measured by bioelectrical impedance. Results were expressed on an intention-to-treat basis. UV, C(Cr), and C(Urea) were similar at randomization (1020 +/- 104 vs. 1040 +/- 130 mL/24 hours, 4.95 +/- 0.51 vs. 4.07 +/- 0.40 mL/min/1.73 m2, 0.91 +/- 0.09 vs. 0.84 +/- 0.08, diuretic vs. control). UV in the diuretic-treated group increased, whereas in the control group, it declined (+176 vs. -200 mL/24 hours at 6 months and +48.8 vs. -305 mL/24 hours at 1 year, P < 0.05). C(Cr) and C(Urea) declined at a constant rate and were unaffected by diuretic administration (0.12 +/- 0.05 vs. 0.071 +/- 0.04 mL/min/1.73 m2/month, 0.020 +/- 0.01 vs. 0.019 +/- 0.01 per month). Urinary sodium excretion increased in the diuretic group and declined in the control group (+0.72 +/- 0.85 vs. -2.56 +/- 1.31 mmol/24 hours/month, P = 0.04). Body weight rose in both groups (4.3 vs. 3.0 kg), but the percentage of total body weight rose in the control group and remained constant in the diuretic group (52 +/- 2.4 vs. 64 +/- 6.6%, P = 0.10). Long-term furosemide produces a significant increase in UV over 12 months when on CAPD and may result in clinically significant improvement in fluid balance. However, furosemide has no effect on preserving residual renal function.

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Effect of allopurinol on the formation of reactive oxygen species during intense exercise in the horse.

Allopurinol was administered to six horses in a cross-over study to determine the relative contribution of xanthine oxidase (XO) activity to the formation of reactive oxygen species (ROS) in the horse during intense exercise. Exercise increased the mean (SEM) plasma lipid hydroperioxide concentration to a maximum of 492.7 (33.4) microM within one minute of exercise completion and maximum levels of both oxidised glutathione (GSSG) in haemolysates of red blood cells and the glutathione redox ratio (GRR) occurred 20 minutes after exercise (87.2 [12.2] microM and 8.9 [0.9] per cent, respectively). Allopurinol significantly reduced lipid hydroperoxides, GSSG and the GRR at the corresponding maximal times after exercise measured during control exercise (217.5 [32.1] microM. 63.8 [8.6] microM and 6.8 [0.7] per cent, respectively). Significantly higher levels of hypoxanthine and xanthine were measured after exercise in the plasma of horses that received allopurinol than in control horses, although uric acid levels remained constant. In control horses, plasma uric acid concentrations increased after exercise to a maximum 20 minutes after exercise of 28.1 (2.6) microM, significantly higher than in horses given allopurinol (9.6 [1.3] microM). The results show that the inhibition of XO by allopurinol leads to a decrease in the formation of ROS during exercise, and thus a reduction in oxidative stress.

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Long-term use of hydrocodone vs. oxycodone in primary care.

Hydrocodone and oxycodone are the Schedule II opioids most often prescribed in primary care. Notwithstanding the dangers of prescription opioid use, the likelihood of long-term use with either drug is presently unknown. Using a retrospective cohort design and data from a commerical healthcare claims repository, we compared the likelihood of long-term use of hydrocodone and oxycodone in primary care patients presenting with acute back pain. Treatment was categorized as long-term if the prescription dates spanned ≥90 days from initial prescription to the run-out date of the last prescription, and included ≥120 days' supply or ≥10 fills. Instrumental variable methods and probit regression were used to model the effect of drug choice on long-term use, estimate the average treatment effect, and correct for confounding by indication. A total of 3,983 patients who were prescribed only hydrocodone or only oxycodone were followed for 270 days in 2016. Long-term opioid use was observed in 320 patients (8%). Controlling for potential confounders including morphine milligram equivalents and dosage, an estimated 12% (95 CI, 10%-14%) treated with hydrocodone transitioned to long-term use vs. 2% (95 CI, 1%-3%) on oxycodone. Among patients who received more than one prescription (n = 1,866), an estimated 23% (95 CI, 19%-26%) treated with hydrocodone transitioned to long-term use vs. 5% (95 CI, 3%-7%) on oxycodone. The difference between drugs was supported in sensitivity and subgroup analyses. Sample selection bias was not detected. Long-term use was substantially greater for patients treated with hydrocodone than oxycodone, despite equianalgesia.

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Obstructive jaundice in autoimmune pancreatitis can be safely treated with corticosteroids alone without biliary stenting.

Autoimmune pancreatitis (AIP) responds dramatically to corticosteroids treatment. We reviewed our experience to determine the safety and effectiveness of treating obstructive jaundice in definitive AIP with corticosteroids alone without biliary stenting. From our AIP database, we retrospectively identified type 1 AIP subjects whose jaundice was treated with corticosteroids alone without biliary stenting. Their medical records were reviewed and clinical data were evaluated to determine the outcomes. Fifteen AIP subjects (87% male, mean age 68.4 years) were treated with corticosteroids at initial presentation (n = 8), first (n = 5) or subsequent (n = 2) relapse. Mean values (upper limit of normal, ULN) of liver tests prior to corticosteroids were aspartate aminotransferase (AST) 203.5u/l (4 × ULN), alanine aminotransferase (ALT) 325.8u/l (6 × ULN), alkaline phosphatase (ALP) 567.4u/l (5 × ULN), and total bilirubin (TB) 5.9 mg/dl (5.9 × ULN). At first follow-up (mean 4 days) the decrease was 54.9% for AST, 51.6% for ALT, 33% for ALP and 47.2% for TB (all p < 0.05). After 15-45 days, all patients had normal AST, 3/15 had ALT > 1.5 × ULN, 1/15 had ALP > 1.5 × ULN, 1/15 had TB > 1.5 × ULN. No patient required biliary stent placement, or developed cholangitis or other infectious complications during steroid treatment. Under the supervision of an experienced pancreatologist and with close monitoring of patients, obstructive jaundice secondary to definitive AIP can be safely and effectively managed with corticosteroids alone, without the need for biliary stenting.

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Dose-Dense Rituximab-CHOP versus Standard Rituximab-CHOP in Newly Diagnosed Chinese Patients with Diffuse Large B-Cell Lymphoma: A Randomized, Multicenter, Open-Label Phase 3 Trial.

Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone administered every 3 weeks (R-CHOP-21) is the standard care for diffuse large B-cell lymphoma (DLBCL). It is unknown whether the dose-dense R-CHOP (R-CHOP-14) could improve the outcome of the disease in Asian population. Newly diagnosed DLBCL patients were centrally, randomly assigned (1:1) to receive R-CHOP- 14 or R-CHOP-21. R-CHOP-14 was administered every 2 weeks, and R-CHOP-21 was administered every 3 weeks. Primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS), progression-free survival (PFS), response rate and toxicities. Seven hundred and two patients were randomly assigned to receive R-CHOP-14 (n=349) or R-CHOP-21 (n=353). With a median follow-up of 45.6 months, the two groups did not differ significantly in 3-year DFS (79.6% for R-CHOP-14 vs. 83.2% for R-CHOP-21, p=0.311), 3-year OS (77.5% for R-CHOP-14 vs. 77.6% for R-CHOP-21, p=0.903), or 3-year PFS (63.2% for R-CHOP-14 vs. 66.1% for R-CHOP-21, p=0.447). Patients with an International Prognostic Index (IPI) score ≥ 2 had a poorer prognosis compared to those with an IPI score < 2. Grade 3/4 hematologic and non-hematologic toxicities were manageable and similar between R-CHOP-14 and R-CHOP-21. R-CHOP-14 did not improve the outcome of DLBCL compared to R-CHOP-21 in Asian population. With manageable and similar toxicities, both of the two regimens were suitable for Asian DLBCL patients. For high-risk patients with IPI ≥ 2, new combination regimens based on R-CHOP deserve further investigation to improve efficacy.

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Influence of the angiotensin II antagonist valsartan on left ventricular hypertrophy in patients with essential hypertension.

Left ventricular hypertrophy (LVH) represents an independent risk factor in patients with essential hypertension. Because reversal of LVH may be associated with an improvement of prognosis, the influence of new antihypertensive compounds, such as angiotensin II AT1 receptor antagonists, on LVH should be determined. In a randomized, double-blind trial, 69 predominantly previously untreated hypertensive patients with echocardiographically proven LVH, ie, left ventricular mass index (LVMI) >134 g/m2 in men and >110 g/m2 in women and/or end-diastolic septal thickness >12 mm, received either the angiotensin II antagonist valsartan or atenolol for 8 months. Echocardiographic data of 58 patients were available. After 8 months of valsartan treatment (n=29), LVMI decreased from 127+/-23 to 106+/-25 g/m2 (ratio [R]=0.83; 95% CI, 0.79 to 0.87; P<0.0001 versus baseline). Under atenolol (n=29), LVMI decreased to a smaller extent, from 127+/-25 to 117+/-27 g/m2 (R=0.92; 95% CI, 0.86 to 0.98; P=0.0082 versus baseline). The mean reduction of LVMI came to 21 g/m2 under valsartan and only to 10 g/m2 under atenolol (R=0.91; 90% CI, 0.85 to 0.97 versus atenolol). Baseline mean blood pressure values were determined to be 163+/-12/101+/-6 mm Hg before treatment with valsartan and 160+/-14/103+/-6 mm Hg before atenolol treatment. After 8 months of treatment, mean blood pressure decreased to 146+/-13/90+/-7 mm Hg with valsartan and to 147+/-18/90+/-7 mm Hg with atenolol. Nine patients in the valsartan group and 8 patients in the atenolol group required additional medication with hydrochlorothiazide. Antihypertensive treatment with the angiotensin II antagonist valsartan for 8 months produced a significant regression of LVH in predominantly previously untreated patients with essential hypertension. The drug may be safely administered in this subset of hypertensive patients; however, the long-term benefit in terms of risk reduction has still to be evaluated in further trials.

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Sublingual administration of detomidine to calves prior to disbudding: a comparison with the intravenous route.

To study the effects of oromucosal detomidine gel administered sublingually to calves prior to disbudding, and to compare its efficacy with intravenously (IV) administered detomidine. Randomised, prospective clinical study. Twenty dairy calves aged 12.4 ± 4.4days (mean ± SD), weight 50.5 ± 9.0 kg. Detomidine at 80 μg kg(-1) was administered to ten calves sublingually (GEL) and at 30 μg kg(-1) to ten control calves IV (V. jugularis). Meloxicam (0.5 mg kg(-1) ) and local anaesthetic (lidocaine 3 mg kg(-1) ) were administered before heat cauterization of horn buds. Heart rate (HR), body temperature and clinical sedation were monitored over 240 minutes. Blood was collected from the V. cephalica during the same period for drug concentration analysis. Pharmacokinetic variables were calculated from the plasma detomidine concentration-time data using non-compartmental methods. Statistical analyses compared routes of administration by Student's t-test and linear mixed models as relevant. The maximum plasma detomidine concentration after GEL was 2.1 ± 1.2 ng mL(-1) (mean ±SD) and the time of maximum concentration was 66.0 ± 36.9 minutes. The bioavailability of detomidine was approximately 34% with GEL. Similar sedation scores were reached in both groups after administration of detomidine, but maximal sedation was reached earlier in the IV group (10 minutes) than in the GEL group (40 minutes). HR was lower after IV than GEL from 5 to 10 minutes after administration. All animals were adequately sedated, and we were able to administer local anaesthetic without resistance to all of the calves before disbudding. Oromucosally administered detomidine is an effective sedative agent for calves prior to disbudding.

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Clearing of cells bearing the bcl-2 [t(14;18)] translocation from blood and marrow of patients treated with rituximab alone or in combination with CHOP chemotherapy.

Patients who were PCR-positive for B-cell leukemia-lymphoma 2 (bcl-2) gene rearrangement [t(14;18)] were evaluated for responses to rituximab alone or combined with CHOP. Patients had relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma (IWF: A-D). The single-agent trial used 375 mg/m2 weekly x 4; combination therapy included six cycles of CHOP and six 375 mg/m2 infusions of rituximab. Bcl-2 analyses of bone marrow (BM) and peripheral blood (PB) samples at base-line and following therapy were performed using a PCR assay. In the single-agent trial, of 70 patients whose peripheral blood (PB) was bcl-2 positive at baseline, 36 became bcl-2-negative, 13 remained positive, and 21 varied between positive and negative. The overall response rates (ORRs) were 72%, 31%, and 57%, respectively. Twelve of twenty-two patients with repeat bone marrow (BM) samples were bcl-2-negative three months post-treatment. Of 18 patients in the combination trial, 8 were bcl-2 positive in PB and/or BM. All of seven patients positive in PB at baseline and six of seven patients positive in BM were negative at the end of therapy; all patients responded to treatment (100% ORR). Rituximab, alone or combined with CHOP, eradicated bcl-2 positive cells from PB and BM in over half of the patients treated and was associated with a high overall clinical response rate. The impact on disease-free and overall survival awaits long-term follow up.

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Effects of recombinant granulocyte colony-stimulating factor (G-CSF) in patients treated with ProMACE-CytaBOM for HIV-related non-Hodgkin's lymphoma (NHL).

The use of hematopoietic growth factors in association with chemotherapy in human immunodeficiency virus (HIV)-related non-Hodgkin's lymphoma (NHL) has been recommended, but few studies have evaluated its cost-effectiveness. The effects of recombinant granulocyte colony-stimulating factor (G-CSF) were analyzed in 33 consecutive patients with HIV-related NHL treated at a single institution with the same chemotherapy program, ProMACE-CytaBOM, with G-CSF, in 21 cases diagnosed after December 31, 1991, or without G-CSF, in 12 cases diagnosed earlier. Pearson's chi-square analysis and the two-sided Student's t-test were used for statistical comparisons. The method of Kaplan-Meyer and the log-rank-test were used for survival analyses. G-CSF support significantly reduced the frequency of day-1 drug dose reductions (p < 0.001) and of chemotherapy delays (p < 0.001), and improved the actual delivered doses of adriamycin, cyclophosphamide and etoposide (p < 0.02). In patients with a CD4+ count < 0.01 x 10(9)/L, chemotherapy could be given at full doses in 90% of cycles with G-CSF compared to only 20% without it. G-CSF affected neither the frequency and duration of fever and hospitalization nor the complete remission and survival rates after stratification according to the CD4+ count. G-CSF support significantly improved dose-intensity in patients with HIV-related NHL treated with aggressive chemotherapy, particularly in the subgroup with a CD4+ count < 0.1 x 10(9)/L, but it did not improve their clinical outcome.

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Renal clearance of lomefloxacin is decreased by furosemide.

The interaction between lomefloxacin, a new quinolone, and furosemide, a loop diuretic, has been examined. Oral lomefloxacin 200 mg and furosemide 40 mg were given together or separately to 8 healthy subjects, and blood and urine samples were obtained over the following 12 h. The plasma concentrations of lomefloxacin following coadministration with furosemide were higher than after lomefloxacin alone and its AUC was increased, and its total and renal clearances were decreased. No change in the pharmacokinetics of furosemide was found after coadministration of lomefloxacin. As quinolones and furosemide are reported to be excreted in urine by the renal tubular anion transport system, the present results suggest that the renal tubular secretion of lomefloxacin is diminished by furosemide. It is not clear whether this pharmacokinetic interaction might be clinically important.

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Hyperlipoproteinemia affects cytokine production in whole blood samples ex vivo. The influence of lipid-lowering therapy.

Low-density lipoprotein (LDL)-receptor deficient mice, thus hypercholesterolemic, combine protection against infection with an ex vivo two- to threefold higher pro-inflammatory cytokine production in macrophages. A pro-inflammatory cytokine profile ex-vivo is also associated with survival of gram-negative sepsis in man. We hypothesized that high lipoprotein levels would be associated with a pro-inflammatory cytokine production and could explain the resistance to fatal infection. We treated 10 patients with familial hypercholesterolemia (FH) with HMG-CoA reductase inhibitors, and 13 patients with endogenous hypertriglyceridemia (HTG) with fibrates. Blood samples were stimulated ex vivo with lipopolysaccharide (LPS), to assess the cytokine production capacity. FH patients had significantly lower tumor necrosis factor-alpha (TNF-alpha) production, compared to normolipidemic controls (P=0. 001). Lipid lowering treatment in FH patients did not affect TNF-alpha production. HTG patients showed significantly higher TNF-alpha production at baseline than matched normolipidemic controls (P<0.001), while lowering of serum triglycerides in these patients resulted in a significant decrease in TNF-alpha production (P=0.019). The IL-10 production was not affected. These data refute our hypothesis that high LDL-cholesterol levels are associated with a pro-inflammatory cytokine production capacity. In contrast, the study suggests that very-low-density lipoprotein (VLDL) in hypertriglyceridemic patients augments TNF-alpha production.

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Statins ameliorate cholesterol-induced inflammation and improve AQP2 expression by inhibiting NLRP3 activation in the kidney.

<b>Background:</b> Chronic kidney diseases (CKD) are usually associated with dyslipidemia. Statin therapy has been primarily recommended for the prevention of cardiovascular risk in patients with CKD; however, the effects of statins on kidney disease progression remain controversial. This study aims to investigate the effects of statin treatment on renal handling of water in patients and in animals on a high-fat diet. <b>Methods:</b> Retrospective cohort patient data were reviewed and the protein expression levels of aquaporin-2 (AQP2) and NLRP3 inflammasome adaptor ASC were examined in kidney biopsy specimens. The effects of statins on AQP2 and NLRP3 inflammasome components were examined in <i>nlrp3^-/-</i> mice, 5/6 nephroectomized (5/6Nx) rats with a high-fat diet (HFD), and <i>in vitro</i>. <b>Results:</b> In the retrospective cohort study, serum cholesterol was negatively correlated to eGFR and AQP2 protein expression in the kidney biopsy specimens. Statins exhibited no effect on eGFR but abolished the negative correlation between cholesterol and AQP2 expression. Whilst <i>nlrp3^+/+</i> mice showed an increased urine output and a decreased expression of AQP2 protein after a HFD, which was moderately attenuated in <i>nlrp3</i> deletion mice with HFD. In 5/6Nx rats on a HFD, atorvastatin markedly decreased the urine output and upregulated the protein expression of AQP2. Cholesterol stimulated the protein expression of NLRP3 inflammasome components ASC, caspase-1 and IL-1β, and decreased AQP2 protein abundance <i>in vitro</i>, which was markedly prevented by statins, likely through the enhancement of ASC speck degradation via autophagy. <b>Conclusion:</b> Serum cholesterol level has a negative correlation with AQP2 protein expression in the kidney biopsy specimens of patients. Statins can ameliorate cholesterol-induced inflammation by promoting the degradation of ASC speck, and improve the expression of aquaporin in the kidneys of animals on a HFD.

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Efficacy of sulfonylureas with insulin in type 2 diabetes mellitus.

In subjects with type 2 diabetes mellitus, glycemic control deteroriates while patients use sulfonylurea drugs during the course of the disease. Adjunctive therapy with insulin at this stage requires a lesser daily insulin dose in comparison with insulin monotherapy while restoring desirable glycemic control. However, data regarding direct comparison between various sulfonylureas in this regard are lacking. To examine comparative efficacies of adjunctive therapy with insulin in subjects with type 2 diabetes manifesting lapse of glycemic control while receiving various individual sulfonylurea drugs. Four groups of 10 subjects, each presenting with glycosylated hemoglobin (HbA(1C)) >8.0% while using either tolazamide, glyburide, glipizide Gastrointestinal Therapeutic System (GITS), or glimepiride, were recruited. Two from each group were randomized to receive placebo; the others continued the same drug. Pre-supper subcutaneous 70 NPH/30 regular insulin was initiated at 10 units and gradually increased and adjusted as necessary to attain fasting blood glucose levels between 80 and 120 mg/dL and maintain the same range for 6 months. Fasting plasma glucose, plasma C-peptide, and HbA(1C) concentrations were determined prior to the addition of insulin and at the end of the study. Daily insulin dose and changes in body weight (BW) were noted at the end of the study, and the number of hypoglycemic events during the last 4 weeks of the study was determined. Daily insulin dose (units/kg BW), weight gain, and number of hypoglycemic events were significantly lower (p < 0.01) in subjects receiving sulfonylureas in comparison with placebo. However, the daily insulin dose alone was significantly lower (p < 0.05) with glimepiride (0.49 +/- 0.10; mean +/- SE) than with other sulfonylureas (tolazamide 0.58 +/- 0.12, glyburide 0.59 +/- 0.12, glipizide GITS 0.59 +/- 0.14). Finally, a significant correlation (r = 0.68; p < 0.001) was noted between suppression of plasma C-peptide level and the daily insulin dose among all participants. By lowering the daily insulin dose, sulfonylurea drugs appear to improve the sensitivity of exogenous insulin in subjects with type 2 diabetes mellitus manifesting lapse of glycemic control. Moreover, glimepiride appears to possess a greater insulin-sparing property than other sulfonylureas.

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[Calcium antagonists in cardiovascular disease. Clinical evidence from morbidity and mortality trials].

Calcium antagonists, particularly the newer, longer-acting agents, are clearly effective in reducing elevated blood pressure with minimal to modest adverse effect profiles, and are therefore used extensively. The goal of antihypertensive therapy, however, is not simply to reduce blood pressure, but also to reduce vascular injury due to hypertension. Prospective controlled clinical trials evaluating cardiovascular morbidity and mortality are needed to test calcium antagonists in patients with hypertension. This review summarises the design and, in some cases, the results of 7 trials (5 of them still ongoing) that have provided insight into the effects of moderate- to long-acting calcium antagonists on mortality and target-organ damage in patients with hypertension. The Systolic Hypertension in Europe (Syst-Eur) trial studied 4695 elderly patients with isolated systolic hypertension, and demonstrated significant reductions in stroke and all fatal and nonfatal cardiac end-points in patients randomised to nitrendipine versus placebo. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) compares the effects of standard diuretic treatment with 3 alternatives (amlodipine, lisinopril, and doxazosin) on the incidence of fatal coronary artery disease and nonfatal myocardial infarction in more than 42,000 hypertensive patients with additional cardiovascular risk factors. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) compares the effects of amlodipine +/- perindopril with atenolol +/- bendrofluazide on fatal coronary artery disease and nonfatal myocardial infarction in 18,000 high risk patients. The Controlled ONset Verapamil INvestigation of Cardiovascular End-points (CONVINCE) study is assessing the incidence of fatal or nonfatal myocardial infarction and stroke, and cardiovascular disease-related death in patients on controlled-onset extended-release verapamil compared with a standard regimen of hydrochlorothiazide or atenolol. The Nordic Diltiazem Study (NORDIL) also compares a calcium antagonist (diltiazem) with conventional antihypertensive drug treatment (diuretics or beta-blockers) with add-on therapy as needed, in preventing cardiovascular mortality or morbidity. The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) tests a similar hypothesis, examining the effects of amlodipine on atherosclerotic lesions. The African-American Study of Kidney Disease (AASK) trial is evaluating the effects of amlodipine in hypertensive patients with renal disease. These important clinical trials of different classes of antihypertensive agents are critical for optimising the treatment of hypertensive patients in order to prevent coronary artery disease and other vascular diseases in this new millennium. Importantly, these randomised trials are free of the major problems of observational studies, i.e., confounding by indication, and should fully address the concerns raised by observational studies and small, under-powered, randomised trials that calcium antagonists may have adverse effects on myocardial infarction, bleeding and cancer. To date, these trials in progress have provided no evidence to support these concerns.

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A comparison of fluoxetine imipramine and placebo in patients with bipolar depressive disorder.

This was a 6-week, double-blind comparison of fluoxetine, imipramine, and placebo in 89 patients with bipolar depression. Using the criteria of greater than or equal to 50% improvement in the HAMD-total score after at least 3 weeks on study drug, endpoint analysis showed 86% of the fluoxetine-treated patients improved compared with 57% of the imipramine-treated and 38% of the placebo-treated patients. Significantly fewer fluoxetine-treated patients discontinued due to adverse events than did imipramine-treated patients (7% vs. 30%, respectively).

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Comparative randomized trial evaluating the effect of proton pump inhibitor versus histamine 2 receptor antagonist as an adjuvant therapy in diffuse large B-cell lymphoma.

The development of drug resistance remains the major obstacle to clinical efficacy of cancer chemotherapy. Consequently, finding new therapeutic options for cancerous patients is an urgent need. Sixty newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients were recruited from Clinical Oncology Department, Faculty of Medicine, Menoufia University, Egypt prospectively randomized to three groups (n = 20 for each group). Group one (control group) received R-CHOP standard chemotherapy {Rituximab, Cyclophosphamide, Hydroxyldaunorubicin (Doxorubicin)®, Vincristine (oncovin)®, prednisolone in the first five days of cycle}, group two received lansoprazole (LAN) 60 mg p.o. bid for only one week before starting each of cycle + R-CHOP and group three received famotidine (FAM) 40 mg p.o. once daily one week before cycle and continues daily through the cycle + R-CHOP for six cycles. Blood samples were obtained for biochemical analysis of transforming growth factor-β (TGF-β), Basic fibroblast growth factor (bFGF), interleukin-9 (IL-9), nuclear factor-kappa B (NF-κB) and Caspase 3 before and after six cycles of therapy. The obtained data showed that LAN and FAM resulted in significant decrease in (LDH, TGF-β, bFGF and IL-9, respectively) and significant increase in (Caspase-3). In addition, LAN produced a significant elevation in the response rate compared to the control group or the FAM group. Both LAN and FAM as adjuvant therapy represents a promising anticancer strategy in DLBCL by modulation of malignancy homeostasis mechanisms and boosting chemotherapy antitumor effects without further toxicity. In addition, LAN has a synergetic effect in improving the response rate.Trial registration Clinical Trial.gov Identifier: NCT0364707.

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Determinants of compliance with methylphenidate therapy in children.

To get more insight into factors that influence compliance with the use of methylphenidate. 22 pharmacies detected children who used methylphenidate. Their parents were sent a questionnaire on the use of methylphenidate. In a case-control study, the influence of patient- and drug-related factors on compliance, as reported by parents, was determined. Parents returned 117 (75%) of 157 questionnaires sent out. Of these, 47.8% of the children missed a dose two times a month or more. Forgetting to take the medication (87.9%) was the most important reason. The case-control study showed that children of 16-18 y were more likely to miss doses. Other patient- and drug-related factors did not influence the missing of doses. A number of known determinants for compliance do not influence the missing of doses of methylphenidate. With about 80% of the parents reporting that their child missed doses of methylphenidate less than 5 times per month, compliance was quite good for the majority of the children.

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Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study.

Cryptococcus is the most common cause of adult meningitis in Africa. We assessed the safety and microbiological efficacy of adjunctive sertraline, previously shown to have in-vitro and in-vivo activity against cryptococcus. In this open-label dose-finding study, we recruited HIV-infected individuals with cryptococcal meningitis who presented to Mulago Hospital in Kampala, Uganda between Aug 14, 2013, and Aug 30, 2014. To assess safety and tolerability, the first 60 participants were given sertraline at escalating doses of 100 mg/day, 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for an additional 8 weeks. From Nov 29, 2013, participants were randomly assigned (1:1) to receive open-label sertraline at predetermined doses of 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for 8 weeks. Dose assignment was made via computer-generated, permuted block randomisation stratified by antiretroviral therapy (ART) status for people with a first episode of meningitis. The primary outcome was 2-week cerebrospinal fluid (CSF) clearance rate of cryptococcus, termed early fungicidal activity, measured in patients with a first episode of culture-positive meningitis and two or more CSF cultures. This study is registered with ClinicalTrials.gov, number NCT01802385. Of the 330 individuals assessed, 172 HIV-infected adults with cryptococcal meningitis were enrolled. We gave 100 mg/day sertraline to 17 patients, 200 mg/day to 12 patients, 300 mg/day to 14 patients, and 400 mg/day to 17 patients. 112 participants were randomly assigned to receive sertraline at 200 mg (n=48), 300 mg (n=36), or 400 mg (n=28) daily for the first 2 weeks, and 200 mg/day thereafter. The final population consisted of 17 participants in the 100 mg group, 60 in the 200 mg group, 50 in the 300 mg group, and 45 in the 400 mg in group. Participants receiving any sertraline dose averaged a CSF clearance rate of -0·37 colony forming units per mL per day (95% CI -0·41 to -0·33). Incidence of paradoxical immune reconstitution inflammatory syndrome was 5% (two of 43 newly starting ART) and no cases of relapse occurred over the 12-week study period. 38 (22%) of 172 participants had died at 2 weeks, and 69 (40%) had died at 12 weeks. Six grade 4 adverse events occurred in 17 participants receiving 100 mg, 14 events in 60 participants receiving 200 mg, 19 events in 50 participants receiving 300 mg, and eight events in 45 participants receiving 400 mg. Grade 4 or 5 adverse event risk did not differ between current US Food and Drug Administration-approved dosing of 100-200 mg/day and higher doses of 300-400 mg/day (hazard ratio 1·27, 95% CI 0·69-2·32; p=0·45). Participants receiving sertraline had faster cryptococcal CSF clearance and a lower incidence of immune reconstitution inflammatory syndrome and relapse than that reported in the past. This inexpensive and off-patent oral medication is a promising adjunctive antifungal therapy. National Institutes of Health, Grand Challenges Canada.

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Detrusor contraction duration may predict response to alpha-blocker therapy for lower urinary tract symptoms.

Baseline pressure/flow parameters have not correlated well with response to medical therapy for lower urinary tract symptoms (LUTS). This open-label, nonrandomized retrospective study was designed to evaluate whether the urodynamic parameter duration (in seconds) of the detrusor contraction (DCD) correlates better with alpha-blocker response than previously described urodynamic parameters. 93 men (mean age 62.6+/-8.5) with LUTS underwent urodynamic evaluation prior to initiating therapy with doxazosin titrated to 8 mg and followed for 6 months. Parameters of evaluation included the AUA symptom score (AUASx), peak urinary flow rate (Q(max)), maximal detrusor pressure (P(max)), detrusor pressure at maximal flow (P(det)) and DCD. The correlation and predictive value of therapeutic response and baseline urodynamic parameters were assessed. 85 patients were evaluable at 6 months. For the entire group, AUASx decreased from 15.1+/-6.9 to 9.7+/-5.1 (-36%) and Q(max) increased from 9.3+/-3.7 to 11.9+/-5.7 ml/s (+28%). Baseline P(max) was 74.8+/-19.6 cm H(2)O, P(det) was 61.6+/-18.9 cm H(2)O and DCD was 107.6+/-28.6 s. There was weak correlation between either baseline P(max) or P(det) and therapeutic response (defined as a decrease in AUASx of 40% and an increase in Q(max) of 30%). Utilizing a baseline DCD of 90 s or more, there was a significant correlation to therapeutic response (r = 0.48, p = 0.002). These preliminary data suggest that DCD may be a useful urodynamic parameter to predict and optimize therapy with a-blockade. The potential utility and cost-effectiveness of DCD remains to be determined.

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Effects of angiotensin II receptor blocker on proteinuria in renal transplant recipients.

Therapeutic approaches directed at reducing proteinuria are under development. The aim of the present study was to prospectively elucidate the impact of losartan treatment in renal transplant recipients with persistent proteinuria. Twenty-eight patients with persistent proteinuria or mild hypertension were assigned to receive losartan. Proteinuria was defined as a ratio of urinary protein to urinary creatinine (U(P)/U(Cr)) >0.5 in continual urinary tests in the outpatient setting. All patients with mild hypertension reached target blood pressure (BP) with losartan treatment, but the change was not significant. In twelve patients with proteinuria before initiation of the study, urinary protein excretion was significantly reduced with treatment. No correlation was observed between reductions in proteinuria and mean BP. A significant decrease was identified in the hemoglobin concentration of patients with serum creatinine concentrations >2.0 mg/dl before the study. Losartan efficiently reduces proteinuria in renal transplant recipients with adequate tolerance. Multicentric prospective studies are required to confirm its clinical effectiveness.

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Gastroduodenal ulcers in the Helicobacter pylori era.

The aim of the study was to evaluate the current spectrum of gastroduodenal ulcers in children referred to a regional paediatric unit in the United Kingdom. During a 5-y period (1994-98), all children with a visibly discrete gastric and/or duodenal ulcer diagnosed at endoscopy were prospectively identified. Patients with ulcers associated with Helicobacter pylori gastritis underwent repeat endoscopy 2-3 mo after medical treatment. Thirty-seven children, 21 boys and 16 girls of median age 11 y (range 7 mo to 16 y), had gastric and/or duodenal ulceration. Specific aetiological factors were identified in 21 of 22 with H. pylori negative ulcers, including Crohn's disease (n = 6), coeliac disease (n = 4) and treatment with ulcerogenic drugs (n = 4). Fifteen children (41%) had ulcers associated with H. pylori gastritis, including all 10 children with a chronic ulcer. Endoscopically confirmed ulcer healing was achieved in 14 of these using a 1 wk triple therapy regimen (omeprazole and a combination of two antibiotics). In conclusion, the recognized spectrum and the management of gastroduodenal ulceration have changed during the last decade. Although H. pylori gastritis is an important aetiological factor, a wide range of other conditions needs to be considered. Surgical intervention is only rarely necessary.

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An improved LC-MS/MS method for quantitative determination of ilaprazole and its metabolites in human plasma and its application to a pharmacokinetic study.

To improve and validate an analytical method based on liquid chromatography and electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) for the quantitative measurement of ilaprazole and its two metablites in human plasma. Separation of analytes and the internal standard (IS), omeprazole, was performed on a Thermo HyPURITY C18 column (150x2.1 mm, 5 microm) with a mobile phase consisting of 10 mmol/L ammonium formate water-acetonitrile solution (50:50, v/v) at a flow rate of 0.25 mL/min. The API4000 triple quadruple mass spectrometer was operated in multiple reactions monitoring mode via positive electrospray ionization interface using the transition m/z 367.2 --> m/z184.0 for ilaprazole, m/z 383.3 --> m/z 184.1 for ilaprazole sulfone, m/z 351.2 --> m/z 168.1 for ilaprazole thiol ether and m/z 346.2 --> m/z 198.0 for omeprazole. The method was linear over the concentration range of 0.23-2400.00 ng/mL for ilaprazole, 0.05-105.00 ng/mL for ilaprazole thiol ether and 0.06-45.00 ng/mL for ilaprazole sulfone. The intra- and inter-day precisions were all less than 15% in terms of relative standard deviation (RSD), and the accuracy was within 15% in terms of relative error (RE) for ilaprazole, ilaprazole sulfone and ilaprazole thiol ether. The lower limit of quantification (LLOQ) was identifiable and reproducible at 0.23, 0.05 and 0.06 ng/mL with acceptable precision and accuracy for ilaprazole, ilaprazole sulfone and ilaprazole thiol ether, respectively. The validated method offered sensitivity and a wide linear concentration range. This method was successfully applied for the evaluation of the pharmacokinetics of ilaprazole and its two metabolites after single oral doses of 5 mg ilaprazole to 12 healthy Chinese volunteers.

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Point-of-care platelet reactivity determination with VerifyNow-P2Y12 following administration of clopidogrel or prasugrel: data from a real-world, clinical care inpatient setting.

To describe VerifyNow-P2Y12 (VN-P2Y12, Accumetrics, San Diego, CA) results from patients treated with either clopidogrel or prasugrel who were seeking care in a hospital setting. VN-P2Y12 is a point-of-care device that measures platelet reactivity to adenosine diphosphate. Past assessments of thienopyridine therapy utilizing VN-P2Y12 have largely come from clinical trial settings. There are limited data from real-world settings. Electronic medical record data from Huntsville Hospital (Huntsville, AL) for those who underwent VN-P2Y12 testing for clopidogrel or prasugrel between January 1, 2009 and October 31, 2010 were analyzed. The VN-P2Y12 data included P2Y12 reaction units (PRUs) and device-reported percentage of inhibition. Descriptive analyses were conducted with t tests, and a logistic regression model was estimated to assess the association between patient characteristics and the likelihood of platelet nonresponse. In total, 2882 tests (2476 with clopidogrel and 406 with prasugrel) were analyzed. For clopidogrel and prasugrel, respectively, mean PRU standard deviation (SD) was 206 (90) and 107 (93; P < 0.0001) and mean % inhibition (SD) was 31% (26%) and 63% (31%; P < 0.0001). Treatment with clopidogrel alone (odds ratio [OR] = 5.25; P < 0.0001), being non-Caucasian (OR = 1.48; P = 0.0440), obese (OR = 1.49; P = 0.0010), anemic (OR = 3.29; P < 0.0001), diabetic (OR = 1.75; P < 0.0001), and having a history of myocardial infarction (OR = 1.57; P < 0.0001) were significant predictors of having PRU ≥ 235. This real-world data analysis shows results that are consistent with clinical trial results, namely that compared with clopidogrel, prasugrel is associated with significantly lower PRU and greater percentage of inhibition, regardless of age, race, gender, diabetes, obesity, or proton pump inhibitor use.

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Management of Severe Bleeding in Patients Treated with Direct Oral Anticoagulants: An Observational Registry Analysis.

The use of prothrombin complex concentrates and the role of plasma concentration of anticoagulants in the management of bleeding in patients treated with direct oral anticoagulants are still debated. Our aim was to describe management strategies and outcomes of severe bleeding events in patients treated with direct oral anticoagulants. We performed a prospective cohort study of 732 patients treated with dabigatran, rivaroxaban, or apixaban hospitalized for severe bleeding, included prospectively in the registry from June 2013 to November 2015. Bleeding was gastrointestinal or intracranial in 37% (212 of 732) and 24% (141 of 732) of the cases, respectively. Creatinine clearance was lower than 60 ml/min in 61% (449 of 732) of the cases. The plasma concentration of direct oral anticoagulants was determined in 62% (452 of 732) of the cases and was lower than 50 ng/ml or higher than 400 ng/ml in 9.2% (41 of 452) and in 6.6% (30 of 452) of the cases, respectively. Activated or nonactivated prothrombin complex concentrates were administered in 38% of the cases (281 of 732). Mortality by day 30 was 14% (95% CI, 11 to 16). Management of severe bleeding in patients treated with direct oral anticoagulants appears to be complex. The use of prothrombin complex concentrates differs depending on bleeding sites and direct oral anticoagulant plasma concentrations. Mortality differs according to bleeding sites and was similar to previous estimates.

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Assessment of echocardiographic left ventricular mass before and after acute volume depletion.

Left ventricular mass calculations are often performed to assess the need or effectiveness of antihypertensive drug therapy. However, there are multiple potential errors that may affect the accuracy of these calculations, which can possibly include acute changes in preload. Therefore, to assess the hypothesis that acute volume depletion might alter calculated left ventricular mass, 15 normotensive healthy male volunteers underwent standard M-mode echocardiographic evaluations (at the level of the chordae tendineae guided by two-dimensional echocardiography) before and 2 h after 40 mg of intravenous furosemide. One patient was eliminated due to hypotension prior to the final echocardiogram. The echocardiograms were blinded to patient identity and the time sequence and read separately by two investigators. Four to five cycles were read per echocardiogram by each investigator. All values measured were the mean of the two investigators. Echocardiographic measurements were derived by both the American Society of Echocardiography and Penn conventions. An average urine volume of 1728 mL was collected, and the mean weight change 2 h after furosemide administration was 1.78 kg (P = .001). Penn left ventricular diastolic diameter (1.8 mm, P = .015) and left ventricular mass index (10 g/m2, P = .04) were significantly decreased; however, there was no significant change in septal, posterior, or relative wall thicknesses. As it is unreasonable to believe that acute remodeling of the left ventricle resulted in a decline in left ventricular mass in 2 hours, it is concluded that acute volume changes resulted in a decrease in left ventricular mass measurement due to the influence of diastolic diameter on the calculation of cardiac mass.

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Facial pain following sinonasal surgery or facial trauma.

The case notes of 22 patients who reported facial pain after sinonasal surgery or trauma out of a cohort of 973 patients seen in a rhinology clinic were reviewed retrospectively. This group included 10 patients who had undergone endoscopic sinus surgery and four who had suffered facial fractures. None of the patients reported any facial pain before surgery or trauma. In only one case was there any evidence, clinically, endoscopically, or radiologically, of any paranasal sinus disease and when this resolved with nasal medical treatment the pain remained. The treatment of these patients' facial pain centred on the use of neurological medical treatment. One third of the patients responded to low-dose amitriptyline, a further third showed some response to other pharmacological agents including carbamazepine, and the remaining third showed no response. These cases illustrate the characteristics and management of facial pain after sinonasal surgery and highlight the importance of medical neurological treatment in the absence of any objective evidence of sinus disease.

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Anti-inflammatory interventions in end-stage kidney disease: a randomized, double-blinded, controlled and crossover clinical trial on the use of pravastatin in continuous ambulatory peritoneal dialysis.

Inflammation is highly prevalent in patients on dialysis. Statins have anti-inflammatory actions but their use has been scarcely studied in continuous ambulatory peritoneal dialysis (CAPD). We undertook this study to compare the effect of pravastatin vs. placebo on the serum concentrations of C-reactive protein (CRP) in patients on CAPD. In a double-blind, controlled and crossover clinical trial, 76 CAPD patients were randomized to either pravastatin or placebo for 2 months. After this first period of treatment, patients had a 1-month wash-out period and, finally, they were crossed-over to receive the other drug (or placebo) for 2 more months. Measurement of clinical and biochemical variables and CRP was performed at the beginning and at the end of each treatment period. Median CRP was only significantly decreased in the pravastatin group in both periods of treatment: first period (baseline vs. final, mg/L): pravastatin 7.4 (2-21) vs. 2.6 (1-6), p <0.05; placebo 3.9 (2-10) vs. 6.8 (3-12), pNS; second period: pravastatin 4.3 (2-15) vs. 1.9 (1-7), p <0.05; placebo 4.9 (2-17) vs. 6.8 (2-19), p <0.05. Results were significantly different (p <0.05) between groups only at the end of each treatment period. Additionally, total and LDL-cholesterol significantly decreased in the pravastatin group. Pravastatin significantly reduced serum levels of CRP and total and LDL-cholesterol compared to placebo. This treatment may be of great help to decrease the inflammatory status and probably the cardiovascular disease of CAPD patients.

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Can type 2 diabetes mellitus be considered preventable?

The primary prevention of type 2 diabetes mellitus (T2DM) is of great importance. There is now substantial evidence that T2DM can be prevented or delayed by lifestyle modification. A statistically significant reduction of relative risk of newly diagnosed T2DM was observed in large clinical trials with metformin, acarbose or orlistat in subjects with impaired glucose tolerance as well as with troglitazone in women with previous gestational diabetes. A relative risk reduction of newly diagnosed diabetes was observed in prospective, double blind clinical studies evaluating the effect of different antihypertensive drugs (ACE-inhibitors, angiotensin repector blockers, calcium channel blockers) or that of lipid-lowering agents (pravastatin) on the cardiovascular morbidity and mortality in high risk patients. In studies with postmenopausal hormone replacement therapy a relative risk reduction of newly developed T2DM was also observed. Thus, T2DM should be considered as a preventable disease. Nevertheless, it is noteworthy that oral antidiabetic drugs with an indication of preventing T2DM are not registered in several countries at present, so that drug therapy should not be used as a routine for preventing diabetes. On the other hand, patients with pre-diabetes (impaired fasting glycaemia, impaired glucose tolerance) should be given counseling on weight loss as well as instruction for increasing physical activity in order to prevent T2DM.

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Occurrence and Genomic Characterization of Clone ST1193 Clonotype 14-64 in Uncomplicated Urinary Tract Infections Caused by Escherichia coli in Spain.

We conducted a prospective, multicenter, specific pilot study on uncomplicated urinary tract infections (uUTI). One-hundred non-duplicated uropathogenic Escherichia coli (UPEC) from uUTI occurred in 2020 in women attending 15 primary care centers of a single health region of northern Spain were characterized using a clonal diagnosis approach. Among the high genetic diversity showed by 59 different phylogroup-clonotype combinations, 11 clones accounted for 46% of the isolates: B2-ST73 (CH24-30); B2-ST73 (CH24-103); B2-ST131 (CH40-30); B2-ST141 (CH52-5); B2-ST372 (CH103-9); B2-ST404 (CH14-27); B2-ST404 (CH14-807); B2-ST1193 (CH14-64); D-ST69 (CH35-27); D-ST349 (CH36-54), and F-ST59 (CH32-41). The screening of the UPEC status found that 69% of isolates carried ≥ 3 of <i>chuA, fyuA, vat</i>, and <i>yfcV</i> genes. Multidrug resistance to at least one antibiotic of ≥ 3 antimicrobial categories were exhibited by 30% of the isolates, with the highest rates of resistance against ampicillin/amoxicillin (48%), trimethoprim (35%), norfloxacin (28%), amoxicillin-clavulanic acid (26%), and trimethoprim-sulfamethoxazole (24%). None extended-spectrum beta-lactamase/carbapenemase producer was recovered. According to our results, fosfomycin and nitrofurantoin should be considered as empirical treatment of choice for uUTI by E. coli (resistance rates 4% and 2%, respectively). We uncover the high prevalence of the pandemic fluoroquinolone-resistant ST1193 clone (6%) in uUTI, which represents the first report in Spain in this pathology. The genomic analysis showed similar key traits than those ST1193 clones disseminated worldwide. Through the SNP comparison based on the core genome, the Spanish ST1193 clustered with isolates retrieved from the Enterobase, showing high genomic similarity than the global ST1193 described in the United States, Canada and Australia. <b>IMPORTANCE</b> Analyzing the clonal structure and antimicrobial resistance of E. coli isolates implicated in uncomplicated urinary tract infections, one of the most frequent visits managed in primary health care, is of interest for clinicians to detect changes in the dynamics of emerging uropathogenic clones associated with the spread of fluoroquinolone resistance. It can also provide consensus concerning optimal control and antibiotic prescribing.

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Effects of trazodone hydrochloride and imipramine on polysomnography in healthy subjects.

Polysomnography was performed on eight healthy men with trazodone hydrochloride, imipramine and placebo. Trazodone hydrochloride increased slow wave sleep significantly. Imipramine prolonged rapid eye movement (REM) latency and decreased the percentage of REM sleep significantly. Trazodone decreased stages 1 and 2 sleep, while imipramine increased it. These findings suggest that the antidepressive effect of trazodone might be different from that of imipramine with the suppression of REM sleep.

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Mortality from tuberculous meningitis reduced by steroid therapy.

In this study of 99 tuberculous meningitis patients from Cali, Colombia, treatment with steroids (in conjunction with antituberculous drugs) was shown to be more effective in reducing mortality than treatment with antibacterial drugs alone. Results further suggest that low dosages of steroids (1 mg/kg of prednisone daily for r 30 days) are equally effective in treating the disease as high dosages (10 mg/kg of prednisone at the start of treatment, gradually reduced over a 30-day period). These results are band 4(-43 and -kk mg/100 ml) demonstrated cerebral release. Arterial blood hyperammonemia can be detoxified safely in the brain as long as the levels do not exceed approximately 300 mug/100 ml. Beyond that level lactic acidosis is observed, particularly in cerebral venous drainage. Arterial blood hyperammonemia was also related to the extent of alveolar hyperventilation. These findings are very similar to those seen in experimental hyperammonemia and support the concept that neurotoxicity in children with Reye's syndrome is at least partly due to impaired oxidative metabolism secondary to hyperammonemia.

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Patients with high-risk DLBCL benefit from dose-dense immunochemotherapy combined with early systemic CNS prophylaxis.

Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We conducted a phase 2 trial in 139 patients aged 18 to 64 years who had primary DLBCL with an age-adjusted International Prognostic Index (aaIPI) score of 2 to 3 or site-specific risk factors for CNS recurrence. The goal was to assess whether a dose-dense immunochemotherapy with early systemic CNS prophylaxis improves the outcome and reduces the incidence of CNS events. Treatment consisted of 2 courses of high-dose methotrexate in combination with biweekly rituximab (R), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-14), followed by 4 courses of R-CHOP-14 with etoposide (R-CHOEP) and 1 course of high-dose cytarabine with R. In addition, liposomal cytarabine was administered intrathecally at courses 1, 3, and 5. Coprimary endpoints were failure-free survival and CNS progression rates. Thirty-six (26%) patients experienced treatment failure. Progression occurred in 23 (16%) patients, including three (2.2%) CNS events. At 5 years of median follow-up, failure-free survival, overall survival, and CNS progression rates were 74%, 83%, and 2.3%, respectively. Treatment reduced the risk of progression compared with our previous trial, in which systemic CNS prophylaxis was given after 6 courses of biweekly R-CHOEP (hazard ratio, 0.49; 95% CI, 0.31-0.77; P = .002) and overcame the adverse impact of an aaIPI score of 3 on survival. In addition, outcome of the patients with BCL2/MYC double-hit lymphomas was comparable to the patients without the rearrangements. The results are encouraging, with a low toxic death rate, low number of CNS events, and favorable survival rates. This trial was registered at www.clinicaltrials.gov as #NCT01325194.

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Prognosis of patients with peripheral T cell lymphoma who achieve complete response after CHOP/CHOP-like chemotherapy without autologous stem cell transplantation as an initial treatment.

Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)/CHOP-like chemotherapy has been mostly applied to patients with untreated peripheral T cell lymphoma (PTCL). Because the long-term outcome of patients with PTCL, especially those achieving complete response (CR), has not been fully elucidated, we retrospectively analyzed 78 consecutive patients initially treated with CHOP/CHOP-like chemotherapy, without high-dose chemotherapy followed by autologous stem cell transplantation (HDC/auto-SCT). Median overall and progression-free survivals in all 78 patients were 44 and 17 months, respectively, with a median follow-up of 62 months. In the 53 patients achieving CR, the median relapse-free survival (RFS) was 21 months, and 2-, 3-, and 5-year RFSs were 46, 45, and 36%, respectively. Although our results showed an unfavorable outcome for PTCL as a whole, those who achieved CR following CHOP/CHOP-like chemotherapy did not always have a poor outcome without the consolidation of HDC/auto-SCT; in particular, 45% of the 65 years or younger patients were alive without disease at 5 years.

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Clinical Characteristics of Severe Histiocytic Necrotizing Lymphadenitis (Kikuchi-Fujimoto Disease) in Children.

To analyze the clinical characteristics of children with Kikuchi-Fujimoto disease focusing on cases with prolonged fever. This was a retrospective study of children diagnosed with Kikuchi-Fujimoto disease from March 2003 to February 2015 in South Korea. Electronic medical records were searched for clinical and laboratory manifestations. Among 86 histopathologically confirmed cases, the mean age was 13.2 (SD ± 3.1) years, and male to female ratio was 1:1.32. Cervical lymph node enlargement, found in 85 of the patients (99%), was predominantly unilateral in 64 (75%), and involved the cervical lymph node level V in 67 (81%). Fever was present in 76% of the cases, with a median duration of 9 days (IQR 0.25-17.0). Multivariate analysis revealed that a high fever peak ≥ 39.0°C (P = .010) and presentation with ≥ 2 systemic symptoms other than fever (P = .027) were factors that were significantly associated with longer fever duration. As the size of the largest lymph node's short diameter increased, the fever duration increased (P = .015). Leukopenia (P = .022) also had a significant association with a longer fever duration. Patients with sonographic findings of conglomerated enlarged lymph nodes had a longer median duration of fever compared with those with separate enlarged lymph nodes (11 vs 4.5 days, P = .019). Patients with high fever, more systemic symptoms, leukopenia, and larger lymph nodes with a conglomerated distribution may benefit from early recognition and selective consideration of corticosteroid therapy.

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Effects of once-daily angiotensin-converting enzyme inhibition and calcium channel blockade-based antihypertensive treatment regimens on left ventricular hypertrophy and diastolic filling in hypertension: the prospective randomized enalapril study evaluating regression of ventricular enlargement (preserve) trial.

The Prospective Randomized Enalapril Study Evaluating Regression of Ventricular Enlargement (PRESERVE) study was designed to test whether enalapril achieves greater left ventricular (LV) mass reduction than does a nifedipine gastrointestinal treatment system by a prognostically meaningful degree on a population basis (10 g/m(2)). An ethnically diverse population of 303 men and women with essential hypertension and increased LV mass at screening echocardiography were enrolled at clinical centers on 4 continents and studied by echocardiography at baseline and after 6- and 12-month randomized therapy. Clinical examination and blinded echocardiogram readings 48 weeks after study entry in an intention-to-treat analysis of 113 enalapril-treated and 122 nifedipine-treated patients revealed similar reductions in systolic/diastolic pressure (-22/12 versus -21/13 mm Hg) and LV mass index (-15 versus -17g/m(2), both P>0.20). No significant between-treatment difference was detected in population subsets defined by monotherapy treatment, sex, age, race, or severity of baseline hypertrophy. Similarly, there was no between-treatment difference in change in velocities of early diastolic or atrial phase transmitral blood flow. More enalapril-treated than nifedipine-treated patients required supplemental treatment with hydrochlorothiazide (59% versus 34%, P<0.001) but not atenolol (27% versus 22%, NS). Once-daily antihypertensive treatment with enalapril or long-acting nifedipine, plus adjunctive hydrochlorothiazide and atenolol when needed to control blood pressure, both had moderately beneficial and statistically indistinguishable effects on regression of LV hypertrophy.

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[Progress in the treatment of multiple myeloma].

Melphalan and prednisolone (MP) have been the standard therapy for multiple myeloma for more than 25 years. Although they produce an objective response in 50-60% of patients, complete remission (CR) is rare and the median survival period is generally 24 to 30 months. Many combination chemotherapeutic agents have been used and resulted in approximately 70% objective response, but the median duration of survival has not significantly been improved. VAD regimen is effective for many patients with myeloma resistant to MP therapy. Furthermore, VAD-cyclosporin combination induces responses in approximately 40% of patients with VAD-resistant myeloma, with increased expression of the multi-drug resistant gene (MDR). Intravenous administration of high dose-melphalan also produces responses in approximately 30% of patients with myeloma resistant to VAD. Interferon-alpha therapy with an alkylating agent-glucocorticoid regimen, shows a higher response rate but similar survival time, compared with those obtained with the MP therapy alone. High-dose therapy with transplantation is promising. High-dose therapy combined with autologous bone marrow transplantation improves the response rate, event-free survival (EFS), and overall survival (OS) in patients with myeloma, demonstrated in the prospective, randomized trial by Attal et al. Total therapy by Barlogie et al. consisted of non-cross-resistant induction regimens, followed by a double autotransplantation (AT) procedure. Compared with the outcome of patients receiving standard therapy, dose intensification with double AT produces not only higher CR rates but also significantly extends EFS and OS in previously untreated patients with myeloma. The reduced mortality rate associated with transplantation, and development of new chemotherapeutic agents will lead to future improvements of the therapy for multiple myeloma.

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A controlled trial of twice daily triamcinolone oral inhaler in patients with mild-to-moderate asthma.

National and international guidelines recommend inhaled anti-inflammatory medications for patients with all but the mildest forms of asthma. Patients may also be more compliant with twice daily dosing. To evaluate the efficacy and safety of triamcinolone acetonide (triamcinolone acetonide), 400 microg bid, in mild-to-moderate asthma patients. A multicenter, randomized, double-blind, placebo-controlled study with a 7- to 21-day baseline and 6-week treatment period. Adult mild-to-moderate asthma patients poorly controlled by beta2-agonists alone were randomized to receive placebo (48) or triamcinolone acetonide (53). Patients recorded daytime and nighttime asthma symptoms, albuterol use, and morning and evening peak expiratory flow (PEF) rates on diary cards. Clinic spirometry measures included FEV1, FEF25-75%, FVC, FEV1/FVC, and PEF. Triamcinolone acetonide treatment resulted in improvement from baseline of 17% for FEV1 (P < .0001); 44% for albuterol use (P = .0009); 9% for FVC (P = .0185); 19% for PEF (P = .0011); 42% for FEF25-75% (P < .0001); 8% for FEV1/FVC (P = .0016); 36% for daytime, 39% for nighttime, and 38% for total asthma symptoms (P < or = .0001); and 12% for morning, and 10% for evening PEF (P < or = .001). These changes were highly significant when compared with placebo (P < or = .0185). Significant improvement for all variables was demonstrated within 1 to 2 weeks of active treatment, and maintained for most variables over the 6-week treatment phase. Both treatments were well tolerated. Respiratory adverse events occurred more frequently with placebo; pharyngitis was reported more frequently with triamcinolone acetonide. Triamcinolone acetonide, administered twice daily, can effectively and safely treat patients with milder forms of asthma. In these patients, triamcinolone acetonide improves asthma symptoms and decreases the need for as-needed beta2-agonists.

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