The Experts below are selected from a list of 45 Experts worldwide ranked by ideXlab platform
Knud H Olesen - One of the best experts on this subject based on the ideXlab platform.
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the supra additive natriuretic effect addition of Quinethazone or bendroflumethiazide during long term treatment with furosemide and spironolactone
Acta Medica Scandinavica, 2009Co-Authors: Knud H Olesen, Bjarne SigurdAbstract:. The additive natriuretic effects of single doses of Quinethazone (50 mg) or bendroflumethiazide (5 mg) have been studied in patients with advanced congestive heart failure receiving longterm treatment with furosemide (160 mg) and spironolactone (100 mg) daily. Three permutation trial tests were performed. In the first trial including 12 patients a significant increase of renal sodium, chloride, potassium and water excretion and osmolal clearance was found after supplementary administration of Quinethazone or bendroflumethiazide. In the second trial including 6 patients the response to supplementary Quinethazone (50 mg) was definitely superior to that of additional furosemide (80 mg). Accordingly the response to supplementary Quinethazone cannot be explained as a dose addition effect of drugs acting on the same renal tubular receptors, but must represent an effect addition of diuretics acting by different mechanisms or at different sites in the nephron. The third trial compared in 6 patients the effects of Quinethazone (50 mg) + spironolactone (100 mg), of furosemide (160 mg) + spironolactone (100 mg), and of Quinethazone (50 mg) + furosemide (160 mg) + spironolactone (100 mg). In terms of natriuresis, chloruresis, cation excretion and weight loss the responses to the combination of all three drugs were significantly larger than the sums of the effects of other treatments. It is concluded that the combined effects of the drugs represent a supra-additive effect addition (or a supra-additive summation). A tentative explanation of the mechanism of this effect in terms of inhibition of renal tubular sodium transport is given. Since the combined effects of all three drugs involve a tendency to development of hypokalaemia, hypochloraemia and alkalosis, it is recommended that the supplementary use of Quinethazone or bendroflumethiazide in this setting is combined with the administration of potassium chloride.
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THE SUPRA‐ADDITIVE NATRIURETIC EFFECT ADDITION OF Quinethazone OR BENDROFLUMETHIAZIDE DURING LONG‐TERM TREATMENT WITH FUROSEMIDE AND SPIRONOLACTONE
Acta Medica Scandinavica, 2009Co-Authors: Knud H Olesen, Bjarne SigurdAbstract:. The additive natriuretic effects of single doses of Quinethazone (50 mg) or bendroflumethiazide (5 mg) have been studied in patients with advanced congestive heart failure receiving longterm treatment with furosemide (160 mg) and spironolactone (100 mg) daily. Three permutation trial tests were performed. In the first trial including 12 patients a significant increase of renal sodium, chloride, potassium and water excretion and osmolal clearance was found after supplementary administration of Quinethazone or bendroflumethiazide. In the second trial including 6 patients the response to supplementary Quinethazone (50 mg) was definitely superior to that of additional furosemide (80 mg). Accordingly the response to supplementary Quinethazone cannot be explained as a dose addition effect of drugs acting on the same renal tubular receptors, but must represent an effect addition of diuretics acting by different mechanisms or at different sites in the nephron. The third trial compared in 6 patients the effects of Quinethazone (50 mg) + spironolactone (100 mg), of furosemide (160 mg) + spironolactone (100 mg), and of Quinethazone (50 mg) + furosemide (160 mg) + spironolactone (100 mg). In terms of natriuresis, chloruresis, cation excretion and weight loss the responses to the combination of all three drugs were significantly larger than the sums of the effects of other treatments. It is concluded that the combined effects of the drugs represent a supra-additive effect addition (or a supra-additive summation). A tentative explanation of the mechanism of this effect in terms of inhibition of renal tubular sodium transport is given. Since the combined effects of all three drugs involve a tendency to development of hypokalaemia, hypochloraemia and alkalosis, it is recommended that the supplementary use of Quinethazone or bendroflumethiazide in this setting is combined with the administration of potassium chloride.
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the combined diuretic action of Quinethazone and furosemide in congestive heart failure a permutation trial test
Acta Medica Scandinavica, 2009Co-Authors: Knud H Olesen, Bo Dupont, Ellen FlenstedjensenAbstract:. The combined diuretic action of Quinethazone and furosemide has been studied in 24 patients with congestive heart failure maintained on a constant diet. The study was performed as a permutation trial test in which the error variance is reduced while permitting the examination of drug effects separate from the variations due to different patients and varying sequence of administration of drugs. The diuretic response to single drugs and to the combination of drugs in half doses showed exactly the same trend in 12 patients with slight to moderate degree of sodium retention as in 12 patients with severe sodium retention given double doses of diuretics. The results obtained indicate an additive effect of the combination of diuretics in terms of osmolal clearance, urinary sodium and chloride output as well as in terms of the development of hypochloraemic, hypokalemic alkalosis. The diuretic action of furosemide differed significantly from that of Quinethazone. The renal tubular response to furosemide was characterized by: (a) a larger increase in natriuresis with rising doses; (b) a significant decrease of tubular reabsorption of solute free water; and (c) a shorter duration of action. Apparently the combined effect of the two drugs is most easily explained when it is assumed that the two diuretics, at least in part, inhibit renal tubular sodium reabsorption at different sites in the nephron. The combination of Quinethazone and furosemide may prove useful in the treatment of refractory cardiac oedema when precautions are taken to avoid serious electrolyte disturbances.
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the natriuretic effect addition of Quinethazone and furosemide in congestive heart failure
Acta Medica Scandinavica, 2009Co-Authors: Knud H OlesenAbstract:. The combined natriuretic effect of Quinethazone and furosemide has been compared to the action of single drugs in 12 patients with congestive heart failure using a permutation trial test. The results indicate that the combined effects of the drugs represent an effect addition of two diuretics which act by different mechanisms.
Claudiu T. Supuran - One of the best experts on this subject based on the ideXlab platform.
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diuretics with carbonic anhydrase inhibitory action a patent and literature review 2005 2013
Expert Opinion on Therapeutic Patents, 2013Co-Authors: Fabrizio Carta, Claudiu T. SupuranAbstract:INTRODUCTION: The benzothiadiazines and high ceiling diuretics (hydrochlorothiazide, hydroflumethiazide, Quinethazone, metolazone, chlorthalidone, indapamide, furosemide and bumetanide) contain primary sulfamoyl moieties acting as zinc-binding groups in the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). These drugs are widely used clinically and were recently shown to weakly inhibit isoforms CA I and II, but to possess stronger activity against isoforms involved in other important pathologies, for example, obesity, cancer, epilepsy and hypertension. AREAS COVERED: The class of clinically used diuretics, with CA inhibitory properties, is the main topic of the review. A patent literature review covering the period from 2005 to 2013 is presented. EXPERT OPINION: This section presents an overview of the patent literature in the sulfonamide diuretic field. Most of the patents deal with the combination of diuretic sulfonamide CA inhibitors with other agents useful in the management of cardiovascular diseases and obesity. Such combinations exert a better therapeutic activity compared to similar diuretics that do not inhibit CAs, raising the question of the polypharmacological and drug repositioning effects of these old drugs. These effects seem to be due to the potent inhibition of such drugs against CA isoforms present in kidneys and blood vessels, which explain both the blood pressure lowering effects as well as organ-protective activity of the drugs. An explanation of these data is provided by the fact that inhibition of the renal CAs leads to a large increase of the nitrite excretion in urine, suggesting that renal CAs are involved in nitrite reabsorption in humans. Important lessons for the drug design of sulfonamide CA inhibitors (CAIs) can be drawn from these data.
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Diuretics with carbonic anhydrase inhibitory action: a patent and literature review (2005 – 2013)
Expert Opinion on Therapeutic Patents, 2013Co-Authors: Fabrizio Carta, Claudiu T. SupuranAbstract:INTRODUCTION: The benzothiadiazines and high ceiling diuretics (hydrochlorothiazide, hydroflumethiazide, Quinethazone, metolazone, chlorthalidone, indapamide, furosemide and bumetanide) contain primary sulfamoyl moieties acting as zinc-binding groups in the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). These drugs are widely used clinically and were recently shown to weakly inhibit isoforms CA I and II, but to possess stronger activity against isoforms involved in other important pathologies, for example, obesity, cancer, epilepsy and hypertension. AREAS COVERED: The class of clinically used diuretics, with CA inhibitory properties, is the main topic of the review. A patent literature review covering the period from 2005 to 2013 is presented. EXPERT OPINION: This section presents an overview of the patent literature in the sulfonamide diuretic field. Most of the patents deal with the combination of diuretic sulfonamide CA inhibitors with other agents useful in the management of cardiovascular diseases and obesity. Such combinations exert a better therapeutic activity compared to similar diuretics that do not inhibit CAs, raising the question of the polypharmacological and drug repositioning effects of these old drugs. These effects seem to be due to the potent inhibition of such drugs against CA isoforms present in kidneys and blood vessels, which explain both the blood pressure lowering effects as well as organ-protective activity of the drugs. An explanation of these data is provided by the fact that inhibition of the renal CAs leads to a large increase of the nitrite excretion in urine, suggesting that renal CAs are involved in nitrite reabsorption in humans. Important lessons for the drug design of sulfonamide CA inhibitors (CAIs) can be drawn from these data.
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Carbonic anhydrase inhibitors. Sulfonamide diuretics revisited--old leads for new applications?
Organic and Biomolecular Chemistry, 2008Co-Authors: Claudia Temperini, Alessandro Cecchi, Andrea Scozzafava, Claudiu T. SupuranAbstract:Sulfonamide diuretics such as hydrochlorothiazide, hydroflumethiazide, Quinethazone, metolazone, chlorthalidone, indapamide, furosemide and bumetanide were tested as inhibitors of the zinc enzyme carbonic anhydrases (CAs, EC 4.2.1.1). These drugs were discovered in a period when only isoform CA II was known and considered physiologically/pharmacologically relevant. We prove here that although acting as moderate to weak inhibitors of CA II, all these drugs considerably inhibit other isozymes known nowadays to be involved in critical physiologic processes, among the 16 CAs present in vertebrates. Some low nanomolar/subnanomolar inhibitors against such isoforms were detected, such as among others metolazone against CA VII, XII and XIII, chlorthalidone against CA VB, VII, IX, XII and XIII, indapamide against CA VII, IX, XII and XIII, furosemide against CA I, II and XIV, and bumethanide against CA IX and XII. The X-ray crystal structure of the CA II–indapamide adduct was also resolved at high resolution, and the binding of this sulfonamide to the enzyme was compared to that of dichlorophenamide, sulpiride and a pyridinium containing sulfonamide. Indapamide binds to CA II in a manner not seen earlier for any other CA inhibitor, which might be important for the design of compounds with a different inhibition profile.
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Carbonic anhydrase inhibitors. Interaction of indapamide and related diuretics with 12 mammalian isozymes and X-ray crystallographic studies for the indapamide-isozyme II adduct.
Bioorganic & Medicinal Chemistry Letters, 2008Co-Authors: Claudia Temperini, Alessandro Cecchi, Andrea Scozzafava, Claudiu T. SupuranAbstract:Diuretics such as hydrochlorothiazide, hydroflumethiazide, Quinethazone, metolazone, chlorthalidone, indapamide, furosemide, and bumetanide containing primary sulfamoyl moieties were reevaluated as inhibitors of 12 human carbonic anhydrases (hCAs, EC 4.2.1.1). These drugs considerably inhibit (low nanomolar range) some CA isozymes involved in critical physiologic processes, among the 16 present in vertebrates, for example, metholazone against CA VII, XII, and XIII, chlorthalidone against CA VB, VII, IX, XII, and XIII, indapamide against CA VII, IX, XII, and XIII, furosemide against CA I, II, and XIV, and bumethanide against CA IX and XII. The X-ray crystal structure of the hCA II–indapamide adduct was also resolved at high resolution.
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Diuretics: from classical carbonic anhydrase inhibitors to novel applications of the sulfonamides.
Current Pharmaceutical Design, 2008Co-Authors: Claudiu T. SupuranAbstract:: The widely clinically used benzothiadiazines and high ceiling diuretics, such as hydrochlorothiazide, hydroflumethiazide, Quinethazone, metolazone, chlorthalidone, indapamide, furosemide and bumetanide, contain SO(2)NH(2) moieties acting as an effective zinc-binding function in carbonic anhydrases (CAs, EC 4.2.1.1) inhibitors. These drugs were launched in a period when only isoform CA II was known and considered physiologically/pharmacologically relevant. Although acting as moderate-weak inhibitors of CA II, all these drugs considerably inhibit other CA isozymes known nowadays to be involved in critical physiologic processes, among the 16 CAs present in vertebrates. Some low nanomolar (or even subnanomolar) inhibitors against such isoforms were recently detected, such as metholazone against CA VII, XII and XIII, chlorthalidone against CA VB, VII, IX, XII and XIII, indapamide against CA VII, IX, XII and XIII, furosemide against CA I, II and XIV, and bumethanide against CA IX and XII. The X-ray crystal structure of the CA II-indapamide adduct was also reported recently, revealing interesting aspects useful for the drug design of CA inhibitors. It has also been proposed that the recently observed beneficial effect of indapamide for the treatment of patients with hypertension and type 2 diabetes might be due to its potent inhibition of CA isoforms present in kidneys and blood vessels, which would thus explain both the blood pressure lowering effects as well as organ-protective activity of the drug. Thus, these old drugs may be useful as leads for new applications.
Bjarne Sigurd - One of the best experts on this subject based on the ideXlab platform.
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the supra additive natriuretic effect addition of Quinethazone or bendroflumethiazide during long term treatment with furosemide and spironolactone
Acta Medica Scandinavica, 2009Co-Authors: Knud H Olesen, Bjarne SigurdAbstract:. The additive natriuretic effects of single doses of Quinethazone (50 mg) or bendroflumethiazide (5 mg) have been studied in patients with advanced congestive heart failure receiving longterm treatment with furosemide (160 mg) and spironolactone (100 mg) daily. Three permutation trial tests were performed. In the first trial including 12 patients a significant increase of renal sodium, chloride, potassium and water excretion and osmolal clearance was found after supplementary administration of Quinethazone or bendroflumethiazide. In the second trial including 6 patients the response to supplementary Quinethazone (50 mg) was definitely superior to that of additional furosemide (80 mg). Accordingly the response to supplementary Quinethazone cannot be explained as a dose addition effect of drugs acting on the same renal tubular receptors, but must represent an effect addition of diuretics acting by different mechanisms or at different sites in the nephron. The third trial compared in 6 patients the effects of Quinethazone (50 mg) + spironolactone (100 mg), of furosemide (160 mg) + spironolactone (100 mg), and of Quinethazone (50 mg) + furosemide (160 mg) + spironolactone (100 mg). In terms of natriuresis, chloruresis, cation excretion and weight loss the responses to the combination of all three drugs were significantly larger than the sums of the effects of other treatments. It is concluded that the combined effects of the drugs represent a supra-additive effect addition (or a supra-additive summation). A tentative explanation of the mechanism of this effect in terms of inhibition of renal tubular sodium transport is given. Since the combined effects of all three drugs involve a tendency to development of hypokalaemia, hypochloraemia and alkalosis, it is recommended that the supplementary use of Quinethazone or bendroflumethiazide in this setting is combined with the administration of potassium chloride.
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THE SUPRA‐ADDITIVE NATRIURETIC EFFECT ADDITION OF Quinethazone OR BENDROFLUMETHIAZIDE DURING LONG‐TERM TREATMENT WITH FUROSEMIDE AND SPIRONOLACTONE
Acta Medica Scandinavica, 2009Co-Authors: Knud H Olesen, Bjarne SigurdAbstract:. The additive natriuretic effects of single doses of Quinethazone (50 mg) or bendroflumethiazide (5 mg) have been studied in patients with advanced congestive heart failure receiving longterm treatment with furosemide (160 mg) and spironolactone (100 mg) daily. Three permutation trial tests were performed. In the first trial including 12 patients a significant increase of renal sodium, chloride, potassium and water excretion and osmolal clearance was found after supplementary administration of Quinethazone or bendroflumethiazide. In the second trial including 6 patients the response to supplementary Quinethazone (50 mg) was definitely superior to that of additional furosemide (80 mg). Accordingly the response to supplementary Quinethazone cannot be explained as a dose addition effect of drugs acting on the same renal tubular receptors, but must represent an effect addition of diuretics acting by different mechanisms or at different sites in the nephron. The third trial compared in 6 patients the effects of Quinethazone (50 mg) + spironolactone (100 mg), of furosemide (160 mg) + spironolactone (100 mg), and of Quinethazone (50 mg) + furosemide (160 mg) + spironolactone (100 mg). In terms of natriuresis, chloruresis, cation excretion and weight loss the responses to the combination of all three drugs were significantly larger than the sums of the effects of other treatments. It is concluded that the combined effects of the drugs represent a supra-additive effect addition (or a supra-additive summation). A tentative explanation of the mechanism of this effect in terms of inhibition of renal tubular sodium transport is given. Since the combined effects of all three drugs involve a tendency to development of hypokalaemia, hypochloraemia and alkalosis, it is recommended that the supplementary use of Quinethazone or bendroflumethiazide in this setting is combined with the administration of potassium chloride.
Fabrizio Carta - One of the best experts on this subject based on the ideXlab platform.
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diuretics with carbonic anhydrase inhibitory action a patent and literature review 2005 2013
Expert Opinion on Therapeutic Patents, 2013Co-Authors: Fabrizio Carta, Claudiu T. SupuranAbstract:INTRODUCTION: The benzothiadiazines and high ceiling diuretics (hydrochlorothiazide, hydroflumethiazide, Quinethazone, metolazone, chlorthalidone, indapamide, furosemide and bumetanide) contain primary sulfamoyl moieties acting as zinc-binding groups in the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). These drugs are widely used clinically and were recently shown to weakly inhibit isoforms CA I and II, but to possess stronger activity against isoforms involved in other important pathologies, for example, obesity, cancer, epilepsy and hypertension. AREAS COVERED: The class of clinically used diuretics, with CA inhibitory properties, is the main topic of the review. A patent literature review covering the period from 2005 to 2013 is presented. EXPERT OPINION: This section presents an overview of the patent literature in the sulfonamide diuretic field. Most of the patents deal with the combination of diuretic sulfonamide CA inhibitors with other agents useful in the management of cardiovascular diseases and obesity. Such combinations exert a better therapeutic activity compared to similar diuretics that do not inhibit CAs, raising the question of the polypharmacological and drug repositioning effects of these old drugs. These effects seem to be due to the potent inhibition of such drugs against CA isoforms present in kidneys and blood vessels, which explain both the blood pressure lowering effects as well as organ-protective activity of the drugs. An explanation of these data is provided by the fact that inhibition of the renal CAs leads to a large increase of the nitrite excretion in urine, suggesting that renal CAs are involved in nitrite reabsorption in humans. Important lessons for the drug design of sulfonamide CA inhibitors (CAIs) can be drawn from these data.
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Diuretics with carbonic anhydrase inhibitory action: a patent and literature review (2005 – 2013)
Expert Opinion on Therapeutic Patents, 2013Co-Authors: Fabrizio Carta, Claudiu T. SupuranAbstract:INTRODUCTION: The benzothiadiazines and high ceiling diuretics (hydrochlorothiazide, hydroflumethiazide, Quinethazone, metolazone, chlorthalidone, indapamide, furosemide and bumetanide) contain primary sulfamoyl moieties acting as zinc-binding groups in the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). These drugs are widely used clinically and were recently shown to weakly inhibit isoforms CA I and II, but to possess stronger activity against isoforms involved in other important pathologies, for example, obesity, cancer, epilepsy and hypertension. AREAS COVERED: The class of clinically used diuretics, with CA inhibitory properties, is the main topic of the review. A patent literature review covering the period from 2005 to 2013 is presented. EXPERT OPINION: This section presents an overview of the patent literature in the sulfonamide diuretic field. Most of the patents deal with the combination of diuretic sulfonamide CA inhibitors with other agents useful in the management of cardiovascular diseases and obesity. Such combinations exert a better therapeutic activity compared to similar diuretics that do not inhibit CAs, raising the question of the polypharmacological and drug repositioning effects of these old drugs. These effects seem to be due to the potent inhibition of such drugs against CA isoforms present in kidneys and blood vessels, which explain both the blood pressure lowering effects as well as organ-protective activity of the drugs. An explanation of these data is provided by the fact that inhibition of the renal CAs leads to a large increase of the nitrite excretion in urine, suggesting that renal CAs are involved in nitrite reabsorption in humans. Important lessons for the drug design of sulfonamide CA inhibitors (CAIs) can be drawn from these data.
Ellen Flenstedjensen - One of the best experts on this subject based on the ideXlab platform.
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the combined diuretic action of Quinethazone and furosemide in congestive heart failure a permutation trial test
Acta Medica Scandinavica, 2009Co-Authors: Knud H Olesen, Bo Dupont, Ellen FlenstedjensenAbstract:. The combined diuretic action of Quinethazone and furosemide has been studied in 24 patients with congestive heart failure maintained on a constant diet. The study was performed as a permutation trial test in which the error variance is reduced while permitting the examination of drug effects separate from the variations due to different patients and varying sequence of administration of drugs. The diuretic response to single drugs and to the combination of drugs in half doses showed exactly the same trend in 12 patients with slight to moderate degree of sodium retention as in 12 patients with severe sodium retention given double doses of diuretics. The results obtained indicate an additive effect of the combination of diuretics in terms of osmolal clearance, urinary sodium and chloride output as well as in terms of the development of hypochloraemic, hypokalemic alkalosis. The diuretic action of furosemide differed significantly from that of Quinethazone. The renal tubular response to furosemide was characterized by: (a) a larger increase in natriuresis with rising doses; (b) a significant decrease of tubular reabsorption of solute free water; and (c) a shorter duration of action. Apparently the combined effect of the two drugs is most easily explained when it is assumed that the two diuretics, at least in part, inhibit renal tubular sodium reabsorption at different sites in the nephron. The combination of Quinethazone and furosemide may prove useful in the treatment of refractory cardiac oedema when precautions are taken to avoid serious electrolyte disturbances.
