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Biomedical subjects

M L Orme

Publications and source records attributed to M L Orme.

At least 19 recordsLinked to original sources
PubMed1992

The in-vitro mucosal conjugation of ethinyloestradiol and the bioavailability of oral contraceptive steroids in patients with treated and untreated coeliac disease.

The ethinyloestradiol (EO2) component of oral contraceptive steroids is extensively conjugated with sulphate by the gut wall. The ability of gastrointestinal mucosa to conjugate EO2 has been examined in vitro in samples of mucosa taken from normal women as well as from women with coeliac disease. The percentage conjugation per mg dry weight for normal tissue (n = 11) was 17.1 +/- 6.4 (mean +/- s.d.) while in untreated coeliac tissue (n = 6) the figure was 6.3 +/- 3.6% (P less than 0.01). In tissue from patients with treated coeliac disease (n = 5) the figure was 12.1 +/- 3.2%. Thus the ability of intestinal mucosa to conjugate ethinyloestradiol was significantly reduced in patients with coeliac disease, and restored towards normal following treatment. However, in patients with coeliac disease the pharmacokinetics of ethinyloestradiol were not significantly different from normal controls.

Administration, Oral↗
PubMed1991

Rapid and sensitive method for the determination of albendazole and albendazole sulphoxide in biological fluids.

A sensitive and selective reversed-phase high-performance liquid chromatographic method for the determination of albendazole and its active metabolite albendazole sulphoxide in plasma has been developed. It involves single-step extraction of plasma with dichloromethane, evaporation of the solvent and chromatography on a muBondapak phenyl column with a mobile phase of water containing 1% (v/v) triethylamine-methanol-acetonitrile (70:10:20, v/v) at pH 3.1. Run time is 12 min. The assay satisfies all of the criteria required for use in clinical pharmacokinetic studies and possesses important advantages, notably speed and expense, over current methods.

Adult↗
PubMed1991

Effect of the progestogens, gestodene, 3-keto desogestrel, levonorgestrel, norethisterone and norgestimate on the oxidation of ethinyloestradiol and other substrates by human liver microsomes.

A number of different progestogens, levonorgestrel (LNG), norethisterone (NET), gestodene (GSD), desogestrel (DG) and norgestimate (NORG) are used in combination with the oestrogen ethinyloestradiol (EE2) in oral contraceptive steroid preparations. All the progestogens are acetylenic steroids and previous studies have indicated the potential of acetylenic steroids to cause mechanism-based or "suicide" inactivation of cytochrome P-450. We have compared the effects of the different progestogens on EE2 2-hydroxylation (a reaction catalyzed by enzymes from the P-450IIC, P-450IIIA and P-450IIE gene families) and also the oxidative metabolism of other drug substrates (cyclosporin, diazepam, tolbutamide) by human liver microsomes. On coincubation with EE2 as substrate, GSD, 3-keto desogestrel (3-KD, the active metabolite of desogestrel) and LNG produced some concentration-dependent inhibition of EE2 2-hydroxylation (maximum 32% inhibition at 100 microM 3-keto desogestrel). Ki values determined for GSD and 3-KD were 98.5 +/- 12.3 and 93.2 +/- 10.3 microM (mean +/- SD; n = 4), respectively. Preincubation of progestogens in a small volume (50 microliters) incubation for 30 min in the presence of an NADPH-generating system enhanced the inhibitory potential of all the steroids (at 100 microM, inhibition was for GSD 39%, 3-KD 46%, LNG 46%, NET 51% and NORG 43%). Inhibitory effects were therefore comparable and also similar to the macrolide antibiotic troleandomycin. The most marked inhibition seen was of diazepam N-demethylation and hydroxylation by GSD (71 and 57%, respectively) and 3-KD (62 and 50%, respectively). In preincubation studies involving cyclosporin as the substrate, the order of inhibitory potency was GSD greater than 3-KD greater than NET greater than LNG for production of both metabolite M17 and M21. The results of the study indicate that all the progestogens in common use have the propensity to inhibit a number of oxidative pathways but there is little evidence for one progestogen being more markedly inhibitory than others.

Contraceptives, Oral↗
PubMed1990

Gastrointestinal metabolism of contraceptive steroids.

A number of oral contraceptive steroids undergo first-pass metabolism in the gastrointestinal mucosa. Ethinyl estradiol (mean systemic bioavailability 40% to 50%) is extensively metabolized, principally to a sulfate conjugate. In vivo studies that use portal vein catheterization and the administration of radiolabeled ethinyl estradiol have shown that the fraction of steroid metabolized in the gut wall is 0.44. In vitro studies with jejunal biopsy samples or larger pieces of jejunum or terminal ileum mounted in Ussing chambers have indicated that more than 30% of added ethinyl estradiol is sulfated. The progestogen desogestrel is a prodrug that is converted to the active metabolite 3-ketodesogestrel. Substantial first-pass metabolism of desogestrel occurs in the gut mucosa, with evidence from Ussing chamber studies for the formation of the active metabolite. Another progestogen, norgestimate, is also metabolized by the gut wall in vitro of which the principal metabolite is the deacetylated product, norgestrel oxime. It seems very likely that this will also occur in vivo. Drug interactions occurring in the gut wall have been reported with ascorbic acid (vitamin C) and paracetamol.

Aged↗
PubMed1990

Factors affecting the enterohepatic circulation of oral contraceptive steroids.

Oral contraceptive steroids may undergo enterohepatic circulation, but it is relevant for only estrogens, because these compounds can be directly conjugated in the liver. Animal studies show convincing evidence of the importance of the enterohepatic circulation, but studies in humans are much less convincing. The importance of the route and the rate of metabolism of ethinyl estradiol are reviewed. Some antibiotics have been reported anecdotally to reduce the efficacy of oral contraceptive steroids, but controlled studies have not confirmed this observation. Although gut flora are altered by oral antibiotics, the blood levels of ethinyl estradiol are not reduced, and one antibiotic at least (cotrimoxazole) enhances the activity of ethinyl estradiol.

Anti-Bacterial Agents↗
PubMed1990

Metabolism of the contraceptive steroid desogestrel by human liver in vitro.

The metabolism of the progestogen oral contraceptive desogestrel (Dg) has been studied in vitro using human liver microsomes. Metabolites have been separated using radiometric high performance liquid chromatography and identified by co-chromatography with authentic standards and by mass spectrometry. All the livers examined (n = 6) were able to form 3-keto desogestrel as the main identifiable metabolite and also the presumed intermediates 3 alpha-hydroxydesogestrel (3 alpha-OHDg) and 3 beta-hydroxydesogestrel (3 beta-OHDg). In addition, a large polar heterogenous peak was evident on the radiochromatograms which did not co-chromatograph with any known metabolites of desogestrel. Inter-individual variability in metabolite formation was seen. A number of drugs were examined for their propensity to inhibit desogestrel metabolism. Primaquine was the most potent tested having an IC50 value (inhibitory concentration reducing overall metabolite production by 50%) of 30 microM. Cimetidine, trilostane and levonorgestrel failed to inhibit at 250 microM. With 3 alpha-OHDg as substrate, 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSDH) activity was 1.0 +/- 0.3 nmol min-1 mg-1 protein which was five times greater than the activity of the 3 beta-HSDH towards 3 beta-OHDg. Miconazole was the most potent inhibitor tested having IC50 values of 14 and 95 microM for 3 alpha- and 3 beta-HSDH respectively. Surprisingly, trilostane was without inhibitory effect on either enzyme, which contrasts with other data involving 3 beta-HSDH in steroidogenic tissue. Our observations with trilostane may reflect tissue differences in the enzyme and/or differences in endogenous vs exogenous steroids (i.e. in the conversion of 3 beta-OHDg to 3-ketodesogestrel there is no requirement for isomerization). Kinetic parameters of 3 alpha-HSDH were also determined.

Adolescent↗
PubMed1990

The disposition of amodiaquine in Zambians and Nigerians with malaria.

1. Oral amodiaquine (AQ) has been used to treat patients with symptomatic malaria in Zambia (n = 14) and Nigeria (n = 5). Clinical cure was obtained in all patients and no serious adverse drug reactions were seen. 2. As in healthy subjects, AQ achieved low plasma concentrations. Plasma concentration vs time profiles of desethylamodiaquine (AQm) from the present study did not differ from those obtained from healthy subjects. 3. In contrast to previous results from healthy subjects, the mean ratio of red cell (RBC): plasma AQm concentration in the present study was 0.80: 1 at the start of the study and rose in a linear manner (r = 0.873; P less than 0.01) to 3.04: 1 by the end (n = 10; P less than 0.01). The final mean value was similar to that seen in healthy subjects. 4. These data show that there are differences in the disposition of orally administered AQ between healthy subjects and patients with clinical malaria. The relevance of this observation to the frequency of adverse reactions to AQ in these two groups is not established.

Administration, Oral↗
PubMed1990

Pharmacokinetic drug interactions with oral contraceptives.

Oral contraceptive steroids are used by an estimated 60 to 70 million women world-wide. Over the past 20 years there have been both case reports and clinical studies on the topic of drug interactions with these agents. Some of the interactions are of definite therapeutic relevance, whereas others can be discounted as being of no clinical significance. Pharmacological interactions between oral contraceptive steroids and other compounds may be of 2 kinds: (a) drugs may impair the efficacy of oral contraceptive steroids, leading to breakthrough bleeding and pregnancy (in a few cases, the activity of the contraceptive is enhanced); (b) oral contraceptive steroids may interfere with the metabolism of other drugs. A number of anticonvulsants (phenobarbital, phenytoin, carbamazepine) are enzyme-inducing agents and thereby increase the clearance of the oral contraceptive steroids. Valproic acid has no enzyme-inducing properties, and thus women on this anticonvulsant can rely on their low dose oral contraceptive steroids for contraceptive protection. Researchers are now beginning to unravel the molecular basis of this interaction, with evidence of specific forms of cytochrome P450 (P450IIC and IIIA gene families) being induced by phenobarbital. Rifampicin, the antituberculous drug, also induces a cytochrome P450 which is a product of the P450IIIA gene subfamily. This isozyme is one of the major forms involved in 2-hydroxylation of ethinylestradiol. Broad spectrum antibiotics have been implicated in causing pill failure; case reports document the interaction, and general practitioners are convinced that it is real. The problem remains that there is still no firm clinical pharmacokinetic evidence which indicates that blood concentrations of oral contraceptive steroids are altered by antibiotics. However, perhaps this should not be a surprise, given that the incidence of the interaction may be very low. It is suggested that an individual at risk will have a low bioavailability of ethinylestradiol, a large enterohepatic recirculation and gut flora particularly susceptible to the antibiotic being used. Two drugs, ascorbic acid (vitamin C) and paracetamol (acetaminophen), give rise to increased blood concentrations of ethinylestradiol due to competition for sulphation. The interactions could have some significance to women on oral contraceptive steroids who regularly take high doses of either drug. Although on theoretical grounds adsorbents (e.g. magnesium trisilicate, aLuminium hydroxide, activated charcoal and kaolin) could be expected to interfere with oral contraceptive efficacy, there is no firm evidence that this is the case. Similarly, there is no evidence that smoking alters the pharmacokinetics of oral contraceptive steroids. These agents are now well documented as being able to alter the pharmacokinetics of other concomitantly administered drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Determination of arteether in blood plasma by high-performance liquid chromatography with ultraviolet detection after hydrolysis acid.

A reversed-phase high-performance liquid chromatographic method is described for determination of the antimalarial agent arteether in blood plasma based on its decomposition in acidic medium and measurement of the major decomposition product, which has been identified as an alpha,beta-unsaturated decalone. Linear calibration curves were obtained in the range 0-250 ng/ml arteether and the recovery of the drug from plasma was found to be quantitative. There is no interference from desoxyarteether, the putative major metabolite of arteether. The method has been applied to the measurement of arteether in the plasma of rats given 110 mg/kg by intramuscular injection of the drug as a solution in sunflower oil.

Animals↗
PubMed1989

Pharmacokinetics of halofantrine in man: effects of food and dose size.

1. Plasma concentrations of halofantrine (Hf) and its putative principal plasma metabolite desbutyl halofantrine (Hfm) have been measured in two separate studies after oral administration of the hydrochloride salt. 2. Six healthy male volunteers each received single oral doses of 250, 500 and 1000 mg administered after an overnight fast. A washout period of at least 6 weeks was allowed between each dose. A further 250 mg single oral dose was administered to the same six subjects in a fasting state and after a standardised fatty meal in a randomised study, again with a washout period of at least 6 weeks. 3. AUC and maximum plasma concentration (Cmax) for Hf increased in proportion to the dose from 250-500 mg. This increase was non-proportional when the dose was increased from 500 to 1000 mg. For Hfm, in the dose range 250-500 mg, AUC but not Cmax increased in proportion in the increase in dose size. The increase in these parameters was non-proportional when the dose was increased from 500 to 1000 mg. Time to reach peak concentrations for Hf and Hfm and the elimination half-life of Hf remained unchanged across the dosage range. 4. Following a fatty meal, Cmax for Hf was increased from 184 +/- 115 micrograms l-1 (fasting) to 1218 +/- 464 micrograms l-1 (fed). AUC for Hf was increased from 3.9 +/- 2.6 mg l-1 h (fasting) to 11.3 +/- 3.5 mg l-1 h following a fatty meal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Adverse drug reactions: a hospital pharmacy-based reporting scheme.

A pharmacy-based adverse drug reaction (ADR) reporting scheme, using pharmacists, nurses and medical practitioners as initiators of reports, was set up at the end of 1984 in the Royal Liverpool Hospital in order to encourage reporting. New reports were inspected at weekly intervals by a staff pharmacist, and a clinical pharmacologist. Reports were forwarded to the Committee on Safety of Medicines if the reaction was considered to be serious by the clinicians, or the ADR team or involved 'black triangle' drugs. The total number of ADR reports was increased eightfold by the introduction of the scheme (from 14 in 1984 to 76, 102 and 94 in 1985, 1986 and 1987 respectively), and this rate of reporting has been sustained.

Drug Prescriptions↗
PubMed1989

Metabolism of the contraceptive steroid desogestrel by the intestinal mucosa.

1. The intestinal mucosal metabolism of the progestogen oral contraceptive desogestrel (Dg) has been studied in vitro using the Ussing chamber technique. Histologically normal ileum or colon was obtained from eight patients undergoing various resections. The mucosal sheets were mounted between two perspex chambers. 2. Two hours after addition of [3H]-Dg (0.2 microCi; 100 ng) to the mucosal chamber, more than 90% of the steroid was present in that chamber. In studies with colon, metabolite analysis showed that 55.4 +/- 11.7% (mean +/- s.d.; n = 6) of drug present was Dg, 28.9 +/- 11.4% as unconjugated Phase I metabolites, 13.3 +/- 2.6% as sulphate conjugates and 2.5 +/- 1.5% as glucuronide conjugates. 3. By co-chromatography with authentic metabolites and mass spectrometry, it was shown that 3-keto desogestrel is formed in the mucosa. This is the active metabolite of desogestrel. A large peak of radioactivity did not co-chromatograph with any known metabolites and has been tentatively identified as ring hydroxylated products of 3-keto desogestrel. 4. The effect of the synthetic oestrogen ethinyloestradiol (EE2) on the metabolite profile of Dg was studied. In the presence of increasing concentrations of EE2 (100 ng, 1 and 10 micrograms), there was competition for sulphation such that the sulphate fraction decreased by 32, 49 and 48% respectively. 5. The results of this study indicate substantial first pass metabolism of desogestrel by the gut mucosa with evidence for the formation of the active metabolite. The extent of phase I metabolism is unusual.

Chromatography, High Pressure Liquid↗
PubMed1988

The relative systemic availability of ivermectin after administration as capsule, tablet, and oral solution.

Administration of 12-mg doses of ivermectin (H2B1a) to 12 healthy volunteers in the form of tablets, capsules, and alcoholic oral solution showed the solution to have approximately twice the systemic availability as either of the solid forms, as evidenced both by the maximum concentrations of drug attained in plasma and by the corresponding areas under the plasma concentration vs time curves. However, the two solid formulations showed similar systemic availability.

Administration, Oral↗
PubMed1988

Evaluation of Committee on Safety of Medicines yellow card reports on oral contraceptive-drug interactions with anticonvulsants and antibiotics.

1. We have searched the adverse reactions register for the years 1968-84 in an attempt to evaluate data relating to reported pregnancies in women on oral contraceptive steroids (OCS) who concurrently received either an antiepileptic drug or an antibiotic. 2. A total of 43 pregnancies were reported in women on OC therapy who concurrently received antiepileptic drugs and 63 pregnancies in women receiving antibiotics. In addition the number of prescriptions for both antiepileptics and antibiotics in England are reported for the years 1973-84.

Anti-Bacterial Agents↗