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Clofibrate and halofenate

These drugs lower plasma lipids but they also inhibit platelet aggregation in wh ich

TXA2 plays a major part and prolong shortened platelet survival (Gilbert & Mustard,

1963; Robinson & LeBeau, 1967; Glynn, Murphy & Mustard, 1967; Steele, Battock &

Genton, 1975; Lin & Smith, 1976; Favis & Colman, 1978). The sensitivity ofplatelets

from patients with familial hyperbetalipoproteinaemia is lessened by these drugs,

possibly through etTects on platelet membrane lipids and hence membrane fluidity

(Carvalho, Colman & Lees , 1974; Colman, Bennett, Sheridan, Cooper & Shattil,

1976; Colman, 1978). Clofibrate has also been reported to decrease prostacyclin

synthesis by human veins (Sinzinger, Clopath & Silberbauer, 1979).

Suloctidil

Suloctidil is a vascular antispasmotic drug that inhibits platelet aggregation in vitro

and after oral administration to animals or man (Roba, Claeys & Lambelin, 1976; de

Gaetano, Miragliotta, Roncucci, Lansen & Lambelin, 1976; Stelzer, Bums &

Saunders,1979).

Ticlopidine

This drug is unusual in that its etTects are not apparent in vitroand are only manifest

24 to 48h after it is administered; however, the etTects persist for several days

(O'Brien, Etherington & Shuttleworth, 1978; Knudsen & Gormsen, 1979). Unlike the

other drugs that have been considered, it inhibits the primary phase ofADP-induced

platelet aggregation (O'Brien et al., 1978; David, Monfort, Herion & Raskinet, 1979).

It also inhibits aggregation by other agents and the release of platelet granule contents. Ticlopidine has been reported to enhance the inhibitory etTect of PGh on rat

platelets (Johnson & Heywood, 1979). It prolongs the bleeding time and has been

shown to prolong shortened platelet survival in rats (Wilkinson, Hawker & Hawker,

1979). Ticlopidine inhibits intimal proliferation in de-endothelialized rabbit aortae

(Reece & Walton, 1979). The biochemical reactions that are atTected by ticlopidine or

its metabolities have not been determined.

Vitamin E

This vitamin is an antioxidant that has inhibitory etTects on platelet aggregation that

result from activation of the arachidonate pathway (Kurokawa, Kimura, Nagai &

Mitsuo, 1971; Fong, 1976; Steiner & Anastasi, 1976). It may atTect the calcium flux

within platelets that is involved in contractile processes (Butler, Gerrard, Peiler,

Stoddard, Rao & White, 1979).

Otherdrugs

Inhibitory etTects on platelet functions have been demonstrated with many other

drugs (Mustard & Packharn, 1978). These drugs include penicillin and related antibiotics; anti histamine and antiserotonin drugs; furosemide; tricyclic compounds such

as imipramine, arnitriptyline, and chlorpromazine; nitrofurantoin; glyccryl

guaiacolate; pyridinolcarbamate; nitroprusside (Pfister & Imhof, 1979; Mehta &

Mehta, 19-79) and many others. The vasodilator nitroglycerin has recently been

shown to induce prostacyclin production by cultured human cndothelial cells (Levin,

Weksler & JatTe, 1980).

DR UG ACTION ON PLATELET AN D VESSEL WA LL FUNCTJON 205

Combinations 01drugs

A great variety of combinat ions of drugs have been used to inhib it plat elet func tions

or plat elets and coagul ation (Packha m & M ustard , 1977; Mu sta rd & Packham, 1978 ).

Sinc e seve ra l mech an ism s may be involved in thrombosis, th is appears to be a

rea sonabl e approa ch.

Conc1usions

Many drugs in hibit plat elet reactions but none o f them blocks all of th e pathways

th at contrib ute to thrombus formatio n. Drugs th at on ly inhibit th e gene ra tion of

TXA z by plat elets cannot be expec ted to in hib it types of thrombosis to whic h thi s

com po und mak es only a min or contributio n. When th ro mbin an d fibrin for ma tion

pla y th e pr incip al role in th rombus formation, heparin or ora l anticoagulants ma y

ha ve beneficial effects . The prosta glan din s th at in hibit plat elet react ions because

th ey stim ulate adeny late cyc1ase are not suitable for long term admi nis tra tion.

Dipyridamole may ac t in other ways than its recognized in hibition of phosphodie sterase. The mechanism s through wh ich many drugs exe rt th eir in hibitory effects

on platelet fun ctions rem a in to be est ablished. One un sol ved problem is th e reason

why some of the drugs suc h as sulphi npy ra zo ne, dipyridamole and clofibrate,

prolong shortened platel et surviva l in man, particul arl y in condition s involvi ng

thromboembolic proce sses. It may be th at some of th e benecial effects of drugs that

affect plat elets will eve ntua lly be shown to invo lve mod ification of other ce llula r

processes.

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63-65.

THE EFFECT OF PLATELET

REGULATORY DRUGS IN

EXPERIMENTAL MODELS OF

THROMBOSIS, ATHEROSCLEROSIS

AND MYOCARDIAL ISCHAEMIA

A. M. WHITE & K. D. BUTLER

Ciba-Geigy Pharmaceuticals Division,

Wimblehurst Road, Horsham,

West Sussex RH124 AB, England

Introduction

Three drugs continue to be under intensive clinical assessment to determine whether

they can reduce mortality and morbidity following thrombo-occlusive cerebrovascular or cardiovascular accidents. These drugs are aspirin, dipyridamole and

sulphinpyrazone. The most recent trials to be completed are those relating to

sulphinpyrazone (Anturane Reinfarction Trial Research Group, 1980), aspirin

(Aspirin Myocardial Infarction Study Research Group, 1980) and aspirin

alone or in combination with dipyridamole (Persantine-Aspirin Reinfarction Study

Research Group, 1980). None of these drugs were invented for use after stroke or

myocardial infarction and much effort has gone into their investigation in animal

models thought to have some bearing on the development or the consequences of

vessel disease in man . In this review attention will be paid to data derived from in

vivo animal models in which either thrombus formation and changes in the intima

and media ofthe vasculature occur as a result of direct injury to the endothelium, or

in which platelet aggregation follows from the administration of a known platelet

agonist. For the most part discussion of the effect of these drugs on the heart will

derive from var iants ofthe well-known coronary ligation models.

Sulphinpyrazone

During the examination of a range of phenylbutazone analogues for uricosuric

activity in man it was observed that one ofthem, a thioether, 1,2-diphenyl-4-(phenylthioethyl)-3,5-pyrazolidinedione was converted through oxidation to a more potent

uricosuric substance, the sulphoxide (Bums, Yu , Ritterbrand, Perel & Gutman,

1957). This substance was called sulphinpyrazone. The reverse transformation is now

known in man and a number of animal species and will be referred to later in this

review .

214 A. M . WHITE & K . D. BUTLER

Inhibition of'pkuelet thrombiform ed as a result ofdirect electrical or mechanical

injury lO the vasculatu re

A favoured method for examining the ability of drugs to inhibit mural thrombus

formation utilises the exposed microcirculation of the hamster cheek pouch

(Berman, 1961; Begent & Born, 1970). In aversion ofthis model Lewis & Westwiek

(1977) placed a glass micropipette filled with IM KCl in contact wun the wall of a

cheek pouch arteriole 40-60 IJm in diameter and then applicd positive square wave

d.c. pulses in order to produce white bodies of platelets adhering to the vessel wall.

The amount of white body formation was assessed by counting the total number of

thrombi adhering during the Irrst 4 min after stimulation. A graded response could be

produced by varying the duration ofstimulation. Following the oral administration

ofsulphinpyrazone 18 hand I h prior to vascular damage there was a reduction in the

amount of white body formation . Statistical significance was achieved at doses of

20 mg kg" and 60 mg kg-I when the plasma concentrations ofsulphinpyrazone were

stated to be 60 lJg mi-I and 82 lJg mi-I respectively. In experiments where arteries on

the surface of the cerebral cortex of rabbits were exposed and damaged by pinching

with forceps (Honour & Ross-Russell, 1962; Honour & MitcheII, 1964) a dose of

sulphinpyrazone of 40 mg kg-I (i.v.) suppressed white body formation for 7 min,

while a second bolus injection of 60 mg kg-I stopped white body formation

completely over a 4 h observation period (Adams & MitcheII, 1979). Heparin did not

inhibit the platelet response to injury.

Inh ibition ofplatelet thrombiformed as a result of imm unological injury to the

vasculature

To examine one aspect of this action of su1phinpyrazone, work in the authors'

laboratory has concentrated on the examination of the drug in the sub-Iethal

Forssman reaction (Butler & White, 1980). In brief, drugs are administered to guinea

pigs prior to the i.v. administration ofForssman antiserum at a sub-lethal dose and

their efTect is observed on the ensuing thrombocytopenic epi sode and on the sequestration ofplatelet aggregation in the vasculature ofthe lungs. The thrombocytopenic

episode is rapid - reaching a maximum in 3 min - and it is accompanied by bronchospasm and endothelial oedema in the lung vasculature, but no other significant

morphological signs apart from platelet aggregation mentioned above. Sulphinpyrazone (100 mg kg-I i.v.) administered I h before the immunological challenge

inhibited the thrombocytopenia and the sequestration of platelets in the lungs. The

plasma concentration would have been about 50 lJg ml! (Butler, Dieterle, Maguire,

Pay, Wallis & White, 1980). Aspirin had no efTect at all at the same dose (Butler &

White,1980).

In other examples of the humoral immune response, where hyperacute transplantation rejection is most probably initiated by damage to the endothelium,

sulphinpyrazone has also been shown to be efTective. In the case of kidney

transplants, dogs were presensitized by full th ickness skin grafts and then underwent

cross-renal transplantation (Sharma, Moore, Merrick & Smith, 1972). The test group

was injected intravenously with sulphinpyrazone (125 mg kg-I) I h before transplantation and maintained on a dose of approximately 10 mg kg-I orally every 6 h

until anoxia ofthe kidney occurred. Urine flow was used as a test ofkidney function .

The mean function time among thirteen animals in the control group was 7.5 h

whereas in the treated group ofl3 animals the mean time ofgraft function was 33.1 h.

Platelet aggregation and vascular injury were absent in the treated group in the

majority of kidneys up to 24 h after transplantation. It was concluded that sulphinpyrazone inhibited platelet aggregation and in so doing prolonged graft function.

Similar results have been obtained using heart transplants (Sharma, Rosensweig,

EXPERIMENTAL MODELS AND PLATELET REG ULATORY DR UGS 215

Chatterjee, Moore & de Champlain, 1973; Vaessen, Benthuis, Hesse & Lameizer,

1977; Jamieson, Burton & Reitz, 1980) but in the third of these studies it was of

interest to note that sulphinpyrazone in combination with azathioprine appeared

more effective than other inhibitors of prostagiandin synthesis such as ibuprofen and

indomethacin . Could these results indicate a 'protective' effect ofsulphinpyrazone on

the endothelium as weil as an antiplatelet act ivity? Such a protective effect has been

c1aimed in cultured human umbilical vein cells by direct mea surement (Harker ,

Wall , Harlan & Ross , 1979) but could not be seen in cultured cells from pig aorta

(Müller, 1980).

Inhibition ofthe developm ent ofexperimental arteriosclerosis and atherosclerosis

In the rat , 'early' atherosclerotic lesion s were produced by a combination of

cholesterol feeding and an immunological challenge. Sub sequent to treatment over

56 days with sulphinpyrazone (160 mg kg! dail y p.o.) aortas were examined histologically. Out of nine animals in the control group, five had lesion s whereas no lesions

were seen in ten treated an imal s (Clopath, Horsch & Dieterle, 1980). In the homocysteinaemic baboon, three months oral do sing with sulphinpyrazone (100 mg kg!

daily) has been c1aimed to reduce intimal hyperplasia in the lower abdominal aorta,

iliac and femoral arteries (Harker, et al., 1979). Cairncross, Bassett & Martin (1979)

have recently shown that the morphological changes in the coronary vasculature of

rats exposed to unpredictable stress for 50 days were markedly reduced when

sulphinpyrazone (8 mg kg-1 daily) was administered orally for the whol e 50 da ys.

Likewis e, in rabbits, a da ily dose of 67 mg kg-I p.o . for 14 days after removing the

endothelium from the iliac artery by balloon catheter cau sed a 30% reduction in the

thickness ofthe neointima (Baumgartner & Studer, 1976).

In contrast to these positive results, no effect of the drug could be seen on intimal

hyperplasia in the aortic arch , the thoracic aorta and the abdominal aorta ofminipigs

over a period of 4 weeks after initial ballooning. The dose of sulphinpyrazone was

30 mg kg-I given twice da ily (Clopath et al., 1980). In the same way no effect of

sulphinpyrazone could be seen on intimal hyperplasia in rabbit aorta when

continuous damage was cau sed by an indwelling catheter (Moore & Ihnatowycz,

1978-).

Direct infusio n of'platelet agonists and understanding ofthe prolonged action of

sulphinpyrazo ne

In rats rendered hyperl ipidaemic by a ten-week period on a high lipid diet ,

thrombosis was induced in the hep atic veins by intravenous injection of Sityphosa

lipopolysaccharide. Sulphinpyrazone (about 1000 mg kg") administered by gastric

lavage 2 h before the injection of endotoxin led to a 66% reduction in hepatic infarcts

(Renaud & Lecompte, 1970). In a similar fashion sulphinpyrazone (100 mg kg-I

,

i.v.) given at various times up to I min prior to the infusion of endotoxin into rabbits

protected the animals against its lethai effects and reduced the number of platelet

aggregates seen in the microcirculat ion (Evans & Mustard, 1968).

Experiments in this laboratory have involved the use of the Arthus rea ction in

guinea pigs and therefore in vivo platelet aggregation resulting from the presence of

circulating and localised Ag/Ab complexes (Butler, Pay , Roberts & White, 1979).

Sulphinpyrazone (50 mg kg-I

, i.v.) I h before the antigenie challenge significantly

inhibits the resulting thrombocytopenia. In this species both after oral and intravenous dosage the maximum platelet inhibitory act ivity occurs 4-6 h after dosing

(Butler, Wallis & White, 1979) and is due to the production of the pot ent thioether

metabolite mentioned abo ve (Butler et al., 1980). Sim ilarl y, the prolonged inhibition

of collagen-induced thrombocytopenia first seen by Buchanari , Rosenfeld & Hirsh

(1978) in rabb its after the administration of 100 mg kg-I (i.v.) has been explained in

216 A. M. WHITE & K. D. BUTLER

this way (pedersen & Jakobsen, 1979). The prolonged action of this drug in man

(Butler et al., 1980) is also due to the production of the thioether (Maguire, Pa y,

Turney, Wallis, Weston, White, Williams & Woods, 1980).

EjJects on models 0/cardiac arrythmia

Kelliher, Dix, Jurkiewicz & Lawrence (1980) studied the efTect of sulphin pyrazone

100 mg kg-1 (i.v.) in anaesthetised cats. The drug was given I h before tying abruptl y

the left anterior de scending coronary artery and its efTects were observed on

arrythmia and death, on heart rate and blood pressure and on infarct size. A

significant reduction was detected in the incidence of ventricular tach ycardia during

a 30 min period immediately following occlusion in those cats which did not

fibrillate . Similar results to these, and in addition, a reduction in the duration of

ventricular tachycardia were seen in cats which were additionally bilaterally

vagotomised. Even though vagotomy nearly doubled the incidence of ventricular

fibrillation this procedure still did not increase the incidence of ventricular fibrillation in the sulphinpyrazone-treated group. No effect ofthe drug was seen on infarct

srze.

In studies in dogs involving occlusion-reperfusion techniques which reliably

produce a ventricular fibrillation (VF), sulphinpyrazone (30 mg kg-1 p.o. for seven

days) produced a marked reduction in VF from 58% to 17% accompanied by a

slight decrease in mortality (75 % to 50%) (Povalski, Ol son , Koria & Furness, 1980).

There was no efTect on infarct size. Mo schos, Escobinas & Jorgensen (1980) , also in

dogs, showed after administering sulphinpyrazone (300 mg/dog) for seven days, that

4 h after coronary occlusion in the anaesthetised dog there was no ventricular fibrillation compared with 39% in control animals.

The antiarrythmic efTects ofsulphinpyrazone do not appear to be related to efTects

on the systemic circulation or on the reaction of the circulation to cardiac function

subsequent to an ischaemic episode. Moschos, Escobinas & Jorgensen (1979)

measured aortic pressure and concluded that drug treatment failed to produce an y

changes. Similarly heart rate and blood pressure of intact or vagotomised cats were

not afTected by sulphinpyrazone before coronary artery occlusion and bradycardia

and the hypotensive response to occlusion of non-vagotornised cats were sim ila r in

control and treated groups (Kelliher et al., 1980). Some work suggests that sulphinpyrazone ma y perha ps increase collateral blood flow to myocardial tissue

(Davenport, Goldstein & Capurro, 1979).

In the work of Folts & Beck (1980) dogs with 70% stenosis of the left circumflex

artery showed cyclical reductions in coronary blood flow wh ich probably reflect the

presence of platelet plugs in the narrowed lumen. Sulphinpyrazone (30 mg kg-I

, i.v.)

abolished the cyclical flow disruptions, caused a reappearance of the reactive

hyperaemic response and prevented the exacerbation of plugging caused by exogenously applied adrenaline. Sulphinpyrazone in the hands of these workers was

claimed to cause a reduction in heart rate but to be without any efTect on blood

pressure.