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Dive into the research topics where Keith Butler is active.

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Featured researches published by Keith Butler.


British Journal of Pharmacology | 1985

CGS 12970: a novel, long acting thromboxane synthetase inhibitor.

John Ambler; Keith Butler; Edmond C. Ku; Eric D. Maguire; J.R. Smith; Robert B. Wallis

1 CGS 12970 is a potent selective inhibitor of human platelet thromboxane synthestase in vitro (IC50 = 12 nM). It is four orders of magnitude less potent as an inhibitor of sheep seminal vesicle cyclo‐oxygenase, bovine aorta prostacyclin synthetase and human leucocyte 15‐lipoxygenase. 2 The compound inhibited collagen‐induced thromboxane B2 production by human platelets in vitro without an effect on the accompanying platelet aggregation induced by collagen, ADP, platelet activating factor, thrombin, arachidonic acid or the prostaglandin mimetic, U 46619. 3 Administration of CGS 12970 to rats inhibited collagen‐induced thromboxane B2 production but had no effect on platelet aggregation ex vivo. It also had no effect on platelet aggregation induced by thrombin or on plasma clotting times. 4 A single oral dose of 1 or 3 mg kg−1 to rabbits inhibited thromboxane B2 production in clotting blood ex vivo for 12 or 24 h respectively. 5 CGS 12970 inhibited thromboxane B2 production in vivo induced by intravenous administration of collagen to rats or calcium ionophore to guinea‐pigs. In both cases there was a concomitant elevation of immunoreactive 6‐keto‐prostaglandin F1α but no effect on the induced thrombocytopenia. 6 As with other thromboxane synthetase inhibitors, CGS 12970 prolonged tail bleeding time in the rat. However, CGS 12970 was not as potent as other thromboxane synthetase inhibitors in this test. 7 In addition to these usual effects of thromboxane synthetase inhibitors, CGS 12970 inhibited the thrombocytopenia induced by the Forssman reaction or ADP administration. In these tests the effect of the compound was of short duration. 8 CGS 12970 had no effect on the thrombocytopenia associated with the Arthus reaction which distinguishes it from cyclo‐oxygenase inhibitors. It also had no effect on thrombus formation on a cotton thread in an arteriovenous shunt in the rat.


British Journal of Pharmacology | 1981

MECHANISMS OF FORSSMAN‐INDUCED BRONCHOSPASM AND THEIR INHIBITION

Keith Butler; J.R. Smith

1 The bronchospasm induced in the guinea‐pig by the injection of Forssman antiserum was biphasic in nature in both the sublethal and the lethal reaction. 2 The development of both phases of the bronchospasm in the sublethal reaction was dependent upon the presence of the intact complement system and circulating platelets. In the lethal reaction the phase II bronchospasm did not appear to depend on these factors. 3 The compounds used in this study inhibited phase I bronchospasm of the sublethal reaction in the order, methysergide > indomethacin > aspirin = sulphinpyrazone and phase II in the order, indo‐methacin > sulphinpyrazone > aspirin. Methysergide was inactive. 4 Aspirin, indomethacin and sodium salicylate all prevented the inhibitory action of sulphinpyrazone in reducing the phase II bronchospasm of the sublethal reaction in the order, indomethacin > sodium salicylate > aspirin, when the drugs were administered prior to sulphinpyrazone. 5 The inhibitory action of aspirin on the sulphinpyrazone effect could be prevented by administering sulphinpyrazone before aspirin. All drug‐induced inhibitions of sulphinpyrazone by aspirin, indomethacin and sodium salicylate were dose‐dependent.


Haemostasis | 1991

The effects of recombinant desulphatohirudin on arterial thrombosis in rats.

Mark Talbot; John Ambler; Keith Butler; Christopher M. Lees; Kevin A. Mitchell; Robin F. Peters; Morris Tweed; Robert B. Wallis

The role of thrombin in the formation of arterial thrombi is poorly understood. With the new availability of the specific thrombin inhibitor, recombinant desulphatohirudin, in large quantities this is now under investigation. A new model of arterial thrombosis in rats is described where a thrombus is formed on a mechanically injured vessel in vivo. Both platelet and fibrin deposition is inhibited by a recombinant hirudin (CGP 39393) at doses which prolong the activated partial thromboplastin time (APTT) to no more than 3-4 times the control level. In contrast, both unfractionated heparin and Fragmin only inhibit thrombosis when the APTT is excessively prolonged (i.e. to greater than 15 times the control value). It is concluded that CGP 39393 is an effective antithrombotic in arterial thrombosis at lower levels of anticoagulation than either heparin or Fragmin.


Bioorganic & Medicinal Chemistry Letters | 2000

the design and synthesis of thrombin inhibitors: the introduction of in vivo efficacy and oral bioavailability into benzthiazolylalanine inhibitors

Judy Hayler; Peter Kane; Darren Mark Legrand; Florence Lugrin; Keith Menear; Richard Price; Mark C. Allen; Xiao-Ling Fan Cockcroft; John Ambler; Keith Butler; Karren Dunnet; Andrew Mitchelson; Mark Talbot; Morris Tweed; Nicholas Wills

The further optimisation of the novel lead compound CGH752 (Fig. 1) is described. By introducing various substituents into the 6-position of the 3,3-dimethyltetrahydroquinoline (DMTHQS) ring we have been able to favourably affect the in vitro and in vivo activity, and the pharmacokinetics of such compounds. One of the inhibitors synthesised (CGH1484) is bioavailable and shows efficacy in animal models of thrombosis.


Bioorganic & Medicinal Chemistry Letters | 1999

Studies towards the identification of potent, selective and bioavailable thrombin inhibitors.

John Ambler; Emma Baker; Dave Bentley; Lyndon Nigel Brown; Keith Butler; Paul Butler; Dave Farr; Karen Dunnet; Darren Le Grand; Judy Hayler; Diana Janus; Darryl Brynley Jones; Keith Menear; Mark Mercer; Garrick Smith; Mark Talbot; Morris Tweed

The application of selection criteria, based on potency and physicochemical parameters, to a candidate library of thrombin inhibitors is described. The utility of the approach is exemplified by the discovery of a potent, selective and bioavailable thrombin inhibitor 62.


British Journal of Pharmacology | 1992

The pharmacological modulation of thrombin-induced cerebral thromboembolism in the rabbit.

Gillian R. May; William Paul; P. Crook; Keith Butler; Clive P. Page

1 Intracarotid (i.c.) administration of thrombin induced a marked accumulation of 111indium‐labelled platelets and 125I‐labelled fibrinogen within the cranial vasculature of anaesthetized rabbits. 2 Thrombin (100 iu kg−1, i.c.) — induced platelet accumulation was completely abolished by pretreatment with desulphatohirudin (CGP 39393; 1 mg kg−1 i.c., 1 min prior to thrombin). Administration of CGP 39393 1 or 20 min after thrombin produced a significant reduction in platelet accumulation. 3 Intravenous (i.v.) administration of the platelet activating factor (PAF) receptor antagonist BN 52021 (10 mg kg−1) 5 min prior to thrombin (100 iu kg−1, i.c.) had no effect on platelet accumulation. 4 An inhibitor of NO biosynthesis, l‐NG‐nitro arginine methyl ester (l‐NAME; 100 mg kg−1, i.c.), had no significant effect on the cranial platelet accumulation response to thrombin (10 iu kg−1, i.c.) when administered 5 min prior to thrombin. 5 Defibrotide (32 or 64 mg kg−1 bolus i.c. followed by 32 or 64 mg kg−1 h−1, i.c., infusion for 45 min) treatment begun 20 min after thrombin (100 iu kg−1, i.c.) did not significantly modify the cranial platelet accumulation response. 6 Cranial platelet accumulation induced by thrombin (100 iu kg−1, i.c.) was significantly reversed by the fibrinolytic drugs urokinase (20 iu kg−1, i.e., infusion for 45 min), anisoylated plasminogen streptokinase activator complex (APSAC) (200 μg kg−1, i.v. bolus) or recombinant tissue plasminogen activator (rt‐PA; 100 μg kg−1, i.c. bolus followed by 20 μg kg−1 min−1, i.c., infusion for 45 min) administered 20 min after thrombin. APSAC had no significant effect when administered 3 h after thrombin. 7 APSAC (200 μg kg−1, i.v. bolus) significantly reversed thrombin (100 iu kg−1, i.c.) — induced intracranial accumulation of 125I‐fibrinogen when administered 20 min after thrombin. 8 These results suggest that neither endogenous PAF nor NO modulate thrombin‐induced intracranial platelet accumulation in the rabbit. However, fibrin deposition appears to play an important role as shown by the ability of fibrinolytic agents to reverse platelet and fibrinogen accumulation induced by i.c. thrombin.


Thrombosis Research | 1987

The kinetics of platelet and fibrin deposition on to damaged rabbit carotid arteries in vivo: involvement of platelets in the initial deposition of fibrin

R.A. Shand; Keith Butler; J.A. Davies; V.C. Menys; Robert B. Wallis

Thrombus formation in the rabbit carotid artery has been studied kinetically in vivo using a minimally invasive technique utilising radioisotopes. Clamping of the carotid artery for 5 min resulted in the simultaneous accumulation of platelets and fibrin at the site of injury over the next 45 min. Under the electron microscope the response was seen to range from platelet monolayer adhesion to mural thrombus formation with fibrin deposition. In animals rendered thrombocytopenic, fibrin deposition was impaired during the first 15-20 minutes after injury. Basic coagulation times and fibrinogen concentration were within normal limits. In addition the injured vessels in these animals accumulated more radiolabelled albumin, but not erythrocytes, than injured vessels in control animals. The results may imply a role for platelets in the enhancement of fibrin deposition during the early part of the response to injury and in contributing to the maintenance of normal permeability following vessel injury.


European Journal of Medicinal Chemistry | 1991

6-(4-Morpholino-phenyl)-4,5-dihydro-2H-pyridazine-3-ones: potent platelet aggregation inhibitors and antithrombotics

R Goeschke; J Gainer; Ga Howarth; Robert B. Wallis; R Kerry; J Ambler; Vs Findlay; Keith Butler

Abstract A series of di- and tri-substituted 6-phenyl-4,5-dihydro-2H-pyridazine-3-ones is described. The compounds were designed to be antithrombotics and were assessed for their inhibitory properties on platelet aggregation and on thrombus formation in an arteriovenous shunt in the rat. The synthesis and physical properties of the compounds are described. The structure-activity relationships reveal that non-aromatic nitrogen-containing heterocycles can confer high activity on the 6-phenyl-pyridazinone system, provided they are combined with an additional electron-withdrawing substituent in the phenyl ring. The most potent compounds ( 8i, 8b ) had an ED min of 1–3 mg/kg after oral administration in the thrombus formation test.


Thrombosis Research | 1987

Prolongation of platelet survival in hypercholesterolaemic rabbits by CGS 12970 (3-methyl-2-(3-pyridyl)-1 indoleoctanoic acid) and dazoxiben

Keith Butler; Pa Butler; R.A. Shand; John Ambler; Robert B. Wallis

In rabbits receiving a normal laboratory diet the platelet half-life was 40.4 +/- 2.5h (mean +/- S.D., n = 35). In animals fed the cholesterol-enriched diet for 12 weeks the platelet half-life was reduced to 31.6 +/- 3.6h (mean +/- S.D., n = 35). Treatment of cholesterol-fed animals with a single daily dose of CGS 12970 (a long acting inhibitor of thromboxane synthase) normalised the platelet half-life. Single daily doses of the relatively shorter acting thromboxane synthase inhibitors (CGS 13080 and dazoxiben) failed to correct the reduced platelet survival. However, twice daily dosing with dazoxiben was effective. The cyclooxygenase inhibitors, aspirin and sulphinpyrazone, failed to correct the reduced platelet survival.


American Journal of Respiratory Cell and Molecular Biology | 2004

Cigarette Smoke Alters Chromatin Remodeling and Induces Proinflammatory Genes in Rat Lungs

John A. Marwick; Paul Kirkham; Christopher S. Stevenson; Henry Danahay; June Giddings; Keith Butler; Ken Donaldson; William MacNee; Irfan Rahman

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Paul Kirkham

University of Wolverhampton

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