Sept., 1947 J TREATMENT OF RELAPSING MALARIA: DESHMUKH 511

up to the expectation. But it soon became Articles clear that they did not control relapse, and Original also that they carry with them a danger of toxicity. Arsenic is notorious for causing to TREATMENT of relapsing malaria damage liver, kidneys and brain. When pregnancy complicates malaria, the use of WITH SPECIFIC ANTIMALARIAL quinine and arsenic may be particularly risky DRUGS IN COMBINATION WITH and one is on the horns of a dilemma as regards PENICILLIN the satisfactory treatment in such circumstances. The writer's experience of arsenicals in By P. L. DESHMUKH, m.d. (Bom.), malaria has been borne out other workers F.C.P.S. by D.T.M.\& II. (Lond.), and their findings in large-scale experiments Poona Sassoon Hospitals, given below will help to dislodge from the minds It must be admitted that even with quinine of the clinicians any lingering faith in arsenic and the synthetic antimalarial drugs like as an ideal antimalarial drug. atabrine, mepacrine, etc. (henceforth called Professor Blacklock (1944) has pointed out specific antimalarials ' for the sake of after long studies at the Liverpool school that tee brevity) treatment of malaria is still very unsatis- though the immediate effects of arsenic in factory. The recognized failure of the specific relapsing malaria were striking, the ultimate antimalarials singly or in combination to control results were disappointing in that practically relapses materially is a matter of great all cases relapsed even after full arsenical concern. A great variation is observed in the treatment. Thus, arsenicals though immediately mterval that may before the occurrence effective against vivax parasites do not eliminate a elapse y relapse. The period is known to extend the liability to relapse. It is also important to from a few days to several years, but for all recognize that the effect of intravenous arsenic practical purposes it is taken as four months. is entirely confined to vivax infection; so that, 1 Sometimes in the absence of a relapse the its usefulness in treatment is limited. Arsenicals lrifectivity of the blood is demonstrated after may have a use in special cases but would appear many years by the appearance of malaria in a to find little place in routine treatment \ Person transfused with the blood of a once 67 cases treated with Malarial Kay (1945) reports patient (Jewish Med. Assoc., 1945). atabrine and mapharsen combination. There is of ' Adler of Palestine opinion was a of 71.6 per cent cases and the mean professorhat, relapse Plasmodium once acquired cannot be got time of relapse interval was shorter than with of, a fact on which amount of quinine atabrine alone. Thus, mapharsen is of no administered has no value as an to atabrine in the ^ bearing practical adjuvant is, sometimes, difficult to check acute treatment of relapsing tertian malaria. exacerbations of malaria with the specific anti- The remarkable activity of the sulphonamide malarials. This is attributed to the difference in bacterial infection led to their ln the compounds strains of the Plasmodium, some being being tried in malaria. After experience with ^ofe resistant to the specific antimalarials. This prontosil (Editorial, 1939), Niven concludes resistance may be natural or acquired. Some that ' has lethal action on although prontosil _ may be more virulent than has no in ethers.grains perhaps the malarial parasite it place practical The difficulty becomes greater when treatment of malaria, owing to its low efficiency, malaria. Pregnancy complicates . possible toxicity and relatively high cost'. ,*he of the antimalarials when toxicity specific The suggestion that sulphonamide derivatives used in full doses over also long periods be able to relapse in malaria where Presents a in which might prevent problem the treatment the infection is already by cannot be The of the clinically suppressed ignored. magnitude a course of one or more of the specific Problem can be assessed from the numerous previous antimalarials, encouraged and others clinical reports of toxic effects of antimalarial Coggeshall to try in the army. They rugs in the medical (1945) sulphadiazine, journals. treated 33 of vivax infection with sul- Ihe general dissatisfaction with the patients specific for two months after the Antimalarials has served to the phadiazine immediately ance emphasize import- clinical were controlled by the specific of new methods of treatment in symptoms developing antimalarials. Follow-up three months later jnalaria. Below we shall discuss some of them thus briefly. showed 16 or 48.5 per cent had relapsed, that has no value Treatment of malaria with demonstrating sulphadiazine in arsenicals, singly in in vivax infection. ?r combination with the preventing relapses specific antimalarials, treated 20 cases of Is relieved as a Coxon and Hayes (1946) by many definite advance in the in malaria with sulphadiazine with relapses one jeatment (Stewart, 1945; Dao, 1945). The writer was month. 1 also, in the earlier part, greatly Gross has suggested the use repressed by the treatment when he found on Recently, (1947) for the of several occasions that it was able to check the of male hormones prevention relapses on which he acute attacks when the anti- in malaria. The rationale bases quickly specific "far from malarials alone failed to do so or did not come the treatment appears convincing. I 512 THE INDIAN MEDICAL GAZETTE [Sept., 1947 have no experience of hi3 treatment but I some action on the mysterious cycle of the seriously doubt whether the treatment will be parasite in the internal organs. In all 6 cases advisable in female patients in view of the were treated with success on this line of treat- possible hormonal effects on the secondary sexual ment. The following is the report of two typical characters. cases so treated : Recent world war has given a great impetus to the research in the therapeutics of malaria. Case 1 to cure the Pacific vivax infection was Difficulty Mrs. S. J., aged 35 years, four months' and new chemicals came on very disconcerting, pregnant, came under observation for fever with the field for clinical trial. are some Following rigors of 15 days' duration. The fever rose every of them : It was found to be less Chloroquine. day to 103 to 104?F. with rigors and came down toxic and more effective than quinacrine against with profuse perspiration. There was a the It is useful in the history Plasmodium. curing of similar attacks one year back. Before but in the case of coming falciparum infection, vivax, under she was to have been to the interval between observation, reported it only tends prolong treated this attack two of it is to during by injections relapses. Thus, though superior quinine quinine and yellow tablets probably as an antimalarial in acute mepacrine. and quinacrine drug A blood film taken the showed 2 to it fails to control the due to during rigor attack, relapses 4 parasites in each field in various stages of vivax. This is believed to be Pamaquine. drug development, denoting clearly that the treatment useful in curing vivax infection. But the thera- given was not able to suppress the infection dose is so close to the toxic dose that it peutic and check the acute bouts. Spleen was is to use it in routine dangerous practice. two She was very anaemic so This is related to enlarged fingers. Pentaquine. closely pama- much so that a few steps made her breathless. It is as effective as and less quine chemically. The rapid development of anaemia can be toxic than the latter and holds a good promise judged from the fact that 15 days back she was to lead to even a still less toxic drug which may well and An of be useful for routine treatment. Paludrine. It is working. injection quinine bihydrochlor gr. vi was given in one buttock too to an on the of early express opinion efficacy and two lac units of in 6 c.c. of normal this but it is believed that it will not control penicillin drug saline were on the other intra- vivax given buttock, relapses materially. muscularly, in the The It is believed that the more morning. temperature generally rose to 100'F. that and came down the treatment of the acute attack only evening thorough by to normal in two hours. Next the the less is the morning only specific antimalarials, likely the dose of was There was occurrence of the This is not penicillin repeated. relapses. assumption no rise of that Third the of and temperature evening. justified by experience Hughes both and were Bomford in West Africa. treated morning quinine penicillin (1944) They as on ' repeated the first day. For the next 5 a series of cases in the 1,200 army thoroughly' days mepacrine tablets were given twice a day. with the antimalarials and after a specific None of the were repeated thereafter. that1 the return cases were drugs follow-up they report Further treatment consisted only of iron mixture no less numerous than anyone else's even after a " " and liver extract injections to combat anaemia. thorough treatment.'. Blood films examined at intervals Another belief is that can fortnightly prevalent relapses did not show any There is no be avoided the constant use of atabrine or parasites. by recurrence of fever to the present i.e. four Such a use of the anti- day, quinine. specific months after. malarials, after all chances of re-infection are will insure freedom from clinical excluded, only Case 2 symptoms as long as taken. They do not cure. If relapses cannot be controlled, the rational Mr. S. V. K., aged 24 years, came for therapy should consist of treatment of relapses repeated attacks of fever with rigors for the last six off on. The fever was as they occur rather than continuous suppression months and checked time the antimalarial by medication. Thus, there is yet no drug or every by specific When he came method of treatment that can be relied on to drugs. under observation he had terminate the malarial infection. enlarged spleen, anaemia and his blood film With a view to finding a treatment that will showed benign tertian infection. He was treated check the acute attack and also control the with injections of quinine and penicillin and relapses the writer decided to try the effect of mepacrine tablets as in the previous case. For quinine in conjunction with the antibiotic the last three months he has no recurrence of blood penicillin. Penicillin is shown to have no action fever and the film does not show parasites. on inoculation (Hindle et al, 1945) malaria and Four other cases were treated similarly but Plasmodium is believed to be insensitive to have been followed only for six to eight weeks penicillin, still the choice of penicillin for without a relapse. therapeutic trial was guided by the fact that Discussion its potentialities are not yet completely known. It was thought that though it' may have no It is very premature to draw conclusions of effect on the peripheral parasites, it may show a definite nature from the meagre clinical Sept., 1947J TREATMENT OF RELAPSING MALARIA : DESHMUKH 513

of in material here. However, it will be delivery parasites the blood would lead to presented the a short-term as in found to be informative regarding infection, falciparum. Con- fairly in the a of in prospects of this combination treatment versely, prolonged period development at fixed tissues with of control of malarial relapses. It will, least, partial expulsion parasites in a in the blood stream, would lead to a be considered as deserving a trial larger relapsing infection, as in vivax. series of cases. In case 1, the outstanding of the acute attack The new concept also explains why even a feature was the early control ' ' treat- thorough treatment of the acute attack is not which was not checked the previous by able to The ment with of quinine and probably prevent relapses. specific anti- injection that malarials which are used act or mepacrine tablets. It clearly appeared commonly only on in mainly on the erythrocytic stage of the parasite. penicillin had a synergic effect quinine for ana The mesenchymal cycle is unaffected the terminating the malarial cycle once all, though four months at peripheral blood may be cleared of parasites. preventing relapse in the next to suppress the Thus the usual antimalarial treatment, however 'east. It also became possible ' oi thorough is not able to de-infect the fixed infection with only a small dose (gr. xn) as it was tissue cells and thus to the invasion of with the of prevent quinine help penicillin exeit the in the blood. Some ieared that in larger doses would erythrocytes peripheral quinine like are believed an abortive effect. drugs pamaquine, paludrine, etc., to act also on the of the Case 2 illustrates the influence of pre-erythrocytic stage clearly and hence their relative in the the combination treatment on the control of parasite efficacy control of 1 elapses in relapse. particular. The control of relapse when penicillin is used Mechanism of relapse and the probable action of in conjunction with the specific antimalarials penicillin can be explained by assuming that penicillin has will be an action on the The problem of control of relapse anti-parasitic pre-erythrocytic of the either or Sreatly elucidated if we are able to formulate stage parasite directly indirectly the metabolism of the ?ur conception regarding its mechanism. Experi- by affecting mesenchymal to cell which the (' host-cell' or ments in avian malaria have tended modify ' lodges parasite the of malarial cycle. According to lodger-cell '). theory will the of the modern concept (National Med. Congress, The theory explain appearance clinical malaria soon after the 1946) the cycle of the parasite in the human suppressive the is and the late host is far more complicated than simple therapy suspended, primary mvasion of the red blood cells. Fairley has manifestations after prolonged prophylactic shown that the disappear from the suppressive measures. sporozoites conclusive of blood stream in 30 minutes after inoculation by Unfortunately, evidence the pre- he blood in man is still to be found mosquito to reappear in the peripheral erythrocytic stage there is much to the the ninth and regularly thereafter. Thus, though support postulation jm day in of its existence. If our claims for usefulness of there appears to be a stage pre-erythrocytic oi treatment for control of Which the invade the endothelial the combination relapses parasites our further work and that of tissue cells where, it is presumed, are supported by mesenchymal other workers in the the of hey a distinct cycle of develop- field, problem undergo blood malaria will be solved once for all with before are discharged in the relapsing ment they rational stream. In blood they begin the so-called therapy. of the infec- ^ythrocytic cycle. The persistence Conclusions in the cells essentially con- mesenchymal From clinical material 'available to the recurrence of malaria. Thus, tihe scanty futes that has a mechanism of the relapse can be explained it is presumed penicillin synergic the on in the control of acute y.the periodic discharge of parasites in action quinine Peripheral blood from the fixed tissue cells. attacks of malaria. Penicillin is also believed is to a selective action on he mesenchymal tissue of healthy persons have the assumed pre- of the malarial The strong enough to have plasmodia constantly erythrocytic stage parasite. of the use of in with eaptiye. But as soon as the resistance penicillin conjunction quinine individual the hold of the mesenchymal and mepacrine is believed to be useful in con- lowers, with and the issue on the plasmodia becomes weaker trolling the acute attacks quickly ueir blood in the future. The.treatment is based consequent escape in the peripheral relapses This on that the usual anti- ,? bring on a recurrence of malaria. the rationale specific are control the stage and neory explains a number of problems that malarials erythrocytic stage of encountered in the study of malaria. penicillin controls the pre-erythrocytic in . tt explains the variation that is observed the malarial parasite. and relapse rates of the tertian malignant^ Summary orms. if well treated in Falciparum malaria, and their to discover a treat- he acute does not tend to relapse while Attempts futility stage, to ment to control in malaria so are infection is notorious for its liability relapses far, x^ax from literature. Taking relapse 1946). A short term of mentioned advantage (Editorial, of new of malaria cycle in a development in fixed tissues with complete the concept man, 514 THE INDIAN MEDICAL GAZETTE [Sept., 1947 combination treatment of malaria with quinine, mepacrine and penicillin is suggested which may be adequate to control the acute as well as the relapsing course of malaria. A report of two from the six cases treated on this line is given in full.

REFERENCES Blacklock, D. B. (1944). Brit. Med. J., ii, 671. Coggeshall, L. T., J. Amer. Med. Assoc., 128, 7. W. and I Martin, B., 1 Bates, R. D. (1945). I#!"*! |!~r I" Coxon, R. V., and Trans. Roy. Soc. Tro-p. Med. Hayes, W. (1946). and Hyg., 39, 207. Dao, L. (1945) .. J. Amer. Med. Assoc., 128, i i 693. Editorial (1939) .. Brit. Med. J., ii, 814. Idem (1946) .. J. Amer. Med. Assoc., 132, 1072. Gross, S. J. (1947) .. Indian Med. Gaz., 82, 65. Hindle, J. A., et al. New England J. Med., 232, (1945). 133. Hughes, S. B., and Brit. Med. J., i, 69. Bomford, R. R. (1944). Jewish Med. Assoc. J. Amer. Med. ^Issoc., 127, (1945). 1143. Kay, C. F. (1945) .. Ibid., 127, 984. National Med. Congress Ibid., 132, 235. (1946). Stewart, W. H. (1945). Ibid., 128, 831.