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PubMed2003

Preparation and characterization of the inclusion complex of furosemide with hydroxypropyl-beta-cyclodextrin.

A highly hydrophobic drug, furosemide, was treated with 2-Hydroxypropyl-beta-Cyclodextrin in an attempt to produce modified compounds with increased water solubility. Following a freeze-drying process, the interactions of furosemide and cyclodextrin led to the formation of an inclusion complex, whose dissolution rate in water was studied by the solubility method. Furthermore, mechanical mixtures of furosemide and cyclodextrin were also prepared and tested for their solubility. The reaction products were characterized in the solid state by differential scanning calorimetry (DSC), which provided some evidence about complexation. Additional evidence was obtained by recording the 1H NMR spectra of aqueous solutions of these same products. The study of phase solubility was based on the Higuchi & Connors method and showed an impressive enhancement of the miscibility of furosemide with water. In fact, a 11 fold increase of the drug solubility was recorded for the inclusion complex, in the first stages of dissolution. The experimental results of this work show that 2-Hydroxypropyl-beta-Cyclodextrin is an efficient complexation agent for furosemide. Combination of those two substances can be carried out by simple techniques, providing easy control and the obtained inclusion complex is characterized by acceptable water solubility and increased dissolution rate.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2001

Effects of intravenous furosemide on mucociliary transport and rheological properties of patients under mechanical ventilation.

The use of intravenous (IV) furosemide is common practice in patients under mechanical ventilation (MV), but its effects on respiratory mucus are largely unknown. Furosemide can affect respiratory mucus either directly through inhibition of the NaK(Cl)2 co-transporter on the basolateral surface of airway epithelium or indirectly through increased diuresis and dehydration. We investigated the physical properties and transportability of respiratory mucus obtained from 26 patients under MV distributed in two groups, furosemide (n = 12) and control (n = 14). Mucus collection was done at 0, 1, 2, 3 and 4 hours. The rheological properties of mucus were studied with a microrheometer, and in vitro mucociliary transport (MCT) (frog palate), contact angle (CA) and cough clearance (CC) (simulated cough machine) were measured. After the administration of furosemide, MCT decreased by 17 +/- 19%, 24 +/- 11%, 18 +/- 16% and 18 +/- 13% at 1, 2, 3 and 4 hours respectively, P < 0.001 compared with control. In contrast, no significant changes were observed in the control group. The remaining parameters did not change significantly in either group. Our results support the hypothesis that IV furosemide might acutely impair MCT in patients under MV.

Adult↗
PubMed1980

Furosemide-induced alterations in the electrolyte status, the function of renin-angiotensin-aldosterone system, and the urinary excretion of prostaglandins in newborn infants.

To assess the responsiveness of the renin-angiotensin-aldosterone system of the neonate to acute furosemide stimulation and the role of renal prostaglandins in mediating the response of the renin-angiotensin-aldosterone system, this study was carried out to determine simultaneously plasma renin activity, plasma aldosterone concentration, urinary aldosterone, prostaglandin E, and prostaglandin F2 alpha excretion along with determination of plasma electrolyte concentration and urinary electrolyte excretion. Measurements were made on 19 newborn infants with mean birth weight and gestational age of 3009 g (range, 2700 to 4150 g) and 38.7 wk (range, 36 to 41 wk) at the age of 4 to 7 days before and after IM administration of furosemide in a dose of 1 mg/kg. It was demonstrated that in response to furosemide, urine volume (P less than 0.001), urinary sodium (P less than 0.001), potassium (P less than 0.05), and chloride (P less than 0.001) excretion increased significantly. Furosemide administration also resulted in a significant increase from 4.41 +/- 2.00 to 9.70 +/- 2.32 ng/ml/hr (P less than 0.02) in plasma renin activity, from 1.17 +/- 0.22 to 1.68 +/- 0.36 ng/ml (P less than 0.025) in plasma aldosterone, from 0.93 +/- 0.16 to 1.53 +/- 0.35 microgram/12 hr (P less than 0.025) in urinary aldosterone, from 17.53 +/- 3.37 to 23.73 +/- 3.16 ng/12 hr (P less than 0.025) in prostaglandin E, and from 16.48 +/- 4.12 to 26.27 +/- 4.12 ng/12 hr (P less than 0.05) in prostaglandin F2 alpha. It is concluded that the renin-angiotensin-aldosterone system of the neonate responds to acute furosemide challenge in spite of its high baseline activity, and its response may be mediated by increased renal prostaglandin production.

Aldosterone↗
PubMed1979

Effect of furosemide on experimental traumatic cerebral edema.

The present study was designed to test the effectiveness of furosemide in reducing cerebral edema due to closed head trauma. A Remington Humane Stunner was used to deliver blows to the heads of anesthetized cats. Impacted animals were divided into three groups: (a) trauma, no drug, and ad lib. fluid intake after head injury; (b) trauma, no drug, and standardized fluid intake (0.9% NaCl; 10 ml/lb/day); and (c) trauma, furosemide (3 mg/lb/day), and standardized fluid intake. For the treated cats, we began furosemide therapy 1 hour after head injury and used three intramuscular injections/day. The animals were killed 48 hours after head trauma. From animals with unilateral contusion, we took bilateral white matter samples from five points along the centrum semiovale and tested for edema using density determinations with an organic density gradient. Serum electrolytes, blood urea nitrogen, and weight were determined before the cats were impacted and before they were killed. All impacted animals demonstrated weight loss. Density data showed a normal water content for white matter in the uncontused hemispheres of all impacted cats. Contused hemispheres showed a significant decrease in density (increase in brain water content) for both treated and untreated cats. In the furosemide-treated animals, however, the brain edema was significantly less than that found in the untreated groups. Analysis of data from individual brain sections of furosemide-treated animals suggested a reduction in the spread of edema fluid 48 hours after head injury.

Animals↗
PubMed1988

Transport of furosemide into the intestinal lumen and the lack of effect of gastrointestinal dialysis by charcoal in rats with acute renal failure.

The characteristics of exsorption and/or excretion of furosemide into the small intestinal lumen in rats with acute renal failure (ARF rat) were investigated by an in situ single-pass perfusion technique. The amount of furosemide, which was exsorbed into the intestinal lumen after an intravenous administration of the drug to rats was only very slight. The exsorption rate of the drug was significantly increased in ARF rats as compared with normal rats. The average amount of the drug exsorbed into the perfusate in normal rats was 0.83% of dose, whereas that in ARF rats was 1.83% of dose. The amounts of furosemide excreted into the bile in normal rats and ARF rats were 1.53% and 2.64%, respectively. The increased exsorption of furosemide in ARF rats appeared to be due primarily to the decreased binding of the drug to the serum protein, because only the unbound drug permeates through the intestinal membrane into the gastrointestinal (g.i.) tract, and, to some extent, to the increased nonrenal excretion caused by poor renal excretion. Oral activated charcoal had little effect on the serum furosemide levels after intravenous administration of the drug at a dose of 10 mg/kg in ARF rats. The lack of effect of activated charcoal on the elimination of the drug may be due to the small amount of the drug excreted into the g.i. tract.

Acute Kidney Injury↗
PubMed1988

Decreased diuretic response to furosemide in rats with acute hepatic failure.

Furosemide diuresis is occasionally reduced in cirrhotic patients with ascites. To define this phenomenon, the amounts of water, electrolytes, and furosemide excreted in urine were measured in control and CCl4-induced acute hepatic failure (AHF) rats. The diuretic action of furosemide (10 mg/kg, i.v.) was reduced in AHF rats, accompanied by increased plasma aldosterone concentration and accelerated urinary K+ excretion rate. Furosemide transiently increased the urinary inulin excretion rate (UVIN) in both control and AHF rats. Then the UVIN quickly returned to the baseline value in control rats, but rapidly dropped below the baseline in AHF rats. To clarify the contribution of aldosterone in these phenomena, AHF rats was adrenalectomized (ADX) and treated with or without exogenous aldosterone. The UVIN in ADX rats given no infusion or a low-dose aldosterone infusion was similar in pattern to that of the control group, but the UVIN in the ADX rats given a high-dose aldosterone infusion showed a pattern similar to that of the AHF rats not adrenalectomized. These findings indicate that an increase in plasma aldosterone concentration is an important factor responsible for the decreased diuretic action of furosemide, along with the reduced glomerular filtration rate.

Adrenalectomy↗
PubMed1983

Clinical pharmacokinetics and diuretic effect of furosemide in plain tablet and retard capsule with normal subjects and cirrhotic patients.

The dissolution profiles of furosemide in various solutions were studied with plain tablet and retard capsule of furosemide. The rate constant and percent dissolution in retard capsule were lower than that in plain tablet. Clinical pharmacokinetics and diuretic effect of furosemide after oral administration of two dosage forms were also studied with 3 normal subjects and 3 cirrhotic patients. In normal subjects, the extent of furosemide absorption from retard capsule was 45% of plain tablet. The daily urine volume after oral administration of two dosage forms was comparable, however, quite different profiles were observed between these dosage forms. In patients, the extent of furosemide absorption in retard capsule was one half that of plain tablet. The dose of retard capsule was increased without adverse reactions, thus decreasing of ascites, which was not observed with plain tablet, was achieved with increasing urine volume.

Adult↗
PubMed1992

Influence of DOCA treatment on administration-time-dependent changes in the effects of furosemide in saline-loaded rats.

We have previously found that the administration-time-dependent change in the effects of furosemide, a loop diuretic agent, is observed in normal rats. The present study was undertaken to examine whether an alteration in this phenomenon occurs in rats with DOCA-saline hypertension. Unilateral nephrectomized rats were divided into three groups. The first group (DOCA-saline) received a 50 mg DOCA tablet intraperitoneally and drank 1% NaCl solution. The other two groups were given sham operations. A 1% NaCl solution was given as drinking water to the second group (control-saline), while tap water was given to the third group (control-water). Furosemide (30 mg/kg) was given orally to each group at 12 a.m. or 12 p.m. Urine was collected for 8 hours after the agent, and urinary excretion of sodium and furosemide were determined. Urine volume and urinary excretion of sodium and furosemide following the agent were significantly greater at 12 a.m. than at 12 p.m. in the control-water and control-saline groups. However, the administration-time-dependent changes in these parameters disappeared in the DOCA-saline rats. These results suggest that the mode of the administration-time-dependent changes in the effects of furosemide is altered in the DOCA-saline hypertensive rats.

Animals↗
PubMed1985

Furosemide ototoxicity: clinical and experimental aspects.

Furosemide is an ototoxic diuretic. Furosemide injection is followed by a rapid, but reversible decrease of the endocochlear potential and eighth nerve action potential with a more gradual decrease of the endolymph potassium concentration. In contrast to the reversible effects of furosemide alone on the cochlea, the combination of kanamycin with furosemide resulted in irreversible changes in cochlear function which were associated with elevated levels of kanamycin in the blood and perilymph of the experimental animals. There was a striking similarity between the blood level measured by high pressure liquid chromatography at the time of recovery of auditory function in experimental animals and the ototoxic blood levels proposed by others in clinical literature. These findings help to provide a pharmacologic basis for the clinical observation of furosemide-induced hearing loss.

Animals↗
PubMed2002

Ototoxicity induced by gentamicin and furosemide.

OBJECTIVE: To present a case of ototoxicity induced by furosemide and once-daily gentamicin therapy. CASE SUMMARY: A 60-year-old white woman presented to the hospital with community-acquired pneumonia and urinary tract infection. The antibiotic regimen included gentamicin and, after 5 doses, the patient reported profound bilateral hearing loss. A Pure Tone Audiogram suggested moderate to moderately severe sensorineural hearing loss bilaterally. The only risk factors present included her age, elevated temperature, and the use of furosemide. DISCUSSION: Several risk factors may predispose a patient to developing aminoglycoside ototoxicity: the 1555 chromosomal mutation, preexisting disorders of hearing and balance, hypovolemia, bacteremia, liver and renal dysfunction, and the simultaneous administration of other ototoxic medications. The cumulative dose and duration of aminoglycoside therapy are more important than serum concentrations. Administration of an aminoglycoside followed by furosemide may increase the risk of ototoxicity. The aminoglycoside interacts with the cell membranes in the inner ear, increasing their permeability. This theoretically allows the loop diuretic to penetrate into the cells in higher concentrations, causing more severe damage. CONCLUSIONS: Auditory toxicity occurred after only 5 days of gentamicin therapy and 1 dose of furosemide. An aminoglycoside followed by furosemide may increase the risk for ototoxicity. Clinicians need to be aware of the synergistic potential of ototoxic medications.

Anti-Bacterial Agents↗
PubMed2003

Combined furosemide and human albumin treatment for diuretic-resistant edema.

OBJECTIVE: To evaluate the clinical usefulness of combined furosemide and human albumin for the treatment of diuretic-resistant edema in patients with nephrotic syndrome and cirrhosis. DATA SOURCES: Clinical literature was accessed through MEDLINE (1966-May 2002). Key search terms included furosemide, albumin, human albumin solution, nephrotic syndrome, and cirrhosis. DATA SYNTHESIS: Hypoalbuminemia, edema, and ascites are often manifestations of nephrotic syndrome and cirrhosis of the liver. Many patients with these conditions are resistant to the effects of diuretics. The combination of furosemide and human albumin solution is occasionally used in these patients. An evaluation of published studies focusing on combined furosemide and albumin in the management of nephrotic syndrome and cirrhosis was conducted. CONCLUSIONS: Published studies report conflicting results regarding the efficacy of combined furosemide and albumin. Although it is difficult to generate firm conclusions, it appears the combination may provide clinical benefits for select patients. Given these findings, we believe that the addition of albumin to enhance diuretic efficacy should be reserved for patients with recalcitrant edema or ascites in whom diuretic doses have been maximized and those with severe hypoalbuminemia.

Albumins↗
PubMed2006

Efficacy and safety of a furosemide continuous infusion following cardiac surgery.

OBJECTIVE: To review the literature regarding the efficacy and safety of continuous intravenous infusion of loop diuretics following cardiac surgery. DATA SOURCES: Articles were identified through a MEDLINE search (1966-March 2006) using the key words furosemide, bumetanide, torsemide, ethacrynic acid, loop diuretics, continuous infusions, intravenous infusions, surgery, cardiac surgery, cardiovascular surgery, and thoracic surgery. Search results were limited to studies in human subjects published in English. Additional references were identified through review of the bibliographies of the articles cited. STUDY SELECTION AND DATA EXTRACTION: All clinical trials and observational reports identified that evaluated or described the efficacy and/or safety of a continuous infusion of a loop diuretic in adult or pediatric patients who had undergone cardiac surgery were included in this review. DATA SYNTHESIS: Loop diuretics are often used to promote diuresis following cardiac surgery. Studies in patients who have undergone cardiac surgery have demonstrated that a more consistent and sustained diuresis is produced by a continuous infusion of furosemide compared with intermittent bolus doses of furosemide. However, there does not appear to be a significant difference in total urine output or change in serum electrolyte levels when furosemide is administered as a continuous infusion compared with intermittent bolus doses. CONCLUSIONS: A continuous infusion of furosemide is an effective and safe method of diuresis in patients undergoing cardiac surgery.

Arrhythmias, Cardiac↗
PubMed1987

Comparison of nitroglycerin, morphine and furosemide in treatment of presumed pre-hospital pulmonary edema.

We compared four treatment protocols in 57 patients with presumed pre-hospital pulmonary edema. Group A patients were treated with nitroglycerin and furosemide, group B patients with morphine sulfate and furosemide, group C with all three agents, and group D with nitroglycerin and morphine, but without furosemide. Twenty-three percent of our patients were ultimately found not to have pulmonary edema, with pneumonia and/or exacerbations of chronic lung disease the most frequent alternate diagnoses. Group A patients had significantly greater improvement, both subjectively and objectively, than group B patients, a substantial number of whom failed to improve, or even worsened. There was no evident synergistic effect of any of the drugs, and some indication that furosemide might have caused clinically important problems with fluid and electrolyte management in some of the patients. Our data suggest that nitroglycerin is beneficial in the management of presumed pre-hospital pulmonary edema, while morphine and furosemide may not add anything to its efficacy, and may be potentially deleterious in some of these patients.

Aged↗
PubMed1998

Furosemide decreases the sensitivity of glucose transport to insulin in skeletal muscle in vitro.

The effects of the diuretic furosemide on the sensitivity of glucose disposal to insulin were investigated in rat soleus muscle in vitro. At basal levels of insulin, the rates of 3-O-methylglucose transport, 2-deoxyglucose phosphorylation and lactate formation were not affected significantly by furosemide (0.5 mmol/l). However, furosemide significantly decreased these rates at physiological and maximal levels of insulin. The contents of 2-deoxyglucose and glucose 6-phosphate in the presence of furosemide were not significantly different from those in control muscles at all levels of insulin studied. It is concluded that furosemide decreases the sensitivity of glucose utilization to insulin in skeletal muscle by directly inhibiting the glucose transport process.

3-O-Methylglucose↗
PubMed2005

Dominant role of prostaglandin E2 EP4 receptor in furosemide-induced salt-losing tubulopathy: a model for hyperprostaglandin E syndrome/antenatal Bartter syndrome.

Increased formation of prostaglandin E2 (PGE2) is a key part of hyperprostaglandin E syndrome/antenatal Bartter syndrome (HPS/aBS), a renal disease characterized by NaCl wasting, water loss, and hyperreninism. Inhibition of PGE2 formation by cyclo-oxygenase inhibitors significantly lowers patient mortality and morbidity. However, the pathogenic role of PGE2 in HPS/aBS awaits clarification. Chronic blockade of the Na-K-2Cl co-transporter NKCC2 by diuretics causes symptoms similar to HPS/aBS and provides a useful animal model. In wild-type (WT) mice and in mice lacking distinct PGE2 receptors (EP1-/-, EP2-/-, EP3-/-, and EP4-/-), the effect of chronic furosemide administration (7 d) on urine output, sodium and potassium excretion, and renin secretion was determined. Furthermore, furosemide-induced diuresis and renin activity were analyzed in mice with defective PGI2 receptors (IP-/-). In all animals studied, furosemide stimulated a rise in diuresis and electrolyte excretion. However, this effect was blunted in EP1-/-, EP3-/-, and EP4-/- mice. Compared with WT mice, no difference was observed in EP2-/- and IP-/- mice. The furosemide-induced increase in plasma renin concentration was significantly decreased in EP4-/- mice and to a lesser degree also in IP-/- mice. Pharmacologic inhibition of EP4 receptors in furosemide-treated WT mice with the specific antagonist ONO-AE3-208 mimicked the changes in renin mRNA expression, plasma renin concentration, diuresis, and sodium excretion seen in EP4-/- mice. The GFR in EP4-/- mice was not changed compared with that in WT mice, which indicated that blunted diuresis and salt loss seen in EP4-/- mice were not a consequence of lower GFR. In summary, these findings demonstrate that the EP4 receptor mediates PGE2-induced renin secretion and that EP1, EP3, and EP4 receptors all contribute to enhanced PGE2-mediated salt and water excretion in the HPS/aBS model.

Actins↗
PubMed2006

Multidrug resistance-associated protein 4 is involved in the urinary excretion of hydrochlorothiazide and furosemide.

The role of ATP-binding cassette transporters in the urinary excretion of diuretics was investigated. Significant ATP-dependent uptake of hydrochlorothiazide (HCT) and furosemide was observed in membrane vesicles that expressed multidrug resistance-associated protein 4 (MRP4) and breast cancer resistance protein (BCRP). Unlike taurocholate uptake, S-methylglutathione had no effect on the ATP-dependent uptake of both compounds by MRP4. The functional importance of MRP4 and BCRP in the urinary excretion of HCT and furosemide was investigated using gene knockout mice. The renal clearance of HCT and furosemide was reduced significantly but not abolished in Mrp4 knockout mice compared with wild-type mice (9.0 +/- 0.9 versus 15 +/- 2 ml/min per kg for HCT and 1.9 +/- 0.3 versus 2.7 +/- 0.1 ml/min per kg for furosemide), and the amount of HCT that was associated with the kidney specimens was greater in Mrp4 knockout mice (21 +/- 3 versus 13 +/- 1 nmol/g kidney). In contrast, Bcrp makes only a negligible contribution because the urinary excretion was unchanged in Bcrp knockout mice. Our results suggest that Mrp4, together with other unknown transporters, accounts for the luminal efflux of HCT and furosemide from proximal tubular epithelial cells.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed1992

Absorption of high dose furosemide (frusemide) in congestive heart failure.

To investigate the influence of the presence of oedema on the pharmacokinetics and pharmacodynamics of furosemide (frusemide) we selected 9 hospitalised patients (mean age 70.3 years, range 59 to 84 years) with severe congestive heart failure (NYHA III to IV) and an assessed amount of peripheral oedema of at least 5 kg. In these patients the absorption of a single oral dose of furosemide 250 mg was studied when their heart failure was decompensated and again, after intensive therapy, when it was clinically compensated. The mean (+/- SEM) weight loss after clinical treatment was 12.0 +/- 2.2 kg. Individual furosemide plasma concentration-time curves could be fitted adequately to a 1-compartment model with 1 first-order absorption and elimination process, in which absorption took place in 2 parts with different lag times. Comparing the decompensated state with the compensated state we did not find significant differences in pharmacodynamics, absorption half-life, elimination half-life, time to peak serum concentration, peak serum concentration itself and area under the plasma concentration-time curve. However, the relative amount of furosemide absorbed in the first fraction was significantly increased after compensation. We conclude that the presence of massive oedema in patients with congestive heart failure has a minor influence on the pharmacokinetics and pharmacodynamics of high dose oral furosemide.

Administration, Oral↗
PubMed1979

Elimination kinetics of furosemide in perilymph and serum of the chinchilla. Neuropharmacologic correlates.

This study was done to determine the comparative elimination kinetics of furosemide from chinchilla perilymph and serum, and to correlate perilymph concentration with changes in endocochlear potential. The elimination kinetics of furosemide (FU) were determined in sera and perilymph obtained from chinchillas injected with 100 mg/kg i.v. of FU. Concentrations of FU exhibited a linear decay pattern in serum and perilymph over the initial 60 minutes. The rate of decline of furosemide levels in perilymph was about four times slower than the rate of fall in serum. Chronic treatment (25 mg/kg i.p. every 12 hours) did not appear to influence the level of drug at 60 minutes after a dose of FU (100 mg/kg IV). Chinchillas were also studied following doses of FU ranging from 25--200 mg/kg i.v. to see the effect on endocochlear potential (EP). A positive correlation was found between FU dosage, the maximum millivolt reduction of EP and the time to initiation of recovery of EP. The perilymph concentration of furosemide when the EP began to recover was 5 microgram/ml (1.5 x 10(-5) M). Knowledge of furosemide kinetics may ultimately be applied to prevent ototoxicity in patients.

Animals↗