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Evaluation of ultrasound-guided adductor canal block with two different concentration of bupivacaine in arthroscopic knee surgery: A feasibility study.

The application of regional anaesthesia techniques as a component of multimodal analgesia in knee arthroscopic surgeries increases the quality of postoperative analgesia. Adductor canal block (ACB) is an effective "motor sparing" analgesia technique used in knee surgeries. This study aimed to evaluate the efficacy of ACB using two different concentrations of local anaesthetic in terms of analgesic requirements and pain density in patients undergoing knee arthroscopy. Prospective, randomised, controlled. Tertiary hospital. A total of 60 patients (ASA I-II) were evaluated in three groups, with 20 patients in each group. Standardised postoperative analgesia was performed in all groups. In addition, ultrasound-guided ACB (same volume/two different concentrations of bupivacaine: 0.25% vs 0.16%) was applied to the experimental groups. Tramadol consumption, rescue analgesic requirement and Numeric Rating Scores (NRS). Tramadol requirement in the first 24 hours was significantly higher in the control group (209.5 ± 23.27 mg) (P < .001), and there was no difference between the experimental groups (63 ± 42.06 mg vs 80.5 ± 36.63 mg). Although the mean NRS scores in the first three hours were higher in the control group when compared with both block groups, it was similar in all groups in the following measurements. In arthroscopic knee surgery, ACB interventions with 0.25% and 0.16% concentrations of bupivacaine were similar in terms of postoperative analgesic efficacy, and they increased the quality of multimodal analgesics when compared with the control group.

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Drug Interactions Between Peficitinib, an Orally Administered, Once-Daily Janus Kinase Inhibitor, and Rosuvastatin in Healthy Subjects.

Peficitinib is an orally administered, once-daily Janus kinase inhibitor in development for the treatment of rheumatoid arthritis. Peficitinib and its major metabolite H2 inhibit the hepatic uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1) in vitro. This article reports a clinical study evaluating the effects of peficitinib on the pharmacokinetics of rosuvastatin, a substrate for the OATP1B1 transporter, and vice versa. In an open-label, single-sequence clinical study, 24 healthy adults of East Asian and non-East Asian origin received a single dose of rosuvastatin 10 mg on days 1 and 10. On days 5-13, subjects received a daily dose of 150 mg peficitinib. Serial blood samples for pharmacokinetic assessment of rosuvastatin were collected up to 96 h post-dose on days 1 and 10, and for peficitinib were collected up to 24 h post-dose on days 9 and 10. Co-administration of peficitinib with rosuvastatin increased rosuvastatin area under the concentration-time curve (AUC) and maximum plasma concentration (C _max) by 18 and 15%, respectively and increased peficitinib AUC and C _max by 16 and 28%, respectively. In East Asian (n = 6) vs. non-East Asian subjects (n = 18), peficitinib mean AUC for a dosing interval was 45 and 21% higher, and mean C _max was 67 and 34% higher, when administered alone or with rosuvastatin. Peficitinib was well tolerated with few adverse events overall. In this study, once-daily oral administration of peficitinib had no clinically significant effect on the pharmacokinetics of rosuvastatin, a probe substrate for OATP1B1. Therefore, it is unlikely that peficitinib will have a clinically significant effect on the exposure of other substrates for OATP1B1. CLINICALTRIALS. NCT01959399.

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Primary breast lymphoma: results of a controlled clinical trial.

To assess the efficacy and toxicity of the most employed therapeutic approaches in the treatment of primary breast lymphoma (PBL). Ninety-six patients with PBL in the early stage (I or II) were enrolled to receive radiotherapy (45 Gy); chemotherapy (six cycles of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), every 21 days), or combined therapy. Complete response was achieved in 20 of 30 patients treated with radiotherapy, 19 of 32 who were treated with chemotherapy and 30 of 34 in the combined arm (p<0.01). Actuarial curves at 10 years showed that event-free survival was 50, 57 and 83%, respectively (p<0.01). Actuarial curves for overall survival were 50, 50 and 76% (p<0.01), respectively. The most common site of relapse was the central nervous system. Acute toxicity was mild. Until now, no second neoplasm or acute leukemia has been observed. In our study combined therapy is the best treatment in this special setting of patients; with improvement in event-free survival and overall survival without acute or severe late side effects. Prophylaxis to the central nervous system will be considered in the initial treatment to improve outcome.

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What the statin trials have taught us.

It has taken a century since Anitschkow began feeding cholesterol to rabbits to study the role of cholesterol in atherosclerosis to be fully appreciated and for the potential of cholesterol reduction to prevent cardiovascular events to be fully realized. The body of clinical trial data testing the effects of statins on coronary heart disease is extensive and convincing. A 1% reduction in low-density lipoprotein cholesterol reduces coronary events by approximately 1%. With large doses of potent statins, low-density lipoprotein cholesterol levels and coronary events can thus be reduced by approximately 50%. The anti-inflammatory effects of large doses of atorvastatin likely contribute to the early event reduction seen early after acute coronary syndromes. Translating this information into clinical practice presents a challenge: many patients who would benefit from statins remain untreated or undertreated or discontinue treatment soon after it is initiated.

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Pharmacokinetic Interactions Between Elbasvir/Grazoprevir and Immunosuppressant Drugs in Healthy Volunteers.

Elbasvir (EBR)/grazoprevir (GZR) may be coadministered with immunosuppressant drugs in posttransplant people who are infected with hepatitis C virus. The aim of the present study was to assess the safety and pharmacokinetic interactions between EBR and GZR and single doses of cyclosporine, tacrolimus, mycophenolate mofetil (MMF), and prednisone. This was a 4-part, open-label study in 58 healthy volunteers. Participants received single doses of cyclosporine 400 mg, tacrolimus 2 mg, MMF 1 g, or prednisone 40 mg alone or in the presence of once-daily EBR 50 mg/GZR 200 mg. Multiple oral doses of EBR + GZR had no significant effect on cyclosporine. However, in the presence of cyclosporine, the 24-hour area under the concentration-time curve of GZR was increased by approximately 15-fold (geometric mean ratio [90%CI] 15.21 [12.83; 18.04]); the concentration of EBR was increased approximately 2-fold in the presence of cyclosporine. Coadministration of EBR/GZR and tacrolimus did not affect the pharmacokinetics of EBR or GZR, but resulted in an increase in tacrolimus AUC (geometric mean ratio [90%CI] 1.43 [1.24; 1.64]). There were no clinically relevant interactions between EBR/GZR and either MMF or prednisone. Data from the present study indicate that EBR/GZR may be coadministered in people receiving tacrolimus, MMF, and prednisolone. EBR/GZR is contraindicated in people receiving cyclosporine because the significantly higher concentrations of GZR may increase the risk of transaminase elevations.

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Single-dose pharmacokinetics of NWP06, an extended-release methylphenidate suspension, in children and adolescents with ADHD.

Extended-release formulations of stimulants provide once-daily treatment options for patients with attention-deficit/hyperactivity disorder (ADHD). Such preparations are more convenient and may improve compliance, and thus, improve outcomes. Currently, there is no extended-release liquid oral preparation of any stimulant. As such, there is a medical need for a liquid extended-release preparation of methylphenidate for the management of ADHD in children who are unable or unwilling to swallow solid formulations. To evaluate the single-dose pharmacokinetics of an extended-release oral liquid formulation of methylphenidate (NWP06) in pediatric subjects with ADHD. Subjects with ADHD received a single oral dose of NWP06 20 or 60 mg. Serial blood samples were obtained before and after drug administration for determination of plasma methylphenidate concentrations and standard pharmacokinetic parameters. Dose- and weight-corrected pharmacokinetic parameters were presented by age group (9-12 years and 13-15 years). A total of 14 youths (7 children aged 9-12 years and 7 adolescents aged 13-15 years) were enrolled and completed the study. Body mass index ranged from 12.08 to 34.08 kg/m(2). Mean values of dose and body weight-adjusted maximum plasma concentration (Cmax) (23.8, 22.3, 22.1, 25.7 [ng/mL]/mg) and area under the concentration-time curve (AUC) (208, 199, 239, 210 [hr·ng/mL]/[mg/kg]) were similar among all age/dose groups, suggesting dose proportionality and a similar rate and extent of absorption in children and adolescents. Values for Cmax were observed between 2 and 4 hours after the dose. The elimination half-life and body weight-adjusted clearance also appeared to be independent of dose and age. NWP06 was well tolerated with no serious adverse events and no adverse event-related treatment discontinuations. There were no age-related pharmacokinetic differences after oral administration of NWP06 to children or adolescents in this small sample. Over the dose range of methylphenidate used in this study (0.45-3.3 mg/kg), the pharmacokinetics of NWP06 were linear and dose proportional.

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Double-blind trial of omeprazole and amoxicillin in the cure of Helicobacter pylori infection in gastric ulcer patients. The Ulcer Study Group, Germany.

Our aim was to investigate the efficacy of omeprazole and amoxicillin in curing Helicobacter pylori infection in gastric ulcer patients. In a double-blind trial 185 H. pylori-positive gastric ulcer patients were prospectively randomized to receive 40 mg omeprazole twice daily and either 750 mg amoxicillin three times daily or 750 mg amoxicillin placebo three times daily on days 1-14, followed by 20 mg omeprazole daily on days 15-56. Twenty-seven patients were excluded because of lack of compliance or missed follow-up examinations; one patient receiving amoxicillin discontinued treatment owing to side effects. On an intention-to-treat basis, omeprazole/amoxicillin led to cure of H. pylori infection in 67.1% (47 of 70) of patients not using non-steroidal anti-inflammatory drugs (NSAIDs)/aspirin (ASA) and in 46.7% (14 of 30) of those taking NSAIDs/ASA (P < 0.05). With the omeprazole/placebo regimen, H. pylori infection was cured in 8.8% (no NSAIDs), and 0% (NSAIDs). The use of NSAIDs/ASA may limit the efficacy of omeprazole/amoxicillin in curing H. pylori infection in gastric ulcer patients.

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Duloxetine in OsteoArthritis (DOA) study: study protocol of a pragmatic open-label randomised controlled trial assessing the effect of preoperative pain treatment on postoperative outcome after total hip or knee arthroplasty.

Residual pain is a major factor in patient dissatisfaction following total hip arthroplasty or total knee arthroplasty (THA/TKA). The proportion of patients with unfavourable long-term residual pain is high, ranging from 7% to 34%. There are studies indicating that a preoperative degree of central sensitisation (CS) is associated with poorer postoperative outcomes and residual pain. It is thus hypothesised that preoperative treatment of CS could enhance postoperative outcomes. Duloxetine has been shown to be effective for several chronic pain syndromes, including knee osteoarthritis (OA), in which CS is most likely one of the underlying pain mechanisms. This study aims to evaluate the postoperative effects of preoperative screening and targeted duloxetine treatment of CS on residual pain compared with care-as-usual. This multicentre, pragmatic, prospective, open-label, randomised controlled trial includes patients with idiopathic hip/knee OA who are on a waiting list for primary THA/TKA. Patients at risk for CS will be randomly allocated to the preoperative duloxetine treatment programme group or the care-as-usual control group. The primary end point is the degree of postoperative pain 6 months after THA/TKA. Secondary end points at multiple time points up to 12 months postoperatively are: pain, neuropathic pain-like symptoms, (pain) sensitisation, pain catastrophising, joint-associated problems, physical activity, health-related quality of life, depressive and anxiety symptoms, and perceived improvement. Data will be analysed on an intention-to-treat basis. The study is approved by the local Medical Ethics Committee (METc 2014/087) and will be conducted according to the principles of the Declaration of Helsinki (64th, 2013) and the Good Clinical Practice standard (GCP), and in compliance with the Medical Research Involving Human Subjects Act (WMO). 2013-004313-41; Pre-results.

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Comparative Effectiveness of Dexamethasone Versus Prednisone in Children Hospitalized With Acute Croup.

To compare the effectiveness of dexamethasone versus prednisone or prednisolone on hospital resource utilization for children hospitalized with acute croup. This is a retrospective cohort study of the Pediatric Health Information System database on children aged 6 months to <6 years who were hospitalized with acute croup between January 1, 2015 and December 31, 2019. Children with a chronic complex condition, transferred from outside hospital, and/or received direction admission to ICU were excluded. Propensity score matching was used to compare length of stay (in hours), escalation of care to ICU, and the need for bronchoscopy with exposure to dexamethasone versus prednisone or prednisolone. We also compared rates of 7 day return to the emergency department and readmissions. A total of 11 740 hospitalizations met inclusion criteria; dexamethasone was used in 95.9%; prednisone or prednisolone was used in 4.1%. In the matched cohort (n = 960), the length of stay was not significantly different between the dexamethasone and prednisone or prednisolone groups (21.3 vs 18.5 hours, P = .35). Although the rates bronchoscopy did not differ between the 2 groups, the dexamethasone cohort was more likely to require ICU transfer (P = .007). The rates of 7-day emergency department returns (2.3% vs 1.3%, P = .24) and readmissions (3.1% vs. 2.1%, P = .37) were low and not statistically different. Hospital resource utilization did not differ significantly for children receiving dexamethasone or prednisone or prednisolone for acute croup. Both corticosteroids may be considered reasonable choices for the treatment of children hospitalized with acute croup.

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Well-being and its measurement in hypertension. A randomized, double-blind cross-over comparison of 5 mg clopamide with 25 mg hydrochlorothiazide. Hunter Hypertension Research Group.

We conducted a randomized, double-blind, cross-over comparison of six weeks' treatment with 5 mg clopamide or with 25 mg hydrochlorothiazide in 17 hypertensive patients (average age 62 years). No significant differences were found between the two treatments in blood pressure control, plasma biochemical values, body weight or response to a comprehensive "quality of life" questionnaire. Despite the apparently identical performance of both drugs, significantly (x2 = 4.76; P less than 0.05) more patients expressed a preference for clopamide (12) than for hydrochlorothiazide (3). Two had no preference. Current quality of life assessments are relatively insensitive and patient preference remains a valid discriminator between otherwise comparable medications.

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Analgesic efficacy of postoperative bilateral, ultrasound-guided, posterior transversus abdominis plane block for laparoscopic colorectal cancer surgery: a randomized, prospective, controlled study.

We assessed whether a postoperative bilateral, ultrasound-guided, posterior transversus abdominis plane (TAP) block could reduce 24 h rescue tramadol requirement compared with placebo in patients undergoing elective laparoscopic colorectal cancer surgery. Patients scheduled to undergo elective laparoscopic surgery following the diagnosis of colorectal cancer were included in this study and randomized into Group and Group Control. The patients received a postoperative bilateral, ultrasound-guided, posterior TAP block in either 20 mL of 0.5% ropivacaine (Group TAP) per side or an equivalent volume of normal saline (Group Control). The primary outcome was the cumulative consumption of rescue tramadol within 24 h after the surgery. Secondary endpoints included (1) resting and movement numerical rating scale (NRS) pain scores at 2, 4, 6, 12, 24, 48, and 72 h; (2) incidences of related side effects; (3) time to the first request for rescue tramadol; (4) patient satisfaction regarding postoperative analgesia; (5) time to restoration of intestinal function; (6) time to mobilization; and (7) the length of hospital stay. In total, 92 patients were randomized, and 82 patients completed the analysis. The total rescue tramadol requirement (median [interquartile range]) within the first 24 h was lower in Group TAP (0 [0, 87.5] mg) than in Group Control (100 [100, 200] mg), P < 0.001. The posterior TAP block reduced resting and movement NRS pain scores at 2, 4, 6, 12, and 24 h after surgery (all P < 0.001) but showed similar scores at 48 h or 72 h. A higher level of satisfaction with postoperative analgesia was observed in Group TAP on day 1 (P = 0.002), which was similar on days 2 (P = 0.702) and 3 (P = 0.551), compared with the Group Control. A few incidences of opioid-related side effects (P < 0.001) and a lower percentage of patients requiring rescue tramadol analgesia within 24 h (P < 0.001) were observed in Group TAP. The time to the first request for rescue analgesia was prolonged, and the time to mobilization and flatus was reduced with a shorter hospital stay in Group TAP as compared with Group Control. A postoperative bilateral, ultrasound-guided, posterior TAP block resulted in better pain management and a faster recovery in patients undergoing laparoscopic colorectal cancer surgery, without adverse effects. The study was registered at http://www.chictr.org.cn ( ChiCTR-IPR-17012650 ; Sep 12, 2017).

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HTX-011 effectively reduces postoperative pain intensity and opioid use in the elderly.

<b>Aim:</b> HTX-011 (ZYNRELEF™) is an extended-release, dual-acting local anesthetic containing bupivacaine and meloxicam. In bunionectomy and herniorrhaphy studies, HTX-011 resulted in less postoperative pain and less opioid consumption versus bupivacaine HCl. Here we evaluate HTX-011 in patients aged ≥65 years. <b>Materials & methods:</b> Patients received placebo, bupivacaine HCl or HTX-011 following surgery. End points included pain intensity, total opioid consumption, opioid-free patients and safety. <b>Results:</b> HTX-011-treated patients reported lower postoperative pain through 72 h versus bupivacaine HCl and placebo. Elderly patients administered HTX-011 used fewer opioids versus bupivacaine HCl, and a greater proportion remained opioid-free through 72 h. HTX-011 was well tolerated with a safety profile similar to bupivacaine HCl and placebo. <b>Conclusion:</b> HTX-011 maintained effectiveness and was well tolerated in elderly patients. Clinical Trial registration numbers: NCT03295721 and NCT03237481.

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Suppression of plasma renin activity by indomethacin in man.

The effect of indomethacin or placebo on aldosterone, plasma renin activity (PRA), sodium excretion, and urinary prostaglandin (PG) levels was investigated in five hypertensive subjects in 100 mEq sodium balance who had experienced malignant hypertension with a disturbance of their renin-aldosterone relationship in the past. Indomethacin significantly lowered aldosterone levels by 43%, PRA by 58%, 24-hour sodium excretion by 49%, and urinary PG excretion, an indicator of renal PG synthesis, by 67%. Angiotensin infusion increased aldosterone to the same level before and after treatment with indomethacin. Similarly, in normal subjects in 150 mEq sodium balance, indomethacin lowered PRA by 47%; sodium excretion fell by 33%, and urinary prostaglandin E (PGE) excretion, by 55%. The acute elevation in PRA 10 minutes after intravenous furosemide was completely abolished by indomethacin. Five subjects with essential hypertension were classified as normal renin hypertensives according to their response to orally administered furosemide. Indomethacin pretreatment resulted in 60% reduction of PRA following furosemide, and three of these subjects now fell into the low renin category. Studies in vitro demonstrated that indomethacin has no effect on the renin-renin substrate interaction. Thus, indomethacin lowers PRA concomitantly with a reduction in renal PG synthetase activity. Whether indomethacin inhibits renin release by an intrarenal, PG-related mechanism or secondarily via sodium retention is discussed.

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Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.

It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure. We randomly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan (300 mg daily), amlodipine (10 mg daily), or placebo. The target blood pressure was 135/85 mm Hg or less in all groups. We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration, the development of end-stage renal disease, or death from any cause. We also compared them with regard to the time to a secondary, cardiovascular composite end point. The mean duration of follow-up was 2.6 years. Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group (P=0.02) and 23 percent lower than that in the amlodipine group (P=0.006). The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group (P=0.003) and 37 percent lower in the irbesartan group than in the amlodipine group (P<0.001). Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups (P=0.07 for both comparisons). These differences were not explained by differences in the blood pressures that were achieved. The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group (P=0.008) and 21 percent more slowly than in the amlodipine group (P=0.02). There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point. The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of the reduction in blood pressure it causes.

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Effects of immediate versus delayed antihypertensive therapy on outcome in the Systolic Hypertension in Europe Trial.

To assess the impact of immediate versus delayed antihypertensive treatment on the outcome of older patients with isolated systolic hypertension, we extended the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial by an open-label follow-up study lasting 4 years. The Syst-Eur trial included 4695 randomized patients with minimum age of 60 years and an untreated blood pressure of 160-219 mmHg systolic and below 95 mmHg diastolic. The double-blind trial ended after a median follow-up of 2.0 years (range 1-97 months). Of 4409 patients still alive, 3517 received open-label treatment consisting of nitrendipine (10-40 mg daily) with the possible addition of enalapril (5-20 mg daily), hydrochlorothiazide (12.5-25 mg daily), or both add-on drugs. Non-participants (n = 892) were also followed up. Median follow-up increased to 6.1 years. Systolic pressure decreased to below 150 mmHg (target level) in 2628 participants (75.0%). During the 4-year open-label follow-up, stroke and cardiovascular complications occurred at similar frequencies in patients formerly randomized to placebo and those continuing active treatment. These rates were similar to those previously observed in the active-treatment group during the double-blind trial. Considering the total follow-up of 4695 randomized patients, immediate compared with delayed antihypertensive treatment reduced the occurrence of stroke and cardiovascular complications by 28% (P = 0.01) and 15% (P = 0.03), respectively, with a similar tendency for total mortality (13%, P = 0.09). In 492 diabetic patients, the corresponding estimates of long-term benefit (P < 0.02) were 60, 51 and 38%, respectively. Antihypertensive treatment can achieve blood pressure control in most older patients with isolated systolic hypertension. Immediate compared with delayed treatment prevented 17 strokes or 25 major cardiovascular events per 1000 patients followed up for 6 years. These findings underscore the necessity of early treatment of isolated systolic hypertension.

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Cachexia index as a potential biomarker for cancer cachexia and a prognostic indicator in diffuse large B-cell lymphoma.

Cancer cachexia is known to adversely affect the clinical course in patients with malignant lymphoma. The cachexia index (CXI) is a potential biomarker of cancer cachexia, and its implications for the prognosis and treatment outcome of lung cancer and aggressive lymphoma has been assessed in previous studies. A total of 267 patients diagnosed with diffuse large B-cell lymphoma who were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy were retrospectively reviewed. The CXI was calculated as the skeletal muscle index (SMI) × serum albumin/neutrophil-lymphocyte ratio (NLR). Although previous studies measured the SMI using the muscles of the L3 vertebral level, the present study used both the L3 vertebral muscles and the pectoralis muscles (PM) at the T4 vertebral level to measure the SMI. Depending on the type of muscles used, the CXI was termed the L3-CXI or PM-CXI. Using sex-specific cutoff values for CXI, the patients were categorized as follows: (i) high-CXI group (high L3-CXI and high PM-CXI), (ii) intermediate-CXI group (high L3-CXI and low PM-CXI), and (iii) low-CXI group (low L3-CXI and low PM-CXI). Complete responses to R-CHOP were obtained in 145/173 (83.8%), 25/36 (69.4%), and 27/57 (47.4%) patients in the high-CXI, intermediate-CXI, and low-CXI groups, respectively (P < 0.001). Treatment-related anaemia (15.6%, 30.6%, and 26.3%, P = 0.038), thrombocytopenia (21.4%, 36.1%, and 43.9%, P < 0.001), febrile neutropenia (23.7%, 44.4%, and 36.8%, P = 0.022), and any nonhaematologic toxicity (31.2%, 44.4%, and 54.4%, P = 0.001) of Grade 3 or more were more common in the lower CXI groups than in the higher-CXI groups. Early treatment discontinuation for reasons other than lymphoma progression also occurred more frequently in the low-CXI group (24/57, 42.1%) compared with the intermediate-CXI (5/36, 13.9%) and high-CXI (18/173, 10.4%) groups (P < 0.001). Median overall survival in the high-CXI, intermediate-CXI, and low-CXI groups was not reached, 50.6 months, and 14.5 months, respectively (p < 0.001). Multivariable analysis showed that low CXI was an independent negative prognostic factor for overall survival (hazard ratio 2.103, 95% confidence interval 1.278-3.460, P = 0.003). We suggest that in patients with diffuse large B-cell lymphoma, the CXI is a biomarker for cancer cachexia that can predict survival, treatment response, treatment-related toxicity, and compliance with R-CHOP. Patients were more clearly stratified by this new CXI category compared with the classifications described in previous studies.

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Infection and colonization by Corynebacterium pseudodiphtheriticum: a 9-year observational study in a university central hospital.

Despite constituting part of the human commensal flora, Corynebacterium pseudodiphtheriticum has been recognized as a potentially infectious agent, most frequently in immunocompromised patients or individuals with other morbidity factors, but significant association to comorbid states remains unproven. This study's purpose was to assess clinical significance, risk factors for infection and antimicrobial susceptibility of C. pseudodiphtheriticum isolates. A retrospective observational study was conducted. Relevance of isolation was determined by clinical, laboratory, and imaging criteria. Forty-nine isolates occurred in 47 episodes. Colonization was assumed in 12% and infection in 78%, of which 51% were nosocomial. Patients with infection were older, with male predominance; both age and gender were statistically significant (p < 0.05) between infection and colonization groups. Although dyslipidemia (58%), arterial hypertension (58%), invasive procedures (56%), and chronic lung disease (50%) were prevalent in the infection group, no comorbidity was a significant risk factor for infection compared with colonization. Charlson comorbidity index showed no statistically difference between groups. Mortality rate was 14% in infection. Respiratory samples were the main isolation product; all tested strains were susceptible to amoxicillin/clavulanate and vancomycin. Resistant strains were observed for clindamycin (77%) and erythromycin (48%). C. pseudodiphtheriticum isolation was associated with infection in most cases. Despite the high prevalence of comorbidities and invasive procedures, no factors other than age and gender were significantly associated with infection. Although C. pseudodiphtheriticum may constitute a contaminant or colonizer in clinical samples, positive cultures in patients with signs and symptoms consistent with infection should not be neglected.

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Apixaban Concentrations with Lower than Recommended Dosing in Older Adults with Atrial Fibrillation.

Lower than recommended doses of direct-acting oral anticoagulants are often prescribed to older adults with nonvalvular atrial fibrillation (NVAF). Our goal was to determine the consequences of lower than recommended dosing on plasma apixaban concentrations during the clinical care of older adults with NVAF. Convenience sample of patients receiving anticoagulation during 2017. Academic medical center. Stable adults older than 65 years with NVAF receiving apixaban on a chronic basis. Patient age, weight, creatinine, co-medications, and apixaban concentrations. A total of 110 older adults with NVAF (mean age = 80.4 y; range = 66-100 y with 45% women) were studied. Overall, 48 patients received recommended dosing of 5 mg twice/day, and 42 received lower than recommended dosing. One patient in each category had concentrations below the expected 5% to 95% range at time of peak concentrations. Differences in proportion of apixaban concentrations within or outside expected ranges were not significant between patients receiving lower than recommended doses and those dosed as recommended at 5 mg twice/day (P = .35). However, in patients dosed as recommended with 5 mg twice/day, four had concentrations above the 5% to 95% range for peak levels expected at 3 to 4 hours after dosing; in two, this occurred around the midpoint of the dosing interval. Twenty patients received 2.5 mg twice/day as recommended. One-third had apixaban concentrations higher than expected peak concentrations compared with the clinical trials, and more than two-thirds had levels above the reported median for peak concentrations. Apixaban concentrations in older adults with NVAF seen clinically were higher than expected based on clinical trial data. The findings raise questions about the optimal dosing of apixaban in older adults with NVAF encountered outside of clinical trials and suggest a role for the monitoring of apixaban concentrations during care of patients that differ from those in randomized trials or when considering dosing outside of published guidelines. J Am Geriatr Soc 67:1902-1906, 2019.

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Influence of anticoagulants on the risk of delayed bleeding after gastric endoscopic submucosal dissection: a multicenter retrospective study.

Delayed bleeding after gastric endoscopic submucosal dissection (ESD) in patients receiving anticoagulants remains an unpreventable adverse event. Although direct-acting oral anticoagulants (DOACs) have superior efficacy in preventing thromboembolism, their effects on the occurrence of delayed bleeding remain unclear. This study aimed to elucidate the clinical effect of DOACs on delayed bleeding after gastric ESD. We retrospectively examined 728 patients who received anticoagulants and were treated for gastric neoplasms with ESD in 25 institutions across Japan. Overall, 261 patients received DOACs, including dabigatran (92), rivaroxaban (103), apixaban (45) and edoxaban (21), whereas 467 patients were treated with warfarin. Delayed bleeding occurred in 14% of patients taking DOACs, which was not considerably different in patients receiving warfarin (18%). Delayed bleeding rate was significantly lower in patients receiving dabigatran than in those receiving warfarin and lower than that observed for other DOACs. Multivariate analysis showed that age ≥ 65, receiving multiple antithrombotic agents, resection of multiple lesions and lesion size ≥ 30 mm were independent risk factors, and that discontinuation of anticoagulants was associated with a decreased risk of bleeding. In multivariate analysis among patients taking DOACs, dabigatran therapy was associated with a significantly lower risk of delayed bleeding. The effects of DOACs on delayed bleeding varied between agents, but dabigatran therapy was associated with the lowest risk of delayed bleeding. Switching oral anticoagulants to dabigatran during the perioperative period could be a reasonable option to reduce the risk of delayed bleeding after gastric ESD.

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Comparison of four single-drug regimens on ventricular rate and arrhythmia-related symptoms in patients with permanent atrial fibrillation.

Rate control of atrial fibrillation (AF) is a main treatment modality. However, data are scarce on the relative efficacy of calcium channel blockers and β blockers or between drugs within each class. The purpose of the present study was to compare the effect of 4 rate-reducing, once-daily drug regimens on the ventricular heart rate and arrhythmia-related symptoms in patients with permanent AF. We included 60 patients (mean age 71 ± 9 years, 18 women) with permanent AF in an investigator-blind cross-over study. Diltiazem 360 mg/day, verapamil 240 mg/day, metoprolol 100 mg/day, and carvedilol 25 mg/day were administered for 3 weeks in a randomized sequence. The 24-hour heart rate was measured using Holter monitoring, and arrhythmia-related symptoms were assessed using the Symptom Checklist questionnaire before randomization and on the last day of each treatment period. The 24-hour mean heart rate was 96 ± 12 beats/min at baseline (no treatment), 75 ± 10 beats/min with diltiazem, 81 ± 11 beats/min with verapamil, 82 ± 11 beats/min with metoprolol, and 84 ± 11 beats/min with carvedilol. All drugs reduced the heart rate compared to baseline (p <0.001 for all). The 24-hour heart rate was significantly lower with diltiazem than with any other drug tested (p <0.001 for all). Compared to baseline, diltiazem significantly reduced both the frequency (p <0.001) and the severity (p = 0.005) of symptoms. In contrast, verapamil reduced symptom frequency only (p = 0.012). In conclusion, diltiazem 360 mg/day was the most effective drug regimen for reducing the heart rate in patients with permanent AF. Arrhythmia-related symptoms were reduced by treatment with the calcium channel blockers diltiazem and verapamil, but not by the β blockers.

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Systemic effects of salbutamol and salmeterol in patients with asthma.

Knowing the extent of the systemic effects of a new beta 2 agonist relative to an established drug is important for the prediction and interpretation of side effects. A recent study in which the effect of cumulative doses of salbutamol was compared with single doses of salmetreol suggested that, weight for weight, salmeterol may be up to 10 times more potent than salbutamol. This current study was designed to investigate further the dose equivalence of salmeterol and salbutamol. Twelve patients with mild asthma inhaled cumulative doses of placebo, salmeterol 25, 50, 100, and 200 micrograms, and salbutamol 100, 500, 1000, and 1000 micrograms on separate days at hourly intervals in a randomised double blind crossover study. Changes in forced expiratory volume in one second (FEV1), heart rate, plasma potassium concentration, systolic and diastolic blood pressure were measured. Dose equivalence was determined as the dose ratio of salmeterol to salbutamol for the 50% maximum response to salbutamol. No important changes occurred in any measurements following placebo. Salmeterol and salbutamol caused a near maximum increase in FEV1 following the first dose so the dose equivalence for the airway effects could not be estimated. Heart rate increased and plasma potassium concentration and diastolic blood pressure decreased in a dose dependent manner following salmeterol and salbutamol, with median dose equivalences for salmeterol compared with salbutamol of 17.7, 7.8, and 7.6, respectively. These results confirm that the systemic activity of salmeterol compared with salbutamol is higher than would be expected from in vitro data, particularly for heart rate. Whether this is because of the relatively high dose of salmeterol used or pharmacokinetic differences between the two drugs is uncertain.

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Decreased Platelet Inhibition by Thienopyridines in Hyperuricemia.

Hyperuricemia carries an increased risk of atherothrombotic events in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). This may at least in part be due to inadequate P2Y12 inhibition. The aim of this study was to prospectively investigate the potential association between hyperuricemia and decreased platelet inhibition by P2Y12 antagonists. Levels of uric acid as well as on-treatment residual platelet reactivity in response to adenosine diphosphate (ADP) were assessed in 301 clopidogrel-treated patients undergoing elective angioplasty and stenting, and in 206 prasugrel- (n = 118) or ticagrelor-treated (n = 88) ACS patients following acute PCI. Cut-off values for high on-treatment residual ADP-inducible platelet reactivity (HRPR) were based on previous studies showing an association of test results with clinical outcomes. Hyperuricemia was significantly associated with increased on-treatment residual ADP-inducible platelet reactivity in clopidogrel- and prasugrel-treated patients in univariate analyses and after adjustment for differences in patient characteristics by multivariate regression analyses. In contrast, ticagrelor-treated patients without and with hyperuricemia showed similar levels of on-treatment residual platelet reactivity to ADP. HRPR occurred more frequently in clopidogrel- and prasugrel-treated patients with hyperuricemia than in those with normal uric acid levels. In contrast, hyperuricemic patients receiving ticagrelor did not have a higher risk of HRPR compared with those with normal uric acid levels. Hyperuricemia is associated with decreased platelet inhibition by thienopyridines but a normal response to ticagrelor. It remains to be established if lowering uric acid increases the antiplatelet effects of clopidogrel and prasugrel in hyperuricemic patients with HRPR.

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Using a graphical risk tool to examine willingness to take migraine prophylactic medications.

Many migraine sufferers use daily prophylactic therapy to reduce the frequency of their headache attacks. The Food and Drug Administration has approved several different medications for migraine prophylaxis, but it is not clear whether sufferers perceive these treatments to provide clinically significant benefits given their side effect profiles. Three hundred headache sufferers were recruited from the community and local headache clinics using print and television advertising. Participants reported experiencing problematic headache attacks with a median (IQR) frequency of 7.0 (4-13) headache days per month. These sufferers participated in a cross-sectional, single-site, study that used a specially designed computer assessment task. Participants were instructed on the probability of experiencing the 3 most commonly experienced side effects for several blinded medication profiles: divalproex sodium, venlafaxine, gabapentin, propranolol, and topiramate. After learning the likelihood of experiencing side effect profiles of each medication, participants were asked whether they would be willing to take the medication for a given headache reduction level, which ranged from 0 to 7 days per month. The side effect profile for divalproex sodium was associated with the smallest willingness to take, with gabapentin, propranolol, and topiramate perceived to be much more agreeable. However, <60% of participants reported willingness to take any of these medications even if they provided a 50% reduction in headache frequency. Several general predictors of willingness to take were observed including high headache-related disability, depressive symptoms, and pain medication concerns including fear of tolerance. These findings suggest that if properly informed of the side effect profiles of these medications, many patients might opt for other treatments.

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Immunosuppressive regimens and their effects on renal allograft outcome.

The distribution and effectiveness of different immunosuppression protocols among recipients of first cadaver donor renal transplants reported to the UNOS Scientific Renal Transplant Registry whose graft survived at least 14 days after transplantation were analyzed. The results showed that between 1988-1993, 50-60% of recipients received triple therapy regimens including cyclosporine, azathioprine and prednisone (CAP). An additional 20% received CAP with antibody induction therapy (OKT3 or ALG). After 1993, there was an increase in the use of other drug combinations which include FK506 and, more recently, Neoral and mycophenylate mofetil. Patient survival was 90% at 3 years regardless of the immunosuppressive protocol. The 3-year graft survival rate was 75% under cyclosporine-based protocols, but was 79% for more recent recipients treated with FK506 (p = 0.015). Antibody induction protocols were not used more frequently for high-risk patients, including those with broadly reactive anti-HLA antibodies, pediatric recipients, transplants with delayed graft function and those with prolonged cold ischemia times. When induction therapies were reported for these higher risk transplants, there was no noticeable improvement in graft survival rates after excluding failures within the first 2 weeks. Any benefit of antibody induction must therefore be manifest with the first 2 weeks after transplantation. Induction protocols significantly reduced the incidence of rejection episodes (prior to hospital discharge) from 31% for those treated with CAP to 12% for those with antibody induction (p < 0.01), however, 24% of those given induction had at least one rejection between discharge and 6 months compared with only 18% of those treated with CAP without induction (p < 0.01). Although graft outcomes might be significantly influenced by the dosing and timing of immunosuppressive drugs, among the different combinations of drugs analyzed, only FK506 resulted in improved graft survival and half life. With the rapid proliferation of newer drugs and immunosuppressive strategies during 1996, it will be interesting to follow the course of these very recent transplants with regard to the effectiveness of changing immunosuppression.

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[Paclitaxel-associated Acute Pain Syndrome Similarly Occurs in the Patients with or without Previously Administered Non-steroidal Anti-inflammatory Drugs Prior to Paclitaxel Administration].

Paclitaxel (PTX)-associated acute pain syndrome (P-APS) is characterized by disabling but transient arthralgia and myalgia in up to 80% of patients administered with PTX. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely administered to patients with cancer who have pain or fever, and are mainly used to manage P-APS. In this study, we investigated how P-APS appear in the patients who were administered NSAIDs prior to PTX injection. The incidence or severity and duration of P-APS in patients previously administered NSAIDs were compared to those of patients who were not administered NSAIDs. The relationship between previously administered NSAIDs and rescue administration for the relief of P-APS was also evaluated. It was revealed that the incidence and duration of P-APS were 72% and 4.67±2.30 d, respectively, in the control group and 84% and 6.19±3.30 d, respectively, in the NSAIDs group. There was no significant difference in the incidence and duration and the severity of P-APS between the two groups. Patients who were previously administered NSAIDs tended to obtain less pain relief from NSAIDs administered as rescue medications, and needed other medication. Univariate and multivariate analysis revealed no correlation between previously administered NSAIDs or patient characteristics and the incidence of P-APS. In this study, it was found that clinical condition that needs NSAIDs and previously administered NSAIDs prior to PTX injection do not affect the incidence, severity, and duration of P-APS. These results will help in educating patients about their medications and will contribute to the management of P-APS.

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Adjuvant radiotherapy to sites of previous bulky disease in patients stage IV diffuse large cell lymphoma.

To evaluate the usefulness of adjuvant radiotherapy to sites of previous bulky disease in patients with advanced diffuse large cell lymphoma (DLCL) who were in complete remission after chemotherapy. Two-hundred and eighteen patients were initially treated with combined chemotherapy CEOP-bleo (cyclophosphamide, epirubicin, vincristine, prednisone, bleomycin) alternating with DAC (dexamethasone, cytosine arabinoside, and cisplatinum). One hundred and fifty-five patients achieved complete remission. Eighty-eight patients with initial bulky disease were randomly assigned to either received (43 patients) or not received radiotherapy (45 patients). Dose ranged from 40-50 Gy. The median time to treatment failure has not been reached in patients who received radiotherapy. At 5 years 72% of the patients treated with the combined therapy remain alive disease in free compared to only 35% in the control group. Projected survival at 5 years was better in the patients with adjuvant radiotherapy: 81% compared to 55% in the patients who received no radiotherapy. Toxicity was mild and manageable. No lethal toxicities were observed. This treatment sequence produced durable control disease in patients with disseminated DLCL and bulky disease with acceptable toxicity. The role of radiation therapy in patients with disseminated DLCL will be confirmed in large clinical trials, but we felt that this sequence of treatment could be useful in patients with this clinical condition.

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Venlafaxine in depressed geriatric outpatients: an open-label clinical study.

A 12-month open-label clinical trial was conducted to evaluate patient acceptance and safety of venlafaxine, a novel antidepressant, in ambulatory geriatric depressed patients. The sample consisted of 58 depressed patients aged 65 years and older who needed long-term antidepressant treatment. The setting was multiple study sites in California, Florida, New York, Utah, and Washington. All patients took venlafaxine; 52 qualified for the intent-to-treat analysis, and 24 completed 12 months of treatment. Repeated-measures analysis of variance within subjects showed significant improvements in Clinical Global Impressions severity and improvement, Modified Symptom Checklist, and Quality of Life Questionnaire scores. One patient developed a rash that was judged to be a serious drug-related side effect. The most common side effects were headache (n = 25), nausea (n = 21), insomnia (n = 18), dry mouth (n = 18), and sweating (n = 18). The results demonstrate the safety and patient acceptance of venlafaxine in depressed geriatric outpatients for acute and maintenance treatment.

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Causes of mortality with ticagrelor compared with clopidogrel in acute coronary syndromes.

To describe specific causes of death and evaluate whether bleeding events and infection contributed to mortality in all ticagrelor-treated and clopidogrel-treated patients with acute coronary syndromes. In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor significantly reduced rates of vascular and total death compared with clopidogrel. In the 905 patients who died postenrolment in the PLATO trial (n=18 624), reviewers, blinded to study treatment, subclassified direct causes of death and evaluated whether infection or bleeding events contributed to fatal events. Among vascular deaths, there were significantly fewer sudden deaths (63 (0.7%) vs 98 (1.1%), p<0.01) but no significant difference in deaths caused by acute myocardial infarction (179 (1.9%) vs 194 (2.1%), p=0.43) or heart failure (31 (0.3%) vs 42 (0.5%), p=0.20) with ticagrelor compared with clopidogrel. For non-vascular deaths, there was no difference between treatments in deaths directly caused by infection. Although, patients treated with ticagrelor were at lower risk for death where infection was either a direct cause or contributed to death (51 (0.5%) vs 76 (0.8%), HR 0.67 (0.47 to 0.95), p<0.05) but not for bleeding (42 (0.5%) vs 42 (0.5%), HR 0.99 (0.65 to 1.53), p=0.98). In this post hoc analysis, ticagrelor compared with clopidogrel reduced total and cardiovascular mortality, which appeared to be mainly mediated by a reduction in sudden death. Importantly, bleeding causing or contributing to death did not differ between treatments. NCT00391872 (http://www.clinicaltrial.gov).

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Dextroamphetamine-induced changes in regional cerebral blood flow.

Regional cerebral blood flow (CBF), blood pressure, pulse rate, respiratory rate, end-tidal carbon dioxide and mood states were measured before and after IV injections of 15 mg dextroamphetamine sulfate or saline in 22 physically and mentally healthy normal volunteers. Amphetamine administration was associated with significant increases in systolic blood pressure and vigor and decrease in end-tidal carbon dioxide. There were no significant differences between the amphetamine and saline groups on CBF changes. However, there was a non-significant trend towards a post-amphetamine CBF reduction, even after the flow values were corrected for the acute changes in CO2.

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Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy.

Chronic heart failure is associated with inflammation and neurohormonal imbalance. The 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, exert anti-inflammatory and vascular protective effects. We hypothesized that short-term statin therapy may have beneficial effects in patients with nonischemic heart failure. Sixty-three patients with symptomatic, nonischemic, dilated cardiomyopathy were randomly divided into 2 groups. One group received simvastatin (n=24), and the other group received placebo (n=27). The initial dose of simvastatin was 5 mg/d, which was increased to 10 mg/d after 4 weeks. After 14 weeks, patients receiving simvastatin exhibited a modest reduction in serum cholesterol level compared with patients receiving placebo (130+/-13 versus 148+/-18, P<0.05). Patients treated with simvastatin had a lower New York Heart Association functional class compared with patients receiving placebo (2.04+/-0.06 versus 2.32+/-0.05, P<0.01). This corresponded to improved left ventricular ejection fraction in the simvastatin group (34+/-3 to 41+/-4%, P<0.05) but not in the placebo group. Furthermore, plasma concentrations of tumor necrosis factor-alpha, interleukin-6, and brain natriuretic peptide were significantly lower in the simvastatin group compared with the placebo group. Short-term statin therapy improves cardiac function, neurohormonal imbalance, and symptoms associated with idiopathic dilated cardiomyopathy. These findings suggest that statins may have therapeutic benefits in patients with heart failure irrespective of serum cholesterol levels or atherosclerotic heart disease.

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Salmeterol/fluticasone propionate combination therapy 50/250 microg twice daily is more effective than budesonide 800 microg twice daily in treating moderate to severe asthma.

Three hundred and fifty-three asthmatic patients who remained symptomatic despite treatment with budesonide 800-1200 microg day(-1) (or equivalent) were randomized to a new combination therapy comprising salmeterol 50 microg and fluticasone propionate 250 microg (Seretide, Advair, Viani 50/250 microg) twice daily or budesonide 800 microg twice daily for 24 weeks. Patients kept daily records of their morning and evening peak expiratory flow (PEF), daytime and night-time symptom scores and daytime and night-time use of rescue salbutamol. Mean morning PEF increased by 451 min(-1) (baseline 361 l min(-1)) in the salmeterol/fluticasone propionate combination (SFC) group and by 19 l min(-1) (baseline 358 l min(-1)) in the budesonide group over the 24 weeks. The adjusted mean morning PEF over weeks 1 to 24 was significantly greater in the SFC group, despite the > three-fold lower corticosteroid dose (406 vs. 380 l min(-1); P < 0.001). A significantly greater improvement in evening PEF was also seen in the SFC group (adjusted mean 416 vs. 398 l min(-1); P<0.001). SFC also provided significantly better control of daytime symptoms and a significantly greater reduction in the requirement for rescue salbutamol compared with budesonide. These results demonstrate that SFC 50/250 microg twice daily is superior to budesonide 800 microg twice daily in the management of patients with moderate to severe asthma who are symptomatic on their existing dose of corticosteroid.

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A medication adherence and persistence comparison of hypertensive patients treated with single-, double- and triple-pill combination therapy.

Fixed-dose combination therapy reduces pill burden and may, therefore, improve medication adherence and health outcomes. This study compared adherence to and persistence with single-, double-, and triple-pill treatment regimens among hypertensive patients in a US clinical practice setting. Adults with hypertension treated with three anti-hypertensive medications were identified. Index date was the first occurrence of a single-, double-, or triple-pill regimen with olmesartan or valsartan plus amlodipine and hydrochlorothiazide from July 2010 to September 2011. Patients were followed for 12 months to assess adherence (proportion of days covered [PDC] ≥ 80%) and time to discontinuation (medication gap ≥ 60 days) of the index regimen. Multivariate regression models were used to compare adjusted outcomes. The number of prescribed pills in the index regimen was monotonically related to adherence with 55.3%, 40.4% and 32.6% of patients having PDC ≥ 80% in the single-, double- and triple-pill cohorts, respectively. In adjusted analysis, patients in the double- (odds ratio [OR]: 0.45; 95% confidence interval [CI]: 0.42-0.48) and triple-pill (OR: 0.26; 95% CI: 0.22-0.30) cohorts were less likely to be adherent to their index regimens than those in the single-pill cohort. Double-pill (hazard ratio [HR]: 1.89; 95% CI: 1.74-2.06) and triple-pill patients (HR: 2.49; 95% CI: 2.14-2.88) were more likely to discontinue treatment than single-pill patients. Greater pill burden was directly and significantly associated with decreased adherence and persistence with antihypertensive therapies in real-practice settings. Use of fixed-dose combinations that reduce pill burden could help patients to continue treatment and may result in improved clinical outcomes. Typical of observational studies, the potential for residual confounding of adherence estimates remains due to lack of randomization of treatment groups.

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[The effects of eradication therapy in patients with chronic atrophic gastritis and seropositivity for anti-HP antibodies and histological negativity for Helicobacter pylori].

The present study was undertaken to analyze both whether the elevated Helicobacter pylori levels in patients with atrophic gastritis without histologic evidence of Helicobacter pylori would be a sign of an ongoing infection and the effects of eradication on gastric atrophy. Twenty patients (10 M e 10 F; mean age 57.25 SD 12.19) with atrophic gastritis and elevated Helicobacter pylori titers without histological evidence for Helicobacter-like organisms were included in the study. Ten patients were randomized into eradication group (Group 1) (amoxicillin at 500 mg twice a day for 14 days, metronidazole at 500 mg twice a day for 10 days and omeprazole at 20 mg twice a day for 20 days) and 10 patients were randomized into the control group (Group 2). For all subjects, serum samples and duplicate biopsy specimens (obtained endoscopically) were collected prior the study period and approximately 6 months after the therapy or the follow-up for serum samples and 8 weeks for biopsy specimens. In the Group 1, the Helicobacter pylori antibody titers dropped significantly in 73.39% of the patients (p < 0.0001), while in the Group 2, the antibody titers declined only in a patient who received antibiotics during the study period (p < 0.00006). In both groups, no significant improvement of atrophic gastritis was observed. In conclusion, in patients with atrophic gastritis, the only histological evaluation of Helicobacter-like organisms colonization in gastric biopsy specimens, appeared in our study to underestimate the true prevalence of current HP infection and the importance of the bacterium in the pathogenesis and progression of such disease. Since HP infection is often associated with an increase of proliferative index, the eradication of HP could induce a mucosal protective effect against the other carcinogen factors, although it is extremely unlikely that it can promote the regeneration of a normal gastric mucosa.

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Methylphenidate increases cigarette smoking in participants with ADHD.

Methylphenidate (Ritalin®) is commonly prescribed for behavioral problems associated with attention deficit/hyperactivity disorder (ADHD). The results of previous studies suggest that methylphenidate increases cigarette smoking in participants without psychiatric diagnoses. Whether methylphenidate increases cigarette smoking in participants diagnosed with ADHD is unknown. In this within-subjects, repeated measures experiment, the acute effects of a range of doses of methylphenidate (10, 20, and 40 mg) and placebo were assessed in nine cigarette smokers who were not attempting to quit and met diagnostic criteria for ADHD but no other Axis I psychiatric disorders other than nicotine dependence. Each dose of methylphenidate was tested once while placebo was tested twice. One hour after ingesting drug, participants were allowed to smoke ad libitum for 4 h. Measures of smoking included total cigarettes smoked, total puffs, and carbon monoxide levels. Snacks and decaffeinated drinks were available ad libitum; caloric intake during the 4-h smoking session was calculated. Methylphenidate increased the total number of cigarettes smoked, total number of puffs, and carbon monoxide levels. Methylphenidate decreased the number of food items consumed and caloric intake. The results of this experiment suggest that acutely administered methylphenidate increases cigarette smoking in participants with ADHD, which is concordant with findings from previous studies that tested healthy young adults. These data indicate that clinicians may need to consider non-stimulant options or counsel their patients before starting methylphenidate when managing ADHD-diagnosed individuals who smoke.

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Comparison of antiproteinuric effects of two different combination therapies in children with IgA nephropathy.

Because moderate or severe proteinuria is a representative factor indicative of longterm poor prognosis in IgA nephrology, an anti-proteinuric treatment which can be administered longterm with few side effects is necessary. We report here a comparison of antiproteinuric effects in two patient groups treated with different combination therapies. Group A comprised 12 patients with IgA nephropathy, who had 24-h proteinuria of 0.5 gm(2) or more, moderately severe renal histology, and normal renal function, and were treated with a combination of drugs, i.e., prednisolone, an immunosuppressant (mizoribine), an anti-platelet drug (dipyridamole), and an angiotensin-converting enzyme inhibitor. Group B consisted of 18 patients who had baseline characteristics similar to those of the patients in group A and were treated with our previous protocol (a combination of prednisolone, cyclophosphamide, and dipyridamole). Twenty-four-hour proteinuria and creatinine clearance were measured every 6 months. The primary endpoint was reduction of 24-h proteinuria by less than 25% compared with the baseline value. The proportion of patients that exhibited the primary endpoint, as assessed by the Kaplan-Meier method, was found to be significantly higher in group A than in group B (logrank test; P = 0.024). None of the patients in the two groups experienced serious adverse effects. The results suggested that the use of drugs in combination with cyclophosphamide was beneficial for patients with moderately severe IgA nephropathy. Because moderate or severe proteinuria is a representative factor indicative of longterm poor prognosis in IgA nephropathy, an anti-proteinuric treatment which can be administered longterm with few side effects is necessary. We report here a comparison of antiproteinuric effects in two patient groups treated with different combination therapies.

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The effects of clopidogrel on elderly traumatic brain injured patients.

Patients are living longer with cardiovascular disease managed with antiplatelet drugs. These seniors are asked to be more physically active and are prone to falls or injuries. Few have studied the mortality or morbidity from anticoagulants in patients with traumatic brain injuries (TBI). With the increasing use of clopidogrel in the elderly, studies on the consequences of TBI are warranted. This is a retrospective case-controlled study using a trauma data registry of 3,817 closed head trauma cases (2001-2005). Patients with preinjury use of clopidogrel, aspirin or warfarin, and evidence of traumatic intracranial bleeding were identified (n = 131). These were compared with a frequency-matched control group (n = 178) with similar age, gender, Glasgow Coma Scale, and Injury Severity Scores. Main outcome measure included mortality, hospital or intensive care unit duration, and discharge disposition. Of 131 patients on anticoagulants, patients on clopidogrel (n = 21) were more likely to die (OR = 14.7; 95% CI: 2.3-93.6) and be discharged to an inpatient long-term facility (OR = 3.25; 95%CI: 1.06-9.96). Length of hospital stay and intensive care unit stay were not different from control. Mortality in aspirin patients (n = 90) and warfarin patients (n = 20) did not differ from control. Warfarin patients had increased hospital and ICU stay (10.6 and 5.3 days) when compared with the control (4.7 and 0.9 days, respectively). TBI patients on clopidogrel may have increased long-term disability and fatal consequences when compared with patients who are not on these drugs or on other anticoagulants. Patients on clopidogrel should be advised of safety when engaging in potentially dangerous activities to avoid the consequences of TBI.

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Key findings towards optimising adalimumab treatment: the concentration-effect curve.

To determine a concentration-effect curve of adalimumab in rheumatoid arthritis (RA) patients taking into account the effect of methotrexate (MTX) on concentration and effect and to identify a therapeutic range for adalimumab concentrations. In a prospective observational cohort study, 221 consecutive patients with RA were treated with 40 mg adalimumab subcutaneously every other week. The relationship between adalimumab trough level and clinical efficacy after 28 weeks of follow-up was determined in a concentration-effect curve. A receiver-operator characteristics (ROC) curve established a therapeutic cut-off concentration. The effect of MTX on adalimumab trough levels was shown by dividing patients that are and are not concomitantly using MTX in the concentration-effect curve and a concentration table. Clinical efficacy improved with increasing adalimumab concentration and reached a maximum (mean disease activity score in 28 joints improvement of 2) with levels between 5-8 μg/mL. Levels exceeding 8 μg/mL were illustrated to have no additional beneficial effect on disease activity. The ROC curve showed an area under the curve of 0.695 (95% CI 0.626 to 0.764) for European League Against Rheumatism response and adalimumab levels: good responders versus non-responders and moderate responders. A cut-off of 5 μg/mL had a sensitivity of 91% and a specificity of 43%. Adalimumab levels are influenced by concomitant MTX use: patients on adalimumab monotherapy had a median adalimumab level of 4.1 μg/mL (IQR 1.3-7.7), whereas patients concomitantly taking MTX had a median level of 7.4 μg/mL (IQR 5.3-10.6, p<0.001). Adalimumab trough levels in a range of 5-8 μg/mL are sufficient to reach adequate clinical response. These levels are influenced substantially by concomitant MTX use.

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Thulium Vaporesection of the Prostate and Thulium Vapoenucleation of the Prostate in Patients on Oral Anticoagulants: A Retrospective Three-Centre Matched-Paired Comparison.

To evaluate the short-term results of thulium vaporesection of the prostate (ThuVEP) and thulium vapoenucleation of the prostate (ThuVARP) in patients with benign prostatic obstruction on oral anticoagulants (OA). A 3-centre retrospective matched-paired comparison of patients treated by ThuVEP (n = 26) or ThuVARP (n = 26) was performed. Thirty-four patients were on aspirin/ticlopidin, 7 on clopidogrel or clopidogrel and aspirin, and 11 on phenprocoumon at the time of surgery. Haemoglobin decrease was higher after ThuVEP compared to ThuVARP (1.5 vs. 0.3 g/dl, p < 0.001). The rate of postoperative blood transfusions (3.9 vs. 0%), clot retention (3.9 vs. 0%), and re-operation (7.7 vs. 0%) was not different between ThuVEP and ThuVARP (p = 0.274). Catheterization time was shorter for ThuVARP (1 vs. 2 days, p < 0.01). Qmax was significantly higher after ThuVEP at 6-month follow-up (31 vs. 21.5 ml/s, p < 0.001), while improvements in International Prostate Symptom Score, quality of life, and post-voiding residual urine showed no differences between the groups. Urethral or bladder neck strictures did not occur during the 6-month follow-up in both groups. ThuVEP and ThuVARP are safe and efficacious procedures in patients on OA. Although patients assigned to ThuVEP had higher Qmax at 6-month follow-up, ThuVARP resulted in similar functional outcomes.

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Limited prognostic value of changes in antineutrophil cytoplasmic antibody titer in patients with Wegener's granulomatosis.

To assess the correlation and prognostic value of antineutrophil cytoplasmic antibody (cANCA) titers with disease activity in patients with Wegener's granulomatosis (WG). One hundred six patients with WG had serum ANCA determinations; 72 had serial titers obtained routinely at 1-3-month intervals. One hundred twelve subjects (19 of whom were healthy donors) served as controls. All serum samples were tested for cANCA by an indirect immunofluorescence technique. A prospective analysis of disease activity and cANCA values was performed. Disease activity was assessed according to clinical, laboratory, radiographic, and histopathologic findings. Positivity for cANCA was a sensitive (88%) marker of active WG. However, changes in serial titers temporally correlated with a change in disease status in only 64% of patients. Furthermore, an increase in the cANCA titer preceded clinical exacerbation of disease in only 24% of patients who had been in remission or had low-grade, smoldering disease. A rise in cANCA titer alone should not be considered adequate evidence of an impending clinical exacerbation, and therefore does not justify initiating or increasing immunosuppressive therapy.

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Antianginal effects of amlodipine at a single dose on exertional angina patients using treadmill exercise testing--a randomized crossover study in comparison with placebo.

With eight cases of stable exertional angina as subjects, the antianginal action and sustained effects of single 10 mg oral doses of new calcium antagonists amlodipine were assessed by treadmill exercise tests in randomized crossover trials with respect to a placebo. Exercise tests were conducted before as well as 4, 8, and 24 hours after administration, and plasma amlodipine concentration was investigated at the same times. The maximal exercise time was 299 +/- 43 seconds before as compared with 346 +/- 49 seconds 4 hours after administration and 368 +/- 50 seconds 8 hours after administration, a significant prolongation in each case (p < 0.01). Moreover, the exercise time elapsed until 1 mm of ST-segment depression, as well as the ST-segment depression measured at the same time, were both significantly improved as compared with the placebo results. The plasma amlodipine concentration reached a peak 8 hours after administration and displayed an effective level even 24 hours after administration. The value of delta PRP measured at the same time during the exercise test was also significantly reduced as compared with the placebo results, even 24 hours after administration of amlodipine. These findings supported the conclusion that single 10-mg doses of amlodipine provide stable antianginal action over a 24-hour period.

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Automated joint space width quantification of hand and wrist joints: a proof of concept study.

To compare as proof of concept the sensitivity to change of automated quantification of radiographic wrist and hand joint space width (JSW) with scoring JSW according to the Sharp/van der Heijde scoring method (SHS) in two strategy groups of a treat-to-target and tight-control early rheumatoid arthritis (RA) study. Digital radiographs were assessed for JSW changes of 134 patients of the 236 patients participating in the second Computer Assisted Management in Early Rheumatoid Arthritis trial, of whom both baseline and year 2 radiographs were available (year 1 radiographs n=125). Of those 134 patients, 70 started with methotrexate and prednisone (MTX+Pred) and 64 with MTX and placebo (MTX+Plac). JSW change over 1 and 2 years of the hands and wrists was assessed, applying both the joint space narrowing (JSN) subscore of the SHS by 2 readers and the automated assessment with the JSW quantification software 'JSQ'. For both methods, progression of JSW change of the hand and wrist was analysed using linear mixed modelling (dependent variable 'JSW', factor 'strategy group', covariate 'follow-up time in years', interaction term 'strategy group*follow-up time'; radiographs of baseline, year 1 and year 2 were used). For each method the standardised mean difference (SMD) for the change in JSW from baseline to year 2 between the treatment strategies was obtained using a non-parametric method. Patient characteristics of the current subpopulation were similar to those of the whole study population. JSN of the hand and wrist according to SHS at 2 years was present in 16 vs. 23% in the MTX+Pred group vs. the MTX+Plac group. The mean yearly progression rates of JSW change of the hands and wrists using JSQ were -0.00mm (95% confidence interval (CI) -0.01; 0.01) for MTX+Pred vs. -0.02mm (95%CI -0.03; -0.01) for MTX+Plac, p=0.045, and using SHS JSN they were 0.19 units (95%CI 0.09; 0.30) vs. 0.30 units (95%CI 0.14; 0.45) for MTX+Pred vs. MTX+Plac, p=0.271. The SMD for the change from baseline to year 2 between the treatment strategies was 0.37 for JSQ and 0.13 for SHS JSN. In this proof of concept study the yearly progression rate of JSW change of hand and wrist joints, according to the automated JSW quantification software package 'JSQ', was higher in the group initiating MTX+Plac than in the group initiating MTX+Pred. A similar trend was seen with the JSN assessment according to the SHS method of the hand and wrist. However, JSN of the hand and wrist according to SHS, the current gold standard to assess radiographic progression, was seen in only about 20%. Therefore, further studies are needed to conclude firmly that JSQ should be incorporated into quantitative scoring of radiographs in RA.

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Effects of acute treatment with pravastatin on cerebral vasospasm, autoregulation, and delayed ischemic deficits after aneurysmal subarachnoid hemorrhage: a phase II randomized placebo-controlled trial.

Statins may improve cerebral vasomotor reactivity through cholesterol-dependent and -independent mechanisms. A phase II randomized controlled trial was conducted to examine the hypothesis that acute pravastatin treatment could improve cerebrovascular autoregulation and reduce vasospasm-related complications after aneurysmal subarachnoid hemorrhage (SAH). A total of 80 aneurysmal SAH (aSAH) patients (18 to 84 years of age) within 72 hours from the ictus were randomized equally to receive either oral pravastatin (40 mg) or placebo daily for up to 14 days. Primary end points were the incidence, duration, and severity of cerebral vasospasm, and duration of impaired autoregulation estimated from transcranial Doppler ultrasonography. Secondary end points were the incidence of vasospasm-related delayed ischemic deficits (DIDs) and disability at discharge. Prerandomization characteristics were balanced between the 2 groups. No treatment-related complication was observed. The incidences of vasospasm and severe vasospasm were reduced by 32% (P=0.006) and 42% (P=0.044), respectively, and the duration of severe vasospasm was shortened by 0.8 days (P=0.068) in the pravastatin group. These measurements were maximal on the ipsilateral side of ruptured aneurysms. The duration of impaired autoregulation was shortened bilaterally (P< or =0.01), and the incidence of vasospasm-related DIDs and mortality were decreased by 83% (P<0.001) and 75% (P=0.037), respectively, in the pravastatin group. Acute treatment with pravastatin after aSAH is safe and ameliorates cerebral vasospasm, improves cerebral autoregulation, and reduces vasospasm-related DID. Unfavorable outcome at discharge was reduced primarily because of a reduction in overall mortality. This is the first demonstration of clinical benefits with immediate statin therapy for an acute cerebrovascular disorder.

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An elective-titration study of the comparative effectiveness of two angiotensin II-receptor blockers, irbesartan and losartan. Irbesartan/Losartan Study Investigators.

This multicenter, randomized, double-masked, elective-titration study was designed to compare the effectiveness, safety, and tolerability of irbesartan and losartan, two angiotensin II subtype AT1-receptor blockers, in the treatment of patients with mild-to-moderate hypertension. After a 3-week, single-masked, placebo lead-in period, 432 patients with a mean seated diastolic blood pressure (SeDBP) of 95 to 115 mm Hg were randomly allocated to receive either irbesartan 150 mg once daily (n = 213) or losartan 50 mg once daily (n = 219). At week 4, if SeDBP at trough (i.e., 24 +/- 3 hours after the previous dose) was > or = 90 mm Hg, the daily dose was doubled (to irbesartan 300 mg or losartan 100 mg). At week 8, if trough SeDBP was > or = 90 mm Hg, hydrochlorothiazide 12.5 mg once daily was added to the regimen; consistent with the prescribing information for losartan, the dose of losartan was reduced to 50 mg once daily on the addition of hydrochlorothiazide. A total of 370 patients (178 irbesartan and 192 losartan) were evaluable for efficacy. The mean change in trough SeDBP at week 8, the primary efficacy end point, was significantly greater in patients receiving irbesartan monotherapy than in those receiving losartan monotherapy (-10.2 mm Hg vs -7.9 mm Hg, respectively). At week 12, reductions in trough SeDBP and seated systolic blood pressure were greater with irbesartan treatment than with losartan treatment (-13.8 mm Hg vs -10.8 mm Hg and -18.0 mm Hg vs -13.9 mm Hg, respectively), and a greater proportion of irbesartan patients responded to therapy (i.e., trough SeDBP < 90 mm Hg or reduction in trough SeDBP > or = 10 mm Hg) compared with losartan patients (78% vs 64%, respectively). Both regimens were well tolerated.

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In search for genetic determinants of clinically meaningful differential cardiovascular event reduction by pravastatin in the PHArmacogenetic study of Statins in the Elderly at risk (PHASE)/PROSPER study.

Statin therapy is widely used in the prevention and treatment of cardiovascular events and is associated with significant risk reductions. However, there is considerable variation in response to statin therapy both in terms of LDL cholesterol reduction and clinical outcomes. It has been hypothesized that genetic variation contributes importantly to this individual drug response. We investigated the interaction between genetic variants and pravastatin or placebo therapy on the incidence of cardiovascular events by performing a genome-wide association study in the participants of the PROspective Study of Pravastatin in the Elderly at Risk for vascular disease--PHArmacogenetic study of Statins in the Elderly at risk (PROSPER/PHASE) study (n = 5244). We did not observe genome-wide significant associations with a clinically meaningful differential cardiovascular event reduction by pravastatin therapy. In addition, SNPs with p-values lower than 1 × 10(-4) were assessed for replication in a case-only analysis within two randomized placebo controlled pravastatin trials, CARE (n = 711) and WOSCOPS (n = 522). rs7102569, on chromosome 11 near the ODZ4 gene, was replicated in the CARE study (p = 0.008), however the direction of effect was opposite. This SNP was not associated in WOSCOPS. In addition, none of the SNPs replicated significantly after correcting for multiple testing. We could not identify genetic variation that was significantly associated at genome-wide level with a clinically meaningful differential event reduction by pravastatin treatment in a large prospective study. We therefore assume that in daily practice the use of genetic characteristics to personalize pravastatin treatment to improve prevention of cardiovascular disease will be limited.

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Triple therapy after PCI - Warfarin treatment quality and bleeding risk.

A combination of warfarin, aspirin and clopidogrel is indicated after percutaneous coronary intervention (PCI) in some patients, despite the higher risk of bleeding inferred by this triple therapy. Whether the treatment quality of warfarin measured by iTTR (individual time within therapeutic INR range) is associated with bleeding complications during triple therapy after PCI. A retrospective register study consisting of 601 triple treated PCI patients from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). The cohort was cross-matched with the Swedish Patient Registry for background characteristics and bleeding complications up to 6 months after PCI using ICD10 codes, the Prescribed Drug Registry for ongoing medications, and the national oral anticoagulation registry Auricula for warfarin treatment quality. The patients were grouped into four iTTR groups: <50%, 50-69.9%, 70-84.9% and >85% as well as iTTR above or below 70%. Of 601 patients, 39 (6.5%) had a bleeding complication (type 2 according to BARC). Bleeding was more common for iTTR<70% compared to iTTR>70%, 28 (9.3%) vs. 11 (3.7%) (p = 0.005). The bleeding frequency increased gradually from the best group, iTTR>85% with four bleeders (3.3%) up to 17 bleeders (13.3%) in the worst group with iTTR<50% (p = 0.003), with a corresponding bleeding rate per 100 treatment years of 8.0 and 44.9, respectively. In multivariate analysis low BMI, HR 1.11 (95% CI 1.01-1.22), a medical history of anemia HR 3.17 (1.16-8.69) and iTTR < 70% HR 2.86 (1.25-6.53) increased the risk of bleeding. Triple therapy after PCI confers a high risk of bleeding events. Warfarin treatment quality measured by iTTR as well as a medical history of anemia are strong independent predictors of bleeding in these patients. Physicians should pay more attention to iTTR after PCI.

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[Ultrasonic spray protection against bronchospasm. Comparison of fenoterol and a combination of salbutamol and ipratropium bromide].

Nine patients with clinically stable bronchial asthma who had received no drug treatment in the preceding 48 hours were examined. The patients were subjected to 5 minutes ultrasound spray after the double blind administration of either fenoterol or salbutamol + ipratropium bromide. Respiratory function was assessed before and 30, 60 and 90 minutes after cessation of the stimulation. The results showed no significant difference in the protection against the ultrasound spray provided by fenoterol and the combination of salbutamol + ipratropium bromide.

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Changes in Coronary Plaque Composition in Patients With Acute Myocardial Infarction Treated With High-Intensity Statin Therapy (IBIS-4): A Serial Optical Coherence Tomography Study.

This study assessed changes in optical coherence tomography (OCT)-defined plaque composition in patients with ST-elevation myocardial infarction (STEMI) receiving high-intensity statin treatment. OCT is a high-resolution modality capable of measuring plaque characteristics including fibrous cap thickness (FCT) and macrophage infiltration. There is limited in vivo evidence regarding the effects of statins on OCT-defined coronary atheroma composition and no evidence in the context of STEMI. In the IBIS-4 (Integrated Biomarker Imaging Study-4), 103 patients underwent intravascular ultrasonography and OCT of 2 noninfarct-related coronary arteries in the acute phase of STEMI. Patients were treated with high-dose rosuvastatin for 13 months. Serial OCT imaging was available in 153 arteries from 83 patients. We measured FCT by using a semi-automated method. Co-primary endpoints consisted of the change in minimum FCT (measured in fibroatheromas) and change in macrophage line arc. At 13 months, median low-density lipoprotein cholesterol had decreased from 128 mg/dl to 73.6 mg/dl. Minimum FCT, measured in 31 lesions from 27 patients, increased from 64.9 ± 19.9 μm to 87.9 ± 38.1 μm (p = 0.008). Macrophage line arc decreased from 9.6° ± 12.8° to 6.4° ± 9.6° (p < 0.0001). The secondary endpoint, mean lipid arc, decreased from 55.9° ± 37° to 43.5° ± 33.5°. In lesion-level analyses (n = 191), 9 of 13 thin-cap fibroatheromata (TCFAs) at baseline (69.2%) regressed to non-TCFA morphology, whereas 2 of 178 non-TCFA lesions (1.1%) progressed to TCFAs. In this observational study, we found significant increase in minimum FCT, reduction in macrophage accumulation, and frequent regression of TCFAs to other plaque phenotypes in nonculprit lesions of patients with STEMI treated with high-intensity statin therapy.

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Gabapentin toxicity in patients with chronic kidney disease: a preventable cause of morbidity.

Gabapentin is frequently used as an analgesic in patients with chronic kidney disease. Although gabapentin is well known for its favorable pharmacokinetics, it is exclusively eliminated renally, and patients with chronic kidney disease are at risk for toxicity. Existing literature on such risk is lacking. We examined the Mayo Clinic Rochester database from 1998 to 2007 in patients with serum gabapentin measurements and known medical outcomes. A total of 729 patients were stratified according to their estimated glomerular filtration rate: group I, 126 individuals with estimated glomerular filtration greater than 90 mL/min/1.72 mm(2) [corrected] ; group II, 594 individuals with estimated glomerular filtration less than 90 mL/min/1.72 mm(2) [corrected] without dialysis; group III, 9 individuals with chronic dialysis. Patients in groups II and III had higher serum gabapentin levels (8.39+/-0.32 microL/mL and 58.8+/-10.22 microL/mL, respectively) than in group I (5.52+/-0.32 microL/mL, P<.01). Toxicity occurred exclusively in groups II (5.56%) and III (77.8%); toxic manifestations were more severe in group III than in group II. Elderly individuals with multiple comorbidities were overrepresented in those with toxic manifestations. Gabapentin toxicity was suspected initially in only 41.5% of symptomatic cases. Gabapentin toxicity in patients with chronic kidney disease is underrecognized. Patients with chronic kidney disease often receive inappropriately high gabapentin dosage for their kidney function, occasioning overt toxicity; advanced age and comorbidity predispose these patients for toxicity. Heightened awareness of such preventable risk, amid the chronic kidney disease epidemic, would be cost-effective and improve healthcare quality.

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[Major agitated-anxious versus blunted-retarded depression: differential effects of fluoxetine].

A multi-centre study was designed to evaluate the efficacy and tolerance of fluoxetine in two groups of major depression: "agitated-anxious" and "blunted-retarded". The study included 50 patients presenting a major depressive episode (following DSM III-R criteria and score > or = 20 on MADRS): 26 in "agitated-anxious" group (score > or = 15 on Hamilton anxiety scale and > or = 10 on Tyrer anxiety brief scale) and 24 in the "blunted-retarded" group (score > or = 15 on Widlöcher retardation scale and > or = 10 on Abrams-Taylor blunted affect scale). After one week period on placebo, all patients were treated in an open design with fluoxetine at a fixed daily dose of 20 mg and followed on a period of 6 weeks with active treatment. In spite of a significant antidepressant efficacy of fluoxetine in the two groups, better results were observed in the "agitated-anxious" depressed group: marked improvement on MADRS total score at day 42 (76% decrease vs 62% in the "blunted-retarded" group, p = 0.012), greater number of "responders" defined by a decrease > or = 50% on MADRS total score and a total score < or = 12 (95% vs 63%, p = 0.04), better patient's global impression on efficacy (54% of "excellent efficacy" vs 18%, p = 0.012), more improvement on HSCL-58 total score (mean decrease of 69% vs 39%, p = 0.016), higher improvement on "hostility/interpersonal hypersensitivity" score (mean decrease of 74% vs 37%, p = 0.001) and on "anger attacks/irritability" sub-score (mean decrease of 73% vs 30%, p = 0.0002).(ABSTRACT TRUNCATED AT 250 WORDS)

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Patterns of compliance with once versus twice daily antihypertensive drug therapy in primary care: a randomized clinical trial using electronic monitoring.

To evaluate patterns of compliance with once versus twice daily administration of antihypertensive therapy (primary-outcome measure) and relevance of partial compliance for blood pressure control (secondary outcome measure). Multicentre, nonblinded, parallel group randomized design. Nonacademic primary care practices across Canada. Patients with mild essential hypertension (diastolic blood pressure 95 to 110 mmHg) of either sex (40% women), age 18 to 80 years (average 55 years). One hundred and ninety-eight patients were randomized to active treatment; 14 patients discontinued the study because of side effects. After a four-week placebo run-in period, patients were randomized to amlodipine 5 mg once-a-day or diltiazem slow release formulation (SR) 90 mg twice daily. Doses were increased to 10 mg and 180 mg to achieve sitting diastolic blood pressure of 90 mmHg or less. During 20 weeks on active treatment, compliance was assessed by pill counts and medication event monitoring system (MEMS), assessing percentage of prescribed doses taken, percentage days correct doses taken, percentage prescribed doses taken on time and blood pressure control as determined by office blood pressure measurement. The percentage prescribed doses taken (by either pill count of MEMS) showed a high degree of compliance, similar for the two treatments. However, other parameters of compliance were significantly better with once versus twice daily therapy. Partial compliance (less than 80% by pill count) led to less blood pressure control with the short acting diltiazem, but did not affect blood pressure control for the long acting amlodipine. Side effects profiles did not differ between the two treatments. Within the constraints of a clinical trial, hypertensive patients in primary care show a high degree of overall compliance with once or twice daily pill-taking, but patterns of pill-taking are more erratic with twice versus once daily medication, particularly in men. The results suggest that the negative consequences of partial compliance for blood pressure control can be offset by choosing agents with a duration of action well beyond the dosing interval.

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Can we induce tolerance in rheumatoid arthritis?

Oral tolerance (OT) has worked well in numerous laboratory animal models of autoimmune diseases. Humans have been orally tolerized to keyhole limpet hemocyanin (KLH); patients with systemic sclerosis (SSc, scleroderma) have been orally tolerized to oral type I collagen (CI). However, clinical trials of oral type II collagen (CII) therapy in rheumatoid arthritis (RA) have had mixed results. Clinical studies show that compounds (such as nonsteroidal antiinflammatory drugs and prednisone) that inhibit generation of PGE(2) block OT induction. In murine OT models, the PGE(1) analog, misoprostol, reverses the NSAID OT block. These animal studies suggest that OT to CII or other antigens in patients with RA should be inducible if measures are taken to maintain normal prostaglandin function in the gut- associated lymphoid tissue (GALT). A clinical trial is underway in patients with RA to assess whether withholding NSAIDs and prednisone will allow OT to to be induced, and whether oral CII has meaningful clinical efficacy in this disease.

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Comparison of Mortality and Nonfatal Cardiovascular Events in Adults With Atrial Fibrillation With Versus Without Levothyroxine Treatment.

Levothyroxine has been suggested to be cardiotoxic, but previous studies on the risk of cardiovascular events associated with levothyroxine treatment have been inconclusive. We aimed to study the association between levothyroxine treatment and all-cause mortality as well as cardiovascular events. Study population included all adults (n = 12,283) ≥ 45 years diagnosed with atrial fibrillation (AF) at 75 primary care centers in Sweden in 2001 to 2007, with (n = 1,189; 283 men and 906 women) or without (n = 11,094) levothyroxine treatment. Outcome was defined as all-cause mortality and cardiovascular events, that is, myocardial infarction, ischemic stroke, and congestive heart failure until December 31, 2010. During a mean 5.8 years (standard deviation 2.4 years) of follow-up, a total of 3,954 patients died (32.2%), among whom 92 men (32.5%) and 266 women (29.4%) were treated with levothyroxine. In fully adjusted Cox regression models (age, co-morbidity, socioeconomic factors, and warfarin treatment), a significant association between levothyroxine treatment and lower mortality was found among women (hazard ratio 0.78, 95% confidence interval 0.68 to 0.91), but not among men (hazard ratio 0.87, 95% confidence interval 0.69 to 1.10). In the secondary analysis, levothyroxine treatment was not associated with the risk of myocardial infarction, ischemic stroke, or congestive heart failure (p > 0.05). In conclusion, in a large representative cohort, we found that levothyroxine treatment decreased the mortality risk in women with AF, which suggests that such treatment could be of benefit in this setting.

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Anti-Interleukin-6 Receptor Tocilizumab for Severe Juvenile Idiopathic Arthritis-Associated Uveitis Refractory to Anti-Tumor Necrosis Factor Therapy: A Multicenter Study of Twenty-Five Patients.

To assess the efficacy of tocilizumab (TCZ) for the treatment of juvenile idiopathic arthritis (JIA)-associated uveitis. We conducted a multicenter study of patients with JIA-associated uveitis that was refractory to conventional immunosuppressive drugs and anti-tumor necrosis factor (anti-TNF) agents. We assessed 25 patients (21 female; 47 affected eyes) with a mean ± SD age of 18.5 ± 8.3 years. Uveitis was bilateral in 22 patients. Cystoid macular edema was present in 9 patients. Ocular sequelae found at initiation of TCZ included cataracts (n = 13), glaucoma (n = 7), synechiae (n = 10), band keratopathy (n = 12), maculopathy (n = 9), and amblyopia (n = 5). Before TCZ, patients had received corticosteroids, conventional immunosuppressive drugs, and biologic agents (median 2 [range 1-5]), including adalimumab (n = 24), etanercept (n = 8), infliximab (n = 7), abatacept (n = 6), rituximab (n = 2), anakinra (n = 1), and golimumab (n = 1). Patients received 8 mg/kg TCZ intravenously every 4 weeks in most cases. TCZ yielded rapid and maintained improvement in all ocular parameters. After 6 months of therapy, 79.2% of patients showed improvement in anterior chamber cell numbers, and 88.2% showed improvement after 1 year. Central macular thickness measured by optical coherence tomography in patients with cystoid macular edema decreased from a mean ± SD of 401.7 ± 86.8 μm to 259.1 ± 39.5 μm after 6 months of TCZ (P = 0.012). The best-corrected visual acuity increased from 0.56 ± 0.35 to 0.64 ± 0.32 (P < 0.01). After a median follow-up of 12 months, visual improvement persisted, and complete remission of uveitis was observed in 19 of 25 patients. Significant reduction in the prednisone dosage was also achieved. The main adverse effects were severe autoimmune thrombocytopenia in 1 patient, pneumonia and then autoimmune anemia and thrombocytopenia in 1 patient, and viral conjunctivitis and bullous impetigo in 1 patient. TCZ appears to be a useful therapy for severe refractory JIA-associated uveitis.

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Relationship between type-2 diabetes and use of metformin with risk of colorectal adenoma in an American population receiving colonoscopy.

The aim of this study is to explore the relationship between type-2 diabetes, its treatments (Use of metformin) and the development of colorectal adenoma. Colonoscopy reports from a total of 66 endoscopists in one big hospital in midwest during 2008-2009 were reviewed. Colonoscopy findings including quality of preparation, polyp size, location, morphology, pathology and history of diabetes and metformin treatment were retrieved. Of the 7382 colonoscopy reports were reviewed, 3465 average risk patients were included in our final analysis. The pathologically proven Adenoma detection rate (ADR) in total population was 24.6 % (30.2% in Men and 19.2% in Women). Old age and male sex were significantly associated with increasing risk of colorectal adenoma. Type-2 diabetes was associated increased risk of colorectal adenoma (OD 1.35, 95% confidence interval 1.08-1.70, p=0.009). A total of 426 subjects (12.29%) had diabetes and 405 of these subjects (11.7%) had type-2 diabetes. Within diabetic patient group, people who were taking metformin have significantly lower risk of colorectal adenoma (OD 0.55, 95% confidence interval 0.34-0.87, p=0.011). Diabetic subjects have increased risk of developing colorectal adenoma. Our study also supports the beneficial effect of metformin in development of colorectal adenoma.

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Variability in metabolism of imipramine and desipramine using urinary excretion data.

Variability in imipramine and desipramine metabolism was evaluated using urinary excretion data from patients with pain. Liquid chromatography-tandem mass spectrometry was used to quantitate concentrations in urine specimens. Interpatient population contained 600 unique imipramine specimens, whereas intrapatient population had 137 patients with two or more specimens. Normal concentration ranges of imipramine, desipramine and the desipramine/imipramine metabolic ratio (MR) were established, and various factors were tested for MR impact. Geometric mean of imipramine urine concentration was 0.46 mg/g of creatinine, and desipramine was 0.67 mg/g of creatinine. Gender, concomitant known CYP2C19 inhibitor use and urine pH did not affect MR. However, proton-pump inhibitor (PPI) users had a significantly lower mean MR than those without a listed PPI. Early age group (18-36 years) had a significantly higher mean MR than middle (37-66 years) and late (67-90 years) age groups. Approximately one-third were positive for one or more of hydrocodone, oxycodone, hydromorphone or oxymorphone. Patients with no opioids reported in the medication list had a significantly lower geometric mean MR than those with prescribed opioids (1.03 vs. 1.54, P = 0.004). Patients with only one prescribed opioid had a lower MR than those with two or more prescribed opioids. Patients with younger age, prescribed opioids and no listed PPI were more likely to have a higher geometric mean urinary desipramine/imipramine MR.

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The impact of antibiotic resistance on the efficacy of three 7-day regimens against Helicobacter pylori.

Antibiotic resistance affects the success of anti-Helicobacter pylori therapies and varies greatly from country to country. To compare the efficacy of three short-term triple regimens in relation to H. pylori primary resistance in our region. We enrolled 210 H. pylori-positive dyspeptic patients for this randomized, open, parallel-group study. Three arms of 70 patients each received the following 1-week regimens: (1) ranitidine bismuth citrate 400 mg b.d. + clarithromycin 250 mg b.d. + metronidazole 500 mg b.d. (RCM); (2) bismuth subcitrate 240 mg b.d. + amoxycillin 1000 mg b.d. + metronidazole 500 mg b.d. (BAM); (3) omeprazole 20 mg o.d. + clarithromycin 250 mg b.d. + metronidazole 500 mg b.d. (OCM). H. pylori was assessed by CLO-test and histology before and 4 weeks after therapy. Antibiotic resistance was assessed by E-test. On intention-to-treat analysis RCM was more effective than OCM (84% vs. 69%; P < 0.03) and BAM (84% vs. 63%; P < 0.004). MIC determination was successful in 117 out of 210 patients (55%); metronidazole resistance was present in 52 out of 117 patients (44%) and clarithromycin resistance was present in 17 out of 117 patients (14%). Excellent cure rates were achieved when strains were sensitive to both antibiotics (100% with RCM and BAM and 90% with OCM), whereas RCM was superior to OCM (P=0.009) and BAM (P=0.001) with respect to overall resistant strains (94% vs. 57% and 38%, respectively). One-week RCM is the best regimen to eradicate H. pylori in our geographical area. This seems to be linked to the better ability of RCM compared to OCM and BAM in overcoming the high prevalence of H. pylori resistance to both metronidazole and clarithromycin in our region.

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Reconsidering idiopathic CK-elevation.

This study investigated the frequency of persisting, idiopathic creatine-kinase (CK)-elevation, how often the cause of idiopathic CK-elevation could be clarified, and the most frequent causes of idiopathic CK-elevation. Among 28 patients with previously idiopathic CK-elevation, CK remained elevated in 32%. The cause of idiopathic CK-elevation could be determined in 46%. Causes were mitochondriopathy (n = 5), seizure (n = 2), stroke (n = 2), myositis (n = 1), intramuscular-injection (n = 1), alcohol myopathy (n = 1), and pravastátin myopathy (n = 1). In 10 of these patients CK was normal at follow-up. CK-elevation remained idiopathic in 54%. Idiopathic CK-elevation should be comprehensively re-evaluated, even if CK is only slightly elevated or normal at follow-up.

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Insulin resistance influences central opioid activity in polycystic ovary syndrome.

This pilot study describes a relationship between insulin resistance and μ-opioid neurotransmission in limbic appetite and mood-regulating regions in women with polycystic ovary syndrome (PCOS), suggesting that insulin-opioid interactions may contribute to behavioral and reproductive pathologies of PCOS. We found that [1] patients with PCOS who are insulin-resistant (n = 7) had greater limbic μ-opioid receptor availability (nondisplaceable binding potential) than controls (n = 5); [2] receptor availability was correlated with severity of insulin resistance; and [3] receptor availability normalized after insulin-regulating treatment.

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[The effect of clopidogrel and aspigrel on myocardial ischemia in patients with unstable angina pectoris].

The modern cardiology pays much attention to research of myocardial ischemia, especially painless myocardial ischemia as the problem of sudden coronary death. Findings from the current study suggest that antianginal therapy which includes antiaggregant and anticoagulant is effective because of decreasing general myocardial ischemia and its painless form.

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Patient accrual and interim statistical analysis in long-term randomized clinical trials: the French chronic lymphocytic leukemia CLL 80 protocol as a case study.

The CLL 80 clinical trial of treatment for chronic lymphocytic leukemia was designed using a three-stage prognostic classification. Within each stage patients received one of two treatments allocated by randomization, two adjacent stages having a common treatment. The fixed-sample design required 850 patients entered over a period of 8.5 years. Active patient recruitment led to 741 patients being randomized in four years. The first interim analysis, carried out at this point, showed a treatment difference in one stage which was statistically significant (p = 0.001) and justified an early termination of the protocol. This paper discusses practical aspects of patient accrual and interim analysis in this study.

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Serologically active clinically quiescent systemic lupus erythematosus: a discordance between clinical and serologic features.

The significance of abnormal serologic tests in systemic lupus erythematosus (SLE) in the absence of active clinical disease is unclear. In this report we describe a group of 14 patients with SLE in whom a discordance between clinical and serologic features was apparent. These patients had persistently positive lupus erythematosus preparations and antinuclear antibody tests, low serum complement levels and high levels of DNA binding. Their lymphocyte response to concanavalin A (Con A) mitogen was suppressed. They have been asymptomatic and have remained untreated for a mean of four and a quarter years.

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Pharmacological treatment of kleptomania and bulimia nervosa.

We describe three patients with concurrent DSM-III-R kleptomania and bulimia nervosa who all demonstrated a partial or complete response of both bulimic and kleptomanic symptoms to fluoxetine, trazodone, or tranylcypromine. These observations raise the possibility that pharmacological treatment may benefit kleptomania, and call for further study of the relationship between kleptomania, bulimia nervosa, and major depression.

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High-dose therapy with autologous stem cell transplantation in first response in mantle cell lymphoma.

We retrospectively investigated the outcome of 30 newly diagnosed patients with mantle cell lymphoma treated with high-dose therapy and autologous stem cell transplantation in first response. With a median follow-up of 55 months, the 5-year overall-survival is 62%, the 5-year progression-free-survival is 40% and no secondary malignancy has occurred.

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Clopidogrel-Paclitaxel Drug-Drug Interaction: A Pharmacoepidemiologic Study.

Paclitaxel is mainly eliminated by CYP2C8 in the liver. CYP2C8 is strongly inhibited by the clopidogrel metabolite acyl-β-D-glucuronide. To determine if this interaction has clinical relevance, we identified 48 patients treated with clopidogrel and paclitaxel using databases and a prescription register. Peripheral sensory neuropathy was retrospectively evaluated from medical charts and compared to that of 88 age- and sex-matched controls treated with paclitaxel and low-dose aspirin. By a cumulative dose of 1,500 mg paclitaxel, 35% of the patients had developed severe neuropathy. The overall hazard ratio between clopidogrel use and severe paclitaxel neuropathy was 1.7 (95% confidence interval, 0.9-3.0). Among those receiving a high-dose paclitaxel regimen, the hazard ratio was 2.3 (95% confidence interval, 1.1-4.5). Our study indicates that clopidogrel is associated with a clinically relevant increased risk of neuropathy in patients treated with high-dose paclitaxel.

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The systolic hypertension in the elderly pilot program: methodological issues.

The Systolic Hypertension in the Elderly Program (SHEP) Pilot Study was conducted to determine the feasibility of conducting a long-term placebo-controlled randomized clinical trial in elderly subjects. Enrolled in the study were 551 men and women between the ages of 60 and 90 years with isolated systolic hypertension (SBP greater than or equal to 160 mmHg and DBP less than 90 mmHg). The study showed that it is possible to recruit old and very old subjects into a clinical trial; the elderly are good compliers (drugs and follow-up visits), with some decline after the age of 80; control of blood pressure was accomplished in the large majority of patients; evaluation of side effects represents a potential problem as varied complaints increase with age thus creating difficulties in distinguishing those attributed to the study drug; and finally, cause-specific mortality is probably preferable to all-cause mortality as an end-point in prevention trials of antihypertensive regimens.

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A randomized, prospective multicenter pharmacoepidemiologic study of cyclosporine microemulsion in stable renal graft recipients. Report of the Canadian Neoral Renal Transplantation Study Group.

The safety, tolerability, and pharmacokinetics of conventional cyclosporine (ConCsA) and cyclosporine microemulsion (MeCsA) were compared under conditions of normal clinical practice in a prospective, randomized, concentration-controlled, pharmacoepidemiologic study. Between September 1994 and March 1995, 1097 stable renal transplant recipients in 14 Canadian centers were randomized 2:1 to treatment with MeCsA or ConCsA. Patients were commenced on each study drug at a dose equal to their previous therapy with ConCsA, and the dose was adjusted to maintain predose whole blood cyclosporine concentrations within the therapeutic range established for each center. Prednisone and azathioprine were continued unless dose adjustment was required for clinical reasons. The mean cyclosporine concentration was comparable in both treatment groups at all time points throughout the 6 months of follow-up. The mean dose of cyclosporine was 3.6 mg/kg/day in both treatment groups at entry to the study, and declined by 0.3% and by 2.8% in patients receiving ConCsA and MeCsA, respectively. The nature and severity of adverse events were similar in both treatment groups, but there was a transient increase in neurological and gastrointestinal complications in the group receiving MeCsA within the first month after conversion (P<0.05). Serum creatinine and creatinine clearance did not change in either treatment group throughout the study. Biopsy-proven acute rejection occurred in three patients (0.8%) receiving ConCsA and in seven patients (0.9%) receiving MeCsA, with non-histologically proven acute rejection in an additional three patients (0.8%) receiving ConCsA and five patients (0.6%) receiving MeCsA (P=NS). Serum creatinine rose transiently in 35 patients (9.8%) receiving ConCsA and 138 patients (18.7%) receiving MeCsA (P<0.05) and resolved either spontaneously or after a reduction in the cyclosporine dose. One graft was lost in the MeCsA group due to irreversible rejection, and seven patients died, three in the group receiving ConCsA and four of those receiving MeCsA (P=NS). Absorption of cyclosporine was more rapid and complete from MeCsA than from ConCsA during the first 4 hr of the dosing interval, resulting in almost 40% greater exposure to the drug (P<0.001). There was close correlation between area under the time-concentration curve (AUC) over the first 4 hr of the 12-hr dosage interval and AUC over the entire 12-hr dosage interval for both formulations, making AUC over the first 4 hr a good predictor of total cyclosporine exposure. Using this parameter, patients with low absorption randomized to receive MeCsA showed a marked increase in drug exposure by months 3 and 6, whereas there was no change in those who continued on ConCsA. A limited sampling strategy utilizing samples at the predose and postdose trough levels provided an excellent correlation with drug exposure, particularly for patients receiving MeCsA (r2=0.94 MeCsA vs. r2=0.89 ConCsA). MeCsA appears to be a safe and effective therapy in stable renal transplant patients and provides superior and more consistent absorption of cyclosporine when compared with ConCsA. Transient toxicity after conversion to MeCsA occurs in some patients, and may reflect the increased exposure to cyclosporine. Use of a limited sampling approach combining trough and 2-hr postdose concentrations may provide an effective way to monitor this exposure.

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Comparative bioavailability and tolerability of a single 20-mg dose of two fluoxetine hydrochloride dispersible tablet formulations in fasting, healthy Chinese male volunteers: an open-label, randomized-sequence, two-period crossover study.

The proprietary formulation of fluoxetine hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. Pharmacokinetic studies investigating the bioequivalence of generic and branded formulations are needed to market generic fluoxetine in China. The aim of this study was to compare the bioavailability and tolerability of the proposed generic formulation with the established reference formulation of fluoxetine hydrochloride 20 mg in a fasting, healthy Chinese male population. This 10-week, open-label, randomized-sequence, single-dose, 2-period crossover study was conducted in healthy native Han Chinese male volunteers. Eligible subjects were randomly assigned in a 1:1 ratio to receive a single 20-mg dose of the test or reference formulation, followed by a 35-day washout period and administration of the alternate formulation. Doses were administered after a 12-hour overnight fast. For analysis of pharmacokinetic properties (including C(max), T(max), AUC(0-t), AUC(0-∞), and t(½)), blood samples were obtained over a 672-hour period after dosing. Plasma concentrations of fluoxetine and its active metabolite, norfluoxetine, were analyzed using a validated LC-MS/MS method. The formulations were to be considered bioequivalent if the ln-transformed ratios (test/ reference) of C(max) and AUC were within the predetermined bioequivalence range of 80% to 125%, as established by the US Food and Drug Administration, and if the P values were <0.05 for the 90% CIs. Signs and symptoms of adverse effects of fluoxetine hydrochloride such as nausea, vomiting, insomnia, somnolence, anxiety, and nervousness, as well as any untoward effects, were collected using a daily written questionnaire and recorded by the study physicians. Tolerability was assessed using monitoring of vital signs, physical ex- amination, ECG, and routine blood and urine tests, along with blood biochemical tests, at the start as well as at the end of the study. Twenty-four subjects were enrolled and completed the study (mean [SD] age, 24.4 [2.3] years [range, 20-30 years]; weight, 63.6 [8.5] kg [range, 51.2-86.8 kg]; height, 1.72 [0.07] m [range, 1.57-1.91 m]). The AUC values for fluoxetine were not consistent with a normal distribution, reflecting the existence of 2 different populations (poor and extensive metabolizers). Data from the one poor metabolizer were excluded from the pharmacokinetics data summarized. In extensive metabolizers, the mean (SD) C(max) for fluoxetine with the test formulation was 11.786 (3.459) ng/mL and T(max) was 5.48 (2.06) hours. With the reference formulation, the corresponding values were 11.754 (3.292) ng/mL and 6.26 (5.77) hours, respectively. The t(½) values with the test and reference formulations were 30.86 (7.61) and 30.96 (6.91) hours, respectively. For norfluoxetine, mean C(max) with the test formulation was 14.177 (4.957) ng/mL and T(max) was 58.48 (31.67) hours; the corresponding values for the reference formulation were 13.828 (4.838) ng/mL and 57.91 (25.75) hours. The t(½) values with the test and reference formulations were 130.91 (42.04) and 128.79 (52.72) hours, respectively. For fluoxetine, the 90% CIs (in extensive metabolizers only) for the In-transformed C(max), AUC(0-168), and AUC(0-∞) were 92.0% to 108.4%, 95.7% to 110.3%, and 97.4% to 111.3%, respectively (all, P < 0.001). For norfluoxetine, the 90% CIs for the ln-transformed C(max), AUC(0-672), and AUC(0-∞) were 93.7% to 110.7%, 98.9% to 111.4%, and 98.8% to 110.9% (all, P < 0.001). No period or sequence effects were observed for any pharmacokinetic variable in the extensive metabolizers. No adverse events were reported by the volunteers or found with results of clinical laboratory testing. This single-dose study found that the test and reference formulations of fluoxetine hydro- chloride met the regulatory criteria for bioequivalence in these fasting, healthy Chinese male volunteers. Both formulations appeared to be well tolerated.

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Association Between Generic-to-Generic Levothyroxine Switching and Thyrotropin Levels Among US Adults.

Switching among generic levothyroxine sodium products made by different manufacturers typically occurs at the pharmacy and may affect serum thyrotropin (TSH) levels. To compare TSH levels between patients who continued taking the same sourced generic levothyroxine product and those who switched. This comparative effectiveness research study with 1:1 propensity matching used data from OptumLabs Data Warehouse, a national administrative claims database linked to laboratory test results. Adults aged 18 years or older were included if they filled a generic levothyroxine prescription between January 1, 2008, and June 30, 2019, and had a stable drug dose, the same drug manufacturer, and a normal TSH level (0.3-4.4 mIU/L) for at least 3 months before either continuing to take the same product or switching among generic levothyroxine products (index date). Patients were excluded if they were pregnant, had diagnosed hypopituitarism or hyperthyroidism, or had a medical condition or used medications that could affect thyrotropin levels. They were also excluded if they filled a prescription for other forms of thyroid replacement therapy between 6 months before the index date and when the first TSH level was obtained 6 weeks to 12 months after the index date. Data were analyzed from December 1, 2019, to November 24, 2021. Proportion of individuals with a normal (0.3-4.4 mIU/L) or markedly abnormal (<0.1 or >10.0 mIU/L) TSH level using the first available laboratory result 6 weeks to 12 months after the index date. A propensity score model was developed to minimize confounding using logistic regression with the binary outcome of continuing the same sourced levothyroxine product vs switching generic levothyroxine. Covariates were demographics, comorbidities, and baseline TSH level. The balance among the treatment groups was evaluated by comparing standardized mean differences of baseline covariates between the groups. A total of 15 829 patients filled generic levothyroxine (mean [SD] age, 58.9 [14.6] years; 73.4% [11 624] were women; 4.5% [705] were Asian, 10.2% [1617] were Black, 11.4% [1801] were Hispanic, and 71.4% [11 295] were White individuals); of these patients, 56.3% [8905] received a daily levothyroxine dose of 50 μg or less. A total of 13 049 patients (82.4%) continued taking the same sourced preparation, and 2780 (17.6%) switched among generic levothyroxine preparations. Among 2780 propensity-matched patient pairs, the proportion of patients with a normal TSH level after the index date was 82.7% (2298) among nonswitchers and 84.5% (2348) among switchers (risk difference, -0.018; 95% CI, -0.038 to 0.002; P = .07). The proportion of patients with a markedly abnormal TSH level after the index date was 3.1% (87) among nonswitchers and 2.5% (69) among switchers (risk difference, 0.007; 95% CI, -0.002 to 0.015; P = .14). The mean (SD) TSH levels after the index date were 2.7 (2.3) mIU/L among nonswitchers and 2.7 (3.3) mIU/L among switchers (P = .94). Results of this comparative effectiveness research study suggest that switching among different generic levothyroxine products was not associated with clinically significant changes in TSH level. These findings conflict with the current guideline recommendation that warns clinicians about potential changes in TSH level associated with switching among levothyroxine products sourced from different manufacturers.

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[Continuous femoral nerve block to control postoperative pain in outpatient orthopedic surgery].

Postoperative pain is one of the most frequent complications of outpatient orthopedic surgery. We therefore studied the efficacy, feasibility, and safety of the continuous femoral nerve block as an analgesic technique for outpatient anterior cruciate ligament reconstruction. We carried out a single-blind prospective study of ASA 1-2 patients who received a continuous femoral nerve block with 0.125% bupivacaine through an elastomeric pump to treat postoperative pain as part of a multimodal approach. Postoperative pain was assessed on a verbal numerical scale from the immediate postoperative period until 48 hours after the operation. Side effects and patient satisfaction were also assessed. Sixty-three patients were enrolled. The continuous femoral nerve block was effective: in the first 24 hours following surgery 90% of patients had mild or no pain, and 92% required no rescue medication. It also proved safe, as there were no significant side effects. The continuous femoral nerve block with 0.125% bupivacaine is a safe, effective option for the management of postoperative pain in outpatient anterior cruciate ligament reconstruction.

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Direct costs in patients with nonvalvular atrial fibrillation newly indicated to apixaban: a retrospective prospective single arm cohort study.

Atrial fibrillation (AF) affects 46.3 million people; its prevalence has tripled over the last 50 years. AF leads to formation of blood clots increasing four-fold the risk of a stroke. Preventive anticoagulant therapy with warfarin has been well established for over 50 years but has efficacy and safety limitations. New anticoagulants do not require laboratory monitoring of prothrombin time, have low risk of adverse events, yet are more costly. This non-interventional (Act 378/2007 Coll.) retrospective-prospective single-arm cohort study consisted of 3 visits. The primary objective was to compare the total direct cost of treatment with warfarin and apixaban. Patients with non-valvular AF were enrolled at the time of discontinuation of warfarin and switching to apixaban. Costs were derived from the care provided and the list of medical procedures (Decrees 268/ 2019 Coll.). Satisfaction was assessed using SAFUCA® questionnaire. Between February 2017 and June 2019, 499 patients were enrolled in 29 Czech internal medicine clinics. The mean age of the patients was 73.6 ± 10.2 years, 36.5% were at high risk of bleeding (HAS-BLED score). Previous warfarin treatment lasted 5.9 ± 2.7 months, 63% were unable to achieve target prothrombin time, 18% switched due to adverse reactions. New apixaban treatment was followed for the first 6 months. Treatment with warfarin was associated with higher rates of major bleeding and adverse events (22 vs. 2), stroke (17 vs. 0), ischemic heart attack (11 vs. 0), and minor bleeding (173 vs. 2). The average daily cost following the switch to apixaban decreased from CZK 65.2 to CZK 4.8 (p.

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Assessing tinnitus and prospective tinnitus therapeutics using a psychophysical animal model.

Subjective tinnitus is a common and often debilitating disorder that is difficult to study because it is a perceptual state without an objective stimulus correlate. Studying tinnitus in humans is further complicated by the heterogeneity of tinnitus quality, severity, and associated hearing loss. As a consequence, the pathophysiology of tinnitus is poorly understood and treatments are often unsuccessful. In the present study, an animal psychophysical model was developed to reflect several features of tinnitus observed in humans. Chronic tinnitus was induced in rats by a single intense unilateral exposure to noise. The tinnitus was measured using a psychophysical procedure, which required the animals to discriminate between auditory test stimuli consisting of tones, noise, and 0 dB. Tinnitus was indicated by a frequency-specific shift in discrimination functions with respect to control subjects not exposed to noise. The psychophysical consequences of the noise exposure were best explained by a tinnitus hypothesis and could not be explained easily by other consequences of noise exposure such as hearing loss. The qualitative features of the tinnitus were determined and related to the duration of noise exposure and the associated cochlear trauma. The tinnitus was found to persist and intensify over 17 months of testing. Finally, the tinnitus was reversibly attenuated by treatment with gabapentin, a GABA agonist. It was concluded that this model reflected several features of human tinnitus, such as its tonality and persistence, and could be useful as a screen for potential therapeutics as well as a tool to help unravel the pathophysiology of the disorder of phantom auditory perception.

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Benefits of Fixed Dose Combination of Ramipril/Amlodipine in Hypertensive Diabetic Patients: A Subgroup Analysis of RAMONA Trial.

Combination of angiotensin-converting enzyme inhibitors and calcium channel blockers has been successfully used in the antihypertensive therapy for many years. Fixed dose combinations of ramipril/amlodipine have a benefit effect for patients to achieve target blood pressure (BP). This study aimed to assess the efficacy and safety of fixed dose combinations of ramipril and amlodipine (Egiramlon®) in hypertensive diabetic patients. Hypertensive diabetic patients who were enrolled into the RAMONA trial were included in this open, prospective, Phase IV observational clinical study. Patients had mild-to-moderate hypertension and failed to reach target BP levels through their previous therapy. During the four months of observation, patients took part in three visits (1st day = visit 1, 1st month = visit 2, and 4th month = visit 3) where they received a fixed dose combination of 5/5, 5/10, 10/5, or 10/10 mg ramipril/amlodipine, respectively, with the possibly required dose titrations, based on the decision of their attending physician. Target BP for diabetic patients was <140/85 mmHg. BP levels were measured in all visits, by taking two readings at 2-min interval. Laboratory tests including full blood count, renal function test, electrolytes, blood glucose, serum cholesterol, uric acid, triglycerides, liver function test, creatinine kinase, and midstream urinalysis were performed at visit 1 and visit 3. The 6423 patients completed the study. Among these patients, 1276 (19.9%) patients suffered from type 2 diabetes mellitus. The mean age of these diabetic patients was 64.2 ± 10.0 years; 707 (55.4%) patients were males. Target BP was achieved by 891 (69.8%) of diabetic patients at visit 3 (primary endpoint). BP decreased from 157.5/91.3 ± 9.6/7.6 mmHg (visit 1) to 130.9/79.6 ± 7.4/5.8 mmHg (visit 3). As for the secondary endpoint of the study, total cholesterol decreased from 5.50 ± 1.13 mmol/L (visit 1) to 5.20 ± 0.95 mmol/L (P = 0.000), low-density lipoprotein cholesterol decreased from 3.20 ± 0.93 mmol/L to 3.00 ± 0.77 mmol/L (P = 0.000), triglyceride decreased from 2.20 ± 1.14 mmol/L to 2.00 ± 1.97 mmol/L (P = 0.000), while high-density lipoprotein cholesterol increased from 1.30 ± 0.42 to 1.35 ± 0.30 mmol/L (P = 0.001) until the end of the 4th month (visit 3). Fasting blood glucose of the hypertensive diabetic patients decreased from 7.20 ± 1.88 mmol/L to 6.70 ± 1.38 mmol/L (P = 0.000), while HbA1c decreased from 7.90 ± 1.78% to 7.60 ± 1.83% (P = 0.000). Various fixed dose combinations of ramipril/amlodipine were well tolerated and no adverse event related to the use of the medicine has appeared. The fixed dose combination of ramipril/amlodipine was effective in hypertensive diabetic patients who failed to reach target BP previously.

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Hemodynamic effects of sublingual nifedipine in acute myocardial infarction.

Twenty-six patients with acute myocardial infarction (mean delay time 6 hours after onset of symptoms) were randomized to control or nifedipine treatment (10 mg sublingually, followed by 10 mg every 6 hours for a total of 24 hours). Nifedipine reduced arterial blood pressure from 127/78 to 115/70 mm Hg at 30 minutes (p less than 0.001) and continued to reduce the blood pressure significantly for 12 to 18 hours. Nifedipine also reduced systemic vascular resistance and the rate-pressure product. Cardiac output increased from 4.9 liters/min before nifedipine to 5.4 liters/min at 60 minutes (p less than 0.05 vs controls). In patients with high initial pulmonary wedge pressures, sublingual nifedipine decreased the wedge pressure (p less than 0.001) more effectively than did 80 mg of furosemide given intravenously. Thus, nifedipine may be useful in patients with early myocardial infarction and left ventricular failure.

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Comparative safety and tolerability of clopidogrel and aspirin: results from CAPRIE. CAPRIE Steering Committee and Investigators. Clopidogrel versus aspirin in patients at risk of ischaemic events.

The objective of this study was to provide a comprehensive comparison of the long term safety and tolerability of clopidogrel, a new adenosine diphosphate (ADP) receptor antagonist that inhibits platelet activation induced by ADP, and aspirin (acetylsalicylic acid). The study population comprised 19,185 patients with symptomatic atherosclerosis manifested as recent ischaemic stroke, recent myocardial infarction or symptomatic peripheral arterial disease. Patients were randomised to receive clopidogrel 75 mg/day or aspirin 325 mg/day for a minimum of 1 year and a maximum of 3 years. Compared with aspirin, clopidogrel reduced the combined risk of ischaemic stroke, myocardial infarction or vascular death by 8.7% (p = 0.043). The incidence of early permanent discontinuations of the study drug due to adverse events was almost identical in both treatment groups (11.94% for clopidogrel vs 11.92% for aspirin). Reported neutropenia was similar in the clopidogrel and aspirin groups (0.10 vs 0.17%, respectively) with corresponding rates (0.05 vs 0.04%, respectively) for severe neutropenia. Thrombocytopenia was identical in the clopidogrel and aspirin groups (0.26%), with the rates of severe thrombocytopenia being 0.19 vs 0.10%, respectively. None of these observed differences was statistically significant. The overall incidence of haemorrhagic events did not differ statistically significantly between treatment groups (9.27% for clopidogrel vs 9.28% for aspirin; p = 0.98). There was a trend towards a lower incidence of intracranial haemorrhage in the clopidogrel group (0.31%) compared with the aspirin group (0.42%). Any reported gastrointestinal haemorrhage was significantly less frequent with clopidogrel (1.99%) than with aspirin (2.66%) [p < 0.002]. The corresponding data for severe gastrointestinal bleeding were 0.49 vs 0.71%; p < 0.05. Overall, there were significantly fewer gastrointestinal adverse events with clopidogrel than with aspirin (27.1 vs 29.8%; p < 0.001), with less abdominal pain, dyspepsia, constipation, or peptic, gastric, or duodenal ulceration with clopidogrel. Diarrhoea was significantly more common in the clopidogrel group (4.46 vs 3.36%; p < 0.001), although the incidence of severe diarrhoea (0.23 vs 0.11%) was low and was not significantly different between groups. There were significantly more patients with rash in the clopidogrel group (6.0%) compared with the aspirin group (4.6%) [p < 0.001]. However, these events were generally mild and transient in nature. Given the favourable benefit/risk ratio, clopidogrel represents a clinically important advance in the treatment of patients with manifest atherosclerotic disease.

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Effect of losartan treatment on the proteinuria in normotensive patients having proteinuria due to secondary amyloidosis.

Secondary amyloidosis (AA amyloidosis) is a well known cause of nephrotic syndrome and renal failure. Several studies in patients with nephrotic syndrome have suggested a beneficial effect of angiotensin-converting enzyme inhibitors (ACEI). Angiotensin II (ATII) receptor antagonists effect on the long term is not known. In this study, we intended to study the effect of losartan, as an ATII receptor antagonist, on proteinuria and renal functions in patients with normotensive secondary amyloidosis. In total 44 patients with biopsy proven AA amyloidosis associated with nephrotic proteinuria were included. The first group of patients (n=22) was treated with losartan 50 mg/day. The second group of patients (n=22) did not receive any specific antiproteinuric treatment. Urinary protein loss was effectively lowered by losartan from 4.38 +/- 1.0 to 2.8 +/- 0.61 g/day (p<0.0001), whereas the control group showed a slight fall in proteinuria as 4.21 +/- 1.06 to 4.12 +/- 1.07 g/day (p = 0.176). Hypoalbuminemia improved significantly from 2.52 +/- 0.69 to 2.78 +/- 0.46 g/dl (p = 0.004), in the losartan group, whereas serum albumin had fallen in the control group from 2.44 +/- 0.57 to 2.27 +/- 0.41 (p = 0.041). Serum creatinine increased in the control group from 1.52 +/- 0.42 to 2.39 +/- 0.51 mg/dl (p<0.0001), and in the losartan group from 1.59 +/- 0.50 to 1.84 +/- 0.6 mg/dl (p<0.001), after 24 months of treatment. The ATII receptor blocker losartan is effective in protecting against the progression of nephropathy due to AA amyloidosis. Symptomatic treatment of proteinuria with losartan is therefore to be considered, especially with severe proteinuria even in normotensive patients.

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Aortic valve calcification in systemic lupus erythematosus.

Aortic valve calcification is associated with atherosclerosis in the general population. We investigated the prevalence of and associates of aortic valve calcification in systemic lupus erythematosus (SLE). One-hundred and ninety-nine SLE patients enrolled in a clinical trial had aortic valve calcification assessed by helical CT. The patients had a mean age of 44.3 +/- 11.4 years and were 92% female, 61% Caucasian, 34% African-American, 2% Asian and 2% Hispanic. Aortic valve calcification was present in 1.5%, whereas coronary calcium was found in 43% and carotid plaque in 17%. Among cardiovascular risk factors, hs-CRP (P = 0.0592), fibrinogen (P = 0.0507), and lipoprotein(a) (P = 0.0250), were associated with aortic valve calcification. Prednisone use (P = 0.049) and use of methotrexate (P = 0.0174) were also associated with aortic valve calcification. Aortic valve calcification was associated with antiphospholipid antibody positivity (0.0287) (lupus anticoagulant, by dilute Russell viper venom time). It was not associated with coronary calcium or carotid plaque. Aortic valve calcification, although rare in SLE, was associated with some novel cardiovascular risk factors and with a marker of hypercoagulability (lupus anticoagulant). In contrast to the general population, aortic valve calcification in SLE is not associated with subclinical measures of atherosclerosis, such as coronary calcium or carotid plaque.

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A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report.

More than 40% of patients with major depressive disorder do not achieve remission even after two optimally delivered trials of antidepressant medications. This study compared the effectiveness of lithium versus triiodothyronine (T(3)) augmentation as a third-step treatment for patients with major depressive disorder. A total of 142 adult outpatients with nonpsychotic major depressive disorder who had not achieved remission or who were intolerant to an initial prospective treatment with citalopram and a second switch or augmentation trial were randomly assigned to augmentation with lithium (up to 900 mg/day; N=69) or with T(3) (up to 50 mug/day; N=73) for up to 14 weeks. The primary outcome measure was whether participants achieved remission, which was defined as a score < or =7 on the 17-item Hamilton Depression Rating Scale. After a mean of 9.6 weeks (SD=5.2) of treatment, remission rates were 15.9% with lithium augmentation and 24.7% with T(3) augmentation, although the difference between treatments was not statistically significant. Lithium was more frequently associated with side effects (p=0.045), and more participants in the lithium group left treatment because of side effects (23.2% versus 9.6%; p=0.027). Remission rates with lithium and T(3) augmentation for participants who experienced unsatisfactory results with two prior medication treatments were modest and did not differ significantly. The lower side effect burden and ease of use of T(3) augmentation suggest that it has slight advantages over lithium augmentation for depressed patients who have experienced several failed medication trials.

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Usefulness of lowering low-density lipoprotein cholesterol to <70 mg/dl and usefulness of C-reactive protein in patient selection.

C-reactive protein levels may identify patients likely to benefit from lowering low-density lipoprotein (LDL) cholesterol to ultra-low levels. We find that above-average C-reactive protein with statin therapy predicts failure of carotid intima-media thickness regression in those with currently defined optimal LDL cholesterol (<100 mg/dl) but not if LDL cholesterol is <70 mg/dl.

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Sertraline treatment of major depression in patients with acute MI or unstable angina.

Major depressive disorder (MDD) occurs in 15% to 23% of patients with acute coronary syndromes and constitutes an independent risk factor for morbidity and mortality. However, no published evidence exists that antidepressant drugs are safe or efficacious in patients with unstable ischemic heart disease. To evaluate the safety and efficacy of sertraline treatment of MDD in patients hospitalized for acute myocardial infarction (MI) or unstable angina and free of other life-threatening medical conditions. Randomized, double-blind, placebo-controlled trial conducted in 40 outpatient cardiology centers and psychiatry clinics in the United States, Europe, Canada, and Australia. Enrollment began in April 1997 and follow-up ended in April 2001. A total of 369 patients with MDD (64% male; mean age, 57.1 years; mean 17-item Hamilton Depression [HAM-D] score, 19.6; MI, 74%; unstable angina, 26%). After a 2-week single-blind placebo run-in, patients were randomly assigned to receive sertraline in flexible dosages of 50 to 200 mg/d (n = 186) or placebo (n = 183) for 24 weeks. The primary (safety) outcome measure was change from baseline in left ventricular ejection fraction (LVEF); secondary measures included surrogate cardiac measures and cardiovascular adverse events, as well as scores on the HAM-D scale and Clinical Global Impression Improvement scale (CGI-I) in the total randomized sample, in a group with any prior history of MDD, and in a more severe MDD subgroup defined a priori by a HAM-D score of at least 18 and history of 2 or more prior episodes of MDD. Sertraline had no significant effect on mean (SD) LVEF (sertraline: baseline, 54% [10%]; week 16, 54% [11%]; placebo: baseline, 52% [13%]; week 16, 53% [13%]), treatment-emergent increase in ventricular premature complex (VPC) runs (sertraline: 13.1%; placebo: 12.9%), QTc interval greater than 450 milliseconds at end point (sertraline: 12%; placebo: 13%), or other cardiac measures. All comparisons were statistically nonsignificant (P> or = .05). The incidence of severe cardiovascular adverse events was 14.5% with sertraline and 22.4% with placebo. In the total randomized sample, the CGI-I (P =.049), but not the HAM-D (P =.14), favored sertraline. The CGI-I responder rates for sertraline were significantly higher than for placebo in the total sample (67% vs 53%; P =.01), in the group with at least 1 prior episode of depression (72% vs 51%; P =.003), and in the more severe MDD group (78% vs 45%; P =.001). In the latter 2 groups, both CGI-I and HAM-D measures were significantly better in those assigned to sertraline. Our results suggest that sertraline is a safe and effective treatment for recurrent depression in patients with recent MI or unstable angina and without other life-threatening medical conditions.

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Progressive lupus glomerulonephritis. Treatment with prednisone and combined prednisone and cyclophosphamide.

We report a prospective randomized study of 39 patients with systemic lupus erythematosus and progressive glomerulonephritis who were assigned to treatment groups that received either prednisone alone or prednisone and cyclophosphamide combined. They received treatment for 6 months and were then followed up for an additional 18 months. No difference in outcome was seen in the two groups at the end of 6 months. Among patients followed up for an average of 24 months, fewer individuals showed later renal progression among those treated with cyclophosphamide and prednisone than among the group treated with prednisone alone.

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The management of the patient with calcium stones.

Results of investigation of 800 patients with renal calculi are presented. The high incidence of medullary sponge kidneys (tubular ectasia) in patients of either sex is stressed as is the low incidence of idiopathic hypercalciuria in the female. Hydrochlorothiazide has been found to be highly effective in preventing recurrence of calcium stones in our personal experience with over 300 patients who have been treated for as long as 14 years with this agent. The efficacy and mode of action of other measures advocated for stone prevention is reviewed.

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Efficacy of atorvastatin and gemfibrozil, alone and in low dose combination, in the treatment of diabetic dyslipidemia.

To compare the effects of atorvastatin, gemfibrozil, and their combination on the components of diabetic dyslipidemia, 44 type 2 diabetic patients with low density lipoprotein cholesterol (LDLc) levels greater than 100 mg/dl and triglyceride levels less than 400 mg/dl were included. Twelve-week treatments with atorvastatin (10-20 mg/d) and gemfibrozil (900-1200 mg/d) were given in random order in an open, cross-over study and then combined (10 mg atorvastatin and 900 mg gemfibrozil) for 12 additional wk. Triglyceride, LDLc, high density lipoprotein cholesterol (HDLc), non-HDLc, apolipoprotein B (apoB), and LDL size were measured at baseline and after each treatment. Atorvastatin was more effective (P < 0.001) in lowering LDLc, non-HDLc, and apoB and in achieving treatment goals, whereas gemfibrozil lowered triglyceride levels more effectively (P < 0.001) and increased LDL size (from 25.59 +/- 0.06 to 25.69 +/- 0.06 nm; P < 0.05). Combined treatment with both drugs reduced LDLc, triglyceride, non-HDLc, and apoB by 26.5%, 24.1%, 30.4%, and 21.8%, respectively; increased HDLc by 4.8% and LDL size by 0.1 nm; and was the most effective treatment in reaching the therapeutic targets, especially in patients with triglyceride levels higher than 150 mg/dl. In conclusion, statins are first choice drugs in diabetic patients with low to moderate risk LDLc, although their combination with fibrates might be the most appropriate treatment, especially when triglyceride levels are above the therapeutic goal.

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[Time of drug intake in hypertension and angina pectoris. A controlled monitoring study].

A prospective cross-over study was performed in a general practice environment to assess and compare compliance data obtained by electronic monitoring on a BID or QD regimen in 113 patients with hypertension or angina pectoris. All patients were on a BID regimen (nifedipine SR) during the first month and switched to QD regimen (amlodipine) for another month. Taking compliance (i.e. the proportion of days with correct dosing) improved in 30% of patients (95% confidence interval 19 to 41%, p < 0.001), when switching from a BID to a QD regimen, but at the same time there was a 15% increase (95% confidence interval 5 to 25%, p < 0.02) in the number of patients with one or more no-dosing days. About 8% of patients had a low compliance rate, irrespective of the dosage regimen. Actual dosage intervals were used to estimate extent and timing of periods with unsatisfactory drug activity for various hypothetical drug durations of action, and it appears that the apparent advantage of QD regimen in terms of compliance is clinically meaningful only, when the duration of activity extents beyond the dosage interval in all patients.

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Epidemiology and impact of bloodstream infections among kidney transplant recipients: A retrospective single-center experience.

Bloodstream infection (BSI) represents an important source of morbidity and mortality, as well as an increasing therapeutic challenge, among solid organ transplant recipients. Understanding the epidemiological and microbiological characteristics of BSI following renal transplantation is paramount to the implementation of appropriate preventative and therapeutic measures. We conducted a retrospective review of all BSI episodes occurring between July 2009 and April 2016 in adult patients, who received a renal transplant at Royal Free London hospital. A total of 116 episodes of BSI occurred in 87 patients, 43 (49.4%) of them men. The mean age at BSI was 54.37 ± 12.81 years. Late-onset BSI (>12 months post transplant) represented 55.2%, with the median time to BSI being 16.28 month. Sixty-seven patients had single BSI and 20 had recurrent episodes. Enterobacteriaceae were responsible for 73.7% of BSI, with Escherichia coli the commonest causative organism (46.6%). The urinary tract was the most frequent source of infection in 56.9%. Among the E. coli infections, 100% of the tested isolates were sensitive to meropenem, ertapenem, tigecycline, and fosfomycin, and >90% were sensitive to piperacillin-tazobactam, amikacin, and colistin. Lower susceptibility rates were encountered for ceftriaxone (70.6%), amoxicillin-clavulanic acid (48.1%), cotrimoxazole (40.4%), trimethoprim (37.3%), and amoxicillin (21.6%). During BSI, the median serum creatinine increased from a reference of 131 μmol/L to a peak of 219 μmol/L. Acute kidney injury (AKI) complicated 75/116 BSI episodes (64.7%)-stage 1: 34, stage 2: 31, and stage 3 AKI: 10 episodes. After 3 months, the median creatinine remained elevated at 146 μmol/L. The 3-month mortality rate was 8% (7/87), and the death-censored graft loss was 6.9% (6/87). No significant difference was seen between BSI of urinary and non-urinary sources in the incidence of AKI (χ²  = 0.24, P = .6) or the percentage of creatinine change between baseline and peak and 3-month creatinines (P = .2 and .7 respectively). Urinary tract infection remains the commonest source of systemic infection among kidney transplant recipients and resistance to commonly used frontline antibiotics is common; thus, prevention and early detection are paramount. The appropriate choice of initial empirical antibiotic is vital to improve the outcome. Each unit needs to understand the epidemiology of organisms causing BSI in their transplant patients and their antibiotic susceptibilities.

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Chronic progressive multiple sclerosis: double-blind controlled study of plasmapheresis in patients taking immunosuppressive drugs.

Fifty-four patients with chronic progressive multiple sclerosis received prednisone plus oral low-dose cyclophosphamide and either true plasmapheresis (PP) or "sham" PP weekly for 20 weeks in a double-blind controlled study. Immunosuppressive drug therapy alone (sham PP group, n = 29) was associated with improvement (greater than or equal to one step in Kurtzke Disability Status Scale [DSS]; mean change of 1.5) in 8 and stabilization of MS in 18 patients, with this status sustained in 23 patients at follow-up, 11 months after entry. In contrast, 14 of 26 patients who received "true" PP improved (greater than or equal to one step in DSS; mean change of 2.6), and 11 more were stable, with these changes sustained in 23 of 26 patients at follow-up. These differences, overall, between the PP and sham PP groups were significant at p less than 0.007.

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Alternate-day versus intermittent prednisone in frequently relapsing nephrotic syndrome. A report of "Arbetsgemeinschaft für Pädiatrische Nephrologie".

23 children with frequently relapsing minimal-change nephrotic syndrome were treated with alternate-day prednisone (35 mg/m2/48 h) and 25 other patients were treated with intermittent prednisone (40 mg/m2 on three consecutive days out of seven) for six months. This was followed by six months without any maintenance steroid treatment except when relapse required a short period of prednisone therapy until remission. The number of relapsers was significantly lower on alternate-day than on intermittent treatment. In the alternate-day group, the number of relapsers and the rate of relapse was significantly less before treatment withdrawal; in the intermittent group, only the number of relapsers was reduced. An alternate-day regiment is therefore preferable to the intermittent regimen in the interrupted steroid treatment of children with nephrotic syndrome.

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The impact of early administration of low-dose atorvastatin treatment on inflammatory process, in patients with unstable angina and low cholesterol level.

Lipid-lowering agents are known to reduce long-term mortality in patients with stable angina or multiple risk factors. However, the effects of lipid-lowering treatment on inflammatory process during and immediately after the acute phase of unstable angina remain unclear. In this study we assessed the effects of low-dose atorvastatin treatment, on inflammatory process in patients admitted for unstable angina with low cholesterol level. Forty-seven normocholesterolemic patients with unstable angina were randomized into two groups, and received atorvastatin 10 mg/day (n = 24) or no statin (n = 23) for 6 weeks. Circulating levels of inteleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF-alpha) and soluble vascular cell adhesion molecule (sVCAM-1) were measured by their admission, and at the 1st and 6th week of the study. Serum levels of MCP-1 and sVCAM-1 were significantly increased in the control group (p < 0.05) while remained unaffected in the atorvastatin-treated group six weeks after admission. However, IL-6 and TNF-alpha levels were similarly decreased in both atorvastatin-treated and control groups. Low-dose atorvastatin treatment modifies inflammatory process in patients with unstable angina and low cholesterol level, an effect seen at 6 weeks but not 1 week after admission.

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Influence of simvastatin on aspects of thrombogenesis in CAPD patients.

Patients on continuous ambulatory peritoneal dialysis (CAPD) are prone to dyslipidemia and have a high risk of cardiovascular death. Statins show beneficial effects on serum lipids and thrombogenesis in various groups of patients, but prospective studies have so far not been performed on CAPD patients. To determine the effects of 6 months' treatment with simvastatin on platelet function and some hemostatic parameters, markers of endothelial cell injury, in 14 CAPD patients with hypercholesterolemia. Simvastatin was given in a dose of 10 mg at bedtime. Commercially available kits were used for all determinations. Cholesterol and low density lipoprotein fell significantly as early as after 1 month of the therapy (p < 0.001). Platelet aggregation in whole blood and platelet-rich plasma was transiently decreased by simvastatin therapy. The fibrinolytic activity index increased significantly after 6 months of simvastatin administration (p < 0.05), reaching values observed in the control group, whereas euglobulin clot lysis time, which was also significantly shortened after 6 months (p < 0.05), did not reach values obtained in healthy volunteers. Vascular cell adhesion molecule, thrombomodulin, and protein Z decreased significantly after 3 months of the therapy (p < 0.05, p < 0.05, and p < 0.01, respectively), whereas intercellular adhesion molecule decreased after 6 months (p < 0.05). Vascular endothelial growth factor and its receptor, protein Z, total tissue factor pathway inhibitor (TFPI),TFPI/Xa complexes, and thrombin activatable fibrinolysis inhibitor concentration and activity fell significantly after 6 months of treatment with simvastatin (all p < 0.05). Tissue plasminogen activator concentration increased after 1 month (p < 0.01 after 1 month, p < 0.05 after 3 and 6 months), whereas total homocysteine fell after 6 months of simvastatin therapy (p < 0.05). Truncated TFPI decreased significantly as early as after 1 month of therapy (p < 0.05 after 1 month, p < 0.01 after 3 and 6 months). Simvastatin is an effective hypolipemic agent in CAPD patients. It favorably affects platelet aggregation and the extrinsic coagulation pathway, improves fibrinolysis, and ameliorates endothelial dysfunction. Simvastatin might reduce the risk of thrombotic complications in CAPD patients.

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Pharmacodynamic effects and pharmacokinetics of atorvastatin after administration to normocholesterolemic subjects in the morning and evening.

The pharmacodynamic effects and pharmacokinetics of atorvastatin, a potent investigational inhibitor of HMG-CoA reductase, were studied in 16 normolipidemic subjects after administration of 40 mg daily for 15 days in the morning or evening. Lipid and apolipoprotein parameters were determined, and plasma atorvastatin equivalent concentrations were measured according to a validated enzyme inhibition bioassay procedure. Atorvastatin was well tolerated by the participants. Overall, mean reductions of 34% in total cholesterol, 48% in low-density lipoprotein (LDL) cholesterol, 37% in very low density lipoprotein (VLDL) cholesterol, 25% in triglycerides, 6% in apolipoprotein A-I, and 34% in apolipoprotein B were observed. Changes in lipid and apolipoprotein values were similar after morning and evening administration of atorvastatin. In contrast, studies with other HMG-CoA reductase inhibitors have consistently shown that evening administration results in larger reductions in total and LDL cholesterol than does morning administration. Rate and extent of equivalent absorption of atorvastatin were lower during evening than morning administration. Mean elimination half-life values were similar, however, suggesting that there is no diurnal variation in disposition of this drug. Pharmacokinetic differences did not correlate with effects on serum lipids.

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Follow-up of children with autoimmune hepatitis treated with cyclosporine.

To evaluate the effectiveness of cyclosporine in inducing and maintaining remission of the inflammatory process in autoimmune hepatitis, when used in combination with low doses of prednisone and azathioprine and to identify the prognostic factors associated with sustained remission. Eighty-four patients with autoimmune hepatitis were consecutively recruited from 5 centers between January 1994 and March 2001. Cyclosporine was administered during the first 6 months. Thereafter, in patients with aminotransferase levels of lower than twice the normal values, prednisone and azathioprine were initiated. Normal aminotransferase levels were observed in 94.05% (79/84) of the patients, 72% of them within the first 6 months of treatment. Total serum bilirubin level of greater than 1.2 mg/dL and portal hypertension at diagnosis jointly predicted a significant delay in remission. Adverse effects related to cyclosporine remained mild and transient. Low doses of prednisone and standard doses of azathioprine were not implicated in relapse of the disease during the follow-up of any patient. This protocol allowed control of the liver inflammatory process and was well tolerated. The response to this immunosuppressive therapy can be predicted with accuracy. Factors delaying remission can be identified early at diagnosis and may contribute to the development of more effective treatment policies for this condition.

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A high incidence of cough associated with combination therapy of hypertension with isradipine and lisinopril in Chinese subjects.

The efficacy and tolerability of combination therapy using Lisinopril (5-20 mg om) and Isradipine (1.25 mg-2.50 mg bd) was assessed in 29/50 Chinese subjects, whose blood pressures were not controlled on Isradipine alone. The addition of Lisinopril produced approximately two-fold reductions in blood pressure compared to Isradipine alone, increasing the responder rate of the original cohort of 50 subjects by 18% and normalization rate, by 32%. No significant changes in haematological or biochemical parameters, CXR or ECG, were observed. However, use of Lisinopril in our subjects was associated with a high incidence of cough (48%), possibly limiting its use in this population.

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Treatment of chronic lymphocytic leukemia in advanced stages. A randomized trial comparing chlorambucil plus prednisone versus cyclophosphamide, vincristine, and prednisone.

Ninety-six patients with advanced chronic lymphocytic leukemia (CLL) (Stage C; anemia and/or thrombocytopenia of nonimmune origin) were randomized to receive either chlorambucil (CLR) (0.4 mg/kg orally, day 6) plus prednisone (PDN) (60 mg/m2 orally, days 1-5) every 2 weeks or cyclophosphamide (600 mg/m2 intravenously, day 6), vincristine (1 mg/m2 intravenously, day 6) and prednisone (60 mg/m2 orally, days 1-5) (COP) each month for 5 months. Complete remission (CR) was defined as the total disappearance of signs and symptoms related to the disease. Partial remission (PR) was considered to be achieved when, after treatment, the clinical stage changed to a less advanced one. Thirty (59%) responses (8% CR) with CLR plus PDN and 14 (31%, 2% CR) with COP were observed (P less than 0.01). The survival was not significantly different for the two groups. Patients previously treated had a lower number of responses (11/35, 31%) than those with no previous treatment (33/61, 54%) (P less than 0.05). Patients who attained a CR or a good PR had longer survivals (median not reached) than those with a poor PR (median, 25.2 months) or those who did not respond to treatment (median, 11.5 months) (P less than 0.005).

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Impact of age on laryngopharyngeal reflux disease presentation: a multi-center prospective study.

The objective is to assess the differences in the severity of symptoms, signs, voice quality, and quality of life before and after treatment according to age in suspected laryngopharyngeal reflux (LPR) patients. The design used in this paper is prospective multi-center study. Eighty clinically diagnosed LPR patients with a reflux finding score (RFS) >7 and a reflux symptom index (RSI) >13 were treated with pantoprazole and diet recommendations for 3 months. Patients were subdivided into three groups according their age: group 1 (18-39 years, N = 21), group 2 (40-59 years, N = 31), and group 3 (≥60 years, N = 28). RSI, RFS, Voice Handicap Index (VHI), Short Form 36 questionnaire (SF36), aerodynamic, and acoustic measurements were evaluated at baseline and after treatment. The response to the empiric treatment was also assessed. Significant improvements in RSI, RFS, and VHI were found in all patient groups. The elderly patients showed a significantly lower RSI score than younger subjects (p = 0.035) without RFS difference among groups. At baseline, the SF36 score was better in group 3 with respect to social functioning (p = 0.049). At the 3-month follow-up, we found significant improvement of acoustic parameters only in the younger age groups (group 1 and group 2). The rate of resistant patients to the empiric treatment was higher in the younger group than in the elderly patient group (42.9 versus 28.6%). Age appears to reduce the subjective LPR symptom perception, leading to a lower rate of uncured patients. The utilization of acoustic parameters as an indicator of treatment effectiveness seems less useful for elderly subjects, probably due to an overlap between an aging voice and LPR.

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Patterns of Lisdexamfetamine Dimesylate Use in Children, Adolescents, and Adults with Attention-Deficit/Hyperactivity Disorder in Europe.

<b><i>Objectives:</i></b> Lisdexamfetamine dimesylate (LDX) is approved in some European countries for the second-line treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents when response to previous methylphenidate (MPH) treatment is considered clinically inadequate, and as a first-line treatment in adults. Limited evidence exists on the real-world use of LDX across Europe. This retrospective study evaluated LDX drug utilization patterns from eight European countries for up to 5 years. <b><i>Methods:</i></b> Data were collected from national registries (Denmark, Finland, Norway, Sweden), electronic medical records (Germany, Spain, United Kingdom), and prescription databases (Switzerland) in eight European countries. Patients were included if they were prescribed LDX at least once since the LDX launch date in each country. Demographic and clinical characteristics, and LDX prescription data included patient age and gender, a recorded diagnosis of ADHD, the number of prescriptions per participant, previous MPH prescription recorded, average daily dose, treatment persistence, discontinuation, and switching of medications. <b><i>Results:</i></b> Overall, information for 59,292 patients (437,272 LDX prescriptions) was analyzed. Most patients were male (58.1%-84.3%) and fewer than 1% were under 6 years of age. Extensive use of LDX in adults was observed in four countries (Denmark, Finland, Norway, and Sweden), including countries where LDX was not approved for this age group. Most patients had a recorded diagnosis of ADHD (61.9%-95.4%). The mean number of prescriptions per patient ranged from 5.4 to 10.0. At least 79.6% of patients with ADHD had a recorded previous MPH prescription. Mean duration of LDX exposure ranged from 233.1 to 410.8 days. The average daily dose of LDX was ≤70 mg/day for most patients (79.4%-99.7%). The 5-year discontinuation rate ranged from 22.8% to 70.6% and was below 40% for most countries. The proportion of patients switching from LDX to other medications was ≤33.8. <b><i>Conclusions:</i></b> This study provides the first long-term, real-world information related to LDX use by children, adolescents, and adults in Europe in the 5 years since its first launch in the region. Most LDX prescriptions fulfilled label requirements regarding a recorded diagnosis of ADHD before treatment initiation, previous MPH use, and an average daily dose of ≤70 mg/day. LDX was largely prescribed within the indicated age range, although adult use of LDX was high in some countries where LDX is not approved for this population.

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Fibrates and risk of cancer in tissues with high PPAR-α concentration: a nested case-control study.

Fibrates are lipid-lowering agents that act as peroxisome proliferator-activated receptor (PPAR)-α agonists. They have been associated with cancers in experimental models, but data in humans are rare, and among published studies none has investigated cancers in tissues with high PPAR-α concentrations. A nested case-control study was performed in a French population-based healthcare database. Adults aged ≥45 years, and free of cancer for 3 years, were followed for 5 years for incident cases of melanoma, non-melanoma skin cancers, thyroid, pancreas, bladder, and kidney cancers. Cases were matched with up to ten controls for age, sex, and diseases that could increase the risk of cancers. Conditional logistic models, adjusted for drug-use as potential confounders, were used to estimate the risk (odds ratio [OR]) of cancers of interest (and individual cancers) associated with cumulative exposure to fibrates (defined daily doses [DDD]). Among the 147,338 eligible subjects, 3,331 (2.3 %) cases of studied cancers were identified. Only use of fibrates >550 DDDs was associated with an increased risk (OR 1.26; 95 % CI 1.12-1.42), and similar results were found for statins (≥1,460 DDDs; OR 1.15; 95 % CI 1.03-1.28). When considering cancers individually, the association was significant for non-melanoma skin-cancer (OR 1.35; 95 % CI 1.14-1.60), and close to significance for bladder cancer (OR 1.26; 95 % CI 0.96-1.64); similar associations with the use of statins were found. The associations found between fibrate exposure and cancers of tissues with high PPAR-α concentrations were most likely related to residual confounding as similar associations were found for statins.

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Duration of effect of lansoprazole on gastric pH and acid secretion in normal male volunteers.

A double-blind, placebo-controlled study to assess the duration of effect of lansoprazole 30 mg o.m. on intragastric pH, acid secretion, gastrin levels, the potential for rebound acidity, and the relationship between gastric acid and drug pharmacokinetic parameters. Sixteen subjects were treated with lansoprazole 30 mg daily or placebo for 14 days, followed by a 7-day post-dosing period and a post-study evaluation on day 28. Ambulatory 24-h pH was recorded and pentagastrin-stimulated acid secretion measured. Plasma kinetics of lansoprazole were determined. Mean intragastric pH in the lansoprazole group increased significantly (P < 0.05) from baseline to day 14 compared to placebo. After cessation of treatment, secretory activity, as measured by intragastric pH, basal acid output and stimulated acid output, returned to baseline in 2 to 4 days without any overshoot, indicating the absence of acid rebound. Lansoprazole's terminal disposition half-life was 1.11 h. Mean pH and serum gastrin returned to baseline with half-lives of 22 and 19 h, respectively. Lansoprazole 30 mg daily significantly increases mean intragastric pH without producing acid rebound. Regeneration of acid production depends primarily on de novo synthesis of the acid pump.

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Duloxetine treatment of dysthymia and double depression: an open-label trial.

Although not as common as major depressive disorder, dysthymia is not rare and is associated with substantial impairment. Antidepressants and some psychotherapies are often effective. We explored the efficacy of the antidepressant duloxetine, a serotonin and norepinephrine reuptake inhibitor. Between February 2005 and April 2006, we recruited 24 adults with DSM-IV dysthymia or dysthymia and concurrent major depression ("double depression") who had an entry score of > or = 17 on the clinician-rated Inventory for Depressive Symptomatology (IDS-C). We excluded subjects with significant medical illnesses and those requiring other psychotropic agents or undergoing psychotherapy. Subjects received duloxetine 60 mg/day for 6 weeks, increased as tolerated to 120 mg/day for the remainder of the 12-week trial for those with an inadequate treatment response. The subjects' mean +/- SD IDS-C scores decreased significantly from baseline (27.3 +/- 6.3) to endpoint (7.8 +/- 7.4, Student t = 12.38, df = 23, p < or = .001). The IDS-C response rate (intent-to-treat [ITT]) was 83% (20/24); the remission rate (ITT) was 79% (19/24). Among study completers, these rates were 89% (17/19) and 84% (16/19). Five subjects (21%) discontinued for side effects. Duloxetine appears to be an effective and well-tolerated treatment for dysthymia and double depression. A double-blind, placebo-controlled study is under way. If duloxetine is found to be effective, studies powered to detect potential, clinically important differences between duloxetine and other antidepressants will be needed. ClinicalTrials.gov identifier NCT00185575.

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Stereoselective effect of amiodarone on the pharmacokinetics of racemic carvedilol.

We investigated whether there was a stereoselective effect of amiodarone on the pharmacokinetics of carvedilol. Among a series of 106 inpatients with heart failure, 52 received carvedilol monotherapy (carvedilol group) and 54 received carvedilol plus amiodarone (carvedilol+amiodarone group). The serum carvedilol concentration administered/dose ratio was compared between the two groups based on HPLC measurement of the serum levels of carvedilol, amiodarone, and desethylamiodarone. In 6 patients from the carvedilol group, serum carvedilol levels were compared before and after coadministration of amiodarone. There was no significant between-group difference of the serum concentration to dose (C/D ratio) for the R-enantiomer carvedilol, however, the C/D ratio for the S-enantiomer and the serum S-carvedilol to R-carvedilol (S/R) ratio were both significantly lower in the carvedilol group than in the carvedilol+amiodarone group(47.8+/-56.7 versus 95.3+/-105 ng/mg/kg, P=0.0048 and 0.460+/-0.207 versus 0.879+/-0.377 ng/mg/kg, P<0.001), respectively. Furthermore, the mean S-carvedilol concentration over 14 days of coadministration with amiodarone was higher than that before coadministration (6.54+/-1.73 ng/mL versus 3.03+/-0.670 ng/mL, P<0.001). These results suggest that metabolism of S-carvedilol was markedly inhibited by coadministration of amiodarone.

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Absence of effects of prolonged simvastatin therapy on nocturnal sleep in a large randomized placebo-controlled study. Oxford Cholesterol Study Group.

1. It has been suggested that lipophilic HMG CoA reductase inhibitors, like lovastatin and simvastatin, may cause sleep disturbance. 2. Six hundred and twenty-one patients at increased risk of coronary heart disease were randomized in a single centre to receive 40 mg daily simvastatin, 20 mg daily simvastatin or matching placebo. To assess the effects of prolonged use of simvastatin on nocturnal sleep quality and duration, a sleep questionnaire was administered to 567 patients (95% of 595 survivors) at an average of 88 weeks (range: 44-129 weeks) after randomization. 3. The main outcome measures were sleep-related problems and use of sleep-enhancing medications reported during routine study follow-up visits, and responses to the sleep questionnaire about changes in sleep duration and about various sleep events during the preceding month. 4. No differences were observed between the treatment groups in the frequency of sleep-related problems reported, in the proportion of follow-up visits at which such problems were reported, or in the use of sleep-enhancing medications. The numbers who stopped study treatment were similar in the different treatment groups, and no patient stopped principally because of insomnia. In response to the sleep questionnaire, there were no significant differences between the treatment groups in reports of various sleep events during the preceding month, except that slightly fewer patients allocated simvastatin reported waking often. No differences in sleep duration were observed. 5. This placebo-controlled trial does not indicate any adverse effects of prolonged treatment with simvastatin on systematically sought measures of sleep disturbance.

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Effects of manidipine/delapril versus olmesartan/hydrochlorothiazide combination therapy in elderly hypertensive patients with type 2 diabetes mellitus.

The purpose of this study was to compare the combination treatments of manidipine/delapril and olmesartan/hydrochlorothiazide (HCTZ) in elderly diabetic hypertensives. After a 4-week placebo period, 158 hypertensive patients with type 2 diabetes (age range: 66 to 74 years) were randomized to receive combination treatment of 10 mg manidipine plus 30 mg delapril or 20 mg olmesartan plus 12.5 mg HCTZ for 48 weeks in a prospective, parallel arm trial. After 12 weeks, manidipine or HCTZ was doubled in nonresponders (systolic blood pressure [SBP] > or =130 mmHg and/or diastolic blood pressure [DBP] > or =80 mmHg). Patients were checked at the end of the placebo period and every 12 weeks thereafter. At each visit, lying, sitting and standing BP as well as fasting glycemia, glycosylated hemoglobin (HbA1c), electrolytes, uric acid, total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C) and triglycerides (TG) were evaluated. Both combinations reduced sitting SBP (-27.7 and -28.3 mmHg, respectively; both p<0.001) and DBP (-15.1 and -14.8 mmHg, respectively; both p<0.01) with no difference between the two treatments. Standing DBP was more markedly reduced by olmesartan/HCTZ (-19.5 mmHg; p<0.001) than by manidipine/delapril (-14.7 mmHg; p<0.05 vs. olmesartan/HCTZ). No changes in metabolic parameters were observed with manidipine/delapril, whereas an increase in HbA1c (+0.7%; p<0.05), uric acid (+0.4 mg/dL; p<0.05) and TG (+41.3 mg/dL; p<0.05), and a decrease in serum potassium (-0.3 mmol/L; p<0.05) and HDL-C (-3.4 mg/dL; p<0.05) were found in the olmesartan/HCTZ group. In conclusion, both combinations were similarly effective in reducing BP in elderly hypertensive diabetic patients. However, manidipine/delapril offered some advantages in terms of the less-pronounced BP orthostatic changes and absence of metabolic adverse effects.

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