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Biomedical subjects

A Johnston

Publications and source records attributed to A Johnston.

At least 73 records · Page 4Linked to original sources
PubMed2000

Clinical pharmacokinetic and in vitro combination studies of nolatrexed dihydrochloride (AG337, Thymitaq) and paclitaxel.

A clinical study of nolatrexed dihydrochloride (AG337, Thymitaq) in combination with paclitaxel was performed. The aims were to optimize the schedule of administration and determine any pharmacokinetic (PK) interactions between the two drugs. In vitro combination studies were performed to assist with schedule optimization. Three patients were entered on each of three different schedules of administration of the two drugs: (1) paclitaxel 0-3 h, nolatrexed 24-144 h; (2) nolatrexed 0-120 h, paclitaxel 48-51 h; (3) nolatrexed 0-120 h, paclitaxel 126-129 h. Paclitaxel was administered at a dose of 80 mg m(-2) over 3 h and nolatrexed at a dose of 500 mg m(-2) day(-1) as a 120-h continuous intravenous infusion. Plasma concentrations of both drugs were determined by high performance liquid chromatography. In vitro growth inhibition studies using corresponding schedules were performed using two head and neck cancer cell lines. In both HNX14C and HNX22B cell lines, synergistic growth inhibition was observed on schedule 2, whereas schedules 1 and 3 demonstrated antagonistic effects. In the clinical study, there was no effect of schedule on the pharmacokinetics of nolatrexed. However, patients on schedules 1 and 3 had a higher clearance of paclitaxel (322-520 ml min(-1) m(-2)) than those on schedule 2 (165-238 ml min(-1) m(-2)). Peak plasma concentrations (1.66-1.93 vs. 0.86-1.32 microM) and areas under the curve (392-565 vs. 180-291 microM min(-1)) of paclitaxel were correspondingly higher on schedule 2. The pharmacokinetic interaction was confirmed by studies with human liver microsomes, nolatrexed being an inhibitor of the major routes of metabolism of paclitaxel. Toxicity was not schedule-dependent. Nolatrexed and paclitaxel may be safely given together when administered sequentially at the doses used in this study. Studies in vitro suggest some synergy, however, due to a pharmacokinetic interaction, paclitaxel doses should be reduced when administered during nolatrexed infusion.

Adult↗
PubMed2000

When texture takes precedence over motion in depth perception.

Both texture and motion can be strong cues to depth, and estimating slant from texture cues can be considered analogous to calculating slant from motion parallax (Malik and Rosenholtz 1994, report UCB/CSD 93/775, University of California, Berkeley, CA). A series of experiments was conducted to determine the relative weight of texture and motion cues in the perception of planar-surface slant when both texture and motion convey similar information. Stimuli were monocularly viewed images of planar surfaces slanted in depth, defined by texture and motion information that could be varied independently. Slant discrimination biases and thresholds were measured by a method of single-stimuli binary-choice procedure. When the motion and texture cues depicted surfaces of identical slants, it was found that the depth-from-motion information neither reduced slant discrimination thresholds, nor altered slant discrimination bias, compared to texture cues presented alone. When there was a difference in the slant depicted by motion and by texture, perceived slant was determined almost entirely by the texture cue. The regularity of the texture pattern did not affect this weighting. Results are discussed in terms of models of cue combination and previous results with different types of texture and motion information.

Analysis of Variance↗
PubMed2000

Accuracy of cyclosporin measurements made in capillary blood samples obtained by skin puncture.

International consensus guidelines suggest that cyclosporin should be measured in whole blood. In some instances it may be advantageous to collect capillary blood, by a finger or ear prick method. However, drug concentrations in skin-puncture blood may not necessarily correlate with those measured in venous blood. This study compared cyclosporin concentrations in blood collected from the fingertip or earlobe with blood collected by standard venipuncture. Patient preference for each of the blood collection methods was also assessed. Specimens were obtained from organ transplant patients receiving cyclosporin, using each of the three methods: venipuncture, finger prick, and earlobe prick. The samples were assayed using a specific radioimmunoassay and the results were compared. In the 102 sets of samples collected, the mean difference (+/- standard deviation) in cyclosporin concentration between finger prick and venipuncture and ear prick and venipuncture was 2.6% (+/- 9.5%) and 2.7% (+/- 12.1%), respectively, while the comparable median (IQR) differences were 1.9% (-3.4% to +6.6%) and -1.1% (-2.8% to +7.2%), respectively. A high degree of correlation was observed between finger prick and venipuncture or ear prick and venipuncture or ear prick and finger prick (r2 > 0.86). Of the three methods of blood collection, finger prick was the patients' preferred method (P < 0.01). These data suggest that capillary blood collected by skin puncture is suitable for use in cyclosporin blood monitoring and acceptable to patients.

Area Under Curve↗
PubMed2000

Mental health in medical students. A case control study using the 60 item General Health Questionnaire.

This paper describes a cross-sectional case control study to measure the prevalence of psychological morbidity in first year medical students and compare it to the prevalence in in a randomly selected control group of other first year students at Edinburgh University. The study was conducted anonymously using the 60 item General Health Questionnaire. Participation rates were over 90% in both subjects and controls. A total of 17% of medical students had symptoms of psychological morbidity which may benefit from treatment and a further 29% of medical students had symptoms of psychological distress which would be expected to remit spontaneously. A similar rate was found in the control group of students. This suggests that if medical students or doctors, later in their careers, fare badly in terms of mental health then this may well be related to aspects of their lives and is not an intrinsic characteristic.

Case-Control Studies↗
PubMed2000

Impact of absorption profiling on efficacy and safety of cyclosporin therapy in transplant recipients.

The optimisation of cyclosporin therapy remains a challenge because of the very narrow therapeutic window and the highly variable pharmacokinetics of the drug. Therefore, there has been a concerted effort in the clinical transplant community to explore and test cyclosporin monitoring tools and techniques that will allow blood concentrations of cyclosporin to be maintained within the narrow therapeutic window in order to maximise efficacy and minimise toxicity. Absorption profiling is a simple and accurate technique for adjusting dosages of cyclosporin microemulsion that utilises an estimation of the rate and extent of cyclosporin absorption in order to optimise immunosuppression in the individual patient. Two estimation tools in particular are an abbreviated area under the concentration-time curve (AUC) for the first 4 hours postdose and a single sampling point at 2 hours postdose. These 2 monitoring strategies have not only been validated as an accurate estimation of cyclosporin bioavailability but have been demonstrated to significantly improve clinical outcomes in patients compared with traditional trough concentration monitoring. The evidence presented in this review demonstrates that absorption profiling results in the following clinical benefits compared with trough concentration monitoring: (i) reduced incidence of acute rejection; (ii) reduced severity of rejection episodes; (iii) reduced nephrotoxicity; and (iv) a rational basis for dosage adjustments. The optimisation of immunosuppressive therapy continues to be a major priority in the management of the organ transplant recipient. Absorption profiling is a sensitive and practical approach for optimising the dosage of cyclosporin microemulsion, and can further extend the benefits of cyclosporin immunosuppression in the individual patient.

Age Factors↗
PubMed2000

Nitric oxide synthesis and isoprostane production in subjects with type 1 diabetes and normal urinary albumin excretion.

The role of nitric oxide (NO) and free radicals in the development of microvascular disease in type 1 diabetes remains unclear. We have measured NO and isoprostane (a stable marker of in vivo lipid peroxidation) production in 13 type 1 diabetic subjects with normal urinary albumin excretion and 13 healthy volunteers. Whole-body NO synthesis was quantified by measuring the urinary excretion of 15N-nitrate after the intravenous administration of L-[15N]2-arginine. The urinary excretion of the major urinary metabolite of 15-F2t-isoprostane (8-iso-prostaglandin-F2alpha), 2,3-dinor-5,6-dihydro-F2t-IsoP, was quantified as a marker of in vivo lipid peroxidation. Whole-body NO synthesis was significantly higher in diabetic subjects compared with control subjects (342 vs. 216 nmol 15N-nitrate/mmol creatinine [95% CI of the difference 45-207], P = 0.005). This increase was not explained by a difference in renal function between the 2 groups. There was no difference in 2,3-dinor-5,6-dihydro-F2t-IsoP excretion between diabetic subjects and control subjects (44.8+/-7.8 vs. 41.4+/-10.0 ng/mmol creatinine, mean +/- 95% CI). However, there was an inverse correlation between NO synthesis and free radical activity in subjects with diabetes (r = -0.62, P = 0.012) that was not observed in control subjects (r = 0.37, P = 0.107). We conclude that whole-body NO synthesis is higher in type 1 diabetic subjects with normal urinary albumin excretion than in control subjects. The inverse correlation between isoprostane production and NO synthesis in diabetic subjects is consistent with the hypothesis that NO is being inactivated by reactive oxygen species.

Adult↗
PubMed1999

Induced motion at texture-defined motion boundaries.

When a static textured background is covered and uncovered by a moving bar of the same mean luminance we can clearly see the motion of the bar. Texture-defined motion provides an example of a naturally occurring second-order motion. Second-order motion sequences defeat standard spatio-temporal energy models of motion perception. It has been proposed that second-order stimuli are analysed by separate systems, operating in parallel with luminance-defined motion processing, which incorporate identifiable pre-processing stages that make second-order patterns visible to standard techniques. However, the proposal of multiple paths to motion analysis remains controversial. Here we describe the behaviour of a model that recovers both luminance-defined and an important class of texture-defined motion. The model also accounts for the induced motion that is seen in some texture-defined motion sequences. We measured the perceived direction and speed of both the contrast envelope and induced motion in the case of a contrast modulation of static noise textures. Significantly, the model predicts the perceived speed of the induced motion seen at second-order texture boundaries. The induced motion investigated here appears distinct from classical induced effects resulting from motion contrast or the movement of a reference frame.

Humans↗
PubMed1999

A Phase II trial of nolatrexed dihydrochloride in patients with advanced hepatocellular carcinoma.

BACKGROUND: Inoperable hepatocellular carcinoma is an incurable malignancy with no accepted standard therapy. Chemotherapy has demonstrated occasional responses and the need is great for a new and effective agent. Therefore the authors conducted this Phase II trial of a novel thymidylate synthase inhibitor, nolatrexed dihydrochloride (designed using structure-based computer modeling), in patients with advanced hepatocellular carcinoma. METHODS: Forty-one patients with unresectable or metastatic hepatocellular carcinoma were treated with nolatrexed, which was administered as a 24-hour outpatient intravenous infusion for 5 days at a dose of 795 mg/m2/day as free base (1000 mg/m2/day as salt) during each 21-day cycle. Prophylactic treatment was given for emesis and rash. RESULTS: Twenty-eight patients received at least 2 courses of treatment and 26 patients were evaluable. Two patients (8%) achieved a partial response and 2 additional patients achieved a minor response that was significant enough to allow surgical resection with curative intent. Fourteen patients (54%) achieved stable disease. The overall median survival was 7 months (10 months among patients who completed 2 cycles) and 1 patient remained free of disease at last follow-up, 37 months after surgery. Toxicity was modest and generally was comprised of stomatitis, nausea, malaise, and rash. CONCLUSIONS: Nolatrexed appears to have modest biologic activity in hepatocellular carcinoma. Due to the lack of alternative treatments, further study of this drug or an oral equivalent may be warranted.

Adult↗
PubMed1999

Influence of motion signals on the perceived position of spatial pattern.

After adaptation of the visual system to motion of a pattern in a particular direction, a static pattern appears to move in the opposite direction-the motion aftereffect (MAE). It is thought that the MAE is not accompanied by a shift in perceived spatial position of the pattern being viewed, providing psychophysical evidence for a dissociation of the neural processing of motion and position that complements anatomical and physiological evidence of functional specialization in primate and human visual cortex. However, here we measure the perceived orientation of a static windmill pattern after adaptation to rotary motion and find a gradual shift in orientation in the direction of the illusory rotation, though at a rate much lower than the apparent rotation speed. The orientation shift, which started to decline within a few seconds, could persist longer than the MAE, and disappeared when the MAE was nulled by physical motion of the windmill pattern. Our results indicate that the representation of the position of spatial pattern is dynamically updated by neurons involved in the analysis of motion.

Afterimage↗
PubMed1999

A multi-centre randomized phase II study of nolatrexed versus doxorubicin in treatment of Chinese patients with advanced hepatocellular carcinoma.

PURPOSE: A multi-centre randomized phase II study of single agent nolatrexed dihydrochloride versus doxorubicin was undertaken in Chinese patients with advanced hepatocellular carcinoma (HCC) to study and compare the clinical efficacy of the two drugs. METHODS: Fifty-four patients with clinical or histological diagnosis of HCC were randomized in a 2:1 ratio to receive nolatrexed or doxorubicin. Nolatrexed 725 mg/m(2)/day was given by continuous infusion via a central venous device for 5 days and doxorubicin 60 mg/m(2) was given as a rapid intravenous infusion every 3 weeks. RESULTS: No objective responses were observed in either treatment arm. Two patients in the nolatrexed arm and none in the doxorubicin arm had >50% decline in serum alpha-fetoprotein. The median survival for the patients in the nolatrexed and doxorubicin arms was 139 days and 104 days, respectively. Moderate toxicities including leukopenia, thrombocytopenia, mucositis and skin rash were observed in both treatment arms. CONCLUSION: Nolatrexed and doxorubicin are minimally active in the treatment of advanced HCC. Given the small sample size, no difference is observed between the two drugs.

Adult↗
PubMed1999

Concurrent measurement of perceived speed and speed discrimination threshold using the method of single stimuli.

Velocity matching using the method of Constant Stimuli shows that perceived velocity varies with contrast [Thompson, P. (1982). Perceived rate of movement depends upon contrast. Vision Research, 22, 377-380]. Random contrast jitter would therefore be expected to increase the slopes of psychometric functions, and thus the velocity discrimination threshold. However, McKee, S., Silverman, G., and Nakayama, K. [(1986) Precise velocity discrimination despite random variation in temporal frequency. Vision Research, 26, 609-620] found no effect of contrast jitter on thresholds, using the method of single stimuli. To determine whether this apparent discrepancy is due to the difference in methodology, or to the different ranges of temporal frequencies used in the two studies, we used the method of single stimuli to measure psychometric functions at three different velocities (0.5, 2.0 and 4.0 degrees/s). We found that contrast jitter increased thresholds at low but not at high velocities. Separate analysis of the psychometric functions at each contrast level showed that increases in contrast increased perceived velocity at low standard speeds (0.5 degree/s) but not at high. We conclude that the effect of contrast on perceived speed is real, and not a methodological artefact, but that it is found only at low temporal frequencies.

Contrast Sensitivity↗
PubMed1999

Contrast inconstancy across changes in polarity.

In this study, we show that negative polarity noise patterns appear to have a higher contrast than positive polarity noise patterns with identical expected Fourier amplitude spectra. This demonstrates a failure of contrast constancy over changes in pattern polarity. An examination of local contrast measures shows that negative polarity noise has a wider distribution of local contrast values than positive polarity noise. We propose that the difference in apparent contrast between the two patterns may be based upon spatial non-linearities in the combination of local contrast measures.

Contrast Sensitivity↗