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Biomedical subjects

L F Prescott

Publications and source records attributed to L F Prescott.

At least 19 recordsLinked to original sources
PubMed1992

Paracetamol elimination in Chinese and Indians in Singapore.

The 24 h urinary excretion of paracetamol and its conjugates after oral administration of about 15 mg/kg was studied in 24 Chinese and 24 Indian healthy young adult male volunteers living in Singapore. The Indians excreted a significantly lower fraction of sulphate conjugate (28.9% compared to 35.9% in the Chinese), and a correspondingly higher fraction as glucuronide conjugate (62.2% compared to 54.5% in the Chinese). There was no difference between the ethnic groups in terms of the urinary recovery of unchanged paracetamol (Indians 3.4%, Chinese 3.6%), glutathione-derived cysteine (Indians 2.3% and Chinese 2.2%) and mercapturic acid (Indians 3.6%, Chinese 3.8%) conjugates. The total fraction of administered paracetamol recovered in the urine was 84.7% and 85.7% in the Indian and the Chinese groups, respectively. Although the total glutathione derived conjugates recovered in the two ethnic groups were similar (Indians 5.9%, Chinese 6%), the values were lower than those reported previously for Caucasians in Scotland (9.3%).

Acetaminophen↗
PubMed1991

Dose-dependent absorption and elimination of cefadroxil in man.

The pharmacokinetic behaviour of cefadroxil was dose-dependent in healthy male volunteers following the oral administration of single doses of 5, 15, and 30 mg.kg-1. As the dose of cefadroxil increased from 5 to 15 and 30 mg.kg-1, the peak plasma concentrations, normalized to 5 mg.kg-1, decreased significantly from 15.1 to 10.7 and 7.6 mg.l-1, while the corresponding normalized areas under the plasma concentration-time curves from 0 to 2 h decreased significantly from 1258 to 946 and 801 min.mg.l-1. When the same subjects were given 5 mg.kg-1 of cefadroxil together with 45 mg.kg-1 of cephalexin, the absorption of cefadroxil was slowed to a similar or greater extent than with the high dose of cefadroxil. Although the absorption rate decreased as the dose increased, the systemic availability of cefadroxil was essentially complete at all doses, as judged by the 24 h urinary recoveries of the antibiotic. Kinetic analysis of the plasma concentration-time curves gave the best fit with a zero-order followed by a first-order absorption process, consistent with saturable intestinal absorption of cefadroxil. The elimination rate of cefadroxil was directly related to dose and plasma concentrations, and the clearance at the dose of 5 mg.kg-1 was significantly increased by the simultaneous administration of high-dose cephalexin. The renal clearance of cefadroxil ranged from 98 ml.min.l-1 at total plasma cephalosporin (cefadroxil + cephalexin) concentrations less than 2.5 mg.l-1 to 156 mg.l-1 at concentrations greater than 40 mg.l-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
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

The disposition of paracetamol and the accumulation of its glucuronide and sulphate conjugates during multiple dosing in patients with chronic renal failure.

We have compared the disposition of oral paracetamol (1.0 g t.d.s. for 10 days) in 6 healthy volunteers and 6 conservatively-managed patients with chronic renal failure (mean plasma creatinine 451 mumol.l-1). Blood was sampled daily for 10 days before the morning dose of paracetamol. Each day the pretreatment plasma concentrations of paracetamol were higher in the renal failure patients than in the volunteers, with mean values over the 10 days of 3.1 and 1.1 mg.l-1 respectively. The mean daily plasma concentrations of the sulphate and glucuronide conjugates of paracetamol were markedly higher in the renal failure group and apparent steady-state concentrations of about 25 and 85 mg.l-1 were reached on the 2nd and 6th days respectively. The mean steady-state plasma concentrations of the glucuronide conjugate on the 7th to 10th days of treatment were positively correlated with the plasma creatinine concentration (r = 0.97), but this relationship did not hold for the sulphate conjugate. Cysteine and mercapturate conjugates could only be detected in one patient. Predictions of steady-state concentrations based on previous studies with single doses of paracetamol in renal failure patients were remarkably accurate for the glucuronide but not for the sulphate conjugate. These results are consistent with some extra-renal elimination of retained paracetamol conjugates in patients with chronic renal failure, with limited regeneration of the parent compound. The sulphate metabolite did not accumulate as predicted, possibly because of depletion of inorganic sulphate.

Acetaminophen↗
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↗
PubMed1991

Gastric emptying following Colles' fracture.

There are few complications associated with intravenous regional anaesthesia but convulsions with loss of consciousness induced by local anaesthetic toxicity may result in pulmonary aspiration. In many hospitals, patients are fasted prior to the procedure although such a delay would be of little value if gastric emptying was inhibited following painful injury. Utilizing the kinetics of paracetamol absorption, we investigated the rate of gastric emptying in patients sustaining a Colles' fracture within the previous 4 h. Post-manipulation control values were obtained at their first out-patient attendance. There was no statistically significant difference in the rate of gastric emptying. Since gastric emptying is not delayed by a recent Colles' fracture, the simple precaution of fasting patients prior to intravenous regional anaesthesia should reduce the risk of pulmonary aspiration.

Acetaminophen↗
PubMed1979

Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning.

One hundred cases of severe paracetamol poisoning were treated with intravenous N-acetylcysteine (acetyl-cysteine). There was virtually complete protection against liver damage in 40 patients treated within eight hours after ingestion (mean maximum serum alanine transaminase activity 27 IU/1). Only one out of 62 patients treated within 10 hours developed severe liver damage compared with 33 out of 57 patients (58%) studied retrospectively who received supportive treatment alone. Early treatment and acetylcysteine also prevented renal impairment and death. The critical ingestion-treatment interval for complete protection against severe liver damage was eight hours. Efficacy diminished progressively thereafter, and treatment after 15 hours was completely ineffective. Intravenous acetylcysteine was more effective than cysteamine and methionine and noticeably free of adverse effects. It is the treatment of choice for paracetamol poisoning.

Acetaminophen↗
PubMed1979

Effect of gel fibre on gastric emptying and absorption of glucose and paracetamol.

To determine the part played by altered gastric emptying in the modification of glucose absorption by gel fibres, glucose tolerance tests were done in seven healthy volunteers with and without the addition of pectin to the ingested glucose solution and after pharmacological inhibition of gastric emptying with propantheline. Compared with the controls, pectin significantly reduced blood-glucose. Propantheline had a similar but more pronounced effect. Pectin and guar gum did not substantially alter glucose tolerance in a patient who had had total gastrectomy. In a further investigation, gastric emptying and paracetamol absorption were studied simultaneously in fourteen subjects. In eight of these the study was repeated after addition of guar gum and pectin to the ingested paracetamol. Both gastric emptying and paracetamol absorption were slower after gel fibre but the total absorption of the drug, reflected in urinary recovery, was not significantly reduced. The results suggest that the effects of guar gum and pectin on glucose tolerance and paracetamol absorption could be due simply to alteration in the rate of gastric emptying.

Absorption↗
PubMed1979

Paracetamol metabolism in chronic liver disease.

The plasma concentrations and urinary excretion of paracetamol and its glucuronide, sulphate, cysteine and mercapturic acid conjugates were measured in eight normal subjects, eight patients with mild liver disease and seven patients with severe liver disease following an oral dose of 1.5 g of paracetamol. The mean plasma paracetamol half-life was similar in normal subjects (2.43 h +/- 0.19) but was significantly prolonged in all patients with severe liver disease (4.25 h +/- 1.15:p = less than 0.001). Prolongation of the paracetamol half-life was related to reduced plasma albumin and increased prothrombin time. The mean ratios of plasma concentrations of unchanged paracetamol to paracetamol glucoronide and sulphate were significantly greater in patients with sever liver disease than the normal subjects. There were no significant differences in the overall 24-h urinary excretion of paracetamol and its glucuronide, sulphate, cysteine and mercapturic acid conjugates in the three groups. The glutathione conjugation of paracetamol did not seem to be impaired in patients with severe liver disease as evidence by the production of normal amounts of the cysteine and mercapturic acid conjugates. There is thus no evidence that they are at increased risk of hepatotoxicity when given a single therapeutic dose of paracetamol.

Acetaminophen↗
PubMed1979

The disposition of intravenous doxapram in man.

The pharmacokinetics of intravenous doxapram in healthy individuals is consistent with a three-compartment open model. Doxapram was administered by bolus injection (1.5 mg . kg-1) and by intravenous infusion (6.5 mg . kg-1 for 2 h) to 5 subjects on separate occasions. There was no significant difference in mean terminal plasma half-lives (355 and 448 min) or in mean total body clearances 5.9 and 5.6 ml . min-1 . kg-1) following i.v. bolus injection or infusion respectively. In 3 subjects plasma doxapram concentrations during and after i. v. infusion agreed with those predicted from pharmacokinetic values obtained from the bolus injection study. Since mean steady-state concentrations (9.9 microgram . ml-1) would be reached only after an extended interval (mean 15.2 h), a variable-rate infusion regimen was calculated to produce and maintain a concentration of 2 microgram . ml-1 from 15--25 min onwards. A regimen in which the infusion rate is reduced step-wise is recommended to achieve early near-constant plasma doxapram concentrations.

Adult↗
PubMed1979

A pharmacokinetic study of doxapram in patients and volunteers.

1. Following intravenous bolus injections or brief infusions in healthy volunteers, plasma concentrations of doxapram declined in a multi-exponential fashion. The mean half-life from 4-12 h was 3.4 h (range 2.4-4.1h), the mean apparent volume of distribution was 1.5 1 kg-1 and the whole body clearance was 370 ml min-1. 2. Enteric-coated capsules of doxapram base were absorbed rapidly after an initial delay, and the systemic availability was about 60%. 3. Doxapram is extensively metabolized and less than 5% of an i.v. dose was excreted unchanged in the urine in 24 h. A metabolite (AHR 5955) was present in plasma in amounts comparable to the parent compound and had a similar half-life. 4. The disposition of doxapram appears to be similar in healthy volunteers and patients with respiratory failure. 5. The previously held belief that plasma concentrations fall rapidly when an infusion is stopped is only true following short duration infusions. The pharmacokinetic properties of doxapram are such that steady-state plasma concentrations will not be achieved for many hours with the recommended constant rate infusion régime.

Administration, Oral↗
PubMed1979

Treatment of severe 2,4-D and mecoprop intoxication with alkaline diuresis.

1 Self-poisoning with a selective weedkiller containing 2,4-D and mecoprop in a 39 year old man resulted in prolonged deep coma, pyrexia, hyperventilation, hypoxaemia, myotonia, skeletal muscle damage and electrocardiographic changes consistent with cardiomyopathy. 2 The admission plasma concentrations of 2,4-D and mecoprop were 400 and 751 microgram/ml respectively. The patient remained gravely ill with no signs of improvement for 2 days with supportive therapy and there was no fall in the 2,4-D level. 3 Alkaline diuresis greatly increased the renal clearance of 2,4-D, and there was a rapid fall in plasma concentration (T1/2 3.7 h) with corresponding clinical improvement. The effect on the elimination of mecoprop was similar, but less dramatic. 4 Forced alkaline diuresis may improve the otherwise very poor prognosis in severe intoxication with 2,4-D and related weedkillers.

2,4-Dichlorophenoxyacetic Acid↗