TRIPASS XR تري باس

 

As far as aspirin is concerned more information is needed on the rate ofrecovery of

the endothelial cyclo-oxygenase in vivo after single doses of aspirin. Equally

important is the assessment of any cumulative effect of a multiple-dose regime on

platelet and endothelial cyclo-oxygenase in order to establish the optimal interval of

administration.

The demonstration ofthe ability of aspirin to prevent thromboembolism in some

circumstances but not in others (Jobin, 1978; Verstraete, 1976) may suggest a

qualitative or quantitative difference in the underlying pathophysiology. Further

clinical trials should be conducted in which aspirin is given at low doses either alone

or combined with phosphodiesterase inhibitors such as dipyridamole. Ideally a more

selective inhibitor ofthromboxane synthetase should be developed to be used alone

or in combination with phosphodiesterase inhibitors (Moncada & Vane, 1977).

A more direct approach to antithrombotic therapy, however, would be to control

platelet cyclic AMP; increasing platelet cyclic AMP inhibits most forms of

aggregation whether or not they are dependent on arachidonic acid metabolic

products. Since prostacyclin is the most powerful substance known in both

preventing aggregation and increasing platelet cyclic AMP (Gorrnan, Bunting &

Miller, 1977b; Tateson, Moncada & Vane , 1977), prostacyclin, or an analogue, alone

or in combination with a phosphodiesterase inhibitor, should be a more

comprehensive approach to the control of platelet aggregation in vivo. Alternatively,

drugs which stimulate endogenous prostacyclin production (Vermylen et al., 1979)

could be developed. Several ofthese possibilities are at present being explored.

Thromboxane AI - Prostacyclin balance in other pathological states

A number of diseases have now been related to an imbalance in the prostacyclin -

TXAI ststem . Platelets from patients with arterial thrombosis, deep venous

thrombosis, or recurrent venous thrombosis produce more PG endoperoxides and

TXAI than normal and have a shortened survival time (Lagarde & Dechavanne,

1977). Platelets from rabbits made atherosclerotic by dietary manipulation

(Shimamoto, Kobayashi, Takahashi, Takashima, Sakamoto & Morooka, 1978) and

from patients who have survived myocardial infarction (Szczeklik , Gryglewski,

Musial, Grodzinska, Serwonska & Marcinkiewicz, 1978a) are abnormally sensitive to

aggregating agents and produce more TXAI than controls. Elevated TXBI (the breakdown product of TXAI) levels have been demonstrated in the blood of patients with

Prinzmetal's angina (Lewy, Smith, Silver, Wiener & Walinsky, 1979).

Platelets from rats made diabetic display an increased release of TXA2 whereas

their blood vessels show a reduced production of prostacyclin (Harrison, Reece &

Johnson, 1978; Johnson, Reece & Harrison, 1978); these effects are reversed by

chronic insulin treatment (Harrison et al., 1978). Prostacyclin production by blood

vessels from patients with diabetes is depressed (Johnson, Harrison, Raftery & Eider,

1979) and circulating levels of 6-oxo-PGFIU are reduced in diabetic patients with

proliferative retinopathy (Dollery, Friedman, Hensby, Kohner, Porta & Webster,

1979). Thrombocytopenic purpura (TTP), like diabetes, is associated with formation

of microvascular thromboemboli, and a deficiency in prostacyclin production may

be responsible for the increased platelet consumption which occurs in TTP

(Remuzzi, Misiani, Marchesi, Livio, Mecca, De Gaetano & Donati, 1978b). This

26 S. MONCADA & J. R. VANE

deficiency is thought to be secondary to a lack of a 'plasma factor' which normally

stimulates prostacyclin production (Maclntyre, Pearson & Gordon, 1978).

An increased prostacyclin production, resulting from an accumulation of this

'plasma factor' has been suggested to explain the haemostatic defect in uraemic

patients (Remuzzi, Cavenaghi, Mecca, Donati & Oe Gaetano, 1977). Patients with

Bartter's syndrome excrete in the urine about four times as much 6-oxo-PGFI a as

controls (Gullner, Cerletti, Bartter, Smith & Gill, 1979). This has led to the suggestion that overproduction of prostacyclin mediates both the hyper-reninaemia and

the hyporesponsiveness to pressor agents observed in these patients (Gullner et al.,

1979). Finally, enhanced prostacyclin production by blood vessels ofspontaneously

hypertensive rats has been demonstrated (Pace-Asciak, Carrara, Rangaraj &

Nicolaou,1978).

As yet, a clear relationship between different diseases and the PGh/TXA2 balance

is not established. However, it seems that conditions which favour the development

ofthrombosis are associated with an increase in TXA2 and a decrease in prostacyclin

forrnation, whereas an increased prostacyclin formation plus decreased TXA2 is

present in some conditions associated with an increased bleeding tendency.

References

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ofaspirin on platelet behaviour and bleeding time in man . Thromb . Res., 16,69-79.

Amezcua, J-L., Parsons, M. & Moncada, S. (1978). Unstable metabolites of arachidonic acid,

aspirin and the formation ofthe haemostatic plug. Thromb. Res., 13, 477-488.

Armstrong, J. M., Chapple, D. J., Dusting , G. J., Hughes , R., Moncada, S. & Vane, J. R. (1977).

Cardiovascular actions of prostacyclin (PGh) in chloralose anaesthetized dogs. Brit. J.

Pharmac., 61, 136p.

Armstrong, J. M., Lattimer, N., Moncada, S. & Vane , J. R. (1978). Comparison of the vasodepressor effects of prostacyclin and ö-oxo-prostaglandin F1a with those of prostagiandin

E2in rats and rabbits . Brit. J. Pharmac., 62, 125-130.

Ashida, S-l. & Abiko, Y. (1978). Effect of ticIopidine and acetylsalicylic acid on generation of

prostaglandin h like substance in rat arterial tissue. Thromb . Res., 13,901-908.

Baenziger, N. L., Dillender, M. J. & Majerus, P. (1977). Cultured human skin fibroblasts and

arterial cells produce a labile platelet-inhibitory prostaglandin. Biochem . Biophys. Res.

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Baumgartner, H. R. & Tschopp, Th .B. (1979). Platelet interaction with aortic subendothelium

(S.E.) in vitro. Locally produced PGh inhibits adhesion and formation ofmural thrombi in

flowing blood. Thrombosis and Haemostasis Abstracts. VII International Congress on

Thrombosis and Haemostasis, pp. 6.

Blackwell, G. J., Flower, R. J., Russell-Smith, N., Salrnon , J. A., Thorogood, P. B. & Vane, J. R.

(1978). l-n-Butylimidazole: A potent and selective inhibitor of 'thromboxane synthetase'.

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Blajchman, M. A., Scnyi, A. F., Hirsh, J., Surya, Y., Buchanan, M. & Mustard, J. F., (1979).

Shortcning of the bleeding time in rabbits by hydrocortisone caused by inhibition of

prostacycIin generation by the vessel wall. J. clin. Invest., 63, 1026-1035.

Block, A. J., Feinberg, H., Herbaczynska-Cedro, K. & Vane , J. R. (1975). Anoxia induccd

release ofprostaglandins in rabbit isolated hcart . Circulation Res., 36, 34-42.

Bolger, P. M., Eisner, G. M., Ramwell , P. W. & Siotkoff, L. M. (1978). Renal actions ofprostacycIin. Nature, 271,457-469.

Boullin , D. J., Bunting, S., Blaso, W. P., Hunt, T. M. & Moncada, S. (1979). Responses of

human and baboon arteries to prostaglandin endoperoxides and biologically generated and

synthetic prostacyclin: Their relevance to cerebral arte rial spasm in man. Brit. J. clin.

Pharmac., 7, 139-147.

Bunting, S., Gryglewski , R., Moncada, S. & Vane , J. R. (l976a). Arterial walls generate from

prostaglandin endoperoxides a substance (prostaglandin X) which relaxes strips of

mesenteric and coeliac arteries and inhibits platelet aggregation . Prostaglandins, 12,

897-913 .

PROSTACYCLl N, PHARMA COLO GY AND CLl NICAL POT ENTIAL 27