Modern Malaria Remedies

By Dr. Adrien Albert, Commonwealth Research Fellow attached to the Department of Organic and Applied Chemistry, University of Sydney. Copyright.

THE RECENT report of an outbreak of malaria in Sydney, affecting several survivors from the “Rangitane”, will come as no surprise to those who know the part of the Pacific where these brave people were marooned. Emirau is indeed favoured by Plasmodium- carrying mos quitos, and medical guardians of the 500 castaways were doubtless prepared for an outbreak of the disease, once the ten days’ incubation period had passed.

Although the expected symptoms were not complained of, it is unlikely that the authorities were lulled into any false sense of security, since an unsuspecting and considerably distracted survivor would easily overlook the first evidence of malarial infection—believing it, if mild, to be a “cold”, and attributing to “sea

sickness” any attack of vomiting.

Moreover, people contracting malaria within the tropics, and passing at once to temperate regions, are well-known to experience a lag in the development of symptoms. In fact, as far back as 1875, cases were recorded of patients, who had not been exposed to mosquitos since the previous summer, developing their first symptoms in spring. Lags of this kind are most common in benign tertian malaria, which makes it almost certain that the present victims are infected with the parasite corresponding to this form.

Survivors to have Synthetics AS IT is understood that the Common wealth is sparing no expense to give the survivors the most speedy and permanent cure known—namely, treat ment with the synthetic anti-malarials— it is interesting to trace the history of these comparatively new drugs, which have to so large an extent, replaced the traditional remedy, quinine.

As is well known, quinine is expensive, because in harvesting the bark of the cinchona tree, the plantation must be felled and much time is lost before the stump burgeons into robust growth. In deed, some planters prefer to uproot the trees and make use also of the less valuable root-bark, rather than to wait until coppicing develops a fresh crop of

marketable bark. . .

The chemical structure of quinine has been known for many years, but all ef forts of scientists to prepare it by arti ficial means have been in vain. For that reason, workers in the field of medical chemistry are always eager to discover some substance as effective as quinine one that could be prepared synthetically, thus rendering dwellers in the tropics independent of the vagaries of crops and of the foreign policy of nations who raise these. , . , .

Germany, in particular, busied herself with this work, realising that tropical colonies must eventually belong to that country which can wage war without falling victim to the diseases prevalent there. This research was entrusted to four particularly skilled workers: Schule mann, Schonhofer, Wingler and Roehl, and it ended in 1926 in the discovery of plasmoquine, a synthetic chemical whose raw materials are benzol, derived from coal-tar, and ethylene, which is the waste-gas obtained in cracking petroleum for motor-spirit. . . But it must not be imagined from con sideration of these humble, starting materials that making plasmoquine would be “a nice business proposition’. Indeed, the extensive processing called for must account for a very considerable pro portion of the current selling price.

Hard to Make ALTHOUGH almost too technical to be referred to in a popular account, such as this, the stages m the syn thesis of plasmoquine are worth citing, if only to afford an impression of their utter complexity. .

First of all, the ethylene gas is treated with “Tropical Bleach”, giving a liquid, epichlorhydrin. The latter is warmed with diethylamine (often obtained as a by-product in explosives complex product is condensed with acetoacetic ester, a fragrant hqmd ob tained from alcohol and acetic acid by means of the explosive metal, s o. dl um.

This same metal, whose important de fence uses cause it to disappear Periodi cally from the market, is also needed to

bring about the reaction now being considered. The product so obtained has to be boiled with sulphuric acid and is then reduced with hydrogen generated from acid and a metal, after which it must be carefully dried and treated with the fuming sulphur compound called thionyl chloride.

The net result is a highly alkaline liquid usually referred to as “the basic side-chain” of plasmoquine and more cor rectly as l-diethylamino-4-chloropentane.

But that is only half the story; for the benzol must be just as tediously fabri cated until it becomes amino-methoxy quinoline, to which the “basic side-chain” is chemically linked.

The product, plasmoquine, was found to cure birds experimentally infected with malaria, and so was recommended for the treatment of human malaria, in the belief that it would take the place of quinine. The results obtained were at first disappointing, until it was realised that the proper use of plasmoquine was to supplement and not to supplant quinine therapy.

The fact is that, whilst quinine acts on the schizonts (that is the form in which 90 per cent, of the parasites exist inside the body) plasmoquine acts on the para sites’ sexual forms, which are responsible for the actual transmission of malaria.

Hence a more complete cure is obtainable with plasmoquine plus quinine, than with either separately.

Atebrin and Quinine Compared A TRUE substitute for quinine was found, however, in 1932, when Mauss and Mietzsch. of the Bayer Com pany, announced the discovery of atebrin, a yellow substance which has since become of the very greatest importance.

In the synthesis of atebrin. the same alkaline liquid is used as a “basic side chain”, but a nucleus of terrific com plexity, derived from a well-known series of yellow dyestuffs, replaces the simple quinoline nucleus of plasmoquine.

Right from the start, atebrin has been

outstanding as a drug for the effective handling of the malaria problem. Its principal advantage over quinine is the freedom from toxic effects experienced by patients who are taking a course of treatment. The headaches, nausea and ringing in the ears, so well known in quinine medication, are completely absent when atebrin is used. As for its efficiency, compared with quinine, the 1933 report of the Malaria Commission of the League of Nations may be quoted:— “Quinine and atebrin seem to be about equally effective for the treatment of attacks of tertian and quartan malaria, but in malignant tertian, atebrin in un doubtedly superior to quinine/’

Atebrin, however, suffers from one dis advantage: It forms a most indigestible combination with plasmoquine, and, whilst quinine and plasmoquine may be given simultaneously with good results, several hours should elapse after a course of atebrin treatment before plasmoquine is given to rid the now schizont-free blood of the remaining sexual forms.

This warning is worth emphasising, as tablets containing both drugs are oc casionally seen. To-day, the following prescription is widely used, and produces quicker and more permanent cures of malaria than were ever obtained by the use of quinine: 0.1 gramme of atebrin is given three times a day for seven days, followed by 0.01 gramme of plasmoquine three times a day for four days.

Various Brands WHEN these remedies were first an nounced in Germany, their chemical composition remained secret. Later on, a group of Russian workers disclosed their true nature. To this very day, any chemist wishing to prepare a batch of atebrin for experimental purposes is ob liged to read, if he can. the outlandish hieroglyphics in which Russian journals continue to be printed.

It is a matter for congratulation that supplies of these vital drugs are still coming forward in wartime. The original

atebrin and plasmoquine are being made in the USA, whilst an English firm is preparing these drugs under the names of Quinacrine and Praequine respectively.

Atebrin has been adopted by the British Pharmacopoeia as an official drug under the name of Mepacrine, and it is most likely that this non-proprietary name will come into general use.

For the treatment of severe cases there will be Mepacrine injections. At present, the Drugs Sub-Committee (of which I am a member) of the Australian As sociation of Scientific Workers is going into the possibility of producing these vital drugs in Australia.

Prophylaxis IT WOULD probably disappoint Islanders if I were to close this article without some reference to the prevention of malaria.

Actually, whether or no this disease can be prevented by medication is a question that has given rise to much controversy.

However, it is now generally admitted that no known drug can greatly reduce the likelihood of one’s catching malaria, but that it is possible, by regular dosage of quinine or atebrin, to experience only mild symptoms when the disease is even tually contracted.

Whether a continuous or intermittent course of prophylactic treatment is ad visable, or whether it would be less strain on the physique to run the risk of an occasional attack of malaria, can be decided only after consultation with a medical man who is well acquainted with local conditions.

Rev. E. A. Clarke, of the Methodist Mission in Papua, has retired, because of ill-health, and at present is in Adelaide.