Biomedical subjects

P N Bennett

Publications and source records attributed to P N Bennett.

At least 19 recordsLinked to original sources

PubMed2002

Lead poisoning: case studies.

Early clinical features of lead toxicity are non-specific and an occupational history is particularly valuable. Lead in the body comprises 2% in the blood (t1/2 35 days) and 95% in bone and dentine (t1/2 20-30 years). Blood lead may remain elevated for years after cessation from long exposure, due to redistribution from bone. Blood lead concentration is the most widely used marker for inorganic lead exposure. Zinc protoporphyrin (ZPP) concentration in blood usefully reflects lead exposure over the prior 3 months. Symptomatic patients with blood lead concentration >2.4 micromol l-1 (50 microg dl-1) or in any event >3.8 micromol l-1 (80 microg dl-1) should receive sodium calciumedetate i.v., followed by succimer by mouth for 19 days. Asymptomatic patients with blood lead concentration >2.4 micromol l-1 (50 microg dl-1) may be treated with succimer alone. Sodium calciumedetate should be given with dimercaprol to treat lead encephalopathy.

Acute Disease↗

PubMed1996

Caffeine as a metabolic probe: NAT2 phenotyping.

1. Caffeine has been used to determine acetylator phenotype for some 15 years but the interpretation of metabolic ratios with this substance raises theoretical and methodological issues. 2. N-acetyltransferase type 2 (NAT2) status was assessed in 23 young healthy subjects using both caffeine overnight and spot urine samples, and sulphadimidine. 3. Frequency distribution analysis of the metabolic ratios of NAT2, indicated two distinct groups for sulphadimidine, and for caffeine spot but not overnight samples. Spearman's rank correlation values were low indicating differences between the data sets for sulphadimidine and spot caffeine samples. Correlation between the two urine collection periods for caffeine was poor. 4. The complex metabolism of caffeine may compromise its value as a probe for determining acetylator phenotype until the effects of important variables are better understood.

Adult↗

PubMed1995

Caffeine as a metabolic probe: a comparison of the metabolic ratios used to assess CYP1A2 activity.

1. Caffeine is widely used as an in vivo probe for CYP1A2; the distribution/activity of this enzyme is reported to be reflected by metabolic ratios. 2. Several metabolic ratios using different combinations of urinary metabolites have been used to measure CYP1A2, with varying conclusions on its distribution. 3. A mathematical comparison of five metabolic ratios claiming to reflect CYP1A2 activity was made using data from 237 healthy volunteers. 4. All five metabolic ratios were symmetrically distributed. The five ratios however, measured at least three different parameters, with no one ratio correlating exactly with any other. 5. Data in the literature claiming to measure CYP1A2 using caffeine may reflect other parameters. 6. The complex metabolism of caffeine together with different parameters controlling the renal clearance of each metabolite, makes the use of urinary metabolic ratios an inaccurate probe for assessing the distribution of CYP1A2 activity in populations.

Adolescent↗

PubMed1995

An in vitro technique for the rapid determination of drug entry into breast milk.

1. A simple in vitro technique that predicts drug transfer into breast milk is described. 2. Drugs of differing physical and chemical characteristics were tested. 3. The technique provides an experimental system for studying plasma to milk transfer with changing milk composition. 4. A mechanism proposing a role of milk proteins in controlling drug entry into milk is discussed.

Fats↗

PubMed1995

Caffeine phenotyping of cytochrome P4501A2, N-acetyltransferase, and xanthine oxidase in patients with familial adenomatous polyposis.

Patients with familial adenomatous polyposis (FAP) and age and sex matched controls were tested for cytochrome P4501A2 (CYP1A2), N-acetyltransferase, and xanthine oxidase activities using caffeine urinary metabolites as a discriminator. FAP patients showed significant underactivity of N-acetyltransferase (which inactivates some carcinogens) and significant overactivity of CYP1A2 (which activates some carcinogens). Xanthine oxidase activity, which can generate free radicals and cause cellular damage, was significantly increased in the FAP patients. All but one of the FAP patients had undergone colectomy. A separate group of six patients was therefore assessed before and at an average time of eight weeks after colectomy. No effect on enzyme activity was seen. The differences in enzyme activities detected in this study could produce an excess of active carcinogenic metabolites in the bile of FAP patients and contribute to the high risk for intestinal cancer in FAP.

Acetyltransferases↗

PubMed1994

Rapid method for the routine determination of caffeine and its metabolites by high-performance liquid chromatography.

Caffeine is a popular compound for phenotyping individuals for CYP4501A2, xanthine oxidase (XO) and N-acetyltransferase (NAT) utilising urinary metabolites. The analysis is complex since at least thirteen metabolites are excreted by man. Past methods have been less than satisfactory in that either not all the metabolites have been resolved and/or extractions selective for particular groups of metabolites are required prior to chromatography. We report a method for the rapid analysis of caffeine and metabolites in urine that negates the requirement for an extraction step, and also a method for plasma analysis.

Biotransformation↗

PubMed1991

Misoprostol does not alter the pharmacokinetics of propranolol.

Twelve healthy volunteers took part in a randomised, double-blind, balanced, cross-over study to investigate the effect of misoprostol on the pharmacokinetics of propranolol. The subjects took propranolol 80 mg twice daily by mouth plus either misoprostol 400 micrograms twice daily or placebo by mouth for 14.5 days, followed by a 2-week washout period, followed by the alternate treatment for 14.5 days. Misoprostol had no significant effect on the t/2, Cmax or AUC of propranolol either after a single dose or at steady state.

Adult↗

PubMed1990

Use of sodium aurothiomalate during lactation.

The report concerns a mother who breast fed her infant whilst receiving sodium aurothiomalate for the treatment of rheumatoid arthritis. The milk:serum concentration ratio was not constant, reflecting the non-concurrence of the concentration-time profiles of gold in milk and maternal serum after i.m. injection. Gold was detected in the infant's serum. Calculations indicate that the weight-adjusted dose to the infant exceeded that received by the mother.

Adult↗

PubMed1990

Metabolism of aspirin after therapeutic and toxic doses.

1 The urinary recovery of metabolites of aspirin (ASA) was studied in 45 volunteers who took a therapeutic dose (600 mg) of ASA by mouth and in 37 patients who took ASA in overdose. 2 The main metabolite recovered from the volunteers was the glycine conjugate, salicyluric acid (SUA), which accounted for 75.01 +/- 1.19% of total urinary metabolites, whereas salicylic acid (SA) accounted for 8.82 +/- 0.56%. Recovery of SUA was negatively correlated with that of SA (r = -0.8625, P less than 0.001). 3. In 24 patients with admission plasma salicylate concentrations of 240-360 mg l-1, SUA accounted for 46.66 +/- 3.22% and SA for 31.88 +/- 4.02%. 4. In 13 patients with admission plasma salicylate concentrations of 715-870 mg l-1, SUA accounted for 21.57 +/- 3.65% and SA for 64.72 +/- 4.82%. 5. Reduced excretion of salicylate as SUA was also accompanied by increased elimination as gentisic acid and salicylic acid phenolic glucuronide indicating that the unsaturated processes that lead to the formation of these metabolites contribute significantly (22-23%) to the inactivation of large doses of salicylate. 6. While the Michalis-Menten kinetics of ASA have been well demonstrated at lower doses, our findings illustrate the progressive saturation of SUA formation under conditions of increasing ASA load to toxic amounts and raise issues about the in-vivo glycine pool when ASA is taken in overdose.

Adolescent↗

PubMed1990

Depletion of plasma glycine and effect of glycine by mouth on salicylate metabolism during aspirin overdose.

1. The metabolism of aspirin was investigated in 45 patients who had taken self-administered overdose of aspirin and were treated with fluids only, glycine, N-glycylglycine by mouth, or by sodium bicarbonate i.v. 2. The major metabolite recovered in the urine of patients treated with oral fluids, glycine or N-glycylglycine was salicyluric acid, which accounted for means of 51%, 47% and 38% of the total, respectively; salicylic acid comprised 19%, 29% and 29%. In contrast, salicylic acid (42%) was the major urinary metabolite recovered from patients treated with sodium bicarbonate. 3. Plasma glycine concentrations in healthy volunteers who had taken no aspirin remained constant through the day and were not affected by a therapeutic dose (500 mg) of aspirin. Plasma glycine was consistently lower in patients with aspirin overdose than in these healthy volunteers, suggesting depletion of available glycine. 4. Orally administered glycine and N-glycylglycine increased plasma glycine. While the fraction of total salicylate recovered as salicyluric acid was not altered, the maximum rate of excretion of salicyluric acid was higher in patients who received glycine than in the control group; there was no significant difference in the maximum rate of excretion of salicyluric acid between the group that received glycine and the group that received N-glycylglycine. 5. The data suggest that exogenous glycine increases the rate of formation of salicyluric acid in salicylate overdose.

Administration, Oral↗

PubMed1990

Comparative metabolism of high doses of aspirin in man and rat.

1. Metabolism of aspirin was studied in 10 human volunteers who took a therapeutic dose (600 mg) by mouth and in nine patients who took aspirin in overdose. 2. Salicyluric acid was the major urinary metabolite in volunteers (63.1 +/- 8.4% of dose in 0-8 h). In overdose patients, salicyluric acid in urine was decreased (30.0 +/- 8.2%, 0-24 h, P less than 0.001) and there was increased elimination of salicyclic acid (34.1%, P less than 0.005), salicyl acyl glucuronide (14.4%, P less than 0.05) and gentisuric acid (5.3%). 3. Metabolism of orally administered 14C-aspirin in rats over a 10-fold dose range (10-100 mg/kg) resulted in excretion of 81-91% dose in urine in the first 24 h. Salicyclic acid was the major urinary metabolite (43-51% dose). Excretion of salicyluric acid decreased with increasing dose, whereas gentisic acid and salicyl phenolic and acyl glucuronides increased. 4. The profile of aspirin metabolites was qualitatively similar in man and rat but there were quantitative differences. Limited capacity to form salicyluric acid was observed in both species. Dependence on this pathway in rat was low and was compensated by increased utilization of other routes; dependence on salicyluric acid formation in man was high and in overdose, compensation by other routes was incomplete.

Adolescent↗

PubMed1988

Metabolic profiling of body fluids by proton NMR: self-poisoning episodes with paracetamol (acetaminophen).

1H NMR spectra of urine and plasma from subjects who had taken paracetamol (acetaminophen) at a therapeutic dose or in self-poisoning episodes (both fatal and nonfatal) are compared. They provide convenient metabolic profiles. For overdose cases, intense resonances corresponding to high levels of both drug and endogenous metabolites are observed. The ratios of glucuronide to sulfate conjugates are unusually high in urine from overdose cases. Elevated levels of the cysteinyl and N-acetyl cysteinyl conjugates reflect increased glutathione conjugation in the liver. The observed excretion of high levels of amino acids by overdose subjects is suggestive of drug-induced hepatic damage. No resonances for drug metabolites are detected in plasma samples. However, characteristic and abnormally intense resonances for the amino acids Phe, Tyr, His, Gln, Pro, Ala, Val, Lys, Met, Ser, and Thr are indicative of severe liver failure and disruption of normal deamination and transamination processes.

Acetaminophen↗

PubMed1988

Detecting adverse reactions to drugs.

1. Present attitudes to drug safety have been shaped largely by a series of disasters. 2. In 1937 about 107 people in the USA died of poisoning by diethylene glycol used as a vehicle for sulphanilamide which led to the requirement that all formulations must be licensed by the FDA before marketing. 3. Up to 1960 the rate of production of new drugs outstripped the ability to introduce them safely. In Germany, thalidomide, an effective sedative, had been introduced in 1956 but it was not until 1961, when an estimated 10,000 babies worldwide had been born with birth deformities, that the teratogenicity of this compound was recognized. 4. Further legislation soon followed, both reducing the number and lengthening the time required to introduce a new drug onto the market. However, problems were encountered with practolol in the 1970s and with benoxaprofen in the 1980s, the latter highlighting the need to make special provision for drug use in the elderly. 5. As to the future, more attention will be paid to the special needs of children and to the possible effects of genetic differences in metabolism.

Abnormalities, Drug-Induced↗

PubMed1988

Potential drug interactions with misoprostol: effects on the pharmacokinetics of antipyrine and propranolol.

First, the pharmacokinetics of antipyrine were studied in 12 healthy male and female volunteers (i) before misoprostol, (ii) after they had received misoprostol 400 micrograms twice daily for 28 days and (iii) after a further 28 days during which no misoprostol was taken. The plasma half-life and area under the plasma concentration-time curve of antipyrine were unchanged. The findings suggest that misoprostol is not an hepatic enzyme inducer. Second, 12 healthy male and female volunteers took propranolol 80 mg twice daily for four weeks; during the second and third of these weeks the volunteers also took misoprostol 400 micrograms twice daily. The plasma concentrations of propranolol under these steady state dosing conditions increased when misoprostol was added to propranolol. The mechanism underlying this finding should be clarified.

Adult↗

PubMed1987

Passage of paracetamol into breast milk and its subsequent metabolism by the neonate.

1 Paracetamol was administered to nursing mothers. The drug passed rapidly into milk and the milk:plasma concentration ratio was approximately unity. 2 The estimated maximum dose to the neonate was 1.85% of the weight-adjusted maternal oral dose of paracetamol 1.0 g. Recovery of paracetamol was greater from the breast from which samples were taken frequently than from the breast which was sampled only once. 3 Paracetamol, its glucuronide, sulphate, cysteine and mercapturate conjugates were found in the urine of the neonates although only the parent drug was detected in breast milk. 4 The neonates excreted significantly greater proportions of unchanged paracetamol (P less than 0.01) and significantly lesser proportions of paracetamol sulphate (P less than 0.001) than did healthy volunteers aged 11-80 years who received a therapeutic dose of paracetamol. 5 The findings are compatible with a deficiency of sulphate conjugation by the neonate.

Acetaminophen↗

PubMed1985

Single-dose pharmacokinetic and pharmacodynamic comparison of polymer-matrix (Slow Trasicor) and Oros dosage forms of oxprenolol in healthy volunteers.

Oxprenolol was administered in single doses by mouth to healthy volunteers either in a polymer-matrix slow-release formulation (Slow Trasicor) or in osmotic drug-delivery systems (oxprenolol Oros). Plasma oxprenolol concentrations and heart rates after exercise were measured. Plasma concentrations of the drug were maximal at 3 h but negligible at 24 h after administration of Slow Trasicor. Following ingestion of the Oros systems measurable concentrations were maintained throughout 24 h. Significant reduction of exercise-induced tachycardia persisted for 24 h after administration of oxprenolol Oros. With Slow Trasicor heart rate responses had returned to baseline values by this time. The osmotic drug-delivery systems appear to sustain significant beta-adrenoceptor blockade for 24 h after a single oral dose.

Adult↗

PubMed1985

Digoxin and cimetidine: investigation of the potential for a drug interaction.

The potential for a pharmacokinetic interaction between digoxin and cimetidine was investigated in a series of studies. In a single-dose cross-over study in healthy volunteer subjects cimetidine increased the area under the plasma digoxin concentration curve and the peak plasma digoxin concentration. In a repeated-dose study in healthy volunteer subjects taking digoxin 0.25 mg daily, co-administration of cimetidine resulted in an average increase in plasma digoxin concentration of 0.15 ng/ml. In a repeated-dose study in healthy volunteer subjects taking digoxin 0.5 mg daily, co-administration of cimetidine resulted in an average increase in plasma digoxin concentration of 0.19 ng/ml. In a repeated-dose study in patients receiving long-term digoxin therapy for atrial fibrillation co-administration of cimetidine had no significant effect on plasma digoxin concentrations. We have shown that co-administration of cimetidine and digoxin in volunteer subjects causes a statistically significant but small increase in plasma digoxin concentration but no such increase was found in patients. We conclude that it is doubtful that this interaction is of any clinical significance.

Adult↗

PubMed1984

European Ethical Review Committee: the experience of an international ethics committee reviewing protocols for drug trials.

An international ethics review committee, founded seven years ago, has several unusual features: it selects its own members, who are independent of the drug industry; it includes members with no medical or paramedical background, such as lay people and lawyers; and it reviews protocols together with the study's sponsor. Membership of 31 from nine European countries enables frequent meetings and there is a full meeting of the committee every year to review progress and consider policy. Of the first 294 protocols for phase I, II, or III trials reviewed, 37 were admitted outright, 243 were amended (usually during the discussion of the protocol), and 14 were rejected. It is suggested that, to overcome the problem of ethics review in smaller institutions, regional health authorities in Britain might consider establishing similar committees.

Clinical Trials as Topic↗