ozolinone and piretanide

A microelectrode was used to measure endocochlear potentials (EP) in adult chinchillas and to study the effects of a series of loop diuretics. EP was measured before, during and for several hours after the intravenous injection of the following loop diuretics: furosemide, piretanide, bumetanide, ethacrynic acid, indacrinone stereoisomers and ozolinone. The first four loop diuretics caused a substantial dose-related reduction of EP. The (-) isomer of indacrinone was found to cause a dose-related reduction of EP to a moderate degree. The (+) isomer of indacrinone and ozolinone caused very little change of EP, even in very high doses. Findings are consistent with data on the mechanism of action of these agents in the kidney.

Topics: Acute Disease; Animals; Bumetanide; Chinchilla; Cochlea; Diuretics; Dose-Response Relationship, Drug; Ethacrynic Acid; Evoked Potentials, Auditory; Furosemide; Indans; Stereoisomerism; Sulfonamides; Thiazoles; Time Factors

A new method for the quantitative assessment of acute ototoxic side effects of drugs is described. It is suitable for screening purposes. The method is based on the determination of the toxic dose (TD50) which causes a defined hearing loss in 50% of the animals tested. The hearing loss is defined as a complete suppression of the compound action potential (CAP) of the auditory nerve, elicited by clicks 30 dB above threshold. This is approximately equivalent to a clinical hearing loss of 30 dB. The TD50 is used to estimate the therapeutic range. With this approach ototoxic side effects of furosemide, piretanide and bumetanide were compared quantitatively in cats. The TD50 values for CAP suppression were 18.37 mg/kg for furosemide; 4.29 mg/kg for piretanide and 2.21 mg/kg for bumetanide. As equipotent diuretic doses are 2.61 mg/kg for furosemide, 0.26 mg/kg for piretanide and 1.16 mg/kg for bumetanide, it appears that the relative ototoxicity is least for piretanide and highest for bumetanide. Plasma concentrations, determined initially and when recovery of CAP to 50% of control had occurred, indicate that bumetanide may be more slowly eliminated from the cochlear spaces than furosemide and piretanide. In addition azosemide and ozolinone were tested. The TD50 for azosemide was less than 10 mg/kg. With ozolinone where there are two isomers, only the diuretic (-)ozolinone was ototoxic; the TD50 was less than 100 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Action Potentials; Animals; Bumetanide; Cats; Cochlea; Diuretics; Dose-Response Relationship, Drug; Female; Furosemide; Hearing Disorders; Kidney; Male; Sulfanilamides; Sulfonamides; Thiazoles

The criteria upon which diuretics are classified are based upon their site of action within the nephron. Carbonic anhydrase inhibitors act in the proximal tubule, high-ceiling diuretics in the ascending loop of Henle, the thiazides in the early distal tubule and the potassium-sparing diuretics in the late distal tubule and in the collecting duct. According to the localization of carbonic anhydrase acetazolamide acts on three different sites in the proximal tubule cells. The loop diuretics inhibit the secondary active chloride reabsorption. Experiments on the isolated stripped rabbit colon under the condition of stimulated chloride secretion reveal striking similarities between the receptors for chloride reabsorption in the luminal cell membranes of the ascending loop of Henle and in the serosal cell membranes of the colon. The potassium-sparing diuretics act by blocking sodium channels in the distal parts of the nephron. The lumen negative potential difference decreases and potassium secretion is diminished.

Topics: Absorption; Chlorides; Diuretics; Ethacrynic Acid; Humans; Ion Channels; Nephrons; Potassium; Sodium; Sulfonamides; Thiazoles

Topics: Action Potentials; Animals; Bumetanide; Cats; Cochlea; Diuretics; Dose-Response Relationship, Drug; Female; Furosemide; Hearing Disorders; Male; Perfusion; Piperidines; Sulfonamides; Thiazoles; Vestibulocochlear Nerve