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Biomedical subjects

D B Barnett

Publications and source records attributed to D B Barnett.

At least 55 records · Page 3Linked to original sources
PubMed1991

Assessment of quality of life.

Assessment of quality of life has emerged in recent years as an important part of the overall evaluation of drug therapy and health care in general. Measurement techniques for this difficult assessment range from simple unqualified questions on patient well-being to complex statistical analyses of a wide range of lifestyle and activity variables. The factors that influence quality of life during chronic drug therapy differ in the treatment of symptomatic (e.g., heart failure) vs asymptomatic (e.g., hypertension) disease, and include drug side effects, relief of symptoms, improved prognosis, return to work, physical activity and the need for further hospital treatments. The manifestation of quality of life varies for different people leading to lack of agreement on the precise definition. The absence of standardization of methods of measurement also contributes to this and leads to lack of comparability of studies and unreasonable claims by some drug manufacturers. Further complicating issues in multicenter trials across countries include language problems and interethnic differences in "sickness" behavior. The recently introduced quality-adjusted life year (QALY) index, designed to take account of both the quality and duration of life in assessing the outcome of treatments, may avoid some of these problems. By classifying illness states (the Rosser index) on the basis of disability and distress, and comparing outcomes in terms of improved prognosis, QALYs have already been used for cost/benefit analyses of a number of new and expensive therapies. Like other methods, QALYs have problems related to variability in individual appreciation of life values. To date, a perfect method of quality of life assessment remains elusive.

Disability Evaluation↗
PubMed1991

The effects of flosequinan on regional blood flow in normal man.

1. The effects of 100 mg and 200 mg flosequinan on limb, hepatic and renal blood flow were investigated in 14 healthy male volunteers in a placebo controlled double-blind randomised three-way crossover study. 2. Heart rate, blood pressure, forearm blood flow and venous capacitance measured by volume plethysmography, were recorded sequentially over 4 h, after oral dosing. 3. Apparent hepatic and renal blood flows were estimated 2 h post-dose by indocyanine green dye clearance and clearance of 125-iodohippuran respectively. 4. Flosequinan produced dose-dependent reductions in resting diastolic blood pressure, accompanied by a rise in heart rate. 5. Forearm blood flow increased to a maximum 4 h after 200 mg and this was accompanied by a fall in forearm vascular resistance. 6. Hepatic blood flow increased, compared with placebo, after 200 mg flosequinan, accompanied by a fall in hepatic vascular resistance. Renal blood flow remained unchanged but renal vascular resistance fell significantly, compared with placebo, following both doses of the drug. 7. In normal man blood flow to the limb, hepatic and renal vascular beds is preserved despite dose-dependent reductions in blood pressure following single doses of flosequinan.

Double-Blind Method↗
PubMed1990

Differential rates of down regulation and recovery of rat myocardial beta-adrenoceptor subtypes in vivo.

We have investigated the differential rate and extent of down regulation and recovery of rat myocardial beta adrenoceptor subtypes during and after short term (up to 72 h) subcutaneous isoprenaline infusions (40 micrograms/kg per h) in vivo using osmotic minipumps. Maximum density (Bmax) of the receptors in ventricular membranes was assessed by radioligand binding, saturation analysis using 125I-pindolol. Groups of animals were sacrificed following various agonist infusion times and then during recovery after removal of minipumps following initial infusion of isoprenaline for 72 h. During agonist infusion, beta 2 adrenoceptors down regulated significantly more rapidly and to a greater extent than the beta 1 subtype (maximum change from control 66% beta 2, 34% beta 1 P less than 0.05). In the recovery phase of the experiments following initial maximum down regulation, beta 2 adrenoceptor density also returned to control values more rapidly (by 24 h) than the beta 1 subtype (greater than 72 h). These results are qualitatively different to those reported in other tissues from this species using selective and non selective catecholamine agonists and in human myocardium in end stage heart failure following chronic sympathetic nervous stimulation. This may be due to differences in tissue cellular composition, the nature/selectivity of the agonist or the length of time of agonist exposure.

Animals↗
PubMed1990

Comparison of the effects of xamoterol and isoprenaline on rat cardiac beta-adrenoceptors: studies of function and regulation.

1. The effects of the beta 1-selective partial agonist xamoterol and the full agonist isoprenaline on rat cardiac beta-adrenoceptors were compared in functional studies of heart rate response in vivo and in vitro. In addition, the ability of both agents to cause receptor down-regulation in the rat heart following chronic (6 days) subcutaneous infusions was assessed by radioligand binding with [125I]-pindolol. 2. In the functional studies, xamoterol produced a maximal effect equivalent to approximately 65% of that of isoprenaline and was overall less potent than the full agonist. 3. Compared to saline control, the density of beta-adrenoceptors was reduced approximately 39% in ventricular membranes prepared from animals after 6 days of isoprenaline infusion but was unaffected by xamoterol. The relative proportions of the beta-adrenoceptor subtypes were unchanged by either active treatment. 4. Plasma xamoterol level at the end of the infusion period was equivalent to that associated with maximum tachycardia in vivo and to the concentration producing maximal stimulation of the rat isolated atrium in vitro. Thus suggesting 100% beta-adrenoceptor occupancy during the period of xamoterol infusion. 5. These results indicate that in this animal model xamoterol does not induce cardiac beta-adrenoceptor down-regulation during chronic treatment, with doses that produce a maximal functional response both in vitro and in vivo.

Animals↗
PubMed1989

Effects of calcium channel blockers on in vitro platelet function in whole blood using single platelet counting.

The effects of various calcium channel blockers on in vitro platelet aggregation were studied using whole blood platelet counting. Diltiazem and verapamil inhibited aggregation caused by adrenaline 5 microM and collagen 2 micrograms/ml, but only at concentrations far in excess of those seen in clinical use. Nifedipine and nimodipine also inhibited aggregation to these agonists, but this seemed to be due to the solvent used. The solvent for these dihydropyridines contains 15% ethanol, 15% polyethylene glycol and 70% water, and the ethanol component is the most likely to have caused an antiaggregatory effect. Other studies showing an antiaggregatory effect of dihydropyridines may not have taken account of this solvent effect.

Adult↗
PubMed1989

Lower than conventional doses of captopril in the initiation of converting enzyme inhibition in patients with severe congestive heart failure.

Angiotensin converting enzyme (ACE) inhibitors are effective long-term therapy for congestive heart failure, improving symptoms, exercise tolerance, biochemical anomalies, and mortality. Captopril, in doses of up to 150 mg daily is relatively free of serious adverse effects. A test dose of 6.25 mg normally precedes regular therapy in an attempt to avoid first-dose hypotension, which may also be prevented by reduction in diuretic dosage and by the avoidance of over-diuresis leading to volume depletion. We report two patients who, despite the above precautions developed symptomatic first-dose hypotension with 6.25 mg, but were subsequently able to recommence captopril therapy by the initial oral administration of doses as low as 1 mg.

Aged↗
PubMed1989

The effects of intravenous and oral nifedipine on ex vivo platelet function.

We have studied the possible anti-platelet effects of an intravenous formulation of nifedipine (0.75 mg as a bolus and an infusion of 1.2 mg.h-1 for 2 h), or equivalent volumes of the vehicle alone, or normal saline, in a double-blind crossover fashion in six healthy subjects. The effects of a standard oral formulation (20 mg sustained-release) compared to identical placebo were also studied in twelve other subjects. Platelet function was assessed by the addition of collagen, adenosine diphosphate, or adrenaline to whole blood followed by single platelet counting. Intravenous nifedipine had no effect on aggregation in response to any of the agonists, but oral nifedipine reduced aggregation caused by collagen by approximately 15%, despite similar plasma nifedipine concentrations after both formulations (18.5 ng.ml-1 after intravenous and 21.5 ng.ml-1 after oral administration). The lack of effect of intravenous nifedipine may be due to endothelial irritation caused by the vehicle. Intravenous nifedipine is unlikely to have a useful anti-platelet effect in patients who have acute coronary insufficiency.

Administration, Oral↗
PubMed1988

Is the human platelet beta 2 adrenoceptor coupled to adenylate cyclase?

The presence of beta 2 adrenoceptors on the human platelet is well established although the coupling of this receptor to adenylate cyclase is disputed. In this study of highly purified platelets isoprenaline did not stimulate whole platelet cyclic AMP alone or in the presence of forskolin. Minimal contamination of the purified platelets (approximately 0.05%) with mononuclear white blood cells may lead to the spurious appearance of isoprenaline stimulated cAMP. These results confirm our previous findings of lack of coupling of the human platelet beta 2 adrenoceptor to adenylate cyclase and indicate the importance of purity of preparation for platelet biochemical studies.

Adenylyl Cyclases↗
PubMed1988

Acute inotropic effects of intravenous nifedipine and its vehicle compared with saline: a double-blind study of systolic time intervals in normal subjects.

1. The inotropic effects of intravenous nifedipine and its vehicle were studied noninvasively in a double-blind placebo controlled crossover fashion using systolic time intervals in 12 normal subjects. 2. Nifedipine caused vasodilation, a fall in systolic and diastolic blood pressure, and increased heart rate. The vehicle alone caused vasodilation and decreased systolic blood pressure, without a change in heart rate. 3. Nifedipine increased left ventricular ejection time (LVET) and decreased pre-ejection period (PEP) and the ratio PEP/LVET, whereas the vehicle alone had the opposite effect. Neither treatment affected the total duration of electromechanical systole. 4. These results suggest that the vehicle has a negative inotropic effect, which is overcome by the indirect positive inotropic effect of nifedipine when they are administered together systemically.

Adult↗
PubMed1988

The haemodynamic effects of intravenous nifedipine in normotensive and hypertensive subjects.

The antihypertensive effects of intravenous nifedipine, given by bolus and 2 hour infusion, were studied at two dose levels in seven hypertensive (mean BP 178/114 mmHg) and five age-matched normotensive controls (mean BP 128/81 mmHg). Nifedipine significantly reduced systolic and diastolic blood pressure in the hypertensive patients by approximately 20%, but not in the normotensive controls. Similar changes in heart rate and forearm blood flow were seen after bolus injection in both groups, but these were not sustained during infusion. Intravenous nifedipine may be a useful acute treatment for hypertensive emergencies.

Adult↗
PubMed1987

Nifedipine infusion in acute myocardial infarction: experience in twelve patients.

Studies of nifedipine have not shown that it reduces myocardial infarct size in humans. These studies did not consider the pharmacokinetics and dynamics of nifedipine. Oral doses of nifedipine cause high plasma concentrations and possibly harmful hemodynamic changes. Intravenous nifedipine infusion can rapidly achieve and maintain a steady concentration without repeated hemodynamic upsets. We studied 24-h intravenous nifedipine infusion in 12 patients with acute myocardial infarct, starting within 6 (mean 4.0 +/- 0.7) h of onset of pain, to determine its safety, pharmacokinetics, and dynamics. An intravenous nifedipine bolus of 15 micrograms/kg was followed by an infusion of 0.9 mg/h for 24 h. After the bolus, pulse rate rose 12.5 +/- 8.0 p less than 0.01) and blood pressure fell (systolic by 20 +/- 34, p less than 0.05, and diastolic by 7.5 +/- 15.6, p less than 0.05). There were similar but lesser changes during the infusion. Myocardial oxygen requirements, as measured by the rate-pressure product, did not increase. The mean nifedipine concentration at steady state was 17.2 +/- 4.2 ng/ml and mean elimination T 1/2 3.57 +/- 2.70 h. Nifedipine was discontinued in 3 patients because of hypotension (SBP less than 90), rapid atrial fibrillation, and complete heart block in one patient each. Seven patients developed thrombophlebitis. Large studies of this preparation examining infarct size limitation and mortality are feasible, although in view of the problems of thrombophlebitis in peripheral veins, shorter infusion times or infusion via central lines would be more acceptable.

Administration, Oral↗
PubMed1987

Pharmacokinetics and pharmacodynamics of nifedipine infusion in normal volunteers.

Two studies of the pharmacokinetics and pharmacodynamics of intravenous nifedipine infusion were performed: the first, a randomised double-blind crossover study of nifedipine and its vehicle in eight subjects, the second a dose ranging study in nine subjects. Nifedipine pharmacokinetics did not vary with dose or duration of infusion up to 8 h, and are similar to those reported for other nifedipine preparations. Nifedipine increased heart rate and forearm blood flow and decreased blood pressure after bolus injection but not during prolonged infusion. The vehicle decreased blood pressure and increased forearm blood flow after bolus injection but not during prolonged infusion. It did not affect heart rate. The vehicle's haemodynamic activity has not been previously recognised and is of potential importance in the study of this and similar preparations of calcium antagonists.

Adult↗
PubMed1987

Human platelet beta 2-adrenoceptors: agonist-induced internalisation and down-regulation in intact cells.

1. The effect of isoprenaline (10 microM at 37 degrees C for 30 min) pretreatment on [125I]-(-)-pindolol ([125I]-(-)-Pin) binding to beta 2-adrenoceptors on intact human platelets has been examined. 2. By use of saturation analysis, maximal binding capacity (Bmax) of [125I]-(-)-Pin binding in control and treated cells was assessed in the presence of 1 microM (-)-propranolol or 1 microM (+/-)-CGP 12177 which were taken to represent total or cell surface beta-adrenoceptors respectively. Assay incubations were performed at 37 degrees C and 4 degrees C, the latter to prevent recycling of internalised receptors. 3. Isoprenaline treatment resulted in an identical, highly significant, loss of binding sites (approximately equal to 25%) defined by (-)-propranolol at both assay temperatures as compared to control cells. Binding sites identified in the presence of (+/-)-CGP 12177 were reduced to a much greater extent (approximately equal to 70%), but this was only seen when assays were performed at 4 degrees C. 4. Agonist-induced changes in receptor numbers were concentration-dependent with half maximal receptor loss occurring at an isoprenaline concentration of approximately 2 x 10(-8) M. These effects were inhibited by the presence of a beta-adrenoceptor antagonist and absent if agonist pretreatment was performed at 4 degrees C. 5. Recovery experiments showed that the isoprenaline-induced reduction in total receptor number defined by (-)-propranolol was irreversible whereas the reduction in cell surface receptors defined by (+/-)-CGP 12177 was rapidly reversible (less than 40 min). 6. These data suggest that isoprenaline treatment of intact human platelets causes redistribution of beta 2-adrenoceptors. A proportion are sequestered away from the cell surface (internalised), becoming inaccessible to the hydrophilic ligand (+/-)-CGP 12177. A smaller proportion defined by (-)-propranolol are apparently totally lost from the cell (down regulated).

Adrenergic beta-Agonists↗