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Biomedical subjects

G Edwards

Publications and source records attributed to G Edwards.

At least 289 records · Page 16Linked to original sources
PubMed1986

The effect of moderate urine alkalinisation on low dose diethylcarbamazine therapy in patients with onchocerciasis.

Twenty-one patients with moderate to heavy infections with O. volvulus were treated with 25 mg of diethylcarbamazine (DEC) citrate twice daily for 10 days. In 11 patients the urine was made alkaline with sodium bicarbonate, 2 g, administered 6 hourly for three doses daily beginning 1 day before DEC was started and continued throughout the DEC therapy. Ten patients served as controls. The mean pre-dose plasma DEC concentration during treatment and the mean plasma DEC half-life were significantly higher in bicarbonate treated patients as compared to controls. Total urinary excretion of DEC was significantly less in the bicarbonate treated group than in controls. Mean overall total reaction was higher in bicarbonate-treated patients but the difference was not significant. The bicarbonate-treated group achieved a significantly greater reduction in skin microfilarial counts than the control group as assessed 1 week after completion of therapy, but there was little difference at 1 month. Microfilarial killing was associated with microfilarial mobilisation, alteration in peripheral leucocytes and elevation in serum aminotransferases in both groups. There was no effect of DEC on the number of adult worms recovered in nodules removed at the end of the therapy. This study indicates that moderate urinary alkalinisation alters the kinetics of DEC and the therapeutic response. However the severity of clinical reaction coupled with the inadequate level of microfilarial killing achieved make it unlikely that manipulation of urinary pH will be of practical value in onchocerciasis chemotherapy.

Adolescent↗
PubMed1986

The pharmacokinetics of pyrimethamine in the rat: effect of mefloquine.

The pharmacokinetics and tissue distribution of pyrimethamine have been determined in the rat. Following administration of pyrimethamine alone, drug concentrations declined biexponentially. By contrast, in the presence of mefloquine, the decline in pyrimethamine concentration more closely fitted a monoexponential pattern and the AUC0-6h for pyrimethamine was significantly reduced. Significantly more pyrimethamine was recovered from the livers but less from the lungs of the mefloquine-dosed rats compared with control. This study outlines a potentially clinically relevant drug interaction.

Animals↗
PubMed1986

A comparison of drug-related problems in London Accident and Emergency Departments 1975-1982.

Drug-related incidents dealt with by ten Accident and Emergency departments in Greater London during July 1982 were compared with those obtained from an identical survey in 1975. The number of incidents remained high, but there was a significant reduction in them and in the number of drug dependent attenders, compared with 1975: hypnotic drugs were used in a significantly smaller percentage of drug overdoses, but there was increased use of minor tranquillisers. The possibility of using A & E departments to monitor drug misuse on a Regional basis is discussed.

Adolescent↗
PubMed1985

The disposition of pyrimethamine in the isolated perfused rat liver.

We have investigated the disposition of pyrimethamine base in the isolated perfused rat liver (IPRL) preparation after the administration of pyrimethamine (0.5 mg, 5 microCi). In the first half hour of the study, pyrimethamine underwent marked hepatic uptake, thereafter perfusate plasma drug levels declined monoexponentially with a half life (t 1/2) of 3.0 +/- 1.0 hr. Area under the perfusate plasma concentration/time curve (AUC)0----infinity was 6.9 +/- 1.9 microgram/hr/ml. Pyrimethamine was found to be a low clearance compound (78.4 +/- 25.3 ml/hr identical to 8.6% of liver perfusate flow) with a large volume of distribution (267.5 +/- 55.3 ml) in the IPRL. The combined AUCS(0----5hr) for pyrimethamine (AUC 4.8 +/- 0.5 microgram/hr/ml) and pyrimethamine 3-N-oxide (AUC0----5hr 0.9 +/- 0.6 microgram/hr/ml) accounted for 57% of the total AUC0----5hr of [14C] radioactivity (10.0 +/- 2.6 micrograms/hr/ml). This indicates the presence of metabolites of pyrimethamine as yet unidentified in the perfusate. Biliary excretion of [14C] during the course of the IPRL preparations was extensive (29.0 +/- 10.3%) though only a small proportion was due to pyrimethamine and the 3-N-oxide metabolite. The majority of radioactivity in the bile was attributable to highly polar, but unidentified metabolites of pyrimethamine. At the conclusion of each experiment (5 hr), a significant proportion of [14C] radioactivity was recovered from the livers (22.9 +/- 5.3%). Subsequent HPLC analysis of the liver tissue indicated this to be unchanged pyrimethamine, with trace levels of the 3-N-oxide metabolite. Sub-cellular fractionation of the homogenized livers revealed the most pronounced localisation of pyrimethamine to be in the lipid rich 10,000 g pellet (13.0 +/- 2.6%), the remainder being distributed equally between the 105,000 g pellet and supernatant. Neither pyrimethamine, [14C] radioactivity, nor pyrimethamine 3-N-oxide were extensively taken up by red cells throughout the study. Therefore, the large volume of distribution (267.5 +/- 55.3 ml) underlines the extent of pyrimethamine localisation in the liver.

Animals↗
PubMed1985

Deaths of drug addicts in the United Kingdom 1967-81.

A search of the Home Office index of notified drug addicts identified 1499 deaths during 1967-81, of which 226 (15%) were of therapeutic addicts--that is, patients who had become addicted during medical treatment with a notifiable drug--and 1273 (85%) were of non-therapeutic addicts. The crude mortality fell from 23.5/1000/year for the period 1968-70 to 18.4/1000/year for 1978-80. Altogether 416 addicts aged under 50 at notification died after 1972, which was 16 times the number of deaths expected in a population with a similar age and sex composition. A more detailed examination of the cohorts of addicts notified each year showed little variation between them in the first two years of follow up. Nineteen addicts (1.6%) had died by 31 December of the year of their notification and 39 (3.3%) one year later. These figures may be an indication of the clinical course of addiction. Most deaths of non-therapeutic addicts in which a drug was implicated (939 cases (74%] were due to medically prescribed drugs--barbiturates at first and later opiates such as dipipanone hydrochloride and dextromoramide. Heroin was implicated in only 65 (7%) of these deaths. The Home Office index is a valuable source for identifying drugs of abuse and serious problems of addiction. The fact that prescribed drugs are causing the death of so many addicts demands a response from the medical profession.

Actuarial Analysis↗
PubMed1985

The effects of primaquine stereoisomers and metabolites on drug metabolism in the isolated perfused rat liver and in vitro rat liver microsomes.

The effect of the antimalarial drug primaquine, its stereoisomers and its proposed metabolites, on the metabolism of substrates for mixed function oxidase, has been studied in isolated perfused rat livers (IPRL) and/or in vitro microsomal suspension. Following acute administration to an IPRL preparation, racemic primaquine produced a dose related reduction in the hepatic clearance of antipyrine which at the highest dose of primaquine (5.0 mg) represented a decrease to 46% of control values. Antipyrine clearance was reduced to a comparable extent by the (+) and (-) isomers and the racemic mixture (each at a dose of 2.5 mg) with mean reductions of 45, 49 and 47%, respectively. These changes in clearance were reflected by significant increases in half-life relative to control. The apparent volume of distribution of antipyrine was unchanged in all experiments. Racemic primaquine and its (+) and (-) isomers were equipotent in inhibiting aminopyrine N-demethylase activity, producing reductions of 56, 59 and 55%, respectively, relative to control values. These three compounds also produced corresponding reductions of 73, 58 and 73% in ethoxyresorufin O-deethylase activity. The N-acetyl and 5-hydroxy derivative of primaquine produced inhibitory effects comparable to that seen for the parent drug. In contrast the carboxylic acid metabolite of primaquine, 6-desmethylprimaquine and 5-hydroxy-6-desmethyl primaquine did not influence aminopyrine N-demethylase activity. These results indicate that the propensity to inhibit drug metabolism by these primaquine related substances, is influenced by functional group substitution rather than the optical activity of the parent drug.

Animals↗
PubMed1985

Relevance and utility of courses in medical ethics. A survey of physicians' perceptions.

In the last decade the teaching of medical ethics has become almost universal in American medical schools. Its effectiveness is, however, just beginning to be evaluated. A stratified random sample of 3,000 practicing physicians who were graduated between 1974 and 1978 was surveyed to evaluate their perceptions of the utility and relevance of medical ethics teaching. Those who had courses in medical ethics perceived it to be of substantial benefit in confronting the actual ethical issues they encountered in daily practice. They favored the continuation and expansion of the teaching of medical ethics and had suggestions for its improvement. Data were also obtained on the relative frequency of specific ethical issues in practices and on the relative influence of home, personal values, medical education, medical practice, and ethics courses on respondents' approaches to ethical issues.

Attitude of Health Personnel↗
PubMed1985

Paradigm shift or change in ownership? The conceptual significance of D.L. Davies's classic paper.

D.L. Davies's paper on 'Normal drinking in recovered alcohol addicts' was published in 1962 (Q.J. Stud. Alcohol, 23, (1962) 94). The 18 commentaries on this report which were published shortly afterwards in the Quarterly Journal of Studies on Alcohol are analysed in terms of the perceived relevance of his findings for clinical practice. This initial and largely negative appraisal of the import of Davies's article is contrasted with later assessments which have seen this study as contributing to a crucial paradigm shift. The question is raised as to whether the concept of paradigm shift can be applied satisfactorily to a field where several different scientific disciplines are defining the nature of the problem, or whether alternatively or in addition the story should be understood in terms of a competition between medicine and psychology for 'ownership' of addiction.

Alcohol Drinking↗
PubMed1985

Pharmacokinetics of primaquine in man. I. Studies of the absolute bioavailability and effects of dose size.

The pharmacokinetics of primaquine have been examined in five healthy volunteers who received single oral doses of 15, 30 and 45 mg of the drug, on separate occasions. Each subject received an i.v. tracer dose of [14C]-primaquine (7.5 microCi), simultaneously with the 45 mg oral dose. Absorption of primaquine was virtually complete with a mean absolute bioavailability of 0.96 +/- 0.08. Elimination half-life, oral clearance and apparent volume of distribution for both primaquine and the carboxylic acid metabolite were unaffected by either dose size, or route of administration. The relationships between area under the curve and dose size were linear for both primaquine (r = 0.99, P less than or equal to 0.01) and its carboxylic acid metabolite (r = 0.99, p less than or equal to 0.01). The mean whole blood to plasma concentration ratios were determined for primaquine (0.81), and for the carboxylic acid metabolite of primaquine (0.84). Primaquine is a low clearance compound (CL = 24.2 +/- 7.4 l h-1), is extensively distributed into body tissues (V = 242.9 +/- 69.5 l) and is not subject to extensive first pass metabolism.

Adult↗
PubMed1985

Pharmacokinetics of primaquine in man. II. Comparison of acute vs chronic dosage in Thai subjects.

We have investigated the pharmacokinetics of primaquine after acute and chronic administration of the drug to five healthy Thai volunteers. After acute dosage (15 mg p.o.) mean (+/- s.d.) peak plasma concentrations of 65.0 +/- 34.7 ng ml-1 were achieved within 2 +/- 1h. Thereafter plasma drug concentrations declined monoexponentially with a mean elimination half life of 4.4 +/- 1.4 h. The mean (+/- s.d.) oral clearance was 37.6 +/- 15.5 1 h-1. These values are in broad agreement with values obtained in healthy Caucasians after administration of an equivalent dose of primaquine. Repeated dosing with primaquine had no effect on the mean pharmacokinetic parameters calculated for this drug. In contrast, individual pharmacokinetic parameters for some subjects exhibited gross and unpredictable changes after chronic dosage. The carboxylic acid metabolite of primaquine accumulated in plasma after repeated dosing such that by day 14 of chronic dosing the mean AUC (0,24) for this metabolite was 74% greater than that obtained after acute administration of primaquine.

Humans↗
PubMed1985

The sustained release of pyrimethamine base or pyrimethamine pamoate from a biodegradable injectable depot preparation in mice.

The pharmacokinetics and mass fate in mice, of pyrimethamine (425 mg kg-1 s.o.) administered subcutaneously either as the base (BASE) or the pamoate salt (PAM) in an injectable oil mixture (benzyl benzoate-peanut oil 50:50 v/v) have been evaluated. Maximum measured plasma pyrimethamine levels after BASE were attained within 24 h, and were twice as high as after PAM. 25% of animals dosed with BASE died; among the survivors plasma drug levels fell rapidly below the minimum inhibitory concentration (MIC) for Plasmodium berghei (100-200 ng ml-1) by 5 weeks. In contrast, no mice dosed with PAM died and plasma levels were sustained above the MIC for 13 weeks, drugs still being detectable in plasma after four months. Overall, there was no significant difference between areas under the curve from zero time to the time of the final sampling of pyrimethamine following PAM or BASE. The rapid initial elimination of 14C-radioactivity (2.64 +/- 0.47% dose day-1 over 4 weeks) seen after dosage with [14C]BASE reflected the plasma disposition of pyrimethamine in the mice dosed with BASE. 90% of the excreted 14C was eliminated by one month by which time less than 1% (0.03 +/- 0.02%) of the [14C]BASE was recovered from the injection site. Both BASE and [14C]BASE studies suggest that exhaustion of this preparation occurred by 7 weeks. Excretion of 14C-radioactivity after [14C]PAM was gradual and sustained with a low mean daily rate, that was maintained throughout the study i.e. 1.21 +/- 0.17% day-1 (4 weeks), 0.88 +/- 0.28% day-1 (8 weeks), 0.5 +/- 0.31% day-1 (12 weeks), 0.42 +/- 0.27% day-1 (16 weeks).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗