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Biomedical subjects

S Heptinstall

Publications and source records attributed to S Heptinstall.

At least 91 records · Page 5Linked to original sources
PubMed1988

Feverfew--an antithrombotic drug?

The effects of an extract of the plant feverfew on the interaction of platelets with surfaces coated with human collagens of type III and IV (CIII, CIV), and on the integrity of the endothelial cell (EC) monolayer in perfused rabbit aorta were studied. It was shown that feverfew extract (FE) inhibited the deposition of [51Cr]-labelled platelets on both CIII and CIV in a dose-dependent way. Similar concentrations of FE were needed to inhibit formation of surface-bound aggregates in CIII and platelet spreading on CIV in both platelet-rich plasma and GFP. When aorta segments were perfused in situ with a physiological salt solution, the addition of FE to the solution protected the EC monolayer from spontaneous injury. The results indicate that feverfew may have antithrombotic potential in addition to its claimed benefit in fever, migraine and arthritis.

Animals↗
PubMed1988

Inhibition of platelet behaviour by feverfew: a mechanism of action involving sulphydryl groups.

Extracts of feverfew inhibit platelet aggregation and the platelet release reaction. The active components are believed to be sesquiterpene lactones such as parthenolide. Evidence is presented that inhibition of platelet behaviour is via neutralization of sulphydryl groups either inside or outside the cell. The precise nature of the sulphydryl groups that are susceptible to feverfew and are involved in platelet aggregation and the release reaction have not yet been defined.

Arachidonic Acids↗
PubMed1988

How can we inhibit 5-HT-induced platelet aggregation and why should we bother?

Different 5-HT receptor antagonists inhibit 5-HT-induced platelet aggregation with different potencies. The inhibitory effects of seven relatively potent antagonists could not be surmounted by increasing the concentration of 5-HT, but the inhibitory effects of seven less potent antagonists could be surmounted by 5-HT. Verapamil has in insurmountable inhibitory effect on 5-HT-induced aggregation at relatively low concentrations. Amlodipine is a very weak inhibitory of 5-HT-induced aggregation. Verapamil is more effective as an inhibitory of 5-HT-induced aggregation than it is of aggregation induced by PAF, adrenaline or ADP. The platelet aggregation obtained in whole blood in response to 5-HT, PAF, U46619 or ADP is not different in patients with peripheral vascular disease and age-sex matched controls.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1987

An extract of feverfew inhibits interactions of human platelets with collagen substrates.

The interaction of platelets with surfaces coated with collagens of type III (C III) or IV (C IV) has been studied by measuring the deposition of 51-Cr-labeled platelets and by scanning electron microscopy (SEM). Experiments were performed using platelet-rich plasma (PRP) and suspensions of gel-filtered platelets (GFP). Platelets were deposited on C III mainly as surface-bound aggregates. In contrast they were deposited on C IV mainly as spread forms of individual cells. Formation of aggregates on C III was more extensive for PRP than for GFP; in contrast platelet spreading on C IV was more extensive for GFP than for PRP. The effects of an extract of the plant feverfew on platelet-collagen interactions were determined. Feverfew extract inhibited the deposition of 51-Cr-labeled platelets on both C III and C IV in a dose-dependent way. Similar concentrations of extract were needed to inhibit the formation of surface-bound aggregates and to inhibit platelet spreading in both PRP and GFP.

Blood Platelets↗
PubMed1987

Extracts of feverfew may inhibit platelet behaviour via neutralization of sulphydryl groups.

It has been suggested that extracts of feverfew may inhibit platelet behaviour via effects on platelet sulphydryl groups. In the present study we have obtained evidence for such a mode of action. Compounds that contain sulphydryl groups such as cysteine and N-(2-mercaptopropionyl)glycine prevented the inhibition of platelet behaviour by feverfew. Feverfew and parthenolide (one of the active components of feverfew) dramatically reduced the number of acid-soluble sulphydryl groups in platelets. This effect occurred at concentrations similar to those that inhibited platelet secretory activity. Feverfew itself did not induce the formation of disulphide-linked protein polymers in platelets but polymer formation occurred when aggregating agents were added to feverfew-treated platelets. Feverfew evoked changes in the metabolism of arachidonic acid that were similar to those observed in glutathione-depleted platelets.

Arachidonic Acid↗
PubMed1987

Platelet aggregation in whole blood from patients with Glanzmann's thrombasthenia.

We examined platelet aggregation in platelet-rich plasma (PRP) and in whole blood from two patients with Glanzmann's thrombasthenia. In PRP, aggregation was measured by monitoring the changes in light absorbance that occurred in response to aggregating agents; to measure platelet aggregation in whole blood, we used a platelet counting technique. In PRP, the patients' platelets showed defective aggregation in response to ADP, adrenaline, arachidonic acid (AA), and collagen, but normal agglutination occurred in response to ristocetin. In whole blood, however, platelet aggregation in response to the aggregating agents appeared to be either very similar to that which occurred in blood from normal subjects or only slightly reduced. There was a reduced response to all concentrations of ADP and to low concentrations of collagen but a normal response to all concentrations of adrenaline, AA, and higher concentrations of collagen. Conversely, there seemed to be an increased agglutination response to ristocetin. The abnormality in our two patients with Glanzmann's thrombasthenia probably lies in the inability of their platelets to form large, macroscopic aggregates rather than in platelet aggregation per se.

Adenosine Diphosphate↗
PubMed1986

Effects of a thromboxane synthetase inhibitor and a cAMP phosphodiesterase inhibitor, singly and in combination, on platelet behaviour.

The effects of dazoxiben, a thromboxane synthetase inhibitor, and AH-P 719, a cAMP phosphodiesterase inhibitor, on arachidonic acid (AA)-induced platelet behaviour were determined. The levels of cAMP present in platelet-rich plasma (PRP) after stimulating the platelets with AA in the absence and presence of the agents were also measured. AH-P 719, as well as dazoxiben, was more effective as an inhibitor of AA-induced platelet behaviour in PRP from some individuals than in PRP from others, and the effectiveness with which it inhibited platelet behaviour paralleled that of dazoxiben. A combination of both agents was more effective than either agent alone. Both AH-P 719 and dazoxiben increased the level of cAMP in AA-stimulated platelets but again they were more effective in PRP from some individuals than others. A combination of AH-P 719 and dazoxiben always resulted in higher levels of cAMP than either agent alone. These results imply that cAMP is involved in determining the effects of thromboxane synthetase inhibitors on platelet behaviour, and indicate that the anti-thrombotic potential of a combination of a thromboxane synthetase inhibitor and a cAMP phosphodiesterase inhibitor may be greater than that of the individual agents.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1986

Platelet behaviour in non-insulin-dependent diabetes--influence of vascular complications, treatment and metabolic control.

Platelet-rich plasma was prepared from 47 patients with non-insulin-dependent diabetes treated with glibenclamide and metformin, and 21 controls. The release of radio-labelled 5-hydroxytryptamine in response to aggregating agents (adenosine diphosphate, adrenaline and sodium arachidonate), and the effects on release of a selective thromboxane inhibitor (UK-34787) were investigated. Subsequently, 20 of the diabetic subjects were chosen at random for treatment with insulin; the remainder continued to take tablets. Platelet studies were then repeated, in all patients, after 4 and 6 months. The results showed an association between platelet behaviour and the presence of vascular complications, and were consistent with previous observations of reduced platelet reactivity in patients taking sulphonylureas. There was no correlation of platelet reactivity with blood glucose, glycosylated haemoglobin or lipid levels.

Adenosine Diphosphate↗
PubMed1986

Inhibition of platelet aggregation in whole blood by dipyridamole and aspirin.

We have examined the effects of dipyridamole on platelet aggregation in whole blood both in vitro and after administration to man. The effects of dipyridamole ex vivo were compared with those of aspirin and a combination of dipyridamole and aspirin. In vitro dipyridamole was most effective as an inhibitor of platelet aggregation induced by platelet activating factor (PAF) and low concentrations of arachidonic acid (AA). Its inhibitory effect was always potentiated by adenosine suggesting that its effect on aggregation may be via inhibition of adenosine uptake into blood cells. Ex vivo, dipyridamole, aspirin and the combination of these drugs inhibited the platelet aggregation induced by PAF and AA. Again, adenosine increased the degree of inhibition. These results stress the importance of measuring platelet aggregation in the natural whole blood environment for detection of the inhibitory effects of dipyridamole and suggest a mode of action for the drug.

Aspirin↗
PubMed1986

Aspirin and dazoxiben as inhibitors of platelet behaviour: modification of their effects by agents that alter cAMP production.

The effects of aspirin and dazoxiben were determined on platelet behaviour in platelet-rich plasma (PRP) from 20 volunteers. Dazoxiben prevented aggregation and the release reaction induced by arachidonic acid (AA) in nine of the samples; in the other eleven aggregation and the release reaction still occurred. Aspirin always prevented aggregation and release but higher concentrations were needed in some of the samples of PRP than with others. When the platelets were sensitive to dazoxiben they were relatively sensitive to aspirin; when they were insensitive to dazoxiben they were relatively insensitive to aspirin. The effects of agents that alter production of cAMP on the sensitivity of platelets to aspirin and dazoxiben were determined. Increasing the intracellular level of cAMP rendered platelets more sensitive to the inhibitory effects of both aspirin and dazoxiben; lowering the level of cAMP made the platelets less sensitive to both agents.

Adenine↗
PubMed1986

Spontaneous platelet aggregation in heparinised blood during pregnancy.

A marked increase in spontaneous platelet aggregation in whole blood was found during pregnancy. The increased spontaneous aggregation was most evident in whole blood anticoagulated with heparin; it was less marked in blood that contained citrate as anticoagulant. Studies of blood that contained both anticoagulants indicated that it is heparin that potentiates aggregation in blood taken during pregnancy rather than citrate that inhibits it. Increased spontaneous aggregation was seen in normotensive pregnancy, in pregnancy complicated by essential hypertension and in pregnancy-induced hypertension. In normotensive pregnancy it was evident at 16 weeks gestation but in pregnancy complicated with essential hypertension it was not evident until 24 weeks gestation. For all the women spontaneous aggregation had returned to normal six weeks after delivery.

Adult↗
PubMed1986

Effects of combinations of 5-hydroxytryptamine receptor antagonists on 5-HT-induced human platelet aggregation.

We have examined the effects of fourteen 5-HT-receptor antagonists on 5-HT-induced platelet aggregation in whole blood. Two different types of inhibitory profile were obtained. The inhibitory effects of seven of the antagonists (designated type 1) could be surmounted by increasing the concentration of 5-HT; the inhibitory effects of the other antagonists (type 2) were insurmountable by 5-HT. The effects of combinations of pairs of different antagonists were investigated. The inhibitory effects of pairs of type 1 antagonists and of pairs of type 2 antagonists were additive. However, a type 1 antagonist interfered with the inhibitory effects of a type 2 antagonist. The two types of antagonist differed in the rate at which they inhibited 5-HT-induced aggregation, a type 2 antagonist exerting its effect more slowly than a type 1 antagonist. Two possible explanations of these results are considered. It is possible that there are two different types of receptors on the surface of platelets, one causing stimulation and the other causing allosteric inhibition of platelet aggregation. Alternatively, the results may stem from different rates of association and dissociation of the agents at a single 5-HT receptor.

Drug Interactions↗
PubMed1986

Arachidonic acid metabolism by peripheral blood cells in psoriasis.

The metabolism of arachidonic acid by mixed suspensions of leukocytes and platelets prepared from peripheral blood has been studied in 20 patients with psoriasis and 21 healthy controls. A lipoxygenase-derived product, identified as 12,20-dihydroxy-5,8,10,14-eicosatetraenoic acid was formed in increased amounts by the cell suspension from the psoriatic patients. This product results from the metabolism of platelet-derived 12-hydroxy-5,8,10,14-eicosatetraenoic acid by the polymorphonuclear leukocyte 20-hydroxylase enzyme. By contrast, synthesis of the cyclo-oxygenase products 12-hydroxy-5,8,10-heptadecatrienoic acid and thromboxane B2 was diminished. Benoxaprofen, which is known to be beneficial in psoriasis, diminished the levels of 12,20-dihydroxy-5,8,10,14-eicosatetraenoic acid formed in vitro.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1986

Compounds extracted from feverfew that have anti-secretory activity contain an alpha-methylene butyrolactone unit.

Extracts of feverfew inhibit secretion of granular contents from platelets and neutrophils and this may be relevant to the therapeutic value of feverfew in migraine and other conditions. In this investigation we fractionated an extract of feverfew and obtained eleven fractions with antisecretory activity. The activity. The active fractions, together with two fractions that were devoid of anti-secretory activity, were examined using 1H NMR and infrared spectroscopy. All the active fractions (but neither of the inactive fractions) contained compounds with an alpha-methylene butyrolactone unit. Five compounds that contain this unit were identified as parthenolide, 3-beta-hydroxyparthenolide, secotanapartholide A, canin and artecanin, all of which are sesquiterpene lactones. It is very likely that these and other sesquiterpene lactones that contain an alpha-methylene butyrolactone unit are responsible for the anti-secretory activity in extracts of feverfew.

4-Butyrolactone↗