A randomized controlled trial comparing zileuton with theophylline in moderate asthma. The Zileuton Study Group.

BACKGROUND: Zileuton, a leukotriene pathway inhibitor, was compared with slowly absorbed theophylline in a randomized, double-blind study of patients with chronic asthma. The primary efficacy measure was improvement in forced expiratory volume in 1 second (FEV1). METHODS: Eligibility criteria included FEV1 of 40% to 80% of predicted, documented reversibility of airway disease, and age 18 to 60 years. Initially, the theophylline dosage was titrated to achieve trough concentrations of 8 to 15 micrograms/mL. After washout and 1-week placebo lead-in, patients were randomly assigned to 13 weeks of the appropriate theophylline dose or zileuton, 400 or 600 mg 4 times daily. The FEV1 was measured before the morning dose at 2-week intervals and serially after the dose on days 36 and 92. Patients kept daily diaries of asthma symptoms, beta-agonist usage, and peak expiratory flow rate; on days 36 and 92, they completed quality-of-life questionnaires. RESULTS: Of 471 eligible patients at 38 centers, 377 were randomly assigned to the study; 313 completed the study. On first-dose administration, all groups showed 11% to 13% improvement in FEV1 within 30 minutes. Patients who received zileuton, 400 mg, had significantly greater improvement at several points than did theophylline-treated patients. The range of long-term maximum improvement in FEV1 in the groups was 30% to 34% (P = .40 for zileuton 600 mg; P = .90 for zileuton 400 mg vs theophylline). Initially, the theophylline group improved significantly more in symptom scores, beta-agonist usage, and peak expiratory flow rate, but at maximal effect there was no significant difference. All groups showed significant improvement in quality of life. No overall differences were observed between the zileuton dosage groups. Adverse events were comparable in all groups. CONCLUSION: Zileuton appears as effective and safe as theophylline in patients with chronic asthma.

A new technique for early detection of portal vein and arterial thromboses. Indwelling mesenteric venous catheterization and relevance to small bowel transplantation.

The aim of this study was to ascertain whether, in an animal model, continuous monitoring of mesenteric venous pressure (MVP) via an indwelling mesenteric venous catheter could assist in early detection of thrombosis of the portal vein (PVT) and superior mesenteric artery (SMAT). The role of portography via the catheter was also studied in confirming these complications. An animal model of PVT and SMAT was developed in pigs. At laparotomy, a 20-cm jejunal loop was isolated and a heparin-coated catheter was inserted into a mesenteric vein of the isolated jejunum and connected to a pressure transducer. Conditions of PVT were simulated by progressive occlusion of the portal vein (PV) using a silastic tourniquet and those of SMAT by superior mesenteric artery (SMA) clamping. MVPs (mm Hg) were found to significantly increase with all degrees of PV occlusion (P < 0.01, Student's t test) and to significantly decrease after SMA occlusion (P < 0.01). Portography clearly demonstrated all degrees of PV stenosis after PV occlusion and stasis of contrast medium during SMA occlusion. The authors feel that this method enables rapid diagnosis of PVT and SMAT and may be useful in the monitoring of the therapy for these complications after small bowel transplantation.

Randomized trial of zileuton in patients with moderate asthma: effect of reduced dosing frequency and amounts on pulmonary function and asthma symptoms. Zileuton Study Group.

This 6-month, randomized, multicenter study was designed to determine whether patients who had been treated with the leukotriene pathway inhibitor zileuton 600 mg four times daily (QID) for 2 months could be maintained at the same level of pulmonary function, symptom control, and beta-agonist use with less frequent dosing--first 600 or 800 mg three times daily (TID) and then twice daily (BID). A total of 278 patients with chronic asthma, ages 16 to 70, participated at 25 US centers. All had a 1-second forced expiratory volume (FEV1) of 35%-75%, reversible airway disease, and a nonsmoking history of 1 year. An 8-week open-label period (zileuton 600 mg QID) was followed by a 16-week double-blind period, in which patients who responded to the QID treatment were randomized to receive zileuton 600 or 800 mg TID for 8 weeks and then rerandomized to receive zileuton 600 or 800 mg BID for another 8 weeks. Primary outcomes were FEV1 and asthma symptom scores; secondary outcomes were peak expiratory flow rate, beta-agonist use, and asthma exacerbations requiring steroid rescue. Patients who showed improvements in lung function when treated with zileuton 600 mg QID demonstrated minimal decreases in FEV1 and comparable peak expiratory flow rates, symptom control, beta-agonist use, and systemic corticosteroid rescue when being treated with lower doses and/or less frequent doses of zileuton. Patients who demonstrate improved asthma control with zileuton 600 mg QID may be able to reduce their daily dosage and/or frequency while still maintaining the same level of symptom control.

Safety and clinical efficacy of zileuton in patients with chronic asthma.

Zileuton, a leukotriene pathway inhibitor used to treat asthma, improves lung function, relieves symptoms, and is well tolerated. The purpose of this 12-month, parallel-group, open-label study was to assess the efficacy of zileuton and evaluate liver function in patients treated with this drug (approximately 2% of patients treated with zileuton in controlled trials had reversible liver enzyme elevations). A total of 2,947 patients at 233 centers in the United States were randomly assigned in a 5:1 ratio to treatment with zileuton plus usual asthma care or usual asthma care alone. Efficacy variables included asthma exacerbations; need for alternative treatment, steroid rescue, emergency care, and hospitalizations; forced expiratory volume in 1 second (FEV1); and asthma symptom scores. The safety evaluation included measurement of alanine aminotransferase levels. Patients treated with zileuton had significantly fewer corticosteroid rescues (P < 0.001), required less emergency care (P < 0.05), had fewer hospitalizations, and had greater increases in FEV1 (P = 0.048). They also had significantly greater improvements in asthma symptoms. Increases in alanine aminotransferase levels to three times or more the upper limit of normal occurred in 4.6% of patients treated with zileuton and 1.1% of those receiving usual care (P < 0.001); most increases occurred during the first 2 to 3 months. Alanine aminotransferase levels decreased to less than two times the upper limit of normal or to baseline levels during zileuton treatment or after drug cessation. Jaundice or chronic liver disease did not develop in any patient. Adding zileuton to the therapeutic regimens of patients with asthma is likely to improve asthma control and lower utilization of healthcare resources.

Indwelling mesenteric venous catheterization for early detection of portal vein thrombosis: possible application to pediatric liver transplantation.

Portal vein thrombosis (PVT) is a well-recognized complication after liver transplantation, particularly in children. When it occurs early in the postoperative period, it has serious consequences, and rapid detection is essential. The purposes of this study were (1) to ascertain whether continuous monitoring of mesenteric venous pressure (MVP), via an indwelling mesenteric venous catheter, could assist in early detection of PVT and (2) to investigate the role of portography, via the catheter, in confirming this complication. An animal model of PVT was developed in pigs. At laparotomy, a heparin-coated catheter was inserted into a jejunal mesenteric vein, delivered percutaneously and connected to a pressure transducer. Conditions of PVT were simulated by progressive occlusion of the portal vein (PV) using a silastic tourniquet, and the degree of PV stenosis was assessed by Doppler ultrasound flow-velocity measurement. MVP was recorded 1 and 3 minutes after PV occlusion, and portography was performed via the indwelling catheter. There were significant increases in MVPs with all degrees of PV stenosis (P < .01, Student's t test). No significant changes in MVP were noted between 1 and 3 minutes postocclusion. Portography clearly demonstrated PV stenosis. There were no instances of PVT, despite repeated and prolonged occlusion of the PV. Progressive degrees of PV stenosis have been clearly detected by an indwelling mesenteric venous catheter in an animal model. This method may be useful for the diagnosis and treatment of PVT after pediatric liver transplantation.

Random effects in paired-comparison experiments using the Bradley-Terry model.

The Bradley-Terry model for paired-comparison experiments assumes that the parameters for treatment ratings are the same for each comparison. We generalize this model by envisioning a population of judges from which a sample is taken to perform the experiment. The preference parameters can then be treated as random variables, and this induces a correlation between outcomes involving the same judge. Such a model may be helpful in isolating variation due to judges, from true variation in the treatments, as well as in accounting for the nonindependence of judgments.

Functional aspects of ano-rectal vascularity.

The blood supply of the ano-rectum has been studied in cadaveric specimens by angiographic methods. The vascular anastomosis between the middle rectal and superior rectal vessels was found to be demonstrable on one side only. There appears to be a midline paucity of vessels in both the posterior and anterior rectal walls, and this may be important in the aetiology of anastomotic dehiscence in low anterior resection.

Laser-Doppler velocimetry and photoplethysmography in the diagnosis of abnormal venous reflux.

Laser-Doppler Velocimetry (LDV) is useful in measurement of relative tissue blood flow. We have found a change in both the variability of the LDV waveform and its absolute level when measured in the supine and dependent limb, in patients with venous reflux. These changes correlated with simultaneous photo-plethysmographic (PPG) assessment of venous reflux and were more pronounced in patients with leg ulcers. These changes were also reduced by compression bandaging.

Gallstone ileus complicating endoscopic sphincterotomy.

A case of gallstone ileus is described complicating an endoscopic sphincterotomy. This rare cause of small bowel obstruction should be considered following endoscopic treatment of very large bile-duct calculi.

Hypoxia and hypotension during endoscopy and colonoscopy.

Sixty-three patients undergoing oesophagogastroduodenoscopy (OGD) (n = 24) or proctosigmoidocolonoscopy (PSC) (n = 39) had continuous monitoring of arterial oxygen saturation (SaO2), pulse and mean blood pressure (BP). The degree of patient distress, duration, dose of sedative and details of the endoscope and operator were recorded. Marked hypotensive (greater than 40% fall in BP) and hypoxic (greater than 8% fall in SaO2) changes occurred in 13% and 17% of the overall group, respectively. There were no significant differences in fall in BP, SaO2 or pulse between the OGD and PSC groups. The dose of sedative was significantly related to the fall in SaO2 (P less than 0.001) but not to the fall in BP. The falls in both SaO2 and BP were related to the duration of the procedure (P less than 0.001, P = 0.03, respectively). There were no correlations between the degree of hypoxia or hypotension and the patient's age or previous medical history. Hypotension and hypoxia occur in both colonoscopy and OGD and are neither predictable nor usually recognizable clinically. Pulse oximetric and BP monitoring throughout gastrointestinal endoscopy are recommended for maximal safety.

A trial of zileuton versus mesalazine or placebo in the maintenance of remission of ulcerative colitis. The European Zileuton Study Group For Ulcerative Colitis.

BACKGROUND & AIMS: Leukotriene B4 is a major neutrophil chemoattractant detected during relapse of inflammatory bowel disease and represents a potentional therapeutic target. The aim of this study was to compare the efficacy of zileuton, an active 5-lipoxygenase inhibitor, with mesalazine and placebo in the maintenance of remission in ulcerative colitis. METHODS: A double-blind, parallel-group, multicenter, and multinational trial was conducted during a 6-month period in hospital-based patients with inflammatory bowel disease. Three hundred five evaluable patients with ulcerative colitis in remission at the start of the trial were randomized into groups to undergo oral treatment with zileuton (600 mg qid; n = 113), mesalazine (400 mg qid; n = 99), or placebo (n = 111). The primary efficacy outcome was maintenance of remission for 6 months. A multivariate analysis was used to investigate determinants of relapse. Safety was assessed by treatment discontinuation, adverse events, vital signs, and laboratory parameters. RESULTS: After 6 months, 54% of patients receiving zileuton remained in remission compared with 43% receiving placebo (P = 0.094) and 63% on mesalazine (P = 0.266). Relapse rates on mesalazine were significantly lower than those for placebo (P = 0.017). All treatments were well tolerated. CONCLUSIONS: Zileuton (600 mg qid) was not significantly better than placebo in the maintenance of remission of ulcerative colitis in this trial and may have limited potential in the treatment of this condition.