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Biomedical subjects

A Johnston

Publications and source records attributed to A Johnston.

At least 145 records · Page 8Linked to original sources
PubMed1994

Comparison of functional mobility performance with clinical vision measures in simulated retinitis pigmentosa.

Simulations of retinitis pigmentosa (RP) under various conditions of retinal illuminance were designed and investigated in order that they might be used in the mobility training of clients with early RP. Goggles incorporating a 2.5 neutral density (ND) filter with a 0.5-mm diameter pinhole were found to be a potentially useful simulation device for this purpose. This investigation also compared mobility performance with clinical vision measures under photopic, mesopic, and scotopic conditions of retinal illuminance. Although none of the clinical vision measures we used was entirely predictive of mobility performance, some measures were better predictors than others. For a severe constriction of the visual field and decreasing retinal illuminance, both edge contrast sensitivity and visual acuity, measured outdoors, accounted for a greater proportion of the variance in mobility performance than did low contrast visual acuity measured under the same circumstances. The same clinical vision measures, taken indoors, were of no value in predicting outdoor mobility performance.

Adult↗
PubMed1994

Effect of terbinafine on the pharmacokinetics of cyclosporin in humans.

Cyclosporin is largely metabolized by hepatic cytochrome P450 enzymes, and azole drugs that inhibit cytochrome P450 may precipitate cyclosporin toxicity. The allylamine terbinafine binds to a small subfraction of hepatic cytochrome P450 in type I fashion, and has no effect upon hepatic metabolism of cyclosporin in vitro. The purpose of this study was to determine whether oral terbinafine alters the pharmacokinetics of oral cyclosporin in vivo. Twenty male volunteers (age 19-44 years), were randomly allocated to two groups. The first group received three single oral doses of cyclosporin 300 mg at intervals of 21 d. The second and third doses of cyclosporin were preceded by a 6-d course of oral terbinafine 250 mg each morning. A further 250 mg of terbinafine was taken with the second and third doses of cyclosporin. Blood levels of cyclosporin and terbinafine were monitored for 36 h after each dose. The second group received a 7-d course of terbinafine 250 mg each morning. On the seventh day a single dose of cyclosporin 300 mg was taken together with the terbinafine. Blood levels of both cyclosporin and terbinafine were monitored for 36 h. Two further single doses of cyclosporin 300 mg were given at intervals of 2 weeks and the cyclosporin levels again monitored. In both groups each cyclosporin dose was preceded by an 8-h fast. The mean peak blood concentration of cyclosporin when taken alone was 958 micrograms/l, and 822 when taken with terbinafine. The mean area under the curve for cyclosporin was 4207 micrograms/l/h when taken alone and 3665 when taken with terbinafine. The mean absorption half-life for cyclosporin when taken alone was 0.29 h, and 0.33 when taken with terbinafine. The mean time of maximum concentration and elimination half-life of cyclosporin were unaltered by terbinafine. The results suggest that terbinafine is likely to prove a safe systemic anti-fungal treatment for patients who are taking cyclosporin.

Absorption↗
PubMed1994

Pharmacokinetics of naftopidil, a novel anti-hypertensive drug, in patients with hepatic dysfunction.

The pharmacokinetics of naftopidil, a novel alpha-1 adrenoceptor-blocking antihypertensive, were investigated in ten patients (9M/1F) with hepatic dysfunction after oral administration (50 mg, tablet) and after an intravenous infusion of 5.0 mg over 2 minutes. Results were compared to a control group of 12 healthy subjects (6M/6F) of a previous investigation, which was carried out according to the identical study protocol. The pharmacokinetic parameters obtained for the i.v. administration were comparable in both groups (half life 3.6 +/- 3.4 hours in liver-impaired subjects versus 3.3 +/- 2.1 hours in controls; clearance 11.9 +/- 4.7 ml/minute/kg versus 11.0 +/- 1.6 ml/minute/kg). Following oral administration the plasma levels and half-life times of naftopidil were significantly increased in liver impairment (t1/2 16.6 +/- 19.3 hours versus 5.4 +/- 3.2 hours in controls; P = 0.012). Mean values for the absolute bioavailability in patients with hepatic dysfunction were significantly higher (mean 75%, median 53%, range 13.4-211.0%) compared to healthy subjects (mean 17%, median 16%, range 6.7-29.6%, P = 0.001). Reduction of functional hepatic blood flow in chronic liver disease or, as evidenced in one case as a consequence of shunt surgery, is the probable cause of the observed alteration in naftopidil kinetics. This phenomenon occurred only following the oral 50 mg dose whereas the intravenous 5 mg dose obviously still could be normally handled. Naftopidil demethylation and hydroxylation were both less and non-uniformly affected. The pharmacokinetic findings suggest that in patients with severe hepatic impairment or evidence for marked changes in hepatic blood flow the dose of naftopidil may require adjustment to the lower end of the therapeutic range and/or may be limited to once daily. However, before definite conclusions can be drawn, further steady-state studies are required. Despite the pharmacokinetic discrepancies no difference in drug tolerability was seen between patients and healthy subjects.

Administration, Oral↗
PubMed1994

Enalapril pharmacokinetics and ACE inhibition, following single and chronic oral dosing.

Twelve normal volunteers were given 10 mg enalapril maleate by single and 2 weeks multiple dose administration, and blood samples were collected for the determination of enalaprilat concentration and angiotensin converting enzyme (ACE) activity. The mean terminal elimination half-life following a single administration of 10 mg enalapril, was 27 hours. The inhibition of ACE activity paralleled enalaprilat concentrations following both single and multiple dosing and the time of maximum inhibition of ACE activity was associated on both occasions with maximum concentration of enalaprilat. Emax modelling of enalaprilat concentration and ACE activity gave comparable values of Emax for both methods of administration. An accumulation factor of 1.7 was calculated from the area under the concentration time curve (AUC) of enalaprilat within a dosing interval at steady-state and the total AUC following single administration of enalapril. There were no significant differences between males and females in the accumulation factor, half-life and AUCinf.

Administration, Oral↗
PubMed1993

Pharmacokinetics of cyclosporine and multiple-dose diclofenac during coadministration.

Pursuant to anecdotal case reports of a possible drug-drug interaction between cyclosporine and diclofenac, an open, two-period crossover study in 24 healthy male volunteers was undertaken in which a single oral dose of 300 mg cyclosporine was administered alone and on day 8 of multiple oral dosing of 50 mg diclofenac every 8 hours. Serial blood samples were obtained over 48 hours after each cyclosporine dose and over a dosing interval for diclofenac on day 7 (diclofenac alone) and day 8 (coadministration of diclofenac with cyclosporine). The mean pharmacokinetic characteristics of cyclosporine were unchanged during coadministration with diclofenac. Based on area under the curve comparison, lack of a pharmacokinetic interaction was conclusively demonstrated for the extent of cyclosporine absorption. The diclofenac maximum plasma concentration and area under the curve over a dosing interval were significantly increased during coadministration; however, a straightforward interpretation of the statistical results was confounded by pronounced variability in diclofenac pharmacokinetics. The results underscore the need for continued caution when cyclosporine and diclofenac are coadministered.

Administration, Oral↗
PubMed1993

Pharmacokinetics of cyclosporine and steady-state aspirin during coadministration.

Anecdotal reports from clinical trials assessing the use of cyclosporine in the treatment of rheumatoid arthritis suggest an association between enhanced renal impairment and combined use of cyclosporine with nonsteroidal anti-inflammatory drugs. To explore possible pharmacokinetic contributions to this phenomenon, a randomized, two-period crossover investigation was performed in 24 healthy volunteers in which a single oral dose of 300 mg cyclosporine was administered alone and on day 10 of multiple oral dosing of aspirin 960 mg three times daily. Serial blood samples were obtained over 48 hours after each cyclosporine dose and over a steady-state dosing interval for aspirin on day 9 (aspirin alone) and day 10 (coadministration of cyclosporine and aspirin). Cyclosporine whole blood concentrations were determined by a specific monoclonal radioimmunoassay and plasma concentrations of acetylsalicylic acid and metabolites by high-performance liquid chromatography. Lack of a pharmacokinetic interaction was conclusively demonstrated for the rate and extent of cyclosporine and acetylsalicylic acid absorption and for the rate and extent of salicylic acid formation after a single dose of cyclosporine was coadministered during steady-state aspirin dosing. If a clear association between enhanced renal impairment and the combined use of cyclosporine and aspirin is substantiated, the underlying mechanism appears to be pharmacodynamic rather than pharmacokinetic.

Adult↗
PubMed1993

Influence of debrisoquine hydroxylation phenotype on the pharmacokinetics of mexiletine.

Marked interindividual variation has been observed in the pharmacokinetics of the antiarrhythmic agent mexiletine. The fact that its urinary excretion is dependent on urinary pH may account, in part, for such variation. The influence that genetic differences in hepatic metabolism of the debrisoquine-type may have on mexiletine pharmacokinetics was considered in this study. The pharmacokinetics and urinary excretion of mexiletine (250 mg administered intravenously) were investigated in 5 rapid extensive metabolisers (EM), 5 slow EM and 5 poor metabolisers (PM) of debrisoquine, under conditions of controlled urinary pH. Mexiletine disposition kinetics was found to be altered in PM individuals. These subjects showed higher total area under the curve (AUC), (15.7 versus 8.16 micrograms.h.ml-1) prolonged elimination half-lives (in serum and urine) (serum: 18.5 versus 11.6 h, urine: 19.2 versus 11.7 h) and lower total clearance values compared with EM (216 versus 450 ml.min-1). In this respect, slow EM individuals generally presented intermediate values of those pharmacokinetic parameters. A higher incidence of adverse-effects was also observed among slow EM and PM subjects. It is concluded that genetic differences in mexiletine oxidation of the debrisoquine-type have an influence on its observed pharmacokinetic variability. The clinical consequences are discussed.

Adult↗
PubMed1993

Quality assurance programs for immunosuppressive drugs: cyclosporine and beyond.

Monitoring blood cyclosporine concentrations as a guide to therapy has become established as a useful guide for optimal prescription of the drug. Quality assurance programs for external assessment of cyclosporine measurements have helped to clarify many of the methodological problems associated with measurement of the drug. A number of new immunosuppressive agents are in development and, although experience in their routine monitoring in clinical practice is still at an early stage, some observations regarding external assessment of their measurement can be made. This article summarizes the lessons to be drawn from the experience of cyclosporine quality assurance programmes and suggests some areas in which these lessons could be applied in the field of new immunosuppressive drugs.

Cyclosporine↗
PubMed1993

External quality assessment scheme for cyclosporin in body fluids.

The United Kingdom Cyclosporin Assessment Scheme has over eight years experience in the measurement of cyclosporin and has over 176 participants World wide. The scheme provides a source of reference material which has been assayed by many laboratories and, thereby, provides external quality assessment for the clinical measurement of cyclosporin. The results also allow the direct comparison of the available analytical methodologies. The data presented are a summary of the results received during the period July 1990 to July 1991, inclusive.

Blood Chemical Analysis↗
PubMed1993

Linkage studies with 17q and 18q markers in a breast/ovarian cancer family.

Genes on chromosomes 17q and 18q have been shown to code for putative tumor suppressors. By a combination of allele-loss studies on sporadic ovarian carcinomas and linkage analysis on a breast/ovarian cancer family, we have investigated the involvement of such genes in these diseases. Allele loss occurred in sporadic tumors from both chromosome 17p, in 18/26 (69%) cases, and chromosome 17q, in 15/22 (68%) cases. In the three familial tumors studied, allele loss also occurred on chromosome 17 (in 2/3 cases for 17p markers and in 2/2 cases for a 17q allele). Allele loss on chromosome 18q, at the DCC (deleted in colorectal carcinomas) locus, was not as common (6/16 cases [38%]) in sporadic ovarian tumors but had occurred in all three familial tumors. The results of linkage analysis on the breast/ovarian cancer family suggested linkage between the disease locus and 17q markers, with a maximum lod score of 1.507 obtained with Mfd188 (D17S579) polymorphism at 5% recombination. The maximum lod score for DCC was 0.323 at 0.1% recombination. In this family our results are consistent with a predisposing gene for breast/ovarian cancer being located at chromosome 17q21.

Adult↗
PubMed1993

Monte Carlo fluorescence verification of experimental results for the combined ultrasonic and spectroscopic imaging of coronary artery disease.

A system is being tested that combines fluorescence spectroscopy and intravascular ultrasound to image both chemical composition and structure of arterial tissue in vitro. In this system, distances obtained from A-mode ultrasound will be used to compensate for decreases in fluorescence intensity due to the detector-sample separation distance r. For concentrated rhodamine, a fluorescent dye, compensation has been experimentally achieved assuming fluorescence is emitted isotropically and decreases as 1/r2. For dilute rhodamine and human arterial tissue, however, compensation must be achieved with different models, since light penetration into the sample is more significant. Using optical properties consistent with those of the aforementioned samples, experimental results are successfully simulated with a Monte Carlo model for tissue fluorescence. Angular profiles are presented that demonstrate the quantitative difference between the fluorescence of these mediums. The profiles support the hypothesis that, although fluorescence is emitted isotropically within tissue, the angular distribution of light exiting the tissue is not isotropic due to reabsorption events.

Aorta↗