Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “ETHACRYNIC ACID”

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 73 records · Page 4Linked to original sources
PubMed1998

GSTP1-1 stereospecifically catalyzes glutathione conjugation of ethacrynic acid.

Using 1H NMR two diastereoisomers of the ethacrynic acid glutathione conjugate (EASG) as well as ethacrynic acid (EA) could be distinguished and quantified individually. Chemically prepared EASG consists of equal amounts of both diastereoisomers. GSTP1-1 stereospecifically catalyzes formation of one of the diastereoisomers (A). The GSTP1-1 mutant C47S and GSTA1-1 preferentially form the same diastereoisomer of EASG as GSTP1-1. Glutathione conjugation of EA by GSTA1-2 and GSTA2-2 is not stereoselective. When human melanoma cells, expressing GSTP1-1, were exposed to ethacrynic acid, diastereoisomer A was the principal conjugate formed, indicating that even at physiological pH the enzyme catalyzed reaction dominates over the chemical conjugation.

Amino Acid Substitution↗
PubMed1971

The effects of ethacrynic acid and other sulphydryl reagents on sodium fluxes in frog muscle.

1. Ethacrynic acid (2 mM) increased the sodium efflux from freshly dissected frog sartorius muscles. This increase was not observed in muscles previously treated with strophanthidin.2. In strophanthidin-treated muscles, the addition of ethacrynic acid (2 mM) caused a reduction of sodium efflux. The value of efflux reached in these muscles is similar to that observed in muscles immersed in sodium-free solutions containing strophanthidin.3. Ethacrynic acid reduced sodium influx into strophanthidin-treated muscles. Potassium influx was not affected by this substance. These findings suggest that the inhibitor blocks an exchange of sodium for sodium.4. The increase in sodium efflux caused by ethacrynic acid did not result from depolarization nor from an increase in [Na](i).5. Ethacrynic acid caused only a reduction of sodium efflux in muscles previously loaded with sodium by prolonged immersion in potassium-free solutions at low temperatures.6. A derivative of ethacrynic acid that lacks the ability to combine with sulphydryl (SH) groups did not reduce sodium efflux from muscles treated with strophanthidin.7. Para-chloromercuribenzoic acid (PCMB) reduced sodium efflux from control and strophanthidin-treated muscles. This reduction seems to be restricted to the sodium dependent component of the efflux.8. The inhibition of the sodium-dependent component of sodium efflux caused by ethacrynic acid and PCMB appears to have a similar mechanism, namely, the combination with SH groups.

Animals↗
PubMed1993

Isoenzyme selective irreversible inhibition of rat and human glutathione S-transferases by ethacrynic acid and two brominated derivatives.

In the present study it has been shown that ethacrynic acid can inhibit glutathione S-transferase (GST) of the pi-class irreversibly. [14C]Ethacrynic acid, 0.8 nmol/nmol human P1-1 and 0.8 nmol/nmol rat GST 7-7 could be incorporated, resulting in 65-93% inhibition of the activity towards 1-chloro-2,4-dinitrobenzene (CDNB). Isoenzymes of the alpha- and mu-class also bound [14C]ethacrynic acid, however without loss of catalytic activity. Incorporation ranged from 0.3 to 0.6 and 0.2 nmol/nmol enzyme for the mu- and alpha-class GST isoenzymes, respectively. For all isoenzymes, incorporation of [14C]ethacrynic acid could be prevented by preincubation with tetrachloro-1,4-benzoquinone, suggesting, that a cysteine residue is the target site. Protection of GST P1-1 against inhibition by ethacrynic acid by the substrate analog S-hexylglutathione, indicates an active site-directed modification. The monobromo and dibromo dihydro derivatives of ethacrynic acid were synthesized in an effort to produce more reactive compounds. The monobromo derivative did not exhibit enhanced irreversible inhibitory capacity. However, the dibromo dihydro derivative inhibited both human and rat GST isoenzymes of the pi-class very efficiently, resulting in 90-96% inhibition of the activity towards CDNB. Interestingly, this compound is also a powerful irreversible inhibitor of the mu-class GST isoenzymes, resulting in 52-70% inhibition. The two bromine atoms only marginally affect the strong (reversible) competitive inhibitory capacity of ethacrynic acid, with IC50 (microM) of 0.4-0.6 and 4.6-10 for the mu- and pi-class GST isoenzymes, respectively.

Animals↗
PubMed1979

Effects of ethacrynic acid on electrolyte and fluid transport by the guinea pig gallbladder.

The effect of ethacrynic acid on fluid and electrolyte transport by the guinea pig gallbladder was investigated in vitro. 10-4M ethacrynic acid, applied to the serosal side, inhibited fluid and sodium chloride absorption. The reduction in salt absorption was accounted for by a 3 muEq/cm2h decrease in the unidirectional fluxes of Na and Cl from mucosa to serosa with no change in the fluxes from serosa to mucosa. Ethacrynic acid (10-4 M) had no effect on HCO3 - Cl exchange, PGE1-induced fluid secretion and inulin permeability. At 10-3 M, ethacrynic acid markedly increased both the serosa to mucosa fluxes of Na and Cl, and the inulin permeability. Examination by light and electron microscopy of gallbladder tissue treated with 10-3 M ethacrynic acid revealed large intracellular vacuoles and occasionally ruptured apical cell membranes. Only slight morphological changes were seen by 10-4 M ethacrynic acid with no changes in the controls and ouabain treated gallbladders. The effects of ethacrynic acid are remarkably different from those of furosemide which has been previously shown to inhibit only the HCO3 secretion leaving fluid and NaCl absorption unchanged.

Absorption↗
PubMed1994

Changes in mitochondrial shape and distribution induced by ethacrynic acid and the transient formation of a mitochondrial reticulum.

We have examined the effect of ethacrynic acid on mitochondrial morphology and distribution as well as on cellular toxicity in cultured human fibroblasts, African Green Monkey B-SC-1 kidney cells, and Chinese hamster ovary cells. Treatment of the above cells with 66 microM ethacrynic acid causes no reduction in cell viability after 2 h but is cytotoxic upon prolonged (6-7 days) exposure. Ethacrynic acid treatment for up to 2 h is found to cause novel shape changes and redistribution of mitochondria, as assessed by immunofluorescence and electron microscopy. Early effects include the transient formation of a mitochondrial reticulum involving the majority of mitochondria, and these reticula are aligned along microtubules. At later times within 2 h, mitochondrial distributions become disoriented (show no association with microtubules), and an aggregation and final positioning of mitochondria around the nucleus is observed. Whole mount electron microscopy shows that mitochondria in treated cells increase in length and form junctions, indicating reticula result from mitochondrial fusion. Electron microscopy of sections through ethacrynic acid induced reticula demonstrates structural continuity in mitochondria at branch points and the presence of regular cristae. Staining of endoplasmic reticulum and mitochondria in intact cells with the cyanine dye 3,3'-dihexyloxacarbocyanine iodide provides evidence of concurrent aggregation of endoplasmic reticulum. Rhodamine 123 staining of living cells followed by immunofluorescent labeling of mitochondria in the same cells indicates that all mitochondria retain a transmembrane potential during the drug-induced shape changes and redistributions. The described effects of ethacrynic acid on mitochondrial morphology as well as on cellular toxicity are completely prevented by 0.5 mM dithiothreitol, indicating that ethacrynic acid is acting as a sulfhydryl reagent to produce the observed effects. The above observations also indicate that ethacrynic acid effects on mitochondrial morphology are an early event in the drug-induced cytotoxicity. The generation of varied mitochondrial morphologies by fusion and fission of mitochondria and its modulation by agents such as ethacrynic acid are discussed.

Animals↗
PubMed2003

Ethacrynic acid can be effective for refractory congestive heart failure and ascites.

Ethacrynic acid is a loop diuretic little used today because of its side-effect profile and the availability of multiple alternative agents. However, in our clinical experience, ethacrynic acid can alleviate acute congestive heart failure and ascites resistant to other diuretics. Two patients aged 89 and 94 in life-threatening pulmonary edema were stabilized by ethacrynic acid after furosemide proved ineffective. A third patient, aged 83, with a pleural effusion and ascites secondary to end-stage hepatitis B and C, responded to ethacrynic acid when spironolactone and furosemide produced little urine output. Ethacrynic acid may have a unique niche as a diuretic of last resort, especially in geriatric practice.

Aged↗
PubMed1981

Comparative ototoxicity of chloramphenicol and kanamycin with ethacrynic acid.

Chloramphenicol is not ototoxic if administered for systemic effect, but topical applications of it to the middle ear produce severe cochlear toxic effects. Ethacrynic acid potentiates the ototoxicity of aminoglycosides. Guinea pigs were administered chloramphenicol or kanamycin sulfate with ethacrynic acid to compare the ototoxicity of chloramphenicol and ethacrynic acid with the ototoxicity of kanamycin and ethacrynic acid. Preyer's reflex audiometry and measurement of the endocochlear dc potential, the cochlear microphonics, and the negative potential of the organ of Corti indicate that ethacrynic acid does not potentiate the ototoxicity of chloramphenicol. There is not even indirect evidence that the blood-cochlear barrier for chloramphenicol is altered by ethacrynic acid. Assuming that the ototoxicity of chloramphenicol and ethacrynic acid are similar for man and guinea pig, the combination of the administration of chloramphenicol and ethacrynic acid of systemic effect in dosages commonly used clinically should not produce greater ototoxicity than either agent administered alone.

Animals↗
PubMed1998

Topical gentamicin and ethacrynic acid: effects on cochlear function.

OBJECTIVE: To determine whether concurrent intravenous administration of the loop diuretic ethacrynic acid potentiates the toxicity of the aminoglycoside antibiotic gentamicin applied topically on the round window. STUDY DESIGN: The authors studied the effects on cochlear sensitivity of co-administered intracardiac ethacrynic acid (40 mg/kg) and high-dose topical gentamicin solution (100%) applied to the round window. Comparisons were made with animals receiving ethacrynic acid plus systemic gentamicin (100 mg/kg); topical gentamicin alone; systemic gentamicin alone; and intravenous ethacrynic acid alone. METHODS: Experiments were carried out on pigmented guinea pigs weighing 400 to 500 g. Changes in cochlear function were characterized by monitoring shifts in compound action potential (CAP) thresholds by use of chronic indwelling electrodes implanted at the round window, vertex, and contralateral mastoid. RESULTS: After 20 days animals receiving ethacrynic acid in combination with topical gentamicin to the round window failed to demonstrate a significant deterioration in cochlear sensitivity, whereas all animals receiving systemic gentamicin plus ethacrynic acid experienced profound increases in CAP thresholds. CONCLUSIONS: This study supports the contention that ethacrynic acid potentiates aminoglycoside ototoxicity by facilitating the entry of the antibiotics from the systemic circulation into the endolymph. In addition, this study answers important clinical concerns regarding the safety of the use of topical aminoglycoside agents in combination with loop diuretics.

Action Potentials↗
PubMed1982

The effect of ethacrynic acid, bumetanide, frusemide, spironolactone and ADH on electrolyte excretion in ponies.

The effect of ethacrynic acid, bumetanide, frusemide, spironolactone and anti-diuretic hormone (ADH) on the urinary and faecal excretion of water and electrolytes by ponies was studied. Ethacrynic acid, bumetanide, and frusemide given intravenously, increased urinary sodium excretion, and, excepting frusemide, decreased faecal sodium excretion. Given by stomach tube ethacrynic acid reduced urinary and faecal sodium. Bumetanide, given intravenously, spironolactone, frusemide and ADH increased urinary sodium and all except frusemide intravenously decreased faecal sodium regardless of route of administration. Ethacrynic acid and bumetanide, given by stomach tube or intravenously decreased urinary and faecal potassium excretion, as did spironolactone and frusemide given orally. Ethacrynic acid and bumetanide given orally or intravenously, frusemide given orally and ADH intranasally reduced urinary chloride excretion; these same drugs by the same routes also reduced faecal chloride excretion. Excepting frusemide given intravenously, and ethacrynic acid orally, the effect of the drugs studied was not the same on urinary sodium excretion as on faecal sodium excretion. This suggested that different mechanisms were involved in the control of sodium excretion by the kidney and in the gut. There were similarities in the treatment of potassium and chloride by these organs.

Animals↗
PubMed1994

Inhibition by ethacrynic acid of NO-mediated relaxations of the rat anococcygeus muscle.

1. The effects of ethacrynic acid were studied on relaxations elicited by nitric oxide (NO), the NO-donors sodium nitroprusside (SNP) and glyceryl trinitrate (GTN), nitrergic nerve stimulation and the NO-independent agent papaverine in isolated preparations of rat anococcygeus muscles. 2. Ethacrynic acid (100 mumol/L) produced complete relaxation of partially contracted anococcygeus muscles, but the tone recovered after the ethacrynic acid was washed out. Following exposure to ethacrynic acid, the relaxant responses to NO, SNP, GTN and nitrergic nerve stimulation were abolished or markedly reduced; however, the response to papaverine was only slightly reduced. 3. The presence of 3 mmol/L L-cysteine during the period of exposure to ethacrynic acid prevented the inhibition of the relaxing effects of SNP, GTN and nitrergic nerve stimulation almost completely, but did not affect the slight reduction in responses to papaverine. 4. The addition of L-cysteine (3 mmol/L) after incubation with ethacrynic acid did not significantly affect the inhibited responses to SNP and GTN; however, the inhibited responses to nitrergic nerve stimulation were slightly but significantly increased. 5. The results suggest that endogenous sulphydryl groups are required for the actions of NO, NO-donating drugs and the nitrergic transmitter in the rat anococcygeus muscle and possibly for the synthesis or release of the nitrergic transmitter.

Amino Acid Oxidoreductases↗
PubMed2001

Sensitization to the cytotoxicity of melphalan by ethacrynic acid and hyperthermia in drug-sensitive and multidrug-resistant Chinese hamster ovary cells.

The ability of physical and pharmacological modulators to increase the cytotoxicity of melphalan was investigated in Chinese hamster ovary cells using a clonogenic cell survival assay. Hyperthermia has potential for use in cancer treatment, particularly as an adjuvant to chemotherapy or radiotherapy. Ethacrynic acid is a glutathione S-transferase inhibitor and also undergoes conjugation with glutathione. Interactions between hyperthermia (41-43 degrees C), ethacrynic acid and melphalan were evaluated in multidrug-resistant (CH(R)C5) cells with overexpression of P-glycoprotein (33.69-fold), and in drug-sensitive (AuxB1) cells. GST alpha was expressed at a higher level (3.65-fold) in CH(R)C5 cells than in sensitive cells, whereas levels of isoforms pi and mu were the same. GST pi was the most highly expressed isoform in the two cell populations. Ethacrynic acid was cytotoxic at elevated temperatures, while it caused little or no cytotoxicity at 37 degrees C. This effect occurred in drug-resistant and drug-sensitive cells, and attributes thermosensitizing properties to ethacrynic acid. Ethacrynic acid (20 microM) alone did not alter the cytotoxicity of melphalan at 37 degrees C. Hyperthermia potentiated drug cytotoxicity in cells, both with and without ethacrynic acid treatment. Ethacrynic acid could be useful in cancer treatment by acting as a thermosensitizer when combined with heat and by enhancing the cytotoxicity of melphalan at elevated temperatures. A major advantage arising from the use of regional hyperthermia is the ability to target drug cytotoxicity to the tumor volume. A useful finding is that ethacrynic acid, heat and/or melphalan are also effective against multidrug-resistant cells with overexpression of P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1986

Selective inhibition of leukotriene C4 synthesis in human neutrophils by ethacrynic acid.

Addition of glutathione S-transferase inhibitors, ethyacrynic acid (ET), caffeic acid (CA), and ferulic acid (FA) to human neutrophils led to inhibition of leukotriene C4 (LTC4) synthesis induced by calcium ionophore A23187. ET is the most specific of these inhibitors for it had little effect on LTB4, PGE2 and 5-HETE synthesis. The inhibition of LTC4 was irreversible and time dependent. ET also had little effect on 3H-AA release from A23187-stimulated neutrophils.

Arachidonic Acid↗
PubMed1996

Ethacrynic acid and 1 alpha,25-dihydroxyvitamin D3 cooperatively inhibit proliferation and induce differentiation of human myeloid leukemia cells.

The active form of vitamin D, 1 alpha,25-dihydroxyvitamin D3 (VD3), inhibits proliferation and induces differentiation of leukemia cells, but its clinical use is limited by the adverse effect of hypercalcemia. In this study we found that the loop diuretic ethacrynic acid, which is used to treat hypercalcemia, enhanced the differentiation of human leukemia cells induced by VD3. Ethacrynic acid alone inhibited the proliferation of human promyelocytic HL-60 cells while only slightly increasing differentiation markers such as nitroblue tetrazolium (NBT)-reducing and lysozyme activities. Ethacrynic acid effectively enhanced the growth-inhibiting action of VD3. In the presence of ethacrynic acid, VD3 increased the NBT-reducing and lysozyme activities and the CD11b expression of HL-60 cells more effectively than VD3 alone. Other loop diuretics, furosemide and bumetanide, also enhanced the differentiation of HL-60 cells induced by VD3, but to a lesser extent than ethacrynic acid. The differentiation of HL-60 cells induced by all-trans retinoic acid, dimethyl sulfoxide or phorbol-12-myristate 13-acetate was also enhanced by ethacrynic acid with increasing NBT-reducing and lysozyme activities and the expression of CD11b or CD14 surface antigen. Morphologically, ethacrynic acid enhanced the monocytic differentiation of HL-60 cells induced by VD3 and phorbol ester and the granulocytic differentiation by retinoic acid and dimethyl sulfoxide. Other human myelomonocytic leukemia ML-1, U937, P39/TSU and P31/FUJ cells were induced to differentiate by VD3 and this was also enhanced by ethacrynic acid. The long-term culture of HL-60 cells showed that ethacrynic acid plus VD3 induced the complete growth arrest of HL-60 cells. Therefore ethacrynic acid, which is used to treat hypercalcemia, enhanced the proliferation-inhibiting and differentiation-inducing activities of VD3 and the combination of ethacrynic acid and VD3 may be useful in therapy for myeloid leukemia.

Calcitriol↗
PubMed1992

The effect of intracameral ethacrynic acid on the intraocular pressure of living monkeys.

Previous studies have shown that the sulfhydryl-reactive ethacrynic acid increases outflow facility in living monkeys when perfused via the anterior chamber. To study its potential clinical use further, living monkeys were intracamerally injected with 10 microliters of ethacrynic acid, with concentrations ranging from 0.5 to 7.5 mmol/l. The fellow control eye was injected with 10 microliters of diluent. The status of the anterior segment was monitored by slit-lamp biomicroscopy and the intraocular pressure was measured by pneumatonometry with the monkeys anesthetized with ketamine. The anterior segment of living monkeys tolerated injections up to 3.0-mmol/l ethacrynic acid without marked adverse effects. One of 13 monkey eyes injected with 3.0-mmol/l ethacrynic acid demonstrated mild reversible segmental corneal edema. The greatest mean intraocular pressure reduction in the 3.0- to 3.75-mmol/l group occurred at six hours, with the experimental intraocular pressure decreasing 2.9 mm Hg compared to a mean intraocular pressure increase of 0.1 mm Hg in the control group (n = 19). Concentrations of ethacrynic acid less than 3.0 mmol/l did not provide reliable reduction of intraocular pressure, whereas concentrations greater than 3.75 mmol/l caused a greater incidence and severity of corneal edema. We believe that the intracameral injection of ethacrynic acid can reliably and safely reduce intraocular pressure in living monkey eyes, and that this drug deserves further investigation as a potential antiglaucomatous agent.

Animals↗
PubMed1968

The action of ethacrynic acid on sodium efflux from single toad oocytes.

1. Ethacrynic acid (10(-3)M) at pH 7.4 caused approximately 83% inhibition of Na efflux from single dissected toad oocytes.2. Less inhibition was found at concentrations below 10(-3)M but higher concentrations did not cause greater inhibition.3. At an external pH of 7.0 the onset of inhibition was more rapid than at pH 7.4.4. Ouabain (10(-3)M) produced only 30% inhibition of the Na efflux, and the subsequent application of ethacrynic acid largely inhibited the remaining efflux.5. Application of ouabain, after ethacrynic acid had produced some 80% inhibition, caused only a further 9% drop in efflux.6. In uninhibited cells, Na efflux was found to be greater at pH 8.0, and less at pH 7.0 than at 7.4.

Animals↗
PubMed1991

Phase I study of thiotepa in combination with the glutathione transferase inhibitor ethacrynic acid.

The glutathione transferases comprise a family of isoenzymes, one or more of which are involved in the conjugation of alkylating agents to glutathione (GSH). Increased GSH transferase activity has been shown to underlie acquired resistance to several alkylating agents. Ethacrynic acid inhibits the isoenzymes of GSH transferase with 50% inhibitory concentration values ranging from 0.3 to 6.0 microM and has been shown to restore sensitivity to alkylating agents in drug-resistant animal tumor models. We entered 27 previously treated patients with advanced cancer on a study of ethacrynic acid (25 to 75 mg/m2 p.o. every 6 h for 3 doses) and thiotepa (30 to 55 mg/m2 i.v. 1 h after the second dose of ethacrynic acid). The major toxicity of ethacrynic acid was diuresis, which was observed at every dose level; in addition, severe metabolic abnormalities occurred at 75 mg/m2. At 50 mg/m2, the diuretic effects were manageable. Myelosuppression was the most important effect of the combination. Two of seven courses of ethacrynic acid, 50 mg/m2, and thiotepa, 55 mg/m2, were associated with grade 3 or 4 neutropenia and/or thrombocytopenia. Nausea/vomiting greater than or equal to grade 2 was observed in 16% of courses. GSH transferase activity was assayed spectrophotometrically in the peripheral mononuclear cells of all patients. At each dose level, activity decreased following ethacrynic acid administration, with recovery by 6 h. Administration of ethacrynic acid, 50 mg/m2, resulted in a mean nadir of transferase activity of 37% of control. The pharmacokinetics of thiotepa and its principal metabolite TEPA were studied in 23 patients. The plasma disappearance of thiotepa fit a two-compartment open model with a terminal half-life of approximately 2 h. Plasma TEPA levels peaked at a mean of 2.16 h following thiotepa administration. The harmonic mean terminal half-life of TEPA was 10.4 h, and the TEPA area under the curve (AUC) did not increase with increasing thiotepa dose. The AUC of thiotepa was approximately twice, and the clearance about one-half, of the values obtained in a previous study of single agent thiotepa. The AUC of TEPA was lower than that previously observed. The data suggest that ethacrynic acid inhibits enzymes involved in the metabolic disposition of thiotepa, including its oxidative desulfuration to TEPA. The severity of the platelet toxicity was correlated with the AUC of thiotepa, but not with that of TEPA. This combination of thiotepa and ethacrynic acid will be tested further in Phase II trials.

Adult↗
PubMed1977

Effects of ethacrynic acid and furosemide on phosphorylation reactions of kidney mitochondria. Inhibition of the adenine nucleotide translocase.

Previous reports that ethacrynic acid and furosemide diminish mitochondrial P : O ratios and reduce (Na+ + K+)-ATPase activity suggested that these diuretics may inhibit mitochondrial phosphorylation reactions. This possibility was initially studied by determining the effects of ethacrynic acid and furosemide on [32P]ATP exchange activity of rat kidney mitochondria. Concentrations of both drugs at 10(-4) M or greater, significantly inhibited [32P]ATP exchange. To investigate the mechanism of this inhibition, the effects of ethacrynic acid and furosemide on the ATPase activity of intract mitochondria and sonicated submitochondrial particles were determined. Both diuretics inhibited ATPase activity of intact mitochondria at 10(-4) M. In contrast, ATPase of submitochondrial particles was significantly less susceptible to inhibition by the diuretics. These results suggested that ethacrynic acid anf furosemide inhibit adenine nucleotide transport across the mitochondrial membrane. This was directly tested by determining the effects of the diretics on the mitochondrial adenine nucleotide translocase. At 5-10(-4) M, both ethacrynic acid and furosemide significantly inhibited adenine nucleotide transport. These findings suggest that ethacrynic acid and furosemide may diminish renal tubular solute reabsorption by direct inhibition of adenine nucleotide transport across the mitochondrial inner membrane.

Adenosine Triphosphatases↗