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S E Clarke

Publications and source records attributed to S E Clarke.

At least 37 records · Page 2Linked to original sources
PubMed1999

Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone.

AIMS: To identify the human cytochrome P450 enzyme(s) involved in the in vitro metabolism of rosiglitazone, a potential oral antidiabetic agent for the treatment of type 2 diabetes-mellitus. Method The specific P450 enzymes involved in the metabolism of rosiglitazone were determined by a combination of three approaches; multiple regression analysis of the rates of metabolism of rosiglitazone in human liver microsomes against selective P450 substrates, the effect of selective chemical inhibitors on rosiglitazone metabolism and the capability of expressed P450 enzymes to mediate the major metabolic routes of rosiglitazone metabolism. Result The major products of metabolism following incubation of rosiglitazone with human liver microsomes were para-hydroxy and N-desmethyl rosiglitazone. The rate of formation varied over 38-fold in the 47 human livers investigated and correlated with paclitaxel 6alpha-hydroxylation (P<0.001). Formation of these metabolites was inhibited significantly (>50%) by 13-cis retinoic acid, a CYP2C8 inhibitor, but not by furafylline, quinidine or ketoconazole. In addition, both metabolites were produced by microsomes derived from a cell line transfected with human CYP2C8 cDNA. There was some evidence for CYP2C9 playing a minor role in the metabolism of rosiglitazone. Sulphaphenazole caused limited inhibition (<30%) of both pathways in human liver microsomes and microsomes from cells transfected with CYP2C9 cDNA were able to mediate the metabolism of rosiglitazone, in particular the N-demethylation pathway, albeit at a much slower rate than CYP2C8. Rosiglitazone caused moderate inhibition of paclitaxel 6alpha-hydroxylase activity (CYP2C8; IC50=18 microm ), weak inhibition of tolbutamide hydroxylase activity (CYP2C9; IC50=50 microm ), but caused no marked inhibition of the other cytochrome P450 activities investigated (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A and 4A). Conclusion CYP2C8 is primarily responsible for the hydroxylation and N-demethylation of rosiglitazone in human liver; with minor contributions from CYP2C9.

Aryl Hydrocarbon Hydroxylases↗
PubMed1999

CYP3A4 drug interactions: correlation of 10 in vitro probe substrates.

AIMS: Many substrates of cytochrome P450 (CYP) 3A4 are used for in vitro investigations of drug metabolism and potential drug-drug interactions. The aim of the present study was to determine the relationship between 10 commonly used CYP3A4 probes using modifiers with a range of inhibitory potency. METHODS: The effects of 34 compounds on CYP3A4-mediated metabolism were investigated in a recombinant CYP3A4 expression system. Inhibition of erythromycin, dextromethorphan and diazepam N-demethylation, testosterone 6beta-hydroxylation, midazolam 1-hydroxylation, triazolam 4-hydroxylation, nifedipine oxidation, cyclosporin oxidation, terfenadine C-hydroxylation and N-dealkylation and benzyloxyresorufin O-dealkylation was evaluated at the apparent Km or S50 (for substrates showing sigmoidicity) value for each substrate and at an inhibitor concentration of 30 microM. RESULTS: While all CYP3A4 probe substrates demonstrate some degree of similarity, examination of the coefficients of determination, together with difference and cluster analysis highlighted that seven substrates can be categorized into two distinct substrate groups. Erythromycin, cyclosporin and testosterone form the most closely related group and dextromethorphan, diazepam, midazolam and triazolam form a second group. Terfenadine can be equally well placed in either group, while nifedipine shows a distinctly different relationship. Benzyloxyresorufin shows the weakest correlation with all the other CYP3A4 probes. Modifiers that caused negligible inhibition or potent inhibition are generally comparable in all assays, however, the greatest variability is apparent with compounds causing, on average, intermediate inhibition. Modifiers of this type may cause substantial inhibition, no effect or even activation depending on the substrate employed. CONCLUSIONS: It is recommended that multiple CYP3A4 probes, representing each substrate group, are used for the in vitro assessment of CYP3A4-mediated drug interactions.

Cytochrome P-450 CYP1A1↗
PubMed1999

Amlodipine lowers blood pressure without affecting cerebral blood flow as measured by single photon emission computed tomography in elderly hypertensive subjects.

AIM: To evaluate the effect of amlodipine on blood pressure and cerebral blood flow in elderly subjects with mild to moderate hypertension. METHODS: A double-blind, parallel group study of 26 patients. After a 4-week placebo run-in period, amlodipine (5-10 mg) or matching placebo was given once daily for 8 weeks. RESULTS: Amlodipine significantly reduced blood pressure compared with baseline. Diastolic blood pressure was significantly reduced by amlodipine compared with placebo (P< 0.02 to P< 0.01). Ambulatory blood pressure monitoring showed that blood pressure control was sustained over the 24-h dosing interval. Relative regional cerebral blood flow, assessed using single photon emission computed tomography, was not significantly affected by amlodipine. Three placebo patients, but no amlodipine patients, withdrew because of adverse events. CONCLUSION: Amlodipine was a well-tolerated and effective antihypertensive agent, and did not reduce regional cerebral blood flow in elderly hypertensive patients.

Aged↗
PubMed1999

Radionuclide therapy in the United Kingdom in 1995.

A postal survey was conducted in the UK in 1996 to determine the facilities available and the level of activity at centres where radionuclide therapy was practised in 1995. A response rate of 79% indicated that 102 centres were providing radionuclide therapy, with 339 clinicians holding ARSAC certificates, 57% of whom were clinical oncologists. There were 84 beds available for therapy and the total number of patients treated was 11,435. Patient numbers treated by disease or procedure were: haematological, 569 (5%); benign thyroid disease, 9059 (79.2%); malignant thyroid disease, 911 (8%); bone pain palliation, 425 (3.5%); radiosynovectomy, 321 (2.8%); neuroendocrine tumour therapy, 76 (0.7%); and intra-cavitary, 56 (0.5%). The total amounts of activity of individual radiopharmaceuticals administered in GBq were: 131I, 16,695; 90Y-colloid, 88; 32P, 94.6; 131I-MIBG, 646; 89Sr, 57.6; and 186Rh-HEDP, 16. Average waiting times varied from 1 to 5 weeks, with a range of 0 to 52 weeks for some therapies. Most centres had the services of a physicist available. Compared with teaching hospitals, the 61 district hospitals had fewer allocated beds, but treated almost half of all patients. The numbers of therapies undertaken were increasing at many centres and this has implications for long-term planning.

Certification↗
PubMed1999

Aldehyde oxidase-catalysed oxidation of methotrexate in the liver of guinea-pig, rabbit and man.

Although 7-hydroxymethotrexate is a major metabolite of methotrexate during high-dose therapy, negligible methotrexate-oxidizing activity has been found in-vitro in the liver in man. The goals of this study were to determine the role of aldehyde oxidase in the metabolism of methotrexate to 7-hydroxymethotrexate in the liver and to study the effects of inhibitors and other substrates on the metabolism of methotrexate. Methotrexate, (+/-)-methotrexate and (-)-methotrexate were incubated with partially purified aldehyde oxidase from the liver of rabbit, guinea-pig and man and the products analysed by HPLC. Rabbit liver aldehyde oxidase was used for purposes of comparison. In-vitro aldehyde oxidase from the liver of man catalyses the oxidation of methotrexate to 7-hydroxymethotrexate, but the turnover is low. However, formation of 7-hydroxy-methotrexate from all forms of methotrexate by the liver in guinea-pig and man was significantly inhibited in the presence of 100 microM menadione and chlorpromazine, potent inhibitors of aldehyde oxidase. Allopurinol (100 microM) had a negligible inhibitory effect on liver aldehyde oxidase from guinea-pig and man. Allopurinol is a xanthine oxidase inhibitor. The production of 7-hydroxymethotrexate was enhanced in the presence of allopurinol. Although aldehyde oxidase is also responsible for some of this conversion, it is also possible that the closely related xanthine oxidase is responsible for the formation of 7-hydroxymethotrexate. By employing potent selective inhibitors of aldehyde oxidase, menadione and chlorpromazine, we have demonstrated for the first time that liver aldehyde oxidase from man is minimally involved in methotrexate oxidation.

Acyclovir↗
PubMed1998

Quality assurance in myocardial perfusion tomography: a collaborative BNCS/BNMS audit programme. British Nuclear Cardiology Society/British nuclear Medicine Society.

The aim of this study was to assess the status of acquisition and reporting of myocardial perfusion tomography in the UK. Centres were asked to provide an expert panel with clinical and technical information, digital and hard copy of raw data and reconstructed tomograms, as well as their report (optional) for five randomly selected studies. Ninety studies were received from 18 centres; report text was provided for 66 studies. Six parameters (stress technique, radiopharmaceutical usage, image acquisition and processing, report images and text) were scored as good (2), adequate (1) or poor (0) by consensus. Centres received the quality scores for each study and a consensus clinical report from the panel. Stress technique was scored as inadequate in 10 (11%) studies, radiopharmaceutical usage and image acquisition as inadequate in 5 (6%) studies, image processing as inadequate in 8 (10%) studies and report images as inadequate in 2 (3%) studies. Report text was felt to be inadequate in 21 of 66 (32%) studies; in 11 of these (52%), the report text was judged to be incorrect and in 10 (48%) it was essentially correct but misleading because of poor phraseology. The mean quality score per study was 1.3 (range 0.5-2.0). Seventeen of 88 (19%) studies scored less than 1.0 and were considered to be of poor quality. In conclusion, a large variation in standards of myocardial perfusion tomography was seen. Data acquisition was generally satisfactory, but 32% of reports were inadequate.

Coronary Disease↗
PubMed1998

Nuclear medicine and endocrinology: diagnosis and management.

Most endocrine disorders result in a disturbance of function, so radionuclide imaging provides a unique view of disordered function which complements the structural information provided by other imaging techniques. Nuclear medicine is used in the management of benign and malignant thyroid, parathyroid and adrenal disorders both diagnostically and by identifying suitable patients for radionuclide therapy.

Adrenal Gland Diseases↗
PubMed1997

Sexually transmitted diseases among teenagers in England and Wales.

A profile of sexually transmitted diseases (STDs) and HIV infections among teenagers in England and Wales was obtained from reports of newly diagnosed STDs among teenagers attending genitourinary medicine (GUM) clinics in 1995, laboratory reports of newly diagnosed HIV infections between 1985 when reporting began and the end of 1995, and the prevalence of HIV (unlinked anonymous programme) among teenagers attending genitourinary medicine clinics and antenatal clinics in 1994 and 1995. STD reports were analysed by sex, age group, and place of residence of patients--whether in the NHS Thames regions or elsewhere in England and Wales. High rates of STDs were reported in teenagers, particularly in girls. The incidences of gonorrhoea, chlamydia infection, and first attack genital wart infections were higher in teenage girls than in any other age group. Boys under 16 years of age had substantially higher rates of infection with all STDs in the Thames regions than elsewhere. Rates of gonorrhoea in teenagers of both sexes in the Thames regions were more than twice those in the rest of the country. Infection rates for genital herpes, and chlamydia in girls, were also higher in the Thames regions, although the geographical differences were less marked. The seroprevalence of HIV among heterosexual teenagers was very low. In contrast, 226 HIV infections among teenage boys had probably been acquired through sexual intercourse with other males. Unlinked anonymous testing revealed HIV antibody in 7.5% of routinely collected serology specimens taken from teenage homosexual or bisexual males attending GUM clinics in London. The high rates of STDs among teenage girls and all teenagers in the Thames regions make these groups a high priority for sexual health promotion, with special consideration given to homo/bisexual male teenagers. Detailed surveillance of risk factors for STDs, and further studies of teenage sexual behaviour will help to effectively target resources to improve the sexual health of teenagers in England and Wales.

Adolescent↗
PubMed1997

Registration bone scan in the evaluation of wrist pain.

We assessed the value of bone scintigraphy combined with X-ray registration for the diagnosis and management of wrist pain in 65 patients. Studies were reported independently by two observers before and after registration. Registration improved localization of scan abnormalities in 53% (observer 1) and 61% (observer 2). In these patients, the bone scan contributed to the diagnosis independently of the X-ray in 37% and the management was altered in 31%. The value of the bone scan in the early diagnosis and management of wrist pain is increased when it is registered with X-rays.

Adult↗
PubMed1997

The development of regional nuclear medicine audit in south Thames.

A programme of audit, including clinical audit, organizational audit and patient/clinician satisfaction surveys, has been implemented in nuclear medicine departments throughout the South Thames Regional Health Authority (RHA). The clinical topics which have been audited include. ventilation-perfusion lung imaging, bone imaging, liver imaging, thyroid imaging and renal static DMSA imaging. Guidelines have been set for nuclear medicine practice in each of these areas against which further audit can be performed. Organizational audits have been performed in 10 nuclear medicine departments in the South Thames RHA and a confidential report supplied to the head of each department, consisting of findings and recommendations. A programme of re-audit has also commenced. The main findings have been a lack of facilities and space. Patient satisfaction surveys have been implemented in nine departments and a high level of patient satisfaction has been demonstrated. A clinical satisfaction survey has been implemented in 13 departments. It is hoped to continue this successful programme of audit to improve nuclear medicine practice by closing audit loops.

England↗
PubMed1997

In vitro oxidation of famciclovir and 6-deoxypenciclovir by aldehyde oxidase from human, guinea pig, rabbit, and rat liver.

Famciclovir, a 9-substituted guanine derivative, is a new antiviral agent which undergoes rapid hydrolysis and oxidation in man to yield the active antiherpes agent, penciclovir. Studies with human liver cytosol have indicated that the oxidation of the penultimate metabolite, 6-deoxypenciclovir, to penciclovir is catalyzed by the molybdenum hydroxylase, aldehyde oxidase. In the present study the oxidation of famciclovir and 6-deoxypenciclovir with partially purified molybdenum hydroxylases from human, guinea pig, rabbit, and rat livers and bovine milk xanthine oxidase has been investigated. Famciclovir and 6-deoxypenciclovir were oxidized predominantly to 6-oxo-famciclovir and penciclovir, respectively, by human, guinea pig, and rat liver aldehyde oxidase. Small amounts of 8-oxo and 6,8-dioxo-metabolites were also formed from each substrate. Famciclovir and 6-deoxypenciclovir were good substrates for rabbit liver aldehyde oxidase but, in each case, two major metabolites were formed. 6-Deoxypenciclovir was converted to penciclovir and 8-oxo-6-deoxypenciclovir in approximately equal quantities; famciclovir was oxidized to 6-oxo-famciclovir and a second metabolite which, on the basis of chromatographic and UV spectral data, was thought to be 8-oxo-famciclovir. Two groups of Sprague Dawley rats were identified; those containing hepatic aldehyde oxidase and xanthine oxidase and those with only xanthine oxidase. These have been designated AO-active and AO-inactive rats, respectively. Famciclovir was not oxidized by enzyme from AO-inactive rats or bovine milk xanthine oxidase although 6-deoxypenciclovir was slowly converted to penciclovir by rat liver or milk xanthine oxidase. Inhibitor studies showed in human, guinea pig, and rabbit liver that xanthine oxidase did not contribute to the oxidation of famciclovir and 6-deoxypenciclovir; thus it is proposed that drug activation in vivo would be catalyzed solely by aldehyde oxidase.

2-Aminopurine↗
PubMed1997

In vitro identification of the P450 enzymes responsible for the metabolism of ropinirole.

The in vitro metabolism of ropinirole was investigated with the aim of identifying the cytochrome P450 enzymes responsible for its biotransformation. The pathways of metabolism after incubation of ropinirole with human liver microsomes were N-despropylation and hydroxylation. Enzyme kinetics demonstrated the involvement of at least two enzymes contributing to each pathway. A high affinity component with a K(M) of 5-87 microM and a low affinity component with a K(M) of approximately two orders of magnitude greater were evident. The high affinity component could be abolished by pre-incubation of the microsomes with furafylline. Additionally, incubation of ropinirole with microsomes derived from CYP1A2 transfected cells readily produced the N-despropyl and hydroxy metabolites. Some inhibition of ropinirole metabolism was also observed with ketoconazole, indicating a minor contribution by CYP3A. Multivariate correlation data were consistent with the involvement of the cytochrome P450 enzymes 1A2 and 3A in the metabolism of ropinirole. Thus, it could be concluded that the major P450 enzyme responsible for ropinirole metabolism at lower (clinically relevant) concentrations is CYP1A2 with a contribution from CYP3A, particularly at higher concentrations.

Biotransformation↗
PubMed1997

In vitro identification of the human cytochrome P450 enzymes involved in the metabolism of R(+)- and S(-)-carvedilol.

Both the R(+) and the S(-) enantiomers of carvedilol were metabolized in human liver microsomes primarily to 4'- (4OHC) and 5'-(5OHC) hydroxyphenyl, 8-hydroxy carbazolyl (8OHC) and O-desmethyl (ODMC) derivatives. The S(-) enantiomer was metabolized faster than the R(+) enantiomer although the same P450 enzymes seemed to be involved in each case. A combination of multivariate correlation analysis, the use of selective inhibitors of P450, and microsomes from human lymphoblastoid cells expressing various human P450s enabled phenotyping of the enzymes involved in the oxidative metabolism of carvedilol. CYP2D6 was primarily responsible for 4OHC and 5OHC production, although considerable activity was observed in a CYP2D6 poor metabolizer liver and the variability of these activities across a human liver bank was not high. There was some evidence that CYP2E1, CYP2C9, and CYP3A4 were also involved in the production of these metabolites. CYP1A2 was primarily responsible for the 8OHC pathway with additional contributions from CYP3A4. The ODMC was clearly associated with CYP2C9 with some evidence for the partial involvement of CYP2D6, CYP1A2, and CYP2E1. With its complex P450 phenotype pattern and the known contribution of non-oxidative pathways of elimination, the activity (or lack of activity) of any particular P450 would have a limited influence on the disposition of carvedilol in an individual.

Adrenergic beta-Antagonists↗