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Biomedical subjects

A L Hamilton

Publications and source records attributed to A L Hamilton.

13 recordsLinked to original sources
PubMed2005

Proteasome inhibition with bortezomib (PS-341): a phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle.

PURPOSE: We performed a phase I study of a day (D) 1 and D4 bortezomib administration once every 2 weeks to determine the recommended phase II dose and toxicity profile, and the extent of 20S proteasome inhibition obtained. PATIENTS AND METHODS: Patients with solid tumors or lymphomas were treated with bortezomib at 0.25 to 1.9 mg/m2 on D1 and D4, every 2 weeks. 20S proteasome levels in blood were assayed at baseline and at 1, 4, and 24 hours postdose in cycle 1. RESULTS: On this D1 and D4 every 2 weeks' schedule, dose-limiting toxicity (DLT) was evident at the 1.75 and 1.9 mg/m2 dose levels, most commonly in patients receiving individual total doses > or = 3.0 mg. The main DLT was peripheral neuropathy evident at the higher doses and in patients previously exposed to neurotoxic agents. Other DLTs included diarrhea and fatigue; grade 3 thrombocytopenia was also noted. Reversible inhibition of 20S proteasome activity was dose dependent and best fit a total dose (mg) per fraction rather than mg/m2; 70% of baseline activity was inhibited by a dose of 3.0 to 3.5 mg given on D1 and on D4 every other week. Antitumor effects short of confirmed partial responses were observed in patients with melanoma, non-small-cell lung cancer, and renal cell carcinoma. CONCLUSION: Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity. DLTs include neuropathy, fatigue, and diarrhea.

Adult↗
PubMed1998

The utility of methacholine airway responsiveness measurements in evaluating anti-asthma drugs.

BACKGROUND: Measurements of airway responsiveness are frequently used to evaluate anti-asthma drugs. OBJECTIVE: This study investigated the utility of methacholine airway responsiveness measurements in evaluating anti-asthma medications, both in terms of a bronchoprotective effect and the ability to attenuate allergen-induced methacholine airway hyperresponsiveness. METHODS: Methacholine airway responsiveness was measured as PC20 on two occasions (separated by 35+/-17 days, mean +/- SD) in 40 subjects with mild, stable asthma. Additional subjects had PC20 measurements made before and after administration of either inhaled salbutamol (200 microg) (n = 20) or allergen inhalation challenge (n = 31). RESULTS: The reproducibility of the methacholine PC20 with this method was high (intraclass correlation coefficient = 0.94). The average shift in PC20 after salbutamol was 4.11 doubling concentrations (SD = 1.08). On the basis of these results, a sample size of 12 subjects would be required to demonstrate a 1 doubling concentration difference in the bronchoprotective effect of two drugs with a 90% power. The average shift in PC20 after allergen was 1.29 doubling concentrations. On the basis of these results and an estimated SD of 0.96, a sample size of 24 subjects would be required to demonstrate that a drug is effective in attenuating 50% of allergen-induced airway hyperresponsiveness with a 90% power. CONCLUSION: These results confirm the high reproducibility of methacholine PC20 measurements in subjects with mild, stable asthma and demonstrate its utility in evaluating the effects of anti-asthma drugs.

Administration, Inhalation↗
PubMed1997

Attenuation of early and late phase allergen-induced bronchoconstriction in asthmatic subjects by a 5-lipoxygenase activating protein antagonist, BAYx 1005.

BACKGROUND: The cysteinyl leukotrienes (LTC4, LTD4 and LTE4) have been implicated in the pathogenesis of allergen-induced airway responses. The effects of pretreatment with BAYx 1005, an inhibitor of leukotriene biosynthesis via antagonism of 5-lipoxygenase activating protein, on allergen-induced early and late asthmatic responses has been evaluated. METHODS: Eight atopic subjects with mild asthma participated in a two period, double blind, placebo controlled, cross-over trial. Subjects were selected on the basis of a forced expiratory volume in one second (FEV1) of > 70% predicted, a methacholine provocative concentration causing a 20% fall in FEV1 (PC20) of < 32 mg/ ml, a documented allergen-induced early response (EAR, > 15% fall in FEV1 0-1 hour after allergen inhalation) and late response (LAR, > 15% fall in FEV1 3-7 hours after allergen inhalation), and allergen-induced airway hyperresponsiveness (at least a doubling dose reduction in the methacholine PC20 30 hours after allergen inhalation). During the treatment periods subjects received BAYx 1005 (500 mg twice daily) or placebo for 3.5 days; treatment periods were separated by at least two weeks. On the third day of treatment, two hours after administration of medication, subjects performed an allergen inhalation challenge and FEV1 was measured for seven hours. RESULTS: Treatment with BAYx 1005 attenuated the magnitude of both the allergen-induced early and late asthmatic responses. The mean (SE) maximal fall in FEV1 during the EAR was 26.6 (3.3)% during placebo treatment and 11.4 (3.3)% during treatment with BAYx 1005 (mean difference 15.2 (95% confidence interval (CI) 9.4 to 21.00) with a mean protection afforded by BAYx 1005 of 57.1%. The mean (SE) maximal fall in FEV1 during the LAR was 19.8 (5.7)% during placebo treatment and 10.7 (4.4)% during BAYx 1005 treatment (mean difference 9.2 (95% CI 1.4 to 17.0) with a mean protection afforded by BAYx 1005 of 46.0%. The area under the time response curve (AUC0-3) was also reduced after treatment with BAYx 1005 compared with placebo by 86.5%.h (mean difference 26.3 (95% CI 17.1 to 38.5)) and the AUC3-7 by 59.6%.h (mean difference 26.9 (95% CI-3.8 to 57.6)). CONCLUSIONS: These results show that antagonism of 5-lipoxygenase activating protein can attenuate allergen-induced bronchoconstrictor responses and support an important role for the cysteinyl leukotrienes in mediating these asthmatic responses.

Adult↗
PubMed1996

Quantification of intensity of sensations during muscular work by normal subjects.

Eleven subjects performed a series of 30-s work bouts on a cycle ergometer at power outputs ranging from 20-120% of the work capacity (Wcap) achieved during an incremental cycle to exhaustion and estimated the intensity of several sensations (leg effort, muscle tension, muscle discomfort, muscle pain, and breathing discomfort) by using Borg's category-ratio scale (range 0-10 units). Leg effort was perceived as "just noticeable" at 31 +/- 15% Wcap, muscle tension was just noticeable at 31 +/- 16% Wcap, muscle discomfort was just noticeable at 47 +/- 21% Wcap, breathing discomfort was just noticeable at 52 +/- 19% Wcap, and muscle pain was just noticeable at 58 +/- 33% Wcap. The intensity of all sensations increased in a positively accelerating manner with increases in power output (P < 0.001). Above 60% Wcap, the intensity of leg effort and muscle tension exceeded the intensity of muscle pain (P < 0.01), and above 100% Wcap the intensity of muscle discomfort also exceeded the intensity of muscle pain (P < 0.01). At 120% Wcap, leg effort, muscle tension, and muscle discomfort were rated between "severe" and "very severe" (6.1 +/- 2.2, 6.4 +/- 2.0, and 5.6 +/- 2.1 Borg units, respectively), whereas muscle pain and breathing discomfort were rated between "moderate" and "somewhat severe" (3.6 +/- 2.1 and 3.3 +/- 1.9 Borg units, respectively). These results suggest that subjects have a perception of muscle pain during muscular work that is distinct from perceptions of leg effort, muscle tension, and muscle discomfort.

Adult↗
PubMed1996

Symptom intensity and subjective limitation to exercise in patients with cardiorespiratory disorders.

The aim of the study was to compare (1) the intensity of leg effort and dyspnea during exercise and (2) subjective limitations to performance in normal subjects, patients receiving medication for cardiac disorders, patients with pulmonary impairment, patients with pulmonary impairment who were also receiving cardiac medications, patients experiencing chest pain during exercise, and patients who had a reduced exercise capacity but did not have pulmonary impairment and were not receiving cardiac medication. Five hundred seventy-eight subjects rated the intensity of leg effort, discomfort with breathing (dyspnea), and chest pain every minute (Borg scale) during an incremental exercise task (100 kpm/min each minute) to maximum work capacity on a cycle ergometer and following exercise indicated their subjective limitation by completing a simple questionnaire. Leg effort and dyspnea increased systematically with power output in a positively accelerating manner in all groups; both symptoms were significantly more intense in the impaired groups compared with the normal group at submaximal power outputs. In all groups, there was a significant relationship between symptom intensity at submaximal power outputs and the maximal power output achieved. Leg discomfort in combination with breathing discomfort was the predominant subjective limitation in all groups; chest pain in combination with leg and breathing discomfort was the major subjective limitation in individuals with angina. Activation of the sensory systems during exercise is accompanied by a perception of discomfort associated with the peripheral exercising muscles and discomfort with breathing; both discomfort associated with the exercising muscles and discomfort associated with breathing contribute to exercise limitation to a large degree in normal subjects and patients with cardiorespiratory diseases.

Angina Pectoris↗
PubMed1995

Muscle strength, symptom intensity, and exercise capacity in patients with cardiorespiratory disorders.

The contribution of muscle strength to symptom intensity and work capacity was examined in normal individuals and patients with cardiorespiratory disorders. Respiratory muscle strengths (maximal inspiratory and expiratory pressures) and peripheral muscle strengths (leg extension, leg flexion, seated bench press, and seated row) were measured in 4,617 subjects referred for clinical exercise testing. Subjects then rated the intensity of leg effort, discomfort with breathing (dyspnea), and chest pain (Borg scale) during an incremental exercise task (100 kpm/min each minute) to capacity on a cycle ergometer. Subjects were classified into groups on the basis of pulmonary function, drug therapy for cardiac disorders, and the presence of chest pain during exercise with electrocardiographic changes indicative of myocardial ischemia. Respiratory and peripheral muscle strengths, normalized for differences in age, sex, and height, were significantly reduced in patients with cardiorespiratory disorders compared with normal individuals. Muscle strength was a significant contributor to symptom intensity and work capacity in both health and disease; a two-fold increase in muscle strength was associated with a 25 to 30% decrease in the intensity of both leg effort and dyspnea and a 1.4- to 1.6-fold increase in work capacity. These results emphasize the need for an integrative approach in the assessment and therapeutic management of exercise intolerance, which considers the contribution of muscle weakness to excessive symptoms and reduced work capacity, in addition to the contribution of ventilatory, gas exchange, and circulatory impairments.

Angina Pectoris↗
PubMed1991

Physiological responses to maximal intermittent exercise: differences between endurance-trained runners and games players.

Six games players (GP) and six endurance-trained runners (ET) completed a standardized multiple sprint test on a non-motorized treadmill consisting of ten 6-s all-out sprints with 30-s recovery periods. Running speed, power output and oxygen uptake were determined during the test and blood samples were taken for the determination of blood lactate and pH. Games players tended to produce a higher peak power output (GP vs ET: 839 +/- 114 vs 777 +/- 89 W, N.S.) and higher peak speed (GP vs ET: 7.03 +/- 0.3 vs 6.71 +/- 0.3 m s-1, N.S.), but had a greater decrement in mean power output than endurance-trained runners (GP vs ET: 29.3 +/- 8.1% vs 14.2 +/- 11.1%, P less than 0.05). Blood lactate after the test was higher for the games players (GP vs ET: 15.2 +/- 1.9 vs 12.4 +/- 1.7 mM, P less than 0.05), but the decrease in pH was similar for both groups (GP vs ET: 0.31 +/- 0.08 vs 0.28 +/- 0.08, N.S.). Strong correlations were found between peak blood lactate and peak speed (r = 0.90, P less than 0.01) and between peak blood lactate and peak power fatigue (r = 0.92, P less than 0.01). The average increase in oxygen uptake above pre-exercise levels during the sprint test was greater for endurance-trained athletes than for the games players (ET vs GP: 35.0 +/- 2.2 vs 29.6 +/- 3.0 ml kg-1 min-1, P less than 0.05), corresponding to an average oxygen uptake per sprint (6-s sprint and 24 s of subsequent recovery) of 67.5 +/- 2.9% and 63.0 +/- 4.5% VO2 max respectively (N.S.). A modest relationship existed between the average increase in oxygen uptake above pre-exercise values during the sprint test and mean speed fatigue (r = -0.68, P less than 0.05). Thus, the greater decrement in performance for the games players may be related to higher glycolytic rates as reflected by higher lactate concentrations and to their lower oxygen uptake during the course of the 10 sprints.

Adult↗
PubMed1985

Reward, performance, and the response strength method in self-stimulating rats: validation and neuroleptics.

The response strength method consists of exposing the subject to a series of variable interval schedules of reinforcement at differing densities. Response rate is plotted against obtained reinforcement rate for each schedule. The data conform to a negatively accelerated curve that is fit well by an analytical representation which contains two parameters. The values of these parameters are obtained from the fitted curve, and are suggested to independently reflect reinforcement and performance functions. In a first experiment, two manipulations were conducted that validated these suggestions. First, lowering the frequency of brain stimulation pulses induced a relatively selective shift in the reinforcement parameter. Second, increasing the force required to press the lever primarily altered the performance parameter. In a second experiment, the effects of neuroleptic administration on these two parameters were noted and compared to the results of the first experiment. In general, neuroleptics were seen to produce both reward and motor/performance impairments in self-stimulating rats.

Animals↗
PubMedDate not supplied

Use of 5-nitroindole-2'-deoxyribose-5'-triphosphate for labelling and detection of oligonucleotides.

The 5'-triphosphate of 5-nitroindole-2'-deoxyriboside has been shown to be a good substrate for terminal deoxynucleotidyl transferase (TdT). An antibody has been prepared for the detection of 5-nitroindole and has been used for the detection of 5-nitroindole tailed DNA both in single-stranded form and after hybridisation to a template. This is therefore a new method for the detection of nucleic acid probes.

Antibodies↗
PubMedDate not supplied

Synthesis and study of the fluorescein conjugate of the nucleotide dPTP.

The synthesis of a fluorescein conjugate on the non-natural base P is described. The ability of the newly synthesised fluorescein--dPTP and of a fluorescein-11-dUTP to compete with the natural nucleotide TTP was also studied. Overall the efficiency of labelling a nucleic acid with a fluorescein moiety was found to be approximately equal.

Binding, Competitive↗