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A new inducer of the monooxygenase system zixoryn (oral dose--100 mg/kg, for 4 days) increased the excretion and maximum tubular transport of cardiotrast (diodrast) in rats. Zixoryn had no effect on daily and water diuresis and renal excretion of sodium, potassium and creatinine.
Diacereine (DAR) is a new anti-arthrosis drug with an unusual action mechanism. Once it was found that, unlike existing FANS, DAR has no effect on prostaglandin synthesis, it was thought interesting to assess its clinical tolerability on two groups of patients. The first was a group of high risk patients with arthrosis or arthritis. The second consisted of patients with a history of duodenal ulcer or cirrhotics in the ascitic phase. In the first group the DAR was given (100 mg per diem per os) for 30 days after oesophagogastroduodenoscopy that was repeated at the end of treatment. DAR treatment of patients with ulcers in the clinical remission phase was reliable in the sense that no recurring ulceration or major endoscopic lesions were observed but the subjective tolerability was not excellent in about half the patients due to the appearance of dyspeptic symptoms that are, however, a notoriously common response to any drug treatment in this kind of case series. In a second group of 5 patients with various types of cirrhosis of the liver, the aim was to assess the effect of DAR treatment on kidney function and ascitic decompensation. The drug was administered orally in doses of 100 mg per diem for 10 days. On the basis of the results observed in this case series only it can be stated that the use of DAR on ascitic cirrhosis patients produces no alterations in kidney function and does not reduce the effectiveness of diuretic treatment. Indeed it may well be that DAR has a positive effect on diuresis, that increased in this series in line with earlier experimental results.
Forced diuresis (FD) is a frequently used method for eliminating toxins. Its therapeutic effect has yet to be evaluated by a controlled clinical trial. In the absence of such a trial its usefulness can be judged only indirectly from urinary excretion rates. In former times the usual clinical laboratory procedures could not differentiate between the unchanged toxin and its metabolites. Using more selective methods, the discussions of the effect of FD in eliminating various drugs were renewed. The problem for the indication of FD is not only a missing knowledge about the kind and amount of the ingested drug, but also when knowing it, the missing evaluation of the effect of FD on its excretion. In such cases the pharmacokinetic behaviour of the drug can be helpful. If paying enough attention to the contraindications, to the principles of electrolyte and water balance, the complication rate is low. Many infusion regimes are proposed for this treatment, but only a standardized procedure can increase the safety and efficiency of this method. More complicated and more expensive methods should be used, when there is an intoxication with a substance of high mortality or when there is no effect of FD on eliminating the toxin.
The effect of furosemide on hepatic hemodynamics was investigated using electromagnetic flow probes positioned around the hepatic-portal vein and common hepatic artery of anesthetized dogs. Furosemide administration induced a vigorous diuresis and concomitantly decreased total hepatic blood flow. Hepatic arterial blood remained relatively stable. Thus, the decrease in total hepatic blood flow was due primarily to a decrease in portal blood flow. When furosemide was given to animals with ureters ligated to prevent extracellular volume contraction, the drug did not reduce total hepatic blood flow, portal blood flow or hepatic arterial blood flow. Thus, furosemide induces a decrease in total hepatic blood flow that appears to involve a mechanism dependent upon the volume contraction produced by the diuretic. The contraction causes a reduction in venous blood flow but not arterial blood flow to the liver.
The authors studied the validity of Wolf and Dorph's test (increase in size of the kidney with increased diuresis) performed during intravenous urography in hypertensive patients. The technical procedure is described, and the results reported: 1 032 kidneys were measured, of which 84 had been also examined by arteriography. The results are analyzed and compared to those obtained after the standard method of early consecutive films, with the following conclusions: -- the test is not as valid as is suggested by the authors who described it; -- the information supplied by the standard method is more consistent and precise; -- the results of these two series are not completely superimposable; -- that even if Wolf and Dorph's test can sometimes supply useful information, it must not be relied upon completely.
Intrarenal haemodynamics were investigated in the dog prior to and after relief of 24 hr bilateral ureteral ligation (BUL), by the radioactive microsphere technique. Prior to release of 24 hr BUL there was an about 50% reduction in total blood flow (RBR), with a nearly proprotional decrease in the perfusion of the four cortical layers. Following release of the obstruction, total renal and outer cortical (zones 1 and 2) blood flow remained diminished, while perfusion of the inner (juxtamedullary) layers (zones 3 and 4) increased as compared to its prerelease values and equalled controls. Glomerular filtration rate (GFR) amounted to about 27% of controls in the postrelease phase. A marked increase in absolute and fractional sodium water excretion was observed after release of 24 hr BUL, as contrasted to normal controls and dogs after 24 hr unilateral ureteral ligation (UUL). This state, designated as postopstructive diuresis, might be explained by redistribution of intrarenal blood flow towards the juxtamedullary zones, and by a powerful natriuretic substance accumulated during complete obstruction.
Water diuresis was induced in dogs, under chloralose anesthesia, by hypotonic volume expansion of 5 to 10% body weight. The average diuretic response was 12.5 ml/hr/kg body weight with a urine osmolality of 175 mOsm/L. Renal hilar lymph flow and thoracic duct lymph flow increased significantly by an average of 125% and 150% respectively. The Na concentration in plasma and lymph fell by approximately 7.0 mEq/L whereas that for Cl was relatively unaffected. Control lymph to plasma ratios of approximately 1.050 for Na and 1.130 for Cl were not significantly altered even when plasma concentrations fell significantly. Urea, glucose and K concentrations were little affected. The results are consistent with the hypothesis that renal hilar lymph reflects in part the composition of the outer medullary interstitium which is directly influenced by the electrolyte pump in the ascending thick limb of Henle.
A phase II clinical trial of high-dose cisplatin (120 mg/m2 iv every 3 weeks), with fluid and mannitol-induced diuresis, was conducted in 81 patients with advanced lung cancer. Partial remissions were documented in 26% of 75 evaluable cases for a median duration of 3.5 months. Adenocarcinoma and small cell anaplastic carcinoma were more responsive than epidermoid carcinoma, with partial response rates of 35%, 30%, and 18%, respectively. The median survival of responders (8.5 months) was significantly longer than the survival of nonresponders (4 months) (P less than 0.02). Myelosuppression was mild. Renal toxicity with peak serum creatinine greater than 2.5 mg/100 ml occurred in eight patients, with one death occurring due to toxicity. Cisplatin is an active drug in advanced lung cancer.
Intravenous (10 micrograms/kg) or intracisternal (1 microgram/kg) clonidine inhibited the diuretic response to negative pressure breathing (NPB) and left atrial distension (LAD) in chloralose anesthetized dogs. The drug reduced the induced tachycardia, but not the increase in respiratory rate caused by NPB, and did not change the blood pressure. Propranolol (1 mg/kg i.v.) did not change the NPB-induced diuresis. Intravenous yohimbine (1 mg/kg i.v.) opposed the effects of intravenous or intracisternal clonidine, whereas prazosin (0.05 mg/kg i.v.) had no effect. These results show that the adrenergic receptor implicated in the volumetric control of vasopressin secretion could be of the alpha 2 subtype. This alpha 2 adrenoceptor could be centrally located. Clonidine might therefore be proposed to combat the dehydration observed after long-term weightlessness.
The results of several previous studies suggest that high urine flow rate has a protective effect in several models of experimentally induced acute renal failure. However, the methods employed to alter urine flow precluded a paired experimental design, left kidney vs. right kidney in the same experimental animal. The purpose of the present studies was to determine whether the unilateral diuresis that results from renal denervation has a protective effect on that kidney in glycerol-induced acute renal failure. Eight groups of rats were studied. The left kidneys of all were either denervated or sham-denervated; 3 to 5 days later, rats were injected with either 150 mM NaCl (controls) or glycerol; then either 3 or 24 hr after injection, renal function was measured in acute experiments. In saline-injected rats, the inulin clearances of right and left kidneys were virtually identical, whether the left kidney was denervated or not; however, in rats with denervated left kidneys, left kidney urine flow exceeded that of the right kidney whereas the opposite was true in rats with sham-denervated left kidneys. In contrast with saline-injected rats, there were highly significant differences in inulin clearances of right and left kidneys in glycerol-injected rats at both 3 and 24 hr after injection; left kidney inulin clearance exceeded that of the right in rats with denervated left kidneys, whereas right kidney inulin clearance exceeded that of the left in rats with sham-denervated left kidneys. Since the kidney with the higher urine flow had the higher inulin clearance at 3 and 24 hr after glycerol, whether or not the kidney was denervated, these results suggest that urine flow per se has a protective effect in glycerol-induced acute renal failure in rats.
13 preterm infants (gestational age 34 weeks or below; birth weight under 1500 g.) with severe respiratory distress, were admitted for intensive care in our Unit between 1980 and 1981. Factors affecting the onset of BPD (bronchopulmonary dysplasia) in these subjects are evaluated by retrospective studies. Diuresis in the third day of life, expressed as a percentage of administered fluids appeared particularly significant. It resulted significantly lower in subjects developing BPD than in non-affected controls. Therefore, along with a PDA and a high fluid input favouring interstitial oedem, the inability of preterm infants to remove fluid overload must be considered. A reduced clearance of interstitial fluid in the lung enhances circulatory status and ventilatory damage and increases the risk of BPD.
Several lines of research suggest that renal lymph is formed totally, or in part, as a filtrate of postglomerular blood. Even so, renal interstitial fluid dynamics is necessarily dominated by the rapid transfer of large volumes of reabsorbate from tubular lumen to peritubular capillary. To determine the effects of tubular reabsorption on lymph formation, renal lymph flow and composition were studied before and during alterations in tubular reabsorption produced by diuresis. A 25% reduction in whole kidney fluid reabsorption rate did not alter renal lymph flow or lymph protein concentration. A concomitant decrease in plasma protein concentration, however, suggests that any deficit in lymph flow resulting from decreased reabsorbate content may have been obscured by an increase in vascular filtration. An increase in renal lymph PAH and creatinine concentrations relative to those of arterial and renal venous blood plasma supports this conclusion. It appears that renal lymph flow may be determined by both vascular filtration and tubular reabsorption.
The method of forced diuresis by furosedium after adenomectomy is an effective method which decreases the postoperative complications of such surgery (haemorrhage, infection, etc.) and reduces the time of hospitalisation.
The dose-limiting toxic effect of high-dose (100 mg/m2) cisplatin is renal insufficiency. Hydration with furosemide- or mannitol-induced diuresis has been reported to ameliorate this toxicity. Animal studies suggest that mannitol may be superior to furosemide in this regard. Twenty-two patients with advanced neoplasms refractory to conventional therapy were treated with cisplatin at a dose of 100 mg/m2 every 21--28 days. Patients were randomized to receive 37.5 g of mannitol by 6-hour infusion with cisplatin or 40 mg of furosemide prior to cisplatin therapy. Hydration with at least 1 liter of normal saline was given prior to cisplatin. Nephrotoxicity (creatinine greater than 2 mg/100 ml, creatinine clearance greater than 50 ml/minute) occurred in 19% of courses in the furosemide-treated group and in 28% of courses in the mannitol-treated group. Peak plasma platinum concentration, terminal half-life, urinary excretion, and percent protein-bound plasma platinum were similar in both groups. The use of cisplatin at this dose schedule resulted in similar toxicity and pharmacokinetics when using hydration with either furosemide or mannitol.
Acute diuresis is considered to alter the hemodynamic responses in the hypertensive state by reducing cardiac preload, mainly due to venodilation. To investigate the magnitude of this event, normotensive and two kidney-one clip hypertensive rats have been subjected to similar plasma volume restrictions by i.v. injection of 0.5 ml of furosemide (1 mg/100 g b.wt.). Two other groups of normotensive and hypertensive rats were subjected to 0.5 ml of 5% dextrose solution injection and served as controls. Mean arterial blood pressure and heart rate did not change after furosemide injection in either the normotensive or the renovascular hypertensive group. Alternatively, cardiac output of the hypertensive rats receiving furosemide injection was significantly lower by 39.9% and total peripheral resistance was significantly higher by 48.4% when compared to hypertensive rats receiving dextrose solution injection, whereas there was no difference concerning these indices in normotensive rats after the same interventions. Due to redistribution of regional blood flow, the coronary, cerebral and renal circulations of the hypertensive rats after furosemide injection have been protected. It is concluded that i.v. injection of furosemide, by decreasing cardiac preload, mainly due to venodilation, reduces cardiac output of renin-dependent hypertensive animals, whereas mean arterial blood pressure and heart rate remain unaltered. Redistribution of blood flow to vital organs prevented a further deterioration of the cardiovascular system.
Effects of azosemide on diuresis, plasma renin activity (PRA), and urinary prostaglandin E (PGE) excretion in normal rats and rats pretreated with indomethacin were studied in comparison with those of furosemide. Azosemide at doses ranging from 10 to 40 mg/kg p.o. dose-dependently increased urinary volume and Na+, K+, and Cl- excretions. In this case, the increases in urinary volume and Na+, K+, and Cl- excretions with 40 mg/kg of this drug were 3.4 and 4.1, 2.9, and 5.8 times, respectively. Pretreatment with indomethacin (10 mg/kg X 3 p.o.), a PG synthesis inhibitor, inhibited the increasing effects of this drug on urinary volume and Na+ and Cl-excretions by 80 or approximately 90%. Moreover, the increasing effects of this drug on PRA and urinary PGE excretion were also inhibited remarkably to the same degree by pretreatment with indomethacin. These effects of azosemide were roughly similar to those of furosemide. From these results, the diuretic action of azosemide, like that of furosemide, may partly be mediated through the activation of the PG system in kidney.
A case of massive meprobamate intoxication (100 g) is reported. On admission, 8 hours later, the plasma meprobamate level was 460 mg/l. The initial shock (hours 8-12) was successfully treated with blood volume expansion and dobutamine. The plasma meprobamate level, which was 340 mg/l when haemodialysis and haemoperfusion were started, fell to 110 mg/l at the end of the treatment. Recovery was uneventful. The amounts of drug eliminated by each method were as follows: (a) gastric lavages at 8 and 26 hours: 66 g; (b) haemodialysis (18-29 hours): 8.5 g; (d) haemoperfusion on Hemopur-charcoal (20-28 hours): 7.5 g (as measured by elution); (e) diuresis (26 hours): 2 g. It may be concluded from these data that sizeable amounts of drug can be extracted by haemodialysis and haemoperfusion, that gastric lavage remains the least invasive and most rewarding method of elimination, and that the role of hepatic metabolism in detoxication has to be taken into account.
Studies were undertaken to develop a standard procedure and to establish reference values for an aqueous vasopressin response test in dogs with normal renal function undergoing water diuresis. After IV administration of 5 mU of aqueous antidiuretic hormone (ADH)/0.45 kg of body weight of 13 water-loaded clinically normal dogs, the mean urine specific gravity increased from 1.002 +/- 0.001 to 1.021 +/- 0.0058; the mean urine osmolality increased form 99 +/- 52 mOsm/kg of water to 933 +/- 252 mOsm/kg. The PCV, total plasma protein concentrations, and serum osmolalities decreased in all dogs during water loading and ADH administration, but slowly returned toward base-line values after discontinuing the ADH infusion.