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Biomedical subjects

P Lumley

Publications and source records attributed to P Lumley.

At least 37 records · Page 2Linked to original sources
PubMed1988

Use of an anti-platelet monoclonal antibody F(ab')2 fragment for imaging thrombus.

Ten patients with suspected thrombus have been studied using 111In-labelled F(ab')2 fragments of P256, a monoclonal antibody which recognizes an epitope on the platelet membrane glycoprotein protein IIb/IIIa complex. The F(ab')2 fragment was radiolabelled with 111In via diethylenetriaminepenta-acetic acid to give a specific activity of up to 190 MBq (5 mCi) mg-1 without impairment of immunoreactivity. In vitro platelet aggregation studies showed that the F(ab')2 fragment caused less platelet aggregation than the whole antibody on a molar ratio and was without significant effect upon the sensitivity of platelets to a range of aggregating agents. Platelets were labelled in ten patients by intravenous injection of approximately 100 micrograms P256 F(ab')2. Of the ten patients studied, six showed localization of activity consistent with platelet accumulation. Localization was clearly seen when associated with thrombus of the lower limbs (three patients: deep vein thrombosis; one patient: aortofemoral graft), and was apparent although less marked in two other cases, one of aortic aneurysm and one of carotid stenosis. Use of radiolabelled P256 F(ab')2 offers a means of non-invasive detection of thrombus which, from in vitro studies, would appear to have less direct effect on platelet behaviour than the whole antibody.

Antibodies, Monoclonal↗
PubMed1988

AH6809, a prostaglandin DP-receptor blocking drug on human platelets.

1. The effect of AH6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid) has been studied upon the anti-aggregatory and aggregatory actions of various agents on human platelets in whole blood. 2. Prostaglandin D2 (PGD2), BW245C, 9 alpha, 11 beta-PGF2, PGI2 and 5'-N-ethylcarboxamide adenosine (NECA) all inhibited ADP-induced platelet aggregation in whole blood. The anti-aggregatory activity of PGD2, BW245C and 9 alpha, 11 beta-PGF2 but not PGI2 or NECA was antagonized by AH6809. NECA was antagonized by AH6809. 3. The antagonism of the anti-aggregatory activity of PGD2 by AH6809 was concentration-related and could be overcome by increasing the concentration of PGD2. Analysis of the data yielded an apparent pA2 for AH6809 of 5.35. 4. At approximately 10 fold higher concentrations than those required to antagonize the action of PGD2, AH6809 also antagonized the aggregatory effect of U-46619 in whole blood (pA2 = 4.45). However, concentrations of AH6809 up to 300 microM were without effect upon either ADP- or platelet activating factor (Paf)-induced aggregation (pA2 less than 3.5). 5. The potency of AH6809 against PGD2 and U-46619 was increased in a resuspended platelet preparation suggesting that the drug is extensively bound to plasma proteins. However, in resuspended platelets the specificity of AH6809 relative to that seen in whole blood was reduced since aggregation by ADP and Paf was also slightly antagonized. 6. In conclusion, AH6809 appears to be a weak but specific DP-receptor blocking drug on human platelets and should prove to be a useful drug tool for defining the involvement of endogenous PGD2 in platelet aggregation and classifying the mode of action of anti-aggregatory prostanoids.

1-Methyl-3-isobutylxanthine↗
PubMed1986

Imaging thrombus with radiolabelled monoclonal antibody to platelets.

Indium-111-hydroxyquinoline labelled platelets, though useful in the detection of thrombus, have not gained widespread use owing to the time and technical skill required for their preparation. A study was therefore conducted evaluating a new method of imaging thrombus with platelets radiolabelled with a 111In labelled monoclonal antibody, P256, directed to the platelet surface glycoprotein complex IIb/IIIa. When the number of receptors occupied by P256 was less than 3% of the total available on the platelet surface platelet function, as assessed by platelet aggregometry, was undisturbed. P256 was radiolabelled with 111In using diethylenetriaminepenta-acetic acid, which achieved a specific activity of 185 MBq (5 mCi)/mg. No impairment of immunoreactivity was detected at this specific activity. Platelets were labelled with radiolabelled monoclonal antibody in vitro in two patients at a receptor occupancy of 6% and in vivo--that is, by direct intravenous injection of P256--in six patients at a receptor occupancy of 1%. In vivo recovery and biodistribution kinetics suggested that after in vitro labelling platelets were minimally activated. The 111In kinetics recorded after intravenous P256 suggested rapid and efficient radiolabelling of platelets and gave no indication of platelet activation. Of the six patients who received intravenous P256, three had documented thrombus, two of whom gave positive results on P256 platelet scintigraphy. The third subject had chronic deep venous thrombosis and was scintigraphically negative. Imaging thrombus using a radiolabelled monoclonal antibody directed to platelets appears to offer great potential as a simple, non-invasive approach to the diagnosis of thrombosis.

Animals↗
PubMed1986

Effect of the specific thromboxane receptor blocking drug AH23848 in patients with angina pectoris.

The effect of the specific thromboxane receptor blocking drug AH23848 was investigated in two double blind placebo controlled studies in male patients with exercise induced angina pectoris and angiographically verified coronary lesions. In the first study cardiac pacing was performed in twenty patients after coronary angiography. Patients were then randomised into two groups and received either AH23848 (70 mg orally) or placebo. One hour later cardiac pacing was repeated. Neither treatment had any significant effect upon time to angina or the rate-pressure product at the onset of chest pain in these patients. In the second study twenty male patients were randomised to seven days' treatment with AH23848 (70 mg three times a day) or placebo followed by a crossover to the other treatment for a further seven days. Clinical assessment was performed before treatment and at the end of each treatment period. There was no significant difference between the placebo and AH23848 treatment periods in exercise tolerance, the rate-pressure product at angina after exercise testing, the number of ischaemic attacks as determined from 24 hour ambulatory electrocardiograms, the number of attacks of pain, or the number of glyceryl trinitrate tablets consumed. This lack of a clinical effect with AH23848 was seen despite a profound inhibition of ex vivo platelet aggregation stimulated by the thromboxane A2-mimetic U-46619. Because in experimental animals in vivo AH23848 blocks vascular thromboxane receptors as well as platelet thromboxane receptors the lack of effect of AH23848 in cardiac pacing and exercise induced angina is unlikely to be the result of inadequate blockade of thromboxane receptors. The lack of effect of the drug is more likely to indicate that thromboxane A2, is not a factor in the aetiology of the pain experienced by these patients during exercise or cardiac pacing.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1984

Effects of intravenous infusions of prostaglandin D2 in man.

Prostaglandin D2 (PGD2) was infused intravenously into normal male volunteers. Seven subjects received infusions of 16, 32, 64 ng/kg/min and six of these a further dose of 128 ng/kg/min. Each individual's maximum dose was limited by discomfort caused by intense facial flushing and nasal congestion. At these doses there was no significant effect on systolic or diastolic blood pressure nor on spirometric measurements. There was a small but statistically significant tachycardia at 64 and 128 ng/kg/min. Collagen- and adenosine diphosphate (ADP)-induced platelet aggregation ex vivo was not affected at any of the infusion rates. Infused PGD2 is unlikely to be a useful antithrombotic agent.

Adenosine Diphosphate↗
PubMed1982

Comparison of the potencies of some prostaglandins as vasodilators in three vascular beds of the anaesthetised dog.

Following close intra-arterial administration to the carotid and femoral arterial beds of the anaesthetised dog the rank order of potency for producing vasodilation was PGE greater than 11-deoxy PGE0 greater than PGA greater than PGI2 greater than PGB with the 1- and 2-series prostaglandins equipotent. PGI2 was about 60 times weaker than PGE1. In the mesenteric arterial bed the rank order of potency for producing vasodilation was the same except PGI2 was about equipotent with PGE1. The absolute potency of the prostaglandins, with the exception of PGI, was similar on all three vascular beds. A similar differential action of PGI2 relative to PGE1 was also observed following both left intraventricular and intravenous administration. We suggest that all three arterial beds contain PGE-receptors mediating vasodilatation at which the E-series prostaglandins are potent and PGI2 is weak. In addition the mesenteric bed contains PGI2-receptors which are absent or sparse in the carotid and femoral beds.

Alprostadil↗
PubMed1982

Studies on the characterisation of prostanoid receptors: a proposed classification.

Comparison of rank orders of agonist potency of the naturally occurring prostanoids, PGD2, PGE2, PGF2 alpha and PGI2 as well as the stable TxA2 mimetic, U-46619, on a range of smooth muscle preparations provides evidence for the existence of distinct receptors for PGE2, PGF2 alpha and TxA2. Since others have provided evidence for the existence of distinct receptors for PGD2 and PGI2, we suggest that receptors exist for each of these naturally occurring 2-series prostanoids. Results obtained with two specific prostanoid receptor blocking drugs, SC-19220 and AH 19437, support and extend these conclusions. SC-19220 selectively blocks some but not all PGE-sensitive receptors, while AH 19437 selectively blocks all U-46619/TxA2-sensitive receptors. A nomenclature for prostanoid receptors is proposed, in which each receptor is designated the letter P preceded by a letter signifying the most potent natural prostanoid agonist at that receptor, such that receptors sensitive to PGs D2, E2, F2 alpha, I2 and TxA2 become DP-, EP-, FP-, IP and TP- receptors respectively. Where some sub-division is required within a receptor group, e.g. EP-receptors (SC-19220-sensitive and SC-19220-insensitive), subscript numbers may be used such that these are EP1 and EP2 subtypes. The resulting scheme is a working hypothesis and its confirmation requires the development of potent selective prostanoid receptor blocking drugs for each postulated type.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1982

Brief marital therapy outcome: personality correlates.

The purpose of the study was to investigate with regression analyses the relationship between personality and background variables and outcome of brief marital therapy. Twenty personality dimensions from the Personality Research Form and data on age, education, number of previous unions, number of children and number of sessions were used as independent variables. The dependent variable was provided by ratings of over-all improvement in affective communication: sexual, verbal, and social, provided by clinical records of 30 couples. The main result was that only the husband's traits were found to be important correlates of improvement in affective communication of both husbands and wives. The important traits involved husband's cognitive efficiency in the area of reflection and accurate judgement of situations, submissiveness, and sensitivity to social approval of his behaviour. The number of individual therapy sessions given to wives was also a notable predictor of improvement. Other personality and background variables were not significantly related to outcome.

Adult↗
PubMed1981

A method for quantitating platelet aggregation and analyzing drug-receptor interactions on platelets in whole blood in vitro.

A method for quantitating platelet aggregation in whole blood is described. The method is rapid and reproducible. By utilizing the Ultra-Flo 100 whole blood platelet count, platelet numbers before and after addition of an aggregating agent are counted electronically, without the need to separate platelets from other blood cell types. Although designed primarily for use with human blood, the Ultra-Flo can also be used successfully with blood from other species. The method has been used to study the antagonism of adrenaline-induced aggregation of platelets in human whole blood by the alpha-adrenoceptor blocking drug phentolamine. The potential of the method for studying drug-receptor interactions on platelets in vitro as well as rapid assessment of platelet function ex vivo is discussed.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1981

Comparison of the actions of U-46619, a prostaglandin H2-analogue, with those of prostaglandin H2 and thromboxane A2 on some isolated smooth muscle preparations.

1 The actions of the prostaglandin H2 (PGH2) analogue, U-46619, have been compared with those of PGH2 on thromboxane A2 (TxA2) on a range of isolated smooth muscle preparations in a superfusion cascade system. 2 U-46619 was a potent agonist on guinea-pig lung strip, dog saphenous vein and rat and rabbit aortae. In contrast, U-46619 was weak or inactive on guinea-pig ileum and fundic strip, cat trachea and dog and cat iris sphincter muscles, preparations on which either PGE2 or PGF2 alpha was the most potent agonist studied. 3 PGH2 was active on all of the preparations and displayed little selectivity. On some of the preparations, the actions of PGH2 may have been mediated indirectly by conversion to other prostanoids. 4 In contrast, TxA2 displayed the same pattern of selectivity as U-46619, being a potent agonist on the lung strip and vascular preparations but weak or inactive on the others. 5 It is suggested that U-46619 is a selective TxA2-mimetic and that it should therefore be a valuable tool in the study of the actions of TxA2.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1977

Analysis of the inotropic: chronotropic selectivity of dobutamine and dopamine in anaethetised dogs and guinea-pig isolated atria.

The previously reported in vivo inotropic selectivity of dobutamine and dopamine compared with isoprenaline has been demonstrated in anaesthetised bivagotamised open chest dogs. Responses of heart rate, right ventricular tension, left ventricular dP/dtmax, and blood pressure were measured. Compared with isoprenaline, dobutamine and dopamine were 1.8 and 2.4 times more active in increasing cardiac contractility than rate. The inotropic selectivity of dopamine but not that of dobutamine was abolished by pretreatment of dogs with syrosingopine. In guinea-pig isolated atria, isoprenaline, dobutamine, and dopamine were all slightly rate selective although this was less for dopamine. In atria incubated with phenoxybenzamine from guinea-pigs pretreated with reserpine only the dopamine dose-response curves were displaced to the right indicating a considerable indirect sympathomimetic component. The in vivo inotropic selectivity of dopamine could therefore be explained on the basis of this indirect activity being manifested at lower doses in the myocardium where the stores of catecholamines are more abundant than at the sinoatrial node. However, it is concluded that the inotropic selectivity of dobutamine seen in vivo is not due to indirect activity, reflex effects, or to a difference in the beta-adrenoceptors mediating the rate and tension responses of the heart. Possible alternative explanations are discussed.

Animals↗
PubMed1977

Selective reserpine-induced supersensitivity of the positive inotropic and chronotropic responses to isoprenaline and salbutamol in guinea-pig isolated atria.

1 Dose-response curves for the positive inotropic and chronotropic responses to isoprenaline were obtained in atria from untreated guinea-pigs and those receiving various reserpine pretreatments. 2 Tension responses were unaffected, whereas rate responses were depressed by the lowest dose of reserpine (0.05 mg/kg i.p. at 24 hours). 3 With larger 24 h doses and a 3 day pretreatment, the rate and tension dose-response curves were progressively displaced to the left, indicating supersensitivity which was greater for tension at each pretreatment. 4 No supersensitivity to histamine or Ca2+ could be detected, leading to the conclusion that it was selective for the beta-adrenoceptor agonists possibly at the receptor level. 5 As an indication of the adrenergic neurone depleting effectiveness of each reserpine dosage, preparations were exposed to test doses of beta-phenylethylamine. 6 Salbutamol was a partial agonist in untreated atria, the maximum rate (63.3%) and tension (10.0%) responses being less than those for isoprenaline. In atria from reserpine pretreated animals the supersensitivity was revealed as an increase of this maximum compared with isoprenaline. 7 The significance of this observation in relation to the possible mechanism of the supersensitivity is discussed.

Albuterol↗