Nov., 1922.] THERAPEUTICS OF CINCHONA ALKALOIDS: CHOPRA. 401

Original Articles.

~%HE THERAPEUTICS OF THE CIN- CHONA ALKALOIDS. 1/

PART 1.

By R. N. CHOPRA, m.a., m.d. (Cantab.), MAJOR, I.M.S.,

Professor of Pharmacology, School of Tropical Medicine, Calcutta.

I have written this paper as, although a great deal of work has been done recently-on the

alkaloids .of cinchona bark, 1 have not been able

to find a connected account of the modern views of their action and therapeutics from the general practitioners' point of view. Further, I have the privilege of being associated with Major H. W. Acton, i.m.sv whose classical researches on the

cinchona alkaloids are well known, in the :further researches which are now being carried out in

this School and have had the opportunity of dis- cussing these alkaloids with him, and this paper embodies his views.

The genus Cinchona, from which this most vain- able 'bark is obtained, is indigenous to South America and embraces 36 species of evergreen shrubs. They are all restricted to the eastern

slopes of the Andes, extending from Western Venezuela through Peru to Bolivia. At an alti- tude between 3,000 to 10,000 feet, these trees

flourish in a warm and moist climate, generally not forming forests or even groups, but attaining a considerable size, 'being as much as 100 feet in

height. The trees growing at a lower altitude contain little alkaloids. 1 he natives of these

parts had only an imperfect knowledge of the

febiifuge properties of the bark, as, although they gave it the name of

" Kinakina," or bark of barks,

they seldom used it. In 1639 the bark found its

way to Spain ; its fame soon spread to Italy and the Jesuits probably were chiefly instrumental in introducing it into France and England. Gradu-

ally the properties of the bark became more and more known, its use became extended and as the

only method of collecting the bark at that time was by felling the tree, fears were entertained that the supply of hark from South America would cease altogether. Attempts were then made to

transplant some of the species into other countries and a German botanist named Hasskarl was

commissioned by the Dutch Government on an

expedition, and he successfully brought plants and seeds by which plantations were started in Java. A few years later Sir Robert Markham was sent on a similar errand 'by the Indian Government and he succeeded in introducing Cinchona suc- cirubra, C. officinalis and some other species into India, and plantations were started in the Nilgiris

and in the Himalayan range near Darjeeling. The cinchona trees are now so extensively culti- vated in Java, and to a lesser degree in India, that the world is entirely independent of South America The Dutch soon realised the great com- mercial possibilities of these plantations and devel- oped the cultivation of trees and collection of the bark on a thoroughly scientific basis, thus making Java the most important cinchona area in the world. Most of the bark at present is derived from C. calisaya var. ledgeriana, which grows luxuriously in that island and has a very high quinine yield. It contains 6 per cent, of this alkaloid and in exceptional cases 10 to 12 per cent ? C. succirubra (red bark) yields 5 per cent of total alkaloids, of which 2 per cent, is quinine ; C. calisaya (yellow bark) has 6 per cent, of alkaloids, of which 3 per cent, is quinine ; and C officinalis contains 5 per cent, of total alka- loids, of which 3^ per cent, is quinine. C. suc- ciruba has proved to be the hardiest and most easily cultivated and is largely grown in India. It o-ives a high yield of total alkaloids 10 per cent. ? but the quinidine and cinchonine contents predominate over that of quinine. The cultivation of C. ledgeriana is, therefore, now being pushed forward in India. The trees possess the maxi- mum amount of alkaloid yield when they are

from 6 to 9 years old. The therapeutic effects of the bark are due to the alkaloids, of which quinine is the best known : other alkaloids, quinidine, cin- chonine and cinchonidine have until recently been little used in medicine. The bark is collected in the rainy season, when

it separates easily from the stem. The old method of felling the trees and stripping the bark was very wasteful, and Maclvor suggested removal of longitudinal strips 4 to 5 cm. wide at intervals, the trunk afterwards being protected with a cover- ing of moss, when a fresh growth takes its place ; this is richer in alkaloid contents. This process is known as " mossing and renewing." "

Shav- ing

" is only a modification of "

mossing," as here only a portion of the bark is removed by shaving, the remainder being left behind to protect the trunk. Another method of collecting is " coppic- ing," in which the tree is cut down to form a stool, and from this shoots arise which yield a very good quality of quill bark.

Composition of Cinchona Bark.?The finely powdered bark is made into a stiff paste with slaked lime, a sufficient quantity of water being added. The paste is dried and ex-

tracted with hot petroleum which dissolves all the alkaloids, and from this they are recovered by shaking with successive quantities of dilute sul- phuric acid. The alkaloids are dissolved in acid solvent and are precipitated by adding excess of caustic soda to neutralize the acid, and this con- stitutes the cinchona febrifuge, which is manufac- tured and issued by the Government of India in the form of tablets, each supposed to contain 3-1 grains of the alkaloids. According to MacGil- christ (1915), the average composition of

402 THE INDIAN MEDICAL GAZETTE. [Nov., 1922.

cinchona febrifuge prepared from C. succirubra bark at Mungpoo, is as follows :?

{Cinchonine ... 16*58%

Quinine ld'n6

7*40% Quinidine ... 23 83%

Amorphous alkaloids ... Grouped under

Quinoidin ... 29*12% Refuse, Moisture, Ash, etc.... ... 16*12%

The bark also contains, in addition, certain

acids, neutral principles, a volatile oil, gums,

starches, and colouring matter.. Since Pelletiere and Dumas first isolated quinine

and cinchonine, fourteen alkaloids have been dis- covered to be present in the bark, but most of these occur in very small quantities and from a therapeutic point of view one need only consider eight alkaloids which can be grouped in two

series :? A. The cinchonine series which include cincho-

nine and its isomeri'de cinchonidine and the hydro- alkaloids of the same, hydro-cinchonine and

hydro-cinchonidine. These alkaloids occur in cinchona and cuprea

barks, though the amount present shows great variations. They can easily be separated from the associated alkaloids, are diacid bases and form two series of salts, i.e., neutral and acid.

B. Methoxy cinchonine or quinine series which includes quinine and its isomeride quinidine and the hydro-alkaloids, hydro-quinine and hydro- quinidine. Like the cinchonine series they also form a mono- and bi-series of salts. Two closely related alkaloids cuprein and its

isomeride cupreidine and hydro-cuprein and

hydro-cupreidine have also to be considered, which are found in cuprea bark?Remijia pedunculata? along with other cinchona alkaloids. Both these alkaloids are hydroxy derivatives of cinchonine. Chemical constitution of the cinchona alkaloids.

?To understand the relationship between the different alkaloids found in cinchona

bark, a brief reference to the constitutional formula will be necessary. This has been now established by the laborious researches of Konig, Skraup and Rabe and is as follows:?

The alkaloidal molecule- is composed of two

portions, the quinoline ring on the left and the quinuclidine nucleus on the right, generally called the second half of the molecule. The two

portions are connected by an alcoholic grouping.

The quinine derivatives are formed by alterations in the three groups, methoxy, hydroxyl and vinyl groups. For example, cinchonidine differs from quinine in the absence of the methoxy group, O. CH3 and if the methoxy group is replaced by an (OH) radicle, we get cupreidine. A large number of insoluble esters of quinine

are prepared by substituting the II of the (OH) group by another group. Such compounds are

insoluble and therefore tasteless and can be easily administered, produce less side actions, though they are not altogether devoid of cinchonism. In

the stomach they remain unchanged, and 011 reach- ing the duodenum, split up into quinine base, producing in this way a gradual and somewhat weaker action. To this group belong aristochin (diquinine carbonic ester), eu-quinine (quinine ethyl carbonic ester), soloquinine (quinine sali-

cylic ester), and chenophenin (phenetidin quinine carbonic ester). The last two compounds exhibit the action of both the constituents, i.e., of quinine and salicylic acid and quinine and phenecetin. Hydro-quinine, from which most of the valuable hydro-derivatives are obtained, is formed by con- version of the vinyl CH : CH2 group into CH2 :

CH;i. In the laboratory they are prepared by pass- ing hydrogen gas through solutions of natural alka- loids in the presence of platinum. This change makes the alkaloids much more stable to the action of oxidising agents and according to MacGilchrist they act more efficiently in the body, as they are not so readily acted on by the tissues. The interesting point in connection with the

pharmacological action of the cinchona alkaloids and their derivatives is that from the piperidine ring they come close to nicotine, and their antisep- tic properties are mainly attributable to the pre- sence of a quinoline ring in the molecule. Attempts to synthesize quinine have so far met

with but partial success. By first preparing N. bromotoxins, then heating with alkali to produce ketones and reducing them, substances resembling cinchona alkaloids in constitution and having a toxic action on infusoria were synthetically pre- pared. Their toxicity on man is, however, very slight, and much more research is needed in this direction before success can be expected.

Stereo-isomerism of the cinchona alkaloids.? The researches of Major H. W. Acton, i.m.s.,

have shown the definite relationship which exists between the optical activities of cinchona alkaloids and their pharmacological action and it will not 'be out of place to say a few words about tjhe stereo-isomeric relationship of the different alkaloids. From the graphic formula of quinine given

above, it is evident that there are four asymmeteric carbon atoms in the molecule (marked 1-4) and it is also obvious that any substance with this formula should have 16 optically active isomerides, 8 of which would be enantimorphic or mirror image forms of the other 8. The number of those

actually known is very limited. Acton has

pointed out that since quinine is laevo-rotatory and

N

AA C2> CI-

CH,0.. (4) (3) ?CHOH?CH

Ch2

CH

w METHOXY GROUP

v HYDROXYL GROUP N

CO CH CH:ch2

VINYL GROUP

CH?

Quinoline ring. Quinuclidine (Second half) QUININE

Where R = H in cinchonine and cinchonidine OH in their hydroxy derivatives?Cupreidine and

cupreine. CH3O in their methoxy derivatives?quinidine and quinine.

R' = CH : CHj the vinyl group of the natural alkaloids. CH2. CHj in the hydro-alkaloids.

Quinoline ring. Quinuclidine (Second half) QUININE

Where R = H in cinchonine and cinchonidine OH in their hydroxy derivatives?Cupreidine and

cupreine. CH30 in their methoxy derivatives?quinidine and quinine.

R' = CH : CHj the vinyl group of the natural alkaloids. CH2. CH3 in the hydro-alkaloids.

Nov., 1922.] THERAPEUTICS OF CINCHONA ALKALOIDS: CHOPRA. 403

cinchonine is dextro-rotatory, quinine is not a

derivative of cinchonine. The true relationship is 'between cinchonidine, cupreine and quinine (with their hydro-alkaloids), which are all lrevo- rotatory ; and cinchonine, cupreidine and quini- dine (with hydro-derivatives), which-are all

dextro-rotatory. The action of these groups is

more marked in certain directions ; for instance, the dextro-rotatory alkaloid quinidine has been shown by him to have a greater destructive action on the benign tertian parasite than has quinine.

Pharmacological action of the cinchona

alkaloids.?To apprehend the rationale of the

therapeutic action of these alkaloids, it is import- ant to have a clear idea of their general pharma- cological action, and I will view it briefly, taking quinine as a typical example. The type of action is the same in case of all the alkaloids. The action of quinine on undifferentiated

protoplasm is quite characteristic. Very dilute solutions such as 1 in 20,000 to 50,000 destroy amoebae and paramsecia in a few hours; the activity of certain forms of non-pathogenic spiro- chsetae, spermatozoa and ova is inhibited at first

and finally stops. Certain protozoa are, however, not affected by quinine at all and some forms of life, such as salt-water amcebae and the spiro- chetes of relapsing fever, are able to flourish in a 1 in 500 solution. On bacteria quinine has a

markedly destructive action, 1 in 1,000 solution being effective against tetanus, streptococcus, pneumococcus, etc. Some of the newer deriva- tives of quinine, for example the cupreines, exert a powerful action on certain micro-organisms and this action as a rule increases as we go up the series from ethyl hydro-cupreine to iso-octyl- hydro-cupreine. Thus quinine in 1 in 1,000 will destroy B. tetanus, of ethyl hydro-cupreine 1 in

25,000 and of iso-octyle 1 in 60,000 and the same is true of streptococcus, staphylococcus, and

B. diphthcriac with some reservations. Ethyl hydro-cupreine, known under the trade

name of Optochin, has a very high degree of toxicity for the pneumococcus, a 1 in 400,000 solution having a destructive effect on this or-

ganism in vitro. This led to its trial in pneumococ- cic septicemia produced in rats and guinea-pigs; but the results were not conclusive. To get a

bactericidal action it was found necessary to igive 0.024 gm. per kilo 'body weight in 24 hours and for an average man this will mean a dose of just over H grammes. But when the pneumococcic condition is at its height, the toxins have already had time to affect the tissue cells and mere des-

truction of pneumococci ̂

will be of little value.

Doses of 20 to 25 grains in 24 hours render the blooid pneumococcicidal, 'but such effects of

quinine as contraction of field of vision and

amblyopia which are met with in therapeutic doses, are very much more marked in the case

of ethyl-hydro-cnpreine and even doses as small

as 8 grains have produced optic atrophy with per- manent blindness. This stopped the further

trial of this drusr in man.

Iso-octyl-hydro-cupreine or vuzin was ex-

tensively employed by the Germans during the war ;for disinfecting suppurating cases of gun- shot wounds, owing to its bactericidal action on

streptococci in very high dilutions (1 in 80,000). It was used in a strength of 0.1 gm. in a litre of

water and proved to be highly efficacious. Iso-amyl-hydro-cupreine has been found to

have a specific effect in Vincent's angina and it

may be useful in other forms of ulceration of

spirochetal origin, such as Naga Sore. We are

investigating the antiseptic properties of the

dextro-rotatory cupreildine compounds, and it is

possible that this series, being more active

pharmacologically, may ultimately give us the

means of coping with these different infections. Ferments.?Interference with the activity of

.ferments is a well marked property of quinine and its inhibiting action on the oxydases in blood

is well known. All the metabolic processes in

the body, whether of anabolic or katabolic nature, are decidedly inhibited and tissue waste and

energy production aie both retarded. Various digestive enzymes are affected to vary-

in<T extents according to the degree of concentra- tion of the alkaloids. Acton has studied the action

of cinchona alkaloids on these enzymes in vitro.

He found that the activity of ptyalin, the starch

digesting ferment of the saliva, was completely inhibited by the acidity produced by the acid salts but as the digestion of starches is over in 10 to 30 minutes, no interference will result if the

alkaloids are given half an hour after a meal.

Pepsin inhibition is more marked with the cin-

chonine series than with the cinchonidine series

and the inhibition is less when the iferment at-

tacks the protein, than when protein is first acted upon by the alkaloids. On tryptic digestion quinidine has a more powerful inhibiting action than quinine ; the action of erepsin is retarded

by the presence of a 1 in 5,000 solution of quinine

or quinidine. The deductions of practical im-

portance drawn from these experiments are that

as the inhibition of peptic digestion is bound to lead to deficient peptone formation, the time of administration of these alkaloids in relation to

meals is of the utmost importance. They should be administered when they can interfere least with the activity of enzymes and he suggests that they should be given when peptic digestion is com-

pleted, i.e., 1 to 2 hours after meals.

Muscle Quinine depresses the voluntary muscle and hastens fatigue. The contractions

of a frog's heart are decidedly weakened by 1 in 5,000 solution and 1 in 50,000 stops the heart in a few minutes.

Intestine.?Acton studied the action of quinine on isolated pieces of rabbit's intestine with a view to determine whether the attacks of diarrhoea

occurring in patients taking large doses of quinine ?were due to any action on the musculature of

the gut. He found that although in concentra- tions of 1 in 10,000 to 20,000, these alkaloids increased the amplitude and slowed the rhythm

404 THE INDIAN MEDICAL GAZETTE. [Nov., 1922.

of the intestinal muscle, such dilutions were

impossible to attain in the body. The diarrhoea is very probably due to an interference with

digestion both in the stomach and intestine.

Uterus.?Quinine has often been employed to

increase the force of contractions in the second

stage of labour under the belief that it favours the contractions of uterine muscle ; it is also be- lieved that given in large doses it has an ecbolic effect. It should be remembered that the high temperature, which often accompanies malaria

against which quinine is employed, may produce death of the foetus and evacuation of this organ. Acton performed some- very interesting

experiments on the pregnant uterus of rats and

guinea-pigs, by rapidly excising this organ and

placing it in a bath of Ringer's solution (with traces of MgCl2) and recording the contractions on a moving drum. The drug to be tested was

put in the bath and allowed to act directly on the excised organ. He found that such dilute solutions as 1 in 300,000 were without any effect, 1 in 150,000 only produced contractions under certain circumstances and 1 in 44,000, a concen- tration which can never be attained in the blood unless the patient was literally poisoned with

quinine, produced a tonic spasm of both the cir- cular and longitudinal fibres, which, if maintained, would kill the foetus. Concentrations of 1 in

150,000, such as occur in the blood normally after ingestion of quinine in moderately large doses, stimulate the intermittent contractions; if now some exciting cause is present, e.g., weak mem- brances or a patulous os, the membranes may rupture and labour be brought on in this manner.

In the treatment of pregnant women suffering from malaria, the temperature should not be allowed to go beyond 103? F., and quinine should be given in divided doses of 3 to 5 grains every two or three hours, till twenty grains are given. General measures to prevent abortion should foe adopted.

Cases of abortion from large doses of quinine are not infrequent in the first month of preg- nancy. though in a large majority of cases no

ill-effects seem to be produced, as it is given indiscriminately by practitioners in this country.

Effects on the blood and blood pressure.?If quinine in large doses is given intravenously to an animal, certain changes are noticed to take place in the blootd corpuscles. The leucocytes loose their amoeboid movements, become round and granular and diapedesis through the capillary walls ceases. Such concentration, however, can- not be attained in man with ordinary therapeutic doses, but the same type of effect is noticeable in the white corpuscles. Their number is also reduced to half the normal per c. mm. of blood or even less, lymphocytes being chiefly affected. This leucopccnia is often preceded by a preli- minary leucocytosis and lasts for several hours. On the erythrocytes, the acid salts of quinine

have a decidedly hsemolytic action in vitro and blackwater fever has been attributed by some

to the toxic effects of quinine salts on the red

blood cells. Quinine circulates in the blood as

quinine base and Acton has demonstrated that

strong solutions of quinine and quinidine base such as 1 in 2,000 of normal saline produce no haemolysis of washed red corpuscles in vitro incubated 'for twenty-four hours. In case of the acid salts, such as the bisulphate, there is faint haemolysis in 1 in 8,000 solution, but none whatever in 1 in 11,000.

Intravenous injections of strong solutions of acid salts are, therefore, highly undesirable and there is no doubt that the rigors which are often observed after such injections, are due to the

haemolysis which is produced. As a matter of fact injection of acid salts of quinine and other cinchona alkaloids, whether intravenous or intra- muscular, is not correct from a physiological point of view, as they always circulate in the blood as bases. They are preferred because they are very soluble and, therefore, convenient to

administer. Blood pressure is definitely lowered after

intravenous injections and Acton has pointed out that this depression is much more marked with the dextro-rotatory cinchonine series, quini- dine being the worst offender in this respect. Experiments show that it is ten times more toxic than quinine : and its effects are more prolonged and it should never be given by this route.

The action of quinidine on the heart has lately been the subject of much study owing to the beneficial effects it produces in auricular fibril- lation and arhythmia and it is generally believed that this action is produced by its depressant effect on the heart muscle, which reduces its

excitability to a point below that at which fibril- lation is possible and also possibly an atropine-like action on the vagus. It is usually given by the mouth in form of sulphate, 0.2 gm. being given on the first day and, if it is well borne, the dose is increased to 0.4 gm. two or three times a day, and this can he kept up for 5 to 8 days. In about 50 per cent, of cases the medication has no effect and these' are generally advanced cases of heart disease with extensive changes in the

rhyocandum. As the drug has a paralysing effect on the heart muscle, it should be given with caution and after a course of digitalis in cases of failure of compensation. Nervous system.?On the cerebrum quinine

has a tendency, though not so marked as other

antipyretics, to allay pain. In ordinary thera-

peutic doses, it has no effect either on the medulla or on the cord; but large doses depress these structures and the respiratory centre is especially attacked. On the peripheral nerves, the cinchona alka-

loids and their derivatives produce a slow and

prolonged abolition of sensation by direct effects on sensory nerve endings. Lately a good deal of attention has been paid to their local anaesthetic

properties and their potencv can be judged from the fact that whilst a 1 in 50 solution of cocaine

Nov., 1922.] THERAPEUTICS OF CINCHONA ALKALOIDS: CHOPRA. 405

hydrochloride will produce anaesthesia on the

cornea of a rabbit, the same effects can be

produced by 1 in 60 quinine hydrochloride, 1 in

100 hydro-quinine, 1 hi 1,000 et hyl-hydro- cupreine (optochin), and 1 in 1,200 of iso-amyl- hydro-cupreine.

Quinine is often combined with urea and is

used as a local anaesthetic. This combination increases its solubility and its power of penetra- tion into the cells, but the combination is decided- ly weaker and has to be used in twice the

strength necessary, when quinine alone is used. As a rule 0.25 per cent, solutions are quite effective.

Quinidine and cupreidine compounds also

possess anesthetic properties, though their action is somewhat weaker ; these are still under

investigation. The disadvantage of all the cinchona deriva-

tives over cocaine and its allied compounds is that the induction takes longer and they are more irritating and in stronger solutions may cause infiltration of the tissues and sloughing may result. They also irritate the conjunctiva and their action is not deep seated, otherwise they would be excellent anaesthetics for ophthalmic opera- tions.

Spccial senses.?Eyes. In toxic doses quinine produces contraction of the visual fields, diminu- tion in acuity, colour blindness, amblyopia and amaurosis. Ophthalmoscopic examination in

these cases shows contraction of the choroidal vessels and the retina looks pale and cedematous. In therapeutic doses it has little effect ? most of the visual disturbances in patients taking ordi- nary doses of quinine in malaria being due to

parasitic emboli in the retinal vessels.

Ear.?The common accompaniments, ringing in the ears and deafness appear to be chiefly due to congestion of this organ. In animals, such effects can be produced experimentally by giving large doses of quinine. Degenerative changes have also been noticed in the cochlear ganglia ;

chronic otitis media may be set up by long stand- ing congestion producing permanent deafness. When giving quinine to patients with middle ear disease, the possibility of its activating a quiescent condition may be borne in mind.

Metabolism.?This is affected by quinine in

very small doses in a most remarkable manner. There is a slight transient increase in the nitro- genous constituents of the urine, followed by a marked decrease especially in urea and uric acid. This is probably due to its effect on the digestive enzymes, which decreases the formation of

amino-acids and, therefore, diminished protein assimilation results. This would by itself decrease the katabolism of proteins in the tissues and lead to decreased heat formation : antipyretic effect. The use of quinine, therefore, in wasting diseases has a rational basis, as it tends to check

the excessive break down o-f proteins which occurs in these diseases.

Absorption, distribution and fate in the body.? In the stomach the quinine salts are dissolved

by the HC1 of the gastric juice and pass into the duodenum, from which they are taken up into the blood and circulate as quinine base. If excess

of alkali is present here, quinine is precipitated by the bile salts and may pass out into the fceces unabsorbed. The soluble salts of the alkaloid

are absorbed a little more quickly than the insolu- ble ones, for compounds like eu-quinine have first to be hydrolysed by the alkali of the duode- num before they can pass through the gut wall. The rate of absorption varies, but there appears to be no doubt that a soluble salt is absorbed with

crreat rapidity, the whole of the quinine being taken up, as none is to be found in the faeces.

It can be detected in the urine very soon after

it is ingested. According to Ramsden and Lipkin quinine does not circulate in the blood for a long time, if injected intravenously; 90 per cent, dis-

appears in about a minute's time. In the various

tissues it is distributed rapidly, only a fraction of from 23 to 60 per cent, appearing in the urine as quinine base ; till now no other recognisable derivatives have been detected. There has been a difference of opinion as regards the distribu- tion of quinine among the constituents of the

blood, but recent researches by King and Acton (1921), show an approximately uniform distri- bution in corpuscles and serum. A certain

proportion of quinine ingested is metabolised. The liver has been known to destroy morphine, nicotine and other alkaloids and probably deals with quinine in the same way. Excretion.?In the faces the excretion is so

small as to be negligible. By the kidneys it is excreted unchanged and if this organ is healthy the process is very rapid, quinine appearing in urine within 15 minutes of administration by the mouth (empty stomach). The excretion continues for 41 hours after a single dose by the mouth and after a succession of doses it may be found in the urine for a^ long as seven days. After a single dose orally the acme of excretion occurs after 4 to 8 hours. Never less than 23 per cent., or

greater than 60 per cent., is eliminated from the

body, the balance being either stored up in the tissues or is destroyed. Probably the latter view is correct, as estimation of the total quinine in the body will not account for all that is missing. A fact of great clinical interest is that when

more than eleven grains of quinine base per litre are passed through the kidneys, temporary albu- minuria is produced. This should be remembered when prescribing a heroic dose of quinine.

Quinine idiosyncrasy.?Some individuals show very peculiar susceptibilities in regard to quinine even when such minute quantities as 1116th grain are given. The symptoms which manifest themselves are urticaria, erythematous or bullous eruptious, dyspncca, fever, nausea

and vomiting. A case has been recorded in

406 THE INDIAN MEDICAL GAZETTE. [Nov., 1922.

which three grains caused fever, bloody stools and severe prostration which disappeared on the following day, but reappeared some weeks later when the dose was repeated.

These idiosyncrasies are not commonly met

with in the tropics, where large doses, such as 30 to 60 grains are given, and the case appears to be similar to that of /Potasium Iodide and

only seen with small doses. Cinchonism.?This name is given to the toxic

effects, chiefly connected with the central nervous system, when quinine or other cinchona alkaloids are given in large doses and should be differen- tiated from idiocyncrasy, which is a condition of increased susceptibility and is brought on by very small doses. The degree of toxicity of the different alkaloids varies, cinchonine being the most toxic, next comes quinine, then cinchonidine and lastly quinidine. The association between the symptoms of intoxication and high concentration of the alkaloid circulating in the blood is very striking. The early symptoms are nausea, head- ache (due to cerebral congestion), vomiting, ringing in ears, giddiness and disturbed vision

(due to selective changes in the vessels). Photo-

phobia. deafness, blindness?at first partial and then complete?appear later. Apathy, mental

depression and general muscular weakness 4super- vene and with very high doses somnolence and loss of consciousness, delirium and finally death from collapse. Large doses paralyse first the brain and respiratory centre and later the heart. Quinine amblyopia and amaurosis have already been referred to.

I saw twenty cases of quinine poisoning in East Africa, where a large dose had been given by mistake to a group of men taking it for prophy- lactic purposes. The exact amount given could not be determined, but judging from the symp- toms which developed, must have been fairly large. All these men suffered from very severe

symptoms of cinchonism starting within a few minutes of ingestion; four were unconscious, or rather semi-conscious for a few hours, -all suffered from amblyopia, amaurosis and deafness for 1 to

7 days, but they all recovered by promptly washing out the stomach, and administration of salines and stimulants. One case developed optic atrophy. The grave effects of cinchonism are only met

with when the dose is increased beyond 40-to 60 (grains a day. These large doses are sometimes prescribed by practitioners in this country and are often continued for long periods, but it is certain that they do harm. In my experience I have found that a maximum of thirty grains in twenty-four hours is as much as is needed ; in most cases twenty grains are quite sufficient. Such doses are quite safe and effective ; they cause no symptoms of cerebral congestion and should not be exceeded. There is no particular point in giving very big doses by the mouth, as

the intravenous and intramuscular methods can

always be resorted to when stronger concentra- tions are required.

I believe there is a form of cachetic condition which occurs in patients taking large doses of

quinine for prolonged periods. In military practice where men who have suffered from malarial fever are put on to quinine for periods ranging from I to 3 months, this condition is not infrequently met with. The patient looks' pale and anaemic, is listless, has no inclination for exertion and has no appetite for food. There is generally a jaundiced tinge about the con-

junctivae and the temperature is usually sub- normal. All these symptoms are put down as

being after effects of malaria, but are probably due to the action of quinine on digestive and other organs, as stoppage of the drug or decrease of dose rapidly improves 'the condition.

That quinine has toxic effects on the liver has been experimentally proved. Intravenous injec- tions of moderate doses in rabbits produce progressive degeneration of liver cells, which increases with the increase of dosage and it is

possible that some such factor comes into play in these cases. The toxic effects of quinine have been attributed by some to the formation of a body called quinotoxin which is formed by action of free organic'acids on quinine and it is suggested that such conditions arise in the gut. It is, how- ever, found that this substance has a very low toxicity and cannot be responsible for these effects.

(To be continued.)