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Clinical trial: the incidence of NSAID-associated endoscopic gastric ulcers in patients treated with PN 400 (naproxen plus esomeprazole magnesium) vs. enteric-coated naproxen alone

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2010
J. L. Goldstein
Aliment Pharmacol Ther 2010; 32: 401,413 Summary Background, Gastroprotective co-therapy may reduce the risk of nonsteroidal anti-inflammatory drug (NSAID)-associated gastric ulcers, but adherence is suboptimal. Aim, To compare the incidence of gastric ulcers with PN 400 [enteric-coated (EC) naproxen 500 mg and immediate-release esomeprazole 20 mg], or EC naproxen. Methods, Two randomized, double-blind, multicentre studies (PN400-301, PN400-302). Patients [stratified by low-dose aspirin (,325 mg) use] aged ,50 years or 18,49 years with a history of ulcer, received PN 400 BID (301, n = 218; 302, n = 210) or EC naproxen 500 mg BID (301, n = 216; 302, n = 210) for 6 months. The primary endpoint was the cumulative incidence of endoscopic gastric ulcers. Results, The cumulative incidence of gastric ulcers was significantly lower with PN 400 vs. EC naproxen (301: 4.1% vs. 23.1%, P < 0.001; 302: 7.1% vs. 24.3%, P < 0.001). PN 400 was associated with a lower combined incidence of gastric ulcers vs. EC naproxen in low-dose aspirin users (n = 201) (3.0% vs. 28.4%, P < 0.001) and non-users (n = 653) (6.4% vs. 22.2%, P < 0.001). The incidence of, and discontinuations due to, upper gastrointestinal (UGI) AEs was significantly lower with PN 400 relative to EC naproxen (P < 0.01, both studies). Conclusions, PN 400 significantly reduces the incidence of gastric ulcers, regardless of low-dose aspirin use, in at-risk patients, and is associated with improved UGI tolerability relative to EC naproxen (ClinicalTrials.gov, NCT00527782). [source]

Duloxetine for the Management of Diabetic Peripheral Neuropathic Pain: Response Profile

PAIN MEDICINE, Issue 5 2007
Yili L. Pritchett PhD
ABSTRACT Objective., The current analysis examines the response profile in patients receiving duloxetine for the management of diabetic peripheral neuropathic pain (DPNP). Patients/Design., Data were pooled from three double-blind, randomized, placebo-controlled 12-week acute therapy trials of patients with DPNP of at least 6 months' duration. Study 1 (N = 457) had treatment groups of duloxetine 20 mg once daily (QD), 60 mg QD, 60 mg twice daily (BID), and placebo; Studies 2 (N = 334) and 3 (N = 348) compared duloxetine 60 mg QD and 60 mg BID with placebo. The primary efficacy measure in each study was the weekly mean score of the 24-hour average pain severity. Treatment response was defined as a 30% reduction in pain severity, although some analyses were repeated using alternative response criteria (50% reduction, or 2-point reduction, in pain severity). Results., Consistently across the three studies, response rates at endpoint were significantly higher among patients receiving duloxetine (60 mg QD or 60 mg BID) than among those receiving placebo, regardless of the chosen response criterion (30% reduction, 50% reduction, or 2-point reduction in weekly mean of 24-hour average pain severity). The proportion of patients achieving pain relief in the duloxetine treatment groups was significantly greater than that in the placebo group at Week 1 and at all subsequent study visits to the end of acute phase therapy. Using diary data (24-hour average pain severity) from the first 7 days of treatment, the first significant separation from placebo in pain severity reduction for duloxetine 60 mg QD occurred at Day 1 (Study 1), Day 2 (Study 2), and Day 4 (Study 3), while significant separation in response rates first occurred at Day 3 when using pooled data. Conclusions., Patients with DPNP receiving duloxetine 60 mg QD or 60 mg BID had significantly higher rates of treatment response, when compared with patients receiving placebo, regardless of the chosen response criterion. Response to duloxetine treatment tended to occur early in therapy. [source]

Calcineurin-Inhibitor-Free Immunosuppression Based on the JAK Inhibitor CP-690,550: A Pilot Study in De Novo Kidney Allograft Recipients

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2009
S. Busque
This randomized, pilot study compared the Janus kinase inhibitor CP-690,550 (15 mg BID [CP15] and 30 mg BID [CP30], n = 20 each) with tacrolimus (n = 21) in de novo kidney allograft recipients. Patients received an IL-2 receptor antagonist, concomitant mycophenolate mofetil (MMF) and corticosteroids. CP-690,550 doses were reduced after 6 months. Due to a high incidence of BK virus nephropathy (BKN) in CP30, MMF was discontinued in this group. The 6-month biopsy-proven acute rejection rates were 1 of 20, 4 of 20 and 1 of 21 for CP15, CP30 and tacrolimus groups, respectively. BKN developed in 4 of 20 patients in CP30 group. The 6-month rates of cytomegalovirus disease were 2 of 20, 4 of 20 and none of 21 for CP15, CP30 and tacrolimus groups, respectively. Estimated glomerular filtration rate was >70 mL/min at 6 and 12 months (all groups). NK cells were reduced by ,77% in CP-690,550-treated patients. In the CP-690,550 arms, there were modest lipid elevations and a trend toward more frequent anemia and neutropenia during the first 6 months. These data suggest that coadministration of CP-690,550 30 mg BID with MMF is associated with overimmunosuppression. At 15 mg BID, the efficacy/safety profile was comparable to the tacrolimus control group, excepting a higher rate of viral infection. Further dose-ranging evaluation of CP-690,550 is warranted. [source]

Safety and Efficacy of Raltegravir in HIV-Infected Transplant Patients Cotreated with Immunosuppressive Drugs

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2009
L. Tricot
Solid organ transplantations (SOT) are performed successfully in selected HIV-infected patients. However, multiple and reciprocal drug,drug interactions are observed between antiretroviral (ARV) drugs and calcineurin inhibitors (CNIs) through CYP450 metabolization. Raltegravir (RAL), a novel HIV-1 integrase inhibitor, is not a substrate of CYP450 enzymes. We retrospectively reviewed the outcomes of 13 HIV-infected transplant patients treated by an RAL + two nucleosidic reverse transcriptase inhibitor (NRTI) regimen, in terms of tolerability, ARV efficacy (plasma viral load, CD4 cell count), drug interactions, RAL pharmacokinetics and transplant outcome. Thirteen patients with liver (n = 8) or kidney (n = 5) transplantation were included. RAL was initiated (400 mg BID) either at time of transplantation (n = 6), or after transplantation (n = 7). Median RAL trough concentration was 507 ng/mL (176,890), which is above the in vitro IC95 for wild type HIV-1 strains (15 ng/mL). Target trough levels of CNIs were promptly obtained with standard dosages of tacrolimus or cyclosporine. RAL tolerability was excellent. There was no episode of acute rejection. HIV infection remained controlled. After a median follow-up of 9 months (range: 6,14), all patients were alive with satisfactory graft function. The use of an RAL + two NRTI-based regimen is a good alternative in HIV-infected patients undergoing SOT. [source]

Phase 1 Dose-Escalation Study of CP-690 550 in Stable Renal Allograft Recipients: Preliminary Findings of Safety, Tolerability, Effects on Lymphocyte Subsets and Pharmacokinetics

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2008
E. Van Gurp
CP-690 550 inhibits Janus kinase 3 with nanomolar potency. In this dose-escalation study, we assessed the safety, tolerability, effects on lymphocyte subsets, and pharmacokinetics of CP-690 550 when coadministered with mycophenolate mofetil in stable renal allograft recipients for 28 days. Twenty-eight patients were enrolled. Six patients received CP-690 550 5 mg twice daily (BID), 6 patients received 15 mg BID, 10 patients received 30 mg BID, and 6 patients received placebo. The most frequent adverse events were infections and gastrointestinal (abdominal pain, diarrhea, dyspepsia, and vomiting). CP-690 550 15 mg BID and 30 mg BID were associated with a mean decrease in hemoglobin from baseline of 11% and a mean decrease in absolute natural killer cell counts of 50%. CP-690 550 30 mg BID was also associated with a mean increase in absolute CD19+ B-lymphocytes of 130%. There were no changes in the number of neutrophils, total lymphocytes, platelets, or CD4+ or CD8+ T cells; clinical chemistry; vital signs; or electrocardiograms from the pretreatment baseline. Administration of CP-690 550 without a concomitant calcineurin inhibitor resulted in CP-690 550 exposures consistent with previous studies in nontransplant subjects. Additional dose-ranging studies are warranted to evaluate the safety and efficacy of CP-690 550 in renal transplant recipients over longer treatment duration. [source]

Rationale and Design of ATHENA: A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg Bid for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in PatiENts with Atrial Fibrillation/Atrial Flutter

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 1 2008
STEFAN H. HOHNLOSER M.D.
Background: Atrial fibrillation (AF) is the most commonly encountered clinical arrhythmia, predominantly affecting elderly patients. There is a continued need for new antiarrhythmic drugs to treat the ever-increasing number of patients with this arrhythmia. Dronedarone is a new antiarrhythmic compound currently being developed for treatment of AF. Methods: The ATHENA trial (A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter) is the largest single antiarrhythmic drug trial ever conducted. More than 4,600 patients with a history of AF or atrial flutter (AFL) have been randomized to receive dronedarone 400 mg bid or matching placebo. The primary study endpoint is time to first cardiovascular hospitalization or death from any cause. The study has completed patient enrollment in December 2006 and is expected to end follow-up 1 year later. Conclusion: ATHENA will be the largest efficacy and safety trial of dronedarone, a multichannel blocker compound with properties from class I, II, III, and IV antiarrhythmic drugs developed to treat patients with AF. [source]

Successful medication withdrawal after cognitive-behavioral therapy in a treatment-resistant preadolescent male with obsessive-compulsive disorder

DEPRESSION AND ANXIETY, Issue 1 2009
Robert B. Goldstein M.D.
Abstract There are no reports of a child taking a selective serotonin reuptake inhibitor and an atypical anti-psychotic being successfully tapered from these medications after completion of cognitive-behavioral therapy (CBT) for obsessive-compulsive disorder. With this in mind, we report the case of an 8.5-year,old male who was taking risperidone 0.5,mg bid, sertraline 100,mg, and atomoxetine 25,mg at presentation. After a successful course of CBT, we describe how medications were systematically withdrawn. Implications of this case on practice parameters (e.g., CBT may be an effective augmenting agent for those non-responsive to initial pharmacological treatments) are highlighted. Depression and Anxiety, 2009. © 2008 Wiley-Liss, Inc. [source]

Effects of short-term metformin treatment on insulin sensitivity of blood glucose and free fatty acids

DIABETES OBESITY & METABOLISM, Issue 1 2004
S. Iannello
Aim:, Based on the known effect of metformin (MET) in improving insulin sensitivity in type 2 diabetes, with the scope to focus the effects on glycaemic and free fatty acids (FFA) levels, we studied the effects of a short-term treatment with this drug in obese subjects and obese patients with diabetes or family history of diabetes (FHD). We used a method to allow us to evaluate the possible difference of insulin sensibility with regard to the insulin action on glycaemia and blood FFA, both in the basal state and during oral glucose tolerance test (OGTT). Methods:, Insulin sensitivity was investigated before and after MET treatment (850 mg bid for 10 days) in seven obese subjects with normal glucose tolerance and without FHD and 13 obese patients with diabetes (n = 7) or FHD (n = 6). By using specifically designed formulae, we calculated four insulin-sensitivity indices (ISI) from basal level (b) and area values (a) (during OGTT) of insulinaemia, glycaemia (gly) or FFA (ffa), namely: ISI (gly)-b, ISI (gly)-a, ISI (ffa)-b and ISI (ffa)-a. Results:, In patients with diabetes or FHD, MET improved ISI (gly)-b (0.79 ± 0.06 vs. 0.59 ± 0.07, p < 0.001) and ISI (gly)-a (0.69 ± 0.09 vs. 0.51 ± 0.07, p < 0.05), whereas only minor changes occurred for ISI (ffa)-b and ISI (ffa)-a. In contrast, in simple obese subjects, MET induced further deterioration of both ISI (gly)-a (0.47 ± 0.07 vs. 0.64 ± 0.10, p < 0.01) and ISI (ffa)-a (0.43 ± 0.07 vs. 0.55 ± 0.08, p < 0.05). Fasting level and total area of lactate were high in the obese patients and were not affected by MET. A statistically significant increase (p < 0.01), however, was observed for the ,decremental' area of lactate in obese subjects with diabetes or FHD, which might probably contribute to the reduction of insulin resistance induced by the drug in these patients. Conclusions:, Although the low number of subjects studied precludes absolute conclusions, data would suggest that MET improved ISI towards glucose but not towards FFA, in the diabetic and ,prediabetic' obese patients, whereas worsened it in the obese subjects without FHD. Therefore, the effects of MET would not be secondary to changes of FFA but rather to a primary action of MET on glucose metabolism. Thus, utilization of MET to treat the insulin resistance in obesity is indicated only in the presence of alterations of glucose metabolism or FHD. [source]

CLINICAL STUDY: Effect of saquinavir/ritonavir (1000/100 mg bid) on the pharmacokinetics of methadone in opiate-dependent HIV-negative patients on stable methadone maintenance therapy

ADDICTION BIOLOGY, Issue 3 2009
Candice Jamois
ABSTRACT This study was performed to determine the effect of two protease inhibitors, saquinavir (SQV, oral 1000 mg bid) boosted by ritonavir (RTV, oral 100 mg bid), on pharmacokinetics (PK) of methadone in opiate-dependent HIV-negative patients on stable methadone maintenance therapy. This was a two-center, open-label, one-sequence cross-over, multiple-dose study in 13 HIV-negative patients who were on stable methadone therapy (oral, 60,120 mg qd). All patients continued methadone treatment on days 2,15. All patients received SQV/RTV in combination with methadone from days 2,15. PK of methadone was assessed on day 1 (alone) and on day 15 when methadone treatment was combined with SQV/RTV at steady state. Twelve patients completed the study. Median age, body weight and height were 50 years (range: 24,54 years), 80 kg (range: 57,97 kg) and 174 cm (range: 163,189 cm), respectively. All patients were Caucasian, and 11 were smokers. Median methadone dose was 85 mg qd. Geometric mean area under curve of the plasma concentration-time curve over 24 hour dosing interval (AUC0,24 hour) ratio of methadone with and without SQV/RTV was 0.81% (90% confidence interval: 71,91%). There was no significant plasma protein-binding displacement of methadone by SQV/RTV. The combination of SQV/RTV and methadone was well tolerated. There were no clinically significant adverse events or significant changes in laboratory parameters, electrocardiograms or vital signs. The 19% decrease in R-methadone AUC0,24 hour in the presence of SQV/RTV was not clinically relevant. There appears to be no need for methadone dose adjustment when methadone (60,120 mg qd) and SQV/RTV (1000/100 mg bid) are coadministered. [source]

,Rescue' Therapy with Rifabutin after Multiple Helicobacter pylori Treatment Failures

HELICOBACTER, Issue 2 2003
Javier P. Gisbert
abstract Aim. Eradication therapy with proton pump inhibitor, clarithromycin and amoxicillin is extensively used, although it fails in a considerable number of cases. A ,rescue' therapy with a quadruple combination of omeprazole, bismuth, tetracycline and metronidazole (or ranitidine bismuth citrate with these same antibiotics) has been recommended, but it still fails in approximately 20% of cases. Our aim was to evaluate the efficacy and tolerability of a rifabutin-based regimen in patients with two consecutive H. pylori eradication failures. Patients and Methods. Design: Prospective multicenter study. Patients: Consecutive patients in whom a first eradication trial with omeprazole, clarithromycin and amoxicillin and a second trial with omeprazole, bismuth, tetracycline and metronidazole (three patients) or ranitidine bismuth citrate with these same antibiotics (11 patients) had failed were included. Intervention: A third eradication regimen with rifabutin (150 mg bid), amoxicillin (1 g bid) and omeprazole (20 mg bid) was prescribed for 14 days. All drugs were administered together after breakfast and dinner. Compliance with therapy was determined from the interrogatory and the recovery of empty envelopes of medications. Outcome: H. pylori eradication was defined as a negative 13C-urea breath test 8 weeks after completing therapy. Results. Fourteen patients have been included. Mean age ± SD was 42 ± 11 years, 41% males, peptic ulcer (57%), functional dyspepsia (43%). All patients took all the medications and completed the study protocol. Per-protocol and intention-to-treat eradication was achieved in 11/14 patients (79%; 95% confidence interval = 49,95%). Adverse effects were reported in five patients (36%), and included: abdominal pain (three patients), nausea and vomiting (one patient), and oral candidiasis (one patient); no patient abandoned the treatment due to adverse effects. Conclusion. Rifabutin-based rescue therapy constitutes an encouraging strategy after multiple previous eradication failures with key antibiotics such as amoxicillin, clarithromycin, metronidazole and tetracycline. [source]

Impact of Furazolidone-Based Quadruple Therapy for Eradication of Helicobacter pylori after Previous Treatment Failures

HELICOBACTER, Issue 4 2002
G. Treiber
Abstract Background. One week of quadruple therapy including metronidazole is recommended for Helicobacter pylori treatment failures after first line therapy regardless of resistance status. This study investigated whether a quadruple regimen containing furazolidone could be effective as a third-line (salvage) therapy. Methods. All patients with previous H. pylori treatment failure after a clarithromycin-metronidazole ± amoxicillin combination plus acid suppression were given lansoprazole 30 mg twice a day (bid), tripotassiumdicitratobismuthate 240 mg bid, tetracycline 1 g bid, metronidazole 400 mg (PPI-B-T-M) three times a day (tid) for 1 week. In the case of treatment failure with this second-line therapy, the same regimen was applied for 1 week except for using furazolidone 200 mg bid (PPI-B-T-F) instead of metronidazole (sequential study design). Results. Eighteen consecutive patients were treated with PPI-B-T-M. Eleven of those 18 remained H. pylori positive (38.9% cured). Pretherapeutic metronidazole resistance was associated with a lower probability of eradication success (10% vs. 75%, p= .04). Ten of these 11 patients agreed to be retreated by PPI-B-T-F. Final cure of H. pylori with PPI-B-T-F was achieved in 9/10 patients (90%) nonresponsive to PPI-B-T-M. Conclusions. In the presence of metronidazole resistance, PPI-B-T-M as a recommended second-line therapy by the Maastricht consensus conference achieved unacceptable low cure rates in our metronidazole pretreated population. In this population, metronidazole based second-line quadruple therapy may be best suited in case of a metronidazole-free first line-regimen (e.g. PPI-clarithromycin-amoxicillin) or a low prevalence of metronidazole resistance. Furazolidone in the PPI-B-T-F combination does not have a cross-resistance potential to metronidazole and is a promising salvage option after a failed PPI-B-T-M regimen. [source]

High Efficacy of Ranitidine Bismuth Citrate, Amoxicillin, Clarithromycin and Metronidazole Twice Daily for Only Five Days in Helicobacter pylori Eradication

HELICOBACTER, Issue 2 2001
Javier P. Gisbert
ABSTRACT Aim. The combination of a proton pump inhibitor (PPI) or ranitidine-bismuth-citrate (Rbc) and two antibiotics for 7,10 days are, at present, the preferred treatments in Helicobacter pylori eradication. However, therapies for fewer than 7 days have been scarcely evaluated and it is unknown whether the length of treatment can be shortened, without a lost of efficacy, if three instead of two antibiotics are used. The aim of our study was to evaluate the efficacy of Rbc plus three antibiotics for only 5 days in H. pylori eradication. Methods. We prospectively studied 80 patients (34% duodenal ulcer, 66% functional dyspepsia) infected by H. pylori. At endoscopy, biopsies were obtained for histological study and rapid urease test, and a 13C-urea breath test was carried out. Urea breath test was repeated 4 weeks after completing eradication treatment with Rbc [400 mg twice a day (bid)], amoxicillin (1 g bid), clarithromycin (500 mg bid) and metronidazole (500 mg bid). All drugs were administered together after breakfast and dinner for 5 days only, and no treatment was administered thereafter. Compliance with therapy was determined from the interrogatory and the recovery of empty envelopes of medications. Results. In 79 out of the 80 patients, H. pylori eradication success or failure was assessed after therapy (one patient was lost from follow-up). All but one of these 79 patients took all the medications (one patient stopped treatment on the day 3 due to nausea/vomiting). Per protocol eradication was achieved in 72/78 (92%; 95% CI, 84,96%) and in 72/80 (90%; 81,95%) by intention-to-treat. Therapy was more effective in patients with duodenal ulcer than in those with functional dyspepsia [100% (87,100%) vs. 85% (73,92%) by intention-to-treat; p < .05]. Adverse effects were described in ten patients (12%), and included the perception of a metallic taste (eight patients), nausea/vomiting (two patients, one of them abandoned the treatment due to this), and diarrhea (two patients). Conclusion. The combination of Rbc, amoxicillin, clarithromycin and metronidazole for only 5 days represents a promising therapy for H. pylori infection, due to its high efficacy, simple posology, low cost and excellent tolerance. [source]

Indinavir/ritonavir-based therapy in HIV-1-infected antiretroviral therapy-naive patients: comparison of 800/100 mg and 400/100 mg twice daily

HIV MEDICINE, Issue 1 2005
D Konopnicki
Objectives To compare the efficacy and tolerability of indinavir (IDV)/ritonavir (RTV) at 800/100 and 400/100 mg twice daily (bid) in antiretroviral therapy (ART)-naive patients. Methods An open comparison of two groups of ART-naive patients treated with IDV/RTV 800/100 or 400/100 mg bid plus two nucleoside analogues was carried out. Viral load, CD4 cell count and tolerability were measured at baseline and at weeks 4, 12, 24 and 48. IDV plasma concentrations were measured retrospectively. Results A total of 107 patients were included in the study. Of these, 57 were treated with 800/100 and 50 with 400/100 mg IDV/RTV bid. At week 48, a viral load of <50 HIV-1 RNA copies/mL was achieved by 77 and 64% of the patients, respectively, and the median CD4 cell count increases were +171 and +164 cells/,L (intent-to-treat; P not significant), respectively. Side effects leading to protease inhibitor discontinuation occurred in 61% of subjects in the 800/100 mg group vs. 20% in the 400/100 mg group (P<0.0001). Switching from 800/100 to 400/100 mg dosage improved adverse events in 16 of 20 patients. IDV concentrations were above 0.15 mg/L in 89% of the 28 patients tested in the 400/100 mg group. Conclusions Indinavir/ritonavir 400/100 mg bid provided the same efficacy as 800/100 mg bid at 48 weeks in an ART-naive population, but safety and tolerance were significantly better for 400/100 mg, while convenience was also improved and cost was reduced. [source]

L -Carnitine in the treatment of HIV-associated lipodystrophy syndrome

HIV MEDICINE, Issue 1 2001
S Mauss
Summary The objective of this pilot study was to assess the effect of L -carnitine on the course of the HIV-associated lipodystrophy syndrome. Twelve patients presenting with combined atrophic and hypertrophic changes of body fat were treated with L -carnitine 1000 mg bid for 3 months. No marked improvement of the body changes was observed. However a reduction in serum cholesterol levels, but not triglycerides, was noted. These preliminary data do not support the use of L -carnitine for the rapid reversal of advanced fat tissue alterations due to HIV-associated lipodystrophy. [source]

New once-daily formulation for trospium in overactive bladder

INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 11 2010
C. Chapple
Summary Aims:, We examined the relative efficacy and safety of trospium 20 mg bid and 60 mg extended release formulations and position this drug against other antimuscarinic agents. Methods:, Data were identified on the pharmacology and pharmacokinetics of trospium chloride. Key publications on trospium 20-mg and 60-mg clinical studies in patients with overactive bladder (OAB) were identified and efficacy and safety compared between these formulations as well as other antimuscarinic agents. Results:, Trospium offers the principal advantage over other antimuscarinic agents that, as it is a quaternary amine, it does not cross the blood,brain barrier and is therefore less likely to cause central nervous system effects observed with several other agents. Moreover, with its minimal liver metabolisation, independent of the main cytochrome pathways, trospium has a low risk of drug,drug interaction in patients taking multiple pharmacological agents. Trospium 60 mg ER is as effective as trospium 20 mg bid in improving the key outcome parameters associated with OAB, but with a lower rate of dry mouth, the most common side effect of these agents. Trospium has comparable efficacy and safety to the other antimuscarinic agents currently marketed. Discussion:, Good patient persistence with treatment has been reported with trospium. There are currently a large number of antimuscarinic drugs on the market without clear evidence to distinguish one agent from another in terms of efficacy, provided that an adequate dose is used in the clinical setting. Conclusion:, The new formulation of trospium is certainly worth considering as a pharmacological treatment of patients with OAB, particularly in the elderly, in whom one wants to avoid the potential for cognitive dysfunction. [source]

Tolterodine: A Safe and Effective Treatment for Older Patients with Overactive Bladder

JOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 6 2001
James G. Malone-Lee MD
OBJECTIVE: To investigate the clinical safety and efficacy of two dosages of tolterodine in older patients with symptoms attributable to overactive bladder. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group, multinational, phase III study. SETTING: Incontinence, older care, urological, and urogynecological clinics in the United Kingdom, France, and the Republic of Ireland. PARTICIPANTS: One hundred and seventy-seven older patients (age ,65 years) with symptoms of urinary urgency, increased frequency of micturition (,8 micturitions/24 hours), and/or urge incontinence (,1 episode/24 hours). INTERVENTION: Tolterodine 1 mg or 2 mg twice daily (bid), or placebo, for 4 weeks. MEASUREMENTS: Safety and tolerability were evaluated through spontaneously reported adverse events, electrocardiogram, and blood pressure measurements. Efficacy was assessed using micturition diary variables: mean change from baseline in frequency of micturition and number of incontinence episodes/24 hours. RESULTS: The mean age of the patient population was 75 years. Overall, ,87% of patients completed the study. Neither dosage of tolterodine was associated with serious drug-related adverse events during the study. No cardiac arrythmogenic events were noted. Dry mouth (mild to moderate intensity) was the most common adverse event in both the placebo and tolterodine treatment groups. Three percent of patients in the tolterodine 2 mg bid group discontinued treatment because of dry mouth, compared with 2% of placebo-treated patients. Compared with placebo, statistically significant decreases in micturition frequency were apparent in both tolterodine treatment groups. Furthermore, patients treated with tolterodine 2 mg bid had statistically significant decreases in urge incontinence episodes/24 hours and increases in volume voided per micturition compared with placebo. CONCLUSION: Tolterodine (taken for 4 weeks) is safe and shows efficacy, particularly at a dosage of 2 mg bid, in the treatment of older patients with urinary symptoms attributable to overactive bladder. J Am Geriatr Soc 49:700,705, 2001. [source]

A Short-Term, Randomized, Double-Blind, Parallel-Group Study to Evaluate the Efficacy and Safety of Dronedarone versus Amiodarone in Patients with Persistent Atrial Fibrillation: The DIONYSOS Study

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 6 2010
JEAN-YVES LE HEUZEY M.D.
Dronedarone versus Amiodarone in Patients with AF.,,Introduction: We compared the efficacy and safety of amiodarone and dronedarone in patients with persistent atrial fibrillation (AF). Methods: Five hundred and four amiodarone-naïve patients were randomized to receive dronedarone 400 mg bid (n = 249) or amiodarone 600 mg qd for 28 days then 200 mg qd (n = 255) for at least 6 months. Primary composite endpoint was recurrence of AF (including unsuccessful electrical cardioversion, no spontaneous conversion and no electrical cardioversion) or premature study discontinuation. Main safety endpoint (MSE) was occurrence of thyroid-, hepatic-, pulmonary-, neurologic-, skin-, eye-, or gastrointestinal-specific events, or premature study drug discontinuation following an adverse event. Results: Median treatment duration was 7 months. The primary composite endpoint was 75.1 and 58.8% with dronedarone and amiodarone, respectively, at 12 months (hazard ratio [HR] 1.59; 95% confidence interval [CI] 1.28,1.98; P < 0.0001), mainly driven by AF recurrence with dronedarone compared with amiodarone (63.5 vs 42.0%). AF recurrence after successful cardioversion was 36.5 and 24.3% with dronedarone and amiodarone, respectively. Premature drug discontinuation tended to be less frequent with dronedarone (10.4 vs 13.3%). MSE was 39.3 and 44.5% with dronedarone and amiodarone, respectively, at 12 months (HR = 0.80; 95% CI 0.60,1.07; P = 0.129), and mainly driven by fewer thyroid, neurologic, skin, and ocular events in the dronedarone group. Conclusion: In this short-term study, dronedarone was less effective than amiodarone in decreasing AF recurrence, but had a better safety profile, specifically with regard to thyroid and neurologic events and a lack of interaction with oral anticoagulants. (J Cardiovasc Electrophysiol, Vol. 21, pp. 597-605, June 2010) [source]

Rationale and Design of ATHENA: A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg Bid for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in PatiENts with Atrial Fibrillation/Atrial Flutter

In GERD patients, mucosal repair associated genes are upregulated in non-inflamed oesophageal epithelium

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 5 2009
D. R. De Vries
Abstract Previous studies addressing the effects of acid reflux and PPI therapy on gene expression in oesophageal epithelium concentrated on inflamed tissue. We aimed to determine changes in gene expression in non-inflamed oesophageal epithelium of GERD patients. Therefore, we included 20 GERD patients with pathological total 24-hr acid exposure of 6,12% and SAP , 95%. Ten patients discontinued PPI treatment (PPI-), 10 took pantoprazole 40 mg bid (PPI+). Ten age/sex-matched healthy controls were recruited. Biopsies were taken from non-inflamed mucosa 6 cm and 16 cm proximal to the squamocolumnar junction (SCJ). Gene expression profiling of biopsies from 6 cm was performed on Human Genome U133 Plus 2.0 arrays (Affymetrix). Genes exhibiting a fold change >1.4 (t-test P -value < 1E, 4) were considered differentially expressed. Results were confirmed by real-time RT-PCR. In PPI- patients, 92 microarray probesets were deregulated. The majority of the corresponding genes were associated with cell,cell contacts, cytoskeletal reorganization and cellular motility, suggesting facilitation of a migratory phenotype. Genes encoding proteins with anti-apoptotic or anti-proliferative functions or stress-protective functions were also deregulated. No probesets were deregulated in PPI+ patients. QPCR analysis of 20 selected genes confirmed most of the deregulations in PPI- patients, and showed several deregulated genes in PPI+ patients as well. In the biopsies taken at 16 cm QPCR revealed no deregulations of the selected genes. We conclude that upon acid exposure, oesophageal epithelial cells activate a process globally known as epithelial restitution: up-regulation of anti-apoptotic, anti-oxidant and migration associated genes. Possibly this process helps maintaining barrier function. [source]

Effects of sub-antimicrobial dose doxycycline therapy on crevicular fluid MMP-8, and gingival tissue MMP-9, TIMP-1 and IL-6 levels in chronic periodontitis

JOURNAL OF PERIODONTAL RESEARCH, Issue 1 2004
Dong-Hoon Choi
Objective:, To investigate whether sub-antimicrobial dose doxycycline (SDD) therapy for 120 d in chronic adult periodontitis patients had significant effects on gingival crevicular fluid (GCF) matrix metalloproteinase-8 (MMP-8) levels, and on gingival tissue MMP-9, tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) and interleukin-6 (IL-6) levels. Background:, Tetracycline can significantly inhibit MMP activity in GCF and in gingival tissue, even in much lower dosage then a traditional antimicrobial dosage used in conventional therapy. Sub-antimicrobial dose doxycycline (SDD) therapy has been shown to reduce periodontal disease activity to control MMP and pro-inflammatory cytokines. Methods:, A total of 32 patients with incipient to moderate (probing pocket depth ,,4,7 mm) chronic adult periodontitis were included in the study. Subjects were randomly assigned to two groups. After scaling and root planning (SRP), the SRP + SDD group received SDD, 20 mg bid, whereas the SRP + placebo group received placebo, 20 mg bid. In the follow-up, efficacy measures included the change in probing pocket depth (PD), clinical attachment level (CAL), bleeding on probing (BOP) and gingival crevicular fluid MMP-8 levels, gingival tissue MMP-9, TIMP-1 and IL-6 levels from baseline to 120 d. Results:, After 120 d, PD and CAL improved significantly in the SRP + SDD group. Initial MMP-8 levels for the SRP + SDD group and the SRP + placebo group were 407.13 ± 114.45 ng/ml and 378.71 ± 189.39 ng/ml, respectively, with no statistical difference between the two groups. MMP-8 levels for the SRP + SDD group and the SRP + placebo group were: 235.35 ± 134.58 ng/ml and 364.04 ± 219.27 ng/ml at 30 d; 157.50 ± 95.95 ng/ml and 236.60 ± 186.16 ng/ml at 60 d; 102.70 ± 67.64 ng/ml and 208.56 ± 124.54 ng/ml at 90 d; and 63.77 ± 53.33 ng/ml and 229.13 ± 168.09 ng/ml at 120 d, respectively. The amount of decrease in MMP-8 levels for the SRP + SDD group was statistically significant compared to that for the SRP + placebo group, especially apparent at 120 d (p < 0.05). TIMP-1 levels in both groups increased from the baseline to 120 d with statistical significance (p -value < 0.05), but there was no significant difference between the two groups. Changes in MMP-9 and IL-6 levels were not statistically significant. Conclusion:, Adjunctive SDD therapy can improve the clinical parameters and this clinical improvement is reflected by controlled level of MMP-8 in chronic adult periodontitis after the therapy. [source]

Liver dysfunction in paediatric obesity: a randomized, controlled trial of metformin

ACTA PAEDIATRICA, Issue 9 2007
Michael Freemark
Abstract Aim: In a previous study we showed that metformin reduced BMI z -scores and fasting glucose and insulin concentrations, and increased whole body insulin sensitivity in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes. We analyzed the data from this study to determine (a) if metformin reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations during the 6-month trial, and (b) if the response to pharmacotherapy varied along gender or ethnic lines. Methods: The 6-month trial was randomized, double blinded and placebo controlled; a total of 14 metformin-treated (500 mg bid) and 15 placebo-treated subjects completed the study. There were no dietary restrictions. Results: In obese adolescents fed ad libitum, metformin (a) prevented the rise in ALT concentrations that were observed in placebo-treated subjects at the 3 to 5 month time-points (p < 0.05); (b) reduced (p < 0.01) the percentage of all ALT values exceeding 40 U/L; and (c) caused a modest (10%) but statistically significant (p < 0.05) reduction in serum ALT in Caucasian subjects. Metformin had no effect on ALT levels or the ALT to AST ratio in the five African American adolescents enrolled in the study but reduced their fasting insulin concentrations from 26.1 to 19.5 ,U/mL (p < 0.05). Conclusions: Our findings suggest that metformin might reduce the rates or severity of liver dysfunction in selected high-risk adolescents. [source]