- Email: [email protected]
Drugs against Viruses: the Search Continued
559
LEADING ARTICLES
thus, when small areas of cytopathic changes were evident, the drug was still effective in preserving cell cultures from destruction by poliovirus type 1 or Coxsackie B5 or A9 viruses. Thirdly, the drug had an effect in vivo in delaying death and, when virus doses were small, in protecting suckling mice challenged with Coxsackie A9 virus. Although increased resistance to the drug in vitro developed when Coxsackie A9 was grown in progressively higher concentrations in cell culture, the increase seemed to be limited to about fourfold. Moreover, the virus recovered from treated added to the cultures;
THE LANCET LONDON
15
MARCH
1969
Drugs against Viruses: the Search Continued THE signs are that drugs capable of curing or preventing virus infections will eventually be found. The
profound effects of age and temperature on viral replication and the phenomenon of viral interference demonstrate that virus growth can be prevented without impairment of cell function. A deeper understanding of the host-cell range of viruses may also lead to methods of interrupting virus replication. The search for antiviral drugs is therefore well worth pursuing, though those that have been marketed so far are not entirely satisfactory. Thus, methisazone, effective in contacts of smallpox and for the complications of vaccinia infection, is too toxic for general use. Idoxuridine has found a place in the treatment of herpes-simplex infections, but it is also too toxic for systemic use. Amantadine, although marginally effective against influenza A2, has come under attack because of its low efficacy and the high incidence of side-effects. A well-established line of investigation is the search for more active variations on a basic structure. RAFELSON et al.1 showed that benzimidazole inhibited the multiplication of a picornavirus, and T AMM and NEMES2 later found that this group of viruses was selectively inhibited by 2-(cx-hydroxybenzyl) benzimidazole (H.B.B.). This compound has since been examined by a number of workers, particularly by O’SULLIVAN and his colleagues at the Courtauld Institute of the Middlesex Hospital. The chief difficulty with H.B.B. has been the selectivity of its action: not only is it mainly active against picornaviruses but also, within this group, it is highly selective, so that at one time EGGERS and T AMM3 suggested it might be used in a diagnostic test. The second problem is the rapid emergence of resistant viruses. O’SULLIVAN et al.4 have studied the 1-propyl derivative of H.B.B. (P.H.B.B.), which has a number of interesting properties. Firstly, it is more active than H.B.B., and against some viruses it is very active indeed -for example, less than 0-1 g. per ml. protects cell cultures against challenge with 1000 T.C.D’50 of rhinovirus 5. Secondly, it is active after the virus has been 1. 2. 3. 4.
Rafelson, M. E., Pearson, M. E., Winzler, R. J. Archs Biochem. 1950, 29, 69. Tamm, I., Nemes, M. M. J. clin. Invest. 1959, 38, 1047. Eggers, H. J., Tamm, I. J. exp. Med. 1961, 113, 657. O’Sullivan, D. G., Pontic, D., Dane, D. S., Briggs, M. Lancet, March 1, 1969, p. 446.
mice
of increased resistance. In the mouse experiments suspensions of drug in corn-oil were given parenterally. It would be of great interest to know whether the drug is absorbed by mouth and, in view of the high activity against the Norman strain of type-5 rhinovirus, whether it reaches the nasal secretions. If it does and if toxicity tests are satisfactory, it would be worth investigating the activity of P.H.B.B. against this virus in volunteers. was not
drugs active against picornaviruses are prospect, how might they be most effectively If
due course ? Picornaviruses
can cause severe
in used in diseases now
(for example, poliomyelitis, encephalitis, or myocarditis), less severe ones (aseptic meningitis), or mild ones (fever with rash and common colds). Vaccination must remain the best method of controlling poliomyelitis, because nearly all of it is caused by polioviruses. But a drug that could be used to cure or treat contacts of the serious manifestations of picornavirus infection would be valuable. P.H.B.B. offers some encouragement here, because when it was added to cell sheets showing virus-induced cytopathic effects the cultures were saved. Moreover, there was a delay in death in suckling mice treated with the drug after infection as well as protection for those given P.H.B.B. prophylactically. The use of a combination of drugs under such circumstances seems worth investigating. Kethoxalis a virus-inactivating agent which has been suggested for use in vaccine production; and it is sufficiently nontoxic to be used topically. It has been found effective in herpes-simplex infections in mice.Such a substance active against the extracellular virus particles might well supplement the activity of an antiviral substance working intracellularly. Moreover, the use of more than one antiviral agent might discourage the emergence of resistant viruses. Thus, both H.B.B. and guanidine inhibit picornaviruses, but resistant mutants rapidly appear, and guanidine was found to be ineffective against poliovirus infection in monkeys, because of the emergence of resistant virus particles. A combination of guanidine and P.H.B.B., or the use of an interferon inducer and P.H.B.B., might be worth examining in the control of experimental infections by picornaviruses. The use of a chemotherapeutic or prophylactic agent for the more mild infections with picornaviruses raises awkward questions. On the one hand, the number of antigenic types makes an approach by vaccine extremely 5. 6.
Underwood, G. E., Weed, S. D. Virology, 1961, 13, 138. Underwood, G. E. Proc. Soc. exp. Biol. Med. 1968, 129, 235.
560
difficult. Yet, on the other hand, the immunity conferred by infection is very valuable, and to convert everyone by means of an antiviral drug to the degree of susceptibility of young children to respiratory viruses seems far from wise. It may ultimately be possible to achieve prophylactic measures which do not prevent the establishment of immunity.
Domiciliary Oxygen DURING acute exacerbations of respiratory illness, controlled oxygen therapy, providing partial correction
hypoxaemia, is a means of avoiding both the Scylla of a hypoxic death and the Charybdis of carbondioxide narcosis. Monitoring of the arterial blood is of the
necessary, so the treatment must be carried out in hospital; this increases awareness of the complications of oxygen therapy and reinforces the deterrent which cost imposes on the use of oxygen in the home. Emphasis has been rightly placed on the relief of airway narrowing by broncho-active drugs, chemotherapy, and avoidance of tobacco smoke. These measures enable the patient to make full use of his ventilatory reserve, but they do not prevent either the long-term complications of hypoxxmia, including pulmonary hypertension, or the immediate stimulant effect of hypoxia upon ventilation during exercise which contributes to breathlessness. In most patients exercise dyspnoea may be reduced by breathing oxygen from a portable apparatus,l2 but the equipment is used by only a small proportion of those who could benefit. The reasons include the need to carry out an exercise test to establish that treatment is appropriate,3 the cost of maintaining the oxygen supply, and the social and physical inconvenience of the equipment, especially the mask. That these difficulties are surmountable, however, has been demonstrated by PETTY and FINIGAN4 in twenty patients with chronic airway obstruction who were treated at their homes in Denver, Colorado, for an average of 8-1 months with almost continuous oxygen.4 The oxygen was delivered through nasal cannulx at a flow-rate of 2-4 litres per minute from a portable container, which was recharged with liquid oxygen by the patient every 2-4 hours. The patients were able to increase their level of activity, their secondary polycythaemia disappeared, and some, because they had fewer episodes of congestive cardiac failure, were able to spend less on medical care. These results cannot be applied directly to conditions at sea level, since the altitude at Denver (5000 ft.) is likely to have contributed to both the patients’ disability5 and their response to treatment. But studies in the United Kingdom point to a similar conclusion. ABRAHAM et al.6 have shown that the pulmonary arterial pressure during air breathing may be reduced by a Cotes, J. E., Gilson, J. C. Lancet, 1956, i, 872. Miller, W. F., Taylor, H. F. Sth. med. J., Nashville, 1962, 55, 1216. Cotes, J. E. Lung Function: Assessment and application in Medicine. Oxford, 1968. 4. Petty, T. L., Finigan, M. M. Am. J. Med. 1968, 45, 242. 5. Mitchell, R. S., Webb, A. C., Filley, G. F. Am. Rev. resp. Dis. 1966, 89, 878. 6. Abraham, A. S., Cole, R. B., Bishop, J. M. Circulation Res. 1968, 23, 147. 1. 2. 3.
period of 4-8 weeks breathing oxygen; and CHAMBERLAIN and MILLARDhave similarly reduced the hxmoglobin concentration of patients with secondary polycythaemia.7I These improvements were achieved during almost continuous treatment with oxygen in concentrations of up to 35%; but they were not sustained when the patients returned to breathing air. In some instances the benefit probably depended on the treatment being continuous, as it was in Denver, but in at least one patient the inhalation of oxygen during the night only was equally effective.8 It is important to find out what proportion of patients respond in this way to nocturnal oxygen at sea level, because for those who do the treatment is both economical and acceptable. For the patient we mentioned, an oxygen point was installed in the bedroom and supplied from large cylinders beneath the stairs; the cost was very similar to that incurred in Denver. Nowadays, oxygen can possibly be supplied more cheaply as a result of the development of an oxygen concentrator
which, by removing
some
nitrogen
from air, produces a continuous flow of gas containing up to 60% oxygen.9 The apparatus in its present form provides a safe and economical source of oxygenenriched gas for hospitals in out-of-the-way places; and it could readily be scaled down for use at home. Thus, on the technical side, the prospect for prolonged use of domiciliary oxygen is encouraging. On the the to the need is establish criteria for medical side, selection of patients and the safeguards required to prevent a tolerable degree of hypercapnia from developing into carbon-dioxide narcosis. In view of encouraging experience with patients measuring their own peak-flow rates one possibility is the measurement in the home of the mixed venous carbon-dioxide tension." There is little risk of the other complications of oxygen therapy,12 since the concentration required by the patient is only of the order of 30%. Meanwhile, as a means of reducing dyspnoea on exertion, more use might be made of existing portable apparatus; one charge lasts for from half an hour to one hour, which is adequate for most activities, whilst the greater safety and lightness offset the possible advantage of the longer duration obtained with a liquid, oxygen container. For use in public places the apparatus could with advantage be adapted to supply an inconspicuous palm breathing device 13 instead of a mask. The procedure for assessment and supervision of patients is likely to be simplified when chest clinics become absorbed into the chest departments of district general hospitals.14 The immediate need is to reduce the cost to the patient of buying his own equipment by increasing its availability through the National Health Service. Chamberlain, D. A., Millard, F. J. C. Q. Jl Med. 1963, 32, 341. Storring, P. J., Cotes, J. E. Lancet, 1964, ii, 473. Cooper, A. G. Hosp. Engineer, 1968, 12, 85. Epstein, S. W., Fletcher, C. M., Oppenheimer, E. A. Br. med. J. Jan. 25, 1969, p. 223. 11. Godfrey, S. ibid. 1965, i, 1163. 12. Morgan, A. P. Anesthesiology, 1968, 29, 570. 13. Cotes, J. E., Matthews, C. R., Tasker, P. M. Lancet, 1963, i, 1075. 14. The Future of the Chest Services: Report by a Sub-Committee of the Standing Medical Advisory Committee of the Central Health Services Council. H.M. Stationery Office, 1968. 7. 8. 9. 10.
LEADING ARTICLES
thus, when small areas of cytopathic changes were evident, the drug was still effective in preserving cell cultures from destruction by poliovirus type 1 or Coxsackie B5 or A9 viruses. Thirdly, the drug had an effect in vivo in delaying death and, when virus doses were small, in protecting suckling mice challenged with Coxsackie A9 virus. Although increased resistance to the drug in vitro developed when Coxsackie A9 was grown in progressively higher concentrations in cell culture, the increase seemed to be limited to about fourfold. Moreover, the virus recovered from treated added to the cultures;
THE LANCET LONDON
15
MARCH
1969
Drugs against Viruses: the Search Continued THE signs are that drugs capable of curing or preventing virus infections will eventually be found. The
profound effects of age and temperature on viral replication and the phenomenon of viral interference demonstrate that virus growth can be prevented without impairment of cell function. A deeper understanding of the host-cell range of viruses may also lead to methods of interrupting virus replication. The search for antiviral drugs is therefore well worth pursuing, though those that have been marketed so far are not entirely satisfactory. Thus, methisazone, effective in contacts of smallpox and for the complications of vaccinia infection, is too toxic for general use. Idoxuridine has found a place in the treatment of herpes-simplex infections, but it is also too toxic for systemic use. Amantadine, although marginally effective against influenza A2, has come under attack because of its low efficacy and the high incidence of side-effects. A well-established line of investigation is the search for more active variations on a basic structure. RAFELSON et al.1 showed that benzimidazole inhibited the multiplication of a picornavirus, and T AMM and NEMES2 later found that this group of viruses was selectively inhibited by 2-(cx-hydroxybenzyl) benzimidazole (H.B.B.). This compound has since been examined by a number of workers, particularly by O’SULLIVAN and his colleagues at the Courtauld Institute of the Middlesex Hospital. The chief difficulty with H.B.B. has been the selectivity of its action: not only is it mainly active against picornaviruses but also, within this group, it is highly selective, so that at one time EGGERS and T AMM3 suggested it might be used in a diagnostic test. The second problem is the rapid emergence of resistant viruses. O’SULLIVAN et al.4 have studied the 1-propyl derivative of H.B.B. (P.H.B.B.), which has a number of interesting properties. Firstly, it is more active than H.B.B., and against some viruses it is very active indeed -for example, less than 0-1 g. per ml. protects cell cultures against challenge with 1000 T.C.D’50 of rhinovirus 5. Secondly, it is active after the virus has been 1. 2. 3. 4.
Rafelson, M. E., Pearson, M. E., Winzler, R. J. Archs Biochem. 1950, 29, 69. Tamm, I., Nemes, M. M. J. clin. Invest. 1959, 38, 1047. Eggers, H. J., Tamm, I. J. exp. Med. 1961, 113, 657. O’Sullivan, D. G., Pontic, D., Dane, D. S., Briggs, M. Lancet, March 1, 1969, p. 446.
mice
of increased resistance. In the mouse experiments suspensions of drug in corn-oil were given parenterally. It would be of great interest to know whether the drug is absorbed by mouth and, in view of the high activity against the Norman strain of type-5 rhinovirus, whether it reaches the nasal secretions. If it does and if toxicity tests are satisfactory, it would be worth investigating the activity of P.H.B.B. against this virus in volunteers. was not
drugs active against picornaviruses are prospect, how might they be most effectively If
due course ? Picornaviruses
can cause severe
in used in diseases now
(for example, poliomyelitis, encephalitis, or myocarditis), less severe ones (aseptic meningitis), or mild ones (fever with rash and common colds). Vaccination must remain the best method of controlling poliomyelitis, because nearly all of it is caused by polioviruses. But a drug that could be used to cure or treat contacts of the serious manifestations of picornavirus infection would be valuable. P.H.B.B. offers some encouragement here, because when it was added to cell sheets showing virus-induced cytopathic effects the cultures were saved. Moreover, there was a delay in death in suckling mice treated with the drug after infection as well as protection for those given P.H.B.B. prophylactically. The use of a combination of drugs under such circumstances seems worth investigating. Kethoxalis a virus-inactivating agent which has been suggested for use in vaccine production; and it is sufficiently nontoxic to be used topically. It has been found effective in herpes-simplex infections in mice.Such a substance active against the extracellular virus particles might well supplement the activity of an antiviral substance working intracellularly. Moreover, the use of more than one antiviral agent might discourage the emergence of resistant viruses. Thus, both H.B.B. and guanidine inhibit picornaviruses, but resistant mutants rapidly appear, and guanidine was found to be ineffective against poliovirus infection in monkeys, because of the emergence of resistant virus particles. A combination of guanidine and P.H.B.B., or the use of an interferon inducer and P.H.B.B., might be worth examining in the control of experimental infections by picornaviruses. The use of a chemotherapeutic or prophylactic agent for the more mild infections with picornaviruses raises awkward questions. On the one hand, the number of antigenic types makes an approach by vaccine extremely 5. 6.
Underwood, G. E., Weed, S. D. Virology, 1961, 13, 138. Underwood, G. E. Proc. Soc. exp. Biol. Med. 1968, 129, 235.
560
difficult. Yet, on the other hand, the immunity conferred by infection is very valuable, and to convert everyone by means of an antiviral drug to the degree of susceptibility of young children to respiratory viruses seems far from wise. It may ultimately be possible to achieve prophylactic measures which do not prevent the establishment of immunity.
Domiciliary Oxygen DURING acute exacerbations of respiratory illness, controlled oxygen therapy, providing partial correction
hypoxaemia, is a means of avoiding both the Scylla of a hypoxic death and the Charybdis of carbondioxide narcosis. Monitoring of the arterial blood is of the
necessary, so the treatment must be carried out in hospital; this increases awareness of the complications of oxygen therapy and reinforces the deterrent which cost imposes on the use of oxygen in the home. Emphasis has been rightly placed on the relief of airway narrowing by broncho-active drugs, chemotherapy, and avoidance of tobacco smoke. These measures enable the patient to make full use of his ventilatory reserve, but they do not prevent either the long-term complications of hypoxxmia, including pulmonary hypertension, or the immediate stimulant effect of hypoxia upon ventilation during exercise which contributes to breathlessness. In most patients exercise dyspnoea may be reduced by breathing oxygen from a portable apparatus,l2 but the equipment is used by only a small proportion of those who could benefit. The reasons include the need to carry out an exercise test to establish that treatment is appropriate,3 the cost of maintaining the oxygen supply, and the social and physical inconvenience of the equipment, especially the mask. That these difficulties are surmountable, however, has been demonstrated by PETTY and FINIGAN4 in twenty patients with chronic airway obstruction who were treated at their homes in Denver, Colorado, for an average of 8-1 months with almost continuous oxygen.4 The oxygen was delivered through nasal cannulx at a flow-rate of 2-4 litres per minute from a portable container, which was recharged with liquid oxygen by the patient every 2-4 hours. The patients were able to increase their level of activity, their secondary polycythaemia disappeared, and some, because they had fewer episodes of congestive cardiac failure, were able to spend less on medical care. These results cannot be applied directly to conditions at sea level, since the altitude at Denver (5000 ft.) is likely to have contributed to both the patients’ disability5 and their response to treatment. But studies in the United Kingdom point to a similar conclusion. ABRAHAM et al.6 have shown that the pulmonary arterial pressure during air breathing may be reduced by a Cotes, J. E., Gilson, J. C. Lancet, 1956, i, 872. Miller, W. F., Taylor, H. F. Sth. med. J., Nashville, 1962, 55, 1216. Cotes, J. E. Lung Function: Assessment and application in Medicine. Oxford, 1968. 4. Petty, T. L., Finigan, M. M. Am. J. Med. 1968, 45, 242. 5. Mitchell, R. S., Webb, A. C., Filley, G. F. Am. Rev. resp. Dis. 1966, 89, 878. 6. Abraham, A. S., Cole, R. B., Bishop, J. M. Circulation Res. 1968, 23, 147. 1. 2. 3.
period of 4-8 weeks breathing oxygen; and CHAMBERLAIN and MILLARDhave similarly reduced the hxmoglobin concentration of patients with secondary polycythaemia.7I These improvements were achieved during almost continuous treatment with oxygen in concentrations of up to 35%; but they were not sustained when the patients returned to breathing air. In some instances the benefit probably depended on the treatment being continuous, as it was in Denver, but in at least one patient the inhalation of oxygen during the night only was equally effective.8 It is important to find out what proportion of patients respond in this way to nocturnal oxygen at sea level, because for those who do the treatment is both economical and acceptable. For the patient we mentioned, an oxygen point was installed in the bedroom and supplied from large cylinders beneath the stairs; the cost was very similar to that incurred in Denver. Nowadays, oxygen can possibly be supplied more cheaply as a result of the development of an oxygen concentrator
which, by removing
some
nitrogen
from air, produces a continuous flow of gas containing up to 60% oxygen.9 The apparatus in its present form provides a safe and economical source of oxygenenriched gas for hospitals in out-of-the-way places; and it could readily be scaled down for use at home. Thus, on the technical side, the prospect for prolonged use of domiciliary oxygen is encouraging. On the the to the need is establish criteria for medical side, selection of patients and the safeguards required to prevent a tolerable degree of hypercapnia from developing into carbon-dioxide narcosis. In view of encouraging experience with patients measuring their own peak-flow rates one possibility is the measurement in the home of the mixed venous carbon-dioxide tension." There is little risk of the other complications of oxygen therapy,12 since the concentration required by the patient is only of the order of 30%. Meanwhile, as a means of reducing dyspnoea on exertion, more use might be made of existing portable apparatus; one charge lasts for from half an hour to one hour, which is adequate for most activities, whilst the greater safety and lightness offset the possible advantage of the longer duration obtained with a liquid, oxygen container. For use in public places the apparatus could with advantage be adapted to supply an inconspicuous palm breathing device 13 instead of a mask. The procedure for assessment and supervision of patients is likely to be simplified when chest clinics become absorbed into the chest departments of district general hospitals.14 The immediate need is to reduce the cost to the patient of buying his own equipment by increasing its availability through the National Health Service. Chamberlain, D. A., Millard, F. J. C. Q. Jl Med. 1963, 32, 341. Storring, P. J., Cotes, J. E. Lancet, 1964, ii, 473. Cooper, A. G. Hosp. Engineer, 1968, 12, 85. Epstein, S. W., Fletcher, C. M., Oppenheimer, E. A. Br. med. J. Jan. 25, 1969, p. 223. 11. Godfrey, S. ibid. 1965, i, 1163. 12. Morgan, A. P. Anesthesiology, 1968, 29, 570. 13. Cotes, J. E., Matthews, C. R., Tasker, P. M. Lancet, 1963, i, 1075. 14. The Future of the Chest Services: Report by a Sub-Committee of the Standing Medical Advisory Committee of the Central Health Services Council. H.M. Stationery Office, 1968. 7. 8. 9. 10.