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FIBRINOGEN DEGRADATION PRODUCTS IN ACUTE MYOCARDIAL INFARCTION
689 SCRAPIE
SIR,—I read with interest the editorial on scrapie (Feb. 19, p. 418). You say that " Ultra-structural investigations have not yet identified the agent ". I think that the fact should be mentioned that intraneuronal accumulations of 35 nm. particles have been described in natural scrapie of sheep1 and in experimental scrapie in mice2 and rat.3 The size of the particles is in close agreement with the size of the scrapie agent as determined by filtration experiments. 4,5 In sheep the particles have been observed within lesions which are characteristic of natural scrapie-i.e., neuronal vacuoles with intravacuolar budding of vesicles and cytoplasmic processes. Department of Pathology, Stanford University and Veterans Administration Hospital, 3801 Miranda Avenue, Palo Alto, California 94304, U.S.A.
A. BIGNAMI.
UNEMPLOYMENT AND HEALTH CARE
SIR There must be many physicians in industrialised countries such as the U.S.A., Canada, and the U.K. who are disturbed by current unemployment levels and the continuing failure to deal effectively with this source of misery and waste of human effort. Assuming that basic changes in the pattern of industrialisation are occurringand few in Britain would dispute this in relation to the coal or textile industries, for example-those of us concerned with health care ought surely to be making a clearer call for a massive influx of the unemployed into health care and particularly into the neglected sectors such as mental health and subnormality and chronic illness. The work of many nurses, for example, could be considerably helped if they had an able-bodied person to assist them with their heavier tasks. Similarly, many of the caring rather than the curing aspects of care could be much improved with extra help from mature and generally experienced adults-even though we could be expected to stigmatise the helpers by constantly referring to them as ‘‘ untrained ". In the U.K., the problem seems to be relatively simple in terms of costs, because we have a central government department that combines health care with social security. To quite an extent, therefore, to pay for perhaps 100,000 extra workers within the field of health would simply require an intelligent book-keeping operation between the social security and the health sides of the bureaucracy. This is not to suggest that special training programmes should not be developed, but rather that the persistent failure to respond to this problem and its associated opportunities seems to result from a misleading method of reckoning social costs. That education and other social services ought to be calling for help also (for instance to the extent of at least halving the average size of classes) is no reason for health services to hold back. But where should the initiative for such a change arise within the health field ? Who is examining seriously the possibility of real advances in health care through our greater abilities to produce essential goods with less human labour ? We need not only to seize an unexpected opportunity but also to examine the causes of our lethargic institutional responses. Given the 1. 2.
3. 4.
Bignami, A., Parry, H. B. Science, 1971, 171, 389. David-Ferreira, J. F., David-Ferreira, K. L., Gibbs, C. J., Jr., Morris, J. A. Proc. Soc. exp. Biol. Med. 1968, 127, 313. Lampert, P., Hooks, J., Gibbs, C. J., Jr., Gajdusek, D. C. Acta neuropath., Berl. 1971, 19, 81. Gibbs, C. J., Gajdusek, D. C., Morris, J. A. Monogr. Nat. Inst. Nerv. Dis. Blindness, no. 2, p. 195. N.I.H., Bethesda, Maryland, 1965.
5.
Hunter, G. D. Sixth p. 802. Paris, 1970.
International
Congress
of
Neuropathology;
size and time-scale of our ecological have another chance. Department of Community Medicine,
problems,
we
may
not
Guy’s Hospital Medical School, London SE1 9RT.
PETER DRAPER.
FIBRIN/FIBRINOGEN DEGRADATION PRODUCTS IN ACUTE MYOCARDIAL INFARCTION SIR,-Dr. Maurer and his colleagues (Dec. 25, p. 1385) report a high incidence of calf-vein thrombosis within 72 hours of acute myocardial infarction. They suggest that the initial formation of a venous thrombus in these patients is not related to long immobilisation. Since increased fibrin/fibrinogen degradation products (F.D.P.) in the serum may be a guide in detecting thrombosis,1-3 we measured serum-F.D.P. during the first 24 hours after admission to the coronary-care unit. Serum-F.D.P.s were determined by a hasmagglutination inhibition immunoassay 4 in 92 patients with established diagnosis of acute myocardial infarction. Blood was SERUM
containing 2 or 3 drops of aprotinin Burroughs Wellcome kit was used for the F.D.P. assays. Specimens were analysed without knowledge of any clinical data, and no selection of patients was performed. No attempt was made to assess the presence of thrombosis from the clinical data or by complementary investigations.
sampled
in
a
(’Trasylol’).
tube The
TABLE I-SERUM-F.D.P. RELATED TO AGE AND MORTALITY
TABLE II-SERUM-F.D.P. RELATED TO SEVERITY OF INFARCTION
High levels of serum-F.D.P. were associated with a striking increase in mortality (table i). No relationship was found between serum-F.D.P. and age. Our preliminary results suggest that the level of serum-F.D.P., determined during the acute phase of myocardial infarction, may have prognostic value. The frequency of complications observed during the whole stay in the coronary-care unit was related to serumCash, J. D., Woodfield, D. G., Das, P. C., Allan, A. G. E. Br. med. J. 1969, i, 576. 2. Cash, J. D., Das, P. C., Ruckley, C. V. Scand. J. Hœmat. 1971, suppl. no. 13, p. 323. 3. Hedner, U., Nilsson, I. M. Acta med. scand. 1971, 189, 471. 4. Merskey, C., Lalezari, P., Johnson, A. J. Proc. Soc. exp. Biol. Med. 1969, 81, 871. 1.
690 F.D.P. levels, determined within the first 24 hours after admission (table II). It is difficult to explain the increase in serum-F.D.p. by the sole presence of a coronary-artery thrombus. The serum-F.D.P. levels, high early after the onset of myocardial infarction, may rather reflect associated thrombosis in other vascular areas. Department of Internal Medicine, State University of Ghent, G. BAELE Academisch Ziekenhuis, MUSSCHE M. De Pintelaan 135, P. VERMEIRE. B-9000 Ghent, Belgium.
PRECAUTION IN PHARMACOKINETIC EVALUATION OF AMPICILLIN PRECURSORS
SIR,—The value of ampicillin as an antibiotic is well recognised and there have been several attempts to enhance its chemotherapeutic usefulness by chemical modification. This has resulted in the appearance of compounds such as metampicillin, pivampicillin, and hetacillin, the last being a condensation product of ampicillin and acetone. Several investigators claim 1.2that hetacillin, which is itself microbiologically inactive,3 has an advantage over ampicillin in that it produces an enhancement of ampicillin plasma levels when given parenterally. However, it can be shown that this apparent increase is the result of a technical artefact caused by assay of hetacillin as ampicillin during the long incubation period which is used for most microbiological The antibacterial activity of blood assay procedures. samples from patients receiving intravenous hetacillin as most commonly measured does not therefore reflect the true in-vivo antibacterial situation. Eight normal subjects received 530-650 mg. molar equivalent doses of intravenous ampicillin and hetacillin (Bristol Laboratories). Blood and urine specimens were collected during the course of 24 hours. These were analysed for 1. Tuano, S. B., Johnson, L. D., Brodie, J. L., Kirby, W. M. M. New Engl. J. Med. 1966, 275, 635. 2. Modr, F., Dvoracek, F. Rev. Czech. Med. 1970, 16, 84. 3. Smith, J. T., Hamilton-Miller, J. M. T. Chemotherapy, 1970, 15, 366.
antibiotic content by two procedures. The total apparent antibiotic concentration was obtained using a conventional agar-plate diffusion microbiological assay 4,5 which require, incubation of the sample and microorganism for 12-lE hours. Agar-gel electrophoresis6 was also used to separate ampicillin and hetacillin in the early plasma samples, which then allowed specific bioautographic measurement of each compound. The plasma concentration and urinary excretion-rate data were subjected to appropriate computer and
pharmacokinetic analyses. 7,8 Apparent plasma concentrations of antibiotic as a function of time after intravenous injection of ampicillin and hetacillin are shown on the left side of the accompanying figure. If the conventional microbiological assay is used without separation of ampicillin and hetacillin, the plasma levels obtained after hetacillin administration (dashed line) appear to exceed those obtained after intravenous ampicillin. Misinterpretation of this type of data has led to the conception 1,2 that hetacillin produces higher blood levels than ampicillin after parenteral administration. The right side of the figure shows the same data where, after hetacillin injection, ampicillin and hetacillin were electrophoretically separated for specific analysis of each The microbiologically inactive hetacillin compound. and dotted line) is chemically distinct in the (triangles body but disappears rapidly by conversion to ampicillin. The time-course of ampicillin concentration in the plasma which is produced resembles that from a slow injection process. As hetacillin hydrolyses, ampicillin levels increase during the early time period to a maximum level at about 30 minutes and
cross the intravenous data curve before Additional data indicate that essentially all of the hetacillin which is injected will form ampicillin in vivo, and thus the plasma level areas for intravenous
decreasing.
4. Jusko, W. J. J. pharm. Sci. 1971, 60, 728. 5. Bennett, J. V., Brodie, J. L., Benner, E. J., Kirby, W. M. M. Appl. Microbiol. 1966, 14, 170. 6. Lightbrown, J. W., de Rossi, P. Analyst, 1965, 90, 89. 7. Rowland, M., Benet, L. Z., Riegelman, S. J. pharm. Sci. 1970, 59, 364. 8. Rescigno, A., Segre, G. Drug and Tracer Kinetics. Waltham, Mass., 1966.
as a function of time after intravenous injection of ampicillin and hetacillin in subject 4. concentrations show after intravenous injection of ampicillin. Left of figure shows total ampicillin and hetacillin Squares ampicillin concentrations after hetacillin injection as measured with the non-specific microbiological assay, while right of figure shows the same data resolved into hetacillin (triangles) and ampicillin (solid line) concentrations by specific analysis. Lines are computer generated and data are normalised for a 500 mg. equivalent dose of each compound.
Plasma antibiotic concentration
SIR,—I read with interest the editorial on scrapie (Feb. 19, p. 418). You say that " Ultra-structural investigations have not yet identified the agent ". I think that the fact should be mentioned that intraneuronal accumulations of 35 nm. particles have been described in natural scrapie of sheep1 and in experimental scrapie in mice2 and rat.3 The size of the particles is in close agreement with the size of the scrapie agent as determined by filtration experiments. 4,5 In sheep the particles have been observed within lesions which are characteristic of natural scrapie-i.e., neuronal vacuoles with intravacuolar budding of vesicles and cytoplasmic processes. Department of Pathology, Stanford University and Veterans Administration Hospital, 3801 Miranda Avenue, Palo Alto, California 94304, U.S.A.
A. BIGNAMI.
UNEMPLOYMENT AND HEALTH CARE
SIR There must be many physicians in industrialised countries such as the U.S.A., Canada, and the U.K. who are disturbed by current unemployment levels and the continuing failure to deal effectively with this source of misery and waste of human effort. Assuming that basic changes in the pattern of industrialisation are occurringand few in Britain would dispute this in relation to the coal or textile industries, for example-those of us concerned with health care ought surely to be making a clearer call for a massive influx of the unemployed into health care and particularly into the neglected sectors such as mental health and subnormality and chronic illness. The work of many nurses, for example, could be considerably helped if they had an able-bodied person to assist them with their heavier tasks. Similarly, many of the caring rather than the curing aspects of care could be much improved with extra help from mature and generally experienced adults-even though we could be expected to stigmatise the helpers by constantly referring to them as ‘‘ untrained ". In the U.K., the problem seems to be relatively simple in terms of costs, because we have a central government department that combines health care with social security. To quite an extent, therefore, to pay for perhaps 100,000 extra workers within the field of health would simply require an intelligent book-keeping operation between the social security and the health sides of the bureaucracy. This is not to suggest that special training programmes should not be developed, but rather that the persistent failure to respond to this problem and its associated opportunities seems to result from a misleading method of reckoning social costs. That education and other social services ought to be calling for help also (for instance to the extent of at least halving the average size of classes) is no reason for health services to hold back. But where should the initiative for such a change arise within the health field ? Who is examining seriously the possibility of real advances in health care through our greater abilities to produce essential goods with less human labour ? We need not only to seize an unexpected opportunity but also to examine the causes of our lethargic institutional responses. Given the 1. 2.
3. 4.
Bignami, A., Parry, H. B. Science, 1971, 171, 389. David-Ferreira, J. F., David-Ferreira, K. L., Gibbs, C. J., Jr., Morris, J. A. Proc. Soc. exp. Biol. Med. 1968, 127, 313. Lampert, P., Hooks, J., Gibbs, C. J., Jr., Gajdusek, D. C. Acta neuropath., Berl. 1971, 19, 81. Gibbs, C. J., Gajdusek, D. C., Morris, J. A. Monogr. Nat. Inst. Nerv. Dis. Blindness, no. 2, p. 195. N.I.H., Bethesda, Maryland, 1965.
5.
Hunter, G. D. Sixth p. 802. Paris, 1970.
International
Congress
of
Neuropathology;
size and time-scale of our ecological have another chance. Department of Community Medicine,
problems,
we
may
not
Guy’s Hospital Medical School, London SE1 9RT.
PETER DRAPER.
FIBRIN/FIBRINOGEN DEGRADATION PRODUCTS IN ACUTE MYOCARDIAL INFARCTION SIR,-Dr. Maurer and his colleagues (Dec. 25, p. 1385) report a high incidence of calf-vein thrombosis within 72 hours of acute myocardial infarction. They suggest that the initial formation of a venous thrombus in these patients is not related to long immobilisation. Since increased fibrin/fibrinogen degradation products (F.D.P.) in the serum may be a guide in detecting thrombosis,1-3 we measured serum-F.D.P. during the first 24 hours after admission to the coronary-care unit. Serum-F.D.P.s were determined by a hasmagglutination inhibition immunoassay 4 in 92 patients with established diagnosis of acute myocardial infarction. Blood was SERUM
containing 2 or 3 drops of aprotinin Burroughs Wellcome kit was used for the F.D.P. assays. Specimens were analysed without knowledge of any clinical data, and no selection of patients was performed. No attempt was made to assess the presence of thrombosis from the clinical data or by complementary investigations.
sampled
in
a
(’Trasylol’).
tube The
TABLE I-SERUM-F.D.P. RELATED TO AGE AND MORTALITY
TABLE II-SERUM-F.D.P. RELATED TO SEVERITY OF INFARCTION
High levels of serum-F.D.P. were associated with a striking increase in mortality (table i). No relationship was found between serum-F.D.P. and age. Our preliminary results suggest that the level of serum-F.D.P., determined during the acute phase of myocardial infarction, may have prognostic value. The frequency of complications observed during the whole stay in the coronary-care unit was related to serumCash, J. D., Woodfield, D. G., Das, P. C., Allan, A. G. E. Br. med. J. 1969, i, 576. 2. Cash, J. D., Das, P. C., Ruckley, C. V. Scand. J. Hœmat. 1971, suppl. no. 13, p. 323. 3. Hedner, U., Nilsson, I. M. Acta med. scand. 1971, 189, 471. 4. Merskey, C., Lalezari, P., Johnson, A. J. Proc. Soc. exp. Biol. Med. 1969, 81, 871. 1.
690 F.D.P. levels, determined within the first 24 hours after admission (table II). It is difficult to explain the increase in serum-F.D.p. by the sole presence of a coronary-artery thrombus. The serum-F.D.P. levels, high early after the onset of myocardial infarction, may rather reflect associated thrombosis in other vascular areas. Department of Internal Medicine, State University of Ghent, G. BAELE Academisch Ziekenhuis, MUSSCHE M. De Pintelaan 135, P. VERMEIRE. B-9000 Ghent, Belgium.
PRECAUTION IN PHARMACOKINETIC EVALUATION OF AMPICILLIN PRECURSORS
SIR,—The value of ampicillin as an antibiotic is well recognised and there have been several attempts to enhance its chemotherapeutic usefulness by chemical modification. This has resulted in the appearance of compounds such as metampicillin, pivampicillin, and hetacillin, the last being a condensation product of ampicillin and acetone. Several investigators claim 1.2that hetacillin, which is itself microbiologically inactive,3 has an advantage over ampicillin in that it produces an enhancement of ampicillin plasma levels when given parenterally. However, it can be shown that this apparent increase is the result of a technical artefact caused by assay of hetacillin as ampicillin during the long incubation period which is used for most microbiological The antibacterial activity of blood assay procedures. samples from patients receiving intravenous hetacillin as most commonly measured does not therefore reflect the true in-vivo antibacterial situation. Eight normal subjects received 530-650 mg. molar equivalent doses of intravenous ampicillin and hetacillin (Bristol Laboratories). Blood and urine specimens were collected during the course of 24 hours. These were analysed for 1. Tuano, S. B., Johnson, L. D., Brodie, J. L., Kirby, W. M. M. New Engl. J. Med. 1966, 275, 635. 2. Modr, F., Dvoracek, F. Rev. Czech. Med. 1970, 16, 84. 3. Smith, J. T., Hamilton-Miller, J. M. T. Chemotherapy, 1970, 15, 366.
antibiotic content by two procedures. The total apparent antibiotic concentration was obtained using a conventional agar-plate diffusion microbiological assay 4,5 which require, incubation of the sample and microorganism for 12-lE hours. Agar-gel electrophoresis6 was also used to separate ampicillin and hetacillin in the early plasma samples, which then allowed specific bioautographic measurement of each compound. The plasma concentration and urinary excretion-rate data were subjected to appropriate computer and
pharmacokinetic analyses. 7,8 Apparent plasma concentrations of antibiotic as a function of time after intravenous injection of ampicillin and hetacillin are shown on the left side of the accompanying figure. If the conventional microbiological assay is used without separation of ampicillin and hetacillin, the plasma levels obtained after hetacillin administration (dashed line) appear to exceed those obtained after intravenous ampicillin. Misinterpretation of this type of data has led to the conception 1,2 that hetacillin produces higher blood levels than ampicillin after parenteral administration. The right side of the figure shows the same data where, after hetacillin injection, ampicillin and hetacillin were electrophoretically separated for specific analysis of each The microbiologically inactive hetacillin compound. and dotted line) is chemically distinct in the (triangles body but disappears rapidly by conversion to ampicillin. The time-course of ampicillin concentration in the plasma which is produced resembles that from a slow injection process. As hetacillin hydrolyses, ampicillin levels increase during the early time period to a maximum level at about 30 minutes and
cross the intravenous data curve before Additional data indicate that essentially all of the hetacillin which is injected will form ampicillin in vivo, and thus the plasma level areas for intravenous
decreasing.
4. Jusko, W. J. J. pharm. Sci. 1971, 60, 728. 5. Bennett, J. V., Brodie, J. L., Benner, E. J., Kirby, W. M. M. Appl. Microbiol. 1966, 14, 170. 6. Lightbrown, J. W., de Rossi, P. Analyst, 1965, 90, 89. 7. Rowland, M., Benet, L. Z., Riegelman, S. J. pharm. Sci. 1970, 59, 364. 8. Rescigno, A., Segre, G. Drug and Tracer Kinetics. Waltham, Mass., 1966.
as a function of time after intravenous injection of ampicillin and hetacillin in subject 4. concentrations show after intravenous injection of ampicillin. Left of figure shows total ampicillin and hetacillin Squares ampicillin concentrations after hetacillin injection as measured with the non-specific microbiological assay, while right of figure shows the same data resolved into hetacillin (triangles) and ampicillin (solid line) concentrations by specific analysis. Lines are computer generated and data are normalised for a 500 mg. equivalent dose of each compound.
Plasma antibiotic concentration