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Levodopa
533
with parkinsonism, but in patients with H.v.A. levels in the normal range the response to levodopa is usually disappointing.7,8 Patients with normal H.V.A. levels respond to treatment with levodopa with an increase in the H.v.A. concentration to the maximum level per unit dose, but paradoxically this response is associated with little or no benefit.8 These findings suggest that most parkinsonian patients have cerebral dopamine depletion, as was originally demonstrated by HORNYKIEWICZ,I-L and these patients respond well to levodopa. Atypical cases in which cerebral dopamine is not depleted are unlikely to respond. At present, non-responders can be identified only by these procedures and not by any simple clinical correlates. In most cases the risks of a trial of treatment for three months are
patients
THE LANCET Levodopa levodopa has been accepted as the effective medical treatment for most patients with parkinsonism, about a third of the patients treated either do not respond or become unable to tolerate the drug in a therapeutic dose. Such failures have probably accounted for some waning of the initial enthusiasm for levodopa. Patients with idiopathic parkinsonism generally respond better to treatment with this drug than postencephalitic doses1 and seldom patients, who tolerate lower derive persisting benefit.2 Arteriosclerotic patients, especially if hypertensive3 or demented, probably also respond less well to treatment; and the incidence of side-effects is relatively high in such patients. Thalamotomy does not affect the response to levodopa but may reduce abnormal movements in the contralateral limbs when these movements are a side-effect of levodopa.3,4 Some patients have been shown to have defective absorption of the drug from the gastrointestinal tract,5 and this may account for some failures of treatment. The concurrent administration of pyridoxine has been shown to antagonise the effect of levodopa 6; hence vitamin preparations containing this substance should be specifically excluded. In most treatment failures with levodopa, however, no explanation is evident. Two reports have suggested ways of predicting responsiveness.7,s Intravenous physostigmine produces a severe temporary exacerbation of the symptoms and signs of parkinsonism in most patients with this disorder but has no comparable effect in normal individuals.9 VAN WOERT and WEINTRAUBhave suggested that patients who do not demonstrate this exacerbation with physostigmine respond poorly to treatment with levodopa. The main cerebral metabolite of levodopa and dopamine is homovanillic acid (H.v.A.) whose concentration in the cerebrospinal fluid provides an estimate of cerebral dopamine turnover.10 Low levels of H.V.A. are usual in the cerebrospinal fluid of ALTHOUGH
most
Calne, D. B., Stern, G. M., Laurence, D. R., Sharkey, J., Armitage, P. Lancet, 1969, i, 744. 2. Hunter, K. R., Stern, G. M., Sharkey, J. ibid. 1970, ii, 1366. 3. Hughes, R. C., Polgar, J. G., Weightman, D., Walton, J. N. Br. med. J. 1971, i, 7. 4. Schwab, R. S. Fourth International Congress of Neurological Surgery and Ninth International Congress of Neurology. Amsterdam, 1969, p. 172. 5. Rivera-Calimlim, L., Dujovne, C. A., Morgan, J. P., Lasagna, L., Bianchine, J. R. Br. med. J. 1970, ii, 93. 6. Duvoisin, R. C., Yahr, M. D., Cote, L. D. Trans. Am. neurol. Ass. 1969, 94, 81. 7. Van Woert, M. H., Weintraub, M. I. Lancet, 1971, i, 1015. 8. Godwin-Austen, R. B., Kantameneni, B. D., Curzon, G. J. Neurol. Neurosurg. Psychiat. 1971, 34, 219. 9. Duvoisin, R. C. Archs Neurol., Chicago, 1967, 17, 124. 10. Guldberg, G. H. in Metabolism of Amines in the Brain (edited by G. Hooper); p. 55. London, 1969. 1.
fully justified. Some patients who benefit from levodopa tolerate therapeutic dosage initially but become intolerant of the drug after continuous treatment over a period of months. The side-effect which leads most commonly to intolerance is abnormal movements. These abnormal movements, which typically affect the mouth, face, or limbs, are rare in patients who derive negligible benefit and are most severe in patients whose improvement is considerable.33 A reduction in dose of levodopa is followed within twenty-four hours by improvement in the abnormal movements but equally by loss of therapeutic effect. It is to be hoped that additional medication will be developed to counteract this side-effect while avoiding any decrement of therapeutic effect. Preliminary reports suggest that decarboxylase inhibitors (which are not yet available for therapeutic purposes in the United Kingdom) may sometimes achieve this result. Nausea and vomiting as side-effects of treatment can usually be overcome by administering levodopa after meals or with an antiemetic. Hypotension is
weeks
or
rarely so severe as to produce symptoms or to require curtailment of dosage. Psychological disturbances include toxic confusional states, which are invariably an indication for reduction in dosage or withdrawal of the drug, and functional psychoses, especially depression, which usually likewise necessitates reduction of dose but may be treatable with tricyclic antidepressants or benzodiazepines.12 Cardiac dysrhythmias may be induced by levodopa and are an indication for stopping this drug. Multiple extrasystoles and recent myocardial infarction are contraindications to treatment, but a history of heart-disease does not preclude the cautious use of levodopa.13 Levodopa is preferably given in addition to an anticholinergic drug, but amantadine provides additional benefit only if the maximum tolerated dose of levodopa is small.14 Treatment is probably best 11. Hornykiewicz, O. Wien. klin. Wschr. 1963, 75, 309. 12. Jenkins, R. B., Groh, R. H. Lancet, 1970, ii, 177. 13. Hunter, K. R., Hollman, A., Laurence, D. R., Stern, G. M. ibid. 1971, i, 932. 14. Godwin-Austen, R. B., Frears, C. C., Bergmann, S., Parkes, J. D., Knill-Jones, R. P. ibid. 1970, ii, 383.
534
started with twice-weekly increments of 500 mg. daily 15 until side-effects occur or daily dosage of 8 g. is reached. When the optimum dosage for the patient has been established, minor adjustments are usually required either in total dose or in the timing of individual doses. Thus these patients need contin-
uing supervision so long as they are being treated; but usually benefit is so well maintained that they require no encouragement to persevere with treatment.
Prevention of Leprosy IT’s an ill wind ... The appearance of chloroquineresistant falciparum malaria in Vietnam led to intensive research based on a chance observation by ARCHIBALD and Ross 16 that dapsone (diaphenylsul-
fone, diaminodiphenylsulphone) was partially effective in preventing malaria in leprosy patients receiving the drug regularly. Among a series of synthetic sulphone derivatives investigated, acedapsone (4,4’-
diacetyldiaminodiphenyl sulphone, D.A.D.D.s.)
was
found to have certain advantages when parenterally administered as a repository drug for malarial prophylaxis.17 ,18 It has suppressed falciparum infection in man for sixty days. A potentially more promising field now seems to be in the treatment and prevention of leprosy. The wheel has turned full circle. Since multiplication of Mycobacterium leprae in the mouse footpad is suppressed by concentrations of dapsone as low as 0.00001 % administered in the diet,19 there is some justification for the trial in man of a repository drug such as acedapsone, which is slowly degraded in the tissues to compounds with demonstrable antimycobacterial activity, such as dapsone or some sulphone metabolite with one free amino group. In man, a single intramuscular injection of 225 mg. of acedapsone in a benzyl-benzoate/castoroil suspension releases dapsone at the rate of 2-4 mg. a day for seventy-seven days, giving a serum level of about 50 ng. per ml., which is above the minimum inhibitory concentration judged from extrapolation of the findings in mice. In the mouse, acedapsone in a dose of 6 mg. per kg. suppressed bacterial activity almost completely for two months. Several clinical trials of acedapsone in the treatment of leprosy 20 have followed the first report from SHEPARD et a1.p and the article by Dr. SLOAN and his colleagues in an earlier page of this issue confirms the findings of workers in other countries. 15.
Godwin-Austen,
R.
B., Frears, C. C., Bergmann, S. Br. med. J.
1971, i, 267. 16. 17. 18.
Archibald, H. M., Ross, C. M. J. trop. Med. Hyg. 1960, 63, 25. Thompson, P. E. Int. J. Leprosy, 1967, 35, 605. Laing, A. G. B., Pringle, G., Lane, F. C. T. Am. J. trop. Med. Hyg.
19. 20.
Shepard, C. C. Soc. exp. Biol. Med. 1967, 124, 430. Russell, D. A., Shepard, C. C., McRae, D. H., Scott, G. C., Vincin, D. R. Am. J. trop Med. Hyg. 1971, 20, 495. Shepard, C. C., Tolentino, J. G., McRae, D. H. ibid. 1968, 17, 192.
1966, 15, 838.
21.
The main interest of this report concerns what the authors call " the chemoprophylactic efficacy " of the drug in the population studied, and the observation that far fewer new overt leprosy infections were seen (6, against the expected 35) in the three years during which most of the people at risk received acedapsone in the same amounts as those given to patients diagnosed as having active leprosy. Since in the great majority of cases leprosy shows itself, after a silent or latent period, within two to four years, it is presumed that very few additional new cases should arise. As in similar investigations, the results presented by SLOAN et al. might be interpreted as confirming the efficacy of treatment of cases of leprosy (known, unsuspected, and preclinical infections), reducing to zero their capacity to disseminate viable bacilli within a few months of the institution of treatment, rather than as providing protection against challenge by M. leprae in the environment. Any such inquiry is hampered by lack of knowledge of the exact mode of transmission of the bacilli and their successful transepithelial implantation into susceptible subjects. A point of some importance is the possibility that drug-resistant strains of M. leprae may emerge in infected patients in whom the organisms are exposed for long periods to low concentrations of the drug. Trials of dapsone as the chemoprophylactic agent in areas of high leprosy prevalence have produced suggestive but equivocal results in respect of lepromatous leprosy.22-25 An effective and cheap prophylactic agent is urgently needed for leprosy control. In the opinion of some investigators, B.C.G. vaccination holds out real prospects of protection of exposed populations, and the simplicity of its administration and its low cost certainly commend it to field workers. The highly satisfactory protection-rates achieved in Uganda 26 have not been paralleled in Burma 27 or Papua and New Guinea,28 for reasons which are still There has been some suggestion that debated. vaccination with B.C.G. might with advantage be followed by chemoprophylaxis with dapsone in order to afford maximum protection to exposed subjects.29 The real test of any reputed prophylaxis in leprosy is the definite prevention of clinical disease in those exposed to leprosy challenge who are innately incapable of developing cell-mediated immunity. However, any reduction in the incidence of tuberculoid leprosy, with its accompaniment of severe peripheral 22. Lancet, 1966, i, 354. 23. Wardekar, R. V. Lepr. India, 1969, 41, 240. 24. Noordeen, S. K. ibid. p. 247. 25. W.H.O. Expert Committee on Leprosy: Fourth Report. Tech. Rep. Ser. Wld Hlth Org. 1970, no. 459. 26. Brown, J. A. K., Stone, M. M., Sutherland, I. Br. med. J. 1968, i, 24. 27. Bechelli, L. M., Garbajosa, G., Uemura, K., Engler, V., Dominguez, V. Martinez, Paredes, L., Sundaresan, T., Koch, G., Matejka, M. Bull. Wld Hlth Org. 1970, 42, 235. 28. Scott, G. C., Wigley, S. C., Russell, D. A. Int. J. Leprosy, 1966,
34, 139. 29. ibid. 1969,
37,
412.
with parkinsonism, but in patients with H.v.A. levels in the normal range the response to levodopa is usually disappointing.7,8 Patients with normal H.V.A. levels respond to treatment with levodopa with an increase in the H.v.A. concentration to the maximum level per unit dose, but paradoxically this response is associated with little or no benefit.8 These findings suggest that most parkinsonian patients have cerebral dopamine depletion, as was originally demonstrated by HORNYKIEWICZ,I-L and these patients respond well to levodopa. Atypical cases in which cerebral dopamine is not depleted are unlikely to respond. At present, non-responders can be identified only by these procedures and not by any simple clinical correlates. In most cases the risks of a trial of treatment for three months are
patients
THE LANCET Levodopa levodopa has been accepted as the effective medical treatment for most patients with parkinsonism, about a third of the patients treated either do not respond or become unable to tolerate the drug in a therapeutic dose. Such failures have probably accounted for some waning of the initial enthusiasm for levodopa. Patients with idiopathic parkinsonism generally respond better to treatment with this drug than postencephalitic doses1 and seldom patients, who tolerate lower derive persisting benefit.2 Arteriosclerotic patients, especially if hypertensive3 or demented, probably also respond less well to treatment; and the incidence of side-effects is relatively high in such patients. Thalamotomy does not affect the response to levodopa but may reduce abnormal movements in the contralateral limbs when these movements are a side-effect of levodopa.3,4 Some patients have been shown to have defective absorption of the drug from the gastrointestinal tract,5 and this may account for some failures of treatment. The concurrent administration of pyridoxine has been shown to antagonise the effect of levodopa 6; hence vitamin preparations containing this substance should be specifically excluded. In most treatment failures with levodopa, however, no explanation is evident. Two reports have suggested ways of predicting responsiveness.7,s Intravenous physostigmine produces a severe temporary exacerbation of the symptoms and signs of parkinsonism in most patients with this disorder but has no comparable effect in normal individuals.9 VAN WOERT and WEINTRAUBhave suggested that patients who do not demonstrate this exacerbation with physostigmine respond poorly to treatment with levodopa. The main cerebral metabolite of levodopa and dopamine is homovanillic acid (H.v.A.) whose concentration in the cerebrospinal fluid provides an estimate of cerebral dopamine turnover.10 Low levels of H.V.A. are usual in the cerebrospinal fluid of ALTHOUGH
most
Calne, D. B., Stern, G. M., Laurence, D. R., Sharkey, J., Armitage, P. Lancet, 1969, i, 744. 2. Hunter, K. R., Stern, G. M., Sharkey, J. ibid. 1970, ii, 1366. 3. Hughes, R. C., Polgar, J. G., Weightman, D., Walton, J. N. Br. med. J. 1971, i, 7. 4. Schwab, R. S. Fourth International Congress of Neurological Surgery and Ninth International Congress of Neurology. Amsterdam, 1969, p. 172. 5. Rivera-Calimlim, L., Dujovne, C. A., Morgan, J. P., Lasagna, L., Bianchine, J. R. Br. med. J. 1970, ii, 93. 6. Duvoisin, R. C., Yahr, M. D., Cote, L. D. Trans. Am. neurol. Ass. 1969, 94, 81. 7. Van Woert, M. H., Weintraub, M. I. Lancet, 1971, i, 1015. 8. Godwin-Austen, R. B., Kantameneni, B. D., Curzon, G. J. Neurol. Neurosurg. Psychiat. 1971, 34, 219. 9. Duvoisin, R. C. Archs Neurol., Chicago, 1967, 17, 124. 10. Guldberg, G. H. in Metabolism of Amines in the Brain (edited by G. Hooper); p. 55. London, 1969. 1.
fully justified. Some patients who benefit from levodopa tolerate therapeutic dosage initially but become intolerant of the drug after continuous treatment over a period of months. The side-effect which leads most commonly to intolerance is abnormal movements. These abnormal movements, which typically affect the mouth, face, or limbs, are rare in patients who derive negligible benefit and are most severe in patients whose improvement is considerable.33 A reduction in dose of levodopa is followed within twenty-four hours by improvement in the abnormal movements but equally by loss of therapeutic effect. It is to be hoped that additional medication will be developed to counteract this side-effect while avoiding any decrement of therapeutic effect. Preliminary reports suggest that decarboxylase inhibitors (which are not yet available for therapeutic purposes in the United Kingdom) may sometimes achieve this result. Nausea and vomiting as side-effects of treatment can usually be overcome by administering levodopa after meals or with an antiemetic. Hypotension is
weeks
or
rarely so severe as to produce symptoms or to require curtailment of dosage. Psychological disturbances include toxic confusional states, which are invariably an indication for reduction in dosage or withdrawal of the drug, and functional psychoses, especially depression, which usually likewise necessitates reduction of dose but may be treatable with tricyclic antidepressants or benzodiazepines.12 Cardiac dysrhythmias may be induced by levodopa and are an indication for stopping this drug. Multiple extrasystoles and recent myocardial infarction are contraindications to treatment, but a history of heart-disease does not preclude the cautious use of levodopa.13 Levodopa is preferably given in addition to an anticholinergic drug, but amantadine provides additional benefit only if the maximum tolerated dose of levodopa is small.14 Treatment is probably best 11. Hornykiewicz, O. Wien. klin. Wschr. 1963, 75, 309. 12. Jenkins, R. B., Groh, R. H. Lancet, 1970, ii, 177. 13. Hunter, K. R., Hollman, A., Laurence, D. R., Stern, G. M. ibid. 1971, i, 932. 14. Godwin-Austen, R. B., Frears, C. C., Bergmann, S., Parkes, J. D., Knill-Jones, R. P. ibid. 1970, ii, 383.
534
started with twice-weekly increments of 500 mg. daily 15 until side-effects occur or daily dosage of 8 g. is reached. When the optimum dosage for the patient has been established, minor adjustments are usually required either in total dose or in the timing of individual doses. Thus these patients need contin-
uing supervision so long as they are being treated; but usually benefit is so well maintained that they require no encouragement to persevere with treatment.
Prevention of Leprosy IT’s an ill wind ... The appearance of chloroquineresistant falciparum malaria in Vietnam led to intensive research based on a chance observation by ARCHIBALD and Ross 16 that dapsone (diaphenylsul-
fone, diaminodiphenylsulphone) was partially effective in preventing malaria in leprosy patients receiving the drug regularly. Among a series of synthetic sulphone derivatives investigated, acedapsone (4,4’-
diacetyldiaminodiphenyl sulphone, D.A.D.D.s.)
was
found to have certain advantages when parenterally administered as a repository drug for malarial prophylaxis.17 ,18 It has suppressed falciparum infection in man for sixty days. A potentially more promising field now seems to be in the treatment and prevention of leprosy. The wheel has turned full circle. Since multiplication of Mycobacterium leprae in the mouse footpad is suppressed by concentrations of dapsone as low as 0.00001 % administered in the diet,19 there is some justification for the trial in man of a repository drug such as acedapsone, which is slowly degraded in the tissues to compounds with demonstrable antimycobacterial activity, such as dapsone or some sulphone metabolite with one free amino group. In man, a single intramuscular injection of 225 mg. of acedapsone in a benzyl-benzoate/castoroil suspension releases dapsone at the rate of 2-4 mg. a day for seventy-seven days, giving a serum level of about 50 ng. per ml., which is above the minimum inhibitory concentration judged from extrapolation of the findings in mice. In the mouse, acedapsone in a dose of 6 mg. per kg. suppressed bacterial activity almost completely for two months. Several clinical trials of acedapsone in the treatment of leprosy 20 have followed the first report from SHEPARD et a1.p and the article by Dr. SLOAN and his colleagues in an earlier page of this issue confirms the findings of workers in other countries. 15.
Godwin-Austen,
R.
B., Frears, C. C., Bergmann, S. Br. med. J.
1971, i, 267. 16. 17. 18.
Archibald, H. M., Ross, C. M. J. trop. Med. Hyg. 1960, 63, 25. Thompson, P. E. Int. J. Leprosy, 1967, 35, 605. Laing, A. G. B., Pringle, G., Lane, F. C. T. Am. J. trop. Med. Hyg.
19. 20.
Shepard, C. C. Soc. exp. Biol. Med. 1967, 124, 430. Russell, D. A., Shepard, C. C., McRae, D. H., Scott, G. C., Vincin, D. R. Am. J. trop Med. Hyg. 1971, 20, 495. Shepard, C. C., Tolentino, J. G., McRae, D. H. ibid. 1968, 17, 192.
1966, 15, 838.
21.
The main interest of this report concerns what the authors call " the chemoprophylactic efficacy " of the drug in the population studied, and the observation that far fewer new overt leprosy infections were seen (6, against the expected 35) in the three years during which most of the people at risk received acedapsone in the same amounts as those given to patients diagnosed as having active leprosy. Since in the great majority of cases leprosy shows itself, after a silent or latent period, within two to four years, it is presumed that very few additional new cases should arise. As in similar investigations, the results presented by SLOAN et al. might be interpreted as confirming the efficacy of treatment of cases of leprosy (known, unsuspected, and preclinical infections), reducing to zero their capacity to disseminate viable bacilli within a few months of the institution of treatment, rather than as providing protection against challenge by M. leprae in the environment. Any such inquiry is hampered by lack of knowledge of the exact mode of transmission of the bacilli and their successful transepithelial implantation into susceptible subjects. A point of some importance is the possibility that drug-resistant strains of M. leprae may emerge in infected patients in whom the organisms are exposed for long periods to low concentrations of the drug. Trials of dapsone as the chemoprophylactic agent in areas of high leprosy prevalence have produced suggestive but equivocal results in respect of lepromatous leprosy.22-25 An effective and cheap prophylactic agent is urgently needed for leprosy control. In the opinion of some investigators, B.C.G. vaccination holds out real prospects of protection of exposed populations, and the simplicity of its administration and its low cost certainly commend it to field workers. The highly satisfactory protection-rates achieved in Uganda 26 have not been paralleled in Burma 27 or Papua and New Guinea,28 for reasons which are still There has been some suggestion that debated. vaccination with B.C.G. might with advantage be followed by chemoprophylaxis with dapsone in order to afford maximum protection to exposed subjects.29 The real test of any reputed prophylaxis in leprosy is the definite prevention of clinical disease in those exposed to leprosy challenge who are innately incapable of developing cell-mediated immunity. However, any reduction in the incidence of tuberculoid leprosy, with its accompaniment of severe peripheral 22. Lancet, 1966, i, 354. 23. Wardekar, R. V. Lepr. India, 1969, 41, 240. 24. Noordeen, S. K. ibid. p. 247. 25. W.H.O. Expert Committee on Leprosy: Fourth Report. Tech. Rep. Ser. Wld Hlth Org. 1970, no. 459. 26. Brown, J. A. K., Stone, M. M., Sutherland, I. Br. med. J. 1968, i, 24. 27. Bechelli, L. M., Garbajosa, G., Uemura, K., Engler, V., Dominguez, V. Martinez, Paredes, L., Sundaresan, T., Koch, G., Matejka, M. Bull. Wld Hlth Org. 1970, 42, 235. 28. Scott, G. C., Wigley, S. C., Russell, D. A. Int. J. Leprosy, 1966,
34, 139. 29. ibid. 1969,
37,
412.