We have previously demonstrated a time-dependent variability in the diuretic effects of S-8666, a new loop diuretic with uricosuric activity, in young rats. The present study was undertaken to determine whether such a daily variation in the effects of the agent exists in aged rats. S-8666 (30 and 90 mg/kg) was orally given at 12:00 a.m. (day trial) or at 12:00 p.m. (night trial) in young (10-11 week old) and aged (23-24 month old) Wistar rats. Urine was collected for 8 hours after the agent; and urinary excretions of sodium, S-8666 and its active metabolite S-8680 were determined. Urinary excretions of volume and sodium following S-8666 at 12:00 a.m. were greater than those at 12:00 p.m. in the young and aged animals. Urinary excretions of S-8666 and S-8680 were also greater in the day trial compared to those in the night trial in both groups of rats. In the day and night trials, there were significant correlations between urinary S-8666 + S-8680 and the diuretic effects in both groups of rats. These findings indicate that the diuretic effects of S-8666 also vary with its time of dosing in aged rats. The time-dependent variations in urinary S-8666 and S-8680 might be involved in this phenomenon.

01 Jan 1991·The Tohoku Journal of Experimental MedicineQ4 · MEDICINE

Effect of S-8666 on Cl- Transport in the Rabbit Connecting Tubule Perfused in Vitro.

Q4 · MEDICINE

Article

Author: IMAI, MASASHI ; SHIMIZU, TOSHIKATSU ; NAKAMURA, MASUHISA

S-8666, [6, 7-dichloro-5-(N, N-dimethylsulfamoyl)-2, 3-dihydrobenzofurancarboxylic acid] is a potent diuretic with uricosuric action. Although the major site of action of S-8666 has been proven by the in vitro microperfusion study to be the thick ascending limb of Henle's loop, clearance studies in the rat suggested that this drug has an additional thiazide-like action. To provide direct evidence that S-8666 acts also on distal nephron segments, we examined effect of S-8666 on Cl- flux across the rabbit connecting tubule perfused in vitro. The drug suppressed the lumen-to-bath Cl- flux by 96 +/- 41 (S.E.)pmol.mm-1.min-1 (n = 9) without affecting transmural voltage. To demonstrate that S-8666 acts on the connecting tubule cell, the target of thiazide diuretics, we compared effects of S-8666 and trichlormethiazide on the basolateral membrane voltage of the connecting tubule cell. Both drugs added to the lumen caused a small but significant hyperpolarization of the basolateral membrane without affecting transmural voltage. We conclude that S-8666 is a unique uricosuric diuretic having actions on both thick ascending limb of Henle's loop and connecting tubule.

01 Jan 1991·The Japanese Journal of Pharmacology

Chronopharmacology of the New Uricosuric Diuretic S-8666 in Rats.

Article

Author: Akio Ebihara ; Kyo-ichi Ohashi ; Akio Fujimura

A new loop diuretic with uricosuric activity, 6,7-dichloro-5-(N,N-dimethylsulfamoyl)-2,3-dihydro-2-benzofuran carboxylic acid (S-8666), was given orally at 12:00 a.m. or 12:00 p.m. in rats. The diuretic of S-8666 and the urinary excretions of the drug and its active metabolite S-8680 (N-demethyl S-8666) were greater at 12:00 a.m. than at 12:00 p.m. Thus, the present study indicates that the diuretic effects of S-8666 varies with its administration time. Time-dependent variations in the amount of urinary excretions of S-8666 and S-8680 might be involved in the mechanisms for this phenomenon.

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Indication	Highest Phase	Country/Location	Organization	Date
Hypertension	Phase 1	JP	Shionogi & Co., Ltd.	-

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