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Biomedical subjects

L F Prescott

Publications and source records attributed to L F Prescott.

At least 37 records · Page 2Linked to original sources
PubMed1993

Impaired absorption of paracetamol in vegetarians.

1. The absorption and disposition of paracetamol was investigated in 10 healthy male Thai vegetarians and 10 similar non-vegetarians following an oral dose of 20 mg kg-1. 2. The absorption rate of paracetamol was significantly impaired in the vegetarians compared with the non-vegetarians as shown by a lower mean Cmax (11.7 +/- 1.4 vs 15.6 +/- 1.6 mg l-1; 95% confidence interval of the difference 2.49 to 5.36), increased tmax (median 1.75, range 0.75 to 3 h compared with 0.75 and 0.25 to 2 h) and an increase in the time for input of 50% of the total amount absorbed (0.54 +/- 0.38 compared with 0.20 +/- 0.10 h; 95% confidence interval of the difference 0.063 to 0.61). 3. A significantly lower total 24 h urinary recovery of paracetamol and metabolites (72.1 +/- 5.4 vs 86.4 +/- 5.4% of the dose; 95% confidence interval of the difference 8.0 to 20.6) indicated a decrease in the extent of absorption in the vegetarians also, although the total AUC values did not differ significantly between the two groups. 4. The plasma paracetamol half-life, partial metabolic clearances and fractional urinary excretion of the glucuronide, sulphate, cysteine and mercapturic acid conjugates of paracetamol were similar in the vegetarians and non-vegetarians.

Absorption↗
PubMed1993

The concentration-dependent disposition of intravenous p-aminohippurate in subjects with normal and impaired renal function.

1. The disposition and kinetics of p-aminohippuric acid (PAH) were studied in 27 healthy male volunteers, 10 healthy female volunteers and 10 patients with chronic renal impairment following rapid intravenous injection of 10 mg kg-1. In addition, the renal clearances of PAH and its metabolite N-acetyl-PAH were measured in 10 of the healthy male volunteers following conventional administration of PAH by loading dose and constant infusion, and in another eight during sequential 'step-up' and 'step-down' infusions intended to maintain low, medium and high plasma concentrations below the threshold for onset of saturation of tubular transport. 2. PAH was eliminated rapidly with a mean half-life of less than 30 min in the healthy volunteers and 72 min in the renal patients. The corresponding estimates for acetyl-PAH were 49 and 153 min. In both groups the rate of disappearance of PAH slowed progressively over the period of observation and there was no true log-linear terminal elimination phase. 3. In the healthy volunteers about 50% of the dose was excreted in the urine in 30 min with quantitative recovery in 3 h. In 8 h, 17% of the dose was recovered as acetyl-PAH. In the patients with renal impairment the 8 h recovery was only 83.6% of the dose with 26.9% of the total appearing as acetyl-PAH. 4. The volume of distribution (Vss) of PAH was 16-18 l in the healthy subjects and renal patients. Acetyl-PAH appeared to have a much larger distribution volume (mean 65.5 l in the healthy volunteers). 5. In the healthy volunteers the renal clearance of PAH fell dramatically from 599 +/- 115 ml min-1 1.73m-2 during the first hour after administration to 300 +/- 208 ml min-1 1.73 m-2 during the second hour (P < 0.001). The corresponding renal clearances of acetyl-PAH were 775 +/- 196 and 916 +/- 212 ml min-1 1.73 m-2. In the patients with renal impairment the renal clearance of PAH fell from 194 +/- 83 ml min-1 1.73 m-2 in the first hour to only 61 +/- 19 ml min-1 1.73 m-2 from 4 to 6 h. Over the same period there was no significant fall in the clearances of acetyl-PAH or total PAH (acetyl-PAH + PAH).(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylation↗
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↗
PubMed1990

The comparative effects of paracetamol and indomethacin on renal function in healthy female volunteers.

1. Renal function was assessed in 10 healthy female volunteers during administration of placebo, paracetamol (acetaminophen) (4.0 g daily) and indomethacin (150 mg daily) for 3 days under conditions of controlled sodium and fluid intake. 2. Paracetamol and indomethacin had no significant effect on the glomerular filtration rate and effective renal plasma flow as measured by the renal clearances of inulin, creatinine and p-aminohippurate (PAH). 3. Compared with placebo, paracetamol reduced the mean urinary excretion of prostaglandin E2 by 43% on the second day and 58% on the third treatment day (P less than 0.01). With indomethacin the corresponding reductions were 73 and 80%. Paracetamol and indomethacin had much less effect on the excretion of prostaglandin 6-keto F1 alpha, and a significant decrease was observed only on the third day. 4. The decreased urinary excretion of prostaglandin E2, produced by paracetamol was associated with a reduction in sodium excretion of more than 50% (P less than 0.01) and delay in the onset of diuresis following an acute water load. 5. The renal effects of paracetamol and indomethacin appear to differ. Although indomethacin reduced prostaglandin excretion more than paracetamol it had a similar effect on sodium excretion and less initial antidiuretic action. Unlike paracetamol, indomethacin also reduced basal plasma renin activity. 6. Paracetamol reduced the total body clearance of PAH and increased its plasma half-life. This effect could be attributed to inhibition of the acetylation of PAH by paracetamol. 7. In normal use paracetamol does not appear to have the adverse renal effects associated with the non-steroidal anti-inflammatory analgesics and further studies are required to establish the clinical significance of these findings.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

Intravenous N-acetylcysteine, hepatotoxicity and plasma glutathione S-transferase in patients with paracetamol overdosage.

The concentration of glutathione S-transferase B1 (GST B1) subunits was measured in sequential plasma samples taken at frequent intervals for 48 h from ten patients with severe paracetamol poisoning who were treated with intravenous N-acetylcysteine. No significant increase in plasma GST B1 concentration was observed over the study period and with 4 h of starting treatment with N-acetylcysteine there were significant decreases in plasma GST B1 concentrations. None of the patients subsequently developed significant liver damage. At the dose used for the treatment of paracetamol poisoning, N-acetylcysteine has no hepatotoxic effects.

Acetaminophen↗
PubMed1989

The disposition and kinetics of intravenous N-acetylcysteine in patients with paracetamol overdosage.

Seventeen patients received standard treatment with intravenous N-acetylcysteine for 18 episodes of severe poisoning with paracetamol (acetaminophen). The dose of N-acetylcysteine was 150 mg/kg given in 15 min followed by 50 mg/kg in 4 h and 100 mg/kg over the next 16 h. Liver damage was absent or mild on 13 occasions (ALT greater than 500 mu/l) and severe on 5 (ALT less than 1000 mu/l). Total plasma N-acetylcysteine was estimated by HPLC. The mean maximum plasma concentration after the initial loading dose was 554 mg/l. Concentrations then fell rapidly and after 12 h a mean steady-state level of about 35 mg/l was maintained. When the infusion was discontinued N-acetylcysteine disappeared with a half-life of 5.7 h. The mean steady-state volume of distribution, AUC, mean residence time and total clearance were 536 ml/kg, 1748 mg.h.l-1, 2.91 h and 3.18 ml.min-1.kg-1. These values are generally consistent with those previously reported with much smaller doses and the disposition of N-acetylcysteine does not appear to be dose-dependent. The elimination of N-acetylcysteine was not impaired in the patients with severe liver damage, and the pharmacokinetic variables and plasma concentrations were similar in patients with and without hepatotoxicity. The dosage schedule for intravenous N-acetylcysteine should probably be modified since adverse reactions invariably occur early when plasma concentrations are at their highest, and liver damage was prevented just as effectively at the lowest as at the highest Cmax. High initial concentrations of N-acetylcysteine can be avoided with simple alternative regimens based on the kinetic data of this study.

Acetaminophen↗
PubMed1989

Paracetamol disposition and metabolite kinetics in patients with chronic renal failure.

The disposition of paracetamol following an oral dose of 1.0 g was compared in 10 healthy volunteers, 7 patients with moderate chronic renal failure and 6 patients with end stage renal failure on maintenance haemodialysis. Paracetamol absorption was normal in the patients with renal failure. The mean plasma half-life of paracetamol from 2 to 8 h was similar in the 3 groups (2.1 to 2.3 h) but from 8 to 24 h it disappeared much more slowly in the renal failure patients (half-life 11.7 compared with 4.9 h in the healthy volunteers). Plasma concentrations of paracetamol glucuronide and sulphate conjugates were greatly increased in the patients with moderate renal failure and the mean plasma half-lives were 30.5 and 21.8 h respectively compared with about 3 h in the healthy volunteers. Plasma concentrations of these metabolites were even higher in the dialysis patients and there was no significant fall over 24 h. The cysteine and mercapturic acid conjugates of paracetamol could only be measured in plasma in the patients with renal failure and concentrations were very low. The fractional urinary recovery of paracetamol and its glucuronide, sulphate, cysteine and mercapturic acid conjugates was similar in healthy volunteers and patients with moderate renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1989

Effect of oral doxapram on morphine-induced changes in the ventilatory response to carbon dioxide.

A double-blind crossover volunteer trial has been carried out to determine if oral doxapram reduces the respiratory depression caused by morphine 0.12 mg kg-1 i.m. Doxapram was given to the subjects 90 min before the morphine and significantly reduced the displacement of the ventilatory response to carbon dioxide caused by the morphine. This occurred despite the fact that the plasma concentrations of doxapram were significantly lower when the subject had been given morphine than when a placebo injection had been administered. Doxapram alone in doses of 300 mg and 600 mg did not alter significantly the respiratory variables measured in this study.

Administration, Oral↗
PubMed1989

Treatment of quinine overdosage with repeated oral charcoal.

In five symptomatic patients with acute quinine poisoning the mean admission plasma concentration was 11.1 mg l-1. After treatment with repeated oral charcoal 50 g 4 hourly, plasma quinine concentrations fell rapidly with a mean half-life of 8.1 +/- 1.1 h (s.d.) compared with more than 24 h in a previous report in similarly poisoned patients. The visual impairment which was expected in a patient with cardiotoxicity and a plasma quinine concentration of 12.6 mg l-1 did not occur, but late treatment with charcoal was of no obvious benefit in another patient who was already blind. Repeated oral charcoal has been shown to increase the rate of elimination of a therapeutic dose of quinine in healthy volunteers. It appears to be the only practical means of enhancing the removal of this drug after overdosage and should reduce the risk of potentially disastrous complications.

Administration, Oral↗
PubMed1989

Plasma glutathione S-transferase and F protein are more sensitive than alanine aminotransferase as markers of paracetamol (acetaminophen)-induced liver damage.

Concentrations of glutathione S-transferase (GST; glutathione transferase; EC 2.5.1.18) B1 subunits, F protein, and the activity of alanine aminotransferase (ALT; EC 2.6.1.2) were measured in sequential plasma samples taken from nine patients with self-administered paracetamol (acetaminophen) poisoning. GST exceeded the reference interval in all patients at the time of admission, and F protein was increased in seven. In contrast, abnormal activities of ALT in plasma were found in only one of the nine on admission, a patient admitted 12 h after poisoning. Subsequent to admission nine, eight, and five patients, respectively, had abnormal concentrations of GST, F protein, and ALT. When expressed as multiples of the upper reference limit, the highest values for GST measured in each patient always far exceeded the greatest abnormalities in ALT; this was true for F protein in only five patients. Patients in whom the concentration of GST exceeded 10 micrograms/L on admission subsequently went on to develop moderate or severe liver damage, despite treatment with N-acetylcysteine. F protein and ALT measurements on admission were not as efficient as GST at predicting the clinical outcome of the patients. We conclude that GST and F protein offer clear advantages over ALT for detecting minor degrees of acute liver dysfunction, particularly when only centrilobular damage may be involved.

Acetaminophen↗