Prospective comparison of radial and linear endoscopic ultrasound for diagnosis of chronic pancreatitis.

BACKGROUND AND STUDY AIMS: Linear endoscopic ultrasonography (EUS) is currently favored by many endosonographers for the evaluation of pancreatic pathology. However, radial EUS was used in early studies validating EUS for chronic pancreatitis. Radial and linear EUS have never been compared for the diagnosis of chronic pancreatitis. The aim of this study was to compare radial and linear EUS for the diagnosis of chronic pancreatitis using the secretin-stimulated endoscopic pancreatic function test (ePFT) as the reference standard. PATIENTS AND METHODS: One hundred consecutive patients evaluated for pain of possible pancreatic origin underwent combined radial EUS, linear EUS, and secretin ePFT during a single endoscopic session. EUS images were acquired on videotape and blindly scored by three reviewers. The main outcome measure was diagnostic accuracy. RESULTS: The accuracy of radial EUS and linear EUS (cutpoint > or = 4 criteria) was 84 % and 74 %, respectively. The statistical test for noninferiority was significant ( P < 0.001) suggesting that the accuracy of radial EUS is as good as or superior to linear EUS. The ratio of accuracy (pi (radial)/pi (linear)) was 1.14 (95 % confidence interval [CI] 0.99 to 1.28). No statistically significant differences were found between radial and linear EUS in terms of sensitivity, specificity, or overall discriminative ability (area under receiver operating characteristic curve 0.84 vs. 0.76, P = 0.10). Interobserver variability was similar for radial (Fleiss' kappa = 0.61, 95 %CI 0.43 to 0.79) and linear EUS (kappa = 0.50, 95 %CI 0.28 to 0.72). CONCLUSIONS: The accuracy of radial EUS is as good as linear EUS for the diagnosis of chronic pancreatitis.

A randomized controlled crossover study comparing synthetic porcine and human secretins with biologically derived porcine secretin to diagnose Zollinger-Ellison Syndrome.

BACKGROUND: Although biologically-derived porcine secretin is approved for the diagnosis of Zollinger-Ellison Syndrome, it is no longer available in the United States. Pure human and porcine secretins have now been synthesized and new drug applications have been filed with the Federal Drug Administration (FDA). METHODS: In the current study we compared secretin testing results in six confirmed Zollinger-Ellison Syndrome patients using the biologically-derived product and both synthetic products (human and porcine) in a three-way, randomized, single-blind Latin-squares crossover study. RESULTS: Using the FDA-approved criterion for positive secretin testing (i.e. a serum gastrin concentration increase of > 110 pg/mL), there was complete agreement between all three agents for all patients. With the more stringent NIH criterion (i.e. a serum gastrin concentration increase of > 200 pg/mL), positive results persisted in five out of six, six out of six and four out of six patients using biologically-derived secretin, synthetic porcine secretin, and synthetic human secretin, respectively (six out of six, six out of six and four out of six if a positive test was defined as a 50% increase in serum gastrin concentration). The time to peak serum gastrin concentration after secretin injection occurred within 15 min in all studies (in 94% by 10 min and in 77% by 5 min). Three-way comparisons of serum gastrin concentrations showed a single statistically significant difference (the change from baseline at 15 min between synthetic human and synthetic porcine secretin, P=0.0274). Statistically significant changes from baseline occurred at 1, 2 and 5 min for biologically-derived porcine secretin and at 2 and 5 min for both synthetic porcine and synthetic human secretin, in keeping with the expected time curve for positive tests. All three agents were well-tolerated. CONCLUSIONS: These data suggest that either synthetic secretin product, when released onto the United States market, can be used to confirm Zollinger-Ellison Syndrome.

A double-blind, randomized, dose response study testing the pharmacological efficacy of synthetic porcine secretin.

BACKGROUND: Biologically derived porcine secretin has been used as a diagnostic agent in clinical gastrointestinal practice for many years. Pure synthetic porcine secretin is now available for investigational clinical use. AIM: To compare the pharmacology of synthetic porcine secretin and biologically derived porcine secretin in healthy volunteers. METHODS: Secretin stimulation tests were performed in 12 volunteer subjects in a double-blind, randomized, Latin square crossover design study comparing three doses of synthetic porcine secretin (0.05, 0.2, and 0.4 microgram/kg) with a standard dose of biologically derived porcine secretin (1 CU/kg). Duodenal aspirates were analysed for total volume and for bicarbonate concentration. Total bicarbonate output was calculated. RESULTS: Twelve subjects completed four dosing regimens. A multiple comparison test was used to compare dosing regimens. The 0.2 and 0.4 microgram/kg doses of synthetic porcine secretin were not different from the 1 CU/kg dose of biologically derived porcine secretin for volume, bicarbonate concentration and total output from 0 to 60 min. Only one patient had an adverse event, which was mild, transient flushing after the 0.2 and 0.4 microgram/kg doses of synthetic porcine secretin and after the 1 CU/kg dose of biologically derived porcine secretin. CONCLUSIONS: Synthetic porcine secretin has identical pharmacologic effects to biologically derived porcine secretin in normal subjects. Both drugs were safe and well-tolerated. This study validates synthetic porcine secretin as a substitute for biologically derived porcine secretin.

Multiple-dose pharmacokinetics and bioequivalence of L-carnitine 330-mg tablet versus 1-g chewable tablet versus enteral solution in healthy adult male volunteers.

The bioavailability and bioequivalence of three oral dosage forms of L-carnitine were studied in 15 healthy volunteers. Recently, an intravenous (iv) dosage form of L-carnitine has been approved to be marketed in the United States. The purpose of this study was to determine after multiple dose administration of the three oral dosage forms (marketed solution, chewable tablet, and marketed tablet) the pharmacokinetics and absolute bioavailability of each of the dosage forms at steady state and compare them with those following administration of a single iv dose. The relative bioavailability and bioequivalence of the chewable and marketed tablet relative to the marketed solution at steady-state replicate design conditions were also studied. Bioavailability based on data that was not corrected for the baseline (uncorrected data) was compared with bioavailability determined from data corrected for baseline. Steady-state conditions, based on free or total L-carnitine plasma concentrations, were achieved by Day 3, and products were bioequivalent based on the analysis of variance and comparisons by the two one-sided t test. Pharmacokinetic evaluations were found to be powerful tools for bioequivalence determinations; the power to detect 20% differences in AUC, Cmax tmax, and Cmin0 was > 80%. Mean absolute bioavailabilities (based on free or total L-carnitine plasma concentrations) on Day 4 (fraction of the dose absorbed) of Carnitor (levocarnitine) tablet, Carnitor (levocarnitine) oral solution, and levocarnitine chewable tablet relative to the first iv dose were approximately 18%. Similarly, absolute bioavailability compared with the last iv dose was approximately 18% for all three oral formulations.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of L-carnitine pharmacokinetics with and without baseline correction following administration of single 20-mg/kg intravenous dose.

L-Carnitine, a naturally occurring compound, is indicated in the treatment of primary systemic carnitine deficiency. To assess the differences in pharmacokinetic parameters calculated from data corrected for baseline versus those from "uncorrected" data, compartmental fitting was carried out for baseline corrected and original plasma concentration data obtained following a single intravenous (iv) dose of 20 mg/kg. For free L-carnitine, mean volumes of distribution at steady state (Vdss) of the central compartment were similar using either approach (9.86 versus 11.2 L). However, Vdss (54.0 versus 29.0 L) and apparent elimination half-life (17.4 versus 5.0 h) were significantly different between the two data bases. Similar observations were noted for pharmacokinetic parameters based on plasma concentrations of total L-carnitine. Although the pharmacokinetic parameters obtained after baseline correction may represent the kinetics of a bolus dose, the pharmacokinetic parameters from uncorrected plasma data probably represent the clinical settings for patients. Baseline correction also probably has its greatest value in attempting to determine and/or define the biological half-life and Vdss for the "exogenously" administered dose and uncorrected data best describes the pharmacokinetics of composite endogenous and exogenous L-carnitine levels.

Phenotypic differences in dextromethorphan metabolism.

Polymorphic differences in dextromethorphan metabolism were observed in three studies conducted in a total of 44 subjects (of Dutch origin) administered 60 mg dextromethorphan hydrobromide as an OROS tablet. Mean plasma dextromethorphan (DM) concentrations after a single dose and at steady state were 4-75 times higher in the poor metabolizers (PM) relative to the extensive metabolizers (EM). Following a single dose, the mean areas under the plasma concentration-time curve (AUC, 0-24 hr) of DM, total dextrorphan (DR), and total 3-hydroxymorphinan (HM) were 6.9-fold higher, 17.4-fold lower, and 11-fold lower, respectively, for the PM than for the EM. Correspondingly, steady-state AUC values were 52.8 times higher, 6.7 times lower, and 3.3 times lower for DM, total DR, and total HM, respectively, for the PM relative to the EM. Drug/metabolite ratios (DMR) for amounts excreted in the urine of DR and HM indicated polymorphism in O-demethylation of DM since DMR for PM was 352 and 338 times higher than that for EM for DR and HM, respectively. However, polymorphism in N-demethylation was not observed. Ratios of conjugated/free dextrorphan and 3-hydroxymorphinan excreted in the urine suggest also a lack of conjugative capacity in the PM, relative to the EM. The overall incidence of PM was 9.1% in this population.

Evaluation of basket and paddle dissolution methods using different performance standards.

Dissolution studies using both basket and paddle methods were carried out to evaluate two prednisone standards. Results of the experiments showed that the USP prednisone calibrator is sensitive to perturbations by the basket method but not to perturbations by the paddle method. However, the National Center for Drug Analysis (NCDA) prednisone performance standard is sensitive to perturbations by the paddle method but not to perturbations by the basket method. These results suggest that no single standard can predict the suitability of the dissolution equipment by the basket and paddle methods.