Pa Meredith

A retrospective analysis of blood-lead in mentally retarded children.

Blood-lead concentrations were measured retrospectively in the blood contained on cards used for testing for phenylketonuria in the first two weeks of life. Cards which belonged to 80 of a group of 77 children with mental retardation of unknown aetiology and 77 controls were identified. Of 77 usable cards, 41 were from mentally retarded children and 36 were from controls; 24 mental-retardation/control pairs were found. There was a highly significant trend towards higher blood-lead concentrations in the mentally retarded children. Water-lead concentrations in the maternal home during pregnancy correlated with blood-lead concentrations in the mentally retarded children. These results reinforce the probable association between lead exposure during pregnancy and the development of mental retardation of otherwise unknown aetiology.

Blood pressure variability and its implications for antihypertensive therapy.

Although it is clear that antihypertensive treatment is beneficial in reducing stroke morbidity and mortality, the results of the major outcome studies show less impact on coronary heart disease. Studies utilizing 24-h blood pressure (BP) monitoring show a positive association between target organ damage and the level of 24-h BP, and with variability in BP, which is an independent determinant of target organ damage. Current understanding of the pathogenesis and pathophysiology of coronary heart disease suggests that optimal antihypertensive treatment should ensure the following: effective 24-h BP control, smooth antihypertensive effect with reduced variability; attenuation of the early morning surge in BP; maintenance of the normal circadian pattern of BP; effective therapeutic coverage in the face of suboptimal compliance; and lack of reflex activation of the sympathetic nervous system. On the basis of our current understanding, this optimum is most likely to be achieved by the use of antihypertensive agents with a long duration of action.

Hepatic drug metabolism and haem biosynthesis in lead-poisoned rats.

1 Pretreatment of rats with intraperitoneal injections of lead was shown to result in a depression of the microsomal mixed function oxidase system, as assessed by a decrease in hepatic microsomal P‐450 and b5 content and by a decrease in the activity of the enzymes aniline hydroxylase and aminopyrine demethylase. Lead had a more marked effect on cytochrome P‐450 than b5. 2 The activity of the rate‐limiting enzyme of haem biosynthesis, δ‐aminolaevulinic acid synthase, was inversely correlated with the microsomal cytochrome P‐450 content. 3 The activity of the haem biosynthetic enzymes δ‐aminolaevulinic acid dehydratase, coproporphyrinogen oxidase and ferrochelatase were decreased by increasing lead pretreatment. 4 The activity of the haem catabolic enzyme, haem oxygenase, was increased by lead pretreatment.

The effects of industrial lead poisoning on cytochrome P450 mediated phenazone (antipyrine) hydroxylation.

SummaryIn a group of ten male adults admitted to hospital with clinical symptoms of lead exposure, phenazone elimination rates, blood δ-amino-laevulinic acid dehydratase (ALA.D) activity, blood lead levels and haemoglobin were measured. Investigations were carried out before, immediately after and again at least 12 weeks after cessation of CaEDTA (sodium calcium edetate) chelation therapy. Following chelation, phenazone elimination rates were increased as assessed by a decrease in half life and increase in clearance. This was significant, both immediately after and 12 weeks after cessation of chelation therapy. The change in rate of phenazone metabolism was associated with improved clinical status, with lowered blood lead levels and raised haemoglobin and ALA.D activity. The results of the study suggest that the depression in phenazone elimination in lead intoxication is possibly due to depressed hepatic cytochrome P450 levels.

Lead exposure and renal failure: Does renal insufficiency influence lead kinetics?

Blood and urine lead concentrations have been measured in 40 subjects with normal and impaired renal function. Derived renal lead clearance varied widely, but was not influenced by the degree of renal impairment. Lead, however, appeared to reduce its own clearance. These findings provide additional evidence of nephrotoxicity from sub-clinical lead exposure.

Changes in serum aluminium, blood zinc, blood lead and erythrocyte δ-aminolaevulinic acid dehydratase activity during haemodialysis

Abstract In a study of 18 patients on haemodialysis, erythrocyte δ-aminolaevulinic acid dehydratase (ALAD), serum aluminium, blood zinc and blood lead concentrations were increased significantly following haemodialysis. The increase in erythrocyte ALAD activity was found to be significantly linearly correlated with the increase in blood zinc concentrations. In comparison with control subjects, the patients had significantly lower activities of ALAD and significantly increased serum aluminium concentrations. When zinc and lead concentrations were corrected for packed cell volume they were found to be significantly higher in the patient group than in the control group.

Kinetics of lead following intravenous administration in man

Whole body retention of lead (Pb) and lead kinetics in blood, urine and faeces were determined over 2 weeks following i.v. administration of 203Pb-labelled chloride to 2 subjects. Pb was retained with a biological half-life of 73 days (mean). After day 1 Pb excreted in urine and faeces remained fairly constant at 1% and 0.3% of administered dose, respectively. There was a daily loss of 0.5% by other routes. There was a rapid clearance of isotope from plasma with a half-life of 1 min (mean). At 60 min 45% of the administered dose was in erythrocytes; this changed little over the 2 weeks.

The determination of trimazosin and its metabolite CP23445 in whole blood by high performance liquid chromatography using fluorescence detection

A sensitive and specific assay for trimazosin and its metabolite CP23445 is described. The method employs reverse-phase high performance liquid chromatography (HPLC) with fluorescence detection. The limit of detection of the assay is 1 ng/ml whole blood for trimazosin and 0.5 ng/ml for CP23445. The coefficient of variation for trimazosin and CP23445 over a typical calibration size is 5.4% and 4.9%, respectively. Various drugs that may be coadministered with trimazosin are shown not to interfere in the assay. The method has been extensively employed to study the pharmacokinetics of trimazosin and CP23445, both in man and in animals.

Prediction and Optimisation of the Antihypertensive Response to Nifedipine

The predictability of the long term antihypertensive response to nifedipine in individual patients has been assessed by an analysis based upon the concentration-effect parameters defined following the first dose administration of 20 mg nifedipine (Retard). The predicted and measured reductions in blood pressure during steady state nifedipine treatment were compared for the trough and peak responses and there was reasonable agreement for the group of patients as a whole. However, when the measured and predicted blood pressure profiles were compared for each individual patient there was close agreement for the majority of patients but there were significant discrepancies in a few cases. Further analysis of the steady state concentrations in these cases revealed that there was no change in their responsiveness to nifedipine and that discrepancies were directly attributable to inappropriate compliance with the drug regimen. The analysis was further extended to simulate the blood pressure responses to alternative fixed dosage regimens. Assessment of these simulations suggests that blood pressure control with nifedipine Retard is significantly improved by three times daily drug administration.

The effect of cimetidine on the pharmacokinetics, pharmacodynamics and alpha1-adrenoceptor responsiveness of trimazosin in man

SummaryThe effect of cimetidine treatment on the pharmacokinetics and pharmacodynamics of single doses of trimazosin was studied in 6 normotensive volunteers. Co-administration of cimetidine did not significantly affect the overall magnitude of the hypotensive effect of trimazosin. However, the time profile of the blood pressure response was significantly modified particularly with attenuation of the delayed component. Co-administration of cimetidine did not alter alpha1-adrenoceptor antagonism by trimazosin.There was no significant change in the clearnace and volume of distribution of trimazosin but there was a significant reduction in the area under the concentration-time curve for the metabolite, 1-hydroxytrimazosin.The reduction in the AUC of 1-hydroxy-trimazosin corresponds in time with the attenuation of the delayed hypotensive response. This is consistent with the suggestion that the delayed hypotensive response is related to an active metabolite, probably 1-hydroxytrimazosin.