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The value of induced diuresis, employing furosemide, on blood loss during and after prostatectomy is evaluated. Two series of 100 patients (consecutive) undergoing prostatectomy, one series with furosemide and one without, are compared. The conclusion drawn from critical analysis is that induced diuresis with furosemide is beneficial in reducing blood loss.
The effect of captopril, furosemide, indomethacin and intake of sodium on the production of PGI2-like material was studied in the rat aorta. Release of PGI2-like material from these vessels was estimated by its ability to inhibit ADP-induced platelet aggregation. Pretreatment with indomethacin (15 mg/kg/day) reduced the capacity of the aorta to release PGI2-like material. Pretreatment with captopril (10 mg/kg/day) had no effect. Intravenous furosemide (60 microgram/ml plasma volume) increased the capacity of the aorta to inhibit by 28% (p less than 0.25). The inhibitory capacity of aorta removed from rats on a low sodium diet did not differ from those on a high sodium diet. We conclude that the action of furosemide in reducing vascular tone may be related to stimulation of PGI2 synthesis in blood vessels whereas the effect of captopril and sodium in reducing vascular tone may involve a mechanism unrelated to PGI2 synthesis or may involve the synthesis of a prostaglandin other than PGI2.
Furosemide causes both diuretic and non-diuretic changes in renal function. We compared responses to intravenous furosemide 0.5 mg.kg-1 in 38 subjects (30 males, 8 females) aged 18 to 30 with those in 14 subjects (9 males, 5 females) aged 50 and over. There were no consistent differences attributable to gender. Older persons showed greater natriuresis (47 percent in males and 26 percent in females) but their increment in plasma renin activity was markedly reduced. The urinary excretion of thromboxane B2 was elevated in older subjects (58 +/- 10 vs. 30 +/- 4 ng/4 h, p less than 0.05 for males; 48 +/- 7 vs. 29 +/- 4 ng/4 hr, p less than 0.05 for females) while that of 6-keto prostaglandin F1 alpha was not different. While differences in the diuretic response to furosemide may be due to pharmacokinetic differences, the non-diuretic response differences may reflect age related changes in renal prostaglandin synthesis.
A patient with long-standing hypertension developed urticaria, angioedema, and hypotension within 5 minutes after the intravenous administration of furosemide. Immediate hypersensitivity was documented by positive skin tests to furosemide as well as to related sulfonamide-based drugs. This is the first finding of an anaphylactic reaction to furosemide and underscores the need to consider such adverse reactions when patients who are sensitive to other sulfonamide-containing drugs are being treated.
A possible role for loop diuretic-sensitive Cl-/cation cotransport in volume regulation in the pancreatic beta-cells was investigated by measuring 86Rb+ efflux from beta-cell-rich pancreatic islets as well as the size of isolated beta-cells under different osmotic conditions. Lowering the osmolarity to 262 mosM (83% of control) resulted in a rapid cell swelling which was followed by regulatory volume decrease (RVD). RVD was completely inhibited by furosemide (1 mM), an inhibitor of Cl-/cation co-transport. The hypotonic medium (262 mosM) induced a rapid and strong increase in 86Rb+ efflux from beta-cell-rich mouse pancreatic islets and the furosemide-sensitive portion of the efflux was significantly increased. A slightly less hypotonic medium (285 mosM, 90% of control) induced only cell swelling and no RVD. With this medium only a marginal increase in 86Rb+ efflux was observed. Increasing the osmolarity by adding 50 mM NaCl (final osmolarity: 417 mosM, 132% of control) induced a rapid cell shrinkage but no regulatory volume increase (RVI). When the osmolarity was increased from a slightly hypotonic medium (262 mosM) to an isotonic medium (317 mosM) an initial cell shrinkage was followed by RVI. This RVI was inhibited by 1 mM furosemide. The data suggest that RVD as well as RVI in the beta-cells are mediated by loop diuretic-sensitive cotransport of chloride and cations and that these cells show a threshold for hypotonic stimulation of RVD.
The renin-angiotensin-aldosterone system is activated by diuretics and involved in the diuretic resistance of cirrhotic patients with ascites and oedema. In previous studies relatively high doses of captopril (25-400 mg daily) were unsuccessful in promoting diuresis and natriuresis in these patients. We analyzed the efficacy of a low dose of captopril in eight patients with massive ascites resistant to therapy of salt/fluid restriction and increasing doses of spironolactone and furosemide. Mean duration of diuretic use was 73 days (range 7-240 days). After at least 3 days of observation on 80 mg furosemide and 100 mg spironolactone only, captopril was added. Four out of eight patients responded with an increase in natriuresis and diuresis; daily dose of captopril was 20.6 mg in responders and 26.5 mg in non-responders. After the addition of captopril the mean weight change was -7.5 kg in responders and +0.25 kg in non-responders. Mean urinary sodium output in responders increased from 72.8 (S.D. = 35.2) to 128.5 (63.5) mmol within 10 days. Increased diuresis in responders made diuretic reduction necessary: mean furosemide from 80 to 53.3 mg, and mean spironolactone from 100 to 68.1 mg. Creatinine clearances remained stable. High levels of plasma renin activity, plasma aldosterone and angiotensin-II were found in all patients. Non-responders showed more severe hyponatremia and higher vasopressin levels. Natriuretic atrial factor (NAF) was in the upper-normal range or slightly elevated in both groups. In non-responders we noticed low levels of cGMP in 24-h urine, compared with responders.(ABSTRACT TRUNCATED AT 250 WORDS)
Previous studies have shown that oral administration of minoxidil on 2 consecutive days produces an increase in heart rate and myocardial necrosis in Beagle dogs. Propranolol treatment (1.0 or 3.0 mg/kg every 8 h) did not abolish tachycardia and did not alter the incidence or severity of minoxidil-induced necrosis. In the present studies, pretreatment with either furosenmide (10 mg/kg) or hydrochlorothiazide (250 mg/kg) reduced serum potassium levels. However, only furosemide (for 11 days) reduced significantly the incidence of minoxidil-induced necrosis; only 2 of 10 animals (20%) developed myocardial lesions compared to 11 of 14 (79%) in the non-treated group. The incidence and severity of lesions in hearts from animals treated with furosemide for 3 days or hydrochlorothiazide for 11 days were essentially the same as in animals given minoxidil alone. Thus, furosemide, under certain conditions, can reduce the incidence of acute ventricular lesions induced by minoxidil.
An ouabain-insensitive, Mg2+-dependent, chloride- and bicarbonate-stimulated ATPase is present in salt gland homogenates of domestic ducks (Anas platyrhynchos). Furosemide and ethacrynic acid are non-competitive inhibitors of this enzyme in vitro. The inhibitor constant of furosemide is Ki = 2.5 mM and of ethacrynic acid Ki = 1.9 mM. In contrast, under the same conditions the salt gland Na+/K+-ATPase activity is not inhibited by furosemide, whereas ethacrynic acid becomes inhibitory only at higher concentrations (10 mM).
An on-line solid-phase extraction technique based on column switching (heart-cutting) was developed for direct injection analysis of furosemide in human serum. In order to minimize the influence of deterioration in pre-treatment column efficiency, which was caused by protein precipitation with repeated injections of serum, furosemide was completely enriched at the top of the analytical column by ion-pair formation with tetra-n-butylammonium ion during heart-cutting. The robustness of the established on-line solid-phase extraction system was confirmed under routine conditions. As a result, almost comparable chromatograms could be obtained even though 50 repeated injections of a 100-microliter volume of serum were carried out using one pre-treatment column. The linearity of the calibration curves was demonstrated by the correlation coefficient which was greater than 0.99999 (5-1000 ng/ml). The relative errors and C.V. of quality control samples were within 4.00 and 5.88%, respectively (furosemide concentrations: 5, 100 and 1000 ng/ml).
A series of organic acid transport inhibitors significantly reduced the endocochlear potential (EP) decline produced by furosemide in the chinchilla. Probenecid, sodium salicylate and penicillin G were much more effective than novobiocin, meclofenamate or diatrizoate. Inhibitors of organic base transport, choline and N-methyl nicotinamide, had no effect on the furosemide-induced drop of the EP. These findings suggest that at least part of furosemide ototoxicity may be mediated by organic acid transport.
Furosemide-induced changes of cochlear potentials were used as a model to study the influence of arachidonic acid metabolites on ion movements within the cochlea. No influence was exerted by the drugs Esculetin - blocking the synthesis of lipoxygenase products - and Dazoxiben - suppressing thromboxane A2 levels within the cochlea. A weakening of the furosemide-induced changes of the endocochlear potential was found when infusing the thromboxane (TX) receptor antagonists BM 13,505 and BM 13,177 before furosemide was given. This effect was also observed when pre-treating the guinea pig with a specific platelet-activating factor receptor antagonist, BN 52,021, before the diuretics was given. Summating potential and cochlear microphonics remained insignificantly changed against controls. The results suggest that a TX receptor contributes to the control of ion movements within the cochlea. A possible involvement of loop diuretics' receptors is discussed.
The effect of the combined administration of cisplatin and furosemide on the electrophysiological hearing thresholds and endocochlear DC potential (EP) was studied in guinea pigs. A lack of interaction was found in animals given repeated intraperitoneal injections of a low dose of cisplatin with a pharmacological dose of furosemide. An ototoxic interaction occurred when a moderately high dose of cisplatin was administered intravenously at a time when the strial function was most affected by a very high dose of furosemide. The interaction was seen both as a decreased EP and a pronounced shift of auditory thresholds. It is concluded that the stria vascularis plays a role in the ototoxic mechanism of cisplatin.
An isocratic high performance liquid chromatographic method is described for the determination of the beta-adrenergic blocking drug, propranolol, and the diuretic, furosemide, in human plasma. The two compounds and the internal standard were extracted from plasma using a two-step extraction technique. Propranolol and pindolol (internal standard) were first extracted from alkaline plasma into diethyl ether; this was followed by extraction of furosemide into acidified ether: hexane (65:35). The two extracts were then combined and evaporated under nitrogen, and the reconstituted residues were analysed on a C18/SCX reversed-phase/cation exchange column with a mobile phase of acetonitrile: 0.1 M sodium acetate pH 4 (33:67). The drugs and the internal standard were detected by UV absorption at 230 nm. The drugs were also extracted from plasma by a column-switching technique utilizing a ten-port valve. The drug compounds were retained on a C18 pre-column. A comparison of RSD for within-batch (intra-assay) and between-batch (inter-assay) runs for both methods was carried out, the liquid/liquid extraction method giving better recovery values. The calibration graphs were linear from 25-300 ng ml-1 for furosemide and 50-400 ng ml-1 for propranolol. Recovery values were > 90.0% by liquid/liquid extraction and > 76.0% by column switching.
Aim of this study was to evaluate the effect on saliva flow rate and composition and on perceived xerostomia. The study used a Latin square design, all subjects being once daily (at 7.00 a.m.) taking the bendroflumethiazide (2.5 mg), furosemide (40 mg), or placebo, in a randomised order. Each treatment period of 7 days was separated by wash-out periods of 14 days. Unstimulated and paraffin chewing stimulated whole saliva, and 3% citric acid stimulated parotid and submandibular-sublingual secretion were collected twice daily, at 7.30 a.m., with the patients in a fasting condition (morning values), and at 10.30 a.m., about 2 h after intake of a standard breakfast (lunchtime values), on day 0 (baseline), day 1 (acute treatment), and day 7 (chronic treatment). Saliva flow rates were measured and all four secretions were analysed for the concentration of sodium, potassium, chloride, and total protein. Xerostomia was assessed by means of a Visual Analogue Scale. Statistical analysis used the Wilcoxon signed rank test. For flow rate, only that of submandibular-sublingual secretion was affected, significantly so in the morning during chronic treatment with both drugs. In resting whole saliva the output of both sodium and chloride tended to decrease especially during treatment with bendroflumethiazide, while in submandibular-sublingual secretion the output of all the electrolytes was decreased, especially for potassium and chloride and during treatment with furosemide. Further, xerostomia tended to increase during treatment with furosemide, statistically significant at lunchtime during chronic treatment. In conclusion, this study has demonstrated a modest effect on salivary flow rate and a more pronounced effect on saliva composition, especially in submandibular-sublingual secretion during treatment of healthy volunteers with therapeutic doses of two different diuretics, encouraging clinical studies in hypertensive patients and basic research as to the presence of a thiazide sensitive Na-Cl cotransporter in human salivary glands.
Pharmaceutical products for humans and animals, as well as their related metabolites end up in the aquatic environment after use. Recent investigations show that concentrations of pharmaceuticals are detectable in the order of ng/l-mug/l in municipal wastewater, groundwater and also drinking water. Little is known about the effects, and the hazard of long-term exposure to low concentrations of pharmaceuticals for non-target aquatic organisms. This study was designed to assess the ecotoxicity of furosemide, a potent diuretic agent, and its photoproduct in the aquatic environment. Bioassays were performed on bacteria, algae, rotifers and microcrustaceans to assess acute and chronic toxicity, while the SOS Chromotest and the Ames test were utilized to detect the genotoxic potential of the investigated compounds. A first approach to risk characterization was to calculate the environmental impact of furosemide by measured environmental concentration and predicted no effect concentration ratio (MEC/PNEC). To do so we used occurrence data reported in the literature and our toxicity results. The results showed that acute toxicity was in the order of mg/l for the crustaceans and absent for bacteria and rotifers. Chronic exposure to these compounds caused inhibition of growth population on the consumers, while the algae did not seem to be affected. A mutagenic potential was found for the photoproduct compared to the parental compound suggesting that byproducts ought to be considered in the environmental assessment of drugs. The risk calculated for furosemide suggested its harmlessness on the aquatic compartment.
The determination of furosemide and spironolactone in a capsule formulation has been investigated using techniques such as Vierordt's method and derivative spectroscopy dA/d lambda and d2A/d lambda2 applying the zero-crossing technique following reported methods. In our hands, using standard mixtures, these methods gave unreliable results. We have therefore investigated the use of ratio spectra derivative spectrophotometry for this determination. The technique of ratio spectra derivative spectrophotometry was developed in 1990, and has recently been used for a number of analyses of co-formulated products. The method was applied to the analysis of standard mixtures of the two drugs and the combined contents of 20 capsules resulting in values (mean +/- standard deviation) of 102.1 +/- 1.9% and 101.4 +/- 4.0% of the stated content for furosemide and spironolactone, respectively. Similarly, the analysis of individual capsules resulted in values of 101.5 +/- 1.6% and 102.2 +/- 1.4% of the stated content for furosemide and spironolactone, respectively.
The ethylene-vinyl acetate (EVA) matrix containing furosemide was prepared by the casting method and the release patterns were observed. The solubility of furosemide was determined as a function of volume fraction of polyethylene glycol 400. The release of drug from the matrix was studied as a function of temperature and drug concentration. Plasticizers such as the citrates and the phthalates were added for preparing the membrane to increase the flexibility of the EVA matrix. The solubility of furosemide was the highest when the concentration of PEG 400 was 40% (v/v). The release rate of drug from the EVA matrix increased with increasing temperature and drug loading doses. A linear relationship was found between the release rate and the square root of the loading dose. The activation energy (Ea), which was measured from the slope of the logP versus 1000/T plots, was 12.33 kcal/mol for the 0.5% loading dose, and 11.58 kcal/mol for the 1.0% loading dose, and 11.00 kcal/mol for the 1.5% loading dose. Among the plasticizers used such as the citrates and the phthalates groups, diethyl phthalate showed the best enhancing effects in drug release. In conclusion, the application of an EVA matrix containing a plasticizer might be useful in the development of a controlled drug delivery system.
In the present study we developed a fast and reliable HPLC assay for the determination of the loop diuretic furosemide in plasma and urine, using a Chromolith RP 18e (100 mm x 4.6 mm) monolithic silica rod HPLC column. After liquid-liquid extraction with diethylether plasma or urine samples were separated with a gradient consisting of solvent A (20% acetonitrile) and solvent B (80% acetonitrile), both in 0.25% acetic acid. The flow rate was 3.5 ml/min and the effluent was monitored by fluorescence with excitation at 230 nm and emission at 410 nm. The retention times for the internal standard (naproxen) and for furosemide were 2.1 and 3.7 min, respectively, and total run time was 8 min. The calibration curves were linear between 7.8 and 1000 ng/ml, and within-assay and between-assay coefficients of variation were <6.5% and <10%, respectively. The proposed assay for furosemide in plasma and urine using monolithic silica rod chromatography is fast, sensitive, and reliable, and, thus, well suited for pharmacokinetic studies.