890 in the rabbit’1 that injection of adrenaline was followed by a rise in the activity of clotting factor vm, the factor defective in classical haemophilia. The observation was confirmed in man;13 and the rise was seen to occur proportionately in mild haemophiliacs having a low but measurable factor-vm level, but there was no effect in severe haemophiliacs having none. A rise was also found 14 in von Willebrand’s disease, in which the same factor is affected. Brisk exercise’5 produced a similar increase in vm activity, both in normals and in mild haemophiliacs; and this also seemed to be mediated by
adrenaline release. 1(3 The effect of a
single stimulus lasts only a few hours," repeated responses can be obtained,’ and it was obviously possible that clinical use could be made of the phenomenon, to raise the factor-vm activity in but
acute situations. However, the side-effects of adrenaline would be rather unpleasant and vigorous exercise would not always be appropriate, so little progress was made beyond occasional attempts to improve the yield of antihaemophilic materials by treating or exercising blood-donors before venesection. Meanwhile other stimuli were investigated. Mannucci and his colleagues19 2U and Cash and his colleagues21 tested other vasoactive drugs, and found that vasopressin also raised the vni activity. Again, unfortunately, side-effects were unpleasant ; but the symptomless analogue 1-desamino-8-Darginine vasopressin (D.D.A.v.P.) worked as well. Like all the other stimuli tested, D.D.A.V.P. also briefly enhanced fibrinolytic activity. Mannucci’s group now report, at the front of this issue, the first clinical trials with D.D.A.V.P. in the management of post-traumatic bleeding in mild haemophilia and von Willebrand’s disease. At a dose of 0-4—0-5pLg/kg, repeated 24-hourly as necessary, hxmostasis was secured after various surgical procedures, provided that the patient’s initial level of factor viu was 0.05-0-1 i.u./ml for minor and 0.1-0.2 i.u./ml for major operations. Fibrinolysis was controlled with the antifibrinolytic drug tranexamic acid; and the antidiuretic effect of D.D.A.v.p. did not seem to be clinically important. Professor Mannucci and his colleagues are to be congratulated on having reached this point in a train of observations and experiments stretching back to the eighteenth century. William Hewson will be smiling in his sleep.
LABETALOL IN HYPERTENSION
over more long-standing drugs of this class. Labetalol is another beta-blocker but with important alpha-blocking actions as well: this property distinguishes it from all other beta-blockers currently marketed for the treatment of hypertension. The clinician will need the answer to one question. Does alpha-blockade help? There can be no dispute that blockade of the artenolar and venous alpha-receptors modulating constriction lowers the blood-pressure in certain circumstances. Such vasoconstriction provides a major mechanism whereby blood-pressure is maintained when an individual stands up or becomes hypovolaemic. Thus, alpha-receptor blockade may greatly reduce blood-pressure in these circumstances despite an absence of effect in the normotensive supine subject. In certain patients with essential hypertension there is some evidence for sympathetic overactivity,’’although there is no general agreement even on this.4 But in most hypertensive patients, who probably do not have overactivity, one would anticipate on theoretical grounds that postural hypotension would be a feature of effective alpha blockade. When the alpha antagonist phenoxybenzamine was combined with propranolol in a fixed dosage in the treatment of hypertension such side-effects were severe. In another study phentolamine, an agent with alpha-blocking activity, was given with oxprenolol, and contributed little to the control of supine and standing blood-pressure, although side-effects were few.6 However, the dose (60 mg daily) was low and at this level phentolamine may be acting as an arteriolar vasodilator rather than an alpha Mockery When phentolamine was originally used in the treatment of hypertension, the doses required to produce alpha blockade (up to 900 mg daily) were associated with severe side-effects.8 It is remarkable therefore that Majid et al. reported excellent control without serious postural hypotension in 6 severely hypertensive patients treated with 60 mg daily of phentolamine and beta blockade. These results require confirmation in a larger group of unselected patients. Since the patients of Majid et al. may have been atypical and since these workers did not examine the possibility that the beneficial action of phentolamine was not due to alpha blockade, this report cannot be cited in support of the addition of alpha to beta blockade in the treatment of hypertension. On existing evidence, therefore, the wise clinician will not rush into prescribing an agent with combined alpha and beta blocking activity: if the alpha-blocking potency of labetalol is sufficient to enhance blood-pressure control substantially, it may also be sufficient to cause dis-
superiority
WE can but utter a sigh of relief that the latest agent be marketed for the treatment of hypertension is not another beta-blocker promoted with doubtful claims for to
Richards, D. A., Woodings, E. P., Stephens, M. D. P., Maconochie, J. G Br. J. clin. Pharmac. 1974, 1, 505. 2. Esler, M., Randall, O., Bennett, J., Zweifler, A., Julius, S., Rydelek, P., Cohen, E., De Quattro, V. Lancet, 1976, ii, 115. 3. Esler, M., Julius, S., Zweifler, A., Randall, O., Harburg, E., Gardiner, H., De Quattro, V. New Engl. J. Med. 1977, 296, 405. 4. Lake, C. R., Ziegler, M. G., Coleman, M. D., Kopin, I. J. ibid. 1977, 296, 1.
12 Marciniak, E. Acta physiol. pol. 1957, 8, 17. 13 Ingram, G. I C. J. Physiol., Lond. 1961, 156, 217. 14 Egeberg, O Scand. J. clin. Lab. Invest. 1963, 15, 539. 15. Rizza, C. R. J. Physiol., Lond. 1961, 156, 128. 16. Hawkey, C. M., Britton, B. J., Wood, W. G., Peele, M., Irving, M. H. Br. J. Hæmat. 1975, 29, 377. 17. Prentice, C. R. M., Forbes, C. D., Smith, S. M. Thrombosis Res. 1972, 1, 493. 18. Egeberg, O. Scand. J. clin. Lab. Invest. 1963, 15, 202. 19. Mannucii, P. M., Barbi, G. L. Proc. Eur. Soc. clin. Invest. Rotterdam, 1973,
abstr.
p. 144.
20 Mannucci, P.
M., Aberg, M., Nilsson, I. M., Robertson, B. Br. J. Hæmat.
1975, 30, 81. 21
Cash, J. D., Gader, A. M. A., da Costa, J. ibid. 1974, 27, 363.
208. 5. Beilen, L. J., Juel-Jensen, B. E. Lancet, 1972, i, 979. 6. Johnson, B. F., LaBrooy, J., Munro-Faure, A. D. Clin. Sci. mol Med 1976, 51, suppl. 3, p. 505s. 7. Taylor, S. H., Sutherland, G. R., MacKenzie, G. J., Staunton, H. P. Donald, K. W. Circulation, 1965, 31, 741. 8. Moyer, J. H., Caplovitz, C. Am. Heart J. 1953, 45, 602. 9. Majid, P. A., Meeran, M. K., Benaim, M. E., Sharma, B., Taylor, S. H. Br. Heart J. 1974, 36, 588.
891
abling symptoms. The question is not whether labetalol reduces blood-pressure-as a beta blocker it almost certainly will-but whether it offers better blood-pressure control than conventional beta blockers, without unacceptable postural hypertension. In a careful double-blind study Pugsley et al." have investigated this by comparing the effect of increasing doses of propranolol and labetalol in 10 mildly hypertensive subjects. As might be and labetalol
effecbut labetalol controlling lying blood-pressures, produced a greater fall on standing or after exercise. Thus the hypotensive action of labetalol (which has been confirmed in other recent reports611) is likely to be partly attributable to its alpha-blocking activity. Whether the postural effect is desirable is another question. Where mild hypertension is being treated the smaller dosage of labetalol may explain the absence of postural symptoms. 10 In this case, one wonders whether the compound has any advantage over conventional beta blockers. In severely hypertensive subjects where a beta blocker alone may be inadequate, labetalol will probably be more effective in upright patients, but perhaps only at the expense of postural hypotension. This response will require very careful monitoring before labetalol can be accepted as having advantages over beta blockers in combination with other hypotensive agents. Intravenous labetalol rapidly reduces blood-pressure in severe hypertension.12 Its use in this context, however, requires great caution. A substantial fall in systemic pressure may reduce cerebral blood-flow dangerously in hypertensive subjects, in whom the range of pressures at which cerebral flow is autoregulated is raised. A beta blocker which prevents cardiac output from rising in the face of a fall in blood-pressure may be particularly likely to produce cerebrovascular complications, although none of the subjects investigated by Rosei et al. 12 showed such complications. Firm evidence that labetalol is superior to existing agents will be required before this agent can be recommended in the unusual situation where intravenous treatment is needed.
predicted, propranolol
were
equally
tive in
AMIKACIN THE search for fungi which produce antibiotics continues but is now less fruitful than it has been in the past. Biochemical manipulation of existing antimicro-
bial agents now seems more rewarding. By attempting to find which sites on the molecule of an antibiotic are important in its activity and at which sites bacterial inactivating enzymes attack, the chemist can synthesise compounds which, he hopes, will show novel properties. Amikacin is one such compound. Derived from kanamycin A, amikacin is inactivated by only one of at least nine enzymes whereas gentamicin is inactivated by six.’ A rule of thumb amongst antibiotics is that drugs D., Armstrong, B., Nassim, M. & Beilen, L. J. Clin. Sci mol. Med. 1976, 51, suppl 3, p. 501s. 11 Prichard, B. N. C., Thompson, F. O., Boakes, A. J., Joekes, A. M. ibid. 1975, 48, suppl 2, p. 97s. 12. Rosei, E. A., Trust, P. M., Brown, J. J., Fraser, R., Lever, A. F., Morton, J. J., Robertson, J. I. S. Clin. Sci. mol. Med. 1976, 51, 497s. 1 Price, K. E., DeFuria., Pursiano, T. A. J. inf. Dis. 1976, 134, suppl. p. 249. 2 Drasar, F. A., Farrell, W., Maskell, J., Williams, J. D. Br. med. J. 1976, ii, 10 Pugsley,
1284.
which are less prone to bacterial enzymic attack tend to be less active than are the more enzyme-susceptible agents. This is true of amikacin, which is about two to four times less active than gentamicin; hence, bigger doses are needed (500 mg twice daily is recommended). The new drug has a broad antibacterial spectrum similar to that of gentamicin,2being active against a wide range of gram-negative organisms (including Pseudomonas æruginosa). Staphylococcus aureus is also sensitive but the streptococci are resistant. The advantage of amikacin lies in its activity against many strains which are resistant to gentamicin. The prevalence of such strains is very variable. In some areas of the United States3 50% of certain gram-negative bacilli are believed to be showing gentamicin resistance and in Paris the figure is 24%.* In the British Isles the rate of resistance is far lower, but staphylococcal infections amongst surgical patients in Bristols and Providencia stuartii6 infections in urological patients in Dublin have caused considerable local concern. There is a mass of data on the clinical use of amikacin. At a meeting in Tegernsee in 1975 results in a wide range of infections were presented.7 It is only after a further two years that good comparative studies are now being reported. Smith et al.8 from Johns Hopkins have described a prospective, randomised double-blind comparison of gentamicin and amikacin in the treatment of gram-negative infections caused by sensitive organisms. No significant differences in the response-rates were found and what was particularly interesting was that there were no differences in ototoxicity (although only auditory function was monitored) or nephrotoxicity-6-11% of patients had these unwanted effects, whichever drug they were on. In another study of tobramycin and amikacin in infections amongst patients with cancer9 almost identical response-rates were obtained. Nephrotoxicity was commoner in this study (about 20%), but this probably reflects the nature of the patients treated. What, therefore, is the role of amikacin in the treatment of infections? Should this drug now replace gentamicin? Widespread use or misuse of antibiotics (including the aminoglycosides) does lead to the emergence of resistant organisms, and since amikacin resistance has been reported to arise during therapy,lU all these drugs should be used with care. Amikacin should be reserved for infections caused by known resistant organisms. If 5-10% of the gram-negative organisms from a hospital or from a unit within that hospital are resistant to gentamicin then, when lifethreatening infections are to be treated before isolation of an organism, amikacin may be the drug of choice. In such circumstances, attention to cross-infection will pay dividends. Finally, amikacin, 500 mg twice daily at about k20 per day, costs about three times as much as gentamicin 120 mg three times a day. 3. Meyer, R. D., Lewis, R. P., Halter, J., White, M. Lancet, 1976, i, 580. 4. Acar, J. F., Witchitz, J. L., Goldstein, F., Talbot, J. N., LeGoffic, F. J. inf. Dis. 1976, 134, suppl. p. 280. 5. Speller, D. C. E., Raghunath, D., Stephens, M., Viant, A. C., Reeves, D. S., Wilkinson, P. J., Broughall, J. M., Holt, H. A. Lancet, 1976, i, 464. 6. Keane, C. T., English, L. F., Wise, R. ibid. 1975, ii, 1045. 7. J. inf. Dis. 1976, suppl 134. 8. Smith, C. R., Baughman, K. L., Edwards, C. Q., Rogers, J. F., Lietman, P. S. New Engl. J. Med. 1977, 296, 349. 9. Feld, R., Valdivieso, M., Bodey, G. P., Rodriguez, V. J. inf. Dis. 1977, 135, 61. 10. Amtrak, I. D., Williams, R. J., Noone, P., Wills, M. R. Lancet, 1977, i, 537.
adrenaline release. 1(3 The effect of a
single stimulus lasts only a few hours," repeated responses can be obtained,’ and it was obviously possible that clinical use could be made of the phenomenon, to raise the factor-vm activity in but
acute situations. However, the side-effects of adrenaline would be rather unpleasant and vigorous exercise would not always be appropriate, so little progress was made beyond occasional attempts to improve the yield of antihaemophilic materials by treating or exercising blood-donors before venesection. Meanwhile other stimuli were investigated. Mannucci and his colleagues19 2U and Cash and his colleagues21 tested other vasoactive drugs, and found that vasopressin also raised the vni activity. Again, unfortunately, side-effects were unpleasant ; but the symptomless analogue 1-desamino-8-Darginine vasopressin (D.D.A.v.P.) worked as well. Like all the other stimuli tested, D.D.A.V.P. also briefly enhanced fibrinolytic activity. Mannucci’s group now report, at the front of this issue, the first clinical trials with D.D.A.V.P. in the management of post-traumatic bleeding in mild haemophilia and von Willebrand’s disease. At a dose of 0-4—0-5pLg/kg, repeated 24-hourly as necessary, hxmostasis was secured after various surgical procedures, provided that the patient’s initial level of factor viu was 0.05-0-1 i.u./ml for minor and 0.1-0.2 i.u./ml for major operations. Fibrinolysis was controlled with the antifibrinolytic drug tranexamic acid; and the antidiuretic effect of D.D.A.v.p. did not seem to be clinically important. Professor Mannucci and his colleagues are to be congratulated on having reached this point in a train of observations and experiments stretching back to the eighteenth century. William Hewson will be smiling in his sleep.
LABETALOL IN HYPERTENSION
over more long-standing drugs of this class. Labetalol is another beta-blocker but with important alpha-blocking actions as well: this property distinguishes it from all other beta-blockers currently marketed for the treatment of hypertension. The clinician will need the answer to one question. Does alpha-blockade help? There can be no dispute that blockade of the artenolar and venous alpha-receptors modulating constriction lowers the blood-pressure in certain circumstances. Such vasoconstriction provides a major mechanism whereby blood-pressure is maintained when an individual stands up or becomes hypovolaemic. Thus, alpha-receptor blockade may greatly reduce blood-pressure in these circumstances despite an absence of effect in the normotensive supine subject. In certain patients with essential hypertension there is some evidence for sympathetic overactivity,’’although there is no general agreement even on this.4 But in most hypertensive patients, who probably do not have overactivity, one would anticipate on theoretical grounds that postural hypotension would be a feature of effective alpha blockade. When the alpha antagonist phenoxybenzamine was combined with propranolol in a fixed dosage in the treatment of hypertension such side-effects were severe. In another study phentolamine, an agent with alpha-blocking activity, was given with oxprenolol, and contributed little to the control of supine and standing blood-pressure, although side-effects were few.6 However, the dose (60 mg daily) was low and at this level phentolamine may be acting as an arteriolar vasodilator rather than an alpha Mockery When phentolamine was originally used in the treatment of hypertension, the doses required to produce alpha blockade (up to 900 mg daily) were associated with severe side-effects.8 It is remarkable therefore that Majid et al. reported excellent control without serious postural hypotension in 6 severely hypertensive patients treated with 60 mg daily of phentolamine and beta blockade. These results require confirmation in a larger group of unselected patients. Since the patients of Majid et al. may have been atypical and since these workers did not examine the possibility that the beneficial action of phentolamine was not due to alpha blockade, this report cannot be cited in support of the addition of alpha to beta blockade in the treatment of hypertension. On existing evidence, therefore, the wise clinician will not rush into prescribing an agent with combined alpha and beta blocking activity: if the alpha-blocking potency of labetalol is sufficient to enhance blood-pressure control substantially, it may also be sufficient to cause dis-
superiority
WE can but utter a sigh of relief that the latest agent be marketed for the treatment of hypertension is not another beta-blocker promoted with doubtful claims for to
Richards, D. A., Woodings, E. P., Stephens, M. D. P., Maconochie, J. G Br. J. clin. Pharmac. 1974, 1, 505. 2. Esler, M., Randall, O., Bennett, J., Zweifler, A., Julius, S., Rydelek, P., Cohen, E., De Quattro, V. Lancet, 1976, ii, 115. 3. Esler, M., Julius, S., Zweifler, A., Randall, O., Harburg, E., Gardiner, H., De Quattro, V. New Engl. J. Med. 1977, 296, 405. 4. Lake, C. R., Ziegler, M. G., Coleman, M. D., Kopin, I. J. ibid. 1977, 296, 1.
12 Marciniak, E. Acta physiol. pol. 1957, 8, 17. 13 Ingram, G. I C. J. Physiol., Lond. 1961, 156, 217. 14 Egeberg, O Scand. J. clin. Lab. Invest. 1963, 15, 539. 15. Rizza, C. R. J. Physiol., Lond. 1961, 156, 128. 16. Hawkey, C. M., Britton, B. J., Wood, W. G., Peele, M., Irving, M. H. Br. J. Hæmat. 1975, 29, 377. 17. Prentice, C. R. M., Forbes, C. D., Smith, S. M. Thrombosis Res. 1972, 1, 493. 18. Egeberg, O. Scand. J. clin. Lab. Invest. 1963, 15, 202. 19. Mannucii, P. M., Barbi, G. L. Proc. Eur. Soc. clin. Invest. Rotterdam, 1973,
abstr.
p. 144.
20 Mannucci, P.
M., Aberg, M., Nilsson, I. M., Robertson, B. Br. J. Hæmat.
1975, 30, 81. 21
Cash, J. D., Gader, A. M. A., da Costa, J. ibid. 1974, 27, 363.
208. 5. Beilen, L. J., Juel-Jensen, B. E. Lancet, 1972, i, 979. 6. Johnson, B. F., LaBrooy, J., Munro-Faure, A. D. Clin. Sci. mol Med 1976, 51, suppl. 3, p. 505s. 7. Taylor, S. H., Sutherland, G. R., MacKenzie, G. J., Staunton, H. P. Donald, K. W. Circulation, 1965, 31, 741. 8. Moyer, J. H., Caplovitz, C. Am. Heart J. 1953, 45, 602. 9. Majid, P. A., Meeran, M. K., Benaim, M. E., Sharma, B., Taylor, S. H. Br. Heart J. 1974, 36, 588.
891
abling symptoms. The question is not whether labetalol reduces blood-pressure-as a beta blocker it almost certainly will-but whether it offers better blood-pressure control than conventional beta blockers, without unacceptable postural hypertension. In a careful double-blind study Pugsley et al." have investigated this by comparing the effect of increasing doses of propranolol and labetalol in 10 mildly hypertensive subjects. As might be and labetalol
effecbut labetalol controlling lying blood-pressures, produced a greater fall on standing or after exercise. Thus the hypotensive action of labetalol (which has been confirmed in other recent reports611) is likely to be partly attributable to its alpha-blocking activity. Whether the postural effect is desirable is another question. Where mild hypertension is being treated the smaller dosage of labetalol may explain the absence of postural symptoms. 10 In this case, one wonders whether the compound has any advantage over conventional beta blockers. In severely hypertensive subjects where a beta blocker alone may be inadequate, labetalol will probably be more effective in upright patients, but perhaps only at the expense of postural hypotension. This response will require very careful monitoring before labetalol can be accepted as having advantages over beta blockers in combination with other hypotensive agents. Intravenous labetalol rapidly reduces blood-pressure in severe hypertension.12 Its use in this context, however, requires great caution. A substantial fall in systemic pressure may reduce cerebral blood-flow dangerously in hypertensive subjects, in whom the range of pressures at which cerebral flow is autoregulated is raised. A beta blocker which prevents cardiac output from rising in the face of a fall in blood-pressure may be particularly likely to produce cerebrovascular complications, although none of the subjects investigated by Rosei et al. 12 showed such complications. Firm evidence that labetalol is superior to existing agents will be required before this agent can be recommended in the unusual situation where intravenous treatment is needed.
predicted, propranolol
were
equally
tive in
AMIKACIN THE search for fungi which produce antibiotics continues but is now less fruitful than it has been in the past. Biochemical manipulation of existing antimicro-
bial agents now seems more rewarding. By attempting to find which sites on the molecule of an antibiotic are important in its activity and at which sites bacterial inactivating enzymes attack, the chemist can synthesise compounds which, he hopes, will show novel properties. Amikacin is one such compound. Derived from kanamycin A, amikacin is inactivated by only one of at least nine enzymes whereas gentamicin is inactivated by six.’ A rule of thumb amongst antibiotics is that drugs D., Armstrong, B., Nassim, M. & Beilen, L. J. Clin. Sci mol. Med. 1976, 51, suppl 3, p. 501s. 11 Prichard, B. N. C., Thompson, F. O., Boakes, A. J., Joekes, A. M. ibid. 1975, 48, suppl 2, p. 97s. 12. Rosei, E. A., Trust, P. M., Brown, J. J., Fraser, R., Lever, A. F., Morton, J. J., Robertson, J. I. S. Clin. Sci. mol. Med. 1976, 51, 497s. 1 Price, K. E., DeFuria., Pursiano, T. A. J. inf. Dis. 1976, 134, suppl. p. 249. 2 Drasar, F. A., Farrell, W., Maskell, J., Williams, J. D. Br. med. J. 1976, ii, 10 Pugsley,
1284.
which are less prone to bacterial enzymic attack tend to be less active than are the more enzyme-susceptible agents. This is true of amikacin, which is about two to four times less active than gentamicin; hence, bigger doses are needed (500 mg twice daily is recommended). The new drug has a broad antibacterial spectrum similar to that of gentamicin,2being active against a wide range of gram-negative organisms (including Pseudomonas æruginosa). Staphylococcus aureus is also sensitive but the streptococci are resistant. The advantage of amikacin lies in its activity against many strains which are resistant to gentamicin. The prevalence of such strains is very variable. In some areas of the United States3 50% of certain gram-negative bacilli are believed to be showing gentamicin resistance and in Paris the figure is 24%.* In the British Isles the rate of resistance is far lower, but staphylococcal infections amongst surgical patients in Bristols and Providencia stuartii6 infections in urological patients in Dublin have caused considerable local concern. There is a mass of data on the clinical use of amikacin. At a meeting in Tegernsee in 1975 results in a wide range of infections were presented.7 It is only after a further two years that good comparative studies are now being reported. Smith et al.8 from Johns Hopkins have described a prospective, randomised double-blind comparison of gentamicin and amikacin in the treatment of gram-negative infections caused by sensitive organisms. No significant differences in the response-rates were found and what was particularly interesting was that there were no differences in ototoxicity (although only auditory function was monitored) or nephrotoxicity-6-11% of patients had these unwanted effects, whichever drug they were on. In another study of tobramycin and amikacin in infections amongst patients with cancer9 almost identical response-rates were obtained. Nephrotoxicity was commoner in this study (about 20%), but this probably reflects the nature of the patients treated. What, therefore, is the role of amikacin in the treatment of infections? Should this drug now replace gentamicin? Widespread use or misuse of antibiotics (including the aminoglycosides) does lead to the emergence of resistant organisms, and since amikacin resistance has been reported to arise during therapy,lU all these drugs should be used with care. Amikacin should be reserved for infections caused by known resistant organisms. If 5-10% of the gram-negative organisms from a hospital or from a unit within that hospital are resistant to gentamicin then, when lifethreatening infections are to be treated before isolation of an organism, amikacin may be the drug of choice. In such circumstances, attention to cross-infection will pay dividends. Finally, amikacin, 500 mg twice daily at about k20 per day, costs about three times as much as gentamicin 120 mg three times a day. 3. Meyer, R. D., Lewis, R. P., Halter, J., White, M. Lancet, 1976, i, 580. 4. Acar, J. F., Witchitz, J. L., Goldstein, F., Talbot, J. N., LeGoffic, F. J. inf. Dis. 1976, 134, suppl. p. 280. 5. Speller, D. C. E., Raghunath, D., Stephens, M., Viant, A. C., Reeves, D. S., Wilkinson, P. J., Broughall, J. M., Holt, H. A. Lancet, 1976, i, 464. 6. Keane, C. T., English, L. F., Wise, R. ibid. 1975, ii, 1045. 7. J. inf. Dis. 1976, suppl 134. 8. Smith, C. R., Baughman, K. L., Edwards, C. Q., Rogers, J. F., Lietman, P. S. New Engl. J. Med. 1977, 296, 349. 9. Feld, R., Valdivieso, M., Bodey, G. P., Rodriguez, V. J. inf. Dis. 1977, 135, 61. 10. Amtrak, I. D., Williams, R. J., Noone, P., Wills, M. R. Lancet, 1977, i, 537.
