Upper gastrointestinal safety evaluation of parecoxib sodium, a new parenteral cyclooxygenase-2-specific inhibitor, compared with ketorolac, naproxen, and placebo.

BACKGROUND: Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of ulcers and upper gastrointestinal (GI) ulcer complications, which has been attributed to the inhibition of cyclooxygenase-1. These risks are usually increased in elderly populations. Parecoxib sodium is an injectable prodrug of the cyclooxygenase-2-specific inhibitor valdecoxib that has exhibited analgesic activity in previous trials. OBJECTIVE: The purpose of this study was to compare the GI safety and tolerability profile of parecoxib sodium with that of ketorolac, naproxen, and placebo in a 7-day endoscopic trial in elderly subjects. METHODS: This was a randomized, double-blind, double-dummy, placebo-controlled, parallel-group study. After a normal baseline endoscopy, healthy elderly subjects aged 66 to 75 years were randomized to receive i.v. parecoxib sodium (10 mg BID), oral naproxen (500 mg BID), or placebo for 7 days, or placebo for 2 days followed by i.v. ketorolac (15 mg QID) for 5 days. Endoscopy was performed again after 7 days. RESULTS: Among the first 17 subjects enrolled, ulcers were observed in all treatment groups except the parecoxib sodium group (ketorolac, 4/4 subjects; naproxen, 2/4 subjects; and placebo, 2/5 subjects). Four subjects in the ketorolac group and 1 subject in the naproxen group had multiple gastric ulcers or combined gastric and duodenal ulcers. Because of the unexpectedly high incidence of gastroduodenal ulcers observed, the study was terminated early and the randomization blind broken. CONCLUSION: These findings suggest that elderly patients may be at risk for GI ulceration even after short-term use of the conventional NSAIDs ketorolac and naproxen.

Lack of effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of amlodipine.

AIMS: To determine whether repeated once daily administration of grapefruit juice altered the pharmacokinetics or pharmacodynamics of the calcium antagonist amlodipine. METHOD: S The effects of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral and intravenous amlodipine were assessed in 20 healthy men in a placebo-controlled, open, randomized, four-way crossover study using single doses of amlodipine 10 mg. For 9 days beginning with the day of administration of amlodipine, grapefruit juice (or water control) was given once daily, and blood samples, blood pressure and heart rate measures were obtained. Plasma concentrations of amlodipine and its enantiomers were determined in separate assays by GC-ECD. RESULTS: Oral amlodipine had high systemic availability (grapefruit juice: 88%; water: 81%). Pharmacokinetic parameters of racemic amlodipine (AUC, Cmax, tmax, and kel) were not markedly changed with grapefruit juice coadministration. Total plasma clearance and volume of distribution, calculated after intravenous amlodipine, were essentially unchanged by grapefruit juice (CL 6.65 ml min-1 kg-1, juice vs 6.93 ml min-1 kg-1, water; Vdss 22.7 l kg-1, juice vs 21.0 l kg-1, water). Grapefruit juice coadministration did not greatly alter the stereoselectivity in amlodipine oral or intravenous kinetics. The sum of S(-) and R(+) enantiomer concentrations correlated well with total racemic amlodipine concentration (r2 = 0. 957; P = 0.0001). Coadministration of grapefruit juice with either route of amlodipine administration did not significantly alter blood pressure changes vs control. CONCLUSIONS: Grapefruit juice has no appreciable effect on amlodipine pharmacodynamics or pharmacokinetics, including its stereoselective kinetics. Bioavailability enhancement by grapefruit juice, noted with other dihydropyridine calcium antagonists, does not occur with amlodipine. Once daily grapefruit juice administration with usual oral doses of amlodipine is unlikely to alter the profile of response in clinical practice.

Steady-state pharmacokinetics and electrocardiographic pharmacodynamics of clarithromycin and loratadine after individual or concomitant administration.

To evaluate the potential for an interaction between clarithromycin and loratadine, healthy male volunteers (n = 24) received each of the following regimens according to a randomized crossover design: 500 mg of clarithromycin orally every 12 h (q12h) for 10 days, 10 mg of loratadine orally q24h for 10 days, and the combination of clarithromycin and loratadine. A washout interval of 14 days separated regimens. The addition of loratadine did not statistically significantly affect the steady-state pharmacokinetics of clarithromycin or its active metabolite, 14(R)-hydroxy-clarithromycin. However, the addition of clarithromycin statistically significantly altered the steady-state maximum observed plasma concentration and the area under the plasma concentration-time curve over a dosing interval for loratadine (+36 and +76%, respectively) and for descarboethoxyloratadine (DCL), the active metabolite of loratadine (+69 and +49%, respectively). Clarithromycin probably inhibits the oxidative metabolism of loratadine and DCL by the cytochrome P-450 3A subfamily. Electrocardiograms (n = 12) were obtained over 24-h periods at baseline and steady state (day 10). The mean maximum QTc interval and area under the QTc interval-time curve on day 10 were modestly increased (<3%) from baseline for all three regimens, but no QTc interval exceeded 439 ms for any subject. Elevated steady-state concentrations of loratadine and DCL do not appear to be associated with adverse cardiovascular effects related to prolongation of the QTc interval. Loratadine and clarithromycin were well tolerated, alone and in combination.

Alpha 2-agonist versus alpha 1-antagonist in mild-to-moderate hypertension: comparison of transdermal clonidine and terazosin monotherapies.

A double-blind, double-dummy, parallel-group trial that used a predominantly Hispanic patient population with mild-to-moderate hypertension was designed to compare the efficacy, safety, and acceptability of monotherapy with either transdermal clonidine applied once a week or terazosin tablets taken once a day. Of 44 patients admitted, 20 of 22 in the transdermal clonidine group and 15 of 21 in the terazosin group (one patient was lost to follow-up) met the response criteria. These criteria included the completion of 1 full week of therapy with the smallest dose that resulted in a seated diastolic blood pressure of <90 mm Hg and the subsequent entrance into an 8-week maintenance therapy phase. At the end of the 8-week maintenance phase the mean seated diastolic blood pressure remained <90 mm Hg in the clonidine cohort but not in the terazosin cohort, yet the difference was not statistically significant. There was a significantly better response to clonidine when all patients who received treatment were considered. No adverse first-dose effects were experienced with terazosin. One patient who received transdermal clonidine developed contact dermatitis and withdrew from the study prematurely. The most common side effects associated with clonidine were dry mouth and fatigue while those associated with terazosin were headache and fatigue. Compliance was excellent in both groups. Seventy-nine percent of patients found transdermal clonidine preferable to the oral regimen.

Treatment of red cell aplasia with antithymocyte globulin: repeated inductions of complete remissions in two patients.

Two patients with red cell aplasia unresponsive to prednisone and cyclophosphamide were treated with antithymocyte globulin (ATG). Both patients developed reticulocytosis within 2-4 days after ATG treatment and had complete remissions. Within 4-6 months, they relapsed, and after retreatment with ATG both again developed reticulocytosis and remission. ATG should be considered for the treatment of patients with red cell aplasia who fail to respond to glucocorticoid/alkylator treatment.

Glucose-dependent respiration in suspensions of rabbit cortical tubules.

The effects of glucose on cellular respiration were examined in suspensions of rabbit cortical tubules. When glucose was removed from the bathing fluid, oxygen consumption (QO2) decreased from 18.6 +/- 0.8 to 15.7 +/- 0.5 nmol O2/mg protein X min (P less than 0.01). The transported but nonmetabolized analogue of glucose, alpha-methyl-D-glucoside (alpha MG), was found to support QO2 to the same extent as glucose. These observations were also evident in the presence of butyrate, a readily oxidized substrate of the renal cortex. Additional studies with nystatin and ouabain indicated that glucose-related changes in QO2 were the result of changes in Na, K-ATPase associated respiration. The effect of glucose was localized to the luminal membrane since phlorizin (10(-5) M), a specific inhibitor of luminal glucose-sodium cotransport, also significantly reduced QO2 by 10 +/- 1%. Phlorizin inhibition of QO2 was also evident in the presence of alpha MG but was abolished when glucose was removed from the bathing medium. Finally, measurement of NADH fluorescence showed that addition of glucose (5 mM) to a tubule suspension causes an oxidation of NAD. These data are all consistent with glucose acting to increase respiration by stimulating sodium entry at the luminal membrane (via glucose-sodium cotransport) followed by increased sodium pump activity and its associated increase in mitochondrial respiration.

(Na+,K+)-ATPase kinetics within the intact renal cell. The role of oxidative metabolism.

The kinetics of oxygen consumption and (Na+,K+)-ATPase-mediated K+ transport was examined by reintroducing K+ into a K+-depleted suspension of renal tubules. In the presence of the substrates glucose, lactate, and alanine, a K+/O2 ratio of 10.4 +/- 0.2 was obtained, and the apparent K1/2 for K+ transport with respect to external K+ concentration was 0.9 mM. Supplementation of the substrates with the short chain fatty acid, butyric, had a 3-fold effect on the kinetic parameters examined: 1) the quantity of (Na+,K+)-ATPase-mediated ion transport per oxygen consumed fell by 17 +/- 2%; 2) the maximum rate of K+ transport increased by nearly 50%; and 3) the apparent K1/2 for transport with respect to external K+ concentration rose to 1.5 mM. These results indicate that despite decreasing the quantity of ATP produced per oxygen consumed, short chain fatty acids are able to increase the overall production of ATP during periods of high metabolic demand. The coupling between the two major metabolic processes of the renal cell, (Na+,K+)-ATPase-mediated ion transport and mitochondrial oxidative phosphorylation, is addressed in the context of these findings.

Mitochondrial respiratory capacity and Na+- and K+-dependent adenosine triphosphatase-mediated ion transport in the intact renal cell.

Cellular oxygen consumption was monitored during stimulation and inhibition of the Na+- and K+-dependent adenosine triphosphatase in a suspension of intact tubules isolated from the rabbit renal cortex. Respiratory rates were compared to the ADP-stimulated respiratory rate (state 3 rate) obtained in mitochondria released directly from the renal tubules by digitonin shock. At 37 degrees C, in the presence of NADH-linked substrates and fats, isolated renal cells respire at 50 to 60% of the state 3 rate. Inhibition of the (Na+,K+)-ATPase with the cardiac glycoside, ouabain, results in a decline in respiration to 25 to 30% of the state 3 rate. Stimulation of the (Na+,K+)-ATPase produced as a result of nystatin-mediated dissipation of plasma membrane Na+ and K+ gradients results in increased respiration with an oxygen consumption rate characteristic of optimal ATP synthesis (state 3). The relationship between metabolic substrate regimen, mitochondrial respiratory capacity, and cellular energy demand is examined in the context of these findings.

Oxygen consumption and cellular ion transport: evidence for adenosine triphosphate to O2 ratio near 6 in intact cell.

Oxygen (O2) consumption and net K+ uptake were measured simultaneously upon reintroduction of K+ into a K+-depleted suspension of renal tubules. The K+/O2 stoichiometries of 11.8 +/- 0.2 and 8.4 +/- 0.6 were obtained for reduced nicotinamide adenine dinucleotide- and flavoprotein-linked substrates, respectively. These values complement classical K+ to adenosine triphosphate (ATP) and ATP/O2 stoichiometries, thereby demonstrating a remarkably efficient coupling between the processes of Na+- and K+-dependent adenosinetriphosphatase-mediated ion transport and oxidative phosphorylation within the intact cell.