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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.