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Biomedical subjects

M L Orme

Publications and source records attributed to M L Orme.

At least 91 records · Page 5Linked to original sources
PubMed1981

Oral contraceptive steroid plasma concentrations in smokers and non-smokers.

A study was performed to find out whether the overall rate of metabolism of oral contraceptives is affected by smoking and whether this explains the increased incidence of cardiovascular disease in users of oral contraceptives who smoke. Plasma ethinyloestradiol and norgestrel concentrations in 311 women using oral contraceptives were similar in smokers and non-smokers. The overall rate of metabolism of contraceptive steroids does not therefore seem to be affected by cigarette smoking.

Adult↗
PubMed1981

The pharmacokinetics of levonorgestrel and ethynylestradiol in women - studies with Ovran and Ovranette.

A radioimmunoassay for levonorgestrel (Ng), which is applicable to plasma samples obtained from women who have taken a combination type oral contraceptive, has been developed and fully validated. Plasma concentrations of Ng rise to a peak of 3.6 ng/ml after an oral dose of 150 microgram and to 5.0 ng/ml after a 250 microgram dose. Following the intravenous administration of Ng, plasma concentrations of the steroid decline bi-exponentially with mean half-lives of 0.76 and 11.55 hours. Comparison of the results of the intravenous and oral administration of the steroid show a mean systemic bioavailability of 89% after the 150 microgram dose and 99% after a 250 microgram dose. This difference was not statistically significant. The values for volume of distribution were approximately half and the values for plasma clearance three times less than that previously reported for norethindrone. The plasma ethynylestradiol levels were also measured following administration of 30 microgram both intravenously and orally. The bioavailability and kinetics were similar to that previously reported for a 50 microgram dose. The peak values after oral dosing were 103 pg/ml and were reached by 1.0 hour in all subjects.

Adult↗
PubMed1981

Studies on the enzymatic cleavage of norethisterone oenanthate.

Norethisterone oenanthate (NET OEN) was extensively hydrolysed in rabbit, rat and guinea pig plasma (99.9%, 76.1% and 46.0% hydrolysed in 90 min, respectively). In contrast, there was negligible hydrolysis (less than 2.5%) in dog, goat and human plasma. Rabbit liver, kidney, gut wall, stomach, heart and muscle showed marked hydrolytic activity in vitro, but there was little hydrolysis of NET OEN by either human muscle or fat. It is proposed that following intramuscular administration of NET OEN to rabbits, the ester is rapidly hydrolysed at the injection site and in the circulation whereas in humans the liver is the main site of hydrolysis since neither muscle nor plasma cause significant breakdown of the ester. The rabbit is not a good model for predicting the pharmacokinetics of NET OEN in humans.

Adipose Tissue↗
PubMed1981

Diethylcarbamazine disposition in patients with onchocerciasis.

Diethylcarbamazine (DEC), 0.5 mg/kg, was taken orally by six patients being treated for onchocerciasis. Blood samples were taken at timed intervals for 48 hr and urine and feces collected for 4 days. Plasma and urinary concentrations of DEC and DEC N-oxide were measured by gas-liquid chromatography. DEC appeared to be rapidly absorbed, with a peak plasma concentration of 150 to 250 ng/ml reached in 2 to 3 hr. There was a secondary rise in plasma DEC concentration at 5 to 6 hr in all patients. In contrast to the way the drug is eliminated in rats, in man it was by both renal and extrarenal routes, with small amounts (+/- 10%) being excreted as an N-oxide metabolite. DEC kinetics were also investigated in five normal subjects and the result were much the same. Clinical implications are discussed.

Adult↗
PubMed1981

The in vitro metabolism of ethinyloestradiol, mestranol and levonorgestrel by human jejunal mucosa.

1 Ethinyloestradiol was extensively metabolised in vitro by human jejunal mucosa to form ethinyloestradiol sulphate. 2 The amount of conjugation was directly related to the weight of biopsy tissue. 3 The degree of conjugation of mestranol and levonorgestrel was much lower than for ethinyloestradiol suggesting that the 17-position of the steroid nucleus is relatively inaccessible for conjugation. 4 No Phase I metabolism of ethinyloestradiol or levonorgestrel was apparent in the conditions used in these experiments.

Adult↗
PubMed1981

The effect of variations in urinary pH on the pharmacokinetics of diethylcarbamazine.

1 The partitioning of diethylcarbamazine (DEC) between octan-1-ol and aqueous buffer was shown to be dependent upon the pH of the buffer. 2 Buccal absorption of DEC in five subjects was shown to increase with increasing pH. 3 In view of these findings, the disposition of DEC was investigated in the same five subjects following the oral administration of 50 mg DEC citrate on two occasions. 4 The elimination half-life (T1/2) of DEC and the area under the plasma concentration v time curve (AUC) were significantly increased when an alkaline urinary pH was maintained compared with the values of these parameters obtained on a second occasion when an acidic urinary pH was maintained. Renal clearance and total urinary excretion of DEC were significantly less at alkaline urinary pH than under acidic conditions. 5 The clinical significance of these observations is discussed both with respect to dose modification under conditions of changing urinary pH and the possibility of the manipulation of urinary pH in order to produce more effective dosage regimens.

Absorption↗
PubMed1981

Studies of metrifonate in onchocerciasis.

Metrifonate has been studied in the treatment of infections with Onchocerca volvulus in West Africa. In doses of 10 mg/kg daily for six days, metrifonate was effective against the microfilariae but produced unpleasant reactions due both to the death of the microfilariae and to the muscarinic effects of the drug. In a comparison of 10 mg/kg metrifonate, for 3 doses at 10 day intervals, with diethylcarbamazine (D.E.C.) in a total dose of 6.6 g, metrifonate was significantly less effective than D.E.C. in killing microfilariae but produced significantly fewer adverse effects. In a final study comparing metrifonate 10 mg/kg/day given for 3 or for 6 days there was little difference in their therapeutic effect. However, metrifonate 10 mg/kg given for 6 days produced more severe adverse reactions due largely to the muscarinic and nicotinic effects of acetylcholine and these effects were not prevented by the administration of belladonna alkaloids. Metrifonate 10 mg/kg given for 3 doses at 10 day intervals is effective in the treatment of onchocerciasis but is unlikely to replace diethylcarbamazine. Metrifonate has no action on the adult worms.

Acetylcholine↗
PubMed1981

Interindividual variation and drug interactions with hormonal steroid contraceptives.

Large interindividual differences occur in the plasma concentration of contraceptive steroids. With the present tendency to decrease the dose of progestagen and oestrogen any factor which reduces the bioavailability of the lower dose preparations becomes very important. The possibility that other drugs and environmental chemicals may interact with contraceptive steroids is currently being investigated. Clinical reports suggest that the most important interacting drugs are the antituberculosis agent rifampicin, anticonvulsants and antibiotics. In the case of the first two, evidence is available suggesting that microsomal enzyme induction, either in the liver or the gut wall, is the operative mechanism. Antibiotics interfere with the pharmacokinetics of contraceptive steroids by interfering with their enterohepatic circulation in animal species: whether this is operative in man is still unclear. Other environmental and constitutional factors such as smoking, variations in diet, and concurrent disease may alter the disposition of contraceptive steroids and affect response accordingly. Additional studies are needed to estimate the significance of such interactions.

Anti-Bacterial Agents↗
PubMed1980

Influence of environmental chemicals on drug therapy in humans: studies with contraceptive steroids.

The effects have been studied of various environmental factors on the variability in response to oral contraceptive steroid therapy in women. Ten- to thirty-fold variations in plasma concentrations of norethisterone, L-norgestrel and ethinyloestradiol have been shown in samples taken 12 h after administration of oral contraceptives in mid-menstrual cycle. Factors shown to be responsible for this variation include passage into the enterohepatic circulation, a variable first-pass effect, and changes in metabolism in the gut wall or liver due to diet, disease, smoking or administration of drugs. Phenobarbitone and the antibiotic rifampicin increase both oestrogen and progestogen metabolism in women and in experimental animals by increasing hepatic and gut wall metabolism. In animals, other antibiotics (ampicillin, neomycin and lincomycin) suppress the gut flora that normally hydrolyse steroid conjugates excreted in bile; enterohepatic circulation or oral contraceptive steroids is thus reduced and their plasma concentrations lowered by up to 90%. In the human, ampicillin has a variable but less dramatic effect on elimination of oral contraceptives. Samples of gut wall mucosa obtained from patients with coeliac disease are defective in their ability to metabolize oral contraceptives. Cigarette smokers eliminate ethinyloestradiol more rapidly than non-smokers; an increased production of reactive steroid metabolites may thus be a cause of vascular disease in women who smoke and take contraceptive steroids.

Animals↗
PubMed1980

The effect of rifampicin on the pharmacokinetics of ethynylestradiol in women.

A single dose of Minovlar (50 microgram ethynylestradiol (EE) and 1 mg norethindrone acetate) was given to seven women during treatment with rifampicin (450-600 mg/day) and again one month after stopping rifampicin. Blood samples were taken at intervals over a 24-hour period. The area under the plasma EE versus time curve increased significantly on stopping rifampicin from 1014 +/- 317 pg/ml x h (mean +/- SE) to 1747 +/- 218 pg/ml x h (p less than 0.01). The terminal plasma half-life increased from 2.9 +/- 0.8 h to 6.3 +/- 1.4 h (p less than 0.005). The sex hormone binding globulin (S.H.B.G.) capacity was also reduced from 213.4 +/- 11.5 nmoles to 129.0 +/- 7.7 nmoles/1 after stopping rifampicin. In one patient starting rifampicin who was taking Minovlar as a long-term oral contraceptive, a fall in the plasma EE concentration was associated with a rise in the plasma follicle stimulating hormone concentration. These effects of rifampicin on EE pharmacokinetics are consistent with induction of the microsomal enzymes that metabolise EE.

Adolescent↗
PubMed1980

The pharmacokinetics of a large (3 mg) oral dose of ethynylestradiol in women.

Plasma levels of ethynylestradiol (EE), EE sulphate (EES), EE glucuronide (EEG) and prolactin were measured in women up to 72 h following the oral administration of 3 mg of EE. The decline in plasma EE levels showed a sharp discontinuity at 10 h which is assumed to be due to the beginning of enterohepatic circulation (EHC). After this event, an apparently terminal monoexponential decline was eventually established with a half-life of 13.1 h. As a result of EHC, the volume of distribution was increased by 60% to 6.0 1.Kg-1 but it does not appear that any significant accumulation of EE would occur during multiple dosing. Plasma levels of EES were, on average, 22.5 times greater than those of EE and this circulating metabolite may act as a reservoir of EE. No circulating EEG could be detected. Comparing these results with those previously obtained with 50 microgram EE, there was no evidence of dose dependency in the pharmacokinetics of this steroid. Plasma prolactin levels were markedly enhanced by this single dose of oestrogen.

Adult↗