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Biomedical subjects

S Freestone

Publications and source records attributed to S Freestone.

At least 37 records · Page 2Linked to original sources
PubMed1991

The concentration-dependent disposition and kinetics of inulin.

The disposition of inulin was studied in 30 healthy male and 10 healthy female volunteers, and 10 patients with stable chronic renal failure (mean creatinine clearance 45 ml.min-1) following intravenous infusion of 70 mg.kg-1 over 5 min. Plasma concentrations fell rapidly initially but the rate of decline decreased continuously over 8 h and a linear terminal elimination phase could not be identified. Inulin was excreted rapidly by the subjects with normal renal function and 97.3% of the dose was recovered in the urine in 8 h. There was a progressive highly significant fall in the renal clearance of inulin after 2 h as plasma concentrations fell below about 150 mg.l-1. Six to 8 h after administration the clearance was less than 50% of the initial value in the healthy volunteers and the corresponding fall in the renal patients was 33%. The concentration-dependent renal clearance of inulin was confirmed in "step-up" and "step-down" constant infusion studies in which clearances were measured at mean plasma concentrations ranging from 35.2 to 186.7 mg.l-1. These studies virtually excluded time, changes in posture and urine flow rate as important factors. There was no statistically significant fall in clearance during the first 2 h and kinetic analysis was based on data obtained over this time.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

A single dose study of the effects of fenoldopam and enalapril in mild hypertension.

To clarify the contribution made by the renin-angiotensin system activation to the short lived hypotensive response to fenoldopam, the haemodynamic effects of a combination of fenoldopam (100 mg) and enalapril (5 mg) were compared with fenoldopam alone, enalapril alone and placebo in a balanced, randomised, double blind, single dose study in eight hypertensive patients. Fenoldopam caused an acute fall in blood pressure which lasted approximately 3 h after dosing and was associated with a reflex tachycardia. Enalapril caused a more gradual fall in blood pressure (onset 2 h) without a reflex tachycardia. The combination of drugs produced greater reductions in blood pressure sustained for a longer period than fenoldopam alone and with a more rapid onset than enalapril alone. In combination the hypotensive effects of fenoldopam and enalapril were clearly additive and not synergistic. Activation of the renin-angiotensin system does not antagonise significantly the hypotensive effect of fenoldopam.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

Reassessment of the single intravenous injection method with inulin for measurement of the glomerular filtration rate in man.

1. Factors influencing the total body and renal clearances of inulin were investigated in a total of 37 healthy adult volunteers and 10 patients with stable chronic renal failure after the single intravenous injection of a dose of 70 mg/kg given over 5 min. 2. The elimination of inulin was highly concentration-dependent, and in healthy volunteers the renal clearance fell from 103.7 +/- 14.4 ml min-1 1.73 m-2 during the first hour after administration to 49.1 +/- 20.9 ml min-1 1.73 m-2 over the period 6-8 h. In the patients with renal failure the renal clearance fell correspondingly from 39.7 +/- 16.5 to 26.6 +/- 8.6 ml min-1 1.73 m-2. There were no changes in the simultaneously measured clearances of creatinine. 3. The values obtained for the total body clearance of inulin after a single injection depend critically on dose, the number and timing of blood samples, the choice of pharmacokinetic model, the number of data points chosen for estimation of the slope of the terminal elimination phase for analysis by the methods of residuals, and the weighting used for curve fitting by non-linear regression analysis. 4. With standardized conditions of sampling from 0 to 2 h and weighted non-linear regression analysis of the plasma concentration-time data, the total body and renal clearances of inulin were almost identical in subjects with normal renal function at 105.2 +/- 10.2 and 102.9 +/- 13.0 ml min-1 1.73 m-2. In the patients with chronic renal failure sampling was continued for 3 h and the corresponding clearances were 40.4 +/- 15.3 and 38.9 +/- 15.7 ml min-1 1.73 m-2. 5. The 0-2 h total body and renal clearances of inulin were measured by the single injection method and the renal clearance was measured by the standard constant infusion method on different occasions in 10 healthy volunteers. The respective clearances were similar at 101.4 +/- 6.6, 94.9 +/- 11.9 and 88.4 +/- 12.1 ml min-1 1.73 m-2. 6. The reproducibility of the single injection and constant infusion methods was compared by measuring the inulin clearance with both techniques on three occasions in separate groups of eight and nine healthy volunteers. The mean coefficient of variation for the total body clearance with the single injection method was only 3.9% compared with 9.5% for the renal clearance determined the same way and 12.0% for the renal clearance during constant infusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1991

Effects of tenoxicam on renal function and the disposition of inulin and p-aminohippurate in healthy volunteers and patients with chronic renal failure.

1. The effects of tenoxicam on renal function were studied in 10 patients with chronic renal failure (creatinine clearance 46.7 +/- 11.9 ml min-1 1.73 m-2) and eight healthy volunteers. A parallel treatment control group of eight healthy volunteers received placebo. Tenoxicam was given orally in a dose of 40 mg daily for 2 days followed by 20 mg daily for a further 8 days. Renal function was assessed by measurement of the renal clearances of inulin and p-aminohippurate (PAH) using the single injection technique before and during administration of tenoxicam. 2. In the healthy volunteers there were no changes in glomerular filtration rate, effective renal plasma flow, or the urinary excretion of N-acetylglucosaminidase and beta 2-microglobulin on the 3rd and 10th days of treatment with tenoxicam. The mean urinary excretion of prostaglandins E2 and 6-keto F1 alpha decreased during treatment but there was great individual variation and the differences were not statistically significant. Tenoxicam had no effect on the half-life, clearance, volume of distribution or urinary recovery of inulin and PAH. 3. There was no significant change in the clearance of inulin and creatinine after treatment with tenoxicam for 10 days in the patients with chronic renal failure. However, in this group there was a significant increase in plasma creatinine on the 3rd and 6th days with a return to pretreatment levels by the 10th day. The administration of tenoxicam for 10 days was associated with a small but significant increase in the plasma half-life and volume of distribution of inulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Effect of lithium on the renal actions of alpha-human atrial natriuretic peptide in normal man.

1. alpha-Human atrial natriuretic peptide (7.5 pmol min-1 kg-1) was infused intravenously into eight healthy men after pretreatment with lithium carbonate (750 mg) or placebo. 2. Baseline sodium excretion was significantly increased after lithium, but the natriuresis during infusion of alpha-human atrial natriuretic peptide was attenuated. 3. Similar decreases in plasma renin activity with infusion of alpha-human atrial natriuretic peptide occurred on both days. 4. Administration of lithium may be associated with pharmacological effects and further work is required to validate the use of lithium clearance as a marker of proximal renal tubular sodium handling.

Adult↗
PubMed1990

Effect of prolonged intravenous infusion of gludopa in humans and a preliminary study of its oral bioavailability.

Intravenous infusion of gamma-glutamyl-L-dopa (25 micrograms/kg/min) for 10 h in normal humans caused a natriuresis of 46.5 mmol of sodium without an increase in plasma renin activity and was associated with small but significant falls in blood pressure. In a second study the oral bioavailability of gludopa was estimated in normal subjects and found to be low (less than 2%). The increase in urine dopamine excretion and the natriuretic effect of gludopa were much larger after intravenous infusion than oral dosing.

Absorption↗
PubMed1990

Mefenamic acid-induced neutropenia and renal failure in elderly females with hypothyroidism.

We report mefenamic acid-induced non-oliguric renal failure and severe neutropenia occurring simultaneously in two elderly females. The neutropenia was due to maturation arrest of the myeloid series in one patient. Both patients were also hypothyroid, but it is not clear whether this was a predisposing factor to the development of these adverse reactions. However, it would seem prudent not to use mefenamic acid in hypothyroid patients until the hypothyroidism has been corrected.

Acute Kidney Injury↗
PubMed1989

The effect of carbidopa and lithium on the systemic and renal response to acute intravenous saline loading in normal man.

To assess a possible role for endogenous renal dopamine in sodium excretion, the dopa decarboxylase inhibitor carbidopa was given during intravenous salt loading. In addition, the effect of lithium on tubular sodium handling was separately determined. Nine males were studied randomly on three occasions, receiving placebo, lithium carbonate (1000 mg, 11 h prior to study) or carbidopa (100 mg x 2). On each day a baseline period was followed by infusion of isotonic saline (20 ml/kg per hour) over 3 h, and 6 h recovery. With placebo, sodium excretion increased markedly to a peak in the hour after infusion (0.15 +/- 0.03 to 0.73 +/- 0.12 mmol/min, P less than 0.01). Urine dopamine excretion increased modestly (1.33 +/- 0.12 to 1.67 +/- 0.13 mmol/min, P less than 0.01). Carbidopa effectively blocked dopamine output during the study. However, the natriuretic response was comparable to values on placebo at all time points. Fractional lithium clearance, a proposed measure of proximal tubular fluid rejection, increased significantly during saline infusion. However, baseline sodium excretion was greater in the presence of lithium, and plasma renin activity (PRA) was significantly elevated. In addition, the peak natriuretic response was smaller and cumulative sodium excretion reduced by 40% (P less than 0.01) compared to placebo. This study provides no evidence for a facilitatory role for dopamine in the natriuretic response to intravenous salt loading. Lithium, at subtherapeutic levels, cannot be presumed to be an inert marker, and clearance data must be interpreted with caution.

Adult↗
PubMed1989

The renal effects of atrial natriuretic peptide in man are not attenuated by (+)-sulpiride.

1. Human alpha atrial natriuretic peptide (ANP) was infused intravenously for 1 h in eight healthy salt-replete men on two occasions, with and without pretreatment with (+)-sulpiride. 2. ANP increased sodium excretion and urine flow rate but did not alter blood pressure or plasma renin activity. 3. (+)-sulpiride had no significant effect on baseline creatinine clearance, sodium excretion or urine flow rate and did not alter the increases in these parameters with ANP. 4. It is unlikely that the renal effects of ANP are mediated by dopamine DA1-receptors in man.

Adult↗
PubMed1988

Reduced felodipine bioavailability in patients taking anticonvulsants.

Felodipine is a dihydropyridine calcium antagonist, structurally related to nifedipine, which undergoes extensive first-pass hepatic metabolism and normally has an oral bioavailability of 15%. Felodipine disposition was studied in 10 patients who had microsomal enzyme induction due to chronic anticonvulsant therapy, and in 12 normal volunteers matched for age and sex. Plasma felodipine concentrations after a 5 mg oral dose were grossly reduced in the epileptic patients: the mean peak concentration was 1.6 (vs 8.9) nmol/l, and the area under the curve was only 2.0 (vs 30.0) nmol.h/l. The relative bioavailability of felodipine in the epileptic patients was thus only 6.6% of that in the normal subjects, and less than 1% of the oral dose was systemically available. Patients on anticonvulsant treatment will require substantially higher doses of felodipine to achieve plasma concentrations equivalent to those in non-induced subjects.

Administration, Oral↗
PubMed1988

(+)-sulpiride antagonises the renal effects of gamma-L-glutamyl-L-dopa in man.

1. gamma-L-glutamyl-L-dopa (gludopa) was given by intravenous infusion to six healthy salt-replete men on two occasions, with and without pretreatment with (+)-sulpiride. 2. Gludopa increased sodium excretion, glomerular filtration rate and effective renal plasma flow whilst decreasing plasma renin activity. 3. (+)-sulpiride had no significant effect on baseline natriuresis, renal haemodynamics or plasma renin activity, but significantly attenuated the rise in sodium excretion, glomerular filtration rate and effective renal plasma flow produced by gludopa. 4. (+)-sulpiride abolished the acute fall in plasma renin activity seen with gludopa. 5. (+)-sulpiride raised serum prolactin concentration but did not affect the ris in urine dopamine excretion rate caused by gludopa. 6. Gludopa exerts its renal effects by stimulating specific dopamine receptors which are principally of the DA1 subtype.

Adult↗
PubMed1987

The effect of intravenous frusemide on urine dopamine in normal volunteers: studies with indomethacin and carbidopa.

1. The urine dopamine response to intravenous frusemide (30 mg) was investigated in 15 salt replete male volunteers. The effects of oral indomethacin (100 mg) and oral carbidopa (100 mg) given before intravenous frusemide were studied in the same group of subjects. 2. Frusemide produced a significant increase in urine dopamine output within 15 min. 3. Indomethacin attenuated the natriuretic and renin responses to frusemide, but did not alter urine dopamine output. 4. Carbidopa lowered urine dopamine to undetectable levels, but did not significantly affect the natriuretic and renin responses to frusemide. 5. We conclude that urine dopamine excretion after frusemide is not directly related to increased sodium excretion or renin response and it is not mediated by the prostaglandins. In addition, dopamine does not contribute to the renal actions of frusemide under normal conditions.

Administration, Oral↗
PubMed1985

Comparison of two slow-release formulations of metoprolol with conventional metoprolol and atenolol in hypertensive patients.

We have compared the beta-adrenoceptor blocking and antihypertensive effects of chronic once daily treatment with conventional metoprolol 200 mg, two 'long-acting' formulations of metoprolol 200 mg and atenolol 100 mg in a cross-over study in 12 hypertensive patients concurrently receiving diuretic therapy. The peak effects of all compounds were similar, with significant reductions in exercise heart rate and blood pressure. Twenty-four hours after dosing only atenolol treatment was consistently associated with a reduction in both exercise heart rate (P less than 0.001) and blood pressure (P less than 0.02) when compared with placebo. Once daily treatment of hypertension with metoprolol, even in 'long-acting' formulations, cannot be recommended because of waning antihypertensive effect which would be missed at routine clinic attendance. Metoprolol should be prescribed twice daily in hypertension. So-called long-acting formulations do not always confer benefits over conventional dose forms.

Adult↗