Dose ranging pharmacokinetic trial of high-dose alicaforsen (intercellular adhesion molecule-1 antisense oligodeoxynucleotide) (ISIS 2302) in active Crohn's disease.

BACKGROUND AND AIMS: To evaluate the safety, pharmacokinetics and clinical efficacy of the intercellular adhesion molecule-1 antisense phosphorothioate oligonucleotide alicaforsen (ISIS 2302) at 250-350 mg in Crohn's disease. METHODS: : Patients (> 50 kg) with active Crohn's disease (Crohn's disease activity index > or = 220) were assigned by gender, randomly, to two alicaforsen treatment groups: 300 or 350 mg, infused intravenously three times a week for 4 weeks. All patients weighing 36-50 kg received 250 mg of alicaforsen. Background aminosalicylates, antibiotics, immunosuppressives and corticosteroids were permitted, but tumour necrosis factor-alphainhibitors were prohibited. The primary end-point was clinical remission (Crohn's disease activity index < or = 150). RESULTS: Twenty-two patients were enrolled with a mean baseline Crohn's disease activity index of 304. Steroids were used by 27%, 5-aminosalicylic acid by 68% and immunosuppressives by 27%; 23% had previously received infliximab. Five subjects withdrew after one to three infusions for infusion-related symptoms. Nine patients (41%) experienced clinical remission. Fifty-three per cent of the evaluable subjects receiving more than three infusions experienced remission (18% at week 8; 29% at week 12). The overall response, using a minimum decrease of 70 in the Crohn's disease activity index, was 41-47% for the evaluable group, at weeks 8 and 12. The median duration of remission was 14 weeks. Plasma pharmacokinetic results showed overlapping levels (Cmax, AUC) for the three doses. The infusion-related reaction profile consisted of fever, chills, headache, nausea, emesis or arthralgias, typically occurring 2-4 h after completion of the first infusion. Reactions were less frequent in patients receiving background corticosteroids. The 2-4-h transient post-infusion partial thromboplastin time prolongation values, a class effect of phosphorothioate oligonucleotides, were 18, 21 and 23 s for 250, 300 and 350 mg, respectively. CONCLUSIONS: Alicaforsen (ISIS 2302), at fixed doses of 300 and 350 mg, achieved the desired drug exposure and may be an effective therapy for Crohn's disease. Infusion-related reactions were observed less frequently in patients on corticosteroids, and with decreasing frequency with continued treatment.

Randomized, controlled trial of recombinant human interleukin-11 in patients with active Crohn's disease.

BACKGROUND: Interleukin-11 is a mesenchymally derived cytokine with pleiotropic activities. A pilot study suggested therapeutic benefit of recombinant human interleukin-11 (rhIL-11) in patients with Crohn's disease. AIM: To determine the safety and preliminary estimate of efficacy of rhIL-11 in treating active Crohn's disease. METHODS: Patients with mild to moderately active Crohn's disease, defined as a Crohn's disease activity index (CDAI) > or = 220 and < or = 450, were enrolled in a multicentre trial. Stable doses of 5-aminosalicylates, antibiotics, 6-mercaptopurine or azathioprine were permitted with appropriate wash-in periods. Oral, intravenous or rectally administered corticosteroids were not allowed. Patients were randomized to 6 weeks of subcutaneous injection with rhIL-11 15 microg/kg or placebo weekly, or rhIL-11 7.5 microg/kg or placebo twice weekly. The primary end-point was per cent change in CDAI at week 6; the major secondary end-point was the proportion of patients in remission, defined as a 100 point decrease in CDAI and absolute CDAI < or = 150. RESULTS: Baseline characteristics were similar among the 148 evaluated patients (49 placebo, 49 rhIL-11 15 microg/kg once weekly, 50 rhIL-11 7.5 microg/kg twice weekly). Treatment was well-tolerated, with mild injection site reactions occurring more frequently among patients treated with rhIL-11. Headache, oedema, and increased platelet count occurred significantly more often in the rhIL-11 7.5 microg/kg twice weekly group, but not the 15 microg/kg once weekly group. There was a trend toward decreased mean per cent change in CDAI in the rhIL-11 15 micro/kg once weekly group vs. placebo (-31.5% vs. -18.5%, 95% confidence interval for the difference -27.9-1.6%). A significantly greater proportion of patients receiving rhIL-11 15 microg/kg once weekly achieved remission compared to placebo (36.7% vs. 16.3%, 95% confidence interval for the difference 3.4-37.4%; 16.4% for rhIL-11 7.5 microg/kg, N.S.). CONCLUSIONS: Weekly subcutaneous injection with rhIL-11 15 microg/kg is safe and effective in inducing remission in a subset of patients with active Crohn's disease.

The ChemTrak Hp Chek fingerstick whole blood serology test for the detection of Helicobacter pylori infection.

OBJECTIVE: To evaluate a new whole blood serology test (Hp Chek; ChemTrak) that detects IgG antibodies to Helicobacter pylori. METHODS: The study was conducted at 10 sites within the United States. Patients undergoing upper endoscopy for dyspepsia were recruited for enrollment. Those treated for H. pylori infection within a year of endoscopy and those who had regularly used proton pump inhibitors, bismuth compounds, or antibiotics within a month of endoscopy were not eligible. During endoscopy, specimens were obtained from the corpus and antrum for histological examination, which was performed by a single experienced pathologist. The Hp Chek was tested using whole blood and serum. Serum was also tested with a reference enzyme-linked immunosorbent assay (ELISA) at a centralized location. Test characteristics for the Hp Chek and ELISA were calculated using histology as the "gold standard." RESULTS: Two hundred eighty-seven patients (140 women and 147 men; mean age 53 +/- 6 yr) were enrolled. The Hp Chek was easy to perform and yielded results 9 min after inoculation of the test cassette with whole blood or serum. When the Hp Chek used with whole blood was compared with histology as the gold standard, the sensitivity was 88%, specificity 85%, positive predictive value 83%, negative predictive value 90%, and percent agreement 86%. There were no statistically significant differences among the results obtained with the Hp Chek using whole blood, the Hp Chek using serum, or reference ELISA. CONCLUSIONS: The Hp Chek whole blood serology test was easy to perform and rapid and yielded performance characteristics comparable to those of a reference ELISA or the Hp Chek used with serum.

Ranitidine for erosive oesophagitis: a double-blind, placebo-controlled study. Glaxo Erosive Esophagitis Study Group.

A multicentre, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of ranitidine 150 mg and 300 mg in 342 patients with erosive oesophagitis. Treatment was given four times daily, and continued for 12 weeks or until healing (that is, normal or only erythematous mucosa). Erosive oesophagitis healing rates, as determined by endoscopy, were significantly greater in ranitidine-treated patients by 4 weeks compared with those of placebo-treated patients. By 12 weeks, erosive oesophagitis healing rates were 83 and 81% for ranitidine-treated patients (150 and 300 mg, respectively) and 58% for placebo-treated patients (P less than or equal to 0.001, ranitidine vs. placebo). Symptomatic relief was achieved within 24 hours after starting either dosage of ranitidine. Heartburn frequency (P less than 0.001) and severity (P less than 0.001), as well as antacid consumed per week (P less than 0.001), were reduced in both ranitidine groups in comparison with placebo. Healing rates and symptom relief were similar in the two ranitidine groups. Both dosages of ranitidine were well tolerated. Ranitidine (150 mg) given four times daily appears to be as effective as 300 mg ranitidine given four times daily in patients with moderate to severe oesophageal erosions.

Graded esophageal balloon distention. A new provocative test for noncardiac chest pain.

The evaluation of suspected esophageal chest pain is frustrating because of difficulty in clearly implicating the esophagus. Balloon distention was considered as a new provocative test in the esophagus because it has been shown to safely produce pain in other hollow gastrointestinal organs. Studies were performed in 50 chest pain patients (mean age 50 years) with negative coronary arteriograms and 30 healthy volunteers (mean age 41 years). A polyvinyl balloon (length 30 mm; maximum diameter after 10 cc distention 25 mm) was positioned 10 cm above the lower esophageal sphincter and inflated with 1-cc increments of air to a total volume of 10 cc. Using a placebo-controlled design, pain response was recorded along with associated balloon volumes. Pain occurred in 28/50 (56%) patients and 6/30 (20%) volunteers (P less than 0.005). Symptoms were unassociated with ECG changes, and resolved immediately with decompression of the balloon. Most patients (24/28) experienced their typical chest pain at less than or equal to 8 cc distention, while all volunteers with pain noted it at greater than or equal to 9 cc distention. For this reason, 8 cc was considered a diagnostic cutoff. Chest pain patients were also studied with two other commonly used provocative tests: intraesophageal acid perfusion and intravenous edrophonium (80 micrograms/kg). These tests reproduced pain in only 12 (24%) patients. Positive balloon studies occurred in 11 of these patients and identified an additional 13 patients, thus increasing the diagnostic yield from 24% to 48%. Only one of 22 (4%) balloon-negative patients had a positive acid-perfusion or edrophonium test.

Abnormal sensory perception in patients with esophageal chest pain.

Many cases of recurrent noncardiac chest pain are considered to be of esophageal origin. The mechanism of this pain is poorly understood and only rarely appears related to abnormal esophageal contractions observed during manometry. We studied the response to intraesophageal balloon distention in 30 patients with noncardiac chest pain (mean age 52 yr) and 30 controls (mean age 41 yr). A polyvinyl balloon (length 30 mm; maximum diameter after 10-ml distention, 25 mm) was positioned 10 cm above the lower esophageal sphincter and inflated with progressively larger volumes of air (each increase = 1 ml). Chest pain was correlated with balloon volumes and pressures, esophageal contractions 5 cm above the balloon, and electrocardiogram changes. Results were as follows: 18 of 30 (60%) patients and 6 of 30 (20%) controls (p less than 0.005) experienced chest pain. Electrocardiogram changes of ischemia were not seen. Neither balloon pressures nor esophageal contractions above the balloon differed significantly during pain in the controls or patients. As assessed by pressure-volume curves, esophageal tone was also similar in all subjects regardless of pain production. Patients were more sensitive to smaller volumes of balloon distention; 15 of 18 patients had chest pain at less than or equal to 8 ml volume while controls only noted chest pain at greater than or equal to 9 ml volume. We therefore arrived at the following conclusions: esophageal balloon distention may provide a nonpharmacologic provocative test for esophageal chest pain; and the mechanism of chest pain in these patients may be related to lower pain threshold to balloon distention, which is independent of esophageal contractions.

Respiratory complications of gastroesophageal reflux.

Gastroesophageal reflux (GER) and its many manifestations are extremely common problems. The pulmonary manifestations are the least well understood and are often unrecognized. We reviewed the available literature on the subject of respiratory tract symptoms secondary to chronic GER in an attempt to promote wider recognition of this relationship. We hope that this review will call attention to the potential importance of GER in those patients in whom such a mechanism might be responsible for pulmonary symptoms.

Complete distal renal tubular acidosis in systemic lupus: clinical and laboratory findings.

We report two patients with systemic lupus erythematosus (SLE) who were found to have complete (acidotic) distal renal tubular acidosis (DRTA). One patient had nephrocalcinosis and renal magnesium wasting with tetany; the other patient had nephrolithiasis and nephrotic syndrome secondary to membranous glomerulopathy. Both patients had decreased urinary citrate excretion but neither had hypercalciuria. We discuss the association of DRTA with immunologic disorders and the possible role of hypocitraturia in promoting renal calcification in these patients. We suggest that patients with renal calcification be evaluated for DRTA, and that patients found to have DRTA be further evaluated for signs, symptoms, and laboratory evidence of immunologic disorders.

Venous thrombosis as a cause of superior vena cava syndrome. Rapid response to streptokinase.

Venous thrombosis, resulting in superior vena cava syndrome, developed in a patient with two permanent transvenous pacemaker wires. Therapy with streptokinase resulted in prompt relief of the obstruction, with no complications. In properly selected patients, streptokinase may be the treatment of choice for this potentially life-threatening problem.