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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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comparative natriuretic and diuretic efficacy of theophylline ethylenediamine and of Bendroflumethiazide during long term treatment with the potent diuretic bumetanide permutation trial tests in patients with congestive heart failure
Acta Medica Scandinavica, 2009Co-Authors: Bjarne Sigurd, Knud H OlesenAbstract:The additive natriuretic and diuretic effects of theophylline ethylenediamine and of Bendroflumethiazide have been compared in permutation trial tests in patients with advanced congestive heart failure receiving long-term treatment with the highly potent diuretic, bumetanide. Statistical analysis of renal water and electrolyte excretion revealed that theophylline ethylenediamine, 400 mg orally, and Bendroflumethiazide, 5 mg orally, had very similar effects, both quantitatively and qualitatively. The mechanism of action of the supplementary diuretics is discussed. It is concluded that theophylline ethylenediamine represents a useful alternative to thiazide diuretics when supplementary natriuretic treatment is considered in patients with congestive heart failure during long-term treatment with potent diuretics. The significance of maintaining the potassium balance during such a combined regimen is stressed.
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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comparative natriuretic and diuretic efficacy of theophylline ethylenediamine and of Bendroflumethiazide during long term treatment with the potent diuretic bumetanide permutation trial tests in patients with congestive heart failure
Acta Medica Scandinavica, 2009Co-Authors: Bjarne Sigurd, Knud H OlesenAbstract:The additive natriuretic and diuretic effects of theophylline ethylenediamine and of Bendroflumethiazide have been compared in permutation trial tests in patients with advanced congestive heart failure receiving long-term treatment with the highly potent diuretic, bumetanide. Statistical analysis of renal water and electrolyte excretion revealed that theophylline ethylenediamine, 400 mg orally, and Bendroflumethiazide, 5 mg orally, had very similar effects, both quantitatively and qualitatively. The mechanism of action of the supplementary diuretics is discussed. It is concluded that theophylline ethylenediamine represents a useful alternative to thiazide diuretics when supplementary natriuretic treatment is considered in patients with congestive heart failure during long-term treatment with potent diuretics. The significance of maintaining the potassium balance during such a combined regimen is stressed.
Sten Christensen - One of the best experts on this subject based on the ideXlab platform.
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Role of Sodium Depletion in Acute Antidiuretic Effect of Bendroflumethiazide in Rats with Nephrogenic Diabetes
2001Co-Authors: Nadeem R. Janjua, Thomas E N Jonassen, Susanna Langhoff, Klaus Thomsen, Sten ChristensenAbstract:The mechanisms underlying the acute antidiuretic response to Bendroflumethiazide (BFTZ; 0.25 mg/h for 3 h) in rats with nephrogenic diabetes insipidus (NDI) was investigated. NDI was induced in conscious chronically instrumented female Wistar rats either by chronic lithium administration (40–60 mmol Li/kg of diet for 4 weeks) or by acute infusion of V2 antagonist OPC-31260 (0.2 mg/h). Renal clearance experi-ments were performed in conscious rats instrumented with permanent catheters. During experiments total body water con-tent was held constant by i.v. replacement of urine production (V) with 150 mM glucose. One group in addition received i.v. replacement of urinary sodium losses. In both models of NDI, BFTZ-induced antidiuresis was associated with a decrease in the delivery of tubular fluid to the distal nephron, as measure
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mechanism of antidiuresis caused by Bendroflumethiazide in conscious rats with diabetes insipidus
British Journal of Pharmacology, 1998Co-Authors: Lene Gronbeck, Soren Nielsen, David Marples, Sten ChristensenAbstract:1 The mechanism underlying the antidiuretic eAect of thiazide diuretics in diabetes insipidus (DI) is unknown. This study addressed two specific questions: is the reduction in urine flow rate (V) related to a decrease in the delivery of fluid from the pars recta of the proximal tubules (‘distal delivery’), and are there any changes in the expression and/or intracellular distribution of vasopressin stimulated water channels (AQP2) in the collecting ducts, during chronic thiazide-induced antidiuresis? 2 Nine Brattleboro rats with vasopressin-deficient DI were treated for 5 days with Bendroflumethiazide (BFTZ), 9 mg kg 71 day 71 orally, and 9 Brattleboro rats were left untreated. BFTZ-treated DI rats showed a fall in V from *200 to *75 ml day 71 and an increase in urine osmolality from *130 to *400 mosmol kg 71 . 3 BFTZ-induced antidiuresis was associated with a persistent loss of sodium, but not of potassium. After 5 days of treatment, clearance studies in conscious rats showed a tendency towards decreases in eAective renal plasma flow (77%), GFR (712%) and lithium clearance (CLi; used as marker for distal delivery) (725%), compared with untreated controls, but none of these changes were statistically significant. There was no apparent relationship between CLi and V in BFTZ-treated or untreated DI rats. 4 BFTZ treatment did not change the expression of AQP2 in homogenates of cortex, outer or inner medulla from DI rats, or from normal Long Evans rats. Light and electron microscopic immunocytochemistry revealed no changes in intracellular distribution of AQP2 in principal cells from inner medullary collecting ducts of BFTZ-treated DI rats. 5 We concluded, (i) that although the antidiuretic eAect of BFTZ in rats with DI is associated with a net loss of Na, the decrease in V shows no association with changes in distal delivery, as estimated by CLi. (ii) Antidiuretic treatment with BFTZ does not alter the expression of subcellular distribution of AQP2 water channels in the collecting ducts. The mechanism underlying the chronic antidiuresis caused by thiazide diuretics in DI remains elusive.
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supra additive natriuretic synergism between Bendroflumethiazide and furosemide in rats
Journal of Pharmacology and Experimental Therapeutics, 1995Co-Authors: Thomas E N Jonassen, F Andreasen, Jorgen Soberg Petersen, Michael Shalmi, L Gronbeck, Sten ChristensenAbstract:To examine the diuretic and natriuretic synergism between Bendroflumethiazide (BFTZ) and furosemide (FUR), the acute diuretic and natriuretic response to BFTZ was compared when given alone, during acute and during chronic FUR infusion. Responses to diuretics were assessed in conscious, chronically instrumented rats and, to avoid confounding influences of diuretic-induced volume contraction, extracellular fluid volume was kept constant by a computer-driven servo-control technique. Two groups were pretreated with osmotic minipumps chronically infusing either FUR (0.25 mg/hr; group CF; n = 9) or vehicle (8% ethanolamine; group CV; n = 8) i.p. for 7 days before the experiment. During the experiment, two other groups received either acute infusion with FUR (0.25 mg/hr; group AF; n = 16) or acute infusion with vehicle (150 mM glucose; group AV; n = 11). After a 60-min control period, BFTZ (0.083 mg; 0.25 mg/hr) was administered for 90 min to all four groups. Whereas the diuretic and natriuretic response to BFTZ was similar in groups AF, AV and CV, a supra-additive response was observed in the CF group (vs. group CV: delta urine flow rate: +78%; delta urinary Na excretion: +69%). BFTZ had no effect on the fractional excretion of Li, which suggests that the supra-additive effect was due to inhibition of an enhanced distal tubular Na reabsorption induced by chronic FUR administration. Because before BFTZ administration urinary Na excretion was 3-fold higher during acute than during chronic FUR infusion, an increased delivery of NaCl to the thiazide segment cannot by itself explain the exaggerated BFTZ response during chronic FUR treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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renal adaptations to continuous administration of furosemide and Bendroflumethiazide in rats
Pharmacology & Toxicology, 1994Co-Authors: Hanne E Lunau, Martin Bak, Jorgen Soberg Petersen, Michael Shalmi, Niels Marcussen, Sten ChristensenAbstract:During continuous treatment with diuretics, the kidney adapts to the initial Na loss by activating antinatriuretic mechanisms which serve to prevent further Na and volume losses. To study the renal sites of adaptations to constant diuretic treatment, Bendroflumethiazide (4 mg daily), furosemide (8 mg daily) or vehicle (0.24 ml daily) was infused intraperitoneally to female Wistar rats by implanted osmotic minipumps. Half of the animals (groups vol.) were randomized to receive a balanced saline solution to drink in addition to water in order to replace Na, K and volume losses. On the 6th day of treatment, clearances of inulin, Na, and Li were determined during four consecutive 6 hr periods. Orcadian changes in renal excretions occurred in all groups with highest excretions of Na, Li and water in the dark period (6 p.m. to 6 a.m.). Renal changes induced by continuous infusion of diuretics were most pronounced in the dark period and would probably not have been disclosed if the clearance experiments had been restricted to the daytime. The average 24-hour clearance for inulin (glomerular filtration rate) was not different among groups, except for a 20% decrease in the furosemide group. The 24-hour fractional Na excretion, being -0.5% in the vehicle group, increased to -0.8% in group (Bendroflumethiazide + vol) and to -2.8% in group (furosemide + vol) but was not different from the vehicle group in the diuretic groups without volume replacement. Fractional Li excretion was -28% in groups (vehicle + vol), -19% in groups (Bendroflumethiazide + vol), -30% in the furosemide group and -37% in group (furosemide + vol). Finally, CNa/CLi was -1.7% in group (vehicle + vol), -3.7% in group (Bendroflumethiazide + vol) and -7.0% in group (furosemide + vol). The results indicate that even though continuous furosemide administration caused a fall in glomerular filtration rate, there was no change in the flow rate of tubular fluid to the distal nephron (CLi) following treatment with loop diuretic. This contrasts the effects of continuous thiazide treatment, being a reduction of CLi in absence of changes in glomerular filtration rate. The reason for this difference may be that the adaptive increase in proximal tubular Na reabsorption is outbalanced by an inhibitory effect of furosemide itself on the proximal tubule. Both diuretics caused an adaptive increase in fractional distal Na reabsorption, probably at nephron sites beyond their respective sites of action. Furosemide but not Bendroflumethiazide induced a persistent increase in urine flow.
Morris J Brown - One of the best experts on this subject based on the ideXlab platform.
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the spironolactone amiloride losartan and thiazide salt double blind crossover trial in patients with low renin hypertension and elevated aldosterone renin ratio
Circulation, 2007Co-Authors: Susan J Hood, Kevin Taylor, Michael J Ashby, Morris J BrownAbstract:Background— There is continuing variation in diagnosis and estimated prevalence of primary hyperaldosteronism. The higher estimates encourage search for adrenal adenomas in patients with elevated ratios of plasma aldosterone to renin. However, it is more likely that patients with normal plasma K+ and aldosterone belong to the polygenic spectrum of low-renin hypertension rather than have the same monogenic syndrome as classic Conn’s. Our primary hypothesis was that in low-renin patients with normal plasma K+ and aldosterone, a thiazide diuretic, Bendroflumethiazide, would be as effective as spironolactone in overcoming the Na+ retention and lowering blood pressure. Secondary objectives were to compare the dose response for each diuretic and to evaluate amiloride as an alternative to spironolactone. Methods and Results— Fifty-seven patients entered and 51 patients completed a placebo-controlled, double-blind, randomized crossover trial. Entry criteria included low plasma renin, normal K+, elevated aldostero...
Leif Mosekilde - One of the best experts on this subject based on the ideXlab platform.
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dose effect relations of loop and thiazide diuretics on calcium homeostasis a randomized double blinded latin square multiple cross over study in postmenopausal osteopenic women
European Journal of Clinical Investigation, 2003Co-Authors: Peter Vestergaard, Lars Rejnmark, Asger Roer Pedersen, Lene Heickendorff, F Andreasen, Leif MosekildeAbstract:Background Thiazide diuretics (TDs) reduce whereas loop diuretics (LDs) increase urinary calcium. We studied the effects of different doses of a TD and LD on electrolytes, calcitropic hormones and biochemical bone markers. Subjects and methods In a five-period crossover study, comparing four active doses with placebo, 40 postmenopausal women with osteopenia were treated with different doses of LD bumetanide (n = 20, 0·5–2·0 mg per day) or TD Bendroflumethiazide (n = 20, 2·5–10 mg per day). Each treatment period lasted 1 week. Results Urinary calcium decreased dose-dependently in response to the Bendroflumethiazide. The best hypocalciuric effect was achieved by 5 mg day−1 of Bendroflumethiazide. Total plasma calcium levels increased, whereas ionised calcium at ambient pH-values decreased because of increased pH-values in response to the Bendroflumethiazide. Plasma PTH levels did not change, whereas a slight dose-dependent increase occurred in plasma 1,25(OH)2D levels. As a marker of bone formation, plasma osteocalcin levels increased. Conversely, bumetanide dose-dependently increased renal calcium losses with a concomitant increase in plasma PTH and 1,25(OH)2D levels. Plasma osteocalcin levels increased and bone-specific alkaline phosphatase levels decreased dose-dependently. Conclusion Whether a LD or TD is chosen as diuretic therapy affects calcium homeostasis. The effects of LDs are potentially harmful to bone. Further studies are needed to evaluate whether long-term treatment with LDs causes osteoporosis. Until then, we suggest using, if possible, a TD rather than a LD as diuretic therapy in order not to risk deleterious effects on bone metabolism.
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loop diuretics alter the diurnal rhythm of endogenous parathyroid hormone secretion a randomized controlled study on the effects of loop and thiazide diuretics on the diurnal rhythms of calcitropic hormones and biochemical bone markers in postmenopausal women
European Journal of Clinical Investigation, 2001Co-Authors: Peter Vestergaard, Lars Rejnmark, Lene Heickendorff, F Andreasen, Leif MosekildeAbstract:Background Thiazide diuretics (TD) reduce urinary calcium, bone loss and fracture risk. Loop diuretics (LD) may have opposite effects. These effects could depend on induced rhythmic changes in bone and calcium homeostasis. Design After a run-in period of 7 days, we studied (in a factorial design) the diurnal rhythms of plasma levels of calcium, phosphate, parathyroid hormone (PTH), 1,25-dihydroxyvitamin D and osteocalcin, as well as renal excretions rates of calcium, phosphate, and cross-linked N-terminal telopeptide of type 1 collagen (NTx) in 50 postmenopausal women randomized to treatment with either a thiazide diuretic (TD; Bendroflumethiazide, n = 14), a loop diuretic (LD; bumetanide, n = 13), LD plus TD (Bendroflumethiazide plus bumetanide, n = 11), or placebo (n = 12). Results In all four groups, all measured quantities showed a diurnal variation. LD caused a steep increase, with a subsequent decrease, in urinary calcium and plasma PTH. The mean 24 h plasma PTH concentration was increased (8·5 ± 0·9 mmol L−1) compared with placebo (4·4 ± 0·4 mmol L−1), whereas net 24 h renal calcium excretion did not differ from that of the placebo group due to a rebound hypocalciuria. Compared with placebo, diurnal rhythms of plasma phosphate and osteocalcin were changed with an increase during daytime and a decrease during the night. TD did not alter the diurnal rhythm of any of the measured quantities. However, the 24-h renal calcium excretion decreased, whereas the mean 24-h plasma calcium concentration increased without PTH suppression. LD plus TD caused changes similar to those observed with LD alone. Conclusion One daily dose of LD increases parathyroid activity with alterations in the diurnal pattern of osteocalcin. This could indicate a potential anabolic effect of LD.
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effects of thiazide and loop diuretics alone or in combination on calcitropic hormones and biochemical bone markers a randomized controlled study
Journal of Internal Medicine, 2001Co-Authors: Lars Rejnmark, Peter Vestergaard, Lene Heickendorff, F Andreasen, Leif MosekildeAbstract:Abstract. Rejnmark L, Vestergaard P, Heickendorff L, Andreasen F, Mosekilde L (Aarhus University, Aarhus, Denmark). Effects of thiazide- and loop-diuretics, alone or in combination, on calcitropic hormones and biochemical bone markers: a randomized controlled study (Original study). J Intern Med 2001; 250: 144–153. Objective. Diuretics are commonly used drugs that in addition to their effect on the cardiovascular system also affect calcium homeostasis and bone metabolism. We evaluated the effects of loop diuretics (LD) and thiazide diuretics (TD) on calcitropic hormones and biochemical bone markers. Design. A total of 50 postmenopausal women were randomized to 7 days of treatment with either the TD Bendroflumethiazide, the LD bumetanide, Bendroflumethiazide plus bumetanide, or placebo. Blood and urine (24 h) were sampled on each day. Statistical inferences were made versus the concomitant changes in the placebo group. Results. Bendroflumethiazide increased the tubular reabsorption of calcium (TRCa) (+0.46 ± 0.11%, P=0.009), plasma levels of parathyroid hormones (PTH) (+24 ± 10%, P=0.06), and 1,25(OH)2D (+12 ± 6%, P=0.03). Bumetanide decreased the TRCa (–0.5 ± 0.1%, P=0.01) and increased plasma PTH and 1,25(OH)2D levels (+27 ± 9%, P=0.02 and +36 ± 12%, P=0.006, respectively). Treatment with either of the drugs did not alter plasma calcium, osteocalcin, bone alkaline phosphatase (bone-ALP) or urinary NTx/creatinine ratio. However, treatment with both drugs caused an increased plasma calcium level (+2.7 ± 1.0%, P=0.007) and decreased plasma levels of bone-ALP (–21 ± 3%, P=0.001), osteocalcin (–6 ± 3%, P=0.03), and urinary NTx/creatinine ratio (–39 ± 6%, P=0.001). Conclusion. Calcium homeostasis and bone metabolism are to a major degree influenced by diuretic treatment. Surprisingly, LD and TD exerted a similar effect on calcitropic hormones despite their opposite effects on the renal calcium excretion. In clinical practice, treatment with diuretics has to be considered as a cause of parathyroid stimulation.