After an oral or intravenous dose of furosemide, there is considerable interindividual variability in the amount of unchanged drug delivered into the urine. On average, approximately half as much reaches the intraluminal site of action with an oral compared to an intravenous dose. However, the natriuretic response to the same dose administered by either route is virtually the same. Similarly, after pretreatment with probenecid, the same total amount of furosemide in urine causes a greater overall response. It has been presumed that this paradox is accounted for by differences in rate of delivery of furosemide to the active site such that after an oral dose, or after pretreatment with probenecid, amounts of drug are for longer periods of time at the "steep" portion of the dose-response curve. Our analysis shows this not to be the case. For furosemide, the "slope factor" of the dose-response curve is such that the amount of diuretic delivered into the urine which is maximally efficient (21.5 micrograms/min) is considerably less than the amount causing half-maximal response (69.8 micrograms/min). Oral administration or pretreatment with probenecid maintains drug close to this maximally efficient amount more persistently than does intravenous administration. By so doing, total response to an oral dose approaches that of intravenous dosing despite delivering half the amount of drug to the active site, and after probenecid an intravenous dose causes a greater response than intravenous dosing alone despite delivering the same amount of drug to the active site. These data emphasize the importance of the time course of delivery of drug to the active site as an independent determinant of overall response.

Indomethacin and other nonsteroidal anti-inflammatory drugs (NSAIDs) decrease solute excretion when administered acutely to normal subjects. We performed clearance studies during water loading of 10 normal volunteers and during hydropenia in eight additional subjects to determine the nephron site of this effect using indomethacin and carprofen as inhibitors of prostaglandin (PG) synthesis. Their administration decreased fractional excretion of sodium, chloride, and volume. During water loading, fractional clearance of free water decreased from 0.13 +/- 0.04 during the control study to 0.09 +/- 0.03 and 0.06 +/- 0.02 with indomethacin and carprofen, respectively. However, fractional delivery of solute to the dilution segment decreased in parallel such that free water clearance corrected for delivery did not change with either drug. In humans, therefore, the decrement in solute excretion that occurs with administration of NSAIDs occurs prior to the diluting segment. During hydropenia, free water reabsorption relative to osmolar clearance increased (P less than 0.01). In both studies, neither the marker of renal perfusion or of proximal nephron function changed with inhibition of PG synthesis. The data indicate that at the tubular level, NSAIDs increase solute reabsorption at the medullary segment of the thick ascending limb of the loop of Henle. Therefore, a physiologic role of renal prostaglandins at this nephron site is implied.

RFsULTATS: L'accord entre les differents observateurs pour chaque element de I'index lAM etait plus elevee pour la prescription appropriee et non appropriee se situait entre 80 et 100% (K: =0.64). En general, I'accord pour Ie resultat total etait bon (correlation = 0.80). CONCLUSIONS: L'index de lAM est un instrument fiable pour evaluer la pertinence medicamenteuse chez une population agee demeurant a domicile. Cet index se veut un outil pratique qui pourrait aider Ie pharrnacien aevaluer la therapie des patients ages~ainsi permettre d'identifier les problemes relies ala pharrnacotherapie des patients. LOUISE MALLETOBJECTIVE: To compare the bioavailability of three generic brands of carbamazepine tablets with that of a proprietary brand in adult patients with epilepsy.DESIGN: A double-blind, randomized, three-phase crossover study. SETIING: A psychiatric facility. PARTICIPANTS: Eighteen patients with epilepsy who had taken carbamazepine at least 5 months before entering the study. MAIN OUTCOME MEASURES: Ten blood specimens from each patient were collected at steady-state. Plasma concentration of carbamazepine was analyzed for pharmacokinetic parameters such as maximum plasma concentration (C max )' mean time to reach maximum concentration (t....), and mean AVe.RESULTS: There were no statistically significant differences in these parameters among four brands of carbamazepine. However, when comparing the 90% CI of AVC of three generic brands with that of the proprietary brand, the AVC of two generic brands lay within a range of 80% to 120%. The effects of gender and each brand of carbamazepine on these pharmacokinetic parameters were also analyzed. Breakthrough seizures occurred even though the plasma concentration of carbamazepine was therapeutic.CONCLUSIONS: The bioavailability of two generic brands of carbamazepine tablets (Carmapine and Carzepine) and the proprietary brand (Tegretol) were equivalent in this sample of adult patients with epilepsy.

Piretanide is a new loop diuretic similar to furosemide in pharmacologic properties and approximately six times as potent. We gave 3-, 6-, and 12-mg oral doses to 21 normal subjects and collected serial blood and urine samples for assessment of the drug's kinetics and dynamics. There was no evidence for dose-dependent elimination with the doses we used. Peak serum concentrations and urinary excretion rates appeared between 30 and 60 min. Elimination t1/2s were 60 to 90 min. Approximately 45% of a dose was recovered unchanged in the urine. Renal clearance rate was 90 to 100 ml/min and oral clearance was 200 ml/min. Examination of the relationship between urinary excretion rate of piretanide and sodium excretion allowed determination of potency at the tubular level. The piretanide dose that induced half-maximal response was 12.1 +/- 2.6 micrograms/min; it is 69.8 micrograms/min for furosemide and 1 micrograms/min for bumetanide. Piretanide kinetics, therefore, resemble those of furosemide and bumetanide, but piretanide is five or six times as potent as furosemide and one tenth as potent as bumetanide.