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Biomedical subjects

J D Harry

Publications and source records attributed to J D Harry.

At least 19 recordsLinked to original sources
PubMed1996

Seventy-two hour comparison of methylprednisolone suleptanate and methylprednisolone sodium succinate in patients with acute asthma.

The efficacy and safety of the methylprednisolone prodrugs methylprednisolone suleptanate and methylprednisolone sodium succinate were evaluated in a multicentre, randomised, double-blind, double-dummy parallel study of 88 patients hospitalised with acute asthma. Each study drug was administered as a bolus intravenous injection of 40mg methylprednisolone equivalents every 6 hours for 48 hours. Methylprednisolone 32mg was administered orally 6 hours after the last dose. Pulmonary function, medical events, and clinical laboratory values were assessed at predefined intervals before and during the 72-hour study. The primary response measure of pulmonary function was per cent predicted forced expiratory volume in one second (FEV1) at 48 hours. Secondary response measures were peak expiratory flow rate (PEFR) and FEV1/forced vital capacity (FVC) ratio. Although both drugs demonstrated within-group mean changes from baseline (starting at 6 hours) that were statistically significant for each response, there were no statistically significant differences between the two groups. The mean percent predicted FEV1 at 48 hours and mean per cent change from baseline were 64% and 13% (p < 0.0001) for the methylprednisolone suleptanate group and 67% and 17% (p < 0.0001) for the methylprednisolone sodium succinate group, respectively. The mean PEFR and FEV1/FVC ratio at 48 hours were 5.77 l/s and 73% for the methylprednisolone suleptanate group and 5.78 l/s and 76% for the methylprednisolone sodium succinate group, respectively. There were no clinically or statistically significant between-group differences in any of the safety parameters. In this study, methylprednisolone suleptanate and methylprednisolone sodium succinate have been shown to be therapeutically equivalent in the treatment of patients hospitalized with acute asthma.

Acute Disease↗
PubMed1995

Safety, tolerance, and pharmacokinetics of atevirdine mesylate (U-87201E) in asymptomatic human immunodeficiency virus-infected patients.

Atevirdine mesylate (U-87201E) is a new nonnucleoside (bisheteroarylpiperazine) inhibitor of human immunodeficiency virus type 1 reverse transcriptase. In a double-blind, escalating single-dose study the safety, tolerance, and pharmacokinetics of atevirdine mesylate were investigated in 24 asymptomatic human immunodeficiency virus-seropositive male patients. Each patient received one single oral dose of atevirdine mesylate and placebo separated by an interval of 1 to 3 weeks. For each dose level (400, 800, 1,200, and 1,600 mg) six patients received drug and placebo on separate occasions. Blood samples were collected before dosing and at intervals afterward for safety evaluation and estimation of atevirdine and metabolite levels. The concentrations of atevirdine and its principal metabolite (U-89255) in serum were determined by high-performance liquid chromatography. The results of the study showed that atevirdine mesylate is well tolerated at all dose levels. No clinically significant effects on vital signs, electrocardiograms, or laboratory tests were observed. Occasional headache and nausea were reported both in the drug group and in the placebo group. The times to peak values were relatively short (0.5 to 1.0 h), suggesting a rapid absorption. The maximum concentrations of drug in serum were 1.4 microM (400 mg), 4.2 microM (800 mg), 7.3 microM (1,200 mg), and 5.8 microM (1,600 mg). The values of the pharmacokinetic parameters for atevirdine were found to have relatively large intersubject variabilities, and consequently, the study had little power to detect dose-dependent changes in the values of the pharmacokinetic parameters. The oral clearance of atevirdine tended to increase by 90% as the atevirdine mesylate doses increased from 400 to 1,600 mg, but this change in oral clearance was not statistically significant. The values of the pharmacokinetic parameters determined in the study were similar to those found in a previous single-dose study in healthy volunteers.

Adult↗
PubMed1994

Storage and release of mechanical energy by contracting frog muscle fibres.

1. Stretching a contracting muscle leads to greater mechanical work being done during subsequent shortening by its contractile component; the mechanism of this enhancement is not known. 2. This mechanism has been investigated here by subjecting tetanized frog muscle fibres to ramp stretches followed by an isotonic release against a load equal to the maximum isometric tension, T(o). Shortening against T(o) was taken as direct evidence of an absolute increase in the ability to do work as a consequence of the previous stretch. 3. Ramp stretches (0.5-8.6% sarcomere strain, confined to the plateau of the isometric tension-length relationship) were given at different velocities of lengthening (0.03-1.8 sarcomere lengths s-1). Isotonic release to T(o) took place immediately after the end of the ramp, or 5-800 ms after the end of the largest ramp stretches. The length changes taking place after release were measured both at the fibre end and on a tendon-free segment of the fibre. The experiments were carried out at 4 and 14 degrees C. 4. After the elastic recoil of the undamped elastic elements, taking place during the fall in tension at the instant of the isotonic release, a well-defined shortening took place against T(o) (transient shortening against T(o)). 5. The amplitude and time course of transient shortening against T(o) were similar at the fibre end and in the segment, indicating that it is due to a properly of the sarcomeres and not due to stress relaxation of the tendons. 6. Transient shortening against T(o) increased with sarcomere stretch amplitude up to about 8 nm per half-sarcomere independent of stretch velocity. 7. When a short delay (5-20 ms) was introduced between the end of the stretch and the isotonic release, the transient shortening against T(o) did not change; after longer time delays, the transient shortening against T(o) decreased in amplitude. 8. The velocity of transient shortening against T(o) increased with temperature with a temperature coefficient, Q10, of approximately 2.5. 9. It is suggested that transient shortening against T(o) results from the release of mechanical energy stored within the damped element of the cross-bridges. The cross-bridges are brought into a state of greater potential energy not only during the ramp stretch, but also immediately afterwards, during the first phase of stress relaxation.

Animals↗
PubMed1994

Effect of age and gender on tirilazad pharmacokinetics in humans.

Tirilazad mesylate pharmacokinetics were assessed in 12 young and 12 elderly volunteers (six men and six women per age group). Subjects received single 10-minute intravenous infusions of 1.5 mg/kg and 3.0 mg/kg tirilazad mesylate. Plasma tirilazad mesylate concentrations were determined by HPLC. There were no significant dose effects on clearance, but half-life increased with dose because of assay insensitivity at the lower dose. Mean half-lives were 16.3 +/- 15.5 and 21.4 +/- 12.6 hours for young and elderly subjects, respectively, at the 3.0 mg/kg dose. At the same dose, mean tirilazad mesylate systemic clearance was 0.630 +/- 0.254 and 0.428 +/- 0.090 L/hr/kg, respectively. The decreased clearance in elderly volunteers was primarily attributable to a lower clearance in elderly women relative to young women. The small effect of age on tirilazad clearance is likely to have minimum clinical impact. Tirilazad clearance was approximately 40% higher in young women than in young men. The clinical importance of this observation is unknown.

Adult↗
PubMed1993

Determining heart-rate variability: comparing methodologies using computer simulations.

Heart rate variation due to respiration is a window onto autonomic nervous system function and many measures exist that quantify this variability. Computer-based simulations of 1-minute deep-breathing tests, along with common artifacts, were used to compare the most frequently used measures. We found distinct differences in the performance of the measures. Some measures (e.g., SDRR and MSSD) are strongly influenced by the underlying mean heart rate while others (e.g., Max-Min and SDHR) are not. All of the measures tested, except R, were influenced by both shifting mean heart rate and single-beat anomalies. R, on the other hand, is strongly influenced by test duration and breathing asynchronies. Sensitivity to phenomena unrelated to ANS function can reduce the diagnostic discrimination of these measures. We suggest simple improvements to the measures and discuss how some measures may be theoretically superior to others.

Computer Simulation↗
PubMed1992

The effects of a selective 5-HT2 receptor antagonist (ICI 170,809) on platelet aggregation and pupillary responses in healthy volunteers.

1. ICI 170,809 (2-(2-dimethylamino-2-methylpropylthio)-3-phenylquinoline hydrochloride) is a potent 5-hydroxytryptamine (5-HT) type 2 postsynaptic receptor antagonist. 2. Effects of ICI 170,809 as single oral doses (3, 7, 15 and 30 mg) or placebo were studied on the duration of antagonism for the ex vivo platelet aggregatory response to 5-HT and to the pupillary light constrictor response in eight healthy male volunteers. 3. Pupillary dark adapted responses to a 0.5 s light stimulus were measured using a portable infrared pupillometer, for up to 24 h after dosing. 4. The in vitro platelet 5-HT aggregation response was reduced by ICI 170,809, with depression of the dose-response curve to 5-HT at all concentrations of 5-HT and with no evidence for a parallel shift. 5. The ex vivo platelet 5-HT response demonstrated a dose related significant (P less than 0.02) decrease in aggregation reaching a maximum at 2 h after dosing with the effect persisting for at least 8 h after dosing with the 7 and 15 mg doses. 6. Resting pupil diameter (RPD), and light induced pupillary responses in the dark adapted pupil, showed a significant (P less than 0.01) dose related reduction with significant (P less than 0.05) effects still present with the 15 and 30 mg doses at 8 h after dosing. 7. We conclude that, changes in both ex vivo platelet aggregation to 5-HT and dark adapted pupil size, are significantly correlated (P less than 0.0001) with log plasma concentrations (ng ml-1) of ICI 170,809, enabling the assessment of 5-HT2-receptor antagonism in man.

Adolescent↗
PubMed1990

Brain volume estimation from serial section measurements: a comparison of methodologies.

Estimation of brain volume from serial sections typically involves using a rectangular. Cavalieri's, parabolic (Simpson's), or a trapezoidal rule to integrate numerically a curve of cross-sectional area measurements plotted against section number. We practically compare the efficacy of each of these methods using mathematical simulations of regularly- and irregularly-shaped "brain volumes" as well as actual morphometric measures from brain regions. There are no meaningful differences between the various estimates when many sections are used--with fewer sections. Cavalieri's estimator is most accurate. This confirms previous theoretical reports demonstrating the efficiency and accuracy of the Cavalieri estimator of volume, particularly when few sections are analyzed. While the Cavalieri approach provides a better approximation of volume under some circumstances, it requires equally spaced sections. We therefore describe methods for the estimation of brain volume from unequally spaced sections, including an estimator based on the fitting of piece-wise parabolic curves to the data. We outline a series of guidelines for the use of these mathematical rules in the estimation of brain volume from serial sections.

Animals↗
PubMed1990

Cross-bridge cycling theories cannot explain high-speed lengthening behavior in frog muscle.

The Huxley 1957 model of cross-bridge cycling accounts for the shortening force-velocity curve of striated muscle with great precision. For forced lengthening, however, the model diverges from experimental results. This paper examines whether it is possible to bring the model into better agreement with experiments, and if so what must be assumed about the mechanical capabilities of cross-bridges. Of particular interest is how introduction of a maximum allowable cross-bridge strain, as has been suggested by some experiments, affects the predictions of the model. Because some differences in the models are apparent only at high stretch velocities, we acquired new force-velocity data to permit a comparison with experiment. Using whole, isolated frog sartorius muscles at 2 degrees C, we stretched active muscle at speeds up to and exceeding 2 Vmax. Force during stretch was always greater than the peak isometric level, even during the fastest stretches, and was approximately independent of velocity for stretches faster than 0.5 Vmax. Although certain modifications to the model brought it into closer correspondence with the experiments, the accompanying requirements on cross-bridge extensibility were unreasonable. We suggest (both in this paper and the one that follows) that sarcomere inhomogeneities, which have been implicated in such phenomena as "tension creep" and "permanent extra tension," may also play an important role in determining the basic force-velocity characteristics of muscle.

Animals↗
PubMed1990

The effect of oral dosing of xamoterol on systolic time intervals in man and xamoterol plasma concentrations in heart failure patients.

1. Six healthy male human volunteers of mean age 30.8 years (range 23-37) were given single oral doses of xamoterol (20, 50, 100 or 250 mg) and placebo with a 1 week interval between each dose. Xamoterol produced a significant decrease in systolic time intervals (QS2I, LVETI and PEPI) and a significant increase in systolic blood pressure indicating a positive inotropic effect on the heart at rest. The changes in QS2I were dose-related. Maximum decreases in QS2I were noted 1 to 2 h after dosing and were achieved with a dose of 100 mg. 2. In a second study, oral administration of xamoterol at 3 doses (100, 200 or 300 mg) and placebo were studied in 12 patients of mean age 60.4 years (range 52-73) with mild to moderate heart failure. Each dose was given twice daily for 7 days in a random order. Each dose of xamoterol produced a significant decrease in systolic time intervals indicating a positive inotropic effect on the heart at rest in patients with heart failure. It was not possible to distinguish between the effects of the three doses of xamoterol. 3. In heart failure patients, peak plasma concentrations of xamoterol occurred 1 to 2 h after dosing at all dosage levels and there was a linear relationship between dose and plasma concentration. 4. In both studies xamoterol was well tolerated and only minor adverse experiences were reported. 5. We conclude that, at rest, xamoterol has a positive inotropic effect on the heart when given orally to healthy volunteers or patients with mild to moderate heart failure.

Adult↗
PubMed1989

Effect of beta-adrenoceptor agents on the blood flow in carotid arteries in normal volunteers.

The effects on carotid artery blood flow of atenolol (a selective beta 1-adrenoceptor antagonist) and xamoterol (a beta 1-adrenoceptor partial agonist with 43% agonist activity) were measured using a Doppler technique in eight healthy volunteers. Atenolol produced a decrease in blood pressure and blood velocity flow, and tended to reduce volume flow. In contrast, there were no changes with xamoterol or placebo. Beta 1-adrenoceptor blockade may reduce cerebral blood flow but the partial agonist xamoterol does not appear to reduce carotid blood flow.

Adrenergic beta-Agonists↗
PubMed1989

Clinical pharmacology of epanolol. Pharmacodynamic aspects.

Epanolol has been shown in animal models to be a selective beta-adrenoceptor partial agonist with agonist activity about 20 to 25% of that of the full agonist isoprenaline. Evidence is presented in this review supporting the conclusion that epanolol has the same pharmacological properties in man and that the agonist activity at the beta-adrenoceptor is less than the activity present in pindolol, but greater than that present in acebutolol. The pharmacodynamic consequences in man of the degree of agonist activity possessed by the beta 1-selective partial agonist epanolol include little reductions at rest in heart rate, blood pressure, various measures of cardiac haemodynamic parameters, peripheral blood flow and renal function. On exercise there is attenuation of the heart rate and systolic blood pressure responses, with less perceived exertion than with atenolol. Evidence is available which shows that attenuation of the tachycardia of exercise persists for 24 hours after a single dose of epanolol 200mg, a dose which retains selectivity for the beta 1-adrenoceptor. This pharmacological profile of epanolol in man suggests that it would be an effective antianginal agent when 200mg once daily is administered. Moreover, its unique profile (compared with other antianginal agents) may make it more tolerable to patients than existing antianginal therapy.

Adrenergic beta-Agonists↗
PubMed1988

The dose in humans at which ICI 118,551 (a selective beta 2-adrenoceptor blocking agent) demonstrates blockade of beta 1-adrenoceptors.

The effects of four single oral doses of ICI 118,551 (a selective beta 2-adrenoceptor blocking agent: doses 10, 20, 50, and 100 mg) have been compared with placebo in five normal, healthy volunteers on some cardiovascular responses to intravenous infusions of dobutamine. Increasing infusions of dobutamine produced reproducible dose-dependent reductions in systolic time intervals and increases in systolic blood pressures, these responses representing positive inotropic effects of dobutamine. These effects of dobutamine were unaffected 2 hours after administration by 10 mg ICI 118,551 and minimally by 20 mg; the 50 mg dose attenuated the systolic time interval effect whereas the 100 mg dose attenuated further the systolic time interval reduction and also the increase in systolic blood pressure. These results allow a conclusion that at unit doses of 50 mg and above, ICI 118,551 will produce demonstrable effects on beta 1-adrenoceptors.

Adrenergic beta-Antagonists↗
PubMed1988

Effects of the beta 2-adrenoceptor antagonist ICI 118,551 on blood pressure in hypertensive patients known to respond to beta 1-adrenoceptor antagonists.

1. The selective beta 2-adrenoceptor antagonist ICI 118,551, 50 mg orally given thrice daily, did not lower blood pressure in hypertensive patients known to respond to therapy with atenolol or propranolol. 2. This dosage regimen resulted in a small decrease in supine heart rate which might represent partial beta 1-adrenoceptor antagonism by ICI 118,551. 3. The results suggest that beta 2-selective antagonism does not play a role in the hypotensive action of beta-adrenoceptor antagonists.

Adrenergic beta-Antagonists↗
PubMed1987

Effects of beta-adrenoceptor blockade on heart rate and physiological tremor in diabetics with autonomic neuropathy. A comparative study of epanolol, atenolol and pindolol.

Eight diabetics with autonomic neuropathy were given single oral doses of epanolol (200 mg), atenolol (50 mg), pindolol (5 mg) and placebo in a double-blind randomised order at weekly intervals. Supine resting heart rate, physiological tremor and blood glucose were measured before, 2 and 4 h after dosing, and ambulatory heart rate monitored for 24 h. Supine resting heart rate was significantly lowered by atenolol both at 2 and 4 h, and increased on pindolol at 4 h. Heart rate was unaffected by epanolol compared with placebo. Heart rate during the 'waking' period (14.00-23.00 h) was lower than placebo after epanolol and atenolol but unaffected by pindolol. During the 'sleeping' period (23.00 h-08.00 h) heart rate was significantly increased by pindolol, lowered with atenolol and unaffected on epanolol. Pindolol significantly increased physiological tremor at 4 h. No differences were seen between epanolol, atenolol and placebo. Plasma glucose was significantly increased by pindolol 2 h after dosing. These results suggest that pindolol probably produces its partial agonist activity at both beta 1- and beta 2-adrenoceptors, while the partial agonist activity of epanolol is beta 1-selective. Despite abnormal cardiovascular reflex tests in these diabetics, the heart rate responses obtained in this study after beta-adrenoceptor blockade were surprisingly normal, and suggest that the concept of 'cardiac denervation' in diabetes requires modification.

Adrenergic beta-Antagonists↗
PubMed1987

Early designs of the myograph.

A surge in quantitative muscle physiology began with the mid-nineteenth century introduction of a new instrument capable of measuring contraction events with millisecond resolution. This strictly mechanical device, called a "myograph" by its designer Hermann von Helmholtz, was based on existing technology but included several important innovations that made it suitable for recording accurately the high speed events of muscle contraction. A variety of different myograph designs, each with its own advantages and disadvantages, ultimately came into existence and populated muscle physiology laboratories into the twentieth century.

Electromyography↗
PubMed1985

Experience with a Doppler technique to investigate the interaction of isoprenaline and various B-adrenoceptor blocking drugs on blood vessels in the lower limb.

A Doppler technique has been used in three separate studies to measure the changes induced by increasing infusion rates of isoprenaline on blood velocity, blood flow and diameters in the femoral and posterior tibial arteries of normal volunteers and to investigate the effects of various B-adrenoceptor antagonists on these changes. Heart rate and blood pressures were also recorded. Isoprenaline produced the expected changes in heart rates and blood pressures in the volunteers and changes induced in these responses by the B-adrenoceptor antagonist were as seen by previous workers. The only expected finding was that systolic blood pressure at the ankle was decreased compared to that in the arm which was increased. Isoprenaline produced reproducible dose-dependent increases in blood velocity, blood flow and diameters in the femoral artery, but little or no effects in the posterior tibial artery. These differences may reflect the difference in distribution of these arteries, the femoral to large muscular beds and the posterior tibial artery essentially to skin vascular beds. The different effects of the B-adrenoceptor blocking drugs with different actions on B1- and B2-adrenoceptors on the responses of the Doppler measurements to isoprenaline would support the differences in distribution of the femoral and posterior tibial arteries and allow a conclusion that the muscle vascular beds contain essentially B2-adrenoceptors with respect to stimulation by isoprenaline. The results obtained in three separate studies using the Doppler technique do suggest that this non-invasive technique may be of value in investigating the physiology, and/or pharmacology of the peripheral circulation in man.

Adrenergic beta-Antagonists↗