Effects of Theophylline, β-Adrenergic Stimulants and Prednisolone on Platelet and Urine Cyclic Guanosine Monophosphate (cGMP)

WYNFORD ROBERT; WILLIAMS; SADANOBU KAGAMIMORI; TAKASHI SHIMIZU; HIROSHIGE KAKIUCHI; YUCHI NARUSE

doi:10.1620/tjem.156.331

WYNFORD ROBERT, WILLIAMS, SADANOBU KAGAMIMORI, TAKASHI SHIMIZU, HIROSHIGE KAKIUCHI, YUCHI NARUSE

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Keywords: anti-asthma drug therapy, cGMP, platelets

JOURNAL FREE ACCESS

1988 Volume 156 Issue 4 Pages 331-340

DOI https://doi.org/10.1620/tjem.156.331

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Published: 1988 Received: October 08, 1987 Available on J-STAGE: August 31, 2006 Accepted: October 11, 1988 Advance online publication: - Revised: -
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Date of correction: August 31, 2006 Reason for correction: - Correction: ABSTRACT Details: Wrong : WILLIAMS, W.R., KAGAMIMORI, S., SHIMIZU, T., KAKIUCHI, H. and NARUSE, Y. Effects of Theophylline, β-Adrenergic Stimulants and Prednisolone on Platelet and Urine Cyclic Guanosine Monophosphate (cGMP). Tohoku J. exp. Med., 1988, 156 (4), 331-340-Experiments were carried out to investigate the effects of anti- asthma drugs on cGMP levels. In vitro, theophylline (5×10^-4M) increased basal and 5-hydroxytryptamine stimulated cGMP formation by platelets (p<0.05) while salbutamol and prednisolone produced no change. No significant differences were found in urine cGMP levels in healthy subjects, after short term treatment with theophylline, isoprenaline or prednisolone. Urinary cGMP levels were lower than normal in the majority (7/10) of asthma patients tested and in female patients this difference was significant (p<0.05). Severity of asthma symptoms were not found to be associated with particular changes in urinary cGMP levels. Fluctuations in the cGMP levels were, however, greater (p<0.01) in asthma patients with a more unstable respiratory condition. The differences between in vitro and in vivo results may demonstrate that β-stimulants and theophylline have different acute and chronic effects on cGMP formation, or show that in vivo these drugs primarily affect tissue enzymes that differ from those on platelets.
Right : Experiments were carried out to investigate the effects of antiasthma drugs on cGMP levels. In vitro, theophylline (5×10^-4 M) increased basal and 5-hydroxytryptamine stimulated cGMP formation by platelets (p < 0.05) while salbutamol and prednisolone produced no change. No significant differences were found in urine cGMP levels in healthy subjects, after short term treatment with theophylline, isoprenaline or prednisolone. Urinary cGMP levels were lower than normal in the majority (7/10) of asthma patients tested and in female patients this difference was significant (p < 0.05). Severity of asthma symptoms were not found to be associated with particular changes in urinary cGMP levels. Fluctuations in the cGMP levels were, however, greater (p < 0.01) in asthma patients with a more unstable respiratory condition. The differences between in vitro and in vivo results may demonstrate that β-stimulants and theophylline have different acute and chronic effects on cGMP formation, or show that in vivo these drugs primarily affect tissue enzymes that differ from those on platelets.

Date of correction: August 31, 2006 Reason for correction: - Correction: AUTHOR Details: Wrong : WYNFORD ROBERT WILLIAMS, SADANOBU KAGAMIMORI¹⁾, TAKASHI SHIMIZU, HIROSHIGE KAKIUCHI¹⁾, YUCHI NARUSE¹⁾
Right : WYNFORD ROBERT WILLIAMS¹⁾, SADANOBU KAGAMIMORI¹⁾, TAKASHI SHIMIZU¹⁾³⁾, HIROSHIGE KAKIUCHI¹⁾, YUCHI NARUSE¹⁾

Date of correction: August 31, 2006 Reason for correction: - Correction: AFFILIATION Details: Wrong :
1) Department of Community Medicine, Toyama Medical and Pharmaceutical University

Right :
1) Department of Community Medicine, Toyama Medical and Pharmaceutical University
2) Asthma Research Unit, Sully Hospital
3) Jyohoku Hospital

Date of correction: August 31, 2006 Reason for correction: - Correction: CITATION Details: Wrong : 1) Ball, J.H., Kaminsky, N.I., Hardman, J.G., Broadus, A.E., Sutherland, E.W. & Liddle, G.W. (1972) Effects of catecholamines and adrenergic-blocking agents on plasma and urinary cyclic nucleotides in man. J. clin. Invest., 51, 2124-2149.
2) Davis, P.B. & Lieberman, P. (1982) Normal alpha₂-adrenergic responeses in platelets with asthma. J. Allergy clin. Immunol., 69, 35-38.
3) Fenger, M., Eriksen, P.B., Andersen, O., Nielsen, M.K. & Knudsen, P.J. (1982) Plasma concentrations of the cyclic nucleotides, adenosine 3', 5'-monophosphate and guanosine 3', 5'-monophosphate in healthy adults treated with theophylline. Pharmacology, 24, 215-221.
4) Hamet, P. & Sands, H. (1980) Pathophysiological Aspects of Cyclic Nucleotide. Advanc. Cyclic Nucleotide Res., 12, Raven Press, New York.
5) Hartley, J.P.R., Davies, C.J., Charles, T.J., Monie, R.D.H., Nogrady, S.G. & Winson, M.D. (1981) Plasma cyclic nucleotide levels in exercise-induced asthma. Thorax, 36, 823-827.
6) Konig, P., Carpenter, M. & White, A.A. (1980) Urinary cyclic adenosine 3', 5'-monophosphate and cyclic guanosine 3', 5'-monophosphate in asthmatic and normal children. Europ. J. resp. Dis., 61, 218-226.
7) Kopp, L., Lin, T. & Tucci, J.R. (1977) Circadian rhythms in the urinary excretion of cyclic 3', 5'-adenosine monophosphate and cyclic 3', 5'-guanosine monophosphate in human subjects. J. clin. Endocr., 44, 673-680.
8) Linklater, H.A., Strickland, K.P., Cunningham, D.A., Griffiths, J.C. & Trevithick, J.R. (1979) Urinary cyclic AMP and GMP in normal and asthmatic subjects during exercise. Med. Sci. Sports, 11, 250-255.
9) Mittal, C.K. & Murad, F. (1982) Guanylate cyclase: Regulation of cyclic nucleotide metabolism. In: Cyclic Nucleotides, edited by J.A. Nathanson & J.W. Kebabian, vol. 1, Springer-Verlag, Berlin, pp. 225-260.
10) Oikarinen, J., Hamalainen, L. & Oikarinen, A. (1984) Modulation of glucocorticoid receptor activity by cyclic nucleotides and its implications on the regulation of human skin fibroblast growth and protein synthesis. Biochim. biophys. Acta, 799, 158-165.
11) Page, C.P. & Morley, P.J. (1984) Platelets and Bronchospasm. Int. Arch. Allergy Appl. Immunol., 74, 347-350.
12) Platshon, L.F. & Kaliner, M. (1978) The effects of the immunologic release of histamine upon human lung cyclic nucleotide levels and prostaglandin generation. J. clin. Invest., 62, 1113-1121.
13) Selinger, Z. & Cassel, D. (1981) Role of guanine nucleotides in hormonal activation of adenylate cyclase. In: Advances in Cyclic Nucleotide Research, edited by J.E. Dumont, P. Greengard & G.A. Robinson. vol. 14, Raven Press, New York. pp. 15-22.
14) Svedmyr, N. (1984) New thoughts about the mechanism of action of corticosteroids and theophylline in asthma. Europ. J. resp. Dis., Suppl. 136, 115-120.15) Szentivanyi, A. (1980) The radioligand binding approach in the study of lymphocytic adrenoceptors and the constitutional basis of atopy. J. Allergy clin. Immunol., 65, 5-11.
16) Turner, G.A., Ellis, R.D., Guthrie, D., Latner, A.L., Skillen, A.W. & Ross, W.M. (1982) Levels of adenosine 3', 5'-cyclic monoghosphate and guanosine 3', 5'-cyclic monophosphate in single urine specimens collected from a large population of healthy subjects. Ann. clin. Biochem., 19, 77-82.
17) Vesely, D.L. (1980) On the mechanism of action of adrenocortical steroids: Cortisol and aldosterone enhance guanylate cyclase activity. J. Pharmacol. exp. Ther., 214, 561-566.
18) Williams, W.R., Kagamimori, S., Dlvies, B.H. & Watanabe M. (1986) Formation of extracellular cGMP in blood mononuclear and platelet cell preparations. J. clin. Lab. Immunol., 20, 89-92.
19) Zschauer, A. & Richardson, B.P. (1983) Mediators of smooth muscle contraction in asthma. In: Proceedings of the XI International Congress of Allergology and Clinical Immunology, edited by J.W. Kerr & M.A. Ganderton, Macmillan Press, pp. 315-319.

Right : 1) Ball, J. H., Kaminsky, N. I., Hardman, J. G., Broadus, A. E., Sutherland, E. W. & Liddle, G. W. (1972) Effects of catecholamines and adrenergic-blocking agents on plasma and urinary cyclic nucleotides in man. J. clin. Invest., 51, 2124-2149.
2) Davis, P. B. & Lieberman, P. (1982) Normal alpha₂-adrenergic responeses in platelets with asthma. J. Allergy clin. Immunol., 69, 35-38.
3) Fenger, M., Eriksen, P. B., Andersen, O., Nielsen, M. K. & Knudsen, P. J. (1982) Plasma concentrations of the cyclic nucleotides, adenosine 3', 5'-monophorphate and guanosine 3', 5'-monophosphate in healthy adults treated with theophylline. Pharmacology, 24, 215-221.
4) Hamet, P. & Sands, H. (1980) Pathophysiological Aspects of Cyclic Nucleotide. Advanc. Cyclic Nucleotide Res., 12, Raven Press, New York.
5) Hartley, J. P. R., Davies, C. J., Charles, T. J., Monie, R. D. H., Nogrady, S. G. & Winson, M. D. (1981) Plasma cyclic nucleotide levels in exercise-induced asthma. Thorax, 36, 823-827.
6) Konig, P., Carpenter, M. & White, A. A. (1980) Urinary cyclic adenosine 3', 5'-monophosphate and cyclic guanosine 3', 5'-monophosphate in asthmatic and normal children. Europ. J. resp. Dis., 61, 218-226.
7) Kopp, L., Lin, T. & Tucci, J. R. (1977) Circadian rhythms in the urinary excretion of cyclic 3', 5'-adenosine monophosphate and cyclic 3', 5'-guanosine monophosphate in human subjects. J. clin. Endocr., 44, 673-680.
8) Linklater, H. A., Strickland, K. P., Cunningham, D. A., Griffiths, J. C. & Trevithick, J. R. (1979) Urinary cyclic AMP and GMP in normal and asthmatic subjects during exercise. Med. Sci. Sports, 11, 250-255.
9) Mittal, C. K. & Murad, F. (1982) Guanylate cyclase: Regulation of cyclic nucleotide metabolism. In: Cyclic Nucleotides, edited by J. A. Nathanson & J. W. Kebabian, vol. 1, Springer-Verlag, Berlin, pp. 225-260.
10) Oikarinen, J., Hamalainen, L. & Oikarinen, A. (1984) Modulation of glucocorticoid receptor activity by cyclic nucleotides and its implications on the regulation of human skin fibroblast growth and protein synthesis. Biochim. biophys. Acta, 799, 158-165.
11) Page, C. P. & Morley, P. J. (1984) Platelets and Bronchospasm. Int. Arch. Allergy Appl. Immunol., 74, 347-350.
12) Platshon, L. F. & Kaliner, M. (1978) The effects of the immunologic release of histamine upon human lung cyclic nucleotide levels and prostaglandin generation. J. clin. Invest., 62, 1113-1121.
13) Selinger, Z. & Cassel, D. (1981) Role of guanine nucleotides in hormonal activation of adenylate cyclase. In: Advances in Cyclic Nucleotide Research, edited by J. E. Dumont, P. Greengard & G. A. Robinson. vol. 14, Raven Press, New York. pp. 15-22.
14) Svedmyr, N. (1984) New thoughts about the mechanism of action of corticosteroids and theophylline in asthma. Europ. J. resp. Dis., Suppl. 136, 115-120.
15) Szentivanyi, A. (1980) The radioligand binding approach in the study of lymphocytic adrenoceptors and the constitutional basis of atopy. J. Allergy clin. Immunol., 65, 5-11.
16) Turner, G. A., Ellis, R. D., Guthrie, D., Latner, A. L., Skillen, A. W. & Ross, W. M. (1982) Levels of adenosine 3', 5'-cyclic monophosphate and guanosine 3', 5'-cyclic monophosphate in single urine specimens collected from a large population of healthy subjects. Ann. clin. Biochem., 19, 77-82.
17) Vesely, D. L. (1980) On the mechanism of action of adrenocortical steroids: Cortisol and aldosterone enhance guanylate cyclase activity. J. Pharmacol. exp. Ther., 214, 561-566.
18) Williams, W. R., Kagamimori, S., Dlvies, B. H. & Watanabe M. (1986) Formation of extracellular cGMP in blood mononuclear and platelet cell preparations. J. clin. Lab. Immunol., 20, 89-92.
19) Zschauer, A. & Richardson, B. P. (1983) Mediators of smooth muscle contraction in asthma. In: Proceedings of the XI International Congress of Allergology and Clinical Immunology, edited by J. W. Kerr & M. A. Ganderton, Macmillan Press, pp. 315-319.

Date of correction: August 31, 2006 Reason for correction: - Correction: PDF FILE Details: -

Date of correction: August 31, 2006 Reason for correction: - Correction: AUTHOR Details: Wrong : WYNFORD ROBERT WILLIAMS¹⁾, SADANOBU KAGAMIMORI¹⁾, TAKASHI SHIMIZU¹⁾³⁾, HIROSHIGE KAKIUCHI¹⁾, YUCHI NARUSE¹⁾
Right : WYNFORD ROBERT¹⁾, WILLIAMS¹⁾²⁾, SADANOBU KAGAMIMORI¹⁾, TAKASHI SHIMIZU¹⁾³⁾, HIROSHIGE KAKIUCHI¹⁾, YUCHI NARUSE¹⁾

Date of correction: August 31, 2006 Reason for correction: - Correction: CITATION Details: Wrong : 1) Ball, J. H., Kaminsky, N. I., Hardman, J. G., Broadus, A. E., Sutherland, E. W. & Liddle, G. W. (1972) Effects of catecholamines and adrenergic-blocking agents on plasma and urinary cyclic nucleotides in man. J. clin. Invest., 51, 2124-2149.
2) Davis, P. B. & Lieberman, P. (1982) Normal alpha₂-adrenergic responeses in platelets with asthma. J. Allergy clin. Immunol., 69, 35-38.
3) Fenger, M., Eriksen, P. B., Andersen, O., Nielsen, M. K. & Knudsen, P. J. (1982) Plasma concentrations of the cyclic nucleotides, adenosine 3', 5'-monophorphate and guanosine 3', 5'-monophosphate in healthy adults treated with theophylline. Pharmacology, 24, 215-221.
4) Hamet, P. & Sands, H. (1980) Pathophysiological Aspects of Cyclic Nucleotide. Advanc. Cyclic Nucleotide Res., 12, Raven Press, New York.
5) Hartley, J. P. R., Davies, C. J., Charles, T. J., Monie, R. D. H., Nogrady, S. G. & Winson, M. D. (1981) Plasma cyclic nucleotide levels in exercise-induced asthma. Thorax, 36, 823-827.
6) Konig, P., Carpenter, M. & White, A. A. (1980) Urinary cyclic adenosine 3', 5'-monophosphate and cyclic guanosine 3', 5'-monophosphate in asthmatic and normal children. Europ. J. resp. Dis., 61, 218-226.
7) Kopp, L., Lin, T. & Tucci, J. R. (1977) Circadian rhythms in the urinary excretion of cyclic 3', 5'-adenosine monophosphate and cyclic 3', 5'-guanosine monophosphate in human subjects. J. clin. Endocr., 44, 673-680.
8) Linklater, H. A., Strickland, K. P., Cunningham, D. A., Griffiths, J. C. & Trevithick, J. R. (1979) Urinary cyclic AMP and GMP in normal and asthmatic subjects during exercise. Med. Sci. Sports, 11, 250-255.
9) Mittal, C. K. & Murad, F. (1982) Guanylate cyclase: Regulation of cyclic nucleotide metabolism. In: Cyclic Nucleotides, edited by J. A. Nathanson & J. W. Kebabian, vol. 1, Springer-Verlag, Berlin, pp. 225-260.
10) Oikarinen, J., Hamalainen, L. & Oikarinen, A. (1984) Modulation of glucocorticoid receptor activity by cyclic nucleotides and its implications on the regulation of human skin fibroblast growth and protein synthesis. Biochim. biophys. Acta, 799, 158-165.
11) Page, C. P. & Morley, P. J. (1984) Platelets and Bronchospasm. Int. Arch. Allergy Appl. Immunol., 74, 347-350.
12) Platshon, L. F. & Kaliner, M. (1978) The effects of the immunologic release of histamine upon human lung cyclic nucleotide levels and prostaglandin generation. J. clin. Invest., 62, 1113-1121.
13) Selinger, Z. & Cassel, D. (1981) Role of guanine nucleotides in hormonal activation of adenylate cyclase. In: Advances in Cyclic Nucleotide Research, edited by J. E. Dumont, P. Greengard & G. A. Robinson. vol. 14, Raven Press, New York. pp. 15-22.
14) Svedmyr, N. (1984) New thoughts about the mechanism of action of corticosteroids and theophylline in asthma. Europ. J. resp. Dis., Suppl. 136, 115-120.
15) Szentivanyi, A. (1980) The radioligand binding approach in the study of lymphocytic adrenoceptors and the constitutional basis of atopy. J. Allergy clin. Immunol., 65, 5-11.
16) Turner, G. A., Ellis, R. D., Guthrie, D., Latner, A. L., Skillen, A. W. & Ross, W. M. (1982) Levels of adenosine 3', 5'-cyclic monophosphate and guanosine 3', 5'-cyclic monophosphate in single urine specimens collected from a large population of healthy subjects. Ann. clin. Biochem., 19, 77-82.
17) Vesely, D. L. (1980) On the mechanism of action of adrenocortical steroids: Cortisol and aldosterone enhance guanylate cyclase activity. J. Pharmacol. exp. Ther., 214, 561-566.
18) Williams, W. R., Kagamimori, S., Dlvies, B. H. & Watanabe M. (1986) Formation of extracellular cGMP in blood mononuclear and platelet cell preparations. J. clin. Lab. Immunol., 20, 89-92.
19) Zschauer, A. & Richardson, B. P. (1983) Mediators of smooth muscle contraction in asthma. In: Proceedings of the XI International Congress of Allergology and Clinical Immunology, edited by J. W. Kerr & M. A. Ganderton, Macmillan Press, pp. 315-319.

Right : 1) Ball, J. H., Kaminsky, N. I., Hardman, J. G., Broadus, A. E., Sutherland, E. W. & Liddle, G. W. (1972) Effects of catecholamines and adrenergic-blocking agents on plasma and urinary cyclic nucleotides in man. J. clin. Invest., 51, 2124-2149.
2) Davis, P. B. & Lieberman, P. (1982) Normal alpha₂-adrenergic responeses in platelets with asthma. J. Allergy elin. Immunol., 69, 35-38.
3) Fenger, M., Eriksen, P. B., Andersen, O., Nielsen, M. K. & Knudsen, P. J. (1982) Plasma concentrations of the cyclic nucleotides, adenosine 3', 5'-monophorphate and guanosine 3', 5'-monophosphate in healthy adults treated with theophylline. Pharmacology, 24, 215-221.
4) Hamet, P. & Sands, H. (1980) Pathophysiological Aspects of Cyclic Nucleotide. Advanc. Cyclic Nucleotide Res., 12, Raven Press, New York.
5) Hartley, J. P. R., Davies, C. J., Charles, T. J., Monie, R. D. H., Nogrady, S. G. & Winson, M. D. (1981) Plasma cyclic nucleotide levels in exercise-induced asthma. Thorax, 36, 823-827.
6) Konig, P., Carpenter, M. & White, A. A. (1980) Urinary cyclic adenosine 3', 5'-monophosphate and cyclic guanosine 3', 5'-monophosphate in asthmatic and normal children. Europ. J. resp. Dis., 61, 218-226.
7) Kopp, L., Lin, T. & Tucci, J. R. (1977) Circadian rhythms in the urinary excretion of cyclic 3', 5'-adenosine monophosphate and cyclic 3', 5'-guanosine monophosphate in human subjects. J. clin. Endocr., 44, 673-680.
8) Linklater, H. A., Strickland, K. P., Cunningham, D. A., Griffiths, J. C. & Trevithick, J. R. (1979) Urinary cyclic AMP and GMP in normal and asthmatic subjects during exercise. Med. Sci. Sports, 11, 250-255.
9) Mittal, C. K. & Murad, F. (1982) Guanylate cyclase: Regulation of cyclic nucleotide metabolism. In: Cyclic Nucleotides, edited by J. A. Nathanson & J. W. Kebabian, vol. 1, Springer-Verlag, Berlin, pp. 225-260.
10) Oikarinen, J., Hamalainen, L. & Oikarinen, A. (1984) Modulation of glucocorticoid receptor activity by cyclic nucleotides and its implications on the regulation of human skin fibroblast growth and protein synthesis. Biochim. biophys. Acta, 799, 158-165.
11) Page, C. P. & Morley, P. J. (1984) Platelets and Bronchospasm. Int. Arch. Allergy Appl. Immunol., 74, 347-350.
12) Platshon, L. F. & Kaliner, M. (1978) The effects of the immunologic release of histamine upon human lung cyclic nucleotide levels and prostaglandin generation. J. clin. Invest., 62, 1113-1121.
13) Selinger, Z. & Cassel, D. (1981) Role of guanine nucleotides in hormonal activation of adenylate cyclase. In: Advances in Cyclic Nucleotide Research, edited by J. E. Dumont, P. Greengard & G. A. Robinson. vol. 14, Raven Press, New York. pp. 15-22.
14) Svedmyr, N. (1984) New thoughts about the mechanism of action of corticosteroids and theophylline in asthma. Europ. J. resp. Dis., Suppl. 136, 115-120.
15) Szentivanyi, A. (1980) The radioligand binding approach in the study of lymphocytic adrenoceptors and the constitutional basis of atopy. J. Allergy clin. Immunol., 65, 5-11.
16) Turner, G. A., Ellis, R. D., Guthrie, D., Latner, A. L., Skillen, A. W. & Ross, W. M. (1982) Levels of adenosine 3', 5'-cyclic monophosphate and guanosine 3', 5'-cyclic monophosphate in single urine specimens collected from a large population of healthy subjects. Ann. clin. Biochem., 19, 77-82.
17) Vesely, D. L. (1980) On the mechanism of action of adrenocortical steroids: Cortisol and aldosterone enhance guanylate cyclase activity. J. Pharmacol. exp. Ther., 214, 561-566.
18) Williams, W. R., Kagamimori, S., Dlvies, B. H. & Watanabe M. (1986) Formation of extracellular cGMP in blood mononuclear and platelet cell preparations. J. clin. Lab. Immunol., 20, 89-92.
19) Zschauer, A. & Richardson, B. P. (1983) Mediators of smooth muscle contraction in asthma. In: Proceedings of the XI International Congress of Allergology and Clinical Immunology, edited by J. W. Kerr & M. A. Ganderton, Macmillan Press, pp. 315-319.

Date of correction: August 31, 2006 Reason for correction: - Correction: PDF FILE Details: -

Abstract

Experiments were carried out to investigate the effects of antiasthma drugs on cGMP levels. In vitro, theophylline (5×10^-4 M) increased basal and 5-hydroxytryptamine stimulated cGMP formation by platelets (p < 0.05) while salbutamol and prednisolone produced no change. No significant differences were found in urine cGMP levels in healthy subjects, after short term treatment with theophylline, isoprenaline or prednisolone. Urinary cGMP levels were lower than normal in the majority (7/10) of asthma patients tested and in female patients this difference was significant (p < 0.05). Severity of asthma symptoms were not found to be associated with particular changes in urinary cGMP levels. Fluctuations in the cGMP levels were, however, greater (p < 0.01) in asthma patients with a more unstable respiratory condition. The differences between in vitro and in vivo results may demonstrate that β-stimulants and theophylline have different acute and chronic effects on cGMP formation, or show that in vivo these drugs primarily affect tissue enzymes that differ from those on platelets.

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