1324
substances inhibited; and although somatostatin may be useful in glucagonoma,23 insulinoma, and the
Zollinger-Ellison syndrome 28 its therapeutic potential is obviously limited by its widely diverse effects. The downswing of hopes about a therapeutic role for somatostatin has lately been accelerated by reports of acute, though reversible, thrombocytopenia in baboons 31 and impaired platelet aggregation 32,33 with increased concentrations of the fibrin degradation product FgE in man.33 These diverse effects have nonetheless permitted some fascinating studies on hormonal regulation of metabolism. Somatostatin is the first agent to be found which will simultaneously inhibit insulin and glucagon secretion. This has led to a resurgence of interest in glucagon. When insulin and glucagon secretion are inhibited simultaneously by somatostatin, blood-glucose concentration falls rather than rises, which has led to the suggestion that glucagon may play a vital role in normal glucose homccostasis. 34,35 This hypothesis is supported by the fact that no direct effect of somatostatin on hepatic 36 or muscle metabolism has been found so far. Work with somatostatin has also clarified the role of glucagon in the pathogenesis of diabetic ketoacidosis. Investigations, first by GERICH et al.,37 ,38 and now by ALBERTI and his co-workers (see p. 1307this week), have shown that insulin withdrawal from insulin-treated diabetics leads to parallel rises in plasmaglucagon, blood-ketone-body, and plasma-F.F.A. concentrations, the rise in glucagon correlating strongly with the rise in ketone body. This points strongly to a role for glucagon. GERICH and his colleagues 39 now report that somatostatin prevents the rise in glucagon, and also of 3-hydroxybutyrate and F.F.A., in such insulin-deprived patients. This adds weight to the hypothesis that glucagon is important in the very early stages of ketoacidosis. There is, however, preliminary evidence that somatostatin cannot reverse a well-established ketoacidosis, so the glucagon-suppressing effect may not be useful in clinical practice. The actions of somatostatin in diabetes at present seem too widespread to allow for an important therapeutic role. But new synthetic analogues may 31.
Koerker, D. A., Harker, L. A., Goodner, C. J. Cited by Besser et
al.32
Besser, G. M., Paxton, A. M., Johnson, S. A. N., Moody, E. J., Mortimer, C. H., Hall, R., Gomez-Pan, A., Schally, A. V., Kastin, A. J., Coy, D. H. Lancet, May 24, 1975, p. 1166. 33. Goodner, C. J. New Engl. J. Med. 1975, 292, 1022. 34. Christensen, S. E., Hansen, Aa. P., Iversen, J., Lundbæk, K., Ørskov, H., Seyer-Hansen, K. Scand. J. clin. Lab. Invest. 1974, 34, 321. 35. Alford, F. P., Bloom, S. R., Nabarro, J. D. N., Hall, R., Besser, G. M., Coy, D. H., Kastin, A. J., Schally, A. V. Lancet, 1974, ii, 32.
974.
Koerker, D. J., Goodner, C. J., Ruch, W. New Engl. J. Med. 1974, 291, 262. 37. Gerich, J. E., Lorenzi, M., Hane, S., Gustafson, G., Guillemin, R., Forsham, P. H. Metabolism, 1975, 24, 175. 38. Gerich, J. E., Tsalikian, E., Lorenzi, M., Karam, J. H., Bier, D. M. J. clin. Endocr. Metab. 1975, 40, 526. 39. Gerich, J. E., Lorenzi, M., Bier, D. M., Schneider, V., Tsalikian, E., Karam, J. H., Forsham, P. H. New Engl. J. Med. 1975, 292, 985. 36.
prolonged and more specific actions, and this approach seems well worth pursuing: a long-acting preparation with selective suppressive effects on glucagon and growth hormone might be a provide
more
in the management of diabetes. Another subtle twist to the somatostatin story has just been added. Previously it was thought that natural somatostatin was confined to the hypothalamus and pituitary. Now PoLAK et a1.40 report that somatostatin may be a natural component of D-cells in both the gut and the pancreas. If this is confirmed then a whole new aspect of somatostatin physiology becomes apparent. Somatostatin may prove to be of fundamental physiological importance in the control of endocrine secretion in the pancreas and the gutand perhaps in the pathogenesis of diabetes mellitus. The story of the physiology and pharmacology of somatostatin has already provided more twists and turns than the best of Le Carre and Conan Doyle combined. We can now only sit back, slightly breathless, and await the next instalment.
big advance
Can
Herpes Simplex Encephalitis
be
Treated ? ALTHOUGH uncommon, encephalitis caused by Herpesvirus hominis has such a high mortality (about
andso aroused a presentation, .1 42 pos’sibility oftreatment 70%a possibility neurologists
that it has aroused of and in the keen interest both among wider world.44,45 There have been many attempts to find some features in the clinical illness that would aid differential diagnosis,43, 46 at least by suggesting herpetic encephalitis, so that further diagnostic measures can be urgently employed. Prospective series large enough for reasonable certainty have yet to be published; but, accepting the bias of hindsight, it does seem that the clinician cannot make this diagnosis unaided (although he may well suspect it in adults with features of acute disturbance of consciousness, epileptiform attacks, and lesions in the temporal lobes 43,47,48). Three types of investigative procedure are likely be applied to such patients. Various radiological methods might confirm the presence of localised tissue damage in the temporal lobe or other areas, and so might scintigraphy. The general value of electroencephalography (E.E.G.) is now accepted even though its exact diagnostic role
ing
a
to
40. 41. 42. 43.
Polak, J. M., Pearse, A. G. E., Grimelius, L., Bloom, S. R. Arimura, A. Lancet, May 31, 1975, p. 1220. Gilbert, D. N., Johnson, T., Luby, H., Sanford, J. P. Medicine, 1973, 52, 331. Rappel, M. Postgrad. med. J. 1973, 49, 419. Illis, L. S., Gostling, J. V. T. Herpes Simplex Encephalitis. Bristol,
1972. 44. Postgrad. med. J. 1973, 49, no. 572. 45. Lancet, 1973, ii, 1426. 46. Juel-Jensen, B. E., MacCallum, F. O. Herpes Simplex, Varicella and Zoster. London, 1972. 47. J. Am. med. Ass. 1968, 203, 882. 48. Olson, L. C., Buescher, E. L., Artenstein, M. S., Parkman, P. D. New Engl. J. Med. 1967, 277, 1271.
1325
ment,44,60 and the result looks conclusively negative dispute. Periodic repetitive complexes as far as encephalitis is concerned. Similar controlled of diffuse slowing, background perhaps against trials 61 with Ara-C, which seems less toxic, 62 localised over the temporal lobes, have been desare much needed: as in the early days of I.D.U., cribed,49 judged diagnostic, 5 denied,51 and on balance isolated successes and failures have been reported,62-65 partly reaffirmed. 52 ,53 EUAN 54 lately reported Most protagonists and critics of these compounds them in serial recordings from 11 patients with herpes have For the first time were paid surprisingly little attention to pharmacothey simplex encephalitis. kinetics and metabolism. I.D.U. is metabolised exobserved at any stage during or after the acute phase of the illness, but only in the 7 patients who died. tremely quickly and is also excreted speedily by the If the prognostic value of this E.E.G. finding is kidney,66,67 with the result that a conventional, slow confirmed, then it will represent a substantial intravenous infusion is unlikely to produce theraadvance. The only other simple diagnostic technique peutically effective levels-particularly not if the is examination of cerebrospinal fluid, and it, too, can drug has to cross even a partly effective blood/brain barrier. 68 Only rapid injection of a bolus will probe no more than suggestive.43 duce adequate levels of activity, although sometimes The more complex diagnostic techniques demand at the cost of toxicity.59,69 Ara-C has greater and services. neurosurgical virological Histological because its half-life in examination of brain tissue can never be more promise plasma and cerebrofluid is it than suggestive and may show only non-specific spinal longer, and passes more readily from blood to brain .70 However, its pharmacokinetic features.55 Electron-microscope demonstration of the virus in tissue seems difficult for routine purposes. properties are not ideal and it might be more effective Isolation of the virus in culture should be more intrathecally than intravenously (half-life 2 hours as success-rates from opposed to 12 and 111 minutes in plasma 70). satisfactory, since very high brain material are now claimed, but it involves a delay Experimental infections of animals may allow various treatments to be tested.71 The proposed U.K. trial of of at least 36-48 hours. Detection of a rising antibody Ara-C in herpes simplex encephalitis 61 should titre in serum or cerebrospinal fluid is necessarily late and the results have anyway been rather varieventually resolve problems of diagnosis and ought to provide a mechanism by which new drugs can be able .41,55 For speed the method of choice may well remains in a
become immunofluorescent demonstration of viral antigens, either in brain-biopsy specimens 56 or perhaps in cells from cerebrospinal fluid,5,5s but only when the technique has become reliable. It is important to confirm the diagnosis of herpes simplex encephalitis because therapy requires potentially toxic compounds. The specific regimens proposed for this disease-one of the very few systemic viral infections that may be susceptible to treatmentinvolve analogues of the pyrimidine bases of D.N.A., usually either 5-iodo-2’-deoxyuridine (idoxuridine, I.D.U.) or cytosine arabinoside (cytarabine, Ara-C), both of which are cytotoxic. There have been many claims of success and failure with l.D.u., but in an investigation just reported from the United States 59 the agent was abandoned because of therapeutic inactivity and unacceptable myelosuppression. The trial had been established to answer doubts about the value of such a potentially hazardous systemic treat49. Millar, J. H. D., 50. 51. 52. 53. 54. 55. 56. 57. 58.
59.
Coly, A. Electroenceph. clin. Neurophysiol. 1959, 11, 582. Upton, A., Gumpert, J. Lancet, 1970, i, 650. Scott, D. F., Prior, P. F. ibid. 1970, ii, 525. Illis, L. S., Taylor, F. M. ibid. 1972, i, 718. Gupta, P. C., Seth, P. Electroenceph. clin. Neurophysiol. 1973, 35, 67. Elian, M. Archs Neurol. 1975, 32, 39. Johnson, R. T., Olson, L. C., Buescher, E. L. ibid. 1968, 18, 260. Flewett, T. H. Postgrad. med. J. 1973, 49, 398. Dayan, A. D., Stokes, M. I. Lancet, 1973, i, 177. Nahmias, A. J., Shore, S. L., Del Buono, I. in Viral Immunodiagnosis (edited by E. Kurstak and R. Morisset); p. 165. New York, 1974. Boston Interhospital Virus Study Group and the NIAID-sponsored Cooperative Antiviral Clinical Study. New Engl. J. Med. 1975, 292, 599.
assessed in this
uncommon
disease.
SALT AND HYPERTENSION
AN old controversy has been given new life in the Medical Journal of Australia.72 Dr Priscilla KincaidSmith and others73 contributed a review of " changing concepts in the management of hypertension, in which reference was made to " The lay belief that salt is ’bad for blood pressure’ ". Two hornets in the shape of Dr Jame Smibert and Dr Trefor Morgan duly emerged from this Australasian nest, and Dr Kincaid-Smith had to defend herself. Her beliefs are (apparently) in direct conflict with three textbooks of medicine by Dr Smibert and with the unpublished work of Dr Morgan. Neither side mentions the previous 70 years’ work devoted to this problem. Theory and practice have diverged over this period. Practice is fairly straightforward : theory is still open to fierce debate. To put it at its simplest, we still do not know what role Johnson, R. T. Archs Neurol. 1972, 27, 97. Lancet, 1975, i, 815. Juel-Jensen, B. E. Postgrad. med. J. 1973, 49, 375. Meyer, J. S., Bauer, R. B., Rivera-Olmos, V. M., Nolan, D. C., Lerner, A. M. Archs Neurol. 1970, 23, 438. 64. Farris, W. A., Blaw, M. E. ibid. 1972, 27, 99. 65. Chow, A. W., Ronald, A., Fiala, M., Hrynink, W., Weil, M. W., Geme, J. S., Guze, L. B. Antimicrob. Agents Chemother. 1973, 3, 412. 66. Calabresi, P. Cancer Res. 1963, 23, 1260. 67. Lerner, A. M., Bailey, E. J. J. clin. Invest. 1972, 51, 45. 68. Clarkson, D. R., Oppelt, W. W., Byvoet, P. J. Pharmac. exp. Ther. 1967, 157, 581. 69. Nolan, D. C., Lauter, C. B., Lerner, A. M. Ann. intern. Med. 1973, 78, 243. 70. Ho, D. H. W., Frei, E. Clin. Pharmac. Ther. 1971, 12, 944. 71. Marks, M. I. J. infect. Dis. 1975, 131, 11. 72. Med. J. Aust. 1975, i, 328. 73. Kincaid-Smith, P., Macdonald, I. M., Hua, A., Laver, M. C., Fang, P. ibid. p. 603.
60. 61. 62. 63.
substances inhibited; and although somatostatin may be useful in glucagonoma,23 insulinoma, and the
Zollinger-Ellison syndrome 28 its therapeutic potential is obviously limited by its widely diverse effects. The downswing of hopes about a therapeutic role for somatostatin has lately been accelerated by reports of acute, though reversible, thrombocytopenia in baboons 31 and impaired platelet aggregation 32,33 with increased concentrations of the fibrin degradation product FgE in man.33 These diverse effects have nonetheless permitted some fascinating studies on hormonal regulation of metabolism. Somatostatin is the first agent to be found which will simultaneously inhibit insulin and glucagon secretion. This has led to a resurgence of interest in glucagon. When insulin and glucagon secretion are inhibited simultaneously by somatostatin, blood-glucose concentration falls rather than rises, which has led to the suggestion that glucagon may play a vital role in normal glucose homccostasis. 34,35 This hypothesis is supported by the fact that no direct effect of somatostatin on hepatic 36 or muscle metabolism has been found so far. Work with somatostatin has also clarified the role of glucagon in the pathogenesis of diabetic ketoacidosis. Investigations, first by GERICH et al.,37 ,38 and now by ALBERTI and his co-workers (see p. 1307this week), have shown that insulin withdrawal from insulin-treated diabetics leads to parallel rises in plasmaglucagon, blood-ketone-body, and plasma-F.F.A. concentrations, the rise in glucagon correlating strongly with the rise in ketone body. This points strongly to a role for glucagon. GERICH and his colleagues 39 now report that somatostatin prevents the rise in glucagon, and also of 3-hydroxybutyrate and F.F.A., in such insulin-deprived patients. This adds weight to the hypothesis that glucagon is important in the very early stages of ketoacidosis. There is, however, preliminary evidence that somatostatin cannot reverse a well-established ketoacidosis, so the glucagon-suppressing effect may not be useful in clinical practice. The actions of somatostatin in diabetes at present seem too widespread to allow for an important therapeutic role. But new synthetic analogues may 31.
Koerker, D. A., Harker, L. A., Goodner, C. J. Cited by Besser et
al.32
Besser, G. M., Paxton, A. M., Johnson, S. A. N., Moody, E. J., Mortimer, C. H., Hall, R., Gomez-Pan, A., Schally, A. V., Kastin, A. J., Coy, D. H. Lancet, May 24, 1975, p. 1166. 33. Goodner, C. J. New Engl. J. Med. 1975, 292, 1022. 34. Christensen, S. E., Hansen, Aa. P., Iversen, J., Lundbæk, K., Ørskov, H., Seyer-Hansen, K. Scand. J. clin. Lab. Invest. 1974, 34, 321. 35. Alford, F. P., Bloom, S. R., Nabarro, J. D. N., Hall, R., Besser, G. M., Coy, D. H., Kastin, A. J., Schally, A. V. Lancet, 1974, ii, 32.
974.
Koerker, D. J., Goodner, C. J., Ruch, W. New Engl. J. Med. 1974, 291, 262. 37. Gerich, J. E., Lorenzi, M., Hane, S., Gustafson, G., Guillemin, R., Forsham, P. H. Metabolism, 1975, 24, 175. 38. Gerich, J. E., Tsalikian, E., Lorenzi, M., Karam, J. H., Bier, D. M. J. clin. Endocr. Metab. 1975, 40, 526. 39. Gerich, J. E., Lorenzi, M., Bier, D. M., Schneider, V., Tsalikian, E., Karam, J. H., Forsham, P. H. New Engl. J. Med. 1975, 292, 985. 36.
prolonged and more specific actions, and this approach seems well worth pursuing: a long-acting preparation with selective suppressive effects on glucagon and growth hormone might be a provide
more
in the management of diabetes. Another subtle twist to the somatostatin story has just been added. Previously it was thought that natural somatostatin was confined to the hypothalamus and pituitary. Now PoLAK et a1.40 report that somatostatin may be a natural component of D-cells in both the gut and the pancreas. If this is confirmed then a whole new aspect of somatostatin physiology becomes apparent. Somatostatin may prove to be of fundamental physiological importance in the control of endocrine secretion in the pancreas and the gutand perhaps in the pathogenesis of diabetes mellitus. The story of the physiology and pharmacology of somatostatin has already provided more twists and turns than the best of Le Carre and Conan Doyle combined. We can now only sit back, slightly breathless, and await the next instalment.
big advance
Can
Herpes Simplex Encephalitis
be
Treated ? ALTHOUGH uncommon, encephalitis caused by Herpesvirus hominis has such a high mortality (about
andso aroused a presentation, .1 42 pos’sibility oftreatment 70%a possibility neurologists
that it has aroused of and in the keen interest both among wider world.44,45 There have been many attempts to find some features in the clinical illness that would aid differential diagnosis,43, 46 at least by suggesting herpetic encephalitis, so that further diagnostic measures can be urgently employed. Prospective series large enough for reasonable certainty have yet to be published; but, accepting the bias of hindsight, it does seem that the clinician cannot make this diagnosis unaided (although he may well suspect it in adults with features of acute disturbance of consciousness, epileptiform attacks, and lesions in the temporal lobes 43,47,48). Three types of investigative procedure are likely be applied to such patients. Various radiological methods might confirm the presence of localised tissue damage in the temporal lobe or other areas, and so might scintigraphy. The general value of electroencephalography (E.E.G.) is now accepted even though its exact diagnostic role
ing
a
to
40. 41. 42. 43.
Polak, J. M., Pearse, A. G. E., Grimelius, L., Bloom, S. R. Arimura, A. Lancet, May 31, 1975, p. 1220. Gilbert, D. N., Johnson, T., Luby, H., Sanford, J. P. Medicine, 1973, 52, 331. Rappel, M. Postgrad. med. J. 1973, 49, 419. Illis, L. S., Gostling, J. V. T. Herpes Simplex Encephalitis. Bristol,
1972. 44. Postgrad. med. J. 1973, 49, no. 572. 45. Lancet, 1973, ii, 1426. 46. Juel-Jensen, B. E., MacCallum, F. O. Herpes Simplex, Varicella and Zoster. London, 1972. 47. J. Am. med. Ass. 1968, 203, 882. 48. Olson, L. C., Buescher, E. L., Artenstein, M. S., Parkman, P. D. New Engl. J. Med. 1967, 277, 1271.
1325
ment,44,60 and the result looks conclusively negative dispute. Periodic repetitive complexes as far as encephalitis is concerned. Similar controlled of diffuse slowing, background perhaps against trials 61 with Ara-C, which seems less toxic, 62 localised over the temporal lobes, have been desare much needed: as in the early days of I.D.U., cribed,49 judged diagnostic, 5 denied,51 and on balance isolated successes and failures have been reported,62-65 partly reaffirmed. 52 ,53 EUAN 54 lately reported Most protagonists and critics of these compounds them in serial recordings from 11 patients with herpes have For the first time were paid surprisingly little attention to pharmacothey simplex encephalitis. kinetics and metabolism. I.D.U. is metabolised exobserved at any stage during or after the acute phase of the illness, but only in the 7 patients who died. tremely quickly and is also excreted speedily by the If the prognostic value of this E.E.G. finding is kidney,66,67 with the result that a conventional, slow confirmed, then it will represent a substantial intravenous infusion is unlikely to produce theraadvance. The only other simple diagnostic technique peutically effective levels-particularly not if the is examination of cerebrospinal fluid, and it, too, can drug has to cross even a partly effective blood/brain barrier. 68 Only rapid injection of a bolus will probe no more than suggestive.43 duce adequate levels of activity, although sometimes The more complex diagnostic techniques demand at the cost of toxicity.59,69 Ara-C has greater and services. neurosurgical virological Histological because its half-life in examination of brain tissue can never be more promise plasma and cerebrofluid is it than suggestive and may show only non-specific spinal longer, and passes more readily from blood to brain .70 However, its pharmacokinetic features.55 Electron-microscope demonstration of the virus in tissue seems difficult for routine purposes. properties are not ideal and it might be more effective Isolation of the virus in culture should be more intrathecally than intravenously (half-life 2 hours as success-rates from opposed to 12 and 111 minutes in plasma 70). satisfactory, since very high brain material are now claimed, but it involves a delay Experimental infections of animals may allow various treatments to be tested.71 The proposed U.K. trial of of at least 36-48 hours. Detection of a rising antibody Ara-C in herpes simplex encephalitis 61 should titre in serum or cerebrospinal fluid is necessarily late and the results have anyway been rather varieventually resolve problems of diagnosis and ought to provide a mechanism by which new drugs can be able .41,55 For speed the method of choice may well remains in a
become immunofluorescent demonstration of viral antigens, either in brain-biopsy specimens 56 or perhaps in cells from cerebrospinal fluid,5,5s but only when the technique has become reliable. It is important to confirm the diagnosis of herpes simplex encephalitis because therapy requires potentially toxic compounds. The specific regimens proposed for this disease-one of the very few systemic viral infections that may be susceptible to treatmentinvolve analogues of the pyrimidine bases of D.N.A., usually either 5-iodo-2’-deoxyuridine (idoxuridine, I.D.U.) or cytosine arabinoside (cytarabine, Ara-C), both of which are cytotoxic. There have been many claims of success and failure with l.D.u., but in an investigation just reported from the United States 59 the agent was abandoned because of therapeutic inactivity and unacceptable myelosuppression. The trial had been established to answer doubts about the value of such a potentially hazardous systemic treat49. Millar, J. H. D., 50. 51. 52. 53. 54. 55. 56. 57. 58.
59.
Coly, A. Electroenceph. clin. Neurophysiol. 1959, 11, 582. Upton, A., Gumpert, J. Lancet, 1970, i, 650. Scott, D. F., Prior, P. F. ibid. 1970, ii, 525. Illis, L. S., Taylor, F. M. ibid. 1972, i, 718. Gupta, P. C., Seth, P. Electroenceph. clin. Neurophysiol. 1973, 35, 67. Elian, M. Archs Neurol. 1975, 32, 39. Johnson, R. T., Olson, L. C., Buescher, E. L. ibid. 1968, 18, 260. Flewett, T. H. Postgrad. med. J. 1973, 49, 398. Dayan, A. D., Stokes, M. I. Lancet, 1973, i, 177. Nahmias, A. J., Shore, S. L., Del Buono, I. in Viral Immunodiagnosis (edited by E. Kurstak and R. Morisset); p. 165. New York, 1974. Boston Interhospital Virus Study Group and the NIAID-sponsored Cooperative Antiviral Clinical Study. New Engl. J. Med. 1975, 292, 599.
assessed in this
uncommon
disease.
SALT AND HYPERTENSION
AN old controversy has been given new life in the Medical Journal of Australia.72 Dr Priscilla KincaidSmith and others73 contributed a review of " changing concepts in the management of hypertension, in which reference was made to " The lay belief that salt is ’bad for blood pressure’ ". Two hornets in the shape of Dr Jame Smibert and Dr Trefor Morgan duly emerged from this Australasian nest, and Dr Kincaid-Smith had to defend herself. Her beliefs are (apparently) in direct conflict with three textbooks of medicine by Dr Smibert and with the unpublished work of Dr Morgan. Neither side mentions the previous 70 years’ work devoted to this problem. Theory and practice have diverged over this period. Practice is fairly straightforward : theory is still open to fierce debate. To put it at its simplest, we still do not know what role Johnson, R. T. Archs Neurol. 1972, 27, 97. Lancet, 1975, i, 815. Juel-Jensen, B. E. Postgrad. med. J. 1973, 49, 375. Meyer, J. S., Bauer, R. B., Rivera-Olmos, V. M., Nolan, D. C., Lerner, A. M. Archs Neurol. 1970, 23, 438. 64. Farris, W. A., Blaw, M. E. ibid. 1972, 27, 99. 65. Chow, A. W., Ronald, A., Fiala, M., Hrynink, W., Weil, M. W., Geme, J. S., Guze, L. B. Antimicrob. Agents Chemother. 1973, 3, 412. 66. Calabresi, P. Cancer Res. 1963, 23, 1260. 67. Lerner, A. M., Bailey, E. J. J. clin. Invest. 1972, 51, 45. 68. Clarkson, D. R., Oppelt, W. W., Byvoet, P. J. Pharmac. exp. Ther. 1967, 157, 581. 69. Nolan, D. C., Lauter, C. B., Lerner, A. M. Ann. intern. Med. 1973, 78, 243. 70. Ho, D. H. W., Frei, E. Clin. Pharmac. Ther. 1971, 12, 944. 71. Marks, M. I. J. infect. Dis. 1975, 131, 11. 72. Med. J. Aust. 1975, i, 328. 73. Kincaid-Smith, P., Macdonald, I. M., Hua, A., Laver, M. C., Fang, P. ibid. p. 603.
60. 61. 62. 63.
