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. Even this concentration mencing treatment and are still able to undergo experimentally maintained for 48 hours failed to sexual in the stomach reproduction of the effect a radical cure in benign tertian malaria. anopheline. Acton has demonstrated that if the How then is the destruction of parasites brought source of supply of asexual parasites is destroy- about ? ed on to and the patient put ordinary tonic treat- The malarial parasites are Hccmosporidia and with no the ment, quinine whatever, gametocytes as far as is known only live in the red blood which are present either die of senility within a cells. The only time when they are free is when few weeks, or are destroyed by the cells of the the mature schizonts rupture, but the merozoites the body ; patient becoming completely cured. soon attach themselves to new corpuscles. It is In benign tertian infections the whole of the possible that quinine may destroy them by asexual cycle takes place in the peripheral blood, changing the erythrocyte in some way and making for the and when quinine is given the young trophozoites it an undesirable habitation parasite ; just -not an emetinized disappear within 24 hours after the first dose, as B. histolytica will ingest thus but the older ones and the developing schizonts R. B. C. The merozoites are prevented are not so can from the red cells and therefore must easily affected. They be seen up entering were true one would to 48 hours ; sporulation is not completely pre- perish. If this expect vented, and a slight attack of fever is often larger doses of quinine to be more efficacious noticed on the third day. The gametocytes dis- because of the special affinity of the erythrocytes absorb more than appear from the blood in 4-5 days, showing that for quinine, of which they CHOPRA. Dec., 1922.] THERAPEUTICS OF CINCHONA ALKALOIDS: 443

seated areas referred to, is 50 per cent, of that circulating in the blood, quinine effective ; in tertian irrespective of its amount : but this is not borne whilst benign infections, where schizo- occurs in the out by clinical experience. gony peripheral blood, it gives a cure rate of 20 cent. The parasites may be destroyed inside the red only per cells. It has been pointed out that the action No satisfactory explanation can therefore be of quinine is most potent on the young offered at present, and all that can be said is that parasites, less on mature asexual forms and relapses are due to incomplete destruction of the practically nil on the gametocytes and this would asexual cycle by quinine. to be inconsistent with this view. Parasi- appear Selective action oj~ the cinchona alkaloids. It ticidal take in the when action may place plasma, has been proved by Acton's researches that al- the merozoites are from one passing corpuscle though the crystallizable alkaloids affect both to the and this view is the other, supported by forms of parasites and cinchonine and quinidine fact that forms are more vulnerable to the young (dextro-rotatory), have a specially marked ac- action of these alkaloids. If the once parasites tion on the benign tertian forms, yet none of these entrance into the gain erythrocytes, schizogony alkaloids has any effect on the closely allied can in of this be completed spite quinine. If infection with halteridium in pigeons. were so quinine should be more efficacious when Until recently quinine was in during an attack of fever ; but this is not quite ^ employed given the treatment of all forms of but by clinical facts. malaria, Acton supported has shown that whilst it cures 90 From this it is evident that it is difficult to per cent, of tertian infections if understand how quinine cures malaria. All that malignant properly adminis- in tertian infections the cure rate -can be said is that the main action of the alkaloid tered, benign is not more than 18-30 per cent, after a two is on the young parasite forms, probably at the months' course. Better results are obtained with moment when they are passing from one erythro- cinchona which contains the total cyte to another, or when they are adherent to but febrifuge the cure rate to 50 have not actually penetrated the alkaloids, going up per cent. erythrocyte. From this one is in Quinine and for that matter some of the other justified concluding that there must be alkaloids other than alkaloids of cinchona bark, even in high dilutions, quinine present in the to which this enhanced cure inhibit the movements of malarial parasites, and bark, rate may be attributed. These other alkaloids were test- it is quite possible that they may prevent their ed and it was found that penetration into red cells and thus deprive them individually cinchonidine of nutrition. and quinidine in ten grain doses twice daily cured 60 tertian Cures and relapses.?It has been per cent, of benign infections after already a out one course of three weeks' treatment and therefore pointed that single dose or even a few these are the alkaloids most doses of quinine will not cure malaria and that! suitable for cure. The viz., and the destruction of the asexual cycle in man is a di-hydrides, hydroquinine hydro- are recommended because are gradual and fractional process. As it is not pos- quinidine they more stable are less sible to determine the exact time when each brood ; they readily oxidised out- side the ; and will be less is liberated the best plan is to give a continuous body presumably affect- a ed the tissues of the and so will treatment, extending over period of six to eight by body maintain their action than and weeks so as to affect 10 to 15 generations of para- parasiticidal longer quinine sites. Relapses, in benign tertian infection cannot quinidine. The salts the cinchona be due to insufficiency of quinine, as in some of of alkaloids.?We have seen that all the alkaloids of cinchona bark are Acton's experiments at Dagshai, it was adminis- di-acid bases and form two series tered under proper supervision for 3 to 5^ of salts, viz., neutral salts and acid salts. months ; and, in spite of this, 50 per cent, of of the cases relapsed. Ramsden attributes to Bi-hydrochlorides alkaloids are very relapses in water the of but freely soluble and for this reason are production quinine-resistant forms, ? for intravenous and this has been disproved by Acton's experiments employed intramuscular ; mono-chlorides are so at Dagshai, where he put a large batch of men injection not soluble. The are insoluble in on to quinine treatment, and if any case relapsed sulphates very water but are soluble in acid solutions and on the whole course was repeated. He found that fairly account of their are the percentage of cures remained constant with cheapness extensively used for oral administration. The acid from one to five courses of treatment. It is sulphates rank in their next to the acid obvious that if the resistance of either the parasite solubility hydrochlorides and are suitable for internal or the host had been altered there would certainly very medication. Bi-hydro- bromides are but do have been an alteration in the cure rate. very expensive, not give rise to cinchonism so and are It has also been argued that there are back- readily especially suit- able for with deafness. waters such as the spleen and bone marrow, persons They are also said to be less to where, owing to absorption of the alkaloids by depressant the medullary cen- tres when the tissues, quinine does not gain access and the given intravenously. Aristochin con- tains 96 cent, of parasites go on unhindered. Against per quinine base and is tasteless multiplying and this view is the fact that in malignant tertian does not upset the stomach. Euquinine is also infections where schizogony occurs in the deep- tasteless but contains only 50 per cent, of the 444 THE INDIAN MEDICAL GAZETTE. [Dec., 1922. base and therefore the dose should be double that cases in which the tongue is red, dry and cracked, of quinine ; it is very suitable for children. quinine is absorbed badly and should preferably malaria is non- Dosage.?In countries where be given intramuscularly. In cases of irritability existent, very small doses of quinine, such as of the stomach or bilious vomiting, which often are but such 2-3 grains, prescribed ; small accompany malignant tertian infections, quinine quantities are useless in controlling malaria and by the mouth is of no use whatever as it is not may give rise to idiosyncracies. In tropical retained by the stomach. countries the is to doses which are tendency give Provided that the circumstances are favour- too The of most clinicians in large. experience able, quinine is as efficacious as this is that the mouth in given orally by country thirty grains by injection as of 24 hours controls malarial fevers. If it regards prevention relapses. always Castellani has recommended that the should does either the method of administration is drug not, be given four hours before the expected attack, at fault or the is After the diagnosis wrong. i.e., at the time when sporulation is due. but from fever has subsided, ten twice a day grains during Acton's experiments it would appear that the the rest of the course is in most cases sufficient. best time to give it is one hour before, so that at The course should last at least one month in the the time of sporulation it will be circulating at case of tertian infections and two malignant its maximum, concentration. It should be re- months in tertian. 0.5 benign Intramuscularly gin. membered however that rupture of the schizonts or or every other day may be 7\ grains daily given is very irregular and goes on for 5 or 6 hours. in cases which do not take well the quinine by It has been amply proved by experience that the mouth. 7% to 15 grains should be Intravenously best way to give quinine is to give it in divided in cases. given urgent doses of 10 two or three times a to 2 is often grains day, j Synergists of quinine.?Quinine given hours after a meal. in combination with arsenic in the treatment of chronic forms of malaria, especially where the Intramuscular injections are very simple and and should be where oral adminis- attacks occur at long intervals, and the combina- safe employed tration is but it is advisable not tion is decidedly more efficient than is quinine contra-indicated, to this method as a routine The alone. In this country and also in East Africa adopt practice. necrotic and other effects of intramuscular in- many practitioners give injections of soamin or of the alkaloids are not other organic arsenical compounds in cases of jections cinchona perhaps malaria which have resisted quinine treatment. fully appreciated by the general practitioner. Acton and I carried out a series of A single injection of 0.5 gm. of novarsenobillon experiments on rabbits and to determine these can control paroxysms of fever with disappear- guinea-pigs effects. of in con- ance of the parasites from the peripheral blood Bi-hydrochloride quinine, the centration in which it is used in a day ; but they reappear and fever relapses clinically, produced unless quinine is also given. It is probable that within a few hours of injection very intense of the arsenic ion acts purely by increasing the vital- oedema the subcutaneous tissues and of the ity of all the tissues in general and of the blood- muscles around the site of injection. Hyperemia of the vessels was marked and forming organs in particular, rather than by any quite haemorrhages were also in the substance of the muscles. specific action on the parasites. present was in Methylene blue has been used in cases of The alkaloid base precipitated the tissues at the site of and the muscle and fascia quartan fever which do not react to quinine, and injection in a zone around were friable and necrosed. its combination with quinine is said to prevent large further attacks. These effects were well in evidence on the third but the cedema With the belief that the re-appearance of day, by the sixth day and haemor- malarial parasites in the peripheral blood, especial- rhages had disappeared completely, whilst the necrotic tissues were still visible on the tenth ly in chronic cases, renders them more vulner- day, able to the action of quinine, certain substances although a good deal of absorption had taken have been employed as activating or provocative place. in agents. For this purpose benzol doses of 0.1 Some authorities have laid stress on the danger to 0.5 mgm. in gelatine capsules has been given of producing tetanus by intramuscular injections. by the mouth, and injection of a few minims of Semple believed that migratory cells such as adrenalin has also been recommended, but the leucocytes pick tip tetanus spores from the efficacy of both is doubtful. They act by pro- intestine, lodge them in the necrosed tissue and a of the fever and ducing relapse re-appearance thus produce a nidus for the bacilli to grow. of in parasites the blood. This however is wrong as Acton has shown that Modes of administration.?The clinical condi- owing to the powerful negative chemotaxis set tion of the patient is the best guide as to what up, no migratory cells come anywhere near the method should be adopted for the administration site of injection and further, the necrosed tissue of quinine. The condition of the tongue is an is replaced by fibroblasts of the endomysium, excellent index to the state of the gastric mucosa. with a complete absence of migratory cells. The In ordinary attacks of fever the tongue is moist only thing which can cause tetanus is faulty and slightly furred, and quinine taken by the technique either in preparation of the solution or mouth will be rapidly taken up from the gut. In injection of it, Dec., 1922.] THERAPEUTICS OF CINCHONA ALKALOIDS: CHOPRA. 445

Intramuscular injections are considered by chloride given clinically undoubtedly cause some oral the and are for some to be superior to the route, with haemolysis probably responsible pro- idea that the drug has a stronger action on the ducing the rigors which often occur a few hours These parasites in the internal tissues, but this effect is after these injections. however soon pass no ill effects. probably due to greater certainty of absorption and off and produce of older writers advised that maintenance of a more gradual and prolonged Some the quinine supply of the drug into the circulation from the should not be given during fever and even now precipitated base lying at the site of injection, this idea is prevalent among the lay public. whereas conditions in the bowel are not favour- Needless to say it is only a fallacy perpetuated able, especially when fever exists. by ignorance. Cinchonine has been largely Quinine prophylaxis in malaria.?For prophy- bi-hydrochloride is used under the erroneous belief that pain and the lactic purposes quinine given with the idea that in the other effects locally produced are much less than by its presence blood it will kill the the with and also that its absorption is much sporozoites when injected by mosquito ; but quinine, to our we found that there is little evidence support this view. The more rapid. In experiments of the tertian are there was not much difference between the local "?ametocytes malignant parasite much less acted on are effects produced by the acid hydrochlorides of readily by quinine than was those of the tertian and therefore the two alkaloids and there no indication that benign there is more more chance of infected cinchonine was absorbed quickly. mosquitoes being from tertian cases Intravenous injections are most efficacious in malignant taking quinine. There has been much difference of producing immediate effects on the parasites and opinion should be expressed as regards the of on symptoms, but they only employed lately employment as a measure in serious and dangerous cases of urgency, where quinine prophylactic against mala- ria. Ouinine is the maximum effect of the drug is required to be very expensive nowadays and when on a attained at once, e.g., cerebral malaria. When given prophylactically large scale, as should in the case of the army in the cost is such symptoms appear intravenous quinine India, very <>reat. It be said at once that be immediately without loss of time and may it is absolutely given if it is in the hesitation. Many cases are lost owing to delay useless, given way it usually is, in without to seasonal variations in tem- on the of the medical attendant applying any regard part It is obvious that if this quick and efficient method of coping with perature. prophylactic doses In certain of the North- are to be of any use, they should be commenced "?rave symptoms. parts as soon as infections are to western Frontier Province, where malignant likely occur and when this is tertian infections of a very severe type prevailed, stopped danger over, and this can be determined the solutions of quinine for intravenous injections only by noting wet-bulb tem- and were as soon perature were always kept ready given readings. few first noticed the as symptoms appeared, and very Hodgson relationship between pernicious the and of cases were lost. temperature humidity the air in con- The injections should be given well diluted so nection with malaria. He observed that there was a marked increase in that they reach the heart in low concentration the incidence of malaria to a the and slowly. The best and the easiest way is fortnight after wet-bull) temperature had of a sterilized con- remained between certain and suck up the contents ampoule points, that this in- c.c. crease lasted as as the taining 0.5 gm. of acid hydrochloride in a 20 long temperature remained with normal saline and between these rise or fall syringe ; fill it up inject points. Any of wet-bulb above or below it slowly, taking at least 5 to 10 minutes. The temperature these two limits pro- duced a in patient should be kept lying down and the pulse decrease incidence of the disease. should be carefully watched. MoCarrison has Although the exact limits have not yet been work- ed pointed out that quinine given intravenously in out, they roughly correspond to the temper- more ature of 18? to large doses affects the respiratory centre 22?C., between which flagellation centre the of the male and fertilization of gravely than the cardiac and advises the female gamete which he much takes whilst the use of hydrobromides has found place ; temperature of insects such as less toxic than hydrochlorides. He prefers that mosquitoes corresponds with the wet- the injection should be controlled by blood-pres- bulb thermometer. Now if flagellation and ferti- in and lization do not take sure observations, especially weak patients, place, the parasite cannot its recommends the preliminary injection of ether undergo extra-corporeal cycle in the mosquito c.c. of for the of or the addition of O.o ordinary commercial transmission sporozoites to the human host. adrenalin solution to the quinine injection. Prophylaxis should therefore start when wet-bulb reads Experiments in vitro show that acid salts of approximately 18?C and stop when on it exceeds 22?C. quinine have a very marked hhemolytic action that the blood. Acton found even a 1 in 2,000 The second point to be considered is whether solution of base has no action doses should be quinine hemolytic prophylactic taken daily or 24 on washed corpuscles incubated at 37 ?C. for intermittently. A dose of quinine takes 41 hours but was noticed when hours to be eliminated from ; that haemolysis the body, and if a solutions of acid salts were employed in dilutions number of doses are taken, excretion continues 1 of solutions of for about a week. From of in 8,000. Injections bi-hydro- this one can reasonably 446 THE INDIAN MEDICAL GAZETTE. [Due., 1922.

conclude that continuous doses are the best and Stress has lately been laid on combining alka- that quinine should be taken daily in doses which lies such as carbonates or bicarbonates of sodium are effective in preventing relapses and can be and potassium with quinine in the treatment of borne without disturbance of health, viz., 10 to cases of malaria showing a tendency to hsemo- 15 grains after a meal. globinuria, the idea being that these drugs inhibit A third factor which should not be overlooked the haemolytic action of the cinchona alkaloids. is that benign tertian infections occur in the early This procedure has not yet received sufficient part of summer, whilst malignant tertian infections trial in this country. take at the end of it, extending well into the place References. winter to October and November. months, right up Acton of Tertian doses will therefore have to be taken (H. W.)?"Treatment Benign Prophylactic Fever."?Lancet, June 12, 1920. practically throughout the year, with the excep- Acton (H. W.)?" Researches on the Cinchona Al- tion of perhaps two or three mid-winter months. kaloids."?Lancet, Jan. 21, 1922. It would therefore that other Acton (H. W.)?"The behaviour of Paramoecium appear preventive caudatuvi towards the Cinchona Alkaloids." Ind. Jl. measures such as the use of electric mosquito nets, Med. Research, Oct. 1921. fans which keep off mosquitoes, etc., are prefer- Acton (H.W.)?"The Value of Quinine Prophy- able. laxis."?Ind. Jl. Med. Research, April, 1921. Acton action of on the Quinine and Blackwater fever.?There are (H. W.)?"The Quinine Pregnant Uterus."?Lancet, Jan. 1921. of which have a destructive many examples drugs Acton (H. W.) and King (H.)?"The Nephelo- action on the red blood cells and arguing from metric Estimation of Quinine in Blood."?Biochevt. Jl., this many authorities consider quinine to be, in Jan. 1921. Acton and some connected with the of this (H. W.), Curjel (D. F.) Dewey (J. O.) way, production "Diagnosis and Treatment of Benign Tertian and not borne out either disease. This however is Malignant Tertian Fevers."?Ind. Jl. Med. Research, by clinical history or animal experiment. Black- April, 1921. water fever is known to have existed in Brahmachari (U. N.)?"Blood-pressure during In- Europe travenous of Dec. was introduced. Injections Quinine."?Lancet, 25, before quinine Bi-hydro- 1920. has an chloride of quinine in vitro undoubted Dixon (W. E.) and others?"Quinine and its Related hasmolytic action on the erythrocytes, but such Alkaloids."?B. M. J., July 24, 1921. the of concentrations as cause haemolysis cannot be Dudgeon (L. S.)?"On Effects of Injections into the Tissues of Man and Animals."?Jl. attained in the blood with doses. Quinine therapeutic R. A. M. C., Jan., 1921. Some observers attribute the condition to lower- Jackson (D. E.), Friedlander (A.) and Lawrence ing of the osmotic pressure of the plasma by (J. V.)?"Experimental Investigation of Pharmacolo- Action of Amcr. Med. water to pass into the gic Quinidin."?Jl. Assn., April quinine, allowing through 22, 1922. which swell and Others erythrocytes, up rupture. Lane (C.)?"Malaria: A Critical Review."?Trop. say quinine sulphate is the exciting cause by its Dis. Bull., Feb., 1922. action on the corpuscles, whose stroma has been McCarrison (R.)?" Pharmacodynamics of Quinine." the malarial and ?I. M. G., Nov., 1920. injured by parasites hemolysins. Manson-Bahr (P.)?"Malaria in the Egyptian Ex- There is no doubt as to the existence of both peditionary Force."?Lancet, Jan. 10, 1920. malarial hemoglobinuria and of quinine haemo- Pratt-Johnson (J.) and others?"On the Action of Certain on Malarial but blackwater fever seems to be a Special Preparations' Parasites, globinuria, etc."?B. M. J., Jan. 15, 1921. definite entity and a specific disease due to some Ramsden (W.), Lipkin (I.J.) and Whitley?"On organism probably of the nature of a piroplasma. Quinine in Animal Tissues, etc."?J I. Trop. Med. and In certain of East Africa and on Parasit, Oct. 1918. parts especially Sollmann the northern of East (T.)?" Quinotoxin Myth."?Jl. Amcr. boundary Portuguese Medl. Assn., April 9, 1921. (Page 999). came across a number cases Africa, I large of of Waters (E. E.)?"The Value of Amorphous Cin- blackwater fever, which from microscopic chona Alkaloids in Malaria."?I-. M. G., March, 1913. examination of blood could be divided into two groups, though so far as clinical symptoms were concerned no differentiation was possible. In one group of cases malarial parasites were found in abundance in the blood, 10 to 15 per cent, of the red corpuscles being infected. In these in- jections of quinine were beneficial and quite a large number of cases recovered. The second group consisted of cases in which no malarial parasites could be detected in the blood and in these the administration of quinine did more harm than good and the patients usually suc- cumbed. Whether this condition was due to any specific infection or whether it was a later stage of the first group, when all the parasites had dis- appeared from the blood because of degenerative changes in the body of the erythrocytes, it is difficult to say.