Biomedical subjects

G R Aronoff

Publications and source records attributed to G R Aronoff.

At least 55 records · Page 3Linked to original sources

PubMed1987

Lung mechanics and neuromuscular output during CO2 inhalation after airway anesthesia.

Airway anesthesia with aerosolized lidocaine has been associated with an increase in minute ventilation (VE) during CO2 inhalation. The increase in VE may be due to increased neuromuscular output or decreased mechanical load on breathing. To evaluate this we measured VE, breathing pattern, mouth occlusion pressure, and lung mechanics in 20 normal subjects during room-air breathing and then inhalation of 6% CO2-94% O2, before and after airway anesthesia. Measurements of lung mechanics included whole-lung resistance, dynamic and static compliance, and functional residual capacity. Airway anesthesia had no detectable effect on any measurements during room-air breathing. During CO2 inhalation, airway anesthesia produced increases in VE and mean inspiratory flow rate (VT/TI) and more negative inspiratory pleural pressure but had no detectable effect on lung mechanics or mouth occlusion pressure. Pleural pressure was more negative during the latter 25% of inspiration. We concluded that airway receptors accessible to airway anesthesia play a role in determining neuromuscular output during CO2 inhalation.

Adult↗

PubMed1987

Kinetics and pharmacodynamics of atrial natriuretic peptide and lithium clearance in the isolated perfused rat kidney.

We used the kinetics of atrial natriuretic peptide (ANP) and fractional lithium excretion to test the hypothesis that ANP-induced natriuresis is related directly to the ANP perfusate concentration and is mediated by a decrease in proximal tubular sodium reabsorption. Wistar rat kidneys were perfused for 90 min after administration of 1 microgram of human ANP. Comparisons were made to control perfusions. ANP had a short half-life (12.4 min) and a renal clearance 6-fold greater than the creatinine clearance. ANP treatment resulted in a significant peak increase in sodium (5.6-fold), lithium (2.1-fold), potassium (2.3-fold) and water (5.1-fold) excretion. The natriuretic response to ANP was delayed 25 min. Exogenous creatinine clearance, perfusion pressure, perfusion flow and renal vascular resistance were not affected. We conclude that the kidney eliminates ANP rapidly by mechanisms that appear to be located primarily in the peritubular circulation. The initial renal response to ANP did not follow perfusate concentrations. Rather, natriuresis increased as ANP concentrations decreased. The relationship was defined by a counterclockwise hysteresis loop. Natriuresis was not mediated by an increased delivery of sodium to the tubule, but may have been due to either a direct or an indirect action of ANP on the kidney.

Absorption↗

PubMed1986

Intra- and interindividual variability in sodium intake in normal subjects and in patients with renal insufficiency.

To elucidate patterns of dietary sodium ingestion in free-living subjects, we collected 26 consecutive 24-hour urine specimens in 18 subjects who had not received instructions to limit the sodium content of their diets, and who were not aware that sodium intake would be estimated from the collections. Nine subjects with plasma creatinine values less than 2 mg/dL had a mean 24-hour UNaV of 156 mEq/d, with an interindividual variability of SD +/- 38 mEq. Their intraindividual variability was 61 mEq. Nine subjects with creatinine values greater than 2 mg/dL had a mean 24-hour UNaV of 108 mEq/d (P less than 0.05). The intraindividual variability of these subjects was 39 mEq/d. Subjects with normal renal function ingested more sodium than subjects with renal insufficiency, although the variability in both groups was extensive. These data confirm and extend earlier observations and illustrate the difficulty in identifying biologic correlations in the presence of considerable intraindividual variability. They underscore the futility of estimating mean dietary sodium intake with a single or occasional 24-hour urine collection in both normal subjects and patients with renal insufficiency.

Adolescent↗

PubMed1986

Short-term augmented calcium intake has no effect on sodium homeostasis.

To test the hypothesis that the supplementation of dietary calcium intake influences sodium homeostasis, the renin-angiotensin system, and sympathetic nervous system in a manner that might evoke a decrease in arterial blood pressure, we gave 16 participants (eight normal and eight with hypertension) placebo for 8 days, followed by 500 mg elemental calcium as the carbonate salt twice a day for 8 days. The same diet was prepared for each meal for the entire study. Sodium intake was fixed for each participant and averaged 150 mEq/day. All urine was collected every day. Blood was drawn at the end of the placebo and calcium periods for determinations of plasma renin, aldosterone, and norepinephrine values. Calcium supplementation increased urinary calcium excretion significantly in both groups. However, calcium supplementation failed to influence sodium or potassium excretion, serum electrolytes, total serum calcium, renin, aldosterone, or norepinephrine levels, or heart rate. Systolic and diastolic blood pressure were not influenced in normal subjects, but in patients with hypertension the supine systolic blood pressure decreased significantly. We conclude that blood pressure lowering effects of calcium, should they occur, are not likely the result of augmented urinary sodium excretion or of straight-forward influences on the renin-angiotensin system or sympathetic nervous system.

Administration, Oral↗

PubMed1986

Pharmacokinetics and protein binding of cefamandole and its 1-methyl-1 H-tetrazole-5-thiol side chain in subjects with normal and impaired renal function.

The 1-methyl-1 H-tetrazole-5-thiol (MTT) side chain present on several new cephalosporins may be an important factor in coagulopathy observed during therapy with these antibiotics. To determine the plasma kinetics and protein binding of the side chain and to test the hypothesis that renal failure alters these parameters, we gave six normal volunteers and six anuric patients a single iv dose of 15 mg of cefamandole/kg. Plasma concentrations of cefamandole and free MTT were measured by high-performance liquid chromatography 14 times during the 48-hr period after the dose was given. A compartment-independent pharmacokinetic analysis showed that MTT was rapidly removed from the plasma of normal subjects, but that peak concentrations of MTT were nearly three times greater and persisted for 48 hr in patients with renal failure. Further, renal failure caused a significant MTT protein-binding defect. If a relation exists between hypoprothrombinemia and plasma concentrations of MTT side chain, patients with reduced renal function may be at increased risk for this adverse effect.

Adult↗

PubMed1986

Ventilatory response during CO2 inhalation after airway anesthesia with lidocaine.

Airway anesthesia with inhaled aerosolized lidocaine has been associated with increases in minute ventilation (VE) and mean inspiratory flow rate (VT/TI) during CO2 inhalation. However, it is unclear whether these increases are local effects of the anesthesia or systemic effects of absorbed and circulating lidocaine. To evaluate this 20 normal subjects were treated on separate days with aerosolized lidocaine, intravenous lidocaine, aerosolized control solution, or intravenous control solution, and the effects of each treatment on VE and VT/TI were determined and compared during room-air breathing and inhalation of 5% CO2-95% O2. None of the treatments altered VE or VT/TI during room-air breathing. Aerosolized lidocaine produced small (5.9-6.0%) increases in VE and VT/TI during CO2 inhalation, but these effects were not present after intravenous lidocaine despite equivalent lidocaine blood levels. We concluded that the increases in VE and VT/TI after aerosolized lidocaine were local effects of airway anesthesia rather than systemic effects of absorbed and circulating lidocaine.

Adult↗

PubMed1986

Atriopeptin III kinetics and pharmacodynamics in normal and anephric rats.

To elucidate the disposition of atriopeptin III in plasma we performed experiments in normal and anephric rats. Bolus, i.v. atriopeptin III (250 ng) was given after which the rats were decapitated at 30-sec intervals. The half-life of atriopeptin III in normal rats was 26.5 sec, the volume of distribution was 352 ml and the plasma clearance was 500 ml/min. In anephric rats the half-life was 56.8 sec, the volume of distribution was 345 ml and the plasma clearance was 206 ml/min. In other rats atriopeptin III was given and urine was collected simultaneously. No atriopeptin III could be measured in the urine. We gave 0.0, 0.067, 0.125, 0.25, 0.5 and 1.0 ng/kg of bolus atriopeptin III to normal rats and measured effects on blood pressure, heart rate and plasma concentration at 30 sec, the time at which maximum effect on blood pressure occurred. Dose, change in blood pressure and plasma concentration were correlated. Heart rate increased, but not in a dose-dependent fashion. We conclude that atriopeptin III is cleared from rat plasma rapidly and that the kidneys account for 59% of its elimination by degradation rather than excretion. Because the effect of atriopeptin III on blood pressure is concentration-dependent, the transient changes exerted by atriopeptin III may be related to its rapid disappearance from plasma.

Animals↗

PubMed1985

The efficacy of quantitative and qualitative chloride titrators in the estimation of human salt intake.

We evaluated the utility of chloride titrator sticks for facilitating the assessment of dietary salt intake, in a systematic series of clinical trials. These inexpensive devices were applied daily to 24-h or nocturnal urine specimens, thereby avoiding the inter- and intra-subject variability in salt excretion which confounds the use of occasional 24-h urine collections. Chloride and sodium concentrations in urine were highly correlated (r greater than 0.92) in either nocturnal, diurnal, or 24-h collections. The quantitative chloride titrator estimates and measured chloride concentrations were highly correlated as well (r greater than 0.99). The qualitative chloride titrator was graded on a simple scale, and was successfully employed by outpatients attempting to limit their salt intake. Commonly used antihypertensive medications did not interfere with the determinations. Additional chloride intake, such as supplemental potassium chloride, interfered with estimates of salt ingestion, but if the daily amount of potassium chloride supplement was constant, adjustments in interpretation could be made. Renal insufficiency introduced a systematic over-estimation of salt intake by the qualitative chloride tirator, but only at high salt intakes. Relative estimates of salt intake in subjects with renal failure were still possible. We conclude that chloride titrators can facilitate the management of patients who require a prescribed salt intake.

Adult↗

PubMed1985

Hepatitis B virus vaccine: a randomized trial of a reduced dose regimen in hemodialysis patients.

To test the hypothesis that increasing the dose enhances response to hepatitis B virus vaccine in hemodialysis patients, we performed a randomized, double blind, controlled clinical trial. Twenty-four hemodialysis patients were randomly assigned to receive either three 20 mcg or the recommended three 40 mcg intramuscular injections over 6 months. In addition, 19 normal volunteers also received three 20 mcg doses of the vaccine. The presence of Anti-HBs was determined qualitatively and quantitatively. Non-uremic subjects seroconverted more frequently than did either of the dialysis patient groups. Doubling the individual doses of vaccine did not improve the response of the dialysis patients. We conclude that the response to the vaccine is not diminished when dialysis patients are given half the recommended dose of the vaccine and that the cost of vaccinating this high-risk population could be substantially reduced.

Adult↗

PubMed1985

Nitrendipine kinetics in normal and impaired renal function.

To test the hypothesis that renal failure alters the absorption and metabolism of nitrendipine and the renal elimination of its metabolites, we gave six normal men and 16 men with various degrees of renal dysfunction a single 20 mg oral dose of nitrendipine. Plasma nitrendipine and nitrendipine pyridine analog metabolite concentrations were measured by HPLC 14 times during 48 hours after dosing. The urinary excretion of four additional metabolites was measured. Standing and supine arterial blood pressure was measured 14 times during the 48 hours after dosing. The mean nitrendipine t1/2 was 2.8 +/- 2.1 hours and that of the metabolite was 3.4 +/- 3.9 hours. No significant effect of decreased renal function on any kinetic parameter was demonstrated. Plasma nitrendipine concentrations correlated with decreased blood pressure, but metabolite concentrations did not. We conclude that renal insufficiency does not alter nitrendipine kinetics in man.

Adult↗

PubMed1985

Effect of protein intake on renal function and structure in partially nephrectomized rats.

To examine the effect of high protein intake on renal function and structure in rats with 5/6 nephrectomy chronic renal failure, we pairfed rats with chronic renal failure and sham-operated control rats diets of 14 or 37% protein content for up to 6 months. High protein intake accelerated mortality in rats with chronic renal failure and resulted in a more rapid rate of decrease in renal function as established by plotting the reciprocal of plasma creatinine versus time. High protein intake also increased urine protein excretion in experimental and control rats. High protein intake was associated with increased tubular dilatation and interstitial inflammation, both of which were striking features in rats with chronic renal failure. Glomerular sclerosis was prominent in rats with chronic renal failure. These rats had smaller glomerular tuft dimensions than control rats irrespective of their protein intake. We conclude that high protein intake accelerates the course of chronic renal failure in rats. The pathologic process involves glomerular sclerosis; however, interstitial inflammation and renal tubular changes leading to cyst formation also appear to influence the process adversely.

Animals↗

PubMed1985

Relationship between rat renal accumulation of gentamicin, tobramycin, and netilmicin and their nephrotoxicities.

Gentamicin, tobramycin, and netilmicin were given to rats in daily doses of either 5 or 20 mg/kg for 30 days to determine the renal accumulation kinetics of the compounds and to correlate steady-state renal parenchymal concentrations with nephrotoxicity. Four rats from each group were sacrificed daily and renal parenchymal tissue concentrations were determined microbiologically. Nephrotoxicity was assessed by changes in creatinine values in serum, renal creatinine clearances, and pathological scores. There was no indication of aminoglycoside-induced nephrotoxicity in any tests performed. The following steady-state levels resulted: 36, 148, and 176 micrograms/g after 5 mg/kg per day and 148, 260, and 510 micrograms/g after 20 mg/kg per day for tobramycin, gentamicin, and netilmicin, respectively. We conclude that aminoglycoside parenchymal accumulation in rats follows this order: tobramycin less than gentamicin less than netilmicin. Therefore, differences in the relative toxicities of gentamicin, tobramycin, and netilmicin do not correlate with the renal parenchymal accumulation of these agents and may be more dependent on intrinsic toxicity to the renal proximal tubule than to the concentration of the aminoglycoside in the kidney.

Animals↗

PubMed1985

Fluoxetine: clinical pharmacology and physiologic disposition.

Fluoxetine (30 mg), administered for 7 days to normal volunteers, produced a 66% inhibition of tritiated serotonin uptake into platelets. Plasma concentrations of fluoxetine correlated positively with inhibition of serotonin uptake. Fluoxetine is well absorbed after oral administration in both the fed and fasted states and demonstrates dose proportionality. Fluoxetine disappears from plasma with a half-life of 1-3 days; its metabolite norfluoxetine has a plasma half-life of 7-15 days. After administration of 14C-fluoxetine, approximately 65% of the administered dose of radioactivity is recovered in urine and about 15% in feces. Fluoxetine, given as a single dose or in multiple doses over 8 days, did not produce significant effects on the plasma disappearance of warfarin, diazepam, tolbutamide, or chlorothiazide. Coadministration of fluoxetine and ethanol did not result in an increase from control values in the blood ethanol levels, nor did it produce significant changes in physiologic, psychometric, or psychomotor activity. Pharmacokinetics of fluoxetine in the elderly and normal volunteers appear to be similar. In addition, pharmacokinetic analyses in patients with varying degrees of renal impairment did not show significant differences from healthy subjects.

Administration, Oral↗

PubMed1985

Activated charcoal in theophylline intoxication.

To test the hypothesis that orally administered activated charcoal alters the elimination kinetics of intravenously administered theophylline, six dogs were twice infused with theophylline, 28 mg/kg, over 20 minutes 1 week apart. In a random sequence separated by 1 week, they received either activated charcoal, 30 gm in a water suspension or water only through a nasogastric tube every 2 hours after theophylline infusion, for a total of four doses. The time needed for plasma levels to fall below 20 mg/L was approximately 5 hours regardless of charcoal treatment. However, activated charcoal decreased theophylline halflife from 4.02 to 2.76 hours and volume of distribution from 0.72 to 0.61 L/kg. We conclude that although activated charcoal hastened the elimination of theophylline in dogs, the usefulness of orally administered activated charcoal in the treatment of theophylline overdose may be limited by the inability to shorten the time during which plasma levels are toxic.

Administration, Oral↗

PubMed1985

Relationship between body store of vitamin B6 and plasma pyridoxal-P clearance: metabolic balance studies in humans.

Factors that regulate the clearance of plasma pyridoxal-P (PLP) are unknown. Four volunteers were given a diet supplying approximately 12 mumol pyridoxine (PN) per day. The pharmacokinetics of plasma PLP clearance were measured in these subjects before and after 4 weeks of intravenous PN supplementation (122 mumol/day). Urinary B6 excretion, mainly as 4-pyridoxic acid (4-PA), increased progressively after initiation of PN supplementation until a new steady state was reached on day 10 of supplementation, whereupon greater than 93% of the daily injected PN could be recovered in the urine. Hence, urinary excretion is almost the sole route for vitamin B6 elimination. Fasting plasma PLP concentration increased with supplementation and also reached a new steady state at this time. When supplementation was terminated, urinary B6 excretion decreased in 5 days to an amount only slightly higher than that before supplementation. This amount was maintained for 2 months. By comparison, plasma PLP decreased more slowly and remained considerably higher than the presupplementation level for the rest of the study. These data confirm that urinary 4-PA excretion is a better indicator of B6 intake than is plasma PLP content, whereas plasma PLP content is a better indicator of the body store of the vitamin. Plasma clearance and volume of distribution of PLP decreased significantly after supplementation, but half-life t 1/2 did not change. Plasma clearance of PLP, therefore, is dependent on the vitamin B6 status of an individual.

Adult↗

PubMed1984

The effect of alloxan, and alloxan-induced diabetes on the kidney.

Alloxan is known to induce diabetic renal changes as well as causing nephrotoxic alterations. However, no ultrastructural study has been performed to differentiate diabetic verses toxic affects of alloxan to the tubule and/or glomerulus. Therefore the present study used the "protected" kidney model to prevent one kidney from being exposed to the alloxan while allowing the other to receive the drug immediately. In all experimental animals the right renal hilum was gently occluded for 5 minutes and then released. This was performed prior to the injection of alloxan. Subsequently, the left renal hilum was occluded at the time of, and for 5 minutes after, alloxan administration (40 mg/kg i.v.). The experimental rats were divided into three groups: untreated diabetics, diabetics treated with protamine-zinc-insulin, and alloxan-treated rats that failed to become diabetic. Three groups of controls were included: one group received an equal volume of saline diluent as the experimental rats but no clamping of either renal hilum; another group received the saline and had the left renal hilum occluded for 5 minutes; and a third group had both the right and left renal hila occluded. All animals were followed and sacrificed after 9 weeks. Endogenous creatinine clearance did not change among groups. Alloxan-treated nondiabetic rats displayed marked interstitial nephritis in unprotected kidneys, while protected kidneys were normal. The diabetic state resulted in mesangial proliferation and focal glomerular basement membrane thickening as well as glomerular capillary endothelial abnormalities and visceral epithelial foot-process fusion. The endothelial changes consisted of focal areas showing a reduction in the size of endothelial fenestrae. All glomerular changes were ameliorated by insulin treatment. We conclude: 1) alloxan per se is distinctly nephrotoxic; and 2) the glomerular endothelium and epithelium are involved early in the course of experimental diabetes.

Alloxan↗

PubMed1984

Fluoxetine kinetics and protein binding in normal and impaired renal function.

The effect of decreased renal function on the disposition and elimination of the nontricyclic antidepressant fluoxetine was examined in 25 adult male subjects after a single 40-mg oral dose. Blood samples for the measurement of fluoxetine and its active metabolite norfluoxetine were drawn 13 times in the first 48 hr after dosing and thrice weekly thereafter for 4 wk. All urine was collected in daily aliquots for 4 wk and was assayed for fluoxetine and norfluoxetine concentrations. The extent of fluoxetine binding to plasma protein was determined by equilibrium dialysis. Kinetic analyses were by noncompartmental methods. The drug and its metabolite were distributed over a large apparent volume and both were eliminated slowly. No correlations between the degree of renal dysfunction and the rate of elimination, volume of distribution, or protein binding were found. Plasma concentrations of fluoxetine and norfluoxetine were not significantly changed by hemodialysis.

Administration, Oral↗

PubMed1984

Interactions of moxalactam and tobramycin in normal volunteers and in patients with impaired renal function.

In studies of the in vivo and in vitro interactions of moxalactam and tobramycin, normal volunteers and anuric patients were given one of the drugs or both drugs simultaneously, and the antibiotics were incubated separately or in combination in pooled human plasma. In both normal volunteers and patients with renal failure, the rate of elimination of tobramycin increased when the drug was given in combination with moxalactam. In patients with normal renal function, the rate of elimination of moxalactam decreased when the drug was given in combination with tobramycin; in contrast, this value did not decrease when the combination was given to anuric patients. In vitro, neither drug was affected by the presence of the other. Thus, the observed changes in elimination rates apparently are not caused by a chemical interaction that can be demonstrated in vitro. However, they are of sufficient magnitude to be of potential clinical significance.

Anuria↗