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PubMed1989

Determination of ethacrynic acid in pharmaceutical formulations by difference ultraviolet spectrophotometry after derivatisation with N-acetylcysteine.

A selective difference spectrophotometric procedure is described for the assay of ethacrynic acid (a diuretic drug) in pharmaceutical dosage forms. The method is based on the reaction of the drug with N-acetylcysteine at pH 7.4 and ambient temperature, affording thiol adducts having different spectral properties, and involves the measurement of the absorbance of the reaction mixture relative to an equimolar solution of unreacted ethacrynic acid. The absorbance at 270 nm (A(270)) and the absorbance difference, delta A=A(270-A(244), obtained from the difference spectrum, were found to be linearly correlated with the drug concentration. The proposed spectrophotometric procedure was applied successfully to the determination of ethacrynic acid in pharmaceutical formulations using a reversed-phase high-performance liquid chromatographic procedure as a reference method.

Acetylcysteine↗
PubMed1975

Urea and sodium in sheep kidneys during ethacrynic acid diuresis.

The possibility of uphill transport of urea from the collecting ducts of sheep fed diets containing 14% protein (HP) and 4.9% protein (LP) was explored by measuring cortex to papilla and urine to papilla gradients of urea during ethacrynic acid diuresis. Clearance studies were done on adult, unanesthetized, hydropenic, vasopressin infused sheep. Saline was given to compensate for urine loss during ethacrynic acid diuresis. Following a period of antidiuresis, ethacrynic acid administration caused and increase in fractional water excretion to 0.33 (HP) and 0.44 (LP), an increase in fractional sodium excretion to 0.28 (HP) and 0.41 (LP), and an average increase in glomerular filtration rate of 14.7%. Fractional potassium excretion showed no consistent change. Renal concentrating ability and medullary sodium accumulation were inhibited. Antidiuretic LP and HP medullary urea accumulation patterns were lost. However, identical but small ascending cortex to papilla urea gradients remained in the LP and HP animals. There was no significant difference between the urea concentration in urine and papilla tissue water. The results fail to provide support for the presence of active urea transport from the collecting ducts of sheep fed high or low protein diets.

Animals↗
PubMed1985

Dissociation of the cochlear microphonics and endocochlear potential after injection of ethacrynic acid.

The cochlear microphonics (CM), endocochlear potential (EP) and summating potential (SP) were simultaneously recorded for 60 min after injection of 30 mg/kg body weight of ethacrynic acid. The EP decreased parallel with the CM for about 20 min after injection, but they differed in the recovery stage. Even when the EP was still negative, the output of CM for 500 Hz acoustic stimulus recovered to its original level and was supernormal. A large SP observed in the recovery stage of CM and EP seemed to suggest that some functional change in the hair cells might be connected with the supernormal CM. Four minutes of anoxia during the supernormal CM decreased CM to only 68% of its level prior to anoxia. A cathodal polarization of the scala media, to change the polarity of the dc potential gradient, reversed the polarity of CM in the anoxic guinea-pig cochlea but not in the guinea-pig cochlea administered ethacrynic acid. These results suggest that supernormal CM observed in this experiment may not be dependent on the dc potential gradient, but due to some functional change in the hair cells after the injection of ethacrynic acid, although CM is essentially dependent on the dc potential gradient between the scala media and the inside of the hair cells.

Acoustic Stimulation↗
PubMed1995

New specific and sensitive HPLC-assays for ethacrynic acid and its main metabolite--the cysteine conjugate--in biological material.

A reversed-phase high-performance liquid chromatography (HPLC) method was developed and validated for the determination of the loop diuretic ethacrynic acid and its potentially active main metabolite, the ethacrynic acid-cysteine conjugate, in biological material. Simple and rapid sample preparation procedures were established using solid-phase extraction for the parent drug and direct injection after one washing step for the metabolite. HPLC separation was performed on a Spherisorb ODS II (3 microns) analytical column using isocratic elution with different mixtures of mobile phases (phosphoric acid-methanol-acetonitrile-tetrahydrofuran or triethylamine buffer-methanol, respectively). The analytes were detected by measuring the UV absorption of the eluate at 275 nm. Stability studies revealed that considerable amounts of ethacrynic acid may be released from the cysteine conjugate unless the urine samples are pH stabilized (pH 3-4). The assay provided high sensitivity with limits of quantification of 20 ng ml-1 for ethacrynic acid in plasma and urine, and 240 ng ml-1 for the cysteine conjugate in urine. All validation parameters were within the required limits. For the presented assays, the applicability to pharmacokinetic studies and routine analyses was proved.

Chromatography, High Pressure Liquid↗
PubMed1978

Early effects of ethacrynic acid on cochlear histochemistry.

We have investigated the histochemical changes in the succinodehydrogenase (SDH) and adenosine triphosphatase (ATPase) enzyme systems of the guinea pig cochlea at 30, 60, and 240 minutes following the intracardiac injection of ethacrynic acid. In control animals, there is intense SDH activity in the stria vascularis, spiral prominence, and hair cells. At all periods after ethacrynic acid injection, there was decreased activity of SDH in the outer hair cells in the basal turn. The activity of SDH in the stria vascularis and spiral prominence was equally as intense as in control animals at all periods, however. Strong ATPase activity in control animals was demonstrated by dark-brown precipitations in the external sulcus cells, stria vascularis, and hair cells. The ATPase activity was decreased at 60 minutes after ethacrynic acid injection only in the stria vascularis. The importance of these results is discussed.

Adenosine Triphosphatases↗
PubMedDate not supplied

[The effect of ethacrynic acid on the functions of the gastrointestinal tract].

During in vitro and in situ experiments ethacrynic acid was shown to reduce the gastric secretion in rats, motility of the small intestine in rats and mice, contractions of the ileum of guinea pigs in response to histamine and acetylcholine. The intestinal water and electrolyte absorption in rats decreased too. All these effects of ethacrynic acid are extrarenal.

Animals↗
PubMed1983

The effect of ethacrynic acid on biliary excretion, concentration of ioglycamide and bile flow in dogs.

The effect of ethacrynic acid (EA), an agent which increases bile acid independent bile flow, on the biliary excretion and concentration intravenously administered biliary contrast agent ioglycamide was studied on cholecystectomized anesthetized dogs equipped with Thomas cannula through which the common bile duct could be cannulated. One hour after cannulation i.v. infusion of ioglycamide at a rate of 4 mu mol./min./kg. was started. Two hours later 1 mg./kg. of ethacrynic acid was injected intravenously. This procedure was repeated three times on four dogs, five dogs receiving comparable volume of saline at comparable time serving as controls. Bile was collected at 15 min. intervals and simultaneous i.v. blood samples were taken. EA injection caused decrease in biliary ioglycamide concentration and biliary excretion of ioglycamide and a slight but statistically not significant decrease in bile flow. Since EA is an organic anion and the increase in bile flow induced by it has been shown to be related to the biliary excretion of its metabolites, it may be suggested that EA as an organic anion inhibited biliary excretion and hepatic uptake of ioglycamide but having lower choleretic effect its excretion could not increase the bile flow.

Animals↗
PubMed1992

Thiol adducts of ethacrynic acid increase outflow facility in enucleated calf eyes.

Ethacrynic acid (ECA), a sulfhydryl (SH)-reactive diuretic drug, has been shown to increase outflow facility (C) both in living monkey eyes and in the calf eye, in vitro (Epstein et al. 1987). In an attempt to increase the therapeutic index of this drug for potential clinical use in glaucoma, we explored the effect of various thiol adducts of ECA on C in the calf eye in vitro. These adducts might be expected to liberate ECA by a reversible retro-Michael type reaction. Enucleated calf eyes were perfused at 25 degrees C at 15 mm Hg for 5 hours with various ECA-thiol adducts. ECA-cysteine at 0.25 mM (for each) increased outflow facility 104% compared to 38% in sham manipulated eyes (n-10; p less than .005). A dose response effect was demonstrated from 0.01 mM to 0.25 mM. A relative potency table (for increasing C) was established for several ECA-thiol adducts: Cysteine = cysteamine greater than glutathione greater than N-Acetyl cysteine greater than thiosalicylic acid greater than N-Acetyl cysteamine. This study identifies the potential of utilizing various derivatives of ECA as outflow pathway acting agents.

Animals↗
PubMed1997

The glutathione conjugate of ethacrynic acid can bind to human pi class glutathione transferase P1-1 in two different modes.

The diuretic drug ethacrynic acid, an inhibitor of pi class glutathione S-transferase, has been tested in clinical trials as an adjuvant in chemotherapy. We recently solved the crystal structure of this enzyme in complex with ethacrynic acid and its glutathione conjugate. Here we present a new structure of the ethacrynic-glutathione conjugate complex. In this structure the ethacrynic moiety of the complex is shown to bind in a completely different orientation to that previously observed. Thus there are at least two binding modes possible, an observation of great importance to the design of second generation inhibitors of the enzyme.

Binding Sites↗
PubMed1991

Mechanisms involved in the effects of phenidone, diclofenac and ethacrynic acid in rat uterus in vitro.

1. The effects of phenidone (P, 10(-4)-10(-3) M), sodium diclofenac (D, 10(-5)-10(-4) M) and ethacrynic acid (E, 10(-5)-10(-4) M), proposed as inhibitors of eicosanoid synthesis, on the contractions of rat uterus induced by several agonists have been studied. 2. P, D and E inhibit the motility induced by oxytocin (4 mU/ml) (IC50: 4.62 x 10(-4), 2.55 x 10(-4) and 2.98 x 10(-5) M, respectively). 3. P (10(-3) M), D (10(-4) M) and E (10(-4) M) also inhibit the contraction induced by methacholine (10(-5) M), prostaglandin F2a (10(-6) M) and CaCl2 (6 mM), and relaxed, in a dose-dependent way, the tonic component of contraction to KCl (60 mM) (IC50: 5.81 x 10(-4), 6.67 x 10(-5) and 7.55 x 10(-5) M, respectively). 4. The CaCl2 (0.1-10 mM) reverted the relaxation of KCl contraction produced by P, but not by D or E. None of the inhibitions on CaCl2 (6 mM) are reverted by Bay K 8644. 5. D and E also relaxed the tonic contraction to vanadate (10(-4) M) in uterus incubated in calcium free solution P, enhances the vanadate-induced contractions.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1992

Inhibition of human hepatic glutathione S-transferase isozymes by ethacrynic acid and its metabolites.

The comparative inhibition of ethacrynic acid (EA) and its known metabolites against glutathione S-transferase (GST) was investigated using human livers procured from kidney donors. EA and all three metabolites of EA had an inhibitory effect against conjugation between 1-chloro-2,4-dinitrobenzene (CDNB) and glutathione (GSH). The GSH adduct of EA (EA-GSH) was the most potent inhibitor of GSTs; EA-GSH was approximately one order of magnitude more potent than the parent EA, while L-cysteine conjugate of EA (EA-cysteine) and N-acetyl-L-cysteine conjugate of EA (EA-mercapturate) were approximately two orders of magnitude less potent than the parent EA. Further metabolism of EA-GSH conjugate is suggested to be a detoxification process in terms of GST activities.

Cytosol↗
PubMed1968

Ethacrynic acid in blood transfusion--its effects on plasma volume and urine flow in severe anaemia in pregnancy.

Thirty grossly anaemic pregnant Nigerian women with venous haematocrit levels varying between 6 and 17%, had their plasma volumes estimated by the Evans blue dye dilution technique, both before and immediately after direct transfusion of packed blood cells. Parenteral ethacrynic acid was added to the blood for transfusion in 20 patients, seven of whom were in anaemic heart failure on admission. Ethacrynic acid used in this way was successful in the prevention of acute pulmonary oedema, and it produced acute diuresis as well as a reduction of plasma volume in the majority of cases. This technique of direct transfusion with ethacrynic acid is simple, and it may well replace exchange transfusion as a means of treating patients with anaemic heart failure.

Anemia↗
PubMed1996

Ethacrynic acid disrupts steady state microtubules in vitro.

PURPOSE: Ethacrynic acid (ECA) has been shown to increase facility of aqueous outflow in whole eyes and perfused anterior segments, to open up spaces between cells in the trabecular meshwork and inner wall of Schlemm's canal, and to cause separation and retraction of trabecular meshwork and endothelial cells in culture. One mechanism by which ECA has been proposed to act in cells is via disruption of microtubules, leading to cell retraction. Although it is known that ECA can inhibit de novo assembly of microtubules from tubulin subunits in vitro, we wanted to determine, as a better correlate to the proposed effect of ECA in cells, whether ECA could disrupt microtubule polymers that had reached steady state. We also wanted to determine whether calcium ion could enhance this process. METHODS: We therefore assembled purified and crude porcine brain tubulin to steady state at 37 degrees C and then added ECA and/or calcium. Reaction kinetics were followed spectrophotometrically. RESULTS: We found that ECA effectively disrupted assembled microtubules in vitro. Although 0.8-1.0 mM ECA was required to produce a half-maximal effect in pure tubulin microtubules and 0.2-0.3 mM ECA was necessary with crude microtubule protein, significant disassembly also occurred in the 0.01-0.2 mM range. Calcium had a greater maximal effect than ECA, and was more potent on a molar basis, showing half maximal effect between 2 and 12 microM free calcium ion. Combination experiments showed that ECA did not act synergistically with calcium to increase microtubule disassembly. CONCLUSIONS: Our results are consistent with the proposed disruptive action of ECA on the assembled microtubules of outflow pathway cells, but do not support a rise in intracellular calcium as being an added factor.

Animals↗
PubMed1997

A mechanism for trabecular meshwork cell retraction: ethacrynic acid initiates the dephosphorylation of focal adhesion proteins.

Ethacrynic acid (ECA) increases aqueous humor outflow facility in human and animal model systems, and causes cellular retraction in cultured trabecular meshwork (TM) cells. ECA-induced retraction, a possible correlate to the opening of spaces in the outflow pathway in vivo, takes place coincident with disruption of cell-cell attachments and actin stress fibers. Tyrosine phosphorylated proteins are located predominantly where actin filaments terminate at sites of cell-to-cell and cell-to-substrate adhesion, and are understood to regulate cellular adhesions and filamentous (F) actin organization in many cell types. In the present study we investigated whether ECA might affect cell adhesions and F-actin in TM cells by altering levels of phosphotyrosine. We analysed levels of phosphotyrosine in cultured human TM and calf pulmonary artery endothelial cells after exposure to ECA. Using immunoflourescence microscopy and antibodies to phosphotyrosinated proteins we found a rapid decrease in phosphotyrosine levels at the focal contacts of cells treated with ECA. Immunoblots of whole cell extracts showed a decrease in phosphotyrosine predominantly in a band running at about 120 kD, with a more subtle decrease in a band about 65 kD. Reprobing the blot with antibodies to pp120 focal adhesion kinase (FAK) or paxillin indicated that the 120 kD band was FAK and the 65 kD band was likely paxillin. Immunoprecipitation of FAK or paxillin and probing the resulting blot with antibodies to phosphotyrosine confirmed that these proteins were rapidly dephosphorylated after ECA addition. Loss of FAK and paxillin proteins in cells was then confirmed using immunofluorescence microscopy. Dephosphorylation of these proteins was detected before the onset of retraction, stress fiber disruption, or complete disruption of focal adhesions. A pure microtubule inhibitor (colchicine), did not cause stress fiber disruption or decrease focal adhesion phosphorylation. We postulate that dephosphorylation of FAK and paxillin by ECA disrupts signaling pathways that normally maintain the stability of the actin cytoskeleton and cellular adhesions, and that this action leads both to cell shape change in culture, and to facility changes in vivo.

Actins↗
PubMed1976

Studies on renin release from isolated superfused glomeruli: effects of temperature, urea, ouabain and ethacrynic acid.

1. The effects of different energy substrates, of low temperature, of urea, and of ouabain and ethacrynic acid were studied on the rate of renin release from viable juxtaglomerular cells during superfusion of isolated rat glomeruli. 2. Neither lactate nor glutamate altered renin release rate from that observed using glucose as the sole energy substrate. Succinate 10 mM elevated release transiently but did not influence the release caused by reductions in osmolality through lowering sucrose concentration. 3. Peak renin release was more prolonged and returned more slowly to control following reductions in osmolality in phosphate-Ringer than in bicarbonate-Ringer. 4. At 37 degrees C, the peak of renin released induced by hypo-osmolality was smaller and delayed, and returned earlier to control than at 30 degrees C. Reduction in temperature from 30 to 4 degrees C resulted in a 32-fold increase in basal release rate. At 4 degrees C a 20 m-osmole/kg reduction in tonicity caused an additional 2-5-fold increase in release rate. 6. Increasing superfusate osmolality with urea did not affect basal renin release but 100 mM urea suppressed the releasing effect of a 15 mM reduction in NaCl concentration. 7. Ouabain (10(-4) M) caused a small (33 +/- 9%, P less than 0-025) transient increase in renin release. Ethacrynic acid (10(-3) M) provoked a progressive increase in release reaching 100 +/- 15% above control within 50 min. In the presence of both inhibitors the release provoked by hyposmolality was prolonged. 8. It is concluded that renin release in vitro is a function of actively regulated cell volume and it is proposed that a similar mechanism could underline both barorecptor and macula densa controls of renin secretion in vivo.

Animals↗
PubMed1995

Inhibition of glutathione-related enzymes and cytotoxicity of ethacrynic acid and cyclosporine.

Glutathione (GSH) is an endogenous thiol that detoxifies active oxygen and reactive species formed during intermediary metabolism and drug detoxification. Compounds with a range of potential toxicities were tested for their abilities to affect GSH reductase and GSH S-transferase activities, which are each components of the two principal detoxification pathways in which GSH participates. A high performance liquid chromatographic method for determining oxidized and reduced GSH was modified to assay GSH reductase activity. With this method it was possible to demonstrate that ethacrynic acid, which inhibits GSH S-transferase, also inhibits the activity of GSH reductase. Inhibition of GSH reductase by ethacrynic acid was similar to that seen with carmustine (BCNU). GSH reductase activity was not affected by cis- or transplatin, buthionine sulfoximine, other loop diuretics, cyclosporine A or aminoglycosides. Cyclosporine inhibited GSH S-transferase at 50 microM and higher concentrations. These results support a role for GSH-mediated detoxification mechanisms in ethacrynic acid- and cyclosporine-associated cytotoxicity, which may mediate their toxicities and their potential as adjunctive agents in antineoplastic therapy. A better understanding of the mechanism of their toxicity can greatly extend the clinical usefulness of these agents, as this toxicity is the basis of both their therapeutic and antitherapeutic actions.

Animals↗
PubMed1976

The ototoxic effects of ethacrynic acid in man and animals.

A review of the literature was carried out to summarize the ototoxic effects of ethacrynic acid on man and animal. The effects of this drug on the electrolytes of the endolymphatic and perilymphatic systems, on the cochlear potentials and the auditory cortical-evoked responses, were reviewed. Histological animal studies determined by light and electron microscopy were described. Potentiation of this drug with previous aminoglycoside therapy was discussed. In this paper, a human case report with temporal bone findings was present in addition to the histopathological effects of this drug which were shown in a series of animals receiving this drug over a period of time. Edematous and cellular changes in the stria vascularis, especially with animals receiving large doses of the drug, were described. No permanent alterations in the cochlear potentials resulted from the long-term therapy with ethacrynic acid.

Animals↗
PubMed1986

The basis for the cellular damage induced by ethacrynic acid in liver slices in vitro. Comparison of structure and function.

The development of cellular damage in response to ethacrynic acid and to amytal has been studied in slices of rat liver. After a preincubation at 1 degree C, the slices were incubated with or without the agents at 38 degrees C. Control slices showed a net extrusion of water, Na+, Cl-, and Ca2+, and a net reaccumulation of K+, during incubation at 38 degrees C. Ethacrynic acid (3 mM) reduced the extrusion of water, Na+ and Cl- during the first 5 minutes at 38 degrees C, but Ca2+ extrusion was not affected. Morphological indications of damage to mitochondria were apparent already at 5 minutes, although unaccompanied by a change of tissue ATP content. The mitochondrial damage was more marked at 15 minutes, when signs of early necrosis were also evident in some cells and ATP content started to fall. At longer times with ethacrynate, water and Ca2+ started to re-enter slices and there were indications of a loss of selective permeability of the plasma membranes; no significant uptake of K+ occurred at any time. Electron-dense particles, apparently of Ca2+, were deposited in the mitochondria and cisternae of the endoplasmic reticulum. The morphological appearance rapidly progressed to a marked disorganization. Slices incubated with 4 mM amytal showed greater and earlier loss of ATP than slices with ethacrynate and complete inhibition of water extrusion; other biochemical and morphological effects were generally less marked than with ethacrynate. Some of the morphological and biochemical effects of the two agents after 15 minutes at 38 degrees C could be reversed upon removal of the drugs. However, Ca2+ contents showed a late rise which started 20 minutes after removal of the drugs, indicating that an early, nonreversible damage of the calcium regulating mechanism had occurred. The results suggest that early effects of ethacrynate are on cell volume regulation and mitochondrial structure and function; there follow more general changes of membrane permeability and loss of control of cell Ca2+. A variety of biochemical and morphological markers of cell damage gave different indications of the level of damage in the early phases of treatment with each of the drugs used here. At longer times (e.g., 60 min) there was a greater degree of uniformity in the indications of cell damage.

Adenosine Triphosphate↗