Jean Spénard

Bismuth-Based Quadruple Therapy Using a Single Capsule of Bismuth Biskalcitrate, Metronidazole, and Tetracycline Given With Omeprazole Versus Omeprazole, Amoxicillin, and Clarithromycin for Eradication of Helicobacter pylori in Duodenal Ulcer Patients: A Prospective, Randomized, Multicenter, North American Trial

OBJECTIVES:This multicenter, randomized, active-controlled trial assessed efficacy of bismuth-based quadruple therapy with omeprazole, bismuth biskalcitrate, metronidazole, and tetracycline (OBMT) using a single-triple capsule of BMT compared with triple therapy with omeprazole, amoxicillin, and clarithromycin (OAC) in treatment of patients with Helicobacter pylori infection and duodenal ulcers.METHODS:Patients with active duodenal ulcer or diagnosed within the past 5 yr and with infection documented by 13C-urea breath test plus histology or culture were randomly assigned to 10-day course of OBMT using a single-triple capsule containing bismuth biskalcitrate 140 mg, metronidazole 125 mg, and tetracycline 125 mg given as three capsules q.i.d. with omeprazole 20 mg b.i.d., or a 10-day course of OAC, omeprazole 20 mg plus amoxicillin 1 g plus clarithromycin 500 mg, all b.i.d. Eradication was confirmed by two negative urea breath tests at >1 month and >2 months after therapy.RESULTS:One hundred thirty-eight patients received OBMT and 137 OAC. Modified intent-to-treat eradication rates were 87.7% for OBMT and 83.2% for OAC (95% CI = −3.9%–12.8%; p = 0.29). OBMT eradicated 91.7% metronidazole-sensitive and 80.4% metronidazole-resistant strains (p = 0.06). OAC eradicated 92.1% clarithromycin sensitive and 21.4% clarithromycin-resistant strains (p < 0.001). Adverse events occurred in 58.5% of OBMT patients and 59.0% of OAC patients.CONCLUSIONS:OBMT regimen using the single-triple capsule is as efficacious and well-tolerated as the widely used OAC regimen for H. pylori eradication. This OBMT therapy largely overcomes H. pylori metronidazole resistance, present in 40% of patients in this study.

A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis

BACKGROUND & AIMS Nonalcoholic steatohepatitis (NASH) is a prevalent liver disease associated with increased morbidity and mortality. Ursodeoxycholic acid (UDCA) may have antioxidant, anti-inflammatory, and antifibrotic properties and may reduce liver injury in NASH. To date, no studies have assessed the efficacy and safety of high-dose UDCA (HD-UDCA) in patients with NASH. METHODS We conducted a 12-month, randomized, double-blind, placebo-controlled multicenter trial to evaluate the efficacy and safety of HD-UDCA (28-35 mg/kg per day) in 126 patients with biopsy-proven NASH and elevated alanine aminotransferase (ALT) levels. The primary study end point was reduction in ALT levels from baseline in patients treated with HD-UDCA compared with placebo. Secondary study end points were the proportion of patients with ALT normalization, relative reduction in the scores of serum markers of fibrosis and hepatic inflammation, and safety and tolerability. RESULTS HD-UDCA significantly reduced mean ALT levels -28.3% from baseline after 12 months compared with -1.6% with placebo (p<0.001). At the end of the trial, ALT levels normalized (≤35 IU/L) in 24.5% of patients treated with HD-UDCA and in 4.8% of patients who received placebo (p=0.003). Both results were not accounted for by changes in weight during the trial. HD-UDCA significantly reduced the FibroTest® serum fibrosis marker (p<0.001) compared with placebo. HD-UDCA also significantly improved markers of glycemic control and insulin resistance. There were no safety issues in this population. CONCLUSIONS Treatment with HD-UDCA was safe, improved aminotransferase levels, serum fibrosis markers, and selected metabolic parameters. Studies with histologic end points are warranted.

NCX-1000, a nitric oxide-releasing derivative of UDCA, does not decrease portal pressure in patients with cirrhosis: results of a randomized, double-blind, dose-escalating study

OBJECTIVES:NCX-1000 (2(acetyloxy) benzoic acid-3(nitrooxymethyl)phenyl ester) is an nitric oxide (NO)-releasing derivative of ursodeoxycholic acid (UDCA), which showed selective vasodilatory effect on intrahepatic circulation in animal models of cirrhosis. This study was aimed at testing the efficacy and tolerability of this compound in patients with cirrhosis and portal hypertension.METHODS:This was a single-center, phase-2a, randomized (4:1), double-blind, parallel-group, dose-escalating study. Patients received progressive oral doses of NCX-1000 or placebo up to 2 g t.i.d. or maximum tolerated doses for 16 days. Efficacy on fasting and postprandial hepatic venous pressure gradient (HVPG) at baseline and after treatment was assessed. Hepatic blood flow (HBF) and arterial blood pressure were also measured.RESULTS:Eleven patients (nine NCX-1000 and two placebo) were enrolled and completed the trial. After NCX-1000 treatment, HVPG did not change (16.7±3.8 vs. 17.1±3.8 mm Hg; P=0.596), and HBF decreased significantly (904±310 vs. 1,129±506 ml/min; P=0.043). The postprandial increase in portal pressure and HBF was not modified by NCX-1000. There was no significant effect on diastolic blood pressure, but systolic blood pressure was reduced by the treatment in a dose-dependent manner (121±11 mm Hg after NCX-1000 vs. 136±7 mm Hg at baseline; P=0.003). Seven non-serious adverse events were experienced by four patients (one on placebo).CONCLUSIONS:In patients with cirrhosis and portal hypertension, NCX-1000 administration was safe, but it was not able to reduce portal pressure. A significant reduction of systolic blood pressure and HBF was observed in the treatment arm, suggesting that the drug had systemic effects and lacked selective release of NO at the intrahepatic circulation.

Massive Diltiazem Overdosage: Clinical and Pharmacokinetic Observations:

was continued for a further three months with good clinical response. Blistering decreased, the rate of cicatrization increased, and there was a striking reduction in the extent of granulomatous tissue on the back (Figure 2). The side effects of treatment were drowsiness and an increase in alkaline phosphatase when plasma levels of phenytoin exceeded 25 ILg/ml; below 20 ILg/ml these side effects disappeared. After eight months, therapy was withdrawn with the informed consent of the patient. The clinical pharmacologist then began a doubleblind placebo treatment that was stopped 44 days later because of a deterioration in the patients condition. With the renewal of phenytoin treatment it took two months to regain a stable steady state. Phenytoin appears to exert a favorable influence on the course of RDEB, as previously reported in the literature; moreover, this drug can dramatically improve even the granulomatous lesions of the rare vegetans variant of this disease.

Efficacy and safety of mesalamine 1 g HS versus 500 mg BID suppositories in mild to moderate ulcerative proctitis: a multicenter randomized study.

Background: Ulcerative proctitis (UP) usually presents as fresh rectal bleeding. Successful treatment using topical mesalamine 5‐aminosalicyclic acid (5‐ASA) 500 mg BID suppository led to developing a once‐a‐day formulation that could contribute to better acceptability and ease of use by patients. The objective of this randomized trial, conducted in 18 centers, was to compare efficacy of 2 modes of treatment with 5‐ASA suppositories. Methods: Ninety‐nine patients with mild or moderate UP limited to 15 cm of the anal margin, evidenced by a disease activity index (DAI) between 4 and 11, were randomized to 5‐ASA 500 mg suppository (Canasa; Axcan Pharma) BID or 1 g at bedtime (HS) for 6 weeks. The study used a noninferiority hypothesis based on the mean difference in DAI values after 6 weeks of treatment on an intent‐to‐treat basis using analysis of covariance. DAI was derived from a composite of the measures of stool frequency, rectal bleeding, mucosal visualization at endoscopy, and general well being. Results: There was no difference between groups at baseline for demographic and clinical parameters. Mean DAIs fell from 6.6 ± 1.5 (SD) to 1.6 ± 2.3 in the 500 mg BID group (n = 48) and from 6.1 ± 1.5 to 1.3 ± 2.2 in the 1 g HS group (n = 39). There was no significant difference (P = 0.74) in mean DAI at week 6 between the 2 groups. Both groups showed a significant reduction (P < 0.0001) in DAI over the course of the 6 weeks. Both formulations showed effectiveness in reducing each individual component of the DAI. There was no significant difference between treatments in adverse events, and both groups had an overall drug compliance of greater than 95%. Conclusion: This study showed that 1 g HS and 500 mg BID mesalamine suppository treatments of UP patients were equivalent in all facets of efficacy, safety, and compliance in a 6‐week trial.

Efficacy and safety of mesalamine suppositories for treatment of ulcerative proctitis in children and adolescents

Background: Treatment of ulcerative proctitis has not been well studied in pediatric populations. We conducted an open‐label trial to evaluate the clinical efficacy of a mesalamine suppository (500 mg) to treat pediatric patients with mild to moderate ulcerative proctitis. Methods: Pediatric patients (5–17 years of age) with ulcerative proctitis were enrolled for baseline evaluations, including a flexible sigmoidoscopic (or colonoscopic) assessment with biopsies performed at study entry. Eligible patients were started on mesalamine suppositories (500 mg) at bedtime. Two follow‐up visits were scheduled after 3 and 6 weeks of treatment. The dose could be increased to 500 mg twice daily at the week 3 follow‐up visit if deemed appropriate by the investigator based on the Disease Activity Index (DAI) assessment. The primary outcome measure was a DAI derived from a composite score of stool frequency, urgency of defecation, rectal bleeding, and general well‐being. Results: Forty‐nine patients were included in the intent‐to‐treat analysis. The mean DAI value decreased from 5.5 at baseline to 1.6 and 1.5 at weeks 3 and 6, respectively (P < 0.0001). Only 4 patients had their dose increased to 500 mg twice daily at week 3. Forty‐one patients experienced at least one adverse event, most of which were deemed mild and unrelated to study therapy. The most common treatment‐emergent adverse events were gastrointestinal (n = 30, 61.2%). Conclusions: This study showed that a daily bedtime dose of a 500 mg mesalamine suppository is safe and efficacious in children with ulcerative proctitis. Inflamm Bowel Dis 2010

Pharmacokinetics and safety of single intravenous and oral doses of dolasetron mesylate in healthy women.

Twenty-four healthy women received 2.4 mg kg-1 dolasetron mesylate (1.8 mg kg-1 dolasetron base) by a 10 min intravenous administration and by oral administration. Pharmacokinetics of dolasetron and of its active reduced metabolite MDL 74156 were monitored for 48 h in plasma. Urine was collected from 0 to 48 h, blood pressure and heart rate were measured at 0, 0.08, 1, 2, 12, 24, and 36 h, and ECGs were measured at 0, 0.08 (intravenous only), 1, 2, and 36 h after dosing. Dolasetron was widely distributed and rapidly reduced (mean t1/2 = 0.23 h) to MDL 74156 (mean t1/2 = 8.05 and 9.12 h after intravenous and oral administration respectively). MDL 74156 was extensively distributed; between 27 (oral route) and 33% (intravenous route) was eliminated unchanged in urine. Safety assessment showed mild to moderate headache, dizziness, and hot flushes after the intravenous administration and headache, abdominal cramps or pain, and constipation after oral administration. Small and clinically non-significant changes in PR, QRS, and QTc intervals were observed. We conclude that there is no obvious difference in dolasetron pharmacokinetics between healthy women and men and that dolasetron can be used as safely in women as in men.

Rectal tissue, plasma and urine concentrations of mesalazine after single and multiple administrations of 500 mg suppositories to healthy volunteers and ulcerative proctitis patients

Objective : Patients with ulcerative proctitis may have rectal mucosal properties different from healthy volunteers. This project compared the pharmacokinetics of rectally administered mesalazine in these two populations.

Pharmacokinetics of Single Intravenous and Oral Doses of Dolasetron Mesylate in Healthy Elderly Volunteers

Dolasetron mesylate (MDL 73,147EF, Anzemet; Hoechst Marion Roussel, Laval, Canada) is a 5‐HT3 receptor antagonist undergoing clinical evaluation for use as an antiemetic agent. The pharmacokinetics of dolasetron and its reduced metabolite (MDL 74,156) were studied after administration of single intravenous and oral doses of dolasetron mesylate 2.4 mg/kg in 18 healthy elderly subjects. Expressed as the dolasetron base, this dose was 1.8 mg/kg. Dolasetron was rapidly metabolized to the reduced metabolite, which appeared in plasma within 10 minutes after intravenous or oral administration. The mean half‐life (t1/2) of dolasetron was 0.24 hours after intravenous administration and 0.50 hours after oral administration. The pharmacokinetic parameters of the reduced metabolite were similar after intravenous and oral administration. The apparent absolute bioavailability of the reduced metabolite was 89%, and it had an elimination t1/2 of approximately 7 hours and an apparent volume of distribution (Vdβ) of 4.69 L/kg. Dolasetron was not detected in urine. Metabolites were excreted in urine almost completely within 24 hours of administration. The primary metabolite detected in urine was the [+]‐enantiomer of the reduced metabolite, which accounted for 25.35% (± 7.79%) and 18.88% (± 7.65%) of the intravenous and oral doses, respectively. Hydroxylated metabolites accounted for 5% or less of the total dose via either route. The pharmacokinetics of the reduced metabolite after single intravenous or oral doses in elderly volunteers were consistent with pharmacokinetics observed in both young healthy men and cancer patients receiving high‐dose cisplatin chemotherapy. Dosage adjustments of dolasetron mesylate on the basis of age do not appear to be necessary.

THE INFLUENCE OF TIME OF ADMINISTRATION ON THE PHARMACOKINETICS OF A ONCE-A-DAY DILTIAZEM FORMULATION: MORNING AGAINST BEDTIME

Twenty-three young, healthy, male volunteers received, in a randomized crossover design, 240 mg of a once-a-day diltiazem formulation at 08:00 (AM) or 22:00 (HS) for 6 days. A 7 day washout period was observed between the two modes of administration. Diltiazem plasma concentrations were monitored every hour for 24 h and at 30, 36, and 48 h after the last dose. Differences were found between AM and HS dosing for Cmin (mean (SD) = 47 center dot 2 (25 center dot 8) against 39 center dot 6 (21 center dot 1) ng mL-1, p = 0 center dot 038), AUC0-24 (2008 (814) against 1754 (714) ng h mL-1, p = 0 center dot 024), and AUC0-48 (2662 (1244) against 2395 (238) ng h mL-1, p = 0 center dot 034). Overall the two modes of administration did not produce bioequivalent pharmacokinetic profiles. Also HS dosing gave significantly higher plasma concentrations of diltiazem in the early morning hours when the incidence of cardiovascular events is higher. If one assumes a strong correlation between plasma concentrations and myocardial protection then HS dosing should be recommended for QD formulation of diltiazem. Clinical studies should be performed to confirm this theoretical pharmacokinetic advantage.