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In vitro effect of cimetidine on platelet aggregation
THROMBOSIS RESEARCH 38; 307-308, 1985 0049-3848/85 $3.00 + .OO Printed in the USA. Copyright (c) 1985 Pergamon Press Ltd. All rights reserved.
LETTER IN
VITRO
EFFECT
TO OF
THE
EDITORS-IN-CHIEF
CIMETIDINE
ON
PLATELET
AGGREGATION
D.P. Mikhailidis, M.A. Barradas, J.Y. Jeremy, P. Dandona Department of Chemical Pathology and Human Metabolism, Royal Free Hospital and School of Medicine, London NW3 2QG U.K.
(Received 14.1.1985; Accepted in original form 5.2.1985 by Editor-in-Chief A.L. Copley)
The observations of Gachalyi and colleagues (1) on the inhibitory effect of cimetidine on ADP-induced platelet aggregation and thromboxane A2 (TXA2) release are of interest to us, since they concur with our previous data demonstrating that this drug (at final concentrations of 0.32 mmol/l) significantly inhibits ADP- as well as adrenaline-induced aggregation in vitro (2). More recently, we have shown a 30% reduction in TXA2 production by platelets pretreated with cimetidine (0.75 mmol/l) in vitro. TXA2 release was induced by ADP, adrenaline or collagen (unpublished observations). Others, as well as ourselves, agree with Gachalyi et al. that this inhibition of platelet aggregation and TXA2 release is probably due to the presence of an imidazole group in the cimetidine molecule (3,4). Neither study (1,2) however is in agreement with that of Horton et a1.(5) which We states that 10.00 mmol/l cimetidine had no effect on platelet function! find this observation hard to believe, especially since in the same study oxmctidine, a cimetidine-related drug, caused significant inhibition at concentrations of 0.50 mmol/l. The reasons for these discrepancies are not clear to us. We agree with Gachalyi et al. that the effect of cimetidine on platelet function needs further clinical investigations. We can only express our surprise that the cimetidine-platelet interaction has not yet been thoroughly investigated, despite: (a) the widespread use of cimetidine, which includes patients who are bleeding or are likely to bleed; (b) a preliminary report showing some inhibition of platelet aggregation after oral administration of conventional doses of cimetidine(6); (c) the fact that cimetidine in gastric fluid may reach concentrations of up to 13.40 mmol/l; these samples were shown to inhibit platelet aggregation in a bioassay system (7); (d) the fact that cimetidine is unsuccessful in the treatment of acute gastrointestinal bleeds and in the prevention of bleeding in patients with cirrhosis (see references 2-4,7).
Key words:
cimetidine,
platelet
aggregation,
307
thromboxane
A2
CIMETIDINE L PLATELET AGGREGATION
308
Vo1.38, No.3
REFERENCES 1.
GACHALYI, B., TIHANYI, K., VAS, A and EALDOR, A. In vitro effect of cimetidine on ADP-induced platelet aggregation and thromboxane A2 synthesis in man. Thromb Res -35, 105-109, 1984.
2.
MIKHAILIDIS, D.P., MIKHAILIDIS, A.M. and DANDONA, P. Prevention or cure for stress-induced gastrointestinal bleeding? Br Med J, 281, 1005-1006, 1980.
3.
MIKHAILIDIS, somatostatin
D-P., MIKHAILIDIS, A.M. and DANDONA, P. Cimetidine in gastroduodenal haemorrhage. Lancet, i, 274-275,
4.
MIKHAILIDIS, somatostatin
D-P., MIKHAILIDIS, A.M. and DANDONA, P. Cimetidine and in gastroduodenal haemorrhage. Lancet, L, 784, 1981.
5.
HORTON, M.A., AMOS, R.J. and JONES, R.J. The effect of histamine H2 Stand J Haematol, receptor antagonists on platelet aggregation in man. 2, is-19, 1983.
6.
XOSTERING, H, ROTMANN, U, WIEDING, J, HOFFSCHMIDT, Ch., OSBURG, B. and SCHRADER, J. Influence of cimetidine on platelet function, blood Thromb Haemost, -50, 432, 1983. coagulation and f ibrinolysis.
7.
MIEHAILIDIS, D.P., BARRADAS, M.A., CHRISTOFIDES, J., JEREMY, J.Y. and The misuse of cimetidine in patients with cirrhosis. DANDONA, P. Hepatology, Q, 573-574, 1984.
.
and 1981.
LETTER IN
VITRO
EFFECT
TO OF
THE
EDITORS-IN-CHIEF
CIMETIDINE
ON
PLATELET
AGGREGATION
D.P. Mikhailidis, M.A. Barradas, J.Y. Jeremy, P. Dandona Department of Chemical Pathology and Human Metabolism, Royal Free Hospital and School of Medicine, London NW3 2QG U.K.
(Received 14.1.1985; Accepted in original form 5.2.1985 by Editor-in-Chief A.L. Copley)
The observations of Gachalyi and colleagues (1) on the inhibitory effect of cimetidine on ADP-induced platelet aggregation and thromboxane A2 (TXA2) release are of interest to us, since they concur with our previous data demonstrating that this drug (at final concentrations of 0.32 mmol/l) significantly inhibits ADP- as well as adrenaline-induced aggregation in vitro (2). More recently, we have shown a 30% reduction in TXA2 production by platelets pretreated with cimetidine (0.75 mmol/l) in vitro. TXA2 release was induced by ADP, adrenaline or collagen (unpublished observations). Others, as well as ourselves, agree with Gachalyi et al. that this inhibition of platelet aggregation and TXA2 release is probably due to the presence of an imidazole group in the cimetidine molecule (3,4). Neither study (1,2) however is in agreement with that of Horton et a1.(5) which We states that 10.00 mmol/l cimetidine had no effect on platelet function! find this observation hard to believe, especially since in the same study oxmctidine, a cimetidine-related drug, caused significant inhibition at concentrations of 0.50 mmol/l. The reasons for these discrepancies are not clear to us. We agree with Gachalyi et al. that the effect of cimetidine on platelet function needs further clinical investigations. We can only express our surprise that the cimetidine-platelet interaction has not yet been thoroughly investigated, despite: (a) the widespread use of cimetidine, which includes patients who are bleeding or are likely to bleed; (b) a preliminary report showing some inhibition of platelet aggregation after oral administration of conventional doses of cimetidine(6); (c) the fact that cimetidine in gastric fluid may reach concentrations of up to 13.40 mmol/l; these samples were shown to inhibit platelet aggregation in a bioassay system (7); (d) the fact that cimetidine is unsuccessful in the treatment of acute gastrointestinal bleeds and in the prevention of bleeding in patients with cirrhosis (see references 2-4,7).
Key words:
cimetidine,
platelet
aggregation,
307
thromboxane
A2
CIMETIDINE L PLATELET AGGREGATION
308
Vo1.38, No.3
REFERENCES 1.
GACHALYI, B., TIHANYI, K., VAS, A and EALDOR, A. In vitro effect of cimetidine on ADP-induced platelet aggregation and thromboxane A2 synthesis in man. Thromb Res -35, 105-109, 1984.
2.
MIKHAILIDIS, D.P., MIKHAILIDIS, A.M. and DANDONA, P. Prevention or cure for stress-induced gastrointestinal bleeding? Br Med J, 281, 1005-1006, 1980.
3.
MIKHAILIDIS, somatostatin
D-P., MIKHAILIDIS, A.M. and DANDONA, P. Cimetidine in gastroduodenal haemorrhage. Lancet, i, 274-275,
4.
MIKHAILIDIS, somatostatin
D-P., MIKHAILIDIS, A.M. and DANDONA, P. Cimetidine and in gastroduodenal haemorrhage. Lancet, L, 784, 1981.
5.
HORTON, M.A., AMOS, R.J. and JONES, R.J. The effect of histamine H2 Stand J Haematol, receptor antagonists on platelet aggregation in man. 2, is-19, 1983.
6.
XOSTERING, H, ROTMANN, U, WIEDING, J, HOFFSCHMIDT, Ch., OSBURG, B. and SCHRADER, J. Influence of cimetidine on platelet function, blood Thromb Haemost, -50, 432, 1983. coagulation and f ibrinolysis.
7.
MIEHAILIDIS, D.P., BARRADAS, M.A., CHRISTOFIDES, J., JEREMY, J.Y. and The misuse of cimetidine in patients with cirrhosis. DANDONA, P. Hepatology, Q, 573-574, 1984.
.
and 1981.