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Biomedical subjects

A Johnston

Publications and source records attributed to A Johnston.

At least 91 records · Page 5Linked to original sources
PubMed1999

A phase I study of the lipophilic thymidylate synthase inhibitor Thymitaq (nolatrexed dihydrochloride) given by 10-day oral administration.

2-Amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)-quinazoline dihydrochloride (nolatrexed dihydrochloride, Thymitaq, AG337), a specific inhibitor of thymidylate synthase, was developed using protein structure-based drug design. Intravenously administered nolatrexed is active clinically. As oral bioavailability is high (70-100%), nolatrexed was administered orally, 6 hourly for 10 days, at 3-week intervals, and dose escalated from 80 to 572 mg m(-2) day(-1) in 23 patients. Common toxicity criteria (CTC) grade 3 toxicities included nausea, vomiting, stomatitis and liver function test (LFT) abnormalities. Thrombocytopenia (grade 1 or 2) occurred at doses > or = 318 mg m(-2) day(-1) and neutropenia (grade 2) at 429 and 572 mg m(-2) day(-1). An erythematous maculopapular rash occurred at dosages > or = 318 mg m(-2) day(-1) (7 out of 19 patients). LFT abnormalities occurred in two out of six patients (grade 3 or 4 bilirubin and grade 3 alanine transaminase) at 572 mg m(-2) day(-1). Nolatrexed plasma concentrations 1 h after dosing were 6-16 microg ml(-1), and trough 3-8 microg ml(-1), at 572 mg m(-2) day(-1). Inhibition of thymidylate synthase was demonstrated by elevation of plasma deoxyuridine. Six-hourly oral nolatrexed for 10 days was associated with antiproliferative effects, but nausea and vomiting was dose limiting at 572 mg m(-2) day(-1). Nine patients were treated at 429 mg m(-2) day(-1); three out of nine experienced grade 3 nausea, but 17 out of 22 treatment courses were completed (with the co-administration of prophylactic antiemetics) and this dose level could be considered for phase II testing.

Administration, Oral↗
PubMed1999

A multi-differential neuromorphic approach to motion detection.

This paper presents a multi-differential neuromorphic approach to motion detection. The model is based evidence for a differential operators interpretation of the properties of the cortical motion pathway. We discuss how this strategy, which provides a robust measure of speed for a range of types of image motion using a single computational mechanism, forms a useful framework in which to develop future neuromorphic motion systems. We also discuss both our approaches to developing computational motion models, and constraints in the design strategy for transferring motion models to other domains of early visual processing.

Animals↗
PubMed1999

Effects of recombinant human insulin-like growth factor I (IGF-I) therapy on the growth hormone-IGF system of a patient with a partial IGF-I gene deletion.

We have previously reported a 17.2-yr-old boy with severe growth retardation and undetectable serum levels of insulin-like growth factor I (IGF-I) due to a partial deletion of the IGF-I gene. The aim of this study was to investigate the effects of recombinant human IGF-I (rhIGF-I) therapy on the GH-IGF system of this patient to gain further insights into its growth-promoting and metabolic actions. To assess the changes in GH, IGFs, IGF-binding proteins (IGFBPs), acid-labile subunit (ALS), and insulin levels, blood samples were obtained before therapy and during the first year of treatment. Hormones were analyzed by specific RIAs. Overnight GH profiles were performed before and at 1, 6, and 12 months of therapy. Fasting ALS, IGF-II, IGFBP-3, IGFBP-2, IGFBP-1, and insulin levels before rhIGF-I treatment were 46.3 mg/L, 1044 microg/L, 5.8 mg/L, 73 ng/mL, 4.7 ng/mL, and 27.3 mU/L, respectively. IGF-II, ALS, and insulin levels were elevated, whereas IGFBP-1 and IGFBP-2 levels were decreased compared to reference values. Twenty-four hours after a single s.c. injection of rhIGF-I (40 microg/kg), the concentrations were 46 mg/L, 888 microg/L, 6.9 mg/L, 112 ng/mL, 5.0 ng/mL, and 21.0 mU/L, respectively. After a single s.c. injection of rhIGF-I of 40 or 80 microg/kg x day and modelling the data using a two-compartment model, the half-lives of elimination were 15.7 and 14.3 h, with a maximum increase in IGF-I levels to 341 and 794 microg/L around 7 h, respectively. An increase in IGFBP-3 levels was observed with both doses of rhIGF-I, with a peak values of 9 mg/L. GH profiles showed a decrease in peak amplitude from 342 to 84 mU/L at 1 month, to 67 mU/L at 6 months, and to 40 mU/L at 1 yr of therapy, with no significant changes in peak number. A significant increase in IGFBP-1 levels was observed during treatment with 80 microg/kg x day IGF-I, reflecting the inhibitory effect of rhIGF-I on insulin secretion. The clinical response to rhIGF-I therapy was an increased height velocity from 3.8 cm/yr before treatment to 6.6 cm/yr. Increased lean body mass correlated with changes in the doses of rhIGF-I and, in turn, with the biochemical changes in the GH-IGF axis. Similar to healthy individuals, this patient had normal IGFBP-3 and ALS levels, which are the major regulators of the pharmacokinetics of rhIGF-I. In summary, rhIGF-I treatment has improved linear growth and insulin sensitivity in this patient by restoring IGF-I levels and by normalizing circulating GH, IGFBP, and insulin levels.

Adolescent↗
PubMed1999

Reduction of left ventricular mass index with blood pressure reduction in chronic renal failure.

AIM: We have reported previously in a study of 85 non-diabetic patients with chronic renal failure (CRF) that 24-h ambulatory blood pressure (ABP) recording and echocardiography are required for accurate diagnosis of inadequate blood pressure (BP) control and early left ventricular hypertrophy (LVH). In this study we found that the only independent determinants of left ventricular (LV) mass were hypertension, male sex, body mass index (BMI) and anemia. Little is known about the progression of LVH in patients as they progress from moderate to end-stage renal failure. PATIENTS AND METHODS: We undertook a follow-up observational study in a cohort of 65 (26 male, 12 black Afro-Caribbean and 7 Asian) of those patients originally investigated. Patients who had reached end-stage renal failure (ESRF) were not studied. RESULTS: A statistically significant correlation was found between change in left ventricular mass index (LVMI) and change in mean ABP parameters (r = 0.27 (p<0.03) for 24-h systolic, r = 0.21 (p<0.05) for 24-h diastolic, r = 0.29 (p<0.02) for mean arterial pressure (MAP), r = 0.24 (p<0.05) for daytime systolic, r = 0.30 (p<0.02) for nocturnal systolic and r = 0.26 (p<0.05) for nocturnal diastolic BP). Hemoglobin concentration and BMI changed little between the two studies and no other statistically significant correlations were found in respect of any other parameters studied, which has allowed us to isolate the effect of one determinant - adequacy of BP control-upon LVH. CONCLUSION: In patients with moderate chronic renal impairment, reduction in BP is associated with reduction of LVMI over time. Among the antihypertensive agents ACE inhibitors appeared to have the greatest ability to reduce LV mass in the subjects with LVH at baseline. Larger interventional studies are needed to determine whether ACE inhibitors are superior to other anti-hypertensive agents in LVH regression in chronic renal failure patients.

Adult↗
PubMed1999

Phase I studies with the nonclassical antifolate nolatrexed dihydrochloride (AG337, THYMITAQ) administered orally for 5 days.

Phase I studies of p.o. administered nolatrexed dihydrochloride (AG337, THYMITAQ), a nonclassical thymidylate synthase inhibitor, were performed to establish the maximum tolerated dose and a recommended dose for Phase II studies. The bioavailability and pharmacokinetic and pharmacodynamic properties of oral nolatrexed were also studied. Forty-five patients were treated with oral nolatrexed every 6 h for 5 days at doses of 288-1000 mg/m2/day. The bioavailability of the oral preparation was determined, and the effect of a standard meal on nolatrexed absorption was investigated at a dose of 800 mg/m2/day. Nolatrexed plasma concentrations were analyzed by high-performance liquid chromatography. Nolatrexed was rapidly absorbed with a median bioavailability of 89% (range 33-116%), with 88% of patients above 70%. The dose-limiting toxicities were gastrointestinal, and the recommended Phase II oral dose was 800 mg/m2/day. After a standard meal, the peak plasma nolatrexed concentration achieved was lower (median, 8.3 microg/ml versus 15.0 microg/ml; P = 0.001), and the time taken to reach the peak was longer (median, 180 min versus 45 min; P = 0.00003), but the trough concentration was higher (median, 3.6 microg/ml versus 2.1 microg/ml; P = 0.004) when compared with the fasted state. The area under the nolatrexed plasma concentration versus time curve was not affected by food. Average trough nolatrexed concentration, but not dose, was significantly related to the % decrease in both thrombocytes (r2 = 0.58; C50 = 6.0 microg/ml, where C50 is the plasma concentration associated with a 50% decrease in thrombocytes) and neutrophils (r2 = 0.63; C50 = 0.6 microg/ml). Nolatrexed can be safely administered as an oral preparation at a dose of 800 mg/m2/day for 5 days. Bioavailability was close to 100% and, because inhibition of thymidylate synthase by nolatrexed is rapidly reversible, the slower absorption after a standard meal may result in a shorter duration of noninhibitory concentrations between doses.

Administration, Oral↗
PubMed1998

Initial clinical trial and pharmacokinetics of Thymitaq (AG337) by 10-day continuous infusion in patients with advanced solid tumors.

PURPOSE: To establish the maximum tolerated dose (MTD), dose-limiting and other major toxicities and the major pharmacokinetic parameters of a 10-day infusion of the nonclassical antifolate Thymitaq. METHODS: The drug was given by 10-day infusion via a portable pump. The starting dose was 286 mg/m2 per day with escalation to 572 and 716 mg/m2 per day. Thymitaq in plasma was assayed by a validated isocratic reverse-phase HPLC assay with detection at 273 nm. RESULTS: The dose of 716 mg/m2 per day x 10 was considered too high as none of three patients completed a 10-day infusion and two of three developed grade IV myelotoxicity. At 572 mg/m2 per day three of four patients completed a 10-day infusion. Dose-limiting myelosuppression was seen in one of four but owing to a high incidence of thrombotic phenomena, no further patients were added. CONCLUSION: Continuous 10-day infusions of Thymitaq should be limited to low doses until further studies can be done.

Adult↗
PubMed1998

Evidence for a difference in nitric oxide biosynthesis between healthy women and men.

There is indirect evidence for a gender difference in nitric oxide (NO) synthesis from vascular endothelium. The aim of the present study was to determine NO production more directly in healthy women and men by the measurement of 15N nitrate excreted in urine after the intravenous administration of L-[15N]2-guanidino arginine. Twenty-four healthy volunteers (13 men aged 22 to 40 years and 11 women aged 23 to 42 years) participated in this study. No subjects were receiving any medication. Women were studied between the 7th and 14th days of their menstrual cycles. Arterial blood pressure was measured oscillometrically, and 1.13 micromol L-[15N]2 arginine was administered intravenously after an overnight fast. Urine was collected for the next 36 hours in separate 12-hour periods. Urinary 15N/14N nitrate ratio was assessed by dry combustion in an isotope ratio mass spectrometer. Mean 36-hour urinary 15N nitrate excretion was greater in women than in men (2111+/-139 versus 1682+/-87 etamol; P<0.05). Furthermore, total urinary 15N nitrate excretion was associated inversely with the mean arterial blood pressure in the whole group of subjects (coefficient of correlation, 0.47; P=0.022). The present data show that whole-body production of NO is greater in healthy premenopausal women than in men under ambulatory conditions. The cellular origin of NO measured in this study is unknown, but differences in endothelial production could underlie differences in vascular function between men and women.

Adult↗
PubMed1997

Structure-based design of substituted diphenyl sulfones and sulfoxides as lipophilic inhibitors of thymidylate synthase.

Six new diphenyl sulfoxide and five new diphenyl sulfones were designed, synthesized, and tested for their inhibition of human and Escherichia coli thymidylate synthase (TS) and of the growth of cells in tissue culture. The best sulfoxide inhibitor of human TS was 3-chloro-N-((3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)-4- (phenylsulfinyl)-N-(prop-2-ynyl)-aniline (7c) that had a Ki of 27 nM. No sulfone improved on TS inhibition by the previously reported 4-(N-((3,4-dihydro-2-methyl-6-quinazolinyl)methyl)-N-prop-2- ynylamino)phenyl phenyl sulfone (Ki = 12 nM). Nevertheless, one sulfone, 4-((2-chlorophenyl)sulfonyl)-N-((3,4-dihydro-2-methyl-4-oxo-6- quinazolinyl)methyl)-N-(prop-2-ynyl)aniline, was selected, on the basis of its inhibition of both TS and cell growth, for antitumor testing; it gave a 61% increase in life span to mice bearing the thymidino kinase-deficient L5178Y (TK-) lymphoma. A crystal structure of N-((3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)-4-((2- methylphenyl)sulfinyl)-N-(prop-2-ynyl)aniline complexed with E. coli TS was solved and revealed selective binding of one sulfoxide enantiomer. AMBER calculations showed that the enantioselection was due to asymmetric electrostatic effects at the mouth of the active site. In contrast, a similar crystal structure of the sulfoxide 7c, along with AMBER calculations, indicated that both enantiomers bound, but with different affinities. The side chain of Phe176 shifted in order to structurally accommodate the chlorine of the more weakly bound enantiomer.

Animals↗
PubMed1997

Speed discrimination thresholds for first--and second-order bars and edges.

Speed discrimination thresholds were measured for first- and second-order Gaussian bars and edges as a function of speed and the spatial scale of the modulation signal. Discrimination thresholds were generally higher for the second-order patterns when compared with modulations of luminance. There were no systematic effects of variations in the width of the bars and edges. The results are discussed in relation to mechanisms for the explicit recovery of contrast modulations and the influence of the form of the carrier signal on visual performance in second-order motion tasks.

Contrast Sensitivity↗
PubMed1997

Perception of motion direction in luminance- and contrast-defined reversed-phi motion sequences.

Nonlinear processing can be used to recover the motion of contrast modulations of binary noise patterns. A nonlinear stage has also been proposed to explain the perception of forward motion in motion sequences which typically elicit reversed-phi. We examined perceived direction of motion for stimuli in which these reversed motion sequences were used to modulate the contrast of binary noise patterns. A percept of forward motion could be elicted by both luminance-defined and contrast-defined stimuli. The perceived direction of motion seen in the contrast-defined stimuli showed a profound carrier dependency. The replacement of a static carrier by a dynamic carrier can reverse the perceived direction of motion. Forward motion was never seen with dynamic carriers. For luminance- and contrast-defined patterns the reversed motion percept increasingly dominated, with increases in the spatial frequency and temporal frequency of the modulation. Differences in the patterns of responses to the two stimuli over spatial and temporal frequency were abolished by the addition of noise to the luminance-defined stimulus. These data suggest the possibility that a single mechanism may mediate the perception of luminance- and contrast-defined motion.

Contrast Sensitivity↗
PubMed1997

First-order motion from contrast modulated noise?

The class of microbalanced motion stimuli is thought to contain no systematic directional biases in motion energy. The fact that we can see motion in such stimuli implies that models of human motion perception based on Fourier decomposition need to be revised. The validity of one widely studied class of microbalanced stimuli, contrast modulated noise, has recently been questioned. It has been proposed that stochastic local biases in the noise carrier give rise to luminance artifacts detectable by a Fourier energy mechanism. However, in this study we show that the response of a motion energy system to contrast modulated noise shows no directional bias over a number of carrier configurations. We conclude that this class of stimuli remains an important tool for researchers wishing to study non-Fourier motion.

Fourier Analysis↗
PubMed1997

Rapid analysis of 226Ra in waters by gamma-ray spectrometry.

Techniques for the determination of 226Ra in waters by gamma-ray spectrometry are examined, with an emphasis on methods capable of completion within 1-3 days of sample collection. Methods discussed utilise either: (i) the 186 keV 226Ra gamma ray, with the contribution from 235U being subtracted after a separate uranium determination, or (ii) measurement of ingrowing 222Rn progeny. An analysis of the statistical and systematic errors associated with each technique is presented. Examples are given of their application to analysis of uranium mine process waters.

Chemical Precipitation↗
PubMed1997

Bubbles before birth.

When a spa bath was installed in the maternity unit of Osborne Park Hospital, a Quality Assurance survey was undertaken to try to identify any potential problems. At the same time a client satisfaction survey was conducted. The study highlighted many benefits to the client as an alternative method of pain management. At the same time no obvious problems were identified. However, due to lack of control of the many variables, and the absence of statistical analysis, no definite conclusions can be drawn from the study. Positive responses from clients encourage us to continue to offer the spa bath as a method of pain management. This is an area which begs research.

Adult↗