Penetration of ofloxacin and ciprofloxacin into the aqueous humor of eyes with functioning filtering blebs: a randomized trial.

OBJECTIVE: To determine concentrations of ofloxacin and ciprofloxacin hydrochloride in aqueous humor after topical or combined topical and oral administration in eyes with filtering blebs. DESIGN: A prospective, investigator-masked, randomized, controlled comparative study involving 36 eyes of 34 patients with functioning filtering blebs who were to undergo cataract surgery. Treatment groups received either topical ofloxacin or topical ciprofloxacin (instillation of 0.3% ophthalmic solution every 30 minutes for 4 hours before surgery), or a combined topical plus oral regimen (ciprofloxacin hydrochloride, four 100-mg tablets, or ofloxacin, one 400-mg tablet, administered 24-26, 12-14, and 2 hours preceding surgery). The main outcome measure was antibiotic concentration measured by chromatographic separation and mass spectrometry of aqueous samples obtained during surgery. RESULTS: Topical antibiotic treatment yielded mean concentrations of ofloxacin, 0.75 microg/mL, and ciprofloxacin, 0.21 microg/mL, in aqueous. With combined topical and oral therapy, significantly more ofloxacin was measured than ciprofloxacin (3.84 microg/mL vs 0.35 microg/mL [P<.001]). The combination regimen produced significantly greater ofloxacin levels than did topical therapy alone (P =.007). CONCLUSIONS: Ofloxacin penetrates better than ciprofloxacin into the aqueous of eyes with filtering blebs, particularly after combined topical and oral administration, by which ofloxacin reaches more than a 10-fold greater concentration than does ciprofloxacin. Combined topical and oral therapy with ofloxacin may be beneficial in the treatment of bleb-associated infections.

Stereoselective high-performance liquid chromatography determination of propranolol and 4-hydroxypropranolol in human plasma after pre-column derivatization.

A stereoselective reversed-phase HPLC assay to quantify S-(-) and R-(+) enantiomers of propranolol and 4-hydroxypropranolol in human plasma was developed. The method involved liquid-liquid extraction for sample clean-up and employed 2,3,4,6-tetra-O-acetyl-beta-glucopyranosyl isothiocyanate as a pre-column chiral derivatization reagent. The internal standard used was 4-methylpropranolol. The derivatized products were separated on an Altex C18 column using a mixture of acetonitrile-water-phosphoric acid-triethylamine (58:42:0.1:0.06 and 50:50:0.15:0.06, v/v, for propranolol and 4-hydroxypropranolol, respectively) as mobile phase. The detection of propranolol derivatives was made at lambda(ex)=280 nm and lambda(em)=325 nm, and the corresponding 325 and 400 nm were used for 4-hydroxypropranolol derivatives. The assay was linear from 1 to 100 ng/ml and from 2 to 50 ng/ml using 0.5 ml of human plasma for propranolol and 4-hydroxypropranolol enantiomers, respectively. The present assay is used to quantify the enantiomers of propranolol and 4-hydroxypropranolol, respectively, in human plasma for pharmacokinetic studies.

Pharmacokinetic interactions between arbaprostil and aspirin in humans.

Arbaprostil is an orally active prostaglandin E2 analogue. It has been developed as a drug to treat ulcers induced by non-steroidal anti-inflammatory drugs. In this study, pharmacokinetic interactions between arbaprostil and aspirin were examined in humans after chronic doses of both drugs. Subjects received either arbaprostil (50 micrograms), aspirin (975 mg) or arbaprostil (50 micrograms) and aspirin (975 mg) four times a day for 6 days and one dose on 7th day. Blood and urine samples were collected after the last dose for 6 h. Pharmacokinetic parameters of arbaprostil, aspirin, and salicylate were determined. Coadministration of arbaprostil significantly lowered the area under curve (5.09 +/- 0.32 micrograms hml-1 vs 5.78 +/- 0.29 micrograms hml-1, mean +/- SE, p less than 0.05) and time (0.45 +/- 0.07 h vs 0.70 +/- 0.12 h, p less than 0.05) to reach maximal plasma concentration of aspirin (acetylsalicylate). The pharmacokinetics of salicylate were not changed by arbaprostil, nor were the pharmacokinetics of arbaprostil affected by aspirin. Coadministration of these two drugs did not appear to potentiate the side-effects of either drug. The results suggest that arbaprostil and aspirin may be administered together without clinically significant changes in pharmacokinetics or adverse side-effects.

Effects of formulation and food on the absorption of hydrochlorothiazide and triamterene or amiloride from combination diuretic products.

The absorption of three combination formulations of hydrochlorothiazide and either triamterene or amiloride was studied over a 5-year period in seven separate investigations under varying conditions of food and fasting. The most widely prescribed combination, containing 25 mg of hydrochlorothiazide and 50 mg of triamterene, demonstrated impaired absorption in the fasting state that was partially corrected by the addition of a breakfast high in fat. The increase in the fat content of the food appeared to correlate directly with the amount of both drugs absorbed from this formulation. The second formulation studied, a new combination formulation of 50 mg of hydrochlorothiazide and 75 mg of triamterene, demonstrated acceptable absorption in the fasting state that was not altered by the concurrent administration of a high-fat breakfast. The absorption of the third formulation, a combination of 50 mg hydrochlorothiazide and 5 mg amiloride, was acceptable in the fasting state and demonstrated a slight reduction in the absorption of the amiloride component when administered concurrently with a high-fat meal. The clinical and biopharmaceutic implications of these observations are discussed.

Absence of a significant pharmacokinetic interaction between hydrochlorothiazide and triamterene when coadministered.

Hydrochlorothiazide, triamterene, and hydroxytriamterene sulfate were monitored in the plasma and urine of 24 healthy young men taking single doses of a liquid preparation containing both hydrochlorothiazide and triamterene, liquid preparations containing either of these drugs alone, and a combination tablet recently formulated with a dose ratio of hydrochlorothiazide : triamterene (1 : 1.5) found to give optimal potassium-sparing effect. In contradiction to a recent publication, no interaction between the drugs affecting the bioavailability or renal clearance of either could be demonstrated. The previous report of drug-drug interaction probably arose from formulation-related problems with bioavailability from the two capsule and two tablet products which had been studied. A well-formulated hydrochlorothiazide-triamterene combination tablet promotes plasma concentrations and urinary excretion of hydrochlorothiazide, triamterene, and hydroxytriamterene sulfate which are virtually identical to those seen after either a combination liquid dosage form or simple liquid forms containing only one of the two drugs.

Hydrochlorothiazide pharmacokinetics and pharmacologic effect: the influence of indomethacin.

It is known that nonsteroidal antiinflammatory drugs such as indomethacin can attenuate the pharmacologic effect of loop diuretics such as furosemide and ethacrynic acid and that indomethacin may also reduce the pharmacologic response to chlorothiazide. To examine further this potential drug-drug interaction, we administered 50- an 100-mg single oral doses of hydrochlorothiazide with and without indomethacin to 10 healthy, normal subjects. We observed no significant influence of indomethacin to 10 healthy, normal subjects. We observed no significant influence of indomethacin either on the pharmacokinetics of hydrochlorothiazide or the pharmacologic response to this diuretic. The adsorption and disposition of hydrochlorothiazide demonstrate that this drug is rapidly absorbed and produces a diuretic and natriuretic response that peaks at approximately 2 hours after dosing and is essentially terminated 12 hours after dosing. There appeared to be no greater pharmacologic response to the 100-mg than to the 50-mg hydrochlorothiazide dose in the ten subjects in this study.

Preliminary evaluation of furosemide-probenecid interaction in humans.

The pharmacokinetics and pharmacodynamics of intravenous furosemide, 40 mg, were studied in four healthy male subjects in a crossover fashion with and without probenecid pretreatment. In each study, 16 plasma and 10 urine samples were collected over 24 hr. Fluid and electrolyte urinary losses were replaced orally throughout the study. Unchanged furosemide and probenecid were measured using high-pressure liquid chromatography; urinary sodium was measured by flame photometry. Although probenecid caused marked changes in the pharmacokinetic parameters of furosemide (increased area under the curve, decreased plasma and renal clearance, increased half-life, and decreased fraction excreted unchanged in the urine), there was no significant difference in its gross 8-hr natriuretic and diuretic effect. However, analysis of the time course of natriuresis showed a pattern similar to that of the urinary furosemide excretion rate, whereas the plasma concentration was poorly correlated over the entire dose-response curve.