MEDICINE

THE CHEMOTHERAPY OF MALARIABy PROFESSOR F. MURGATROYD, M.D., F.R.C.P., D.T.M.*

Wellcome Professor of Clinical Tropical Medicine, University of London, and Director, Department of Clinical TropicalMedicine, London School of Hygiene and Tropical Medicine; Physician, Hospital for Tropical Diseases, London

The chemotherapy of malaria is complicatedby the fact that no anti-malarial drug so far dis-covered is therapeutically effective against allstages of human malaria. Not only do malarialparasites differ in their reactions to drugs atdifferent stages in their complicated life cycles,but different species of parasites at comparablestages of development show different responses,and finally, strains within a given species mayshow significant differences in susceptibility totreatment. Furthermore, the treatment of patientsin whom immunity may be disregarded is notnecessarily that most suitable for the partiallyimmune and indigenous patients of a malariousregion.These matters must be kept in mind if treat-

ment is to be intelligently applied, and as a basissome understanding of modern views regardingthe development of malaria in man is necessary.Malarial Cycle in ManThere are four human species of malarial para-

site, namely, Plasmodium fakiparum, which pro-duces the severe and dangerous malignant tertianmalaria, P. vivax, the parasite of benign tertianmalaria, P. malariae, producing quartan malaria,and P. ovale, with which is associated tertianfever resembling that of vivax malaria. Theseparasites follow the same general pattern ofdevelopment, but P. falciparum shows certaindifferences which have an important bearing ontreatment.

Infective forms of the malaria parasite, known assporozoites, are injected into man with the saliva of thebiting infective female anopheline mosquito, and thesecirculate for a short time, less than an hour, in the blood.They then disappear from the circulation, and the bloodthen remains non-infective for some seven to nine days,during which time, the incubation period of the disease,the patient remains free from significant symptoms. Inthis period the parasites undergo development andmultiplication in the parenchyma cells of the liver and,as this multiplication precedes the invasion of the redblood corpuscles, this stage of development is known asthe pre-erythrocytic phase. This pre-erythrocyticschizogony finally produces ovoid plasmodial bodieswhich reach 40 to 6o0L in diameter and come to contain,by nuclear division, some 1o,ooo to 30,000 small nuclei.

Segmentation and rupture of these mature pre-erythro-cytic schizonts on the seventh to the ninth day liberatenumerous small parasites known as merozoites, themajority of which are destroyed by phagocytes while thesurvivors invade the red blood corpuscles of the cir-culation to initiate the normal erythrocytic cycle ofmalaria with which is associated the characteristic signsand symptoms of the disease.

Having entered the red blood corpuscle, the mero-zoite develops a vacuole and forms the typical malarial'ring'; the parasite is now known as a trophosoite andsteadily grows. The trophozoite becomes amoeboid,develops granules of pigment from metabolism ofhaemoglobin, and its nucleus divides repeatedly, givingrise to an erythrocytic schizont. Segmentation of theparasite and rupture of the erythrocyte liberates anumber of merozoites which immediately invade furtherred blood corpuscles. This asexual erythrocytic cycle isthen repeated serially, and with it is associated thecharacteristic periodic fever of malaria. With P. falci-parum, P. vivax and P. ovale the cycle takes about 48hours and with P. malariae about 72 hours, so that thefirst three parasites produce a tertian type of fever andthe last a quartan fever.

After a time certain erythrocytic parasites enlarge with-out nuclear division and form gametocytes, which are dif-ferentiated into male and female parasites; they appearin irregular waves in the blood and survive for abouta week. Gametocytes as such cause no symptoms inman, and are solely concerned with carrying on thedevelopment of the parasite after ingestion by suitableanopheline mosquitoes, the other forms of the parasitemerely dying after being taken up by the mosquito.

It seems that with P. vivax and probably alsowith P. malariae and P. ovale, some of the pre-erythrocytic parasites persist in an exo-erythrocyticphase forming a reservoir of parasites from whichcirculating erythrocytes may from time to timebecome re-infected when immunity is waning,and perhaps long after the initial attack, thusgiving rise to the relapses which are so charac-teristic of these infections. With P. falciparum itseems that the exo-erythrocytic phase does notcontinue long beyond the pre-erythrocytic period.Consequently, a recrudescence of fever withP. falciparum is probably due to persisting infec-tion of the red blood corpuscles and follows theprimary attack at a short interval. These factshave important bearings on the nature and dura-tion of treatment that are required, and on the

* As this goes to press, we learn with the greatest regret of the sudden death ofProfessor Murgatroyd on December i6th.

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6 POSTGRADUATE MEDICAL JOURNAL January 1952

long-term prognosis in the various types ofinfection.

General Chemotherapeutic ConsiderationsFrom what has been said, it is clear that there

are several different stages at which a drug mayact upon the malarial parasite. For example, adrug which could Fe taken continuously withouttoxic effects and which would maintain in theblood a concentration lethal to sporozoites, wouldkill these parasites on their introduction by themosquito, and such a drug would therefore act asa true cau3al prophylactic agent. Unfortunately,there is no such compound which is sufficientlynon-'oxic to man that it can be so used in practice.Furthelmore, there is no drug in practical usewhich alone can with certainty be relied upon todestroy all pre-erythrocytic parasites; proguanil intherapeutic doses destroys pre-erythrocytic para-sites of certain strains of P. falciparum but doesnot appear to destroy all strains, and it is relativelyinactive against pre-erythrocytic forms of theother species.The e are, however, several drugs which in

therapeutic doses have a very powerful actionagainst the erythrocytic trophozoites and schizontsof malaria, and as these stages of the parasites areresponsible for the clinical manifestations ofmalaria, s-ch drugs, commonly known asschizonticiles, furnish most powerful weaponsfor the control of the acute stages of the disease.They do not, however, destroy exo-erythrocyticforms of vivax, quartan or ovale parasites, andconsequently with any of these infections suc-cessful ti etment of the acute attack does notnecessarily mean that relapse may not occur.Many of the schizonticidal drugs are suffi-

ciently non-toxic to be taken continuously indoses which maintain a schizonticidal concen-tration in the blood and thereby suppress theinitial development of the erythrocytic parasitesfrom the pre-erythrocytic stages. This sup-pressive action is greatly used in practice to keepindividuals who are exposed to the risk of malariafree from symptoms of the disease. It is obvious,however, that such drugs, acting only on theerythrocytic forms, will not prevent delayedprimary attacks, arising from a persisting exo-erythrocytic reservoir of infection, from becomingmanifest after the suppressive treatment is dis-continued. This often happens in patients aftertheir return from the tropics when they discon-tinue their anti-malarial drug. Such attacks ofvivax, quartan and ovale malaria may occurmonths after leaving the tropics owing to the longpersistence of the exo-erythrocytic reservoir inthese infections.

Finally, certain drugs bring about the dis-

appearance of gametocytes or prevent their furtherdevelopment in the mosquito. Because gameto-cytes as such give rise to no symptoms in man,drugs acting on them are of no direct therapeuticinterest, although they may be of some indirectvalue in limiting the spread of malarial infection.

Specific DrugsBesides the standard anti-malarial drugs, many

other compounds exert some anti-malarial activitybut their potency is usually limited. On theother hand, a number of new and promising com-pounds are under trial, but these have not yetcome into practical use. The drugs at presentused in practice fall into five groups:-

I. Cinchona alkaloids. Of these quinine invarious salts is most used, although other cinchonaalkaloids have been employed; on the grounds ofcheapness considerable use has been made oftotaquina, a standardized mixture of total cin-chona alkaloids containing not less than 70 percent. of crystallizable alkaloids of which not lessthan 15 per cent. is quinine.

2. 9-amino-acridine- compounds. The out-standing representative is mepacrine.

3. 4-amino-quinoline compounds. These in-clude chloroquine, camoquin, and a number ofrelated compounds.

4. Biguanide derivatives. Of these the practicalexample is proguanil.

5. 8-amino-quinoline compounds. These in-clude pamaquin, pentaquine and isopentaquine.The first four act as schizonticidal agents,

destroying the asexual parasites in the erythro-cytes. Through this action they can be usedeither to control acute malarial attacks or, if takencontinuously, to suppress the development ofparasites in the blood, thereby preventing thedevelopment of clinical symptoms. In addition,proguanil destroys pre-erythrocytic forms of cer-tain strains of P. falciparum and also preventsgametocytes from developing fully in the mosquito.Compounds of the fifth group, the 8-amino-

quinoline derivatives, are mainly used for theiraction against the exo-erythrocytic parasites.They are used in conjunction with one of theschizonticidal drugs in the treatment of attacks ofvivax, quartan and ovale malaria. They appearto devitalize the exo-erythrocytic parasites, par-ticularly if given along with quinine, and conse-quently they diminish the tendency of theseinfections to relapse. They also are capable ofdestroying sporozoites or pre-erythrocytic forms,but the dose required for this action is so closeto the toxic dose that they cannot be used aspractical causal prophylactic agents; they alsodestroy gametocytes.

Quinine o.65 g. (io gr.), preferably in solution,

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January 1952 MURGATROYD: The Chemotherapy of Malaria 7

for which a soluble salt or the addition of sufficientacid is required, given three times a day bymouth for about a week, will control an acuteattack of malaria provided the drug is absorbed.If the patient is vomiting, if the circulation is sodepressed that the absorption is slow, in thepresence of cerebral malaria or some severe com-plication demanding very rapid control, it isnecessary to administer the first one or two dosesparenterally. For this purpose quinine dihydro-chloride, 0.5 g., may be given slowly intravenouslyand, to prevent thrombosis, preferably in dilutesolution; the drug may also be given intra-muscularly but then sometimes produces painand local necrosis.

QUININEHC

H,C CH-CH=CH2HO-CH-HC CH2

CH2i

CH30/\/% NiiN

6-methoxy-c-(5-vinyl-2-quinuclidyl)-4-quinolinemethanol

For suppressive treatment a daily dose of0.3-0.6 g. is often used, but it is not alwayseffective and repeated low-grade falciparum infec-tions may become established and so conditionthe individual for the development of blackwaterfever, which is therefore common in areas wherequinine is relied upon for malarial suppression.

Therapeutic doses may give rise to tinnitus anddeafness; more rarely to vertigo, visual disturb-ances, nausea, headache, and very occasionally tourticarial rashes.

Quinine has a good therapeutic action againstasexual erythrocytic parasites, although with somestrains of malaria the disappearance of parasitesand subsidence of fever do not always occur asrapidly as with. a large dose of mepacrine orchloroquine. Quinine is without action on exo-erythrocytic parasites and therefore does notprevent relapses of vivax or quartan infections,and vivax malaria in some cases may relapse asearly as one or two weeks after treatment. Thedrug has some action on the gametocytes of vivaxand quartan infections, but none on those offalciparum infections.

Quinine is rapidly metabolized and excreted,plasma concentrations falling by 90 per cent.within 24 hours after ceasing administration ofthe drug. The drug appears to retard the growth,arrest development and produce degenerative

changes in the asexual parasites in the earlierstages of their cycle, possibly through interferingwith their carbohydrate metabolism by inhibitingthe oxidization of pyruvic acid, but the exactmechanism of action is obscure, as it is for all theanti-malarial drugs.

Mepacrine (atebrin, quinacrine, acriquine) isused, commonly as the hydrochloride, in doses of0.2 g. three times daily by mouth for one or twodays, followed by o.I g. three times daily. bymouth for five to seven days, for the control ofacute malarial attacks. Where parenteral injectionis indicated the drug may be given intramuscularly;it may cause irritation and mepacrine methane-sulphonate may be substituted. The drug maybe given intravenously but the margin of safetyby this route appears small; if so used, the drugshould be given in very dilute solutions andslowly.

MEPACRINE

CH3NH-CH(CH2)3N(C2H5)2

h/\Y/\(OCH 3

Cl N6-chloro-2-methoxy-9(4-diethylamino-

i-methylbutylamino) acridine

For suppressive treatment o.i g. mepacrinedaily, taken by mouth, usually is very efficient butcertain rare strains of P. falciparum may require0.2 g. daily for their suppression. As it takessome time for the plasma concentration to reach aschizonticidal level with a dosage of-o.i g. daily,suppressive treatment should commence withloading doses as advised for the treatment of acuteattacks, or alternatively the normal suppressiveregime should be started two' weeks before theindividual will be exposed to the risk of infection.

In therapeutic doses mepacrine does not usuallycause serious side effects although it may stainthe skin yellow, and occasionally produce a bluepigmentation seen especially over the nail beds,nose, palate, epiglottis and tracheal rings. Some-times the drug produces gastro-intestinal symp-toms, including nausea, vomiting and diarrhoea;more rarely mental excitation or toxic psychoses,visual disturbances and anaemia; while in a fewpersons mepacrine has been associated with skinlesions which may be excematoid, lichenoid andexfoliative.

In its action the drug resembles quinine, andif loading doses are given it controls'acute attacksas rapidly as does quinine. Exo-erythrocyticparasites are not affected and consequentlyrelapses of vivax or quartan malaria may occur,

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but possibly owing to the slow elimination of thedrug the parasites do not usually reappear untilat least four to six weeks after treatment. Thedrug also resembles quinine in being inactiveagainst gametocytes of P. falciparum.

Mepacrine accumulates, especially in the leuco-cytes, liver, spleen, heart and lungs, and is onlyslowly eliminated so that the plasma concen-trations fall only about 50 per cent. per weekafter the drug is discontinued. The drugdiminishes the amoeboid movement of the earlyasexual erythrocytic parasites, and producesabnormal forms with clumping and extrusion ofthe pigment; it possibly acts by interfering withsome phosphorylation reaction necessary for theutilization of glucose by the parasite, or byinhibiting reactions involving riboflavin.

Chloroquine (aralen, resochin, nivaquine,SN 7618, 3377 RP) in the treatment of acutemalaria is normally given as the diphosphate, bymouth, in an initial dose of i g. followed aftersix to eight hours by three doses each of o.5 g. at24-hour intervals. Where rapid action is requiredchloroquine hydrochloride, 0.5 g., may be givenintramuscularly or very slowly intravenously.

CHLOROQUINECH3

NH-CH-(CH,)3N(C2H5)2/\/\

Cl N7 - chloro - 4 - (4 - diethylamino - i - methylbutylamino)

quinolineFor malarial suppression, o.5 g. diphosphate

by mouth once a week suffices, because degrada-tion and excretion of the drug are very slow.

In therapeutic doses the drug is relatively freefrom side effects. Occasionally gastro-intestinaldisturbances, pruritus, headache, and visual dis-turbances, such as blurring of vision or difficultyin accommodation, may occur; administration ofthe drug has also been associated with the occur-rence of a toxic psychosis, but this appearsextremely rare.

Chloroquine acts mainly against asexual ery-throcytic parasites and it rapidly brings about thetermination of a malarial attack. It does noteradicate exo-erythrocytic parasites; consequentlyvivax and quartan relapses may occur, although notusually until at least two to three months aftertreatment. ,Gametocytes of P. falciparum appearresistant to the drug.The drug accumulates in the liver, spleen,

kidney, lungs and leucocytes. Excretion of thecompound is extremely slow and plasma concen-

trations drop only about 60 per cent. per weekafter the last dose. Because of the drug's slowexcretion and powerful effect, relatively few dosesare required for the control of an acute malarialattack and, in the case of falciparum infections,for radical cure; for the same reasons suppressivedoses can be widely spaced, for example at weeklyintervals.

Proguanil (paludrine, chlorguanide, M.4888) isused for the treatment of acute malaria, as thehydrochloride, in doses of 0.3-0.6 g. divided intotwo or three doses daily, by mouth, for ten days.For parenteral use acetate and lactate are moresoluble and are recommended, but in severefalciparum infections where there is great urgencymany physicians prefer quinine or mepacrine.

PROGUANIL

NH-C-NH-C-NH.CH(CH-)2II

/\ NH NHII

ClN1-(p-chlorophenyl) N5 -isopropyl biguanide

For malarial suppression, o.I g. proguanil perday may be used.

Proguanil is relatively non-toxic, very highdosage only sometimes producing gastro-intestinalsymptoms, evidence of renal irritation, andincrease in myelocytes or lymphocytes in theblood.

In its action on asexual erythrocytic parasitesproguanil resembles the drugs previously men-tioned but it does not eradicate the exo-erythro-cytic phases, and relapses of vivax infection occurwith about the same frequency and at the sametime as after mepacrine. Proguanil has, however,an action on the pre-erythrocytic parasites of manystrains. of P. falciparum; it also renders gameto-cytes of these parasites incapable of completingtheir development in the mosquito. Thereappear to be certain African strains of P. falciparumwhich show some resistance to the action ofproguanil, and overt infections have been reportedwhere the drug has been relied upon as a sup-pressant. Similarly, when used for the treatmentof acute attacks with such strains, the drug hasfailed to eradicate the infections, particularlyprimary infections; certain of these infectionswere radically cured when either quinine ormepacrine was given on the first day of thecourse of proguanil. Parasites also appear tobecome resistant to proguanil rather easily and inareas where proglanil is used, proguanil-resistantstrains of parasites may arise.

Proguanil is fairly rapidly absorbed from thealimentary tract, and appears localized in the

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erythrocytes, leucocytes, kidney and liver. Al-though it is fairly quickly degraded and disappearsfrom the plasma after cessation of dosage, there issome evidence that a part of it may be convertedinto a plasmodicidal product. Asexual erythro-cytic parasites exposed to proguanil develop untilthe early stage of their schizogony is reached; atthis point development is arrested and the para-sites then undergo degeneration. Although thedrug appears to have no direct action on gameto-cytes, it nevertheless prevents their subsequentdevelopment in the mosquito. The mode ofaction of proguanil is unknown, but it has beensuggested that it may interfere with the utilizationof pteroylglutamic acid or with the porphyrinmetabolism of the parasite, or inhibit the oxidiza-tion of glucose, pyruvate and lactate.

Pamaquin (plasmochin, praequine) is used, asnaphthoate or monohydrochloride, in doses ofo.oI g. base two or three times daily by mouthfor 10-14 days.

PAMAQUINCH30O\/\

N

NH-CH--(CH2)3-N(C2H )2CH3

6 - methoxy - 8 - (4 -diethylamino - i -methylbutylamino)quinoline

Its action on asexual erythrocytic parasites isslight, and its usefulness depends upon the factthat it devitalizes exo-erythrocytic parasites whichwould otherwise give rise to relapses in vivax,quartan and ovale malaria; this effect seems to beenhanced by the concurrent administration of aschizonticidal drug, especially quinine. It isoften said that the drug should not be given con-currently with mepacrine because in such circum-stances the toxicity of both drugs appears to beincreased, but in many cases the combination hasbeen given without trouble. Pamaquin alsodestroys gametocytes, especially those of P. fali-parum. It also has some action on sporozoitesand pre-erythrocytic parasites, but the necessaryconcentration can only be attained by dosesbordering upon the toxic and consequently thedrug is of no practical use as a true causalprophylactic agent.The drug tends to give rise to abdominal dis-

comfort and it often produces methaemoglobin-cythaemia, clinically manifest by cyanosis; occa-sionally its use is associated with intravascularhaemolysis, which may be acute, or with granulo-cytopaenia.

Pamaquin is found concentrated in the liver,

lungs and brain but is quickly metabolized. Theplasma concentration is raised by the concurrentadministration of quinine, mepacrine, or pro-guanil, especially by that of the two latter.

Pentaquine resembles pamaquin in its effects,but is perhaps a little less toxic and, as a phosphate,is used in twice the dosage recommended forpamaquin.

PENTAQUINE

CH3O/\/\NI

NH-(CH2)5-NH.CH(CH3)26 - methoxy - 8 - (5 - isopropylaminoamylamino) quinolinePractical Treatment of Non-ImmunePersons

Acute falciparum malaria. Of the four speciesof human malarial parasites, P. falciparum pro-duces the most serious and dangerous illness, butfortunately, because of its response to drugs andthe absence of any persisting exo-erythrocyticphase, it is the easiest infection to cure completely.The use of quinine is now declining becausealthough it will control most infections, its ulti-mate action is inferior to that of some of thenewer synthetic antimalarial drugs. Probablybecause of its incomplete action against falciparuminfections its use appears to be associated with arelatively high incidence of blackwater fever. Atthe same time many prefer to use it initially infalciparum infections of grave urgency, butnormally in acute attacks of falciparum malaria,non-immune persons should be treated by one ofthe schizonticidal drugs, chloroquine, mepacrine,or proguanil, in the doses indicated. Theresponse is usually rapid. If the patient is notobviously under control within two or three days,the absorption of the drug or the diagnosis shouldbe suspect.

Acute vivax, quartan and ovale malaria. Acuteattacks of these infections can be controlled by anyof the schizonticidal drugs such as quinine,mepacrine, chloroquine or proguanil given in thedoses recommended, but these infections sotreated may relapse, because of their persistingexo-erythrocytic parasites which are unaffected bythese schizonticidal drugs alone. Consequentlythe schizonticidal drugs should be reinforced bythe additional use of pamaquin or pentaquine.It has been stated that pamaquin is most effectivewhen given with quinine, but if quinine is to beused the possibility of an accompanying althoughcryptic falciparum infection and the possible asso-ciation of quinine with blackwater fever should bekept in mind. If a patient proposes to carry on

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indefinitely with suppressive treatment immedi-ately following the control of the acute attack,there may be no need to give the pamaquin orpentaquine, because any blood infection from anypersisting exo-erythrocytic reservoir will beinhibited by the suppressive treatment before anysymptoms can become manifest.

Suppressive treatment. As quinine appears in-ferior to the newer antimalarial drugs, it isgradually falling out of favour for suppression.It does not always adequately suppress falciparuminfections or prevent low-grade infections, andconsequently it allows patients to become con-ditioned for the development of blackwater fever.The drugs most commonly now used are mepa-crine or proguanil daily, or chloroquine weekly.These drugs are most efficient and where they areregularly employed the malarial incidence showsa striking fall, and blackwater fever practicallydisappears. A certain number of failures ofsuppression are reported whatever drug is beingused, and reference has already been made to thesuggestion that certain African strains of P. fali-parum are relatively resistant to proguanil. Inindividual cases, however, it is sometimes verydifficult to be sure that the drug has been takenregularly.

Treatment of Partially Immune PersonsAcute attacks. Partially immune patients tend

to suffer from only relatively mild and shortattacks of fever, and these attacks are usuallyreadily controlled by a very few doses of one of

the schizonticidal drugs. Futhermore, it is arguedthat it is impossible on economic and administra-tive grounds to treat large indigenous populationsof malarious areas sufficiently to keep them freefrom infection, and that anything short of thistends to deprive them of the natural immunityand protection that they obtain from infection.Consequently, it is suggested that in partiallyimmune persons all that is desirable is to give oneof the schizonticidal drugs in the doses recom-mended above, but only for a period sufficient tocontrol the acute manifestations of the attack.Such treatment may only require one or two doses,and at the most does not usually take more thantwo or three days. Where there is a well-markedseasonal incidence of malaria it may be desirableto treat each attack thoroughly, in the case ofvivax or quartan infections using pamaquin orpentaquine together with a schizonticidal drug,but the most desirable regime to be adopted inany given circumstances can only be decided aftercareful consideration of all the factors, includingthe effects of the infections on the health andeconomic balance of the community, the partplayed by immunity in the protection of thepopulation, and the cost of any proposed line oftreatment.

Suppressive treatment. In partially immunepopulations relatively less frequent doses of sup-pressive drugs may be used, for example, mepa-crine or proguanil once or twice a week, or smalldoses of chloroquine once a week, but again theexact regime that seems desirable depends upon afull consideration of all the factors involved.

NEW PRODUCT

'KEMADRIN'A new product for the treatment of paralysis

agitans (Parkinsonism) has undergone initial trialsand is now available from Burroughs Wellcome &Co. Issued under the title ' Kemadrin' branddi-l-cyclo hexyl-l-phenyl-3-pyrrolidinopropan-l-olhydrochloride, it causes a decrease of rigidity andleads to better muscle coordination. Patients areable to indulge in greater physical activity and re-veal increased well-being and alertness. ' Kema-drin' causes less dryness of the mouth, lessconstipation, less retention of urine and lessmydriasis than do the belladonna and stramoniumalkaloids. Further trials are in progress. ' Kema-drin' is available as 5 mgm. compressed productsin bottles of 25 and Ioo.

MANUFACTURERS NOTES

The Distillers Company (Biochemicals), Ltd.,announces the availability of ' Distivit' B12 in-jection solution of crystalline vitamin B12 throughthe distribution facilities of Burroughs Well-come & Co., Evans Medical Supplies, Ltd., andImperial Chemical (Pharmaceuticals), Ltd. ' Dis-tivit ' B12 is issued in ampoules of i ml. containing20 micrograms; boxes of 5 x I ml. ampoules re-tailing at 4s. 3d. Literature is available uponrequest.The Distillers Company (Biochemicals) Ltd.,

announces the availability, through their usualdistributors, of Dihydrostleptomycin SulphateDC(B)L in vials of I million units (equivalent toi gm. dihydrostreptomycin base) retailing at 5s.per vial.

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