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PubMed1992

Resistance circumvention strategies tested in clinical leukaemia specimens using the MTT colorimetric assay.

We have used a 4-day MTT colorimetric assay to study drug sensitivity of leucocytes from leukaemia patients and from normal donors. Response to Adriamycin, vincristine, aclacinomycin A, 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin (MX2), and melphalan has been determined, together with the effects of the resistance modifiers verapamil, cyclosporin A, and ethacrynic acid. Sensitivity of chronic lymphoblastic leukemia (CLL) lymphocytes to vincristine was much greater than that of normal lymphocytes or of leucocytes from myeloid leukaemia patients. These cells were also more sensitive to melphalan. Verapamil and cyclosporin A at clinically achievable doses of 1 microgram/ml produced significant chemosensitisation in normal and leukaemic specimens, but the sensitisation ratio was greater than or equal to 2 only in a minority of specimens, except in the case of sensitisation to vincristine seen in the majority of CLL specimens. Sensitisation was generally greater in the more chemo-resistant specimens. The ratio of sensitivities of cells to Adriamycin compared with aclacinomycin A was greatest in the more Adriamycin-resistant specimens which supports the idea that cross-resistance between these agents may not be great. This was not, however, true for the ratio of Adriamycin/MX2 sensitivity. Use of the MTT assay may allow the identification of patients who would benefit from treatment with resistance modifiers or with 'low-resistance' anthracyclines.

Antineoplastic Agents↗
PubMed1992

[Molecular pharmacology in diuretics].

Recently, much knowledge of the molecular mechanism of diuretic actions has been accumulated. Molecular cloning of carbonic anhydrase revealed a difference in isozymes and the localization of each isozymes was also identified. Carbonic anhydrase VI, located in brush border of the proximal tubules, is inhibited by acetazolamide. Loop diuretics, furosemide, bumetanide, piretanide and ethacrynic acid, inhibit Na(+)-K(+)-Cl(-)-cotransport system in the thick ascending limb of the Henle's loop. The histochemical localization and biological characterization were investigated by using [3H]-bumetanide. Loop diuretics cotransport protein and inhibit Na+ and Cl- reabsorption. Spironolactone inhibits the binding of aldosterone and cytosol mineralocorticoid receptor in the cortical connecting tubule competitively.

Carbonic Anhydrase Inhibitors↗
PubMed2004

Glutathione-S-transferases from chloroquine-resistant and -sensitive strains of Plasmodium falciparum: what are their differences?

Glutathione-S-transferases (GSTs) from chloroquine-resistant (CQR, K1) and -sensitive (CQS, T9/94) strains of Plasmodiumfalciparum were studied. The enzymes from both strains exhibited the optimal pH for enzyme catalysis, at pH 7.5, and were stable at temperatures below 60 degrees C. They also showed the highest specific activities toward CDNB and moderate activities to ethacrynic acid (40% of the activity to CDNB) but little or no activity for other substrates. Km and Vmax values for CDNB and GSH, calculated by Lineweaver-Burk plot from both CQR- and CQS-GSTs, were not statistically different (p<0.05). However, the GSTs activity from CQR appeared to be significantly higher than that from CQS. Therefore, we proposed that GSTs from both malarial strains are identical in their functional domain but different in level of gene expression. Furthermore, protein sequence alignment between P. falciparum GST and GSTs from other organisms suggested that the malarial enzyme is closely similar to other GSTs in Sigma, Alpha, Mu and Pi subclasses, probably most to the Alpha group. Characterization of the purified malarial GST in detail would reveal more precise classification and better understanding of its role in malarial detoxification.

Animals↗
PubMedDate not supplied

Glutathione-related enzymes contribute to resistance of tumor cells and low toxicity in normal organs to artesunate.

The anti-malarial artesunate (ART) also inhibits the growth of cancer cells. The active moiety is an endoperoxide bridge whose cleavage generates reactive oxygen species and free radicals. We analyzed whether glutathione-related enzymes contribute to tumor resistance to ART and to the low toxicity of ART towards normal organs. The microarray-based mRNA expression of dihydrodiol dehydrogenase, gamma-glutamylcysteine synthase (gamma-GCS), glutathione S-transferases GSTM4, GSTT2, GSTZ1, and microsomal glutathione S-transferase MGST3 showed significant relationships (p <0.05) to cellular response to ART in 55 cell lines of the National Cancer Institute, USA. A tendency for correlation (0.05<p<0.1) was observed for GSTA1, GSTA2, GSTP1 and MGST1. A further 12 glutathione-related genes were not linked to ART resistance. MSC-HL13 cells transfected with cDNAs for heavy and light subunits of gamma-GCS were more resistant to ART than mock control vector-transfected MSV-PC4 cells. L-buthionine sulfoximine, a gamma-GCS inhibitor that depletes cellular glutathione pools, completely reversed ART resistance in MSV-HL13 cells, while a partial reversion was obtained by ethacrynic acid, an inhibitor of GST. The expression of GST-P was analyzed immunohistochemically in normal rat organs. GST-P immunostaining was found in all organs analyzed, albeit with varying staining intensities and in different histological structures of the organs. GST expression in normal organs may, therefore, contribute to the good tolerability and minimal toxicity of ART in normal organs.

Antimalarials↗
PubMed1991

Metallothionein content correlates with the sensitivity of human small cell lung cancer cell lines to cisplatin.

We have established cis-diamminedichloroplatinum(II) (cisplatin) resistant human small cell lung cancer cell lines, H69/CDDP0.2 and H69/CDDP, to investigate the mechanism of acquired resistance to cisplatin. H69/CDDP0.2 and H69/CDDP were 6- and 11-fold resistant to cisplatin compared with the H69 parental cell line. H69/CDDP was also resistant to cadmium chloride (2-fold), cis-diammine(glycolato)platinum (4-fold), 4-hydroperoxycyclophosphamide (3-fold) and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosour ea (4-fold) if the drug concentrations that inhibit cell growth by 50% from growth inhibition assay were compared. There was no significant difference in the cisplatin accumulation among these cell lines. Although DNA interstrand cross-link formations, determined by filter elution assay in H69/CDDP0.2 and H69/CDDP, was decreased to 20 to 30% of that in H69 parental cells, the repair capacity of DNA interstrand cross-links was equivalent in all three cell lines. Intracellular glutathione content was equal in all cell lines. H69/CDDP had the highest glutathione S-transferase activity (H69, 11 nmol/min/mg protein, H69/CDDP0.2, 12 nmol/min/mg protein; H69/CDDP, 74 nmol/min/mg protein, respectively) and an overexpression of glutathione S-transferase pi mRNA. The drug concentrations that inhibit cell growth by 50% for cisplatin in all cell lines were decreased by treatment with ethacrynic acid, an inhibitor of glutathione S-transferase pi, but this did not alter the relative degree of resistance. Intracellular metallothionein content (H69, 14 pmol/mg protein, H69/CDDP0.2, 22 pmol/mg protein; H69/CDDP, 33 pmol/mg protein, respectively) and expression of metallothionein mRNA were correlated with the drug concentrations that inhibit cell growth by 50% of the three cell lines for cisplatin and cadmium chloride. The present study suggested the importance of metallothionein in the mechanisms of cisplatin resistance.

Antineoplastic Agents↗
PubMedDate not supplied

[Diuretic therapy in heart failure].

Diuretic therapy is a drug therapy that increases urine volume, but not glomerular filtration rate (GFR). The diuretics act predominantly on tubular sites; the drugs that increase GRF are the aminophyllines, the positive inotropy or vasoactive substances that increase afferent arteriolar flux or intraglomerular pressure. We can divide the diuretics into six categories: 1) carbonic anhydrase inhibitors: acetazolamide, dichlorphenamide, methazolamide; 2) osmotic diuretics: glycerol, mannitol, urea; 3) loop diuretics: furosemide, bumetanide, ethacrynic acid, piretanide, torsemide; 4) thiazide and thiazide-like diuretics: chlorothiazide, trichlormethiazide, indapamide, chlorthalidone, metolazone; 5) potassium-sparers: a) kidney epithelial sodium channel inhibitors: amiloride and triamterene; b) aldosterone receptor antagonists: spironolactone, canrenoate potassium, eplerenone; 6) ADH antagonists: lithium salts, demeclocycline and ethanol. Diuretic therapy is useful in treating acute and chronic renal insufficiency, congestive heart failure, cirrhosis, overhydration and hypertension. Diuretic therapy increases urine volume, ion loss (except Na+, K+), and modifies diffusion (dilute urine) and convection mechanisms (reduced tubular absorption). Therefore, diuretics are very useful non-dangerous drugs.

Diuretics↗
PubMed1991

Antineoplastic drug resistance in brain tumors.

For all neoplasms, extraneural as well as brain, intrinsic, and acquired resistance to antineoplastic drugs constitutes a multifactorial problem. Much information has been generated concerning the individual mechanisms that play a role in drug resistance. The present decade will see a great deal of laboratory research emphasis in two related areas: (1) the molecular biology of resistance, including processes that regulate gene expression for critical detoxifying and transport proteins, and (2) further identification of DNA repair mechanisms in normal and neoplastic cells. In addition to continued research directed toward the identification of specific mechanisms, further study of the interrelationship between these mechanisms will be essential. Finally, there is a growing awareness that in vitro determination of the rank order of mechanisms contributing to resistance for a given drug may be quite different from that determined in vivo. The complexity of this problem is increased for brain tumors in that the understanding of the fundamentals of brain tumor biology is less advanced than for many of the systemic tumors. Ultimately, the identification of resistance mechanisms will lead to the development of clinically useful approaches to reverse cellular resistance and to increase drug sensitivity. Examples of such strategies that have or will find their way into clinical trial include: (1) use of buthionine sulfoximine to reverse glutathione-mediated resistance, (2) use of ethacrynic acid to reverse glutathione S-transferase-mediated resistance, and (3) use of calcium channel blockers and calmodulin inhibitors to reverse MDR. There will also be considerable emphasis on the rational modification of existing antineoplastic agents and the development of new drugs designed to circumvent important resistance mechanisms. For brain tumor treatment, additional strategies to circumvent intrinsic and acquired resistance by increasing drug delivery, such as high-dose chemotherapy with marrow or growth factor rescue and local drug delivery to brain tumors by drug-impregnated biodegradable polymers, will continue to be examined. Previous experience with efforts to augment antineoplastic drug cytotoxicity indicates that this process may decrease the margin of cytotoxicity between normal tissue and tumor, often referred to as the therapeutic index. To avoid serious neurotoxicity as a dose-limiting or treatment-limiting factor for potentially important clinical strategies to modulate drug resistance, it will be important to develop a greater understanding of the relative treatment sensitivities of brain capillary endothelium, glial cells, and neurons, as well as their individual abilities to transport, detoxify, and repair the effects of these drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Multifactorial mechanisms associated with broad cross-resistance of ovarian carcinoma cells selected by cyanomorpholino doxorubicin.

The cyanomorpholino derivative of doxorubicin (MRA-CN) is a DNA intercalator and alkylator that is a highly potent cytotoxin, non-cross-resistant in multidrug-resistant cells, and noncardiotoxic in comparison with doxorubicin. To further examine mechanisms of action and resistance to MRA-CN, a cell line resistant to MRA-CN, ES-2R, was established by growing a human ovarian carcinoma cell line, ES-2, in increasing concentrations of the drug. The resistant subline was 4-fold resistant to MRA-CN and cross-resistant to other DNA cross-linking agents, cisplatin (7-fold) and carmustine (3-fold), as well as to the DNA strand-breaking agents etoposide (6-fold), doxorubicin (2-fold), bleomycin (5-fold), and ionizing radiation (2-fold). In contrast, ES-2R cells were not cross-resistant to vinblastine. Several months of additional growth of ES-2R cells in MRA-CN did not yield higher, stable levels of drug resistance. A low level of P-glycoprotein was detectable in the ES-2R cells. However, the extent of intracellular accumulation of [3H]MRA-CN by this resistant cell line was identical to that of the sensitive line. The number of DNA cross-links formed by cisplatin in ES-2R was only 50% of that of the ES-2 cells and was associated with a 50% increase in the rate of repair of these cross-links in the resistant cells. Ionizing radiation induced similar amounts of single- and double-strand breaks in the ES-2 line as well as in the ES-2R cells. There was no apparent difference between the two cell lines in the rate and extent of repair of these DNA breaks. Thus, enhanced DNA repair cannot explain the phenomenon of cross-resistance to radiation. Comparisons of glutathione (GSH) content and the enzymes involved in GSH homeostasis showed significant differences. Resistant cells contained 1.5-fold more GSH, a 2.2-fold increase in gamma-glutamyltranspeptidase activity, and a 2.4-fold increase in GSH reductase compared with ES-2 cells (all P less than 0.05). Total glutathione-S-transferase (GST) activity was 2.6-fold higher (P less than 0.01) in the ES-2R line. The pi-class GST subunit by Western blotting and GST activity toward ethacrynic acid were increased 2-fold in the resistant cells. Depletion of GSH levels in ES-2R cells by buthionine sulfoximine restored the sensitivity of ES-2R to MRA-CN. These findings implicate a role for GSH metabolism in the resistance phenotype of ES-2R cells. We have previously reported that these cells have an increased generation time and decreased topoisomerase II content. Thus, the ES-2R cell line exhibits a complex phenotype of broad cross-resistance, which is likely to involve multiple mechanisms, and includes enhanced DNA repair and increased GSH content and GST activity.

Bleomycin↗
PubMed1991

L-cysteine selectively potentiates nitroglycerin-induced dilation of small coronary microvessels.

Nitroglycerin potently dilates large coronary arteries but has minimal effect on coronary resistance vessels. Thus, nitroglycerin is not likely to be converted to vasoactive intermediates in small coronary microvessels (less than 100 microns diameter). Because nitroglycerin biotransformation may involve sulfhydryl groups, the effect of L-cysteine on the dilation caused by nitroglycerin (1 nM to 10 microM) was examined in small (80-100 microns in diameter) and large (190-300 microns in diameter) porcine coronary microvessels. Vessels were pressurized in a no-flow state and preconstricted with acetylcholine, then visualized by means of an in vitro microvessel imaging apparatus. Under control conditions, nitroglycerin caused potent dilations of large coronary microvessels, while having minimal effects on small coronary microvessels [peak relaxations 90 +/- 3 vs. 20 +/- 7% (mean +/- S.E.M.) of preconstricted diameter, respectively]. L-Cysteine (100 microM) markedly enhanced relaxations of small coronary microvessels (peak relaxation 96 +/- 2%), while having no effect on relaxations of large coronary microvessels. Ethacrynic acid, which alkylates sulfhydryl groups, markedly inhibited relaxations of large coronary microvessels (peak relaxation = 31 +/- 9%) yet had a minimal effect on the small relaxations of small coronary microvessels to nitroglycerin. Thus, when sulfhydryl groups are made available, small coronary microvessels are markedly responsive to nitroglycerin. This suggests that small coronary microvessels normally lack the reductive capacity to convert nitroglycerin to its active metabolites. Prussian blue stains of sulfhydryl groups in large and small coronary microvessels were qualitatively similar. Thus, small coronary microvessels do not lack sulfhydryl groups but may be deficient in a critical pool necessary for nitroglycerin biotransformation.

Animals↗
PubMed1991

Antineoplastic drug sensitivity of human MCF-7 breast cancer cells stably transfected with a human alpha class glutathione S-transferase gene.

Studies have suggested that the alpha class glutathione S-transferase (GST) may protect cells from the chemotherapeutic drugs chlorambucil and melphalan. In order to further define the function of human alpha class GST, a complementary DNA which encodes it was ligated into an expression vector under the direction of the human metallothionein-IIA promoter and stably transfected into human MCF-7 breast cancer cells in conjunction with the G418-selectable plasmid pSV2neo. Clonal cell lines were identified which expressed increased levels of GST enzyme activity (2.2- to 5.6-fold). The transfected cell lines also had increased peroxidase activity using cumene hydroperoxide as the substrate (1.9- to 3.8-fold) which is consistent with the intrinsic peroxidase activity of alpha class GSTs. Southern blot analysis indicated that genomic DNA from these cells contained a fragment indistinguishable from the transfected alpha class GST complementary DNA (850 base pairs); Northern blot analysis of total cellular RNA indicated that these cells contained appropriately sized alpha class GST RNA (980 nucleotides); and Western blot analysis indicated that, while MCF-7 cells contained no detectable alpha class GST protein, the transfected cells contained markedly elevated levels of alpha class GST but no detectable mu or pi class GST. These alpha class GST transfected cells had increased resistance to ethacrynic acid (2.1- to 3.0-fold). However, the transfected cells failed to show any increased resistance measured at the drug dosage which inhibited 50% of the colony formation to the chemotherapeutic drugs chlorambucil, melphalan, Adriamycin, or cisplatin under conditions of either continuous or 1-h drug exposure. Neither was there any change in sensitivity to the cytotoxins benzo(a)pyrene, benzo(a)pyrene-trans-7,8-dihydrodiol-9,10-epoxide (anti), or 1-chloro-2,4-dinitrobenzene. These studies indicate that expression of this human alpha class GST by itself in MCF-7 human breast cancer cells does not confer resistance to the chemotherapeutic drugs tested under the conditions used in these studies.

Antineoplastic Agents↗
PubMed1990

A new class of rat glutathione S-transferase Yrs-Yrs inactivating reactive sulfate esters as metabolites of carcinogenic arylmethanols.

A glutathione (GSH) S-transferase (GST), catalyzing the inactivation of reactive sulfate esters as metabolites of carcinogenic arylmethanols, was isolated from the male Sprague-Dawley rat liver cytosol and purified to homogeneity in 12% yield with a purification factor of 901-fold. The purified GST was a homo-dimeric enzyme protein with subunit Mr 26,000 and pI 7.9 and designated as Yrs-Yrs because of its enzyme activity toward "reactive sulfate esters." GST Yrs-Yrs could neither be retained on the S-hexylglutathione gel column nor showed any activity toward 1,2-dichloro-4-nitrobenzene, 4-nitrobenzyl chloride, and 1,2-epoxy-3-(4'-nitrophenoxy)propane. 1-Chloro-2,4-dinitro-benzene was a very poor substrate for this GST. 1-Menaphthyl sulfate was the best substrate for GST Yrs-Yrs among the examined mutagenic arylmethyl sulfates. The enzyme had higher activities toward ethacrynic acid and cumene hydroperoxide. N-terminal amino acid sequence of subunit Yrs, analyzed up to the 25th amino acid, had no homology with any of the known class alpha, mu, and pi enzymes of the Sprague-Dawley rat. Anti-Yrs-IgG raised against GST Yrs-Yrs showed no cross-reactivity with any of subunits Ya, Yc, Yb1, Yb2, and Yp. Anti-IgGs raised against Ya, Yc, Yb1, Yb2, and Yp also showed no cross-reactivity with GST Yrs-Yrs. The purified enzyme proved to differ evidently from the 12 known cytosolic GSTs in various tissues of the rat in all respects. Immunoblot analysis of various tissue cytosols of the male rat indicated that apparent concentrations of the GST Yrs-Yrs protein were in order of liver greater than testis greater than adrenal greater than kidney greater than lung greater than brain greater than skeletal muscle congruent to heart congruent to small intestine congruent to spleen congruent to skin congruent to 0.

Amino Acid Sequence↗
PubMedDate not supplied

[New concepts of nephron function and the mechanisms of action of diuretics].

The hypothesis of gate charges of intracellular junctions of nephron wall is proposed. According to the hypothesis, negative charges at the entrance of the channel fixed on the lumenal side of nephron epithelium permit cation entry and block anion flow in the channel. The interaction of ions and fixed charges with sodium leads to increased reabsorption of various cations including sodium and also enhanced excretion of chloride and hydrogen ions in the urine resulting from osmotic fluid and ion diffusion through intracellular junctions. Mercurial diuretics, ethacrynic acid and osmotic agents but not furosemide enhance permeability of intracellular junctions for ions and eliminate the selective function of the fixed charges.

Animals↗
PubMed1990

Management of elevated intracranial pressure.

The pathophysiology, clinical manifestations, monitoring techniques, and management of elevated intracranial pressure (ICP) are reviewed. The use of barbiturate coma to treat ICP is discussed in detail. Elevated ICP can be associated with severe head injuries and diseases of the central nervous system such as brain tumors and stroke. Symptoms of elevated ICP may be difficult to distinguish from symptoms of other disease states. ICP monitoring techniques such as the intraventricular catheter and the Camino fiber optic system are useful for determination of ICP elevations before any changes in vital signs or neurological status occur. Conventional treatment and control of ICP elevations includes general and physiologic management (cerebrospinal fluid removal, fluid restriction, controlled hyperventilation, sedation, and elevating the patient's head) and pharmacologic management. Osmotic diuretics, (e.g., urea, mannitol, glycerol) and loop diuretics (e.g., furosemide, ethacrynic acid) are first-line pharmacologic agents used to lower elevated ICP. Corticosteroids may be beneficial in some patients. Patients with elevated ICP refractory to conventional treatment may benefit from therapy with high-dose barbiturates. Pentobarbital has been used in the majority of the clinical studies. Pentobarbital serum concentrations should be determined every 24-48 hours when a patient is in a barbiturate coma because pentobarbital clearance increases with continued high-dose therapy. The treatment of elevated ICP requires aggressive therapy and intensive monitoring. In patients whose ICP is refractory to conventional therapies alone, survival rates have been improved by combining high-dose barbiturates with conventional therapies.

Adrenal Cortex Hormones↗
PubMed1990

Management of hypertension in the diabetic patient.

Therapeutic considerations regarding the treatment of hypertension in patients with diabetes mellitus are reviewed. Good blood pressure control is essential in diabetic patients to prevent morbidity and mortality associated with cardiovascular diseases. Hypertension may also accelerate complications of diabetic microvascular disease, nephropathy, and retinopathy. Diuretics (e.g., thiazides, furosemide, ethacrynic acid, bumetanide) and beta blockers have traditionally been used as initial therapy for most patients with hypertension; however, these agents may not be the best choice for diabetics. Adverse metabolic consequences include alteration of glucose metabolism and plasma lipids. Beta blockers may also blunt the ability of patients to recognize symptoms of hypoglycemia. Both diuretics and beta blockers can cause sexual dysfunction in men. Adrenergic agents and vasodilators are associated with a high prevalence of orthostatic hypotension in diabetic patients. The calcium-channel blockers are considered safe and well tolerated when given at low and moderate doses. The angiotensin-converting-enzyme (ACE) inhibitors are able to slow the progression of diabetic nephropathy by reducing the glomerular hypertension that causes it. For the treatment of mild hypertension in diabetic patients, the drugs of choice should include (in descending order) ACE inhibitors, calcium-channel blockers, diuretics, and beta blockers. Severe or resistant hypertension usually requires treatment with combinations of drugs, including a diuretic. Tailoring therapy to individual complications and close monitoring of the patient are essential for safe, effective treatment of hypertension in the diabetic patient.

Antihypertensive Agents↗
PubMed1990

Effect of PO2 and metabolic inhibitors on ionic fluxes across the isolated rabbit corneal endothelium.

Bicarbonate and sodium fluxes were measured across the isolated rabbit corneal endothelium under the influence of several inhibitors. Depression of PO2 in the bathing medium decreased net sodium movement but increased bicarbonate movement. Furosemide did not alter bicarbonate fluxes at either 10(-4) or 10(-5) M, but increased passive sodium flux leading to a decrease in net flux. Thiocyanate, at 5 x 10(-3) or 5 x 10(-2) M, decreased active bicarbonate flux and hence net flux, but had no effect on sodium fluxes. Dinitrophenol increased only the passive bicarbonate flux while decreasing both active and passive sodium fluxes, albeit unequally, leading to a decreased net flux. Ethacrynic acid affected only passive bicarbonate flux, while decreasing net sodium flux. The stilbene derivatives, SITS and DIDS caused opposite effects on both sodium and bicarbonate fluxes. SITS decreased net bicarbonate flux by decreasing active and increasing passive flux, yet increased net sodium flux. DIDS, however, increased net bicarbonate flux but decreased net sodium flux. The results may be explained by current models for endothelial ion transport that include a Na+/H+ antiport and a HCO3-/Na+ symport system in parallel with an independent pathway for HCO3- exit from the endothelial cells. When compared with prior corneal swelling data using these same inhibitors, the maintenance of corneal thickness appears to be dependent on the variation of ion fluxes from normal values, and the dissociation of the two active ion fluxes. In addition, there appears to be a significant ability of ion transport systems to compensate for disturbances to other ion exchange or transport mechanisms.

Animals↗
PubMed1990

Combination of metolazone and furosemide in the treatment of edema in the first month of life.

A combination of metolazone (0.2 mg/kg/day) and furosemide (4 mg/kg/day) was used in the treatment of a 2-week-old neonate who developed severe edema after cardiac surgery. The edema, which was initially responsive to furosemide, became resistant to high doses of this diuretic even with the concomitant use of ethacrynic acid. The addition of metolazone to furosemide induced prompt diuresis and natriuresis. This combination of diuretics can be helpful in the treatment of refractory edema in young infants.

Drug Therapy, Combination↗
PubMed1990

Brain anti-cytoxic edema agents.

The work described in this chapter has indicated that improved outcome from an experimental head injury model can be achieved by drugs which are non-diuretic derivatives of loop diuretics, namely indanyl and fluorenyl compounds which are derivatives of ethacrynic acid. These drugs were originally identified by us on the basis of their efficacy in inhibiting [K+]-stimulated, HCO3(-)-dependent swelling of brain cerebrocortical slices. Swelling of glial cells (astrocytes) has long been known to be associated with such slice swelling and astrocyte swelling is a major locus of cytotoxic or cellular brain edema. Qualitative and quantitative electron microscope studies have shown that L644,711, a particularly effective member of the fluorenyl class of drugs, inhibits astrocytic swelling associated with an experimental animal head injury model. We have suggested that astrocytic swelling in pathological states may be partly due to activation of Cl-/HCO3- and Na+/H+ exchange systems driven by increased astrocytic intracellular hydration of CO2, and recent work has indeed shown that the ability of the indanyl and fluorenyl drugs to inhibit brain slice swelling and protect against head injury correlates closely with their ability to inhibit Cl-/HCO3- exchange. All these data suggest that astrocytic swelling, which seems to precede neuronal degeneration and breakdown of the blood-brain barrier, is deleterious and that prevention of such swelling can lead to effective therapy. We have used primary astrocytic cultures to explore reasons why astrocytic swelling could be harmful. Exposing such astrocytes to hypotonic medium causes rapid swelling with a slower return to normal volume in the continued presence of hypotonic medium, a process known as regulatory volume decrease or RVD. Such RVD is associated with marked release of several amino acids, including L-glutamate. L644,711 and other Cl-/HCO3- transport inhibitors such as SITS and furosemide, but not the selective Na+ + K+ + 2Cl- co-transport inhibitor bumetanide, inhibit such swelling-induced release of L-glutamate. Thus, L644,711 and other drugs may be effective in promoting recovery from head injury and other pathological states in which astrocytic swelling occurs either by initially preventing the swelling or inhibiting the release of excitotoxic excitatory amino acids if swelling does occur, perhaps depending at what time the drug is given.

Animals↗
PubMed1990

Glutathione-S-transferase pi as a determinant of drug resistance in transfectant cell lines.

A series of glutathione S-transferase pi (GST-pi) transfectant cell lines have been constructed in activated c-H-ras-transformed NIH-3T3 cells (pT22-3) by using a pKOneo plasmid and an expression vector containing cDNA for GST-pi with a beta-actin gene promoter. From the wild type pT22-3 cells, two clones were selected and designated RGN1 and RGN2. The degree of overexpression of GST-pi was estimated by Northern and Southern blot analysis to be incrementally higher in RGN2 compared with RGN1. Translation of mRNA was estimated by Western blot analysis using isozyme-specific polyclonal antibodies and confirmed the relative GST-pi levels. Each cell line, including the wild type, expressed alpha and mu class isozymes to the same degree and had similar but negligible expression of the mdr 1 gene. Sensitivity to various anticancer drugs and radiation was estimated by a series of cytotoxicity assays. The data confirmed that GST-pi provided a degree of protection against the toxicity of ethacrynic acid and adriamycin, but sensitivity to alkylating agents such as chlorambucil, melphalan, and cis-platinum was not influenced by GST-pi. Similarly, the response to ionizing radiation was similar for each line. Since the levels of intracellular GSH were also not significantly different, the availability of co-substrate was not a factor in determining response. In creating the GST-pi transfectants, these data establish that while increased isozyme levels can play a role in determining sensitivity to some agents, the protective effect is selective.

Actins↗