The Therapeutics of the Cinchona Alkaloids
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CHOPRA. 441 Dec., 1922.] THERAPEUTICS OF CINCHONA ALKALOIDS: does not become re-infected during this time. A large number of cases after leaving the tropics Articles. are generally cured within a couple of years, cases which Original though one comes across may persist for five years or more. ' Natural cures are therefore brought about by ~^THE THERAPEUTICS OF THE excessive gametocyte production. A second fac- CINCHONA ALKALOIDS. tor also comes into play and that is the senility of the about resi- Bv R. Isi. CHOPRA, m.a., m.d., (Cantab), gametocytes brought by long ) in countries. I.M.S., dence non-malarious Gametocytes MAJOR, stomach of can only multiply in the anophelines Calcutta School Professor of Pharmacology, of Tropical and unless they leave the host under favourable Medicine. conditions, they die or are destroyed in the spleen. Artificial cures are the adminis- PART II. produced by tration of certain alkaloids of cinchona baric, which act by destroying the asexual parasites, The Cinchona Alkaloids in Malaria.?Malaria gametocytes being little affected. Two main is of all diseases, the greatest source of sickness factors are here chiefly concerned, vis., the rate in tropical and sub-tropical and invaliding of of parasites and the percentage the Great War it was respon- multiplication climates. During of each brood destroyed. It is known that a tremendous loss of effective man- sible for tertian parasites multiply at the rate of In this country there are few places malignant power. 8-12 merozoites in 48 hours and are vulnerable where it attains such a marked degree of inten- to the action of quinine, whilst the benign tertian and virulence as, for instance, in South Italy sity forms 16-24 merozoites in the same the disease is so that parasite or Salonica, yet wide-spread with more in period and is destroyed difficulty. That India ranks as the most malarious country this difference in the rate of multiplication is not world and this is amply borne out the the by the factor concerned is evident from the fact statistics. The thorough study of the action of only that the parasite, which forms 8-12 mero- the cinchona alkaloids is therefore of vital quartan import- is resistant to in zoites in 72 hours, very quinine. ance to every medical man this country. The percentage of each brood destroyed by Binz, ago, from his researches on long quinine administration of these alkaloids is therefore an and the that the protozoa, predicted organism factor in cure. It has been calculated causing malaria belonged to the protozoa and this important that an adult man of 68 kilograms weight pos- was verified when the plasmodium was discovered sesses about billion red corpuscles, and Laveran: Examination of blood containing 25,000 by Ross found that in severe infections as many as malarial parasites on the warm stage of a 12 per cent, of these were infected with parasites; microscope in the presence of 1 in 10,000 quinine a total number of roughly 3,000 billion in- solution shows slowing, and finally arrest, of their giving fected R. B. Cs. When the parasites fall below amoeboid movements. If quinine is given by the 2,50 millions, i.e., one parasite in 100,000 mouth this inhibition and stoppage of movements erythro- cytes, which is the limit diagnosable by the also takes place, but generally not until a few microscope, they produce little or no symptoms. hours after The parasites become ingestion. one would suffi- lose their affinity for certain stains and Theoretically parasite multiply granular, to fever in three weeks' time and, die. The cinchona alkaloids are found not to ciently produce therefore, to get a complete cure every the in all stages of their develop- parasite attack parasites should be From clinical asexual are destroyed. experience ment ; as a rule it is the forms which one knows that in latent malaria a large number more vulnerable. of parasites can exist and multiply in the body The life of a parasite depends upon the life the without producing apparent symptoms. of its host ; if the host dies, millions of para- which lowers the of sites living in it die also. Conservation of the Any condition vitality the the latent life of the host is therefore of the utmost import- host will convert into active disease. for its own As the rate of destruction of ance to the parasite self-preservation. regards parasites, a we a dose of This is accomplished by decrease of the rate know that single quinine does not cure, but a series of doses have to be of multiplication or by formation of non-multi- given. In mero- the case of tertian infections plying forms such as gametocytes from malignant experi- ence the course zoites of the asexual cycle. The brake-like has shown that has to extend a action of the gametocytes on the asexual multi- over a month to effect complete cure. From an it would that the rate of plication rate in this way establishes equili- this appear destruction brium, which is beneficial, alike to the parasite must be below 100 per cent., otherwise a few would a and to its host. This is illustrated in untreated intravenous injections effect complete as cure. calculation it has been cases of malignant tertian infection, in which By found that the in the fever destruction rate is 95 as soon as gametocytes appear blood the per cent., otherwise the subsides. A patient suffering from malaria course of treatment would have to be prolonged therefore becomes cured of the disease after a for more than one month to effect a complete fairly long period, provided of course that he cure. In cases of benign tertian infections 442 THE INDIAN MEDICAL GAZETTE. [Dec., 1922. Rennie, Acton, Curjel and Dewey found that they are less resistant to quinine than are the even after a course of treatment lasting for four malignant tertian gametocytes. months only 50 per cent, of cases were cured. The method of administration is an important Our every-day experience of the treatment ? of factor in the rapidity of cures ; the intravenous malaria with quinine shows that it causes a rapid is the most rapid, next conies the intramuscular amelioration of symptoms in both malignant and and last of all the oral method. As regards the benign tertian types of fever and parasites dis- various alkaloids of cinchona bark, it has been appear from the peripheral -blood. According to definitely proved that amorphous alkaloids of the Ross this effect is due to reduction of the para- quinoidin type have little effect on the parasites sites from 3,000 billions or more?(febrile whilst the crystallizable alkaloids are the stage)?to 250 millions or less (afebrile stage). chief active principles and of these the rate of Under such circumstances the destruction most effective are cinchonidine and quini- by quinine of benign tertian parasites should be dine. Sometimes it happens that during about 90 cent. These workers at per Dagshai the course of treatment, parasites reappear found the cure rate to be, after one month's treat- in the blood or symptoms become active ment with quinine 20 per cent., with cinchonine again. This means either that the patient is 40 per cent., with cinchona febrifuge 50 per cent, avoiding treatment, or the interval between the and with cinchonidine and quinidine 60 per cent. doses is too long, or the alkaloid is not being Thus the last named alkaloids must cause a absorbed. I have never come across a case of greater percentage of destruction of each genera- benign or malignant tertian in which the asexual tion. As the rate of multiplication of benign forms did not disappear from the peripheral tertian parasites is twice that of malignant tertian, blood after administration of proper doses of the treatment should be carried on for two months quinine. instead of one as in the former class of cases. Hozv quinine acts.?As has already been Phases of cure.?In the production of artificial pointed out, Ramsden's researches have shown that cures several factors have to be taken into con- when quinine is injected intravenously, 90 sideration. The immediate effect of giving the per cent, of it disappears from the blood in one minute. alkaloids is to cause a rapid disappearance of King and Acton experimentally esti- asexual parasites from the peripheral blood and mated the concentration of quinine in the blood. relief of symptoms. Too much importance Fifteen grains of the alkaloid were taken on an however should not be attached to the picture empty stomach, 5 c.c. of blood was removed from presented by the peripheral blood, as this gives a vein and the quantity of alkaloid estimated us little indication of what is happening in deep every hour. They obtained the following re- seated foci such as the spleen. The curative sults :? effect varies with the particular alkaloid used and Time of Quinine con- . Percentage the of In examina- centration in ... of dose species parasite present. malignant tion. blood. Quantity. takgn tertian infections occurs in the schizogony deeper 1 hovr afte 1 in 150,000 33 mgm. 3*3% vessels and the schizonts, which are adhesive, ingestion. 2 Do. form clumps and block the smaller vessels of the 1 in 187,000 27 ? 27% 3 Do. 1 in 22 ? brain and intestines giving rise to pernicious 225,000 2-2% Administration of causes the con- symptoms. quinine Ordinarily it is very difficult to bring the of within 24 disappearance trophozoites hours centration in the blood up to 10 mgms. per litre; after the first dose, but gametocytes if present the highest figure obtained experimentally being are not affected at as have been all, they found 16.5 mgms., which was associated with very severe to exist for as as com- long forty days after symptoms of poisoning.