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EFFECT OF ANTI-INFLAMMATORY AGENTS ON PLATELETS
894 the request of the patient, and she died. Hertz (1947/48) reported the first patient in whom a preoperative radiological diagnosis and removal of the gallstone was followed by recovery. Figiel et al. (1956) gave a good description of the radiological features of this condition. The clinical features characterising the aetiology and diagnosis in the published cases are summarised in the
at
table. Gallstone obstruction of the duodenal bulb has accounted for less than 10% of all published cases of intestinal obstructions due to gallstones. The condition was secondary to a cholescytoduodenal fistula in most cases. The condition may be an earlier stage of gallstone ileus, which in most cases is secondary to a cholecystoduodenal fistula. If the gallstone is large and the first portion of the duodenum is already narrowed by the fistula, then the stone may impact in the bulb. In some, the stone may later migrate toward the ileum as shown by Brocq et al. (1929) and Figiel and Figiel (1956). Awareness that a gallstone may be a cause of high intestinal obstruction is the most important factor in diagnosis which can be confirmed by radiological means. In a plain X-ray film of the abdomen, a large calcified density in the right upper quadrant, especially if its long axis is horizontal, is a clue to diagnosis. Air in the biliary tree is additional evidence. In the case reported here, re-examination of a preoperative film showed a radiolucent calculus delineated as a filling defect, obstructing the duodenal cap, together with contrast material in the cholecystoduodenal fistula and gallbladder (see figure). Differential diagnosis includes duodenal neoplasm, duodenal polyp, pedunculated gastric neoplasm prolapsing into the bulb, foreign body, bezoar, and pressure from aberrant pancreatic tissue. The average age was 60 years, in forty-six patients. The youngest patient was 31 and the eldest was 86. Jaundice was not a presenting symptom. Preoperative diagnosis was made in only seventeen of forty-six patients (37%)
and twelve of these patients, in whom a correct diagnosis had been made, recovered after treatment. Once obstruction of the duodenal cap by a gallstone is suspected the patient should be prepared for surgery and the gallstone should be removed, usually, through a healthy portion of the alimentary tract. In general, treatment of the primary biliary disease should be postponed. A third (15/46) of the patients died. Awareness of this complication of biliary disease will lead to an earlier diagnosis and a reduction in the mortality. The late Mr. W. A. D. Adamson gave me permission to report this case under his care. I thank Dr. Henry Brown and Dr. John V. Pikula for helpful discussions. REFERENCES
Bouveret, L. (1896) Rev. méd., Paris, 16, 1. Brocq, P., Brodin, P., Aimé. (1929) Bull. Mém. Soc. nat. Chir. 55, 1194. Butterworths Medical Dictionary (1965) (edited by A. Macnalty); p. 214. London.
Figiel, L. S., Figiel, S. J. (1956) Am. J. Roentgenol. 76, Halasz, N. A. (1964) Am. J. digest. Dis. 9, 856. Hertz, J. (1947/48) Acta chir. scand. 96, 233.
24.
EFFECT OF ANTI-INFLAMMATORY AGENTS ON PLATELETS
J. R. O’BRIEN M.A., D.M. Oxon., F.C.Path. HÆMATOLOGIST, PORTSMOUTH AND ISLE OF WIGHT PATHOLOGICAL SERVICE, MILTON ROAD, PORTSMOUTH
CONSULTANT
A number of compounds sharing one or more of the pharmacological properties of aspirin were tested for their ability to inhibit plateletaggregation effects. Most of those with anti-inflammatory activity were inhibitory. It is concluded that inflammation and platelet function may be connected. Summary
Introduction
ASPIRIN has various effects on platelets (Evans and Mustard 1967, Morris 1967, Weiss and Aledort 1967, O’Brien 1968a, Zucker and Peterson 1968); in particular it blocks the release of adenosine diphosphate (A.D.P.) in at least five different test situations, while sodium salicylate is almost inactive (O’Brien 1968b). These findings prompted an investigation of other compounds in the general category of anti-inflammatory, analgesic, and antipyretic agents. Methods To human citrated platelet-rich plasma was added sufficient of the compound to give the final concentrations shown in table i. These mixtures were incubated at 37°C for exactly 15 minutes before challenged either with strong adrenaline (0-0005 M) or a critical strength of tendon extract called collagen " for convenience (O’Brien et al. 1966). The results from repeated experiments were graded from 4 indicating total inhibition of the adrenaline-induced second wave of aggregation or gross inhibition of the collagen response, to 0 a "
response
indistinguishable
from control
tests
(saline solution).
Results
Barium meal showing (1) calculus, (2) cholecystoduodenal fistula, and (3) gallbladder.
Table i shows that with many compounds the degree of inhibition in the adrenaline and collagen tests runs almost exactly parallel, indicating that these two tests depend, at least in part, on the same mechanism. In both tests many compounds at a concentration of 0-0005M produce gross inhibition: a strength tenfold weaker shows up relative differences between the active compounds. Meclofenamate (Winder et al. 1965) inhibited the tests marginally better than did aspirin. Indomethacin and ibuprofen (Adams et al. 1967) were approximately as
895 TABLE I-INHIBITORY EFFECT OF THE COMPOUNDS ON TWO PLATELET TESTS
as aspirin when tested in equimolar concentrations. A single dose of aspirin 150 mg. taken by mouth produced striking and lasting changes in these tests (O’Brien 1968 a and b); 100 mg. phenylbutazone usually did so on the few occasions on which it was tested. In a few tests indomethacin 100 mg. produced a striking but transient (4 hours) change and ibuprofen 300 mg. produced a minor transient change; dextropropoxyphene 130 mg. and sodium salicylate 2 g. were inactive. Thus in vivo the effects of many compounds on the platelets are probably similar to the effects in vitro, which were more extensively examined. These findings were compared with other published in-vivo experiments: (1) the inhibition of erythema (inflammation) produced in guineapigs by ultraviolet light (Adams and Cobb 1958); (2) the inhibition of erythema (inflammation) produced in man by thurfyl nicotinate (Adams and Cobb 1963); and (3) the inhibition of bradykinin-induced bronchospasm in guineapigs (Collier and Shorley 1960, Berry and Collier 1964). These workers’ results were converted to approximate to the 4-0 scale used above; table 11 also includes a summary of whether or not the drugs have, in general,
inhibitory
TABLE II-EFFECT OF THE COMPOUNDS ON THREE IN-VIVO TESTS
anti-inflammatory and other pharmacological properties. There is reasonably good agreement between the platelet tests and those measuring other activities. The persistence for several days of the effect of a single small dose of aspirin both on the thurfyl-nicotinate test (Adams and Cobb 1963) and on the platelet tests is a further remarkable similarity. Different compounds have, in general, the same relative effect in all these various tests and in different animals, although the parallelism is not exact (e.g., ibufenac and phenylbutazone). Almost all compounds that have an’effect on platelets also have anti-inflammatory properties, and compounds inactive in the platelet tests mostly have no anti-inflammatory activity (but see sodium salicylate). The inhibition of the platelet tests does not run parallel to analgesic or antipyretic activity. Two alternative conclusions might be drawn: (1) since these drugs inhibit both the inflammatory changes and the platelet response in a similar manner, perhaps the same mechanism is operating in all these situations but on different cells; or (2) perhaps the effect of these compounds on inflammation is at least partially mediated through their effect on platelets, in which case platelets must play a part in inflammation, and A.D.P. release from platelets is also involved. I thank Mrs. S. M. Shoobridge and Mrs. W. J. Finch, for technical assistance, the Wellcome Trust for a research grant, and Dr. S. S. Adams and Dr. H. 0. J. Collier for helpful advice. Bayer Products, Boots Pure Drug Co., Duncan Flockhart, Geigy, Eli Lily, Merk Sharp and Dohme, and Parke Davis and Co., kindly gave me pure
compounds. REFERENCES
S., Cliffe, E. E., Lessel, B., Nicholson, J. S. (1967) J. pharm. Sci. 56, 1686. Cobb, R. (1958). Nature, Lond. 181, 773. (1963) in Salicylates (edited by A. St. J. Dixon, B. K. Martin, M. J. H. Smith, P. A. N. Wood; p. 127. London. Berry, P. A., Collier, H. O. J. (1964) Br. J. Pharmac. Chemother, 23,
Adams,
S.
—
—
—
201.
Collier, H. O. J. (1968) Personal Communication. Shorley, P. G. (1960) ibid. 15, 601. Evans, G., Mustard, G. F. (1967) Lancet, ii, 724. Morris, C. D. W. (1967) ibid. i, 279. O’Brien, J. R. (1968a) ibid. i, 203. (1968b) ibid. 779. Heywood, J. B., Heady, J. A. (1966) Thromb. Diath. hœmorrh. 16, -
-
-
752.
Weiss, H. J., Aledort, L. M. (1967) Lancet, ii, 495. Winder, C. W., Wax, J., Welford, M. (1965) J. Pharmac. exp. Ther. 148, 1345.
Zucker, M. B., Peterson, J. (1968) Proc. Soc. exp. Biol. Med. (in the press).
at
table. Gallstone obstruction of the duodenal bulb has accounted for less than 10% of all published cases of intestinal obstructions due to gallstones. The condition was secondary to a cholescytoduodenal fistula in most cases. The condition may be an earlier stage of gallstone ileus, which in most cases is secondary to a cholecystoduodenal fistula. If the gallstone is large and the first portion of the duodenum is already narrowed by the fistula, then the stone may impact in the bulb. In some, the stone may later migrate toward the ileum as shown by Brocq et al. (1929) and Figiel and Figiel (1956). Awareness that a gallstone may be a cause of high intestinal obstruction is the most important factor in diagnosis which can be confirmed by radiological means. In a plain X-ray film of the abdomen, a large calcified density in the right upper quadrant, especially if its long axis is horizontal, is a clue to diagnosis. Air in the biliary tree is additional evidence. In the case reported here, re-examination of a preoperative film showed a radiolucent calculus delineated as a filling defect, obstructing the duodenal cap, together with contrast material in the cholecystoduodenal fistula and gallbladder (see figure). Differential diagnosis includes duodenal neoplasm, duodenal polyp, pedunculated gastric neoplasm prolapsing into the bulb, foreign body, bezoar, and pressure from aberrant pancreatic tissue. The average age was 60 years, in forty-six patients. The youngest patient was 31 and the eldest was 86. Jaundice was not a presenting symptom. Preoperative diagnosis was made in only seventeen of forty-six patients (37%)
and twelve of these patients, in whom a correct diagnosis had been made, recovered after treatment. Once obstruction of the duodenal cap by a gallstone is suspected the patient should be prepared for surgery and the gallstone should be removed, usually, through a healthy portion of the alimentary tract. In general, treatment of the primary biliary disease should be postponed. A third (15/46) of the patients died. Awareness of this complication of biliary disease will lead to an earlier diagnosis and a reduction in the mortality. The late Mr. W. A. D. Adamson gave me permission to report this case under his care. I thank Dr. Henry Brown and Dr. John V. Pikula for helpful discussions. REFERENCES
Bouveret, L. (1896) Rev. méd., Paris, 16, 1. Brocq, P., Brodin, P., Aimé. (1929) Bull. Mém. Soc. nat. Chir. 55, 1194. Butterworths Medical Dictionary (1965) (edited by A. Macnalty); p. 214. London.
Figiel, L. S., Figiel, S. J. (1956) Am. J. Roentgenol. 76, Halasz, N. A. (1964) Am. J. digest. Dis. 9, 856. Hertz, J. (1947/48) Acta chir. scand. 96, 233.
24.
EFFECT OF ANTI-INFLAMMATORY AGENTS ON PLATELETS
J. R. O’BRIEN M.A., D.M. Oxon., F.C.Path. HÆMATOLOGIST, PORTSMOUTH AND ISLE OF WIGHT PATHOLOGICAL SERVICE, MILTON ROAD, PORTSMOUTH
CONSULTANT
A number of compounds sharing one or more of the pharmacological properties of aspirin were tested for their ability to inhibit plateletaggregation effects. Most of those with anti-inflammatory activity were inhibitory. It is concluded that inflammation and platelet function may be connected. Summary
Introduction
ASPIRIN has various effects on platelets (Evans and Mustard 1967, Morris 1967, Weiss and Aledort 1967, O’Brien 1968a, Zucker and Peterson 1968); in particular it blocks the release of adenosine diphosphate (A.D.P.) in at least five different test situations, while sodium salicylate is almost inactive (O’Brien 1968b). These findings prompted an investigation of other compounds in the general category of anti-inflammatory, analgesic, and antipyretic agents. Methods To human citrated platelet-rich plasma was added sufficient of the compound to give the final concentrations shown in table i. These mixtures were incubated at 37°C for exactly 15 minutes before challenged either with strong adrenaline (0-0005 M) or a critical strength of tendon extract called collagen " for convenience (O’Brien et al. 1966). The results from repeated experiments were graded from 4 indicating total inhibition of the adrenaline-induced second wave of aggregation or gross inhibition of the collagen response, to 0 a "
response
indistinguishable
from control
tests
(saline solution).
Results
Barium meal showing (1) calculus, (2) cholecystoduodenal fistula, and (3) gallbladder.
Table i shows that with many compounds the degree of inhibition in the adrenaline and collagen tests runs almost exactly parallel, indicating that these two tests depend, at least in part, on the same mechanism. In both tests many compounds at a concentration of 0-0005M produce gross inhibition: a strength tenfold weaker shows up relative differences between the active compounds. Meclofenamate (Winder et al. 1965) inhibited the tests marginally better than did aspirin. Indomethacin and ibuprofen (Adams et al. 1967) were approximately as
895 TABLE I-INHIBITORY EFFECT OF THE COMPOUNDS ON TWO PLATELET TESTS
as aspirin when tested in equimolar concentrations. A single dose of aspirin 150 mg. taken by mouth produced striking and lasting changes in these tests (O’Brien 1968 a and b); 100 mg. phenylbutazone usually did so on the few occasions on which it was tested. In a few tests indomethacin 100 mg. produced a striking but transient (4 hours) change and ibuprofen 300 mg. produced a minor transient change; dextropropoxyphene 130 mg. and sodium salicylate 2 g. were inactive. Thus in vivo the effects of many compounds on the platelets are probably similar to the effects in vitro, which were more extensively examined. These findings were compared with other published in-vivo experiments: (1) the inhibition of erythema (inflammation) produced in guineapigs by ultraviolet light (Adams and Cobb 1958); (2) the inhibition of erythema (inflammation) produced in man by thurfyl nicotinate (Adams and Cobb 1963); and (3) the inhibition of bradykinin-induced bronchospasm in guineapigs (Collier and Shorley 1960, Berry and Collier 1964). These workers’ results were converted to approximate to the 4-0 scale used above; table 11 also includes a summary of whether or not the drugs have, in general,
inhibitory
TABLE II-EFFECT OF THE COMPOUNDS ON THREE IN-VIVO TESTS
anti-inflammatory and other pharmacological properties. There is reasonably good agreement between the platelet tests and those measuring other activities. The persistence for several days of the effect of a single small dose of aspirin both on the thurfyl-nicotinate test (Adams and Cobb 1963) and on the platelet tests is a further remarkable similarity. Different compounds have, in general, the same relative effect in all these various tests and in different animals, although the parallelism is not exact (e.g., ibufenac and phenylbutazone). Almost all compounds that have an’effect on platelets also have anti-inflammatory properties, and compounds inactive in the platelet tests mostly have no anti-inflammatory activity (but see sodium salicylate). The inhibition of the platelet tests does not run parallel to analgesic or antipyretic activity. Two alternative conclusions might be drawn: (1) since these drugs inhibit both the inflammatory changes and the platelet response in a similar manner, perhaps the same mechanism is operating in all these situations but on different cells; or (2) perhaps the effect of these compounds on inflammation is at least partially mediated through their effect on platelets, in which case platelets must play a part in inflammation, and A.D.P. release from platelets is also involved. I thank Mrs. S. M. Shoobridge and Mrs. W. J. Finch, for technical assistance, the Wellcome Trust for a research grant, and Dr. S. S. Adams and Dr. H. 0. J. Collier for helpful advice. Bayer Products, Boots Pure Drug Co., Duncan Flockhart, Geigy, Eli Lily, Merk Sharp and Dohme, and Parke Davis and Co., kindly gave me pure
compounds. REFERENCES
S., Cliffe, E. E., Lessel, B., Nicholson, J. S. (1967) J. pharm. Sci. 56, 1686. Cobb, R. (1958). Nature, Lond. 181, 773. (1963) in Salicylates (edited by A. St. J. Dixon, B. K. Martin, M. J. H. Smith, P. A. N. Wood; p. 127. London. Berry, P. A., Collier, H. O. J. (1964) Br. J. Pharmac. Chemother, 23,
Adams,
S.
—
—
—
201.
Collier, H. O. J. (1968) Personal Communication. Shorley, P. G. (1960) ibid. 15, 601. Evans, G., Mustard, G. F. (1967) Lancet, ii, 724. Morris, C. D. W. (1967) ibid. i, 279. O’Brien, J. R. (1968a) ibid. i, 203. (1968b) ibid. 779. Heywood, J. B., Heady, J. A. (1966) Thromb. Diath. hœmorrh. 16, -
-
-
752.
Weiss, H. J., Aledort, L. M. (1967) Lancet, ii, 495. Winder, C. W., Wax, J., Welford, M. (1965) J. Pharmac. exp. Ther. 148, 1345.
Zucker, M. B., Peterson, J. (1968) Proc. Soc. exp. Biol. Med. (in the press).