Moricizine pharmacokinetics in renal insufficiency: reevaluation of elimination half-life.
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Aged↗
Biomedical subjects
U F Michael
Publications and source records attributed to U F Michael.
Dietary fish oil interferes with renal arachidonic acid metabolism in rats: correlations with renal physiology.
Dietary fish oil has been reported to have both beneficial and deleterious effects in animal models of renal disease, which may be related to alterations in renal eicosanoid metabolism. The influence of dietary fish oil on glomerular and renal tubular responses that are linked to arachidonic acid metabolism was examined. Dietary fish oil had antidiuretic and antinatriuretic effects, which correlated with reduced renal cortical endogenous prostaglandin E2 (PGE2). Fish oil altered the renal balance of dienoic prostacyclin (PGI2) to thromboxane (TXA2) in favor of vasodilation, which may explain the observed exaggerated compensatory increases in glomerular function in response to uninephrectomy. Intact rats fed fish oil for 6 months developed proteinuria and impaired glomerular filtration rates (GFR). These deleterious effects were associated with evidence of increased renal lipid peroxidation. These results suggest that dietary fish oil modifies glomerular and renal tubular function in rats, and worsens age-associated proteinuria and declines in GFR. These effects may reflect the impact of dietary fish oil on renal fatty acid composition and arachidonic acid metabolism.
Analysis of Variance↗
The beneficial effects of thyroxine on nephrotoxic acute renal failure in the rat.
We were able to confirm previous studies demonstrating that administration of thyroxine is capable of ameliorating the severity of acute nephrotoxic renal failure in the rat. Nephrotoxic acute renal failure was induced by the subcutaneous injection of potassium dichromate (6.25 mg/kg) into Sprague-Dawley rats. Twenty-four hours after this injection, rats received an intraperitoneal injection of either thyroxine (80 micrograms/kg body wt) or normal saline. Forty-eight hours after the potassium dichromate injection, renal clearance studies were performed. Inulin clearance was significantly higher in the thyroxine-treated than in the saline-treated acute renal failure rats: 1.12 +/- 0.13 (SEM) mL/g versus 0.75 +/- 0.07 mL/min/g kidney wt (P = 0.025). Thyroxine treatment also effected an increase of p-aminohippuric acid extraction from 0.23 +/- 0.03 to 0.33 +/- 0.02 (P = 0.011) and a decrease in the fractional excretion of sodium from 0.38 +/- 0.21 to 0.11 +/- 0.03% (P = 0.037 by Mann-Whitney U test). In order to investigate one potential mechanism of the beneficial effect of thyroxine we studied renal tubular regeneration in this model of acute renal failure. Renal cortical uptake of labeled thymidine into DNA was significantly increased 48 h after the injection of potassium dichromate, and thyroxine administration further enhanced this repair process: 53.9 +/- 3.6 versus 81.4 +/- 5.3 dpm/200 pg of DNA (P = 0.0033).
Acute Kidney Injury↗
Effects of dietary fish oil on renal growth and function in uninephrectomized rats.
The basic mechanisms of renal growth remain poorly understood. The work hypertrophy theory holds that after an acute reduction in renal mass, the growth of the kidney occurs as a consequence of increased renal function. Pharmacological inhibition of renal prostaglandin synthesis impairs the acute adaptive increases in both renal function and mass following partial nephrectomy. The present study examines the effects of four weeks of dietary fish oil on renal growth, function and arachidonic acid metabolites in intact and uninephrectomized male Sprague-Dawley rats. Dietary fish oil interferes with dienoic prostaglandin and thromboxane production in favor of synthesis of trienoic analogues. Control animals were pair-fed an identical diet with the exception that the fat was replaced by beef tallow. Renal cortical concentrations of arachidonic acid metabolites were reduced in animals fed fish oil, and urinary excretion of prostaglandin E2 was impaired. Fish oil feeding resulted in increased kidney weight without concomitant increases in renal function in intact animals. Glomerular filtration rate and renal plasma flow were greater in uninephrectomized rats fed fish oil compared to uninephrectomized controls pair-fed beef tallow. Augmentation of the compensatory increases in renal function observed with fish oil feeding was not associated with any additional renal hypertrophy. These data indicate that dietary fish oil has a profound impact on renal growth and function, which may be the consequence of altered renal and/or extrarenal arachidonic acid metabolism. Furthermore, the direction of the alterations in renal mass oppose that of renal function, providing clear and unique evidence against the work hypertrophy theory of renal growth.
Animals↗
Nitrendipine protects against aminoglycoside nephrotoxicity in the rat.
Aminoglycoside nephrotoxicity is a common clinical problem among hospitalized patients despite close attention to pharmacokinetics and dosing schedules. The present study was designed to evaluate the potential protective effect of nitrendipine, a calcium channel blocker, on the natural history of gentamicin renal injury in the rat. Gentamicin was administered intramuscularly in a dose of 40 mg/kg/day for 12 days to adult Fischer rats. Nitrendipine was given by gavage on a b.i.d. schedule in a dose of 30 mg/kg/day or 10 mg/kg/day. Gentamicin alone caused a significant decrease in glomerular filtration rate (GFR) and renal plasma flow (RPF). Concurrent administration of nitrendipine did not influence RPF, but promoted a significant increase in GFR. Nitrendipine also prevented the increase in urinary excretion of N-acetyl-glucosaminidase and beta-glucosidase, enzymatic markers of renal tubular injury in the gentamicin-treated animals. Gentamicin-induced pathologic injury was significantly ameliorated by nitrendipine. Renal cortical gentamicin content was diminished, but not significantly, by nitrendipine. The exact mechanism of action of nitrendipine in aminoglycoside-induced renal injury remains unknown. These observations suggest a potential pharmacologic approach to preventing a common problem with substantial morbidity.
Acetylglucosaminidase↗
Inhibition of compensatory renal growth by indomethacin.
Renal prostaglandins may be important in the modulation of compensatory renal growth. Reductions in renal mass are associated with increased synthesis of these substances by the remaining kidney, and inhibition of prostaglandin synthesis diminishes renal function in partially nephrectomized animals and in patients with reduced functioning renal mass. We examined the effects of uninephrectomy and treatment with indomethacin on renal prostaglandin E2 and 6-keto prostaglandin F1 alpha concentrations in adult male Sprague Dawley rats. The renal content of these prostaglandins was significantly increased in the remaining kidney two days following uninephrectomy (p less than 0.01). Treatment with 5 mg/kg/day of indomethacin over this period abolished the compensatory increase in renal prostaglandin synthesis and significantly attenuated compensatory increases in renal mass, protein and RNA concentrations (p less than 0.05). No alterations in kidney weight, protein or RNA concentrations were found in intact animals treated with the same dose of indomethacin. These findings suggest renal prostaglandins may participate in the biological events leading to compensatory renal growth.
6-Ketoprostaglandin F1 alpha↗
Disposition kinetics of cefamandole during continuous ambulatory peritoneal dialysis.
Cefamandole disposition kinetics were examined in six male subjects with renal impairment who were undergoing continuous ambulatory peritoneal dialysis. Creatinine clearance values ranged from less than 1 to 11 ml/min. Cefamandole was given as a 1-g intravenous dose infused over 30 min. Cefamandole concentrations were determined in serum, urine, and dialysis fluid by a high-performance liquid chromatographic method. The following average parameter values were obtained (range): half-life, 6.1 h (4.6 to 9.7); systemic clearance, 21.9 ml/min (8.4 to 35.5); renal clearance, 11.5 ml/min (0.03 to 22.3); dialysis clearance, 0.92 ml/min (0.7 to 1.3); nonrenal clearance, 12.2 ml/min (2.9 to 27.0); volume of distribution, 0.18 liter/kg (0.09 to 0.25); steady-state volume of distribution, 0.17 liter/kg (0.09 to 0.24). Approximately 5% of the dose was dialyzed (range, 2.8 to 8.3), indicating that there is no need to supplement a dosing regimen of cefamandole due to loss by dialysis. There was a positive correlation between creatinine clearance and the terminal elimination rate constant of cefamandole (r2 = 0.41) and cefamandole renal clearance (r2 = 0.83).
Cefamandole↗
Dietary calcium deprivation and secondary hyperparathyroidism in patients treated with chronic dialysis.
In 33 patients with end-stage renal disease undergoing chronic dialysis, serum parathyroid hormone (PTH) levels were correlated with serum concentrations and dietary intakes of calcium and phosphate. The average dietary calcium intake (549 +/- 54 mg/24 h) was lower than the recommended dietary allowance. There was a weak correlation between serum PTH and serum calcium concentrations (r = 0.39, p less than 0.03). There was also a significant negative exponential relationship between dietary calcium intake and serum PTH (y = 162e-0.0016x, r = 0.61, p less than 0.002). Likewise, when divided into low calcium (less than 500, 304 +/- 27 mg/24 h) and modest calcium (greater than 500, 809 +/- 56 mg/24 h) intake groups, in the low calcium-intake group, serum PTH (128 +/- 20 pg/ml) was more than 2-fold greater than that in the modest calcium-intake group (53 +/- 8 pg/ml, p less than 0.003). These results suggest that low dietary calcium intake may contribute to the occurrence of secondary hyperparathyroidism in patients with chronic renal failure undergoing chronic dialysis.
Adult↗
The protective effect of nitrendipine on gentamicin acute renal failure in rats.
Aminoglycoside nephrotoxicity was produced in two groups of Fischer rats by intraperitoneal injection of gentamicin, 40 mg/kg/day for 2 weeks. Beginning 3 days prior to, and continuing throughout the 2-week treatment period, one of the groups (control) received the inert vehicle, polyethylene glycol, while the experimental group was given nitrendipine, a calcium channel blocker, in a dose of 25 mg/kg/day by gavage. Both groups received food and water ad libitum. Gentamicin with vehicle caused a marked decrease in inulin clearance (4.9 ml/min/kg) and paraaminohippurate (PAH) extraction (26%), and extensive renal tubular necrosis. In comparison, the nitrendipine-treated rats had a significantly increased clearance (9.8 ml/min/kg) and PAH extraction (48%), and less histopathologic damage. Renal tissue content of gentamicin was not influenced by nitrendipine after 4 days of dosing. Nitrendipine, a diisopyridine derived calcium channel blocker, offers significant functional and histologic protection against aminoglycoside nephrotoxicity in Fischer rats. Its mode of action in this regard is unknown.
Acute Kidney Injury↗
The effects of diltiazem and captopril on glycerol-induced acute renal failure in the rat. Functional, pathologic, and microangiographic studies.
To evaluate the effects of pharmacologic vasodilatation on glycerol-induced acute renal failure, we studied untreated animals and those given Captopril and Diltiazem at periods ranging from 30 minutes to four weeks after the onset of acute renal failure. At each time frame, comparative coded assessments of renal function, histology, and microangiography were performed. Diltiazem, a calcium channel blocker, significantly reduced the severity of the renal failure, decreased the extent of tubular cell necrosis, and was associated with a more rapid histologic and functional recovery. Captopril, an angiotensin converting enzyme inhibitor, did not influence renal function or pathology throughout the four-week observation period. Microangiography revealed marked differences among the experimental groups. Most notably, there was better visualization of the microvasculature in Diltiazem-treated kidneys at one and two weeks. However, at four weeks, all groups showed similar, severe microangiographic abnormalities. Diltiazem offers significant protection against glycerol-induced acute renal failure in rats. Its mechanism of action in this context remains unknown. Renal function and pathology do not correlate well with microangiographic perfusion patterns in this model of acute renal failure.
Acute Kidney Injury↗
Acute renal failure.
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Acute Kidney Injury↗
Impaired renal bicarbonate reabsorption in the hypothyroid rat.
We previously demonstrated a decrease of sodium reabsorption in the proximal superficial nephron of the hypothyroid rat. The present clearance studies were designed to examine the renal handling of bicarbonate in hypothyroid rats. Hypothyroidism was induced by the intraperitoneal injection of Na131I and the animals were studied 10 or more wk thereafter under anesthesia and compared to their age-matched litter-mates. As is characteristic of hypothyroid animals, insulin clearance was lower and fractional urine flow and sodium excretion rates were higher than in the control rats. At the peak of the bicarbonate diuresis and at similar blood pH, PCO2, and bicarbonate levels, fractional renal bicarbonate excretion was significantly higher in the hypothyroid animals: 22 +/- 2 vs. 15 +/- 1%, P less than 0.02. This perturbation of bicarbonate reabsorption of the hypothyroid rats was independent of the influence of extracellular fluid volume expansion and appears closely related to the impaired sodium reabsorptive capacity characteristic of experimental hypothyroidism.
Animals↗
Dose response to chlorthalidone in patients with mild hypertension. Efficacy of a lower dose.
A multicenter study of chlorthalidone was performed to determine the relative antihypertensive efficacy and side effects of doses lower than those usually recommended for therapy. After a 4-wk placebo control period 100 patients with mild hypertension were randomly assigned doubleblind to 12.5-, 25-, 50-, or 75-mg regimens of chlorthalidone or to placebo for 12 wk. The groups of patients taking 25, 50, and 75 mg had declines in blood pressure which were not significantly different from each other. Serum potassium decreased in the 50- and 75-mg groups but not significantly in the 25-mg group. We conclude that chlorthalidone, 25 mg daily, was at least as effective for hypertension as 50 and 75 mg with less perturbation of potassium. Use of smaller initial diuretic doses may provide equal efficacy with fewer side effects for many patients.
Adult↗
Polyuric syndromes.
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Diabetes Insipidus↗
Impaired urinary acidification in the hypothyroid rat.
Since abnormalities in the renal handling of sodium and water in both the proximal and distal tubule have been described in primary hypothyroidism, this study was undertaken to examine renal tubular hydrogen secretion in this disorder. Metabolic acidosis was induced in hypothyroid rats (H) and their age matched controls (C) by the administration of an oral ammonium chloride load of 0.15 g/24 h/kg for three days. On day 3 animals were prepared for clearance and acid-base studies, receiving an infusion of Ringer's solution of 0.6 ml/hr/100 g during surgery and the experimental procedure. A 26% decrease in GFR (P less than 0.005) and a doubling in fractional excretion of sodium (P less than 0.02) were observed in H rats. The lowest blood pH and average bicarbonate concentration and the excretion of chloride were similar in the two groups, indicating that the acid load was reabsorbed and led to similar degrees of systemic acidification. Urine flow also was comparable in the two groups. Minimal urine pH after NH4Cl was 6.21 +/- 0.06 in H and 5.68 +/- 0.09 in C (P less than 0.001). Ammonium excretion was 28% (P less than 0.05) lower in H than in C. The defect in urine acidification in H was only partially corrected after 5 days on a low sodium diet and DOCA administration for 2 days. Fractional bicarbonate excretion at normal blood pH and bicarbonate concentration was not different in the two groups. These data indicate that hypothyroid rats have a mild defect in urine acidification and that it is localized predominantly in the distal tubule.
Acidosis, Renal Tubular↗
Antihypertensive effectiveness of oxprenolol administered twice daily.
Oxprenolol, a beta-blocker, is an effective antihypertensive when administered 3 or 4 times daily. We evaluated the antihypertensive effect of oxprenololgiven twice daily (bid). The subjects were 15 ambulatory men whose standing diastolic blood pressure (BP) was at least 100 mm Hg after 3 wk of treatment with hydrochlorothiazide and oxprenolol placebo. Oxprenolol 40 mg twice daily was then substituted for the placebo. On subsequent weekly vists oxprenolol was titrated to 80 and 160 mg bid if the standing diastolic BP was greater than 90 mm Hg. BLood pressures on the last visit on placebo were compared to those on the last visit on oxprenolol. Standing BP declined from 145 +/- 4/108 +/- 1 to 130 +/- 4/98 +/- 4 on a mean dose of 256 mg of oxprenolol (p less than 0.001 syst.; p less than 0.01 diast.). Recumbent BP fell from 146 +/- 4/107 +/- 1 to 138 +/- 5/93 +/- 2 (p less than 0.06 syst.; p less than 0.01 diast.). During the final week, 13 of the 15 patients were admitted to the hospital for 24-hr monitoring of BP. The 24-hr BP readings showed a mean coefficient of variation of 6.6% recumbent and 7.2% standing. we conclude that bid oxprenolol will maintain 24 hr BP control in most patients.
Administration, Oral↗
Antihypertensive effects of oxprenolol and propranolol.
The antihypertensive effects of the beta blockers oxprenolol and propranolol were compared in a randomized double-blind study of patients with standing diastolic pressures (SDP) exceeding 99 mm Hg when receiving hydrochlorothiazide alone. After 3 wk of hydrochlorthiazide with placebo, the latter was replaced with oxprenolol (n= 12) or propranolol (n = 14), 20 mg three times daily. Beta blocker was increased subsequently to 40 and 80 mg three times daily if SDP exceeded 89 mm Hg. Nine oxprenolol and 7 propranolol subjects were hospitalized for 24-hr monitoring. With oxprenolol, standing pressure declined from 135 +/- 2 (SE)/104 +/- 1 MM Hg to 128 +/- 3/90 +/- 2. SDP declined to under 91 mm Hg in 7 of 12 subjects, and to from 91 to 95 in 3 subjects. With propranolol, findings were 138 +/- 3/106 +/- 2 to 123 +/- 3/89 +/- 3; in 7 of 12 to less than 91 mm Hg and from 91 to 95 in 4 subjects. Decrements in supine and SDP were slightly (4 mm Hg) greater for propranolol than for oxprenolol. Both drugs gave similar 24-hr blood pressure control. We conclude that oxprenolol and propranolol used to supplement hydrochlorothiazide provide comparable reductions in blood pressure and smooth control over a 24-hr period in most patients with hypertension.
Adult↗
Role of distal delivery of filtrate in impaired renal dilution of the hypothyroid rat.
Free water clearance (CH2O) was measured during hypotonic saline infusion in Sprague-Dawley and in Brattleboro (DI) rats with 131I-induced hypothyroidism and their age-matched controls. At peak urine flow, which was similar in hypothyroid DI (HDI) and control DI (CDI) rats, inulin clearance (CIn/kg) and CH2O/kg were 23 and 20% (P less than 0.02) lower in HDI. Fractional urine flow and fractional sodium excretion were 30 and 40% (P less than 0.001) higher in HDI. Utilization of distal delivery of filtrate for CH2O, formation was 16% less in HDI (P less than 0.01). Papillary osmolality was not higher in HDI rats. Data in Sprague-Dawley rats were similar to those of the DI rats, indicating that endogenous ADH was effectively suppressed. It is concluded: 1) delivery of filtrate out of the proximal tubule was not diminished in hypothyroid rats in spite of a decrease in CIn; 2) despite a similar delivery of filtrate to the distal diluting site, CH2O formation was less in hypothyroid rats than in controls; 3) these data suggest that a defect in the diluting segment could be unmasked at high rates of filtrate delivered to the distal nephron; 4) this defect could be either due to impaired sodium chloride reabsorption or due to increased backdiffusion of water in the distal nephron.
Animals↗