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Long-term Treatment (long-term + treatment)
Terms modified by Long-term Treatment Selected AbstractsChanges in quality of life and sexual health are associated with low-dose peginterferon therapy and disease progression in patients with chronic hepatitis CALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 7 2010K. K. SNOW Aliment Pharmacol Ther,31, 719,734 Summary Background, Primary analysis of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) Trial showed long-term peginterferon therapy did not reduce complications in patients with chronic hepatitis C and advanced fibrosis or cirrhosis. Aim, To assess the effects of long-term peginterferon therapy and disease progression on health-related quality of life (HRQOL), symptoms and sexual health in HALT-C patients. Methods, A total of 517 HALT-C patients received peginterferon alfa-2a (90 ,g/week); 532 received no additional treatment for 3.5 years. Patients were followed up for outcomes of death, hepatocellular carcinoma and hepatic decompensation. Sexual health, SF-36 scores and symptoms were serially assessed by repeated-measures analyses of covariance. Results, Patients with cirrhosis (n = 427) reported lower general well-being and more fatigue (P < 0.001) than patients with fibrosis (n = 622). Physical scores declined significantly over time, independent of treatment, and patients with cirrhosis reported lower scores. Vitality scores were lower in those with cirrhosis, and treated patients experienced a greater decline over time than untreated patients; HRQOL rebounded after treatment ended. Patients with a clinical outcome had significantly greater declines in all SF-36 and symptom scores. Among men, Sexual Health scores were significantly worse in treated patients and in those with a clinical outcome. Conclusion, Clinical progression of chronic hepatitis C and maintenance peginterferon therapy led to worsening of symptoms, HRQOL and, in men, sexual health in a large patient cohort followed up over 4 years (NCT00006164). [source] ORIGINAL RESEARCH,ED PHARMACOTHERAPY: Intracavernous Injections of Prostaglandin E1 for Erectile Dysfunction: Patient Satisfaction and Quality of Sex Life on Long-Term TreatmentTHE JOURNAL OF SEXUAL MEDICINE, Issue 2 2007Benjamin Alexandre MD ABSTRACT Introduction., Since the availability of oral type 5 phosphodiesterase (PDE5) inhibitors for the treatment of erectile dysfunction (ED), patients' views on the use of intracavernous injections (ICI) of prostaglandin E1 (PGE1) may have changed. Aim., To assess the satisfaction of patients with long-term ICI. Methods., Patients with ED (>18 years old) who had used ICI of PGE1 for at least 3 months were asked to complete the "EASY" (Evaluation de l'Acceptation des injectionS dans la dYsfonction érectile) questionnaire. Main Outcome Measures., Overall patient satisfaction with ICI, impact on quality of life, ease of use, satisfaction with the quality of erections, and perceived partner satisfaction. Results., Overall, 596 questionnaires met our inclusion criteria. Mean patient age was 62.1 years, mean duration of ED was 61 months, and mean duration of ICI treatment was 35 months. Before using ICI, 43% of patients had taken at least one PDE5 inhibitor; 81% discontinued PDE5 for want of efficacy. The overall satisfaction rate with ICI was 78.3%. ICI met expectations each time in 78.6% of patients and at least half the time in 90% of patients; 86% were ready to recommend ICI to friends. Patients noted improvements in their sex life (70.1%), relationship with their partner (50%), quality of life (44.8%), and confidence in attempting sexual intercourse (80.3%). The mean number of injections was 4.4 per month. Most patients (81.1%) found the injections easy to use. The mean score for pain on injection was 2.09/10 and for pain on erection was 2.15/10. Three-quarters of patients (73.1%) thought that their partners were satisfied with ICI. Conclusion., Patients on long-term ICI/PGE1 can recover a very satisfying sex life. ICI met patients' expectations in terms of efficacy, ease of use, tolerance, and improved sex life. These results should encourage physicians and patients to use ICI when PDE5 fails, is not well tolerated, or is contraindicated. Alexandre B, Lemaire A, Desvaux P, and Amar E. Intracavernous injections of prostaglandin E1 for erectile dysfunction: Patient satisfaction and quality of sex life on long-term treatment. J Sex Med 2007;4:426,431. [source] Quantitative tests of liver function measure hepatic improvement after sustained virological response: results from the HALT-C trialALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2009G. T. EVERSON Summary Backgroud, The impact of virologic response on hepatic function has not been previously defined. Aim, To determine the relationships of quantitative liver function tests (QLFTs) with virological responses to peginterferon (PEG) ± ribavirin (RBV) in patients with chronic hepatitis C and to use serial QLFTs to define the spectrum of hepatic improvement after sustained virological response (SVR). Methods, Participants (n = 232) were enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial, had failed prior therapy, had bridging fibrosis or cirrhosis and were retreated with PEG/RBV. All 232 patients had baseline QLFTs; 24 patients with SVR and 68 nonresponders had serial QLFTs. Lidocaine, [24- 13C]cholate, galactose and 99mTc-sulfur colloid were administered intravenously; [2,2,4,2- 2H]cholate, [1- 13C]methionine, caffeine and antipyrine were administered orally. Clearances (Cl), breath 13CO2, monoethylglycylxylidide (MEGX), perfused hepatic mass (PHM) and liver volume were measured. Results, Rates of SVR were 18,26% in patients with good function by QLFTs, but ,6% in patients with poor function. Hepatic metabolism, measured by caffeine kelim (P = 0.02), antipyrine kelim (P = 0.05) and antipyrine Cl (P = 0.02) and the portal circulation, measured by cholate Cloral (P = 0.0002) and cholate shunt (P = 0.0003) and PHM (P = 0.03) improved after SVR. Conclusion, Hepatic dysfunction impairs the virological response to PEG/RBV. SVR improves hepatic metabolism, the portal circulation and PHM. [source] Portal-systemic shunting in patients with fibrosis or cirrhosis due to chronic hepatitis C: the minimal model for measuring cholate clearances and shuntALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2007G. T. EVERSON Summary Background, Measurement of portal inflow and portal-systemic shunt using cholate clearances could be useful in monitoring patients with liver disease. Aim, To examine relationships of cholate clearances and shunt to cirrhosis and varices and to define minimal sampling requirements. Methods, Five hundred forty-eight studies were performed in 282 patients enrolled in the Hepatitis C Antiviral Long-term Treatment to prevent Cirrhosis (HALT-C) trial. Stable, non-radioactive isotopes of cholate were administered intravenously and orally, clearances (Cliv and Cloral) were calculated from [dose/area under curve (AUC)] and cholate shunt from [(AUCoral:AUCiv) x (Doseiv:Doseoral) x 100%]. Results, Cholate Cloral and cholate shunt correlated with prevalences of both cirrhosis and varices (P < 0.0001 for all). Peripheral venous sampling at 5, 20, 45, 60 and 90 min defined the minimal model. Linear regression of cholate shunt determined from five points within 90 min vs. the standard method of 14 points over 3 h yielded slope of 1.0 and intercept 0.5% (r2 = 0.98, P < 0.0001). Results were identical in the 189 validation studies (slope 1.0, intercept 0.5%, r2 = 0.99, P < 0.0001). Conclusions, Cholate Cloral and cholate shunt may be useful in monitoring patients with liver disease. The 5-point model enhances application of cholate Cloral and cholate shunt in the non-invasive assessment of the portal circulation. [source] Insulin therapy in type 2 diabetes patients failing oral agents: cost-effectiveness of biphasic insulin aspart 70/30 vs. insulin glargine in the US,DIABETES OBESITY & METABOLISM, Issue 1 2007J. A. Ray Objectives:, To project the long-term clinical and economic outcomes of treatment with biphasic insulin aspart 30 (BIAsp 70/30, 30% soluble and 70% protaminated insulin aspart) vs. insulin glargine in insulin-naďve type 2 diabetes patients failing to achieve glycemic control with oral antidiabetic agents alone (OADs). Methods:, Baseline patient characteristics and treatment effect data from the recent ,INITIATE' clinical trial served as input to a peer-reviewed, validated Markov/Monte-Carlo simulation model. INITIATE demonstrated improvements in HbA1c favouring BIAsp 70/30 vs. glargine (,0.43%; p < 0.005) and greater efficacy in reaching glycaemic targets among patients poorly controlled on OAD therapy. Effects on life expectancy (LE), quality-adjusted life expectancy (QALE), cumulative incidence of diabetes-related complications and direct medical costs (2004 USD) were projected over 35 years. Clinical outcomes and costs were discounted at a rate of 3.0% per annum. Sensitivity analyses were performed. Results:, Improvements in glycaemic control were projected to lead to gains in LE (0.19 ± 0.24 years) and QALE (0.19 ± 0.17 years) favouring BIAsp 70/30 vs. glargine. Treatment with BIAsp 70/30 was also associated with reductions in the cumulative incidences of diabetes-related complications, notably in renal and retinal conditions. The incremental cost-effectiveness ratio was $46 533 per quality-adjusted life year gained with BIAsp 70/30 vs. glargine (for patients with baseline HbA1c , 8.5%, it was $34 916). Total lifetime costs were compared to efficacy rates in both arms as a ratio, which revealed that the lifetime cost per patient treated successfully to target HbA1c levels of <7.0% and , 6.5% were $80 523 and $93 242 lower with BIAsp 70/30 than with glargine, respectively. Conclusions:, Long-term treatment with BIAsp 70/30 was projected to be cost-effective for patients with type 2 diabetes insufficiently controlled on OADs alone compared to glargine. Treatment with BIAsp 70/30 was estimated to represent an appropriate investment of healthcare dollars in the management of type 2 diabetes. [source] Long-term efficacy and safety of insulin detemir compared to Neutral Protamine Hagedorn insulin in patients with Type 1 diabetes using a treat-to-target basal,bolus regimen with insulin aspart at meals: a 2-year, randomized, controlled trialDIABETIC MEDICINE, Issue 4 2008P. C. Bartley Abstract Aims This 24-month, multi-national, open-label, parallel group trial investigated the long-term efficacy and safety of insulin detemir and Neutral Protamine Hagedorn insulin in combination with mealtime insulin aspart in patients with Type 1 diabetes using a treat-to-target concept. Methods Patients were randomized 2 : 1 to detemir (n = 331) or NPH (n = 166) groups. Basal insulin was initiated once daily (evening) and titrated individually based on self-measured plasma glucose (PG) levels, aiming for pre-breakfast and pre-dinner targets , 6.0 mmol/l. A second basal morning dose could be added according to pre-defined criteria. Results After 24 months, superiority of glycated haemoglobin (HbA1c) was achieved with detemir compared to NPH (detemir 7.36%, NPH 7.58%, mean difference ,0.22% points) [95% confidence interval (CI) ,0.41 to ,0.03%], with reductions of 0.94% and 0.72% points, respectively. Fasting PG (FPGlab) was also lower with detemir (detemir 8.35 mmol/l, NPH 9.43 mmol/l; P = 0.019). Twenty-two per cent of patients treated with detemir reached an HbA1c , 7.0% in the absence of confirmed hypoglycaemia during the last month of treatment vs. 13% on NPH (P = 0.019). Risk of major and nocturnal hypoglycaemia was 69% and 46% lower with detemir than with NPH (P < 0.001), respectively; patients treated with detemir gained less weight (detemir 1.7 kg, NPH 2.7 kg; P = 0.024). The overall safety profile was similar in the two groups and treatment with detemir did not result in any unexpected findings. Conclusions Long-term treatment with the insulin analogues detemir + aspart was superior to NPH + aspart in reducing HbA1c, with added benefits of less major and nocturnal hypoglycaemia and less weight gain. [source] Long-term treatment of the anaemia in Type 1 diabetes mellitus with erythropoietinDIABETIC MEDICINE, Issue 3 2000A. S. Winkler First page of article [source] Effects of chronic treatment with valproate and oxcarbazepine on ovarian folliculogenesis in ratsEPILEPSIA, Issue 7 2008Ali Cansu Summary Purpose: We aimed to define the morphologic effects of valproate (VPA) and oxcarbazepine (OXC) on ovarian folliculogenesis in rats. Methods: Forty female wistar rats (21,24 days old and weighted between 46.4 and 55.3 g) were divided equally into 4 experimental groups, which were applied tap water (control group), 300 mg/kg/day VPA, 100 mg/kg/day OXC, and both VPA and OXC via gavage for 90 days. Ovaries of the rats on proestrous and diesterous phase of estrous cycle according to daily vaginal smear were taken out and placed in a fixation solution. Immunohistochemical and apoptosis (TUNEL) staining protocols were applied. Results: The number of follicles decreased and that of corpora lutea increased significantly in OXC, VPA, and OXC+VPA treated groups compared with control group (p < 0.05). The number of TUNEL positive ovarian follicles was 1.40 ± 0.52 in control group, but it significantly increased to 3.50 ± 0.53, 3.50 ± 0.53, and 4.90 ± 0.88 in VPA, OXC, and VPA+OXC groups (p < 0.0001). The increase in the number of TUNEL positive granulosa cells was also significant for OXC and VPA+OXC groups (p < 0.0001). Immunohistochemical HSCORE decreased for TGF,1 and IGF1 staining and increased for P53 staining in all drug groups compared with control group (p < 0.001). Intensity of P53 labeling increased, while intensity of TGF,1, IGF-1, and GDF-9 immunoreactivity decreased significantly in all drug groups compared with control group (p < 0.001). Conclusion: Long-term treatment with VPA or OXC from prepuberty to adulthood causes apoptosis and deterioration of folliculogenesis in rat ovarian follicles. [source] Rapamycin delays tumor development in murine livers by inhibiting proliferation of hepatocytes with DNA damage,HEPATOLOGY, Issue 2 2009Laura Elisa Buitrago-Molina In this study, everolimus (RAD001) was used to determine the role of mammalian target of rapamycin (mTOR) in hepatocarcinogenesis. We show that RAD001 effectively inhibits proliferation of hepatocytes during chronic liver injury. Remarkably, the ability of RAD001 to impair cell cycle progression requires activation of the DNA damage response; loss of p53 significantly attenuates the antiproliferative effects of mTOR inhibition. RAD001 modulates the expression of specific cell cycle,related proteins and the assembly of cyclin,cyclin-dependent kinase complexes to prevent cell cycle progression. Furthermore, RAD001 sustains the apoptosis sensitivity of hepatocytes during chronic liver injury by inhibiting p53-induced p21 expression. Long-term treatment with RAD001 markedly delays DNA damage,induced liver tumor development. Conclusion: We provide evidence that mTOR inhibition has a substantial effect on sequential carcinogenesis and may offer an effective strategy to delay liver tumor development in patients at risk. (HEPATOLOGY 2009;50:500,509.) [source] Hepatotoxic effect of cyclosporin A in the mitochondrial respiratory chainJOURNAL OF APPLIED TOXICOLOGY, Issue 4 2007Lilia Cristina De la Cruz Rodríguez Abstract Cyclosporin A (CyA), a potent immunosuppressant, was used to determine the hepatotoxic effect in long-term treatments. Male Wistar rats were used in these experiments. They were given CyA chronically at doses used in patients for 120 days, and at doses of 5, 10, 15 and 20 mg kg,1 day,1. These doses amount to CyA values in blood of 200 ± 24, 314 ± 40, 445 ± 33 and 598 ± 53 ng ml,1, respectively. A significant increase in glutamate dehydrogenase (GLDH) was found in the groups treated with 15 and 20 mg kg,1 day,1, which would point to mitochondria as the potential target of the toxic action of CyA. The mitochondrial respiratory chain of rat livers was studied in enzyme complexes I and II. Enzyme complex I was determined by spectrophotometry at 340 nm using NADH oxidase with the respirable substrate 10 mm NADH; enzyme complex II was determined by monitoring succinate dehydrogenase by oxymetry using the respirable substrate 10 mm succinate. The results show the inhibition of NADH oxidase in the groups treated with 10, 15 and 20 mg kg,1 day,1, an effect dependent both on time and on CyA concentration. Enzyme complex II showed a decrease in oxygen consumption. These findings were confirmed by histological studies (hematoxylin-eosin technique). Conclusions: Long-term treatment with CyA at doses of 15 and 20 mg kg,1 day,1, amounting to concentrations in blood of 445 ± 33 and 598 ± 53 ng ml,1, causes alterations in the mitochondria, revealed by the increase in serum GLDH and by the functional alteration of enzyme complexes I and II of the mitochondrial respiratory chain. Copyright © 2007 John Wiley & Sons, Ltd. [source] Bone Material Properties in Trabecular Bone From Human Iliac Crest Biopsies After 3- and 5-Year Treatment With Risedronate,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2006Erich Durchschlag Abstract Long-term effects of risedronate on bone mineral maturity/crystallinity and collagen cross-link ratio in triple iliac crest biopsies of osteoporotic women were evaluated. In this double-blinded study, 3- and 5-year treatment with risedronate arrested the tissue aging encountered in untreated osteoporosis and in osteoporosis treated with other antiresorptives. This effect may be contributing to risedronate's antifracture efficacy. Introduction: Risedronate is widely used in the treatment of osteoporosis. It reduces bone turnover, increases BMD, and decreases fracture risk. To date, there are no data available on the long-term effects of risedronate on bone material properties in humans. Materials and Methods: Osteoporotic women enrolled in the VERT-NA trial received either risedronate (5 mg/day, orally) or placebo for up to 5 years. All subjects received calcium. They also received vitamin D supplementation if deficient at baseline. Triple iliac crest biopsies were collected from a subset of these subjects at baseline, 3 years, and 5 years. Mineral maturity/crystallinity and collagen cross-link ratio was measured in these biopsies using Fourier transform infrared imaging. Results: Patients that received placebo exhibited increased mineral maturity/crystallinity and collagen cross-link ratio after 3 and 5 years compared with baseline values. On the contrary, patients that received risedronate retained baseline values in both bone material indices throughout. A more spatially detailed analysis revealed that this was achieved mainly through beneficial effects on active bone-forming areas. Surprisingly, patients that received risedronate achieved premenopausal values at bone-forming areas in both indices after 5 years of treatment. Conclusion: Long-term treatment with risedronate affects bone material properties (mineral maturity/crystallinity and collagen cross-link ratio) and arrests the tissue aging apparent in untreated osteoporosis. These changes at the material level of the bone matrix may contribute to risedronate's rapid and sustained antifracture efficacy in osteoporotic patients. [source] Long-term treatment of localized gastric marginal zone B-cell mucosa associated lymphoid tissue lymphoma including incidence of metachronous gastric cancerJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 4 2010Shouko Ono Abstract Background and Aim:, According to a few recent reports on the long-term clinical outcome of gastric marginal zone B-cell mucosa associated lymphoid tissue lymphoma (MALT lymphoma); localized gastric MALT lymphoma generally has a favorable prognosis. However, the risk of metachronous gastric cancer has not been evaluated. In this study, we analyzed long-term outcomes of localized gastric MALT lymphoma including the incidence of metachronous gastric cancer. Methods:, Between April 1996 and May 2008, 60 patients (31 men and 29 women; mean age 58.1 years) with localized gastric MALT lymphoma (stage I and II1 according to Lugano classification) were analyzed retrospectively. Results:, Forty-eight patients (82.6%) achieved complete remission by eradication therapy. Radiation therapy was conducted on eight patients as second-line treatment, and all of them achieved remission. The median follow-up period was 76 months (range, 12,157 months). One patient had local relapse after remission for 5 years and three patients developed early gastric cancer without recurrence of lymphoma (5%). All of the three gastric cancers appeared in the same areas where MALT lymphoma had been eradicated. Conclusion:, Eradication therapy and radiation therapy for localized gastric MALT lymphoma have a favorable long-term outcome, though regular follow-up endoscopy should be performed for detecting metachronous early gastric cancer. [source] Efficacy of Enalapril for Prevention of Congestive Heart Failure in Dogs with Myxomatous Valve Disease and Asymptomatic Mitral RegurgitationJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2002Clarence Kvart We evaluated the long-term effect of early angiotensin-converting enzyme (ACE) inhibition (enalapril maleate) as monotherapy to postpone or prevent congestive heart failure (CHF) in asymptomatic dogs with mitral regurgitation (MR) attributable to myxomatous valvular disease (MVD) in a prospective, randomized, double-blinded, placebo-controlled multicenter trial involving 14 centers in Scandinavia. Two hundred twenty-nine Cavalier King Charles (CKC) Spaniels with MR attributable to MVD but no signs of CHF were randomly allocated to treatment with enalapril 0.25,0.5 mg daily (n = 116) or to placebo groups (n = 113). Each dog was evaluated by physical examination, electrocardiography, and thoracic radiography at entry and every 12 months (±30 days). The number of dogs developing heart failure was similar in the treatment and placebo groups (n = 50 [43%] and n = 48 [42%], respectively; P= .99). The estimated means, adjusted for censored observations, for the period from initiation of therapy to heart failure were 1,150 ± 50 days for dogs in the treatment group and 1,130 ± 50 days for dogs in the placebo group (P= .85). When absence or presence of cardiomegaly at the entrance of the trial was considered, there were still no differences between the treatment and placebo groups (P= .98 and .51, respectively). Multivariate analysis showed that enalapril had no significant effect on the time from initiation of therapy to heart failure (P= .86). Long-term treatment with enalapril in asymptomatic dogs with MVD and MR did not delay the onset of heart failure regardless of whether or not cardiomegaly was present at initiation of the study. [source] Long-term treatment of patients with gastro-oesophageal reflux disease in routine care , results from the ProGERD studyALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2007M NOCON Summary Background Gastro-oesophageal reflux disease (GERD) is a common condition frequently requiring long-term pharmacological treatment. Aim To describe the long-term pattern of GERD medication use in GERD patients receiving routine care. Methods Patients were recruited as part of the ongoing ProGERD study, a 10-year-cohort study including 6215 patients at baseline. GERD medication and symptoms were assessed with patient questionnaires. During follow-up, medical treatment was prescribed by participating primary care physicians. Associations between patient characteristics and medication were analysed by logistic regression. Results The percentage of patients who reported using any GERD medication remained constant from year 1 to year 4 (74%, 74%, 73% and 71%). Of patients who reported using GERD medication, the majority were taking proton pump inhibitors (PPI) (79%, 84%, 85%, and 87%). Continuous PPI intake was the predominant prescription pattern (53%, 49%, 56% and 56%), followed by on-demand treatment (26%, 35%, 29% and 29%). Continuous PPI intake was strongly associated with the presence of erosive GERD. Conclusion Three-quarters of the GERD population in our study reported long-term treatment with a PPI. Continuous PPI intake was the predominant treatment pattern, and the proportion of patients taking a PPI on a continuous basis remained constant over time. [source] Long-term treatment with botulinum toxin type A in cervical dystonia has low immunogenicity by mouse protection assay,MOVEMENT DISORDERS, Issue 10 2008Mitchell F. Brin MD Abstract To evaluate the immunogenicity of botulinum toxin type A (BoNTA; BOTOX) in cervical dystonia (CD). Subjects diagnosed with CD for ,1 year and previously naďve to BoNTs were treated with BoNTA in a prospective, open-label, multicenter study. Serum samples were analyzed for BoNTA neutralizing antibodies using the Mouse Protection Assay (MPA). Clinical resistance was assessed with a test injection of 20 U BoNTA placed unilaterally into the frontalis (Frontalis Antibody Test; FTAT) or corrugator muscle (Unilateral Brow Injection; UBI). Efficacy was assessed and adverse events were recorded. Of 326 subjects enrolled, 251 (77%) completed the study. Subjects received a median of 9 BoNTA treatments (mean dose per session ranged from 148.4 to 213.0 U over a mean of 2.5 years [range: 3.2 months,4.2 years]). Only 4 of 326 subjects (1.2%) tested positive for antibodies in the MPA; three of these subjects stopped responding clinically to BoNTA (of whom one also showed clinical resistance in the FTAT) and one continued to respond. Consistent improvements in the signs/symptoms of CD were noted. The most frequent treatment-related adverse events were mild to moderate weakness, dysphagia, neck pain, and injection-site pain. The current formulation of BoNTA rarely causes neutralizing antibody formation in CD subjects treated ,4 years. © 2008 Movement Disorder Society [source] Leucine metabolism in regulation of insulin secretion from pancreatic beta cellsNUTRITION REVIEWS, Issue 5 2010Jichun Yang Leucine, a branched-chain amino acid that must be supplied in the daily diet, plays an important role in controlling protein synthesis and regulating cell metabolism in various cell types. In pancreatic , cells, leucine acutely stimulates insulin secretion by serving as both metabolic fuel and allosteric activator of glutamate dehydrogenase to enhance glutaminolysis. Leucine has also been shown to regulate gene transcription and protein synthesis in pancreatic islet , cells via both mTOR-dependent and -independent pathways at physiological concentrations. Long-term treatment with leucine has been shown to improve insulin secretory dysfunction of human diabetic islets via upregulation of certain key metabolic genes. In vivo, leucine administration improves glycemic control in humans and rodents with type 2 diabetes. This review summarizes and discusses the recent findings regarding the effects of leucine metabolism on pancreatic ,-cell function. [source] (647) Evaluation of the Long-Term Efficacy and Safety of Transdermal Fentanyl in the Treatment of Noncancer Pain: The Interim AnalysisPAIN MEDICINE, Issue 2 2000Article first published online: 25 DEC 200 Authors: K Milligan, South Cleveland Hospital, L Haazen and L Bijnens, Janssen Research Foundation Aim of Investigation: To document long-term efficacy and safety of transdermal (TTS) fentanyl for the management of noncancer pain. Methods: The study was an open-label, international, multi-center, phase III trial in 532 patients (mean age 51.5 years) with a median pain duration of 6 years. Two hundred sixty-two patients (50%) had neuropathic pain and 367 (70%) had predominantly somatic, nociceptive pain. TTS-fentanyl was started at an equi-analgesic dose to the pretrial opioid, and given for 12 months. Main outcome measures were weekly assessment of pain control, global treatment satisfaction and quality of life scores. Results: At interim analysis, 120 patients had completed the trial, 211 were continuing treatment, and 201 patients had discontinued. The mean dose of TTS-fentanyl increased from 48 ,g/h to 105 ,g/h over 12 months, with most increases occurring in the first months. During treatment the number of subjects reporting very good, good, or moderate pain control remained stable at 65% (range 61% to 75%). Global satisfaction (very good or good) was also stable at 42% (range 38% to 46%). Eighty-six percent of patients reported preference for TTS-fentanyl over their previous treatment, stating the main reason as better pain relief. SF-36 scores improved from baseline for physical pain and physical summary measurements. The most frequently occurring adverse events were nausea (28%), sonmolence (17%), constipation (15%), vomiting (15%), and increased sweating (14%). Conclusions: Long-term treatment with TTS-fentanyl provides a stable degree of pain control in the majority of patients with moderate-to-severe noncancer pain. It was preferred by the majority of subjects to their previous medication and favorably improved their quality of life. Acknowledgments: Supported by the Janssen Research Foundation. [source] Prophylactic effect of clarithromycin in skin flap complications in cochlear implants surgery,THE LARYNGOSCOPE, Issue 10 2009Juan Garcia-Valdecasas MD Abstract Objectives/Hypothesis: To assess the usefulness of postoperative clarithromycin versus classical postoperative prophylaxis with occlusive dressing to prevent cochlear implant skin flap complications. Study Design: Cohort study. Methods: Surgical site infections were compared in four groups: 1) ceramic/classical postoperative cares (21 patients), 2) titanium-silicon/classical postoperative cares (75), 3) ceramic/clarithromycin (24), and 4) titanium-silicon/clarithromycin (76). Preoperative ceftriaxone was systematically used in all patients in all four groups. Patients were followed up for at least 4 months. Attributable risk and number needed to treat were calculated. Results: All infections appeared in titanium-silicon covered implants, and the risk of surgical site infection was 8.1 times higher in patients treated only with ceftriaxone and classical postoperative prophylaxis compared to those also given clarithromycin. Eleven patients needed to receive clarithromycin to avoid surgical infection. Conclusions: Long-term treatment with low-dose clarithromycin may reduce the incidence of surgical site infections. Laryngoscope, 2009 [source] Enhancement of intervertebral disc cell senescence by WNT/,-catenin signaling,induced matrix metalloproteinase expressionARTHRITIS & RHEUMATISM, Issue 10 2010Akihiko Hiyama Objective To determine whether intervertebral disc (IVD) cells express ,-catenin and to assess the role of the WNT/,-catenin signaling pathway in cellular senescence and aggrecan synthesis. Methods The expression of ,-catenin messenger RNA (mRNA) and protein in rat IVD cells was assessed by using several real-time reverse transcription,polymerase chain reaction, Western blot, immunohistochemical, and immunofluorescence analyses. The effect of WNT/,-catenin on nucleus pulposus (NP) cells was examined by transfection experiments, an MTT assay, senescence-associated ,-galactosidase staining, a cell cycle analysis, and a transforming growth factor (TGF,)/bone morphogenetic protein (BMP) pathway,focused microarray analysis. Results We found that ,-catenin mRNA and protein were expressed in discs in vivo and that rat NP cells exhibited increased ,-catenin mRNA and protein upon stimulation with lithium chloride, a known activator of WNT signaling. LiCl treatment inhibited the proliferation of NP cells in a time- and dose-dependent manner. In addition, there was an increased level of cellular senescence in LiCl-treated cells. Long-term treatment with LiCl induced cell cycle arrest and promoted subsequent apoptosis in NP cells. Activation of WNT/,-catenin signaling also regulated the expression of aggrecan. We also demonstrated that WNT/,-catenin signaling induced the expression of matrix metalloproteinases (MMPs) and TGF, in NP cells. Conclusion The activation of WNT/,-catenin signaling promotes cellular senescence and may modulate MMP and TGF, signaling in NP cells. We hypothesize that the activation of WNT/,-catenin signaling may lead to an increased breakdown of the matrix, thereby promoting IVD degeneration. [source] Long-term management of vulval lichen sclerosus in adult womenAUSTRALIAN AND NEW ZEALAND JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Issue 2 2010J. BRADFORD Background:, Adult vulval lichen sclerosus (VLS) is usually a lifelong disease with an estimated remission rate after treatment of only 16% [Arch Dermatol 2004; 140 (6): 709]. Although superpotent topical corticosteroid (TCS) is the validated gold standard treatment to induce remission, little data are available on how remission should be maintained. Aims:, We present a retrospective chart review of 129 adult patients with VLS who have been under surveillance by the authors for a minimum duration of three years. Methods:, Remission was maintained in most patients with low-to-moderate potency TCS. All subjects' symptoms, signs, treatment regimes and response to treatment including compliance, symptom remission, disease progression with scarring, squamous cell carcinoma and side effects were recorded. Data were compared for the compliant and non-compliant groups. Fischer's exact test was used to identify significant differences. Results:, The mean age at presentation was 53.6 years and mean duration of follow-up was 6.2 years. Compliance was excellent: 84 (65%) of patients' self-reporting as being fully compliant. Symptom remission was achieved in 98% of compliant and 75% of non-compliant patients (P = 0.001) Progression of disease with scarring was not encountered in any of the compliant patients, but was seen in 35% of non-compliant patients (P = 0.0001). One patient had squamous cell carcinoma on first presentation. Carcinoma subsequently occurred in none of the compliant patients, and in five partly compliant patients (P = 0.004). Mild, reversible corticosteroid side effects were encountered in 7% of patients. Conclusions:, Long-term treatment of adult VLS with individualised regimes using moderate potency TCS is safe and effective. Patients require long-term follow-up. [source] Differential effects of medroxyprogesterone acetate on thrombosis and atherosclerosis in miceBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2009Till Freudenberger Background and purpose:, The risk for cardiovascular events including venous and arterial disease and stroke is elevated after treatment with estrogen and medroxyprogesterone acetate (MPA) in postmenopausal women. Here, we have investigated the effect of MPA on arterial thrombosis and atherosclerosis in a murine model of atherosclerosis. Experimental approach:, Apolipoprotein E (ApoE),/, mice were bilaterally ovariectomized and treated with placebo, MPA (27.7 µg·day,1) and MPA + 17-,-oestradiol (E2; 1.1 µg·day,1) for 90 days, on a Western-type diet. Thrombotic response was measured in a photothrombosis model, platelet activation by fluorescence activated cell sorting (FACS) analysis (CD62P) and thrombin generation by the endogenous thrombin potential (ETP). Furthermore, aortic plaque burden and aortic root plaque composition were determined. Key results:, MPA and MPA + E2 -treated animals showed an aggravated thrombotic response shown by significantly reduced time to stable occlusion. The pro-thrombotic effect of MPA was paralleled by increased ETP whereas platelet activation was not affected. Furthermore, MPA + E2 reduced the number of cells positive for ,-smooth muscle actin and increased hyaluronan in the plaque matrix. Interestingly, total plaque burden was reduced by MPA but unchanged by MPA + E2. Conclusion and implications:, Long-term treatment with MPA and MPA + E2 increased arterial thrombosis despite inhibitory effects of MPA on atherosclerosis in ApoE-deficient mice. Increased thrombin formation, reduced smooth muscle content and remodelling of non-collagenous plaque matrix may be involved in the pro-thrombotic effects. Thus, MPA exhibits differential effects on arterial thrombosis and on atherosclerosis. [source] Long-term anti-arthritic and anti-osteoporotic effects of raloxifene in established experimental postmenopausal polyarthritisCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2008C. Jochems Summary Both oestrogen deficiency and the inflammatory disease contribute to the generalized bone loss seen in postmenopausal rheumatoid arthritis (RA). Oestradiol and the selective oestrogen receptor modulator raloxifene have been shown to ameliorate the disease in collagen-induced arthritis (CIA), a well-established animal model for human RA. The aim of this study was to investigate whether raloxifene-treatment would be beneficial in long-term treatment of established CIA, both regarding anti-arthritic and anti-osteoporotic properties. Female dilute brown agouti mice were ovariectomized and CIA was induced. Raloxifene or vehicle treatment was administered 5 days per week, and the clinical arthritis score was evaluated continuously. At termination, bone mineral density was analysed, paws were collected for histological examination and sera were analysed for markers of bone and cartilage turnover, as well as antibodies to type II collagen and levels of interleukin (IL)-6. Treatment with raloxifene is beneficial in long-term treatment of established CIA. It hampers the disease severity and frequency, protects the joints from destruction and protects against the development of osteoporosis. The proinflammatory cytokine IL-6 was down-regulated in raloxifene-treated mice compared with controls. The serum levels of antibodies to collagen were not affected by raloxifene-treatment. Long-term treatment with raloxifene has both anti-arthritic and anti-osteoporotic effects in established experimental postmenopausal polyarthritis. [source] End organ protection by calcium-channel blockersCLINICAL CARDIOLOGY, Issue 2 2001Dan Tzivoni M.D. Abstract In recent years, much attention has been given to end organ protection by antihypertensive, anti-heart failure, and anti-ischemic medications. This review describes the available information on end organ protection by calcium-channel blockers (CCBs). In normotensive patients and patients with hypertension treated with long-acting dihydropyridines, medial thickness was thinner than in patients treated with atenolol or in untreated hypertensive patients. Long-term treatment was associated with significant reduction in left ventricular mass. Calcium-channel blockers also improved endothelial-dependent relaxation and reversed the vasoconstrictive response to nitric oxide inhibitors. In diabetic patients. CCBs were effective in preserving kidney function and microalbuminurea. The combination of angiotensin-converting enzyme (ACE) inhibitors and CCBs was more effective than ACE inhibitors alone in preserving kidney function. In animal experiments, CCBs prevented development of coronary atheroschlerosis; however, in humans only limited data are available on their antiatherogenic effect. Some studies suggest that CCBs exert antiplatelets properties and may therefore be beneficial in patients with coronary artery disease. [source] Novel antipsychotics in bipolar and schizoaffective maniaACTA PSYCHIATRICA SCANDINAVICA, Issue 6 2004G. J. R. Mensink Objective:, Novel antipsychotics are increasingly used in the treatment of bipolar and schizoaffective mania. This paper presents an overview of the controlled studies in this field. Method:, Using cross-references, a computerized search was performed on MEDLINE and EMBASE psychiatry covering the period 1990,2002. Results:, Olanzapine and risperidone, added to mood stabilizers, and olanzapine as monotherapy enjoy the most evidential support in terms of efficacy and side-effect profile for their use in acute bipolar mania. The use of modern antipsychotics in bipolar prophylaxis and in both the short- and long-term treatment of schizomania has not been widely studied yet. Conclusion:, More controlled trials are still needed comparing modern antipsychotics as monotherapy and adjunctive to mood stabilizers with conventional antipsychotics, lithium, anticonvulsants and with each other in short-term and, especially, maintenance treatment of (schizo)mania. Partly based on controlled studies, olanzapine, risperidone and other modern antipsychotics could become preferable for these indications. [source] Rapid-cycling bipolar disorder: effects of long-term treatmentsACTA PSYCHIATRICA SCANDINAVICA, Issue 1 2003L. Tondo Objective: To compare responses to long-term treatment of rapid-cycling (RC) vs. non-RC bipolar disorder patients and assess relative effectiveness of specific agents in RC patients. Method: Studies identified by literature searching were analyzed for effects of RC status and treatment-type on clinical outcome (recurrence or non-improvement per exposure-time), using random-effects methods to estimate pooled rates and their 95% CI for quantitative meta-analytic modeling. Results: Data were obtained from 16 reports with 25 trial-arms involving 1856 (905 RC and 951 non-RC) patients treated with carbamazepine, lamotrigine, lithium, topiramate, or valproate, alone or with other agents over an average of 47.5 months (7347 total patient-years). Estimated RC prevalence was 15.4%. Crude rates (%/month) of recurrence (2.31/1.20) and clinical non-improvement (1.93/0.49) averaged 2.9-fold greater in RC vs. non-RC subjects. The pooled RC/non-RC risk ratio (RR) for inferior treatment-response (in 13 direct comparisons) was 1.40 (CI 1.26,1.56; P < 0.0001). Pooled crude recurrence and non-improvement rates suggested no clear advantage for any treatment, nor superiority for anticonvulsants over lithium. However, only lithium vs. carbamazepine could be directly compared (in four treatment-arms) meta-analytically in RC patients (RR = 0.93, CI 0.74,1.18, indicating no difference in effectiveness). Conclusion: As expected, RC was associated with lower effectiveness of all treatments evaluated. Direct comparisons of specific treatment alternatives for RC patients were rare, and provided no secure evidence of superiority of any treatment. Additional long-term studies comparing RC/non-RC patients randomized to specific treatments are required. [source] Stratified analyses for selecting appropriate target patients with diabetic peripheral neuropathy for long-term treatment with an aldose reductase inhibitor, epalrestatDIABETIC MEDICINE, Issue 7 2008N Hotta Abstract Aims The long-term efficacy of epalrestat, an aldose reductase inhibitor, in improving subjective symptoms and nerve function was comprehensively assessed to identify patients with diabetic peripheral neuropathy who responded to epalrestat treatment. Methods Stratified analyses were conducted on data from patients in the Aldose Reductase Inhibitor,Diabetes Complications Trial (ADCT). The ADCT included patients with diabetic peripheral neuropathy, median motor nerve conduction velocity , 40 m/s and with glycated haemoglobin (HbA1c) , 9.0%. Longitudinal data on HbA1c and subjective symptoms of the patients for 3 years were analysed (epalrestat n = 231, control subjects n = 273). Stratified analyses based on background variables (glycaemic control, grades of retinopathy or proteinuria) were performed to examine the relationship between subjective symptoms and nerve function. Multiple logistic regression analyses were conducted. Results Stratified subgroup analyses revealed significantly better efficacy of epalrestat in patients with good glycaemic control and less severe diabetic complications. In the control group, no improvement in nerve function was seen regardless of whether symptomatic benefit was obtained. In the epalrestat group, nerve function deteriorated less or improved in patients whose symptoms improved. The odds ratio of the efficacy of epalrestat vs. control subjects was approximately 2 : 1 (4 : 1 in patients with HbA1c , 7.0%). Conclusion Our results suggest that epalrestat, an aldose reductase inhibitor, will provide a clinically significant means of preventing and treating diabetic neuropathy if used in appropriate patients. [source] Effect of long-term treatment with rosiglitazone on arterial elasticity and metabolic parameters in patients with Type 2 diabetes mellitus: a 2-year follow-up studyDIABETIC MEDICINE, Issue 11 2007M. Shargorodsky Abstract Aims, Thiazolidinediones may influence the atherogenic process by improving cardiovascular risk factors. The present study was designed to determine the long-term effect of rosiglitazone on arterial compliance and metabolic parameters in patients with Type 2 diabetes. Methods, In an open-label, prospective study, 65 diabetic patients received rosiglitazone orally (4,8 mg/day) for 6 months. After 6 months, the patients continued an open follow-up study and were divided into two groups: group 1 included patients continuing rosiglitazone for 2 years, group 2 included patients discontinuing rosiglitazone and receiving other oral glucose-lowering agents. Lipid profile, glycated haemoglobin (HbA1c), insulin, C-peptide, fibrinogen, high-sensitivity-CRP and homeostasis model assessment,insulin resistance were measured. Arterial elasticity was assessed using pulse wave contour analysis. Results, In patients treated with rosiglitazone for 2 years: the large artery elasticity index (LAEI) increased from 10.0 ± 4.6 to 13.9 ± 4.7 ml/mmHg × 100 after 2 years (P = 0.003). The small artery elasticity (SAEI) index increased significantly from 3.2 ± 1.2 to 5.1 ± 1.9 (P < 0.0001). In patients who discontinued rosiglitazone: LAEI did not change after 6 months, but decreased from 12.1 ± 5.4 to 8.9 ± 3.9 ml/mmHg × 10 (P < 0.0001) at the end of 2 years. SAEI increased during the first 6 months of treatment, from 3.9 ± 1.8 to 5.1 ± 1.5 ml/mmHg × 100 (P < 0.0001) and decreased after discontinuation of rosiglitazone (P = 0.042). Conclusions, Prolonged treatment with rosiglitazone improved arterial elasticity. However, significant deterioration in LAEI and SAEI was observed in patients who discontinued rosiglitazone. The beneficial vascular effect of rosiglitazone on arterial elasticity was independent of glycaemic control. [source] The Bech,Rafaelsen Melancholia Scale (MES) in clinical trials of therapies in depressive disorders: a 20-year review of its use as outcome measureACTA PSYCHIATRICA SCANDINAVICA, Issue 4 2002P. Bech Bech P. The Bech,Rafaelsen Melancholia Scale (MES) in clinical trials of therapies in depressive disorders A 20-year review of its use as outcome measure. Acta Psychiatr Scand 2002: 106: 252,264. © Blackwell Munksgaard 2002. Objective:,To evaluate the psychometric properties of the Bech,Rafaelsen Melancholia Scale (MES) by reviewing clinical trials in which it has been used as outcome measure. Method:,The psychometric analysis included internal validity (total scores being a sufficient statistic), interobserver reliability, and external validity (responsiveness in short-term trials and relapse prevention in long-term trials). Results:,The results showed that the MES is a unidimensional scale, indicating that the total score is a sufficient statistic. The interobserver reliability of the MES has been found adequate both in unipolar and bipolar depression. External validity including both relapse, response and recurrence indicated that the MES has a high responsiveness and sensitivity. Conclusion:,The MES has been found a valid and reliable scale for the measurement of changes in depressive states during short-term as well as long-term treatment. [source] Lower suicide risk with long-term lithium treatment in major affective illness: a meta-analysisACTA PSYCHIATRICA SCANDINAVICA, Issue 3 2001Leonardo Tondo Objective:,To compare suicide rates with vs. without long-term lithium treatment in major affective disorders. Method:,Broad searching yielded 22 studies providing suicide rates during lithium maintenance; 13 also provide rates without such treatment. Study quality was scored, between-study variance tested, and suicide rates on vs. off lithium examined by meta-analyses using random-effects regression methods to model risk ratios. Results:,Among 5647 patients (33,473 patient-years of risk) in 22 studies, suicide was 82% less frequent during lithium-treatment (0.159 vs. 0.875 deaths/100 patient-years). The computed risk-ratio in studies with rates on/off lithium was 8.85 (95% CI, 4.12,19.1; P<0.0001). Higher rates off-lithium were not accounted for by treatment-discontinuation. Conclusion:,Suicide risk was consistently lower during long-term treatment of major affective illnesses with lithium in all studies in the meta-analysis, including the few involving treatment-randomization. [source] Pharmacologic profile of zoledronic acid: A highly potent inhibitor of bone resorptionDRUG DEVELOPMENT RESEARCH, Issue 4 2002Jonathan R. Green Abstract Bisphosphonates are effective in treating benign and malignant skeletal diseases characterized by enhanced osteoclastic bone resorption (i.e., osteoporosis, Paget's disease, tumor-induced osteolysis). The nitrogen-containing bisphosphonate pamidronate is currently the standard treatment for hypercalcemia of malignancy (HCM) and skeletal complications of bone metastases. Zoledronic acid, a novel nitrogen-containing bisphosphonate with an imidazole substituent, has demonstrated more potent inhibition of osteoclast-mediated bone resorption than all other bisphosphonates, including pamidronate, in both in vitro and in vivo preclinical models. Zoledronic acid inhibited ovariectomy-induced bone loss in adult monkeys and rats, and long-term treatment prevented skeletal turnover and subsequent bone loss, reduced cortical porosity, and increased mechanical strength. Zoledronic acid also significantly inhibited bone loss associated with arthritis, bone metastases, and prosthesis loosening. The increased potency of zoledronic acid vs. pamidronate has been demonstrated clinically: zoledronic acid (4 or 8 mg iv) was superior to pamidronate (90 mg iv) in normalizing corrected serum calcium in patients with HCM. In patients with bone metastases, low doses of zoledronic acid (, 2 mg) suppressed bone resorption markers , 50% below baseline, whereas pamidronate 90 mg yielded only 20 to 30% suppression. Importantly, the increased potency of zoledronic acid is not associated with an increased incidence of local (bone) or systemic adverse events. Zoledronic acid does not impair bone mineralization and, compared with pamidronate, has a greater renal and intestinal tolerability therapeutic index. Thus, based on preclinical assays and clinical data, zoledronic acid is the most potent bisphosphonate tested to date. Given its potency and excellent safety profile, zoledronic acid is now poised to become the new standard of treatment for HCM and metastatic bone disease. Drug Dev. Res. 55:210,224, 2002. © 2002 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||||||||||||||||||||||||||