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1325 LEADING ARTICLES THE LANCET LONDON : : SATURDAY, DEC. 24, 1955 Continuous Chemotherapy of Tuberculosis THERE have been no striking additions to the anti- tuberculous drugs since isoniazid appeared three years ago. But an important change has come about in the way they are used ; and surprisingly little has been said about it. The chemotherapy of tuber- culosis has evolved in this country largely from the foundations laid by the Medical Research Council’s clinical trials, in which the duration of treatment was limited for the purposes of the experiment to periods of a few months only. The facts discovered were very valuable ; but more has been inferred from them than is justified, for the investigations were not designed to answer the question how long antibacterial drugs can safely and usefully be given. At first streptomycin was scarce and rationed, and by the time it became freely available and the addi- tion of p-aminosalicylic acid (P.A.s.) had reduced the fear of resistance, treatment by conservative bursts of chemotherapy was already well established. In the United States chemotherapy developed under quite different circumstances ; and both in clinical trials and everyday practice it appears to have been used in a much more adventurous way. In 1953 we suggested that the risk of bacterial resistance may have been exaggerated and that continued, even life-long, antibacterial treatment might sometimes be justified ;. and last year we noted 2 that there seemed to be much less opposition to long courses of treatment. On an earlier page of this issue we publish the first full report in this country of the results of such treatment. Since 1950 Dr. HoYLE and his colleagues have treated 142 patients for nine months or longer, and they have observed 63 of them for more than a year after treatment was stopped. 46 had bilateral disease affecting four or more zones and 92 had cavities in the lungs. All received combinations of two of the three drugs, streptomycin, P.A.s., and isoniazid ; and in most of them the streptomycin was given daily for the first three or four months. 119 have been treated for longer than a year and 12 for longer than two years. All but 41 received no other treatment than rest, drugs, and convalescence : of the 41, resection was done in 16 and some form of lung collapse in 25. The results were excellent. Radiographic improvement continued for considerably longer than 1. Lancet, 1953, ii, 237. 2. Ibid, 1954, ii, 691. might have been expected, for half the patients kept on improving after the first six months, which was the longest period of treatment used in the M.R.C. trials. In 64 of the 92 patients with lung cavities, the cavities closed without further treatment. Tubercle bacilli were isolated before treatment in 111 ; after a year they were found in only 9. Bacilli resistant to streptomycin and P.A.S. were grown at some time from all sputum-positive patients, but only 1 patient in whom resistant strains have been detected has so far deteriorated. 4 patients have died, but death was due to other diseases in 2, and 1 died after a thoraco- plasty. 126 patients are leading their normal lives and only 3 are known to be infectious. The most important observations were that no patient has relapsed while under treatment, and that some have relapsed since it was stopped. STEINIGER and HOWARD, in the United States, report similar striking results with long-continued treatment of patients with less favourable prospects.3 They treated 300 with rest and chemotherapy for more than a year. Two-thirds had far advanced bilateral disease and slightly less than half were unsuitable for any more radical treatment. By the twelfth month 77% had consistently negative sputum cultures. Only 1 (with long-standing pulmonary fibrosis and emphysema) died while taking the drugs, and 1 died two months after refusing further treatment. DOONEIEF and HITE, of the Montefiore Hospital, New York, who first reported their experience with long-continued chemotherapy in 1954,4 say in their second report 5 that " tuberculosis of the lung is the ... most insidious of the relapsing infections : " 15% of those discharged from their hospital in 1951 relapsed in the next three years. Dr. HoYLE and his colleagues mention that 12% of 90 patients dis- charged from Frimley Sanatorium in 1950 who had received less than seven months’ chemotherapy relapsed within three years, although 61 had been treated with collapse or ablation as well. DOONEIEF et al. go further than recommending long periods of treatment : as relapse is so rare while treatment con- tinues, and as it is impossible to predict which patients are going to relapse when it is stopped, they believe that treatment should be continued indefinitely or until some reliable guides to the best length of treat- ment have been discovered. They have treated 101 patients with pulmonary tuberculosis for periods of twelve to forty-five months, 23 of them for more than three years. 31 had a resection. Only 1 patient (with a manic-depressive psychosis) relapsed under treat- ment and in that case the lung cavities had not closed. But 2 others relapsed after stopping the drugs against advice. Chemotherapy is continued at home and at work and some patients have even been taught to inject streptomycin themselves. Toxic effects have not been troublesome, and DOoNEEEF et al. say that " patient acceptance is good." Nor have Dr. HoYLE and his colleagues found it hard to persuade their patients to take the drugs continuously for long periods. They say that the results make continuous chemotherapy a direct competitor to surgical resection. As we suggested a few months ago,6 it is a pity that 3. Steiniger, W. J., Howard, W. L. Dis. Chest. 1955, 28, 177. 4. Dooneief, A. S., Hite. K. E. Amer. Rev. Tuberc. 1954, 70, 219. 5. Dooneief, A. S., Hite, K. E., Bloch, R. G. Arch. intern. Med. 1955, 96, 470. 6. Lancet, Aug. 13, 1955, p. 330.

Continuous Chemotherapy of Tuberculosis

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Page 1: Continuous Chemotherapy of Tuberculosis

1325LEADING ARTICLES

THE LANCETLONDON : : SATURDAY, DEC. 24, 1955

Continuous Chemotherapy of TuberculosisTHERE have been no striking additions to the anti-

tuberculous drugs since isoniazid appeared three

years ago. But an important change has come aboutin the way they are used ; and surprisingly littlehas been said about it. The chemotherapy of tuber-culosis has evolved in this country largely from thefoundations laid by the Medical Research Council’sclinical trials, in which the duration of treatmentwas limited for the purposes of the experiment toperiods of a few months only. The facts discoveredwere very valuable ; but more has been inferredfrom them than is justified, for the investigationswere not designed to answer the question how longantibacterial drugs can safely and usefully be given.At first streptomycin was scarce and rationed, andby the time it became freely available and the addi-tion of p-aminosalicylic acid (P.A.s.) had reducedthe fear of resistance, treatment by conservativebursts of chemotherapy was already well established.In the United States chemotherapy developed underquite different circumstances ; and both in clinicaltrials and everyday practice it appears to have beenused in a much more adventurous way. In 1953 we

suggested that the risk of bacterial resistance mayhave been exaggerated and that continued, even

life-long, antibacterial treatment might sometimesbe justified ;. and last year we noted 2 that thereseemed to be much less opposition to long coursesof treatment. On an earlier page of this issue we

publish the first full report in this country of theresults of such treatment.

Since 1950 Dr. HoYLE and his colleagues havetreated 142 patients for nine months or longer, and theyhave observed 63 of them for more than a year aftertreatment was stopped. 46 had bilateral disease

affecting four or more zones and 92 had cavities inthe lungs. All received combinations of two of thethree drugs, streptomycin, P.A.s., and isoniazid ;and in most of them the streptomycin was given dailyfor the first three or four months. 119 have beentreated for longer than a year and 12 for longer thantwo years. All but 41 received no other treatmentthan rest, drugs, and convalescence : of the 41,resection was done in 16 and some form of lung collapsein 25. The results were excellent. Radiographicimprovement continued for considerably longer than

1. Lancet, 1953, ii, 237.2. Ibid, 1954, ii, 691.

might have been expected, for half the patients kepton improving after the first six months, which wasthe longest period of treatment used in the M.R.C.trials. In 64 of the 92 patients with lung cavities, thecavities closed without further treatment. Tuberclebacilli were isolated before treatment in 111 ; aftera year they were found in only 9. Bacilli resistantto streptomycin and P.A.S. were grown at some timefrom all sputum-positive patients, but only 1 patientin whom resistant strains have been detected has sofar deteriorated. 4 patients have died, but death wasdue to other diseases in 2, and 1 died after a thoraco-plasty. 126 patients are leading their normal livesand only 3 are known to be infectious. The most

important observations were that no patient has

relapsed while under treatment, and that some haverelapsed since it was stopped.

STEINIGER and HOWARD, in the United States,report similar striking results with long-continuedtreatment of patients with less favourable prospects.3They treated 300 with rest and chemotherapy formore than a year. Two-thirds had far advancedbilateral disease and slightly less than half wereunsuitable for any more radical treatment. By thetwelfth month 77% had consistently negative sputumcultures. Only 1 (with long-standing pulmonaryfibrosis and emphysema) died while taking the drugs,and 1 died two months after refusing further treatment.DOONEIEF and HITE, of the Montefiore Hospital,New York, who first reported their experience withlong-continued chemotherapy in 1954,4 say in theirsecond report 5 that " tuberculosis of the lung is the... most insidious of the relapsing infections : "15% of those discharged from their hospital in 1951relapsed in the next three years. Dr. HoYLE and his

colleagues mention that 12% of 90 patients dis-

charged from Frimley Sanatorium in 1950 who hadreceived less than seven months’ chemotherapyrelapsed within three years, although 61 had beentreated with collapse or ablation as well. DOONEIEFet al. go further than recommending long periods oftreatment : as relapse is so rare while treatment con-tinues, and as it is impossible to predict which patientsare going to relapse when it is stopped, they believethat treatment should be continued indefinitely or

until some reliable guides to the best length of treat-ment have been discovered. They have treated 101patients with pulmonary tuberculosis for periods oftwelve to forty-five months, 23 of them for more thanthree years. 31 had a resection. Only 1 patient (witha manic-depressive psychosis) relapsed under treat-ment and in that case the lung cavities had not closed.But 2 others relapsed after stopping the drugs againstadvice. Chemotherapy is continued at home and atwork and some patients have even been taught toinject streptomycin themselves. Toxic effects havenot been troublesome, and DOoNEEEF et al. saythat " patient acceptance is good." Nor haveDr. HoYLE and his colleagues found it hard to persuadetheir patients to take the drugs continuously for longperiods. They say that the results make continuouschemotherapy a direct competitor to surgical resection.As we suggested a few months ago,6 it is a pity that3. Steiniger, W. J., Howard, W. L. Dis. Chest. 1955, 28, 177.4. Dooneief, A. S., Hite. K. E. Amer. Rev. Tuberc. 1954, 70, 219.5. Dooneief, A. S., Hite, K. E., Bloch, R. G. Arch. intern. Med.

1955, 96, 470.6. Lancet, Aug. 13, 1955, p. 330.

Page 2: Continuous Chemotherapy of Tuberculosis

1326

this method of treatment is not being more closelyinvestigated in this country by controlled clinicaltrials. The rapidly accumulating evidence, mainlyunpublished, of the safety and efficacy of long-continued rational chemotherapy with proven com-binations of drugs may make such a trial more

acceptable. Three years ago, when isoniazid arrived,the idea of using drugs for as long as an artificialpneumothorax would have been much frowned onin this country: "physician acceptance" may nowbe better.

Reserpine and the Nervous SystemRESERPINE, which first aroused interest as a remedy

for hypertension, is now increasingly used in psychi-atry. In several disorders, notably schizophrenia, itis widely credited with valued tranquillising effects ;but a few controlled studies 1 2 induce a more criticalattitude towards its usefulness in psychoneuroses.Research is proceeding along two parallel paths. Onthe one hand, clinicians are learning to define moreprecisely the effects of the drug, and to decide whattype of patient will respond favourably. At the sametime, experimental pharmacologists have been study-ing its intimate actions on nervous structures, andtheir findings not only help us to understand its actionsbut lead to new ideas about organisation within thenervous system.3Many - of the effects of reserpine-hypotension,

bradycardia, diarrhoea, miosis-suggest an action in theautonomic nervous system, and BEIN 4 first put forwardthe view that the drug depressed the central controlof the sympathetic outflow in the hypothalamus.An extension of this concept by SCHNEIDER 5 indicatedthat the prime action was not direct sympatheticdepression, but rather blockade of those afferent

impulses which otherwise provoked efferent sympa-thetic discharge. The tranquillising effect of reserpine,and the development of parkinsonism after large doses,suggested an additional site of action outside theautonomic nervous system. BEIN failed to demon-strate any effect of reserpine on peripheral nervousstructures ; but SC]EINEMER gave very large dosesof reserpine to cats (doses comparable to those whichinduce parkinsonism in man) and succeeded in show-ing that such doses increased the knee-jerk response. 6This effect was due to facilitation of the passage ofimpulses across monosynaptic pathways in the spinalcord. Further evidence that reserpine acts in otherparts of the nervous system came from the demon-stration that it could lower the threshold to con-vulsive seizures in mice stimulated by electricity.More information about the ability of reserpine tofacilitate nervous processes emerged from a study ofits characteristic sedative or tranquillising property.Though reserpine usually causes drowsiness, it doesnot induce narcosis, and persons apparently asleepunder its influence can be easily roused. Electro-encephalographic records in rabbit, monkeys,9 and1. Davies, D. L., Shepherd, M. Lancet, July 16, 1955, p. 117.2. Folkson, A., May, A. R. Brit. med. J. Nov. 5, 1955, p. 1121.3. Bein, H. J. Ann. N.Y. Acad. Sci. 1955, 61, 4.4. Bein, H. J. Experientia. 1953, 9, 107.5. Schneider, J. A. Amer. J. Physiol. 1955, 181, 64.6. Schneider, J. A., Plummer, A. J., Earl, A. E., Gaunt, R. Ann.

N.Y. Acad. Sci. 1955, 61, 17.7. Chen, G., Ensor, C. R., Bohner, B. Proc. Soc. exp. Biol., N.Y.

1954, 86, 507.8. Rinaldi, F., Himwich, H. E. Ann. N.Y. Acad. Sci. 1955, 61, 27.9. Schneider, J. A., Earl, A. E. Fed. Proc. 1954, 13, 130.

man 10 showed that sleep patterns did not appear inthe tracing after full doses of reserpine. This is in

sharp contrast to the changes induced by barbiturates.In the normal animal, tactile or auditory stimuli

applied during sleep produced characteristic changesin the electro-encephalogram. This " arousal pattern

"

could also be induced by electrical stimulation of themedullary reticular formation. In the curarisedrabbit 8 asleep under the influence of barbiturates,progressively stronger tactile and auditory stimuli andelectrical stimulation of the reticular formation were

required to produce arousal changes in the electro-encephalogram, and the pattern so induced was itselfabnormal. After reserpine in doses up to 1 mg. per kg.the " sleep pattern " was not seen, but the arousalresponse was produced more easily than in normalsleep, and the threshold of electrical stimulation of thereticular formation was lowered. With larger dosesof reserpine the electrographic pattern of alertnesswas continuously present, replacing the normal rhythm.Thus reserpine facilitated the brain-stem arousalmechanism. Although these findings do not explainwhy reserpine causes drowsiness, they demonstratehow the sedative effect of reserpine differs from thatof barbiturates. It is also known that electricalstimulation of the brain-stem reticular formation inanimals can produce a rhythmically alternating tremorwhich is abolished by atropine. RiNALDi andHiMWiCH 8 suggest that the capacity of reserpine tostimulate the reticular formation may underlie the

parkinsonism produced in man. The facilitation ofconvulsions 7 is another indication for care in theuse of reserpine, and increased frequency of seizureshas been noted in epileptics treated with the drug.12Reserpine competitively antagonises phenytoin 13 andthe two drugs should not be given together. Par-ticular care is also needed when patients under treat-ment with reserpine are given electroconvulsion

therapy.The physician treating hypertensive patients with

relatively small doses of reserpine will be concernedabout the mental side-effects of the treatment.14 Themechanism of this effect can still only be guessed atin terms of facilitation of nervous transmission withinthe central nervous system. More clinical informationis now available.15-19 Serious mental effects are

likely in about 5% of patients under treatment withdoses of the order of 1-2 mg. of reserpine daily, orequivalent amounts of whole-root preparations. Itseems that treatment must last two months or morebefore the effects appear. Patients previously in goodmental health can be affected but mental changes arecommoner in those who were previously unstable.19Recovery is the rule but is often slow. The poten-tialities for good and for ill of rauwolfia alkaloids havenot yet been fully explored, and much remains to belearned about what reserpine does in the nervous

system.10. Monroe, R. R., Heath, R. G., Mickle, W. A., Miller, W. Ann.

N.Y. Acad. Sci. 1955, 61, 56.11. Jenkner, F: L., Ward, A. Arch. Neurol. Psychiat. 1953, 70, 489.12. Zimmerman, F. T., Burgemeister, B. B. Ann. N.Y. Acad. Sci.

1955, 61, 215.13. Chen, G., Ensor, C. R. Proc. Soc. exp. Biol., N.Y. 1954, 87, 602.14. See Lancet, Aug. 13, 1955, p. 330.15. Tweedy, P. S. Ibid, July 30, 1955, p. 249.16. Macarthur, J. G., Isaacs, B. Ibid, Aug. 13, 1955, p. 347.17. Miller, J. C., Pryor, W. W., Gibbons, J. E., Orgain, E. S.

J. Amer. med. Ass. 1955, 159, 836.18. Schroeder, H. A., Perry, H. M. Ibid, p. 839.19. Achor, R. W. P., Hanson, N. D., Gifford, R. W. Ibid, p. 841.