Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Ticrynafen”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1998

Effect of ticrynafen on aqueous humor dynamics in monkeys.

OBJECTIVE: To determine the effect of ticrynafen, a nonsulfhydryl-reactive compound similar to ethacrynic acid, on outflow facility in normotensive monkey eyes and on intraocular pressure (IOP) in monkey eyes with laser-induced glaucoma. METHODS: In normotensive eyes, facility (perfusion) was measured shortly before and after bolus or exchange intracameral infusion of ticrynafen or vehicle in opposite eyes, and 3.5 to 4.5 hours after 5 days of twice-daily 2% ticrynafen or vehicle ointment. In glaucomatous eyes, baseline and vehicle diurnal IOP curves were established, 2% ticrynafen ointment was given twice daily for 5 days, and IOP was measured immediately before and 0.5 to 6 hours after each morning treatment. RESULTS: In normotensive eyes, exchange 2-mL influsion of 0.2-, 1-, or 4-mmol/L ticrynafen increased facility by 33% +/- 6% (mean +/- SEM), 73% +/- 18%, and 60% +/- 11%, respectively. Day 5 posttreatment facility was higher in the ticrynafen group than in controls by 28% +/- 9%. In glaucomatous eyes, maximum IOP decline, from approximately 35 mm Hg, was 7.5 +/- 2.0 mm Hg on day 4 and 9.8 +/- 2.4 mm Hg on day 5 of twice-daily ticrynafen treatment. CONCLUSION: The facility-increasing, IOP-lowering action of ticrynafen, ethacrynic acid, and derivatives may not depend entirely on sulfhydryl reactivity. CLINICAL RELEVANCE: Whether such drugs as ethacrynic acid and ticrynafen prove valuable for glaucoma therapy, at the least they are useful probes to study aqueous outflow mechanisms.

Administration, Topical↗
PubMed1979

Renal sites of natriuretic and uricosuric activity of ticrynafen in the mongrel dog.

Following establishment of steady state plasma concentrations of ticrynafen in the mongrel dog, the intravenous injection of large doses of p-aminohippurate (PAH) or sodium salicylate reduced or blocked the urinary excretion of ticrynafen. In a similar manner, the intravenous administration of ticrynafen reduced the urinary excretion of PAH in preloaded dogs. Since PAH and salicylate are actively secreted by a renal tubular organic anion transport system, these data were interpreted as evidence of an active tubular secretion of ticrynafen. The natriuresis and uricosuria which result from the administration of ticrynafen to the mongrel dog were reduced by PAH and salicylate at doses of these compounds which effectively blocked the secretion of ticrynafen. These results demonstrate that in the dog, the natriuretic and uricosuric activity of ticrynafen results from the presence of ticrynafen in the tubular lumen.

Animals↗
PubMed1983

Mechanism of ticrynafen potentiation of coumarin anticoagulant action.

Administration of the antihypertensive drug ticrynafen [2,3-dichloro-4-(2-thienylcarbonyl)-phenoxyacetic acid] has been reported to potentiate the effects of coumarin anticoagulants and to have caused hemorrhagic incidents in some patients. This drug interaction has now been reproduced in the rat. Ticrynafen administration enhanced the degree of hypoprothrombinemia and altered plasma and hepatic vitamin K epoxide concentrations in warfarin-treated rats. Ticrynafen did not affect vitamin K-dependent carboxylase or vitamin K epoxide reductase activities in vitro. Cytosolic DT-diaphorase was very sensitive to ticrynafen inhibition in vitro, and inhibition of vitamin K reduction via this enzyme is a possible mechanism by which ticrynafen potentiates coumarin anticoagulant action. Inhibition of this enzyme may also contribute to the reported hepatotoxicity of ticrynafen.

Animals↗
PubMed1982

Ticrynafen-racemic warfarin interaction: hepatotoxic or stereoselective?

To examine the ticrynafen-warfarin interaction, normal subjects received large single doses of 1.5 mg/kg racemic warfarin with and without daily oral doses of 250 mg ticrynafen beginning 3 days before warfarin and continuing for the duration of hypoprothrombinemia. Daily blood samples were analyzed for one-stage prothrombin time (Quick method) and warfarin concentrations (high-pressure liquid chromatography). Ticrynafen induced augmentations of both prothrombin time and warfarin concentration (P less than 0.001). The interaction was evaluated further with separated warfarin enantiomorphs. Ticrynafen induced augmentation of prothrombin times and warfarin concentrations of S-warfarin, but had little effect on R-warfarin. Thus, ticrynafen probably augments the hypoprothrombinemia of racemic warfarin by reducing metabolic clearance of S-warfarin. The lack of effect of ticrynafen on R-warfarin suggest that the interaction is stereoselective rather than hepatotoxic.

Adult↗
PubMed1978

Ticrynafen and hydrochlorothiazide in hypertension.

In a double-blind study, 28 patients having mild to moderate essential hypertension were randomly assigned to a 6-week regimen of ticrynafen, hydrochlorothiazide, or placebo. Blood pressure fell after ticrynafen and hydrochlorothiazide. Serum uric acid fell strikingly with ticrynafen whereas it rose with hydrochlorothiazide. Serum potassium declined very little with ticrynafen; much less than with hydrochlorothiazide. Serum creatinine and blood urea nitrogen rose slightly more with ticrynafen than with hydrochlorothiazide. There were no clinical adverse effects to either of the medications. Ticrynafen appears to be an effective antihypertensive with a substantial hypouricemic effect.

Adult↗
PubMed1979

Comparative effects of ticrynafen and hydrochlorothiazide in the treatment of hypertension.

Two dose levels of ticrynafen, a new uricosuric diuretic, and of hydrochlorothiazide were randomly assigned, double-blind to 240 men with initial diastolic blood pressures in the range of 95 to 114 mm Hg. A dose of 500 mg of ticrynafen once daily exerted an antihypertensive effect comparable to that of 50 or 100 mg of hydrochlorothiazide. Whereas serum uric acid levels rose in patients treated with hydrochlorothiazide, they fell markedly in those receiving ticrynafen. Otherwise, both diuretics produced similar chemical changes in serum. Patients tolerated ticrynafen as well as they did hydrochlorothiazide over a period of six months of observation, and there was no evidence of serious toxicity or loss of therapeutic effect with ticrynafen. This antihypertensive agent, in appropriate doses, appears to be as effective and well tolerated as hydrochlorothiazide, and in addition ticrynafen prevents hyperuricemia.

Blood Pressure↗
PubMed1980

Ticrynafen in anephric patients: effects on uric acid and pharmacokinetics.

Ticrynafen was given to 6 anephric patients undergoing maintenance hemodialysis. Ticrynafen was given daily for the 3 days between hemodialyses. Ticrynafen had no effect on the interdialysis rise in serum uric acid levels. Ticrynafen did not accumulate in serum, but levels of metabolites continued to rise over the 3 days. Hemodialysis (5 hr) reduced levels of ticrynafen by 38% but had less effect on metabolite levels. There was no effect on serum cholesterol or triglycerides.

Adult↗
PubMed1979

Mechanism of the uricosuric activity of ticrynafen.

Studies employing pyrazinamide, which have included the measurements of clearances of pyrazinamide and pyrazinoate, as well as of ticrynafen itself and its principal metabolite, have lent support to the hypothesis that ticrynafen inhibits the tubular reabsorption of both filtered and secreted urate by nephrons of the human kidney. The inhibition of the reabsorption of secreted urate by ticrynafen appears to be quantitatively important for eliciting its uricosuric and hypouricemic responses. Because the uricosuric and natriuretic responses correlate with urinary ticrynafen concentrations, the drug appears to inhibit tubular reabsorption after gaining access to tubule fluid. As a consequence of its extensive binding to plasma proteins, clearance data suggest that tubular secretion of ticrynafen is necessary for its action.

Diuretics↗
PubMed1979

The effects of ticrynafen in the rat.

The effects of ticrynafen, a uricosuric diuretic, were examined utilizing free-flow micropuncture and clearance techniques in the rat. The intravenous infusion of ticrynafen (50 mg/kg body wt/hr) had no effect on glomerular filtration rate, but resulted in significant increases in urine flow from 4.4 +/- 0.7 microliter/min/g kidney wt to 19.2 +/- 2.6 (p less than 0.001); in urinary sodium excretion from 0.14 +/- 0.07 micronEq/min/g kidney wt to 2.35 +/- 0.52 (p less than 0.01); and in urinary urate excretion from 2.8 +/- 0.2 microgram/min/g kidney wt to 4.0 +/- 0.2 (p less than 0.005). There was no change in urinary phosphate excretion. The end-proximal TF/Pinulin ratio was 2.66 +/- 0.18 in control and 2.67 +/- 0.16 in experimental periods (p=NS). In awake animals, ticrynafen administration resulted in a decrease in CH2O from 6.47 +/- 0.12% to 3.50 +/- 0.69 (p less than 0.05), but no change in TCH2O. These studies demonstrate that ticrynafen is a uricosuric and diuretic agent in the rat. The natriuresis appears to derive from an inhibitory action of this agent in the cortical diluting segment of the nephron. In comparison to a related uricosuric diuretic, MK-196, ticrynafen is a less potent agent with respect to both its uricosuric and diuretic properties in the rat.

Absorption↗
PubMed1982

A dissolution anomaly involving ticrynafen in simulated intestinal fluid without enzyme.

Data are presented showing that the anomalous dissolution behavior of ticrynafen in simulated intestinal fluid without enzyme is due to the presence of potassium ions in the dissolution medium. Solubility studies indicate that an insoluble 1:1 complex is formed between ticrynafen and its potassium salt. This complex apparently creates an insoluble barrier that prevents complete dissolution of ticrynafen. To determine whether this might also occur in clinical use, a three-way cross-over study in 12 subjects was done. Data from this investigation show that concomitant administration of ticrynafen tablets and potassium in the form of a commercial supplement does not adversely affect bioavailability.

Body Fluids↗
PubMed1982

Ticrynafen and hydrochlorothiazide. A comparison in hypertensive patients with renal impairment.

The efficacy of ticrynafen in the treatment of hypertension in patients with moderate renal impairment was compared with that of hydrochlorothiazide in a randomised, double-blind crossover trial in eleven subjects with renal insufficiency. Significant reductions in blood pressure occurred with both treatments, with the maximum responses occurring at different time intervals and to different degrees in individual patients. Thus, although ticrynafen caused a significant reduction in blood pressure in this group of hypertensive patients with renal insufficiency, it was not consistently different from that which could be achieved with hydrochlorothiazide. Ticrynafen also significantly reduced the serum uric acid concentration, compared with a significant rise with hydrochlorothiazide. No major biochemical abnormalities or side-effects were encountered in any subject. Thus, in these patients with renal insufficiency, ticrynafen still demonstrated a uricosuric effect as well as a useful anti-hypertensive action.

Adult↗
PubMed1981

Ticrynafen-induced acute renal failure.

Two cases of acute renal failure associated with ticrynafen administration are reported. Both patients had received hydrochlorothiazide prior to the institution of ticrynafen therapy and were mildly hyperuricemic. Flank pain, oliguria, and azotemia developed after the institution of ticrynafen in both cases. Clinical and laboratory features were consistent with acute uric acid nephropathy in both patients. In addition, a newly formed collection of radiolucent material was found by intravenous urography in the renal pelvis of one of the patients. Both patients were treated with intravenous fluids and sodium bicarbonate. One of the patients received allopurinol as well. Complete recovery of renal function was observed in both patients. Ticrynafen-induced hyperuricosuria in these previously volume-depleted and hyperuricemic subjects is felt to have been responsible for intrarenal and extrarenal deposition of uric acid in our patients.

Acute Kidney Injury↗
PubMed1979

Ticrynafen and hydrochlorothiazide. A double-blind study of antihypertensive properties with an open crossover.

Twenty-eight patients completed a double-blind study of the antihypertensive effects of ticrynafen compared with those of hydrochlorothiazide. The results of blood pressure reduction were comparable in the two groups. After six months, 12 patients were crossed over to ticrynafen therapy from hydrochlorothiazide. They maintained their blood pressure reduction. The most striking difference between the two groups was in the uric acid response. The uric acid level in the patients receiving hydrochlorothiazide therapy rose from a baseline of 5.9 to 7.5 mg/dL (normal range, 3.0 to 8.0 mg/dL). The uric acid level of those patients receiving ticrynafen therapy decreased from a baseline of 6.4 mg/dL to a low of 3.3 mg/dL. In view of ticrynafen's appreciable antihypertensive and uric-acid-lowering effects, it appears to be a useful new antihypertensive drug.

Adult↗
PubMed1978

Ticrynafen, a uricosuric antihypertensive diuretic.

Ticrynafen, a diuretic-uricosuric also effective as an antihypertensive, was compared in single doses with several other diuretics. Over an 8-hr period, a 250- mg dose exerted natriuretic activity comparable to that of 25 mg of chlorthalidone and 50 mg of ethacrynic acid; a 500-mg dose was comparable to 50 mg chlorthalidone and 50 mg hydrochlorothiazide. Ticrynafen combined with furosemide had an additive effect, whereas a combination with hydrochlorothiazide was not additive. In both doses ticrynafen was a uricosuric and this effect was maintained when given with furosemide and hydrochlorothiazide, both of which individually were slightly antiuricosuric. Ticrynafen may be useful in patients requiring a diuretic in whom it is desirable to avoid hyperuricemia.

Adult↗
PubMed1979

Comparison of ticrynafen and probenecid in patients with elevated uric acid levels.

Ticrynafen, 125--250 mg/day was compared with probenecid 0.5--1.0 g/day in patients with elevated serum uric acid values in a randomized, double-blind crossover study. Each treatment period lasted 12 weeks. The mean reduction in serum uric acid from 9.4 +/- 1.2 to 6.22 +/- 1.2 mg/dl (33.8%) during ticrynafen was greater (p less than 0.01) than that from 9.46 +/- 1.1 to 7.0 +/- 1.3 mg/dl (26%) during probenecid treatment. There were slight increases in serum creatinine and BUN and decreases in body weight during ticrynafen treatment. There were no statistically significant changes in serum electrolytes. The hypouricemic effect of ticrynafen was well maintained during its subsequent open-label administration for 18 months without any deterioration of renal function.

Aged↗
PubMed1979

Evaluation of a new uricosuric diuretic--ticrynafen.

Ticrynafen is an orally administered diuretic that is similar to the thiazides in its therapeutic actions, but unlike the thiazides, it increases urate excretion and lowers serum uric acid levels. Ticrynafen is useful in the treatment of hypertension and in selected cases of chronic congestive heart failure. At present, it appears to be indicated primarily in patients with these disorders who have a history of gout. Patients who are currently receiving a thiazide should not have their therapy arbitrarily changed to ticrynafen because of asymptomatic hyperuricemia.

Diuretics↗
PubMedDate not supplied

Ticrynafen-associated hepatic injury: analysis of 340 cases.

Ticrynafen, a uricosuric diuretic, was withdrawn from clinical use in the United States in 1980 after having been implicated as the cause of a number of instances of serious hepatic injury. In this report, we analyze 340 cases of ticrynafen-associated hepatic disease reported to the manufacturer from the time of initial marketing until shortly after the drug had been recalled. Jaundice was recorded in 246 of 287 patients with sufficient clinical information, and 25 (10.2%) of these icteric patients died. The high levels of serum aminotransferase and the case fatality rate are consistent with the hepatocellular injury that was evident in all of the histologic material. In three-fourths of the cases available to us for histologic study, the lesion was that of acute hepatocellular injury. In the remaining cases there was evidence of chronic active hepatitis and/or cirrhosis. Comparison of demographic characteristics of the total population exposed to ticrynafen with the subset developing hepatic injury suggests a proportionately higher risk of injury for females over the age of 60 years. The variable and unusually prolonged latent period and lack of reported eosinophilia or rash generally suggest a mechanism other than hypersensitivity. However, the recurrence of hepatic injury in 15 of the 16 patients challenged with the drug and the prominence of eosinophils in hepatic tissue in some of the cases suggests that hypersensitivity may also play a pathogenetic role. Accordingly, there is reason to incriminate both metabolic idiosyncrasy and hypersensitivity in the mechanism of injury.

Acute Disease↗
PubMed1984

Acute effects of alkylating agents on canine renal function and ultrastructure: high-dose ethacrynic acid vs. dihydroethacrynic acid and ticrynafen.

Ethacrynic acid (EA) is unique among diuretics in that it is both an avid alkylating agent and is actively secreted by renal proximal tubular cells. EA might therefore be expected to produce detrimental proximal tubular changes at elevated doses. Because of this possibility, we examined the renal effects of two relatively high doses of EA (i.e., 66 and 151 mumol/kg i.v.) and an equivalent high dose (i.e., 151 mumol/kg) of two nonalkylating relatives of EA [dihydro-EA (EA-H2) and ticrynafen]. Twelve renal function parameters were monitored in pentobarbital-anesthetized dogs for a period of 2 hr after administration of EA, EA-H2 and ticrynafen and renal tissue was acquired at the end of the 2 hr of study for light and electron microscopic evaluation. Both doses of EA produced a profound diuresis of similar magnitude. However, only the larger dose was associated with a concomitant reduction in the glomerular filtration rate, a downward trend in the renal blood flow, a proteinuric response in four of the seven dogs in the treatment group and a reproducible vacuolation of the initial portion of the proximal convoluted tubules (i.e., the S1 cells). EA-H2 induced a small, transient increase in the excretion rates of sodium, chloride and potassium, but failed to elicit a proteinuric response or alter proximal tubular ultrastructure. Ticrynafen, a far more efficacious diuretic agent than EA-H2, likewise failed to trigger a proteinuric response or changes in renal ultrastructure. The combination of acidic (anionic) and alkylating properties of EA is thought to be responsible for the proximal tubular effects observed in this study.

Animals↗