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Biomedical subjects

D B Barnett

Publications and source records attributed to D B Barnett.

At least 19 recordsLinked to original sources
PubMed1992

Effects of age, sex and the oral contraceptive on the platelet membrane fibrinogen binding site (glycoprotein IIb/IIIa).

1. We have studied the effects of age, sex and the oral contraceptive pill on platelet fibrinogen 'receptor' density (Bmax) and affinity (Kd). 2. [125I]-fibrinogen binding to gel-filtered platelets was assessed after stimulation with adenosine 5-diphosphate (ADP) and thrombin in 60 normal subjects; 37 females and 23 males. 3. For both agonists there was no significant difference in Bmax or Kd between the sexes. A trend towards increasing affinity (reduced Kd) with age was noted in the female group following ADP stimulation. This was not considered to be physiologically relevant. In the group as a whole no significant relationship of Bmax and Kd with age was demonstrated. 4. A further group of eight women taking low dose oestrogen combined oral contraceptive pill were studied on days 7, 14, 21 and 28 of the treatment cycle and compared with eight women with regular ovulatory cycles. No significant variations in Bmax or Kd were detected within or between cycles in these two groups.

Adenosine Diphosphate↗
PubMed1991

125I-fibrinogen binding to platelets in myeloproliferative disease.

Recent reports have suggested a variation in the density and affinity of fibrinogen binding sites in platelets from patients with myeloproliferative disorders (MPD) which may reflect platelet functional abnormalities in these subjects. We have investigated the binding of 125I-fibrinogen (125I-Fb) to gel-filtered platelets from a large relatively homogeneous group of patients with MPD compared to normal age matched controls. Twenty-two of the patients investigated had polycythaemia vera and four essential thrombocythaemia. The maximal density and affinity (Kd) of 125I-Fb binding was assessed by saturation analysis in gel-filtered platelets (GFP) stimulated with either 10 microM ADP or 150 mU thrombin. In addition the functional significance of the binding sites was studied by evaluating the response of GFP from the two experimental groups by assessing the effects of increasing concentrations of added fibrinogen on the response to 10 microM ADP using standard light transmission aggregometry. In both groups the density of fibrinogen binding sites expressed in response to thrombin stimulation was significantly higher (approximately 2-3 fold) than that found in response to ADP. However, fewer binding sites were detected in the MPD group as compared with the control group in response to both ADP and thrombin. The Kd for 125I-Fb was similar for both agonists in normal controls and was significantly lower than that found in the MPD subjects. Although the 125I-Fb binding study results indicate a significant reduction in both the number and affinity of fibrinogen binding sites in patients with myeloproliferative disorders, the clinical and functional significance of these findings remain uncertain.

Blood Platelets↗
PubMed1991

Cardiac beta-adrenoceptor regulation and the effects of partial agonism.

The in vivo effects of xamoterol on the regulation of rat cardiac beta adrenoceptors were investigated. Rats were implanted subcutaneously with osmotic minipumps and exposed to the following treatment regimens: (1) subcutaneous infusion of saline (control), isoprenaline or xamoterol for 6 days, (2) subcutaneous infusion of isoprenaline with co-administration of xamoterol for various periods up to 96 hours, and (3) subcutaneous infusion of xamoterol for up to 96 hours after previous treatment with isoprenaline for 72 hours. Xamoterol did not induce beta-adrenoceptor down-regulation after short-term (72-hour) or long-term (6-day) infusions. When coadministered with isoprenaline xamoterol did not affect the rate or extent of down-regulation induced by isoprenaline alone. In addition, recovery of beta adrenoceptors down-regulated by isoprenaline treatment was not influenced by xamoterol treatment. In all studies, doses of xamoterol were equivalent to those producing full functional responses to the drug in vivo.

Adrenergic beta-Agonists↗
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↗