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A previous placebo-controlled trial has shown that biodegradable 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers (Gliadel wafers) prolong survival in patients with recurrent glioblastoma multiforme. A previously completed phase 3 trial, also placebo controlled, in 32 patients with newly diagnosed malignant glioma also demonstrated a survival benefit in those patients treated with BCNU wafers. Because of the small number of patients in that trial, a larger phase 3 trial was performed to confirm these results. Two hundred forty patients were randomized to receive either BCNU or placebo wafers at the time of primary surgical resection; both groups were treated with external beam radiation postoperatively. The two groups were similar for age, sex, Karnofsky performance status (KPS), and tumor histology. Median survival in the intent-to-treat group was 13.9 months for the BCNU wafer-treated group and 11.6 months for the placebo-treated group (log-rank P -value stratified by country = 0.03), with a 29% reduction in the risk of death in the treatment group. When adjusted for factors affecting survival, the treatment effect remained positive with a risk reduction of 28% ( P = 0.03). Time to decline in KPS and in 10/11 neuroperformance measures was statistically significantly prolonged in the BCNU wafer-treated group ( P

We performed a randomized, double-blind, placebo-controlled, multicenter trial to evaluate the relative efficacy and safety of cilostazol and pentoxifylline.We enrolled patients with moderate-to-severe claudication from 54 outpatient vascular clinics, including sites at Air Force, Veterans Affairs, tertiary care, and university medical centers in the United States. Of 922 consenting patients, 698 met the inclusion criteria and were randomly assigned to blinded treatment with either cilostazol (100 mg orally twice a day), pentoxifylline (400 mg orally 3 times a day), or placebo. We measured maximal walking distance with constant-speed, variable-grade treadmill testing at baseline and at 4, 8, 12, 16, 20, and 24 weeks.Mean maximal walking distance of cilostazol-treated patients (n = 227) was significantly greater at every postbaseline visit compared with patients who received pentoxifylline (n = 232) or placebo (n = 239). After 24 weeks of treatment, mean maximal walking distance increased by a mean of 107 m (a mean percent increase of 54% from baseline) in the cilostazol group, significantly more than the 64-m improvement (a 30% mean percent increase) with pentoxifylline (P0.001). The improvement with pentoxifylline was similar (P = 0.82) to that in the placebo group (65 m, a 34% mean percent increase). Deaths and serious adverse event rates were similar in each group. Side effects (including headache, palpitations, and diarrhea) were more common in the cilostazol-treated patients, but withdrawal rates were similar in the cilostazol (16%) and pentoxifylline (19%) groups.Cilostazol was significantly better than pentoxifylline or placebo for increasing walking distances in patients with intermittent claudication, but was associated with a greater frequency of minor side effects. Pentoxifylline and placebo had similar effects.

Abstract —Cilostazol is an antiplatelet agent and vasodilator marketed in Japan for treatment of ischemic symptoms of peripheral vascular disease. It is currently being evaluated in the United States for treatment of symptomatic intermittent claudication (IC). Cilostazol has been shown to improve walking distance in patients with IC. In addition to its reported vasodilator and antiplatelet effects, cilostazol has been proposed to have beneficial effects on plasma lipoproteins. We examined the effect of cilostazol versus placebo on plasma lipoproteins in 189 patients with IC. After 12 weeks of therapy with 100 mg cilostazol BID, plasma triglycerides decreased 15% ( P P P 3 and HDL 2 subfractions were increased by cilostazol; however, the greatest percentage increase was observed in HDL 2 . Individuals with baseline hypertriglyceridemia (>140 mg/dL) experienced the greatest changes in both HDL-C and triglycerides with cilostazol treatment. In that subset of patients, HDL-C was increased 12.2% and triglycerides were decreased 23%. With cilostazol, there was a trend (3%) toward decreased apoB as well as increased apoA1, resulting in a significant (9.8%, P P =0.0015) and a 9.03% increase in ankle-brachial index ( P

Background: Asimadoline, a peripherally-restricted highly selective kappa-opioid receptor (KOR) agonist, has been shown to be efficacious in relieving pain or discomfort, urgency, stool frequency and other symptoms in diarrhea-predominant-IBS (D-IBS) patients with at least moderate pain (Mangel et al 2008). The mechanism of action for this therapeutic effect is thought to involve activation of up-regulated KORs on visceral afferent terminals in the gut wall. KOR activation in the central nervous system (CNS) can lead to aquaresis, dysphoria, and sedation. Penetration of asimadoline into the CNS is poor due to its amphiphilic structure and because it is a substrate for P-glycoprotein (P-gp), thus, there is no evidence for CNS effects of asimadoline in the IBS dose range (1-2 mg/day). Aim: The potential for drug interaction-induced CNS effects with ketoconazole, an inhibitor of P-gp and cytochrome P450 3A4 (CYP3A4), which plays a role in the metabolism of asimadoline, was assessed in this study. Methods: This was a single center, double-blind, placebo-controlled, randomized, two-period, crossover drug interaction study. Twelve healthy male subjects (Caucasian, 1840 years) received ketoconazole 200 mg bid for 3 days followed by a combination of ketoconazole 200 mg and asimadoline 1.5 mg bid (3 fold higher than the 0.5 mg bid clinical dose for IBS) from Days 4 to 9 and a single morning dose on Day 10 in one period and the same treatments but with ketoconazole placebo in a second period, with a 14 day washout between treatments. Pharmacodynamic tests aimed at detecting activity of asimadoline in the CNS included plasma antidiuretic hormone concentrations, the Critical Flicker Fusion test, the Profile of Mood State and the Bond & Lader visual analogue scale of mood and alertness, performed on Days 1, 4, 7 and 10. Primary pharmacokinetic variables were plasma asimadoline Cmax and AUC0-τ after a single dose on Day 4 and after multiple doses on Day 10. Results: The Cmax of asimadoline was approximately doubled with ketoconazole compared to placebo co-administration (from 46.2 to 98.9 ng/mL on Day 4 and from 50.7 to 112.1 ng/mL on Day 10). Mean AUCτ values were 3-fold higher during ketoconazole compared to placebo treatment. Although co-administration of ketoconazole led to a 2to 3-fold increase in asimadoline Cmax and AUC, no effects were observed on any of the CNS pharmacodynamic endpoints. Conclusions: There were no CNS pharmacodynamic effects even at plasma asimadoline levels 8-fold higher than those achieved at the IBS dose. These data provide further evidence for the peripheral restriction of asimadoline and suggest that dose adjustment when co-administered with ketoconazole or other CYP3A4 / P-gp inhibitors is not required.

Background: Radiation proctitis (RAP) is defined as damage to the rectal mucosa resulting from radiotherapy to adjacent pelvic organs. More than 50 % of patients undergoing radiotherapy for prostate cancer (PC) will encounter symptoms such as diarrhea, blood and mucus in stool and tenesms that might alter qualitiy of life and might be dose limiting. The symptoms of radiation proctitis can be quantified by the acute EORTC/RTOG lower GI toxicity or the RAP score . Material and Methods: Patients undergoing radiotherapy (XRT) for PC were randomised to rectal budesonide (BUD) or placebo (PLB) treatment over 8 weeks. EORTC/RTOG lower GI toxicity score, RAP score and quality of life scores were taken at baseline and after 2, 4, 8 and 14 weeks as well as after 1 year. Flexible rectoscopy and assessment of the Vienna rectoscopy score (VRS) was done at baseline, after 8 weeks, 14 weeks and 1 year. 17 patients were included (n=8 budesonide, n=9 placebo) into the study. Results: 6/8 BUD patients and 6/9 PLB patients developed clinical signs of acute radiation proctitis, i.e. acute EORT/RTOG lower GI toxicity ≥ 1 for at least 2 consecutive days, during 8 weeks of treatment (p=0.8167). However, BUD ameliorated the severity of RAP by significantly reducing stool frequency at week 14 and after 1 year and numerically the number of tenesms at week 8. The endoscopic score for late radiation proctitis was diminished in the budesonide group compared to placebo. Conclusions: Rectal treatment with budesonide did not significantly prevent acute radiation proctitis in this pilot study. However, clinical symptoms of proctitis could be significantly reduced and the appearance of late radiation proctitis was diminished. Therefore BUD deserves further evaluation in the context of high dose XRT with curative intent to prevent or to ameliorate side effects that might be dose limiting.

(F0-F1 12.0 kPa). Genotypes were determined using Taqman assays. Results: Most patients suffered from chronic viral hepatitis C (58.9%), followed by alcoholic (10.6%) and autoimmune (AIH, PBC, PSC) liver diseases (8.1%). Mean 25(OH)-vitamin D3 levels were 28.4±15.8 ng/ml. Patients with advanced fibrosis (>12.0 kPa) had significantly lower 25(OH)-vitamin D3 levels as compared to patients with 7.0 kPa), the rare allele was significantly associated with increased liver stiffness (TT & TG vs GG: 5.1±1.0 kPa vs. 5.4±1.0 kPa; p < 0.05). Conclusion: A common SNP close the DHCR7 gene is associated with 25(OH)-vitamin D3 serum concentrations in patients with chronic liver disease. Interestingly, the association of this SNP with liver fibrosis was restricted to patients with no or mild fibrosis, suggesting that the modifier effect of vitamin D might only be discernible during fibrosis initiation and early fibrosis stages.

The clinical relevance and taxonomy of motile Aeromonas species are areas of current controversy. Strains of motile Aeromonas isolates (n = 60) from various sources were identified to species level using the following tests (all incubated at 30 degrees and 37 degrees C): esculin hydrolysis; formation of gas from glucose; production of acetoin; production of acid from mannitol and arabinose; decarboxylation of lysine and ornithine, dihydrolation of arginine; and pyrazinamide hydrolysis in a semisolid medium. The tests' results were similar at incubation temperatures of 30 degrees and 37 degrees C. Of the strains, 59 (98%) of 60 were identified to species level by the full battery of tests: 25 as A. hydrophila, 18 as A. caviae, 14 as A. sobria, one as A. veronii, and one as A. schubertii. (The only A. veronii and A. schubertii isolates identified were ATCC strains). All (25 of 25) strains of A. hydrophila and 17 (94%) of 18 of A. caviae hydrolyzed pyrazinamide in less than 24 hr, whereas all strains of A. sobria showed no pyrazinamidase activity. Absence of pyrazinamidase was, thus, a convenient phenotypic marker for A. sobria. Four additional tests (esculin hydrolysis, acetoin production, lysine decarboxylation, and gas production from glucose) identified within 24 hr all examples of the three common species of Aeromonas. Recently proposed species did not contribute to our ability to discriminate among stool, other clinical, and environmental isolates of Aeromonas spp.

Mesalamine granules (MG) are the first 5-aminosalicylate (5-ASA) formulation to use an innovative delivery system that combines delayedand extended-release mechanisms to release mesalamine directly in the ileum and colon. Agents with a low pill burden and favorable safety profile are more likely to enhance patient compliance in the long-term maintenance of UC remission. Two similarly designed multicenter, randomized, doubleblind, placebo-controlled, phase 3 trials (RCTs) have individually demonstrated significant efficacy of MG (1.5 g, q. d.) for the long-term maintenance of ulcerative colitis (UC). Additionally, an open-label extension trial (OLT) with new and rollover subjects from the two phase 3 trials was conducted to study the long term safety of MG for maintenance of UC remission. The integrated safety data in the expanded population of subjects who received MG from all three trials are presented here (All MG population). Methods: Data for the All MG analyses (n=557) included subjects who received MG in the two RCTs (n=367) and the OLT. The OLT included 197 MGtreated patients who rolled over from the RCTs; and 190 MG naive patients (83 placebo-treated patients from the RCTs, and 107 new patients) all in UC remission. Results: Of 557 patients included in the analysis, 250 patients were exposed for >1 year and 354 were exposed to MG (1.5 g, q.d.) for >6 months. Incidence of treatment-emergent adverse events (TEAEs) was 69.7% in the All MG group. Majority of TEAEs were mild or moderate in intensity, with a profile similar to that during the 6month RCTs. The notably lower incidence of UC flare observed in the RCTs for MG (10.9%) versus placebo (24.3%) was maintained (10.4%) in the OLT. Other common TEAEs in the All MG group were headache (13.8%), diarrhea (9.7%), nasopharyngitis (8.8%), abdominal pain (7.7%), sinusitis (5.4%), and nausea (5.2%). Incidences of serious adverse events and TEAEs leading to study discontinuation were comparable between the 6-month RCT group and the All MG population in the open label study. Occurrences of renal, hepatic, and pancreatic adverse events in patients in the open-label study were ≤1%. Long term compliance for the once-daily treatment regimen was high: mean compliance was ≥ 95% in each treatment group in the RCT population, and 88% for the All MG population. Conclusions: The favorable safety profile of MG when combined with a high compliance of once-daily dosing may support its dispensation as first-line therapy for long-term maintenance of UC remission.

Mesalamine granules (MG) are the first 5-aminosalicylate (5-ASA) formulation to use an innovative delivery system that combines delayedand extended-release mechanisms to release mesalamine directly in the ileum and colon. Agents with a low pill burden and favorable safety profile are more likely to enhance patient compliance in the long-term maintenance of UC remission. Two similarly designed multicenter, randomized, doubleblind, placebo-controlled, phase 3 trials (RCTs) have individually demonstrated significant efficacy of MG (1.5 g, q. d.) for the long-term maintenance of ulcerative colitis (UC). Additionally, an open-label extension trial (OLT) with new and rollover subjects from the two phase 3 trials was conducted to study the long term safety of MG for maintenance of UC remission. The integrated safety data in the expanded population of subjects who received MG from all three trials are presented here (All MG population). Methods: Data for the All MG analyses (n=557) included subjects who received MG in the two RCTs (n=367) and the OLT. The OLT included 197 MGtreated patients who rolled over from the RCTs; and 190 MG naive patients (83 placebo-treated patients from the RCTs, and 107 new patients) all in UC remission. Results: Of 557 patients included in the analysis, 250 patients were exposed for >1 year and 354 were exposed to MG (1.5 g, q.d.) for >6 months. Incidence of treatment-emergent adverse events (TEAEs) was 69.7% in the All MG group. Majority of TEAEs were mild or moderate in intensity, with a profile similar to that during the 6month RCTs. The notably lower incidence of UC flare observed in the RCTs for MG (10.9%) versus placebo (24.3%) was maintained (10.4%) in the OLT. Other common TEAEs in the All MG group were headache (13.8%), diarrhea (9.7%), nasopharyngitis (8.8%), abdominal pain (7.7%), sinusitis (5.4%), and nausea (5.2%). Incidences of serious adverse events and TEAEs leading to study discontinuation were comparable between the 6-month RCT group and the All MG population in the open label study. Occurrences of renal, hepatic, and pancreatic adverse events in patients in the open-label study were ≤1%. Long term compliance for the once-daily treatment regimen was high: mean compliance was ≥ 95% in each treatment group in the RCT population, and 88% for the All MG population. Conclusions: The favorable safety profile of MG when combined with a high compliance of once-daily dosing may support its dispensation as first-line therapy for long-term maintenance of UC remission.

Mesalamine granules (MG) are the first 5-aminosalicylate (5-ASA) formulation to use an innovative delivery system that combines delayedand extended-release mechanisms to release mesalamine directly in the ileum and colon. Agents with a low pill burden and favorable safety profile are more likely to enhance patient compliance in the long-term maintenance of UC remission. Two similarly designed multicenter, randomized, doubleblind, placebo-controlled, phase 3 trials (RCTs) have individually demonstrated significant efficacy of MG (1.5 g, q. d.) for the long-term maintenance of ulcerative colitis (UC). Additionally, an open-label extension trial (OLT) with new and rollover subjects from the two phase 3 trials was conducted to study the long term safety of MG for maintenance of UC remission. The integrated safety data in the expanded population of subjects who received MG from all three trials are presented here (All MG population). Methods: Data for the All MG analyses (n=557) included subjects who received MG in the two RCTs (n=367) and the OLT. The OLT included 197 MGtreated patients who rolled over from the RCTs; and 190 MG naive patients (83 placebo-treated patients from the RCTs, and 107 new patients) all in UC remission. Results: Of 557 patients included in the analysis, 250 patients were exposed for >1 year and 354 were exposed to MG (1.5 g, q.d.) for >6 months. Incidence of treatment-emergent adverse events (TEAEs) was 69.7% in the All MG group. Majority of TEAEs were mild or moderate in intensity, with a profile similar to that during the 6month RCTs. The notably lower incidence of UC flare observed in the RCTs for MG (10.9%) versus placebo (24.3%) was maintained (10.4%) in the OLT. Other common TEAEs in the All MG group were headache (13.8%), diarrhea (9.7%), nasopharyngitis (8.8%), abdominal pain (7.7%), sinusitis (5.4%), and nausea (5.2%). Incidences of serious adverse events and TEAEs leading to study discontinuation were comparable between the 6-month RCT group and the All MG population in the open label study. Occurrences of renal, hepatic, and pancreatic adverse events in patients in the open-label study were ≤1%. Long term compliance for the once-daily treatment regimen was high: mean compliance was ≥ 95% in each treatment group in the RCT population, and 88% for the All MG population. Conclusions: The favorable safety profile of MG when combined with a high compliance of once-daily dosing may support its dispensation as first-line therapy for long-term maintenance of UC remission.