NEW DRUGS NEEDED FOR TUBERCULOSIS
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33 NEW DRUGS NEEDED FOR TUBERCULOSIS SINCE streptomycin was discovered in 1944 the efforts of scientists and pharmaceutical firms have yielded nine further drugs of proven therapeutic value in tuberculosis- thiacetazone, p-aminosalicylic acid (P.A.S.), isoniazid, tetracycline, viomycin, cycloserine, pyrazinamide, kana- mycin, and ethionamide. But only two of these have come into general use; and only one-isoniazid-approaches the ideal of a chemotherapeutic agent, being highly efficacious in small doses, only slightly toxic, and remarkably cheap. Thiacetazone may prove to be no less effective than P.A.S. as a companion drug with isoniazid 1; and it too is cheap. Streptomycin retains its value, but its greater use is restricted by cost and the fact that it has to be injected. In countries with well-developed, efficient medical and social services the economic importance of tuberculosis is rapidly declining; and interest in it is waning. Most patients can be made non-infectious by relatively simple treatment, if applied with diligence. The expensive " secondary " drugs are needed only for the few. But the disease persists, and any complacency should be dispelled by the thought that over 20,000 new cases were notified in England and Wales in 1960.2 In the less highly developed countries the situation is completely different. In India, for instance, Frimodt-M6]ler 3 estimates that only a quarter to a half of the infectious patients in the cities are treated in chest clinics; the rest either receive no treatment at all or are treated by private practitioners or unqualified people. Keeny,4 in an outspoken comment on the in- adequacy of treatment in Asia, says: " If I were a poor man in Asia today and had tuberculosis my morale would be lower than a duck’s belly.... If I saw a doctor at all it would probably be for only a minute or two.... If he were the wrong kind of doctor, he would write the pre- scription for a proprietary drug, including a dash of vitamins with the isoniazid.... I would have to go to the pharmacist in the nearest town and pay from ten to twenty times what the isoniazid costs wholesale. I should pay once or twice and then forget the whole matter. I should have to: my children would be hungry." Control of tuberculosis is, of course, not merely a matter of getting better and cheaper drugs. There must be the organisation to deliver them, not just into the chemists’ shops or the government’s drug stores, but in the right combinations and the right doses into the right patients’ stomachs. The need for new, cheap drugs is, however, great and urgent; for the value of the most potent of the old ones-isoniazid-may be rapidly decreasing as more people become infected with isoniazid- resistant tubercle bacilli. An investigation by a W.H.O. team 5 in Kenya showed that 14 (29%) of 49 infectious patients detected by mass radiography were excreting isoniazid-resistant bacilli. Of a total of 74 patients in the study 29 (39%) had cultures resistant to one or more drugs, and 23 of these admitted to having had previous treatment. 47 denied previous treatment; and, of these, 6 (13%) had resistant cultures, 4 (8-5%) being resistant to isoniazid. Figures for isoniazid resistance of 5-9% in Madras 6 and 9-1% in Ghana 7 1. East African and British Medical Research Council Thiacetazone/ Diphenylthiourea Investigation. Tubercle, Lond. 1960, 41, 399. 2. Report of Ministry of Health for 1960: part II, p. 75. H.M. Stationery Office, 1961. 3. Frimodt-Möller, J. Tubercle, Lond. 1962, 43, 88. 4. Keeny, S. Quarterly Review, International Union against Tuberculosis, January, 1962, p. 6. 5. W.H.O. Tuberculosis Chemotherapy Centre, Nairobi. Bull. Wld Hlth Org. 1961, 25, 831. 6. Devadatta, S., Bhatia, A. L., Andrews, R. H., Fox, W., Radhakrishna, S., Ramakrishnan, C. V., Selkon, J. B., Velu, S. ibid. p. 807. 7. Bell, W. J., Brown, P. P. Tubercle, Lond. 1960, 41, 247. have been reported in the past few years. In some coun- tries, perhaps about 1 in 10 of newly diagnosed patients have been infected with isoniazid-resistant bacilli. Treat- ing them with isoniazid and P.A.S. or with isoniazid alone will have little effect. Devadatta et al. at the Tuberculosis Chemotherapy Centre in Madras compared the results of treating 20 such patients with those obtained in 315 whose cultures were sensitive before treatment was started. At the end of twelve months’ treatment 5 out of 6 patients with resistant cultures being treated with isoniazid and P.A.S. showed an unfavourable bacterio- logical response, compared with only 8 (9%) of 86 with sensitive cultures. With isoniazid alone the corresponding proportions were 86% and 43%. There was evidence that isoniazid treatment did, in fact, evoke some response in the patients with resistant cultures, probably because the bacillary population in the lesion was heterogenous, some of the bacilli being normally sensitive to isoniazid and others with low levels of resistance being inhibited by the doses of isoniazid used. But the results after a year’s treatment were poor. Treatment with other drugs-for instance, streptomycin and pyrazinamide 8-would pro- duce much better results, but the high cost prohibits their widespread use. For treating the tuberculous millions of the world cheap drugs are needed. Most anti-tuberculosis drugs are for the rich individuals or communities. We hope that those who have already done so much to provide drugs to counter this disease will not be persuaded by the position in the more fortunate countries that no further effort is required. ACUTE TOXIC ENCEPHALOPATHY OF CHILDREN THE sudden development of fever, convulsions, and loss of consciousness in a child presents a problem familiar to all paediatricians. When recognisable clinical states such as meningitis, viral encephalitis, intracranial haemorrhage, various metabolic and toxic disorders, hypertension, and simple febrile convulsions have been excluded, there remains an ill-defined group of cases designated by different workers as acute toxic encephalo- pathy, serous, non-suppurative, or productive encephali- tis, and acute brain swelling. The syndrome arises in children between the ages of 6 weeks and 12 years who may have been previously healthy, or may have some other disorder, generally minor. It has been described as a complication of upper respiratory infection, gastroenteritis, and various exanthematous diseases, and may also follow vaccination. The duration of the illness varies from a few hours to several weeks; many succumb and some have residual brain damage, while a few recover completely. The clinical picture is characterised by recurrent con- vulsions, flaccidity or rigidity of the extremities, extensor plantar responses, and impairment of consciousness varying from drowsiness to profound coma. Pupillary abnormalities, loss of corneal and pharyngeal reflexes, and respiratory embarrassment or hyperpnoea are usual. The cerebrospinal fluid may be under increased pressure, but is otherwise generally normal, although pleocytosis has occasionally been recorded. There are no significant changes in blood or urine. The clinical and pathological features are illustrated by Lyon et al. 9 in a series of sixteen cases; only two patients 8. Velu, S., Andrews, R. H., Angel, J. H., Devadatta, S., Fox, W., Jacob, P. G., Nair, C. N., Ramakrishnan, C. V. ibid. 1961, 42, 136. 9. Lyon, G., Dodge, P. R., Adams. R. D. Brain, 1961, 84, 680.
Transcript of NEW DRUGS NEEDED FOR TUBERCULOSIS
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NEW DRUGS NEEDED FOR TUBERCULOSIS
SINCE streptomycin was discovered in 1944 the effortsof scientists and pharmaceutical firms have yielded ninefurther drugs of proven therapeutic value in tuberculosis-thiacetazone, p-aminosalicylic acid (P.A.S.), isoniazid,tetracycline, viomycin, cycloserine, pyrazinamide, kana-mycin, and ethionamide. But only two of these have comeinto general use; and only one-isoniazid-approaches theideal of a chemotherapeutic agent, being highly efficaciousin small doses, only slightly toxic, and remarkably cheap.Thiacetazone may prove to be no less effective than P.A.S.as a companion drug with isoniazid 1; and it too is cheap.Streptomycin retains its value, but its greater use isrestricted by cost and the fact that it has to be injected.
In countries with well-developed, efficient medical andsocial services the economic importance of tuberculosis israpidly declining; and interest in it is waning. Most
patients can be made non-infectious by relatively simpletreatment, if applied with diligence. The expensive" secondary " drugs are needed only for the few. But thedisease persists, and any complacency should be dispelledby the thought that over 20,000 new cases were notified inEngland and Wales in 1960.2 In the less highly developedcountries the situation is completely different. In India,for instance, Frimodt-M6]ler 3 estimates that only a
quarter to a half of the infectious patients in the cities aretreated in chest clinics; the rest either receive no treatmentat all or are treated by private practitioners or unqualifiedpeople. Keeny,4 in an outspoken comment on the in-adequacy of treatment in Asia, says:
" If I were a poor man in Asia today and had tuberculosismy morale would be lower than a duck’s belly.... If I saw adoctor at all it would probably be for only a minute or two....If he were the wrong kind of doctor, he would write the pre-scription for a proprietary drug, including a dash of vitaminswith the isoniazid.... I would have to go to the pharmacist inthe nearest town and pay from ten to twenty times what theisoniazid costs wholesale. I should pay once or twice and then
forget the whole matter. I should have to: my children wouldbe hungry."
Control of tuberculosis is, of course, not merely amatter of getting better and cheaper drugs. There mustbe the organisation to deliver them, not just into thechemists’ shops or the government’s drug stores, but in theright combinations and the right doses into the rightpatients’ stomachs. The need for new, cheap drugs is,however, great and urgent; for the value of the mostpotent of the old ones-isoniazid-may be rapidlydecreasing as more people become infected with isoniazid-resistant tubercle bacilli.An investigation by a W.H.O. team 5 in Kenya showed
that 14 (29%) of 49 infectious patients detected by massradiography were excreting isoniazid-resistant bacilli. Ofa total of 74 patients in the study 29 (39%) had culturesresistant to one or more drugs, and 23 of these admitted tohaving had previous treatment. 47 denied previoustreatment; and, of these, 6 (13%) had resistant cultures,4 (8-5%) being resistant to isoniazid. Figures for isoniazidresistance of 5-9% in Madras 6 and 9-1% in Ghana 7
1. East African and British Medical Research Council Thiacetazone/Diphenylthiourea Investigation. Tubercle, Lond. 1960, 41, 399.
2. Report of Ministry of Health for 1960: part II, p. 75. H.M. StationeryOffice, 1961.
3. Frimodt-Möller, J. Tubercle, Lond. 1962, 43, 88.4. Keeny, S. Quarterly Review, International Union against Tuberculosis,
January, 1962, p. 6.5. W.H.O. Tuberculosis Chemotherapy Centre, Nairobi. Bull. Wld Hlth
Org. 1961, 25, 831.6. Devadatta, S., Bhatia, A. L., Andrews, R. H., Fox, W., Radhakrishna,
S., Ramakrishnan, C. V., Selkon, J. B., Velu, S. ibid. p. 807.7. Bell, W. J., Brown, P. P. Tubercle, Lond. 1960, 41, 247.
have been reported in the past few years. In some coun-
tries, perhaps about 1 in 10 of newly diagnosed patientshave been infected with isoniazid-resistant bacilli. Treat-
ing them with isoniazid and P.A.S. or with isoniazid alonewill have little effect. Devadatta et al. at the Tuberculosis
Chemotherapy Centre in Madras compared the results oftreating 20 such patients with those obtained in 315whose cultures were sensitive before treatment was
started. At the end of twelve months’ treatment 5 out of6 patients with resistant cultures being treated withisoniazid and P.A.S. showed an unfavourable bacterio-
logical response, compared with only 8 (9%) of 86 withsensitive cultures. With isoniazid alone the correspondingproportions were 86% and 43%. There was evidence thatisoniazid treatment did, in fact, evoke some response inthe patients with resistant cultures, probably because thebacillary population in the lesion was heterogenous, someof the bacilli being normally sensitive to isoniazid andothers with low levels of resistance being inhibited by thedoses of isoniazid used. But the results after a year’streatment were poor. Treatment with other drugs-forinstance, streptomycin and pyrazinamide 8-would pro-duce much better results, but the high cost prohibits theirwidespread use.
For treating the tuberculous millions of the world
cheap drugs are needed. Most anti-tuberculosis drugs arefor the rich individuals or communities. We hope that thosewho have already done so much to provide drugs to counterthis disease will not be persuaded by the position in themore fortunate countries that no further effort is required.
ACUTE TOXIC ENCEPHALOPATHY OF CHILDREN
THE sudden development of fever, convulsions, andloss of consciousness in a child presents a problemfamiliar to all paediatricians. When recognisable clinicalstates such as meningitis, viral encephalitis, intracranialhaemorrhage, various metabolic and toxic disorders,hypertension, and simple febrile convulsions have beenexcluded, there remains an ill-defined group of casesdesignated by different workers as acute toxic encephalo-pathy, serous, non-suppurative, or productive encephali-tis, and acute brain swelling.The syndrome arises in children between the ages of 6
weeks and 12 years who may have been previously healthy,or may have some other disorder, generally minor. It hasbeen described as a complication of upper respiratoryinfection, gastroenteritis, and various exanthematous
diseases, and may also follow vaccination. The durationof the illness varies from a few hours to several weeks;many succumb and some have residual brain damage,while a few recover completely.The clinical picture is characterised by recurrent con-
vulsions, flaccidity or rigidity of the extremities, extensorplantar responses, and impairment of consciousnessvarying from drowsiness to profound coma. Pupillaryabnormalities, loss of corneal and pharyngeal reflexes,and respiratory embarrassment or hyperpnoea are usual.The cerebrospinal fluid may be under increased pressure,but is otherwise generally normal, although pleocytosishas occasionally been recorded. There are no significantchanges in blood or urine.The clinical and pathological features are illustrated by
Lyon et al. 9 in a series of sixteen cases; only two patients8. Velu, S., Andrews, R. H., Angel, J. H., Devadatta, S., Fox, W., Jacob,
P. G., Nair, C. N., Ramakrishnan, C. V. ibid. 1961, 42, 136.9. Lyon, G., Dodge, P. R., Adams. R. D. Brain, 1961, 84, 680.
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