(57/869) Lack of efficacy of ridogrel, a thromboxane synthase inhibitor, in a placebo-controlled, double-blind, multi-centre clinical trial in active Crohn's disease.
BACKGROUND: Thromboxanes are produced in excess and platelets are activated in active Crohn's disease. Preliminary reports have suggested that ridogrel, a dual thromboxane synthase inhibitor and receptor antagonist, may have therapeutic benefit in patients with inflammatory bowel disease. AIMS: To investigate the efficacy of ridogrel in patients with active Crohn's disease. PATIENTS AND METHODS: This was an international, multicentre, randomized, double-blind, placebo-controlled trial of 5 mg/day oral ridogrel for 12 weeks in 85 patients with moderately active Crohn's disease. Sixty patients were randomized to receive ridogrel, and 25 to placebo. The Crohn's disease activity index (CDAI) was used to assess disease activity: remission was defined as a CDAI < 150. Changes in clinical condition, as assessed by the Harvey-Bradshaw index, global evaluation by the investigator and the patient, and blood measures of inflammation, were used as secondary outcomes. RESULTS: The patients' mean (s.d.) CDAI at recruitment was 277 (68) in the ridogrel treated group and 265 (70) in the placebo group. At their final assessment, 20 out of 60 (35%) patients who had been given ridogrel in an intention-to-treat analysis and seven out of 25 (28%) patients given placebo were in remission (no significant difference). No significant differences in Harvey- Bradshaw index or global evaluation were noted between patients given ridogrel and those given placebo. Adverse events were similar in both groups. CONCLUSION: A 5-mg dose of oral ridogrel was not more effective than placebo in inducing remission in patients with moderately active Crohn's disease. If thromboxane synthesis and platelet function are to be targeted for the treatment of Crohn's disease, more potent agents require development and assessment. (+info)
(58/869) Saquinavir and ritonavir pharmacokinetics following combined ritonavir and saquinavir (soft gelatin capsules) administration.
AIMS: To investigate the influence of combined ritonavir (RTV) and saquinavir (soft-gelatin capsule formulation; SQV) on systemic exposure to SQV with a view to optimizing the dosing regimen of combined RTV and SQV antiretroviral therapy. METHODS: In this open labelled, randomized, parallel group study, SQV and RTV were administered twice daily for 14 days to groups of eight healthy subjects. The two antiretrovirals were either administered alone (800 mg SQV, regimen A, and 400 mg RTV, B) or in combination at various dose levels (RTV : SQV: 400 : 400 mg, C; 300 : 600 mg, D; 200 : 800 mg, E; 300 : 800 mg, F; 400 : 800 mg, G; and 400 : 600 mg, H). Pharmacokinetic parameters of saquinavir and ritonavir were determined and adverse events, vital signs, and clinical laboratory variables recorded. RESULTS: RTV substantially increased the plasma concentration of saquinavir for all dose combinations, compared with SQV alone. Based on the primary statistical analysis there was an overall 17-, 22-, and 23-fold increase in saquinavir AUC(0,24 h) on day 14 with regimens E, F, and G, respectively (with confidence intervals of 10-30, 13-37, and 13-39). The lowest combination dose of RTV (200 : 800 mg; E) significantly increased the saquinavir AUC(0,24 h) from below 5 to 57 microg ml(-1) h, which was higher than the exposure obtained with the 400 : 400 mg twice daily regimen (i.e. 36 microg ml(-1) h). RTV also reduced intersubject variability in AUC(0,24 h) for saquinavir from 105% to 32-68%, and C(max)(0,24 h) from 124% to 30-49%. In contrast, SQV showed no clinically significant effect on the pharmacokinetics of ritonavir. The combination regimens were well tolerated, with the least number of adverse events recorded for the 200 : 800 mg (RTV : SQV) combination regimen. CONCLUSIONS: RTV significantly increases saquinavir exposure as a consequence of inhibiting SQV metabolism and possibly P-glycoprotein efflux. Pharmacokinetic and safety profiles obtained in the current study indicate that the use of a combination with a lower dose of RTV and a higher dose of SQV than the 400 : 400 mg combination frequently used in clinical practice should be further explored. (+info)
(59/869) Erectile dysfunction in chronic peritoneal dialysis patients: incidence and treatment with sildenafil.
OBJECTIVES: Sexual and erectile dysfunction (ED) have been reported to occur frequently in male patients with end-stage renal disease maintained on dialysis. Numerous etiologies for this ED have been suggested. Although a variety of therapies for the ED of the dialysis patient have been suggested, most clinicians indicate that patients report a poor response to therapy. Recently, sildenafil has been reported to be beneficial in treating patients with ED of both organic and psychogenic causes. The present study was designed to document the incidence of ED in male patients maintained on chronic peritoneal dialysis (CPD) and to determine the efficacy of prescribing sildenafil therapy to treat their ED. METHODS: All male patients in our CPD unit were notified by letter of the availability of sildenafil as a treatment modality for ED. A sexuality/erectile dysfunction assessment was conducted in all male patients by their primary nephrologist. Patients who reported ED and who had no medical contraindication to sildenafil were offered this therapy. Those patients who were interested in this treatment were interviewed by a social worker, and patients were asked to complete the International Index of Erectile Function questionnaire. Sildenafil was prescribed at a starting dose of 25 mg and increased to a maximum of 100 mg during a 12-week study trial. Patients were re-evaluated 6 and 12 weeks after the start of therapy. RESULTS: There were 68 male patients maintained on CPD at the time of the study. Mean age of all patients was 60.8 +/- 15.3 years and mean duration on PD was 32.6 +/- 25.6 months. Thirty-three patients had diabetes, 66 hypertension, 35 peripheral vascular disease, and 32 coronary artery disease. Thirty-two of 68 male patients in the CPD unit were assessed to have ED. Only 17 of the 32 patients expressed interest in pursuing sildenafil therapy. Two of these patients were excluded because they were receiving nitrate therapy. Of the 15 patients who agreed to take sildenafil, only 6 completed the 12-week study. Two of these patients responded to sildenafil. CONCLUSION: Erectile dysfunction is common in male patients maintained on CPD. Only about half of patients with ED in the present study were willing to consider sildenafil therapy to treat the ED and, of those who agreed to treatment, only a minority completed the 12-week trial; 2 of these 6 patients reported a satisfactory response. (+info)
(60/869) A Phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120-h infusion schedule.
PURPOSE: Sodium phenylbutyrate (PB) demonstrates potent differentiating capacity in multiple hematopoietic and solid tumor cell lines. We conducted a Phase I and pharmacokinetic study of PB by continuous infusion to characterize the maximum tolerated dose, toxicities, pharmacokinetics, and antitumor effects in patients with refractory solid tumors. PATIENTS AND METHODS: Patients were treated with a 120-h PB infusion every 21 days. The dose was escalated from 150 to 515 mg/kg/day. Pharmacokinetics were performed during and after the first infusion period using a validated high-performance liquid chromatographic assay and single compartmental pharmacokinetic model for PB and its principal metabolite, phenylacetate. RESULTS: A total of 24 patients were enrolled on study, with hormone refractory prostate cancer being the predominant tumor type. All patients were evaluable for toxicity and response. A total of 89 cycles were administered. The dose-limiting toxicity (DLT) was neuro-cortical, exemplified by excessive somnolence and confusion and accompanied by clinically significant hypokalemia, hyponatremia, and hyperuricemia. One patient at 515 mg/kg/day and another at 345 mg/kg/day experienced this DLT. Toxicity resolved < or =12 h of discontinuing the infusion. Other toxicities were mild, including fatigue and nausea. The maximum tolerated dose was 410 mg/kg/day for 5 days. Pharmacokinetics demonstrated that plasma clearance of PB increased in a continuous fashion beginning 24 h into the infusion. In individuals whose V(max) for drug elimination was less than their drug-dosing rate, the active metabolite phenylacetate accumulated progressively. Plasma PB concentrations (at 410 mg/kg/day) remained above the targeted therapeutic threshold of 500 micromol/liter required for in vitro activity. CONCLUSION: The DLT in this Phase I study for infusional PB given for 5 days every 21 days is neuro-cortical in nature. The recommended Phase II dose is 410 mg/kg/day for 120 h. (+info)
(61/869) Tolerability and safety of a calcium channel blocker in comparison with a diuretic in the treatment of elderly patients with hypertension: secondary analysis of the NICS-EH.
A randomized prospective controlled study, the National Interventional Cooperative Study in Elderly Hypertensives (NICS-EH), previously demonstrated that the preventive effect of the long-acting calcium channel blocker nicardipine on the cardiovascular endpoint was similar to that of the diuretic, trichlormethiazide. The present report is a sub-analysis in which we compare the tolerability and safety of the calcium channel blocker with that of a diuretic in the long-term treatment of elderly hypertensives. A total of 429 elderly patients with hypertension were assigned to the nicardipine group or the diuretic group by the double-dummy method and were followed up for 5 years. Two hundred four patients in the nicardipine group and 210 patients in the diuretic group were analyzed. The incidences of fatal and nonfatal cardiovascular (CV) events in the two groups were comparable, and there was no significant difference in the cumulative event-free rate. However, the total incidence of adverse reactions, including non-CV events and unfavorable BP changes, was 31 cases (15.2%) in the nicardipine group, which was significantly lower than the 47 cases (22.4%) in the diuretic group (log-rank: p=0.026, G. Wilcoxon: p=0.01). The total number of medical endpoints, including CV events, the withdrawal of the patient from the study, was 52 (25.5%) in the nicardipine group, which was significantly lower than the 65 (31.0%) in the diuretic group (log-rank: p=0.078, G. Wilcoxon: p=0.044). It was concluded that sustained-release nicardipine is better tolerated, as it exhibits a lower incidence of medical-related withdrawals such as adverse drug reactions, non-cardiovascular events and unfavorable BP responses during the treatment. (+info)
(62/869) Information given to patients before appointments and its effect on non-attendance rate.
PROBLEM: Wasted outpatient appointments as a result of clinic non-attendance, exacerbating outpatient waiting times. DESIGN: Single centre, prospective, non-randomised, controlled study. BACKGROUND AND SETTING: Diabetes clinic in a district general hospital run by a consultant, one or two diabetes nurse specialists, a dietitian, and a podiatrist. Clinic receives 10-15 new referrals a week in a health district with a population of 340 000. KEY MEASURE FOR IMPROVEMENT: Non-attendance rate in 325 new patients who attended after the intervention compared with 1336 historical controls from the same clinic in the three years before the scheme. STRATEGY FOR CHANGE: Two weeks before their outpatient appointment new patients were sent an information pack telling them when and where to come, where to park, what to bring, who they will see, and what to expect. One week before the appointment they received a supplementary phone call. EFFECTS OF CHANGE: Telling patients what to expect reduced non-attendance rate overall from 15% (201/1336) to 4.6% (15/325), P<0.0001. Non-attendance rate was 7.3% (13/178) in those sent a pack but not phoned and 1.4% (2/147) in those sent a pack and phoned, P=0.01. LESSON LEARNT: Giving new patients detailed information reduces non-attendance to almost 1%. (+info)
(63/869) Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list for liver transplantation.
BACKGROUND: Survival after liver transplantation for early hepatocellular carcinoma (HCC) is worsened by the increasing dropout rate while waiting for a donor. AIMS: To assess the cost effectiveness of adjuvant therapy while waiting for liver transplantation in HCC patients. METHOD: Using a Markov model, a hypothetical cohort of cirrhotic patients with early HCC was considered for: (1) adjuvant treatment-resection was limited to Child-Pugh's A patients with single tumours, and percutaneous treatment was considered for Child-Pugh's A and B patients with single tumours unsuitable for resection or with up to three nodules < 3 cm; and (2) standard management. Length of waiting time ranged from six to 24 months. RESULTS: Surgical resection increased the transplantation rate (>10%) and provided gains in life expectancy of 4.8-6.1 months with an acceptable cost ($40,000/ year of life gained) for waiting lists > or = 1 year whereas it was not cost effective ($74,000/life of year gained) for shorter waiting times or high dropout rate scenarios. Percutaneous treatment increased life expectancy by 5.2-6.7 months with a marginal cost of approximately $20,000/year of life gained in all cases, remaining cost effective for all waiting times. CONCLUSIONS: Adjuvant therapies for HCC while waiting for liver transplantation provide moderate gains in life expectancy and are cost effective for waiting lists of one year or more. For shorter waiting times, only percutaneous treatment confers a relevant survival advantage. (+info)
(64/869) The prevalence and correlates of untreated serious mental illness.
OBJECTIVE: To identify the number of people in the United States with untreated serious mental illness (SMI) and the reasons for their lack of treatment. DATA SOURCE/STUDY DESIGN: The National Comorbidity Survey; cross-sectional, nationally representative household survey. DATA COLLECTION: An operationalization of the SMI definition set forth in the Alcohol, Drug Abuse, and Mental Health Administration Reorganization Act identified individuals with SMI in the 12 months prior to the interview. The presence of SMI then was related to the use of mental health services in the past 12 months. PRINCIPAL FINDINGS: Of the 6.2 percent of respondents who had SMI in the year prior to interview, fewer than 40 percent received stable treatment. Young adults and those living in nonrural areas were more likely to have unmet needs for treatment. The majority of those who received no treatment felt that they did not have an emotional problem requiring treatment. Among those who did recognize this need, 52 percent reported situational barriers, 46 percent reported financial barriers, and 45 percent reported perceived lack of effectiveness as reasons for not seeking treatment. The most commonly reported reason both for failing to seek treatment (72 percent) and for treatment dropout (58 percent) was wanting to solve the problem on their own. CONCLUSIONS: Although changes in the financing of services are important, they are unlikely by themselves to eradicate unmet need for treatment of SMI. Efforts to increase both self-recognition of need for treatment and the patient centeredness of care also are needed. (+info)