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Clinical toxicity of furosemide in hospitalized patients. A report from the Boston Collaborative Drug Surveillance Program.

Of 17,068 hospitalized medical patients monitored in a drug surveillance program, 2,367 (13.9 per cent) received furosemide. Of these patients, 53 per cent were hospitalized with a primary (first) diagnosis of cardiovascular disease; many other patients had cardiovascular disorders coincident with other diseases. In 78 per cent of cases the indication for furosemide therapy was congestive heart failure. Adverse reactions were attributed to furosemide in 239 patients (10.1 per cent), but in only 14 instances were the unwanted effects considered life-threatening. The most common adverse reactions were: intravascular volume depletion (4.6 per cent of furosemide recipients), hypokalemia (3.6 per cent), and other eletrolyte disturbances (1.5 per cent). Many patients experienced more than one manifestation of toxicity. The over-all frequency of adverse reactions increased progressively with higher daily doses of furosemide, but was not correlated with total furosemide dose. Among furosemide recipients who also recieved potassium-supplements or potassium-sparing diuretics, hypokalemia was less frequent, less severe, and of slower onset. Coadministration of other diuretics with furosemide was associated with a higher frequency of volume depletion. The findings indicate that furosemide is a relatively safe diuretic in a wide range of clinical situations. Serious adverse reactions are uncommon, and occur primarily in the seriously ill.

Adult↗

Anticonvulsant actions of furosemide in vitro.

Anticonvulsant properties of furosemide have been suggested to reduce neuronal synchronization via its inhibitory effect on the Na+/K+/2Cl- co-transport system. We have studied effects of furosemide on spontaneous epileptiform activity and analysed effects of furosemide on amplitudes of stimulus-induced population-spikes, on stimulus-induced K+ changes, on extracellular pH changes at rest and during stimulation, and on changes in the extracellular space-volume. We used three different in vitro models of epilepsy in the combined hippocampal-entorhinal cortex slice preparation. Furosemide reversibly suppressed low Ca2+-induced epileptiform activity in hippocampus proper and blocked or significantly reduced different types of epileptiform discharges in the low Mg2+ model and the 4-aminopyridine model. Amplitudes of evoked field potentials underwent an initial slight increase followed by a significant reduction after prolonged treatment with furosemide. Stimulus-induced increases in extracellular potassium were also significantly reduced. Furosemide caused an alkaline shift at rest. Stimulus-induced pH transients changed from a biphasic alkalotic-acidotic sequence to a monophasic alkalotic shift. Stimulation-induced shrinkage of extracellular space-volume was reduced by furosemide, whereas no effect on baseline extracellular space-volume was seen. We conclude, that furosemide possesses strong anticonvulsive effects in various in vitro models of epilepsy. The anticonvulsive properties of furosemide cannot be explained by its effects on extracellular pH changes but appear in part to be mediated via a reduced excitability with consequent reduction of activity-induced potassium rises. Finally, partial inhibition of activity-induced extracellular space shrinkage may contribute to its anticonvulsant properties.

4-Aminopyridine↗

Physicochemical characterization of solid dispersion of furosemide with TPGS.

The D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) was used to increase the aqueous solubility and dissolution rate of furosemide. The solid dispersion of furosemide with TPGS was prepared by solvent method using methanol. The aqueous solubility and the dissolution rate of furosemide were rapid and markedly enhanced from the 1:2 furosemide-TPGS solid dispersion. The X-ray diffractometry showed that pure furosemide and furosemide contained within the physical mixture were crystalline in nature, whereas furosemide in the solid dispersion was not in crystalline form. The infrared spectroscopic analysis showed that an interaction, in the solid dispersion, such as an association between the functional groups of furosemide and TPGS might occur in the molecular level. The infrared spectroscopy and differential thermal analysis showed the physicochemical modifications of the furosemide from the solid dispersion. The solid dispersion technique with TPGS provides a promising way to increase the solubility and dissolution rate of poorly soluble drugs.

Chemical Phenomena↗

Flow injection and HPLC determination of furosemide using pulsed amperometric detection at microelectrodes.

The flow-injection and HPLC determination of the diuretic drug furosemide using pulsed amperometric detection (PAD) at cylindrical carbon fibre microelectrodes (CFMEs) is reported. Experimental conditions such as pH (6.5) and buffer concentration (0.05 mol l(-1) HPO4(2-)/H2PO4(-)) were optimized using square-wave voltammetry (SWV). Repetitive flow-injection amperometric measurements at +1.25 V for furosemide showed a continuous decrease in the peak current, probably as a consequence of the microelectrode surface fouling. However, a suitable amperometric detection of furosemide was achieved using a PAD program consisting of a two-step potential waveform with alternating anodic and cathodic polarization. The anodic (detection) potential was +1.25 V (time of application 0.1 s), and the cathodic (cleaning) potential was -0.20 V (t=0.2 s). A linear calibration graph was obtained for furosemide in the 5.0 x 10(-7)-1.0 x 10(-4) mol l(-1) concentration range, with a limit of detection of 1.7 x 10(-7) mol l(-1). HPLC-PAD at carbon fibre microelectrodes was used for the determination of furosemide in the presence of several thiouracil drugs and oxytetracycline (OTC). The mobile phase selected was a 25:75 acetonitrile:5.0 x 10(-3) mol l(-1) NaH2PO4 (pH 5.0) mixture. A linear calibration graph was obtained for furosemide in the 1-100 microM range, with a limit of detection of 0.55 microM. The usefulness of this method for the determination of furosemide in real samples was evaluated by performing the analysis of commercial milk samples spiked with furosemide at a concentration level of 4.5 x 10(-7) mol l(-1) (150 ng ml(-1)), as well as with other thiouracil drugs and OTC. A mean recovery of 95+/-5% furosemide was obtained.

Chromatography, High Pressure Liquid↗

Resistive index in rabbits with experimentally induced hydronephrosis: effect of furosemide.

RATIONALE AND OBJECTIVES: The purpose of this study in rabbits was to evaluate the effect of furosemide on resistive index (RI) in the diagnosis of partial hydronephrosis. MATERIALS AND METHODS: In 14 rabbits the left ureter was ligated by being tied to an angiographic guide wire. Doppler sonography was performed before and 1 and 6 hours, 1 and 3 days, and 1, 2, and 4 weeks after ureteral ligation. At each interval it was performed both before and after intravenous injection of saline and furosemide. RIs were compared (a) between obstructed and contralateral kidneys and (b) before and after furosemide administration, and the statistical significance of any differences was determined. RESULTS: Obstructed kidneys had significantly higher RIs than the contralateral kidneys before furosemide administration at five of seven postligation measurements and after furosemide administration at all seven. The differences between obstructed and contralateral kidneys were significantly higher after furosemide administration (P < .05). The increase in RI after furosemide administration was significantly greater in obstructed than in contralateral kidneys (P < .05). CONCLUSION: The results in a rabbit model indicate that Doppler sonography with furosemide administration is a valuable method for evaluating hydronephrosis. The administration of furosemide accentuates the difference in RI between obstructed and nonobstructed kidneys.

Animals↗

Hyperkalemic renal tubular acidosis: effect of furosemide in humans and in rats.

Furosemide increases urinary acidification in control subjects and in certain patients with normokalemic or hypokalemic distal renal tubular acidosis (RTA). We studied the effect of furosemide in 14 patients with hyperkalemic distal RTA. In a group of patients with pure selective aldosterone deficiency, furosemide increased net acid and K excretion in a fashion indistinguishable from controls. This effect of furosemide was observed both in the presence and in the absence of acute mineralocorticoid administration. In another group of patients with hyperkalemic distal RTA, furosemide failed to decrease urine pH and to increase net acid excretion despite acute mineralocorticoid administration. Plasma aldosterone was variable in this group in that some patients had appropriate levels of aldosterone for the degree of hyperkalemia, whereas in the other patients the levels were low. The failure of these patients to respond to furosemide, despite pharmacologic doses of mineralocorticoid, suggests that these patients had a defect in H+ secretion other than that attributable to aldosterone deficiency alone. To gain insight into the mechanism whereby furosemide increases urinary acidification, we studied control and amiloride-treated rats pretreated with mineralocorticoid. In response to furosemide, control rats had a significantly lower urine pH and higher net acid and K excretion than that observed in amiloride-treated rats. These data suggest that furosemide increases H+ and K excretion, at least in part, by creating a favorable electric gradient for secretion of these ions since these effects were blunted in presence of inhibition of distal Na transport by amiloride.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis, Renal Tubular↗

Effect of furosemide on water and urea transport in cortical and inner medullary collecting duct.

The present in vitro microperfusion study examined whether furosemide has an effect on hydraulic conductivity (Lp X 10(-6) cm/sec.atm) and 14C-urea permeability (Pu X 10(-5) cm/sec) in inner medullary collecting ducts (IMCD) and cortical collecting tubules (CCT) isolated from rat and rabbit kidneys. Furosemide added to the bath fluid decreased arginine-vasopressin (AVP)-stimulated Lp of rat IMCD in a dose-dependent manner, with the threshold effect at 10(-6) M. Furosemide (10(-4) M) reduced Lp from 20.5 +/- 2.3 to 12.1 +/- 1.2 (P less than 0.01) reversibility, but had no effect when added to the perfusate. In addition, furosemide reduced dibutyryl cyclic AMP-stimulated Lp from 20.3 +/- 1.1 to 11.2 +/- 1.6 (P less than 0.01). This effect of furosemide was also observed with indomethacin, a PGE2 synthesis inhibitor. The addition of indomethacin (10(-4) M) to AVP (50 microU/ml) increased Lp from 24.7 +/- 2.3 to 29.7 +/- 2.8 (P less than 0.001), which was reduced to 20.3 +/- 2.6 (P less than 0.001) when furosemide was added to indomethacin in the bath. The inhibitory effect of furosemide on AVP-stimulated Lp was also observed in rabbit IMCD (Lp decreased from 12.8 +/- 0.8 to 5.15 +/- 1.46, P less than 0.02), but it was not observed in the CCT isolated from rabbit kidneys (7.96 +/- 1.87 with AVP vs. 7.94 +/- 1.41 with AVP + furosemide). Furthermore, in rat IMCD the stimulatory effect of AVP on Pu from 7.7 +/- 0.4 to 26.8 +/- 1.3 was reduced by furosemide to 19.7 +/- 1.2 (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Pulmonary vascular pressures of thoroughbred horses exercised 1, 2, 3 and 4 h after furosemide administration.

Furosemide premedication of horses 4 h prior to exercise significantly attenuates exercise-induced pulmonary capillary hypertension which may help diminish the severity of exercise-induced pulmonary haemorrhage. As pulmonary hemodynamic effects of furosemide may be mediated via a reduction in plasma volume (which is most pronounced 15-30 min postfurosemide administration, with plasma volume recovering thereafter), we hypothesized that administration of furosemide at intervals shorter than 4 h before exertion may be more effective in attenuating the exercise-induced rise in pulmonary capillary blood pressure. Thus, our objective was to determine whether furosemide-induced attenuation of exercise-induced pulmonary arterial, capillary and venous hypertension would be enhanced when the drug is administered at intervals shorter than 4 h before exercise. Using established techniques, right atrial, and pulmonary arterial, capillary and wedge (venous) pressures were ascertained in seven healthy, sound, exercise-trained Thoroughbred horses in a randomized split-plot experimental design. Measurements were made at rest and during exercise performed at maximal heart rate (217 +/- 3 beats/min) in the control (no medications) experiments and following furosemide administration (250 mg intravenously (i.v.)) at 1, 2, 3 and 4 h before exercise. Sequence of treatments was randomized and 7 days were allowed between experiments on each horse. Although furosemide administration in the four treatment groups caused only insignificant changes in the pulmonary arterial, capillary and wedge pressures of standing horses, furosemide-induced reduction in mean right atrial pressure achieved statistical significance in the 2 h postfurosemide experiments. In the control studies, exercise was attended by statistically significant increments in mean right atrial, as well as pulmonary arterial, capillary and wedge pressures. Although exercise in each of the four furosemide experiments was also attended by significant increments in right atrial as well as pulmonary vascular pressures, in the 1, 2 and 3 h postfurosemide experiments, mean right atrial pressure increased to a significantly lower value than in the control study. Exercise-induced changes in pulmonary vascular pressures in the 1 h postfurosemide experiments were not different from the pressures in the control study. There was a significant attenuation of exercise-induced pulmonary capillary and venous hypertension in the 2, 3 and 4 h postfurosemide experiments, but significant differences among these treatments were not found. Thus, these data did not support the contention that administration of furosemide at intervals shorter than 4 h before exercise is more effective in attenuating exercise-induced pulmonary capillary or venous hypertension in Thoroughbred horses.

Animals↗

Furosemide-probenecid interaction as a laboratory exercise for undergraduate education in clinical pharmacology.

OBJECTIVE: The aim of this study was to determine the easiness, reproducibility, and safety of a laboratory exercise for a drug interaction between furosemide and probenecid. METHODS: From 1995 to 1999 approximately 100 medical students participated in the exercise each year after they gave written informed consent. The students were randomly assigned to one of the three groups in a double-blind fashion: group 1, placebo plus 20 mg of furosemide; group 2, 250 mg of probenecid plus 20 mg of furosemide; and group 3, 1000 mg of probenecid plus 20 mg of furosemide. The students took probenecid or its placebo 1 hour before furosemide. Urine volume and urinary sodium excretion were measured for 3 hours after furosemide. At the end of the exercise in 1999, students responded to several questionnaires concerning the utility of furosemide. RESULTS: The entire course of the exercise was completed within half a day. The following findings were obtained every year. (1) Probenecid dose dependently blunted the diuretic effects of furosemide. (2) Time courses of the diuretic effects were altered by probenecid. Ten to twenty percent of the students had slight complaints but completed the exercise without any medications. Finally, more than 80% of the students considered the exercise to be useful. CONCLUSIONS: The data suggest that the exercise of the drug interaction between furosemide and probenecid is easy to perform, reproducible, and safe. Through the experience of the laboratory exercise, students will develop an attitude to assess and estimate potential drug interactions before they prescribe drugs.

Diuresis↗

Torsemide versus furosemide after continuous renal replacement therapy due to acute renal failure in cardiac surgery patients.

Diuretic therapy in ARF (acute renal failure) is mainly done with loop diuretics, first of all furosemide. Torsemide has a longer duration of action and does not accumulate in renal failure. In chronic and acute renal failure, both diuretics have been effectively applied, with a more pronounced diuretic effect for torsemide. In this study, the effects of torsemide versus furosemide on renal function in cardiac surgery patients recovering from ARF after continuous renal replacement therapy (CRRT) were studied. Twenty-nine critically ill patients admitted to an intensive care unit at a university teaching hospital after cardiac surgery recovering from ARF after CRRT were included in this prospective, controlled, single-center, open-labeled, randomized clinical trial. Inclusion criteria were urine output >0.5 mL/kg/h over 6 h under CRRT. Torsemide and furosemide dosages were adjusted with the target urine output being 0.8-1.5 mL/kg/h. Hemodynamic data, urine output, volume balance, serum creatinine clearance, electrolytes, blood urea nitrogen, serum creatinine, renin, and aldosterone concentrations were measured. Fourteen patients were included in the furosemide group and 15 patients in the torsemide group. Dosages of 29 (0-160) mg torsemide and a dosage of 60 (0-240) mg furosemide were given every 6 h in each group, respectively. The dosage given at the end of the study decreased significantly in furosemide and torsemide treated patients. Urine output, 24 h balance, and serum creatinine clearance did not differ significantly between groups. Urine output decreased in both groups, mostly dose-dependent in the torsemide group. The intragroup comparison of the first time-interval after inclusion with the last time-interval showed a significant increase in serum creatinine and blood urea nitrogen in the furosemide group. Renin and aldosterone concentrations did not show significant differences. In conclusion, torsemide and furosemide were effective in increasing urine output. Torsemide might show a better dose-dependent diuretic effect in ARF patients after CRRT treatment. Serum creatinine and blood urea nitrogen elimination were less pronounced in the furosemide group.

Acute Kidney Injury↗

Medullary nephrocalcinosis associated with long-term furosemide abuse in adults.

BACKGROUND: The use of furosemide is well recognized as a predisposing factor of nephrocalcinosis in infants. Although furosemide is widely used for various medical conditions in adults, its association with nephrocalcinosis in adults is not well established. METHODS: We studied 18 consecutive adult patients (male:female ratio 1:17, age range 21-59 years) who habitually took furosemide to control weight or oedema for long periods of time (range 3-25 years). The daily dose of continuous intake of furosemide ranged from 40 to 2800 mg. Nephrocalcinosis was evaluated using renal ultrasonography (US), computed tomography (CT), or kidney biopsies. RESULTS: Renal US and CT revealed bilateral nephrocalcinosis of the medullary pyramids in 15 (83.3%) out of 18 patients. The duration of furosemide abuse was similar between nephrocalcinosis positive (NC(+)) and nephrocalcinosis negative (NC(-)) groups. The daily dose of furosemide was nearly 10 times higher in the NC(+) group (range 120-2800 mg, mean 538 mg) than the NC(-) group (range 40-80 mg, mean 67 mg). All patients showed variable degrees of renal insufficiency and there was no difference in creatinine clearance between the NC(+) and NC(-) groups (P>0.05). Kidney biopsies performed in three patients showed focal tubulo-interstitial fibrosis and atrophy and calcifications were observed in outer medullary tubulo-interstitium. CONCLUSIONS: Long-term furosemide abuse can cause medullary nephrocalcinosis in adults, and the risk of developing of nephrocalcinosis seems to be correlated with the daily dose of furosemide. We suggest that long-term furosemide abuse should be suspected in adult patients when medullary nephrocalcinosis is incidentally detected by US or CT.

Adult↗

Differential regulation of collecting duct Na+, K+-ATPase and K+ excretion by furosemide and piretanide: role of bradykinin.

In response to chronic treatment with furosemide, collecting ducts adapt their function to the initial loss of Na+ to prevent further Na+ loss and extracellular volume decrease. This adaptation, which includes the overexpression of Na+, K+-ATPase, is thought to account for most of the kaliuretic effect of furosemide. Because piretanide is reported to be less kaliuretic than equidiuretic doses of furosemide, the authors compared the effects of 1-wk treatment with the two loop diuretics on urinary potassium excretion and on Na+, K+-ATPase activity in the collecting duct. At equidiuretic and equinatriuretic doses, furosemide increased urinary potassium excretion as well as collecting duct Na+, K+-ATPase activity, whereas piretanide had no effect on either parameter. These effects of furosemide were curtailed by concomitant administration of the angiotensin-converting enzyme inhibitor enalapril, but they were not altered either by clamping changes in plasma aldosterone or by blocking type I angiotensin receptors. Treatment with the antagonist of bradykinin B2 receptors Hoe140 mimicked the two effects of furosemide. In addition, the effects of Hoe140 and furosemide were not additive. Finally, piretanide increased urinary bradykinin excretion, whereas furosemide did not. These results suggest that induction of collecting duct Na+, K+-ATPase (a) accounts for the kaliuretic effect of furosemide, (b) is independent of the renin/angiotensin/aldosterone system, (c) results from increased Na+ delivery to the collecting duct and enhanced intracellular Na+ concentration, and (d) is prevented in piretanide treated rats by increased bradykinin production that may limit apical Na+ entry in collecting duct principal cells.

Animals↗

Role of nitric oxide pathway in hypotensive and renal effects of furosemide during extracellular volume expansion.

OBJECTIVE: In previous studies we demonstrated that the administration of furosemide associated with L-arginine contributes to enhanced hypotension and induces greater water than electrolyte excretion, in both normal and expansion conditions. The aim of the present study was to elucidate the interaction between furosemide and the nitric oxide (NO) system in renal and vascular responses during extracellular volume expansion. DESIGN AND METHODS: Expanded [10% body weight (bw)] and non-expanded anaesthetized male Wistar rats were treated with furosemide (7.5 mg/kg bw). Mean arterial pressure, nitrite and nitrate excretion (NOx) were determined. NADPH-diaphorase activity, a marker of nitric oxide synthase (NOS) activity, was measured histochemically in different segments of the nephron, aorta and renal arteries. NOS activity was determined using an L-[U14C]-arginine substrate in the kidney and aorta of expanded and non-expanded rats, in basal conditions and after furosemide (10 micromol/l). RESULTS: The hypotensive effect of furosemide was enhanced when NO production was stimulated in expanded and non-expanded animals. The diuretic treatment induced a significant increase in NOx excretion, in NADPH-diaphorase activity in the thick ascending limb of Henle, renal arteries and aorta, and in NOS activity in aorta and kidney in both groups. CONCLUSIONS: Our results suggest that the hypotensive effect of furosemide may be attributed to NO-mediated vasodilation. The enhanced NOS activity, observed in the renal artery of furosemide-treated rats, could explain the increased renal plasma flow induced by furosemide. In addition, NO-pathway stimulation in the kidney could be one of the mechanisms by which furosemide exerts its diuretic and natriuretic effects, in control and in expansion conditions.

Animals↗

Effects of cyclosporin A, gentamicin and furosemide on rat renal function: a lithium clearance study.

1. This study applied clearance methods of inulin, lithium, potassium, sodium and para-aminohippuric acid (PAH) for investigation of the effects of cyclosporin A (CyA), furosemide and gentamicin on rat (n = 92) renal function. The drugs were dosed for 2 weeks; CyA 12.5 mg/kg per day, gentamicin 32 mg/kg per day and furosemide 5 mg/kg per day. 2. The questions asked were: could these methods differentiate the effects of drugs with different sites of action, and would gentamicin or furosemide exaggerate the nephrotoxicity of CyA? 3. Furosemide increased sodium clearance (CNa) 74% and fractional sodium clearance (FENa) 105%, while fractional sodium reabsorption in the distal nephron (FDNR) was reduced, compared with placebo-treated controls. 4. Gentamicin reduced CPAH 29% and Cin 37%, while FENa increased 335%. Proximal fractional reabsorption (PFR) and absolute proximal reabsorption (APR) decreased. 5. CyA depressed CPAH 32% and lithium clearance (CLi) 56%, and increased PFR. 6. The effects of CyA and furosemide in reducing renal function were not additive. 7. CyA plus gentamicin reduced CPAH to 35% of the value in untreated controls, equal to 52% of the CPAH of CyA-treated rats; Cin was reduced to 46% of the Cin of CyA-treated rats. 8. Rats given CyA, furosemide and gentamicin had decreased Cin, CPAH and CLi compared with rats given either CyA plus furosemide or gentamicin plus furosemide. 9. Thus, in this investigation of drugs known to have different sites of actions, the differences in renal and tubular function were discernible with the lithium clearance method. 10. The nephrotoxicities of CyA and of gentamicin were additive, while furosemide did not aggravate CyA nephrotoxicity.

Animals↗

The use of HPLC to elucidate the metabolism and urinary excretion of furosemide and its metabolic products.

Three principles for the use of HPLC with spectrophotometric detection to determine the concentration of furosemide and of 4-chloro-5-sulfamoyl anthranilic acid (CSA) were studied. A reversed phase microbondapack C18 column was used for the separation of either unchanged furosemide (I), CSA (II) or the diazo product of CSA (III). The sensitivity of the methods for the determination of furosemide added to serum in vitro were for I 0.05, for II 0.020 and for III 0.01 microgram/ml. The methods I and II were used to study the excretion pattern in the urine of furosemide and CSA after intravenous injection of 80 mg to 10 normal subjects. An average of 48.1 +/- 9.8% (S.D.) of the furosemide was excreted during the first hour as unchanged furosemide. Simultaneously 1.9 +/- 0.8% of the dose was excreted as CSA. Only very low concentrations of CSA were found in serum and that metabolite apparently was excreted with a higher renal clearance than furosemide during the period 30-60 min. after the administration (30.3 +/- 145 ml/min. for CSA and 88 +/- 23 ml/min. for furosemide). During the 24 hour period following the administration 52.6 +/- 8.1 mg was excreted as unchanged furosemide and 11.4 +/- 5.2 mg as a glucuronidated product.

Adult↗

Furosemide reverses multidrug resistance status in bladder cancer cells in vitro.

BACKGROUND: Multidrug resistance (MDR) has a potentially serious influence on cancer treatment and should be taken into consideration in the design and application of therapeutic regimens. It is mediated through the activity of cellular pumps. AIM: To investigate whether furosemide, itself a pump-blocker, reverses MDR in an in vitro model. MATERIALS AND METHODS: An MDR bladder cancer cell line (MGH-u 1R) and its parental (drug sensitive) clone were exposed to epirubicin and furosemide, with the concentration of one drug fixed and that of the other serially diluted in a 96-well plate format. Both drugs formed the variable component in separate experiments. After a 1-h exposure, the cells were washed and replenished with fresh medium. To examine the toxicity of epirubicin and furosemide separately and in combination, monotetrazolium-based assays were carried out. Intracellular epirubicin distribution was assessed by confocal microscopy as a second index of resistance status after in vitro exposure. RESULTS: MGH-u 1R cells incubated with furosemide showed distribution of drug similar to that in the parental cells (MGH-u 1 sensitive). Controls (without furosemide) continued to show a resistant pattern of fluorescence. In cytotoxicity assays furosemide appeared substantially non-toxic. Resistant cells in the toxicity titration experiments showed increased resistance to levels of furosemide over 500 mug/ml. Parental cells were made only marginally more sensitive against increased background toxicity. CONCLUSION: Furosemide is effective in reversing MDR status in bladder cancer cell lines in vitro. It may also have an increment of intrinsic cytotoxicity, but only at higher concentrations. We propose a potential for further investigation of furosemide as an adjunct to chemotherapy for superficial bladder cancer.

Antibiotics, Antineoplastic↗

Phosphaturic effect of furosemide: role of PTH and carbonic anhydrase.

The first objective of this study was to examine the effects of furosemide on renal phosphate excretion in the presence and absence of a constant level of parathyroid hormone (PTH) while extracellular fluid volume was held constant. In the absence of PTH, furosemide did not significantly increase fractional phosphate excretion (FEP%, 4.2 +/- 2.7 to 6.2 +/- 1.9%; five dogs). In the presence of PTH, furosemide increased FEP% from 23.4 +/- 3.7 to 33.8 +/- 6.0% (P less .025; five dogs). Thus, the phosphaturia induced by furosemide was dependent on the presence of PTH. The second objective was to evaluate the hypothesis that furosemide exerts its phosphaturic effect through carbonic anhydrase inhibition, and therefore we tested for additivity of the phosphaturic effect of furosemide, and acetazolamide. In the presence of a constant level of PTH, acetazolamide increased FEP % from 24.5 +/- 1.8% to 40.7 +/- 5.1% P less than .025, five dogs. The subsequent administration of furosemide did not further increase FEP%, delta 3.3 +/- 8.9%; NS. Thus, the phosphaturic effect of furosemide was not additive to that of acetazolamide, indicating that acetazolamide and furosemide may share similar mechanisms for inhibiting phosphate reabsorption.

Acetazolamide↗

Prostaglandin E2 but not I2 restores furosemide response in indomethacin-treated rats.

Indomethacin attenuates furosemide's natriuretic response. Although this has been attributed to cyclooxygenase inhibition, attempts to correlate prostaglandin (PG) production with furosemide's natriuresis have led some investigators to conclude that prostaglandins are not involved in this response. This study was designed to evaluate the effects of intraaortic administration of PGE2, PGI2 (100 ng X kg-1 X min-1), or the vasodilators secretin or bradykinin (75 microU X kg-1 X min-1) on the furosemide-indomethacin antagonism. Fractional sodium excretion (FENa) during furosemide administration was 4.59 +/- 0.50% in control rats but 1.84 +/- 0.33% in indomethacin-treated rats (Indo) (P less than 0.001). PGE2 prevented indomethacin from attenuating furosemide's response (FENa, 3.91 +/- 0.25%; P = NS vs. control; P less than 0.01 vs. Indo). PGI2, however, failed to prevent the furosemide-indomethacin antagonism (FeNa, 1.94 +/- 0.59%, P less than 0.001 vs. control; P = NS vs. Indo). Inulin clearance, arterial pressure, filtered sodium load, and renal blood flow were not different between groups. Neither secretin nor bradykinin prevented the indomethacin-furosemide antagonism. This study is consistent with the hypothesis that indomethacin antagonizes furosemide's natriuretic response by prostaglandin synthesis inhibition. Furthermore, PGE2 seems to restore furosemide's response through actions other than a vasodilatory effect.

Animals↗