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PubMed1992

Effects of sulfobromophthalein and ethacrynic acid on glyceryl trinitrate relaxation.

The effects of sulfobromophthalein (SBP) and ethacrynic acid (ECA), both inhibitors of glutathione S-transferase (GST), or glyceryl trinitrate (GTN)-induced vasorelaxation were investigated in rabbit aortic strips. The aortic strips were pre-contracted with phenylephrine, followed by relaxation with 0.5 microM GTN, with or without 0.1 mM SBP or ECA. ECA was observed to inhibit GTN relaxation approximately 32%, whereas SBP did not alter the GTN activity. The dinitrate metabolites (GDN) of GTN in the tissues were also measured. The amounts of both GDNs were decreased in the ECA-treated, but not the SBP-treated group. Moreover, in the ECA-treated group, a strong correlation was obtained between the loss of GTN activity and the decrease in GTN metabolism. Concentration-response studies also revealed that ECA attenuates GTN relaxation. The slope factor of the concentration-response curves was decreased by ECA, but not by SBP, although both inhibitors caused a mild decrease in Emax. In the 9000 g supernatant of rabbit aorta, ECA was also observed to inhibit GTN metabolism more significantly than SBP. The results suggest that the mechanism of GTN activation may involve a GST isozyme that possesses high activities towards ECA.

Animals↗
PubMed1994

Partial hearing loss in the macaque following the co-administration of kanamycin and ethacrynic acid.

Co-administration of kanamycin (KA) with the loop diuretic ethacrynic acid (EA) rapidly produces a profound hearing loss in the cat while maintaining normal renal function [Xu et al., Hear. Res. 70, 205-215 (1993)]. In the present paper we have applied this deafening procedure to the old world monkey Macaca fascicularis (macaque). Following the co-administration of KA and EA, the hearing loss in the macaque developed far slower than we observed in the cat. Moreover, unlike the cat, there was evidence of a partial recovery in the animal's hearing, resulting in a bilaterally symmetrical high frequency hearing loss. The extent of this hearing loss was dependent on the dose of the EA administered. Finally, the most unexpected result of the present study was the degree of acute nephrotoxicity experienced by these animals following the drug administration. The sensitivity of this species to renal failure restricted the dose of EA that could be safely administered. In conclusion, the co-administration of KA and EA cannot reliably produce a profound hearing loss in the macaque. While it can produce a dose dependent high frequency hearing loss the animal will also experience acute renal failure that requires careful management.

Animals↗
PubMed2004

Controlled release of ethacrynic acid from poly(lactide-co-glycolide) films for glaucoma treatment.

Ethacrynic acid (ECA) is a potential glaucoma drug that can reduce intraocular pressure. However, conventional methods of ECA administration may cause toxicity to normal eye tissues and are inconvenient to patients. Therefore, we developed and characterized an ECA loaded poly(lactide-co-glycolide) (PLGA) copolymer film, and quantified the therapeutic efficacy of the film implanted in the rabbit eye. In the aqueous medium, the release of ECA from the PLGA50:50 film was time dependent and more than 90% of ECA was released within a week. This release profile was consistent with the kinetics of water uptake and microstructural changes of PLGA50:50 films as revealed by an electron microscopy examination. ECA release and PLGA degradation caused a gradual pH decrease in the release medium. The total pH decrease was 0.4 unit in 3 days. We also observed that the initial rate of ECA release was positively correlated with the weight ratio of ECA versus PLGA and inversely correlated with the molar ratio of lactide versus glycolide in PLGA films. At the end of a 3-day incubation, the cumulative release of ECA from PLGA50:50, PLGA85:15 and PLGA100:00 films were 78.8%, 9.35% and 3.60%, respectively. When the PLGA50:50 film loaded with ECA was implanted into the sclera of rabbit eyes, the intraocular pressure was significantly reduced and the reduction was maintained for at least 10 days. These data indicate that PLGA films have a potential to be used as a controlled ECA release device for glaucoma treatment.

Absorption↗
PubMed1994

Pharmakokinetics and bioavailability study of ethacrynic acid as a modulator of drug resistance in patients with cancer.

Ethacrynic acid (EA) is an inhibitor of the glutathione S-transferases (GSTs), a family of detoxification enzymes the expression of which has been associated with resistance to several classes of anticancer drugs. We performed a two-way randomized crossover study to investigate the pharmacokinetics and bioavailability of EA and describe any toxicities of EA associated with i.v. administration. We administered EA (100 mg) either by the p.o. or i.v. route on days 1 and 2 for pharmacokinetic analysis. After i.v. administration, plasma EA disappearance was biphasic in seven patients and monophasic in two patients with a terminal half-life of 30 and 8 min, respectively. Mean total body clearance was high; 1405 ml/min in patients described by using a one-compartment model and 611 ml/min in those patients described by a two-compartment model. After p.o. administration, peak EA plasma concentrations were less than 10% of i.v. EA and the absolute bioavailability was less than 21% (range, 7-35%). The urinary output as a result of EA treatment was equal following either route of administration and together with the large first-pass effect suggests that a metabolite(s) may be the active diuretic agent(s). Burning at the injection site was the only toxicity unique to the i.v. route of EA administration. We concluded that the systemic availability of EA after p.o. administration is low and variable. This finding supports the potential utility of the i.v. route of administration for the treatment of drug resistance.

Aged↗
PubMed1993

Profound hearing loss in the cat following the single co-administration of kanamycin and ethacrynic acid.

Co-administration of kanamycin (KA) with the loop diuretic ethacrynic acid (EA) has previously been shown to produce a rapid and profound hearing loss in guinea pigs. In the present study we describe a modified technique for developing a profound hearing loss in cats. By monitoring the animal's hearing status during the intravenous infusion of EA the technique minimizes the effects of individual variability to the drug regime. Seven cats received a subcutaneous injection of KA (300 mg/kg) followed by intravenous infusion of EA (1 mg/min). Click-evoked auditory brainstem responses (ABRs) were recorded to monitor the animal's hearing during the infusion. When the ABR thresholds rose rapidly to levels in excess of 90 dB SPL the infusion of EA was stopped. This occurred at EA doses of 10-25 mg/kg, indicating considerable individual variability to the deafening procedure. However, there was a strong negative correlation (r = -0.93) between the EA dose and body weight which accounted for much of this variability. Subsequent ABR monitoring showed that this profound hearing loss was both bilateral and permanent. Significantly, blood urea and creatinine levels, monitored for periods of up to three days after the procedure, remained within the normal range. Furthermore, there was no clinical evidence of renal dysfunction as indicated by weight loss or oliguria. Cochlear histopathology, examined after a two months to three year survival period, showed an absence of all inner and outer hair cells in the majority of cochleas. The extent of loss of spiral ganglion cells was dependent on their distance from the round window and the period of survival following the deafening procedure. Clearly, the degeneration of spiral ganglion cells continued for several years following the initial insult. Finally, we observed no evidence of renal histopathology. In conclusion, the co-administration of KA and EA produces a profound hearing loss in cats without evidence of renal impairment. Monitoring the animal's hearing status during the procedure ensures that the dose of EA can be optimised for individual animals. Moreover, it may be possible to adapt this procedure to produce animal models with controlled high frequency hearing losses.

Animals↗
PubMed1996

Transport of the glutathione conjugate of ethacrynic acid by the human multidrug resistance protein MRP.

The multidrug resistance protein MRP has been shown to mediate the transport of glutathione S-conjugates across membranes. In this study we demonstrate that the glutathione S-conjugate of the diuretic drug ethacrynic acid, which is an efficient inhibitor of glutathione S-transferases, is a high-affinity substrate and inhibitor of the glutathione S-conjugate pump associated with MRP. This implies that ethacrynic acid may modulate drug resistance of tumor cells not only by inhibiting glutathione S-transferase activity, but also by inhibiting the export of drug conjugates from the cell by MRP.

ATP-Binding Cassette Transporters↗
PubMed1981

Lacrimal gland flow and potentials during dinitrophenol, ouabain, and ethacrynic acid perfusion.

Acetylcholine (ACh)-evoked flow from the main excretory duct as well as ACh-induced secretory and resting membrane potentials from cells of the rabbit lacrimal gland were recorded during perfusion with inhibitors. During perfusion with 2,4-dinitrophenol (DNP), ouabain, or ethacrynic acid, ACh-induced flow was 5%, 20%, and 8% of control, respectively; ACh-induced hyperpolarizing secretory potential was 64%, 50%, and 63% of control, respectively; and the resting membrane potential was 79%, 64%, and 73% of control, respectively. Only during perfusion with ethacrynic acid was there a significant increase in the number of cells that did not respond to ACh with a change in potential. We have concluded that (1) ACh-induced secretion is highly dependent on oxidative metabolism and Na-K ATPase; (2) ACh-induced hyperpolarization is dependent on changes in ionic permeabilities, Na-K ATPase, and to lesser extent oxidative metabolism; and (3) the resting membrane potential is much less dependent on oxidative metabolism and Na-K ATPase activity.

Acetylcholine↗
PubMed2004

Differential response of bipolar and normal control lymphoblastoid cell sodium pump to ethacrynic acid.

BACKGROUND: While the pathogenesis of manic-depressive, or bipolar, illness is unknown, an excess of intracellular sodium and calcium concentrations is thought to contribute to the development of the illness. Previous work has demonstrated a reduced adaptive response of the sodium pump to ethacrynic acid in lymphocytes obtained from bipolar subjects compared to psychiatrically normal controls. METHODS: To further examine this phenomenon, we investigated several aspects of sodium pump response (transcription, translation, activity, and intracellular ion concentration) in lymphoblastoid cell lines derived from bipolar subjects and matched normal controls. Cells were treated with ethacrynic acid 100 microM for 3 days. RESULTS: Normal control-derived cells exhibited an upregulation of sodium pump mRNA synthesis, protein expression, pump-specific binding and activity, and were able to maintain a normal intracellular sodium concentration. Cells derived from bipolar individuals did not alter sodium pump parameters in any way, and consequently, had a higher intracellular sodium concentration. LIMITATIONS: While bipolar lymphoblasts were from an inbred Old Order Amish population, the normal controls were from an outbred population. CONCLUSIONS: The results suggest that bipolar illness is associated with an abnormality in cellular sodium homeostatic regulation.

Adult↗
PubMed1971

Ethacrynic acid effect on the composition of cochlear fluids.

Ethacrynic acid, when administered to six dogs, caused a fall in the concentration of potassium in endolymph from 145 to 21 milliequivalents per liter and a rise in the concentration of sodium from 5.9 to 146 milliequivalents per liter. The composition of perilymph is unaffected. Perilymph and endolymph are slightly hypertonic as compared to plasma.

Animals↗
PubMed1988

Effects of lithium chloride and ethacrynic acid on experimental polycystic kidney disease.

Hydrocortisone acetate is known to produce polycystic kidney disease when administered to susceptible animals in the perinatal period. To assess whether sodium and water transport mechanisms are involved in cyst pathogenesis, we administered lithium, an inhibitor of such transport in the distal nephron, and ethacrynic acid, an inhibitor of sodium transport in the Loop of Henle, to hydrocortisone acetate treated newborn rats. Hydrocortisone acetate alone resulted in significant polycystic kidney disease with the development of uremia, hypokalemia, and shortened life span. Co-administration of lithium and hydrocortisone acetate increased the severity of cystic tubular change and further compromised renal function. Ethacrynic acid reduced the degree of cyst formation induced by the combination of lithium chloride and hydrocortisone acetate but otherwise had no effect. We conclude that fluid and electrolyte disturbance plays a significant role in cyst formation, but we are unable to ascribe that effect to a single ion. We also conclude that the antinatriuretic effect of glucocorticoids is not the principal factor in glucocorticoid induced polycystic kidney disease.

Animals↗
PubMed1996

Ethacrynic acid: effects on postsynaptic GABA responses and electric activity of CA3 neurones.

Ethacrynic acid (ETA) inhibits somatic Cl(-)-extrusion from hippocampal pyramidal neurones. We analysed the dependence of postsynaptic gamma-aminobutyric acid (GABA) responses on this Cl- extrusion. ETA irreversibly reduced the 'somatic' hyperpolarizing GABAA response (hGABAA) within a few minutes, without altering the following depolarizing GABAA (dGABAA) and hyperpolarizing GABAB responses. GABA-induced changes of the membrane resistance were not affected by ETA, indicating that ETA does not act primarily on receptor-operated channels. In about 50% of the tested CA3 neurones spontaneous activity and caffeine-induced epileptiform discharges increased initially after adding ETA. All neurones lost their activity during prolonged ETA exposure. The early ETA-induced increase of neuronal activity coincided with the decrease of hGABAA (disinhibition). The late suppressive action may be caused by intracellular acidosis.

Animals↗
PubMed2003

Effect of ethacrynic acid on sodium pump alpha isoforms in SH-SY5Y cells.

BACKGROUND: Ethacrynic acid (ECA), a diuretic that has several cellular actions, increases expression of the sodium and potassium-activated adenosine triphosphatase (Na, K-ATPase or Na pump) in normal lymphocytes, but not in lymphocytes of bipolar patients. While this has been proposed to be important in the pathophysiology of bipolar illness, the response of neural tissues to ECA is unknown. METHODS: Human neuroblastoma SH-SY5Y cells differentiated with 10-microM retinoic acid were treated with various ECA concentrations for 3 days, and changes in Na-pump alpha-isoform expression were quantified with densitometric analysis of Western bands. RESULTS: Expression of alpha1 and alpha3 Na pump isoforms significantly increased with 10-5 M ECA. Cells treated with 10-6 or 10-7 M ECA showed no change in Na-pump expression, while cells treated with 10-4 M ECA died. The alpha2 isoform could not be detected in differentiated SH-SY5Y cells. CONCLUSIONS: The effect of ECA on alpha1-isoform in neural tissue is similar to that observed in lymphocytes. As alpha3 isoform is not expressed in lymphocytes, however, we conclude that lymphocytes are an incomplete model of neural tissue.

Bipolar Disorder↗
PubMed1975

Effects of ruthenium red, quinacrine hydrochloride, ethacrynic acid and 2,4-dinitrophenol on the water receptor of the frog tongue.

Effects of some chemicals, which are known as inhibitors of Ca2+-dependent ATPases, on the water receptor of the frog tongue were examined by using single fungiform papilla preparations. When a sufficient amount of ruthenium red, quinacrine hydrochloride, ethacrynic acid or 2,4-dinitrophenol was added to the standard stimulating solution (5mM CaCl2+100 mM NaCl), which has been shown to stimulate sufficiently the water receptor of the frog tongue, no neural response was elicited. The concentrations necessary for 50% inhibition were approximately 3 X 10(-6)M for ruthenium red, 1 X 10(-5) M for quinacrine hydrochloride, 1 X 10 (-3) M for ethacrynic acid and 2 X 10(-4) M for 2,4-dinitrophenol. Organic mercurials, mersalyl acid and p-chloromercuribenzoic acid, had no effect on the nueral response, but repeated application of these chemicals led to a permanent depression in receptor activity. Ouabain had no effect on either the neural response or receptor activity. These observations indicate that the receptor molecule of the frog water receptor has a similar property to that of the Ca2+-dependent ATPase of red-cell membrane in respect to the susceptibility to inhibitors.

Adenosine Triphosphatases↗
PubMed1986

Culture duration alters the glutathione content and sensitivity to ethacrynic acid of rat hepatocyte monolayer cultures.

Many of the differentiated functions of hepatocytes are lost in culture, yet addition of certain medium supplements can aid in the retention of differentiated character. Therefore, the effect of time in monolayer culture on rat hepatocyte glutathione (GSH) synthesis and sensitivity to the GSH detoxicated xenobiotic ethacrynic acid was examined in cultures with and without medium supplementation by transferrin and sodium selenite. GSH content was found to be about 12 nmol/micrograms DNA at 4 hr in culture and to approximately triple by 24 hr. Intracellular GSH levels continued to increase in transferrin/sodium selenite-supplemented cultures, from 32 to 41.6 nmol/micrograms DNA, while GSH levels in unsupplemented cultures declined to 18 nmol/micrograms DNA. However, the rate of GSH synthesis after diethylmaleate depletion was found to decrease from 4.2 to 2.8 nmol/hr/micrograms DNA at 4 and 24 hr after inoculation, respectively. GSH repletion rate increased to 3.9 nmol/hr/micrograms DNA at 48 hr. The GSH accumulation rate after depletion in supplemented cultures did not vary significantly over the initial 48 hr. Incubation for 3 hr with 100 microM ethacrynic acid (EA) did not elicit an increase in LDH leakage in hepatocyte monolayers after 4 or 48 hr in culture or in cultures with supplemented medium at any time point tested. Cultures 24 hr in medium without transferrin/sodium selenite supplementation exhibited significant LDH leakage after 3 hr of EA treatment. Over the 3 hr EA treatment, intracellular GSH content was decreased in all cultures. Only in the 24 hr unsupplemented cultures did GSH depletion exceed the 90% level previously associated with depletion of the mitochondrial pool of GSH and EA toxicity in hepatocytes. The experiments show that during the redifferentiation of hepatocytes in culture, a transient period occurs when apparent GSH synthesis is depressed and enhanced sensitivity to GSH-detoxicated compounds is observed. This period of increased sensitivity is prevented or at least delayed by inclusion of supplemental transferrin and sodium selenite, suggesting that redifferentiation can be regulated by extracellular influences.

Animals↗
PubMed1996

Modulation of doxorubicin cytotoxicity by ethacrynic acid.

Energy-dependent membrane efflux pumps have been implicated in mediating resistance to doxorubicin (DOX). Membrane-transport mechanisms distinct from P-glycoprotein, capable of transporting DOX and glutathione conjugates have been reported in human cells. Since glutathione-conjugate-forming compounds may be candidates for modulating the cytotoxicity of certain anti-neoplastic agents transported by such transport mechanism, the present studies were performed (i) to determine whether ethacrynic acid, a glutathione-conjugate-forming diuretic, can increase DOX cytotoxicity, and (ii) to study the kinetics of DOX transport and its inhibition by the glutathione conjugate of ethacrynic acid (EA-SG) in the H69 human small-cell-lung-cancer cell line and 2 derived DOX-resistant sublines. Our results indicate that more than one DOX transport mechanism may exist in these cell lines, and that glutathione conjugates may be useful for modulating the cytotoxic effects of DOX.

ATP-Binding Cassette Transporters↗
PubMed2005

Novel antiglaucoma prodrugs and codrugs of ethacrynic acid.

The purpose of this study was to synthesize a novel prodrug of ethacrynic acid (ECA) with short chain polyethylene glycols (PEGs) and codrugs of ECA with the beta-adrenergic blocking agent atenolol (ATL) or timolol (TML) to overcome the adverse effects of ECA and to enhance its physicochemical properties.

Adrenergic beta-Antagonists↗
PubMed1996

Ethacrynic acid: a novel radiation enhancer in human carcinoma cells.

PURPOSE: Because agents that interfere with thiol metabolism and glutathione S-transferase (GST) functions have been shown to enhance antitumor effects of alkylating agents in vitro and in vivo, the present study was conceived on the basis that an inhibitor of GST would enhance the radiation response of some selected human carcinoma cells. Ethacrynic acid (EA) was chosen for the study because it is an effective inhibitor of GST and is a well known diuretic in humans. METHODS AND MATERIALS: Experiments were carried out with well-established human tumor cells in culture growing in Eagle's minimum essential medium (MEM) supplemented with 10% fetal calf serum (FCS). Cell lines used were MCF-7, MCF-7 adriamycin resistant (AR) cells (breast carcinoma), HT-29 cells (colon carcinoma), DU-145 cells (prostate carcinoma), and U-373 cells (malignant glioma). Cell survival following the exposure of cells to drug alone, radiation alone, and a combined treatment was assayed by determining the colony-forming ability of single plated cells in culture to obtain dose-survival curves. The drug enhancement ratio was correlated with levels of GST. RESULTS: The cytotoxicity of EA was most pronounced in MCF-7, U-373, and DU-145 cells compared to MCF-7 AR and HT-29 cells. The levels of GST activity were found to be lower in those EA-sensitive cells. A significant radiation enhancement was obtained with EA-sensitive cells exposed to nontoxic concentrations of the drug immediately before or after irradiation. The sensitizer enhancement ratio (SER) of MCF-7 cells was 1.55 with EA (20 micrograms/ml), while the SER of MCF-7 AR was less than 1.1. Based on five different human tumor cells, a clear inverse relationship was demonstrated between the magnitude of SER and GST levels of tumor cells prior to the combined treatment. CONCLUSION: The present results suggest that EA, which acts as both a reversible and irreversible inhibitor of GST activity, could significantly enhance the radiation response of human cancer cells and the level of GST in tumor cells may predict the magnitude of radiation enhancement with EA. Ethacrynic acid would be an excellent drug as a radiosensitizer for further in vivo tumor study.

Brain Neoplasms↗
PubMed1999

Rapid development of glutathione-S-transferase-dependent drug resistance in vitro and its prevention by ethacrynic acid.

Exposure of A2780 human ovarian tumor cells to a low concentration of melphalan in vitro for 7 days resulted in the development of melphalan resistance. This resistance was not a stable characteristic of the cells since it was lost after 2 weeks in culture in the absence of drug. The melphalan-resistant cells exhibited significant cross-resistance to cisplatin but only minor cross-resistance to doxorubicin. The resistant cells had elevated levels of glutathione-S-transferase activity and mRNA. Exposure of the cells to the ethacrynic acid resulted in a decrease in enzyme activity as well as a reversal of their drug-resistant phenotype, indicating that the enzyme is involved in the resistance. When ethacrynic acid was present during the 7-day exposure of the cells to melphalan, the development of drug resistance was prevented. This system may serve as a useful preliminary step in screening for agents which can prevent the development of chemotherapy-induced drug resistance in human cancer.

Antineoplastic Agents, Alkylating↗