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THE PRINCIPLES OF CHEMOTHERAPYBy C. A. KEELE, M.D., F.R.C.P.

Reader in Pharmacology and Therapeutics, Middlesex Hospital Medical School

This introduction to the collected articles onchemotherapy which have appeared recently inthe POSTGRADUATE MEDICAL JOURNAL, is intendedto deal only with general aspects of the subject.Some of the principles will doubtless appear veryobvious, but there is perhaps no harm in repetitionconcerning such an important branch of medicalscience. No references to the literature are givenhere as they are provided by individual authors intheir articles.As in the therapeutic use of any drug, there is

really only one aim in chemotherapy, namely, tochoose the appropriate drug for the purpose andto administer it in such a way and for such timeas are necessary for it to bring about the desiredactions without producing unwanted side-effects.

Selection of the Appropriate DrugIn selecting drugs for the treatment of in-

fections due to invading parasites the guidingprinciple is ' selective toxicity,' which means thatone wants to choose drugs which are maximallyharmful to the parasite and at the same timeminimally harmful to the infected patient. Thisfactor, first so clearly enunciated by Ehrlich, isfundamental in selecting new chemical substancesfor therapeutic use. Innumerable compoundswhich can kill off parasites in vitro are of no thera-peutic value because effective parasiticidal dosesare also toxic to the cells of the host.Thus advances in chemotherapy depend on the

discovery of drugs which are increasingly selectivein poisoning pathogenic parasites. Consider thecase of syphilis. Mercury, which was used fromearly in the Isth century until quite recently, hadlittle if any spirochaeticidal action and readilyproduced toxic actions; the organic arsenicals,introduced by Ehrlich, are very potent spiro-chaeticidal agents but are sometimes rather toxicto the patient; bismuth is less toxic than thearsenicals, but has a weaker, though more pro-

longed, action on the Treponema pallidum. How-ever, the combined arsenical-bismuth treatmentwas undoubtedly an effective regime with a curerate of about 90 per cent. in patients with earlysyphilis who completed the long course of treat-ment. But the position has now been radicallychanged, and, as Dr. R. R. Willcox has stated,penicillin is now first choice for the treatment ofall stages of syphilis. It may not be quite so toxicto the spirochaete as the organic arsenicals, but itis far less harmful to the infected patient. Itsfavourable ' therapeutic ratio ' (the minimum dosewhich produces toxic effects/the dose which pro-duces a full therapeutic effect) means that peni-cillin may be given in curative doses with far lesslikelihood of serious toxic complications.

In some instances it is important to rememberthat the various stages of development of aparasite are differentially affected by drugs andProf. Murgatroyd has discussed this question inrelation to the treatment of malaria. The actionsof proguanil (paludrine) on the pre-erythrocyticparasites of certain striins of P. falciparum; theschizonticidal actions of quinine, mepacrine,chloroquine and proguanil, and the gametocidalactions of pamaquine and pentaquine illustratesuch differences in sensitivity to drugs of thedifferent stages of the malarial parasite. Inamoebic dysentery, too, the choice of drug de-pends on the phase of infection. As Dr. Adamspoints out, emetine hydrochloride is still best forthe treatment of the acute attack or complications,whereas there are many drugs, including aureo-mycin, which may help in the control of chronicamoebiasis.One should add that an acute infection, or the

early stages of what may become a chronic one, isalways easier to eradicate than a chronic infection.This is probably due to the development of tissuechanges which may be irreversible and which maymake the infecting organisms less accessible to

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drugs. The early stages of syphilis and the moreacute forms of tuberculosis are much more sus-ceptible to chemotherapy than the later stages ofthese diseases.

In bacterial chemotherapy there have been somany advances since the introduction of the sul-phonamides in I935 that the problem often is todecide which of perhaps three or four drugs is thebest for a given infection. In many cases therehave not been sufficiently thorough clinical trialsto justify a final judgment, but there are certainpoints which can be made.The antibiotics and other powerful antibacterial

drugs should only be given when there are clearindications for their use. The micro-organismssusceptible to these drugs are now well known andtheir presence may justifiably be presumed onclinical grounds in many instances, but wherethere is any doubt the appropriate bacteriologicalinvestigations should be undertaken. It must beemphasized that these drugs are inactive againstnearly all virus infections. There is therefore nopoint in giving them for the treatment of influenza,unless, as Dr. Joules has stressed, staphylococcalpneumonia has supervened, when penicillinwould be the drug of choice.There may be certain strains of an organism

which are abnormally resistant to drugs. Thismay occur primarily as, for example, with strepto-coccus viridans, or it may be the consequence ofdrug administration, when the term ' acquireddrug resistance ' is used. Drug resistance can de-velop either during the treatment of an individualinfection, e.g. the resistance of M. tuberculosistowards streptomycin, or over a long period aparticular bacterial species can become increasinglyresistant to a drug to which it was originally verysensitive, e.g. sulphonamides and the gonococcus,and penicillin and Staphylococcus aureus.The occurrence of drug-resistant organisms is

becoming less serious now that there are alterna-tives to the original drugs of choice. The sul-phonamides have been replaced by penicillin inthe treatment of gonorrhoea, and infections dueto penicillin-resistant staphylococci respond toaureomycin; in the treatment of tuberculosis,streptomycin is now given together with p-amino-salicylic acid, which greatly reduces the likelihoodof the development of streptomycin-resistant or-ganisms. However, as Dr. Scadding points out,the development of resistance to streptomycinstill restricts the value of this drug in the treat-ment of the chronic fibrotic forms of pulmonarytuberculosis.

Combined ChemotherapyThe question as to whether two drugs are

better than one is obviously important. In some

instances a combined attack is useful; for ex-ample, in pneumococcal meningitis the administra-tion of sulphonamides to reach the infected areavia the blood stream plus intrathecal penicillingives better results than follow the use of eitherdrug alone. Penicillin and streptomycin, whichboth have bactericidal actions, may also actsynergistically on organisms susceptible to both;the conjoint actions of streptomycin and p-amino-salicylic acid in tuberculosis, and the combinedeffects of quinine and pamaquin in the radicalcure of benign tertian malaria also illustrate thesame point.

However, as Dr. Brownlee has described, thereis experimental evidence to show that antibioticsmay actually antagonize each other. For ex-ample, a bacteriostatic substance such as aureo-mycin may reduce the effectiveness of penicillin.The suggested explanation is that penicillin isbactericidal and acts best on rapidly multiplyingorganisms; if the bacterial metabolism is de-pressed by bacteriostatic agents the rate ofmultiplication is slowed and the effectiveness ofpenicillin is thereby decreased. It is not estab-lished that such an action would occur in humaninfections, but it is certainly best not to give more-than one antibiotic at a time.

Cost of ChemotherapyThe striking differences in the cost of treatment

with the various drugs have been well stressed byDrs. Joules, Kilpatrick and Maclean. It ismost desirable that adequate therapeutic trialsshould be done to establish the relative merits ofthe cheaply produced sulphonamides and the ex-pensive newer antibiotics in the treatment ofinfections susceptible to both groups of drugs.

Administration and DosageTo produce its actions a drug must gain access

to those parts of the body where its effects are re-quired. In most instances we rely on the blood-stream to distribute drugs in the body, but inothers we apply drugs directly to the desired siteof action. Thus the problems of administrationand dosage depend ultimately on factors such asthe absorption of the drug from the alimentarytract or site of injection, its distribution in theblood and body fluids, its diffusion into bodycells, the metabolic changes undergone by thedrug and, finally, the route of elimination fromthe body.Absorption(i) Alimentary TractThe drugs used in chemotherapy are absorbed

.to different degrees and at different rates from thealimentary tract. After administration by mouth

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most of the sulphonamides are absorbed quicklyand fairly completely, but only about 25 per cent.of sulphaguanidine and about 5 per cent. each ofsuccinylsulphathiazole and phthalylsulphathiazoleare absorbed. Chloramphenicol and aureomycinare both well absorbed when given by mouth andthis is their usual route of administration. Peni-cillin is absorbed irregularly even when thedestructive action of gastric HCI is prevented bygiving antacids, and oral administration of evenfive to ten times the injected dose is not con-sistently satisfactory. However, this route isjustified in young children in whom injections areundesirable. Streptomycin is absorbed hardly atall from the alimentary tract, but it is not destroyedand can therefore act upon susceptible micro-organisms in the lower bowel.

(2) Sites of InjectionAfter intramuscular injection the rate of absorp-

tion depends on the nature of the compound andthe composition of the medium in which the drugis dissolved or suspended. This problem was atone time much discussed in relation to the variouspreparations of bismuth used in the treatment ofsyphilis, but is now of greatest interest in con-nection with penicillin. With watery solutions ofsodium penicillin II, absorption is rapid and highblood levels are produced, reaching a peak in I5to 30 mins. The duration of an effective bloodlevel naturally depends on the dose, but accordingto Garrod is about 3 hours after 5o,ooo units and7i hours after 500,000 units of penicillin. Whenallowances are made for the time needed forbacteria to recover from the actions of penicillinit is probable that 50,000 units are effective for4 hours and 500,000 units for I1 hours.

After intramuscular injection of 300,000 units ofa suspension of procaine penicillin in oil or water,absorption of active penicillin is greatly delayed sothat the peak blood concentration (i unit/ml.) isreached only after 4 hours, but a detectable bloodlevel persists for about 24 hours. The addition ofaluminium monostearate delays absorption stillfurther, and when 600,000 to 1,200,000 units aregiven penicillin is present in the blood for severaldays.

For the treatment of acute infections waterysolutions of sodium penicillin II are most satis-factory, but in the treatment of syphilis a main-tained low blood concentration of penicillin is best,and therefore procaine penicillin+aluminiummonostearate in oil is the preparation of choice.

Intravenous injection of drugs for chemotherapyis useful in those cases where one wants to producea high blood level as quickly as possible (e.g.sodium sulphadiazine in meningococcal meningitis)or where a drug is too irritant to give by other

routes of injection (e.g. organic arsenicals insyphilis).The high blood levels which follow intravenous

injection of a drug may sometimes be toxic to theheart. Emetine, which may cause cardiac arrhy-thymias and other signs of cardiac damage, shouldtherefore never be given by this route. Intra-venous administration is sometimes very wasteful,as in the case of drugs which are excreted rapidlyvia the kidney, and for this reason penicillin isnot so given today.

DistributionThe distribution of drugs via the bloodstream

is usually very satisfactory but certain regions ofthe body are not very accessible. For examplemany drugs do not penetrate at all well into thecerebrospinal fluid (or into the intraocular fluids).Penicillin appears in normal C.S.F. only in traces,and even in meningitis the amounts are quiteinadequate to control an infection due to a sus-ceptible organism such as the meningococcus.Streptomycin passes from the blood to C.S.F.more readily than penicillin, but to be effectivein the treatment of meningitis, both these drugsmust be administered directly into the C.S.F.Sulphonamides pass into the C.S.F. much moreeasily and for this reason they are the drugs ofchoice (sulphadiazine is best) in the treatment ofmeningococcal meningitis. Chloramphenicolenters the C.S.F. and intraocular fluids morereadily than does aureomycin.

Diffusion of drugs into abscesses, pleuraleffusions and infected joints is also poor.

Occasionally a drug becomes greatly con-centrated in a particular organ of the body. Forexample, Dr. Adam refers to the fact that theantimalarial drug, chloroquine, becomes so muchconcentrated in the liver that it is effective in thetreatment of hepatitis due to Entamoeba histolytica,the much lower concentrations found in the bloodbeing quite ineffective against the acute infectionof the large bowel. Certain esters of penicillin(e.g. ' Estopen') which are excreted in high con-centrations in sputum are for that reason useful inthe treatment of suppurative chest conditions.Where distribution via the blood stream is

inadequate local applications may be necessary.For example, in the eye it is very difficult toproduce antibacterial concentrations of penicillinby systemic administration, but subconjunctivalinjection of the drug produces highly effectivelevels in the anterior chamber. With local applica-tions to mucous surfaces and wounds the chiefproblem is to ensure adequate penetration forsufficient length of time to all parts of the area.This is best achieved by applying the drug in theform of a powder or suspension.

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Fate of DrugsDrugs, including antibiotics, are chemical com-

pounds of known composition which undergometabolic changes in the body. Sometimes thesechanges produce the active antibacterial agent.For example, the original inactive ProntosilRubrum is converted in the body to the activesulphanilamide. Ehrlich's famous ' Salvarsan'is oxidised to the much more active oxophenarsive(mapharsen) and proguanil is activated to a com-pQund of at present unknown composition.

Metabolic breakdown products of drugs areusually therapeutically inactive, but sometimesthey may be toxic. The well-known insolubilityof certain acetylated sulphonamides will be re-called in this connection.

ExcretionMost chemotherapeutic drugs appear in the

bodily secretions. Their presence in bile might'lead one to suppose that they would be effectivein the treatment of biliary tract infections; un-fortunately this is usually not the case as anyinfection which damages the liver greatly reducesthe concentration of drug in the bile.

Excretion is mostly via the kidney and the con-centration of drug in the urine greatly exceeds theblood level. This means that even though thedrug be largely inactivated in the body (e.g.chloramphenicol and aureomycin), effective anti-bacterial concentration still occur in the urine.Moreover, in the case of penicillin which is ex-creted mainly by the renal tubules, the rate ofexcretion can be greatly decreased by certain sub-tances which selectively depress renal tubularfunction (caronamide, benemid). In this wayhigher blood penicillin levels can be attained.

It is often said that owing to the high concentra-tions which appear in the urine, sulphonamidesmay be given in smaller doses for the treatment ofurinary tract infections. However, since the in-fection is often a pyelonephritis some of theorganisms are only accessible via the blood stream,so that ordinary dosage might be required.

DosageThe principles of dosage are simple enough.

First a large loading dose is required to produce anadequate drug concentration in blood and bodyfluids as soon as possible, and this is followed bysmaller maintenance doses at such intervals as willsustain the required levels until the infection isbrought under control. In nearly all cases thedrug should be stopped when the temperature hasbeen normal for three days, and usually treatmentwith these drugs should not exceed a week. Ifadministration is prolonged the incidence of toxic

effects is greatly increased, and the developmentof drug resistant organisms might occur.

Toxic EffectsThe parasiticidal action of drugs cannot be ex-

pected to be so specific that no harm whatever isdone to the host. It is always a question of themargin between the therapeutic and toxic doses,and in some cases this is very small, or the thera-peutic and toxic ranges may even overlap. At thepresent day, when there may be several drugswhich can kill off a particular organism, the mostvaluable will clearly be the least toxic member ofthe series. For this reason penicillin has replacedthe organic arsenicals in the treatment of syphilis,and the older sulphonamides, e.g. sulphapyridrine,have been supplanted by compounds such assulphamerazine and sulphadimidine in the treat-ment of bacterial infections. Thus, many toxicactions may nowadays be avoided by using a morespecific, less toxic compound and this is the firstand most satisfactory way of tackling the problemof drug toxicity.The occurrence of nausea and vomiting is some-

times very troublesome with drugs given orally.It occurred particularly with sulphapyridine but ismuch less frequent with the newer sulphonamides;P.A.S., chloramphenicol and aureomycin are alsoliable to irritate the alimentary tract. To avoidgastric irritation a drug should either be given inenteric coated capsules which do not disintegratein the stomach (e.g. emetine bismuth iodide) ortablets should be crushed and taken with a fewounces of water or milk so that the substancepasses rapidly through the stomach. If the drugcauses vomiting solely by peripheral irritationinjection of the drug may avoid this complication,but some drugs (e.g. digitalis and sulphonamides)excite vomiting by both peripheral and centralmechanisms, whereas others, e.g. apomorphineand streptomycin, appear to act centrally.

Toxic Effects on the Nervous SystemPeripheral nerve degeneration has been seen

following the administration of a number ofdrugs, and was rather frequent with some of theearlier sulphonamides. The most importantnervous complications in chemotherapy today arethe eighth nerve changes produced by strepto-mycin and dihydrostreptomycin. Streptomycinacts predominantly to depress vestibular functionthough larger doses cause deafness as well; con-versely dihydrostreptomycin, originally claimed tobe less neurotoxic than streptomycin, acts on theauditory mechanism before it affects vestibularfunction, and since its effects are irreversible itshould never be used. The vestibular damage dueto streptomycin depends on the dose, which is the

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reason why the daily dosage of this drug intuberculous infections has been reduced from 2 g.daily to i g. daily. In such a grave condition astuberculous meningitis it is, however, necessary togive 2 g. intramuscularly+Ioo mg. intrathecallydaily, and it is not surprising that vestibulardamage occurs quite frequently with the highconcentrations of streptomycin so produced (seeDr. Buxton's article). But vestibular damage isoften reversible and compensatory mechanisms candevelop.

Sensitization Reactions (Drug Allergy)Drug rashes (e.g. maculopapular, urticarial) and

drug fever (alone or with rashes) are the com-monest manifestations of drug sensitization orallergy. It is important to realize that, in patientswho are having a drug for the first time, the processof sensitization usually takes five to seven days todevelop. Therefore if the course of drug ad-ministration is completed within this time theliability to sensitization reactions is greatly re-duced. Of course, in patients who have previouslybecome sensitized to a particular drug, the veryfirst administration of a second course may evokethe reactions of sensitization, as has happened withsome of the sulphonamides, especially sulpha-thiazole. It is worth remembering that veryoccasionally serious, and indeed fatal, complica-tions such as periarteritis nodosa as well as focalnecroses in the myocardium, bone marrow, spleenand liver and kidney may follow administration ofthe sulphonamides. The commonest complicationwith penicillin is urticaria, often with extensiveoedema as in ' serum sickness.' Although thenumber of reported cases is so far small it alreadyappears that chloramphenicol and aureomycin cancause drug fever and rashes.Another sign of sensitization is the develop-

ment of ' contact dermatitis' from local applica-tions to the skin, particularly if the drug is appliedto an abraded surface. This has occurred quitefrequently with sulphonamides, and also withpenicillin, but sensitization of this type occurs mosteasily with streptomycin, and workers employed inits manufacture, and nurses who are concernedwith its administrition, are very liable to developdermatitis, unless appropriate precautions are taken.Many would include among the reactions of

sensitization the bone marrow reaction which leadsto granulocytopaenia or agranulocytosis. Thisrare, complication has been associated particularlywith sulphonamides. and does not occur afterpenicillin (which indeed is used in its treatment),but it is not yet known whether it can be elicited bythe newer antibiotics. Agranulocytosis usuallydevelops only after prolonged treatment (e.g. twoweeks or more) with full doses of the offending

drug, and the risk of its occurrence is anotherindication for keeping the period of treatment asshort as possible.Thus it is most important to take account of

these sensitization reactions in assessing thesignificance of rashes or fever which developduring chemotherapy. If the fever due to theoriginal infection has subsided and the patient hashad a normal temperature for two days, a suddenrise of temperature might be due to a recrudescenceof the infection, to drug fever or perhaps toagranulocytosis. It is important to consider thisquestion carefully as the remedy for the two latterstates is so simple.

Nowadays, when there is often a choice of drugsfor the treatment of a particular infection, apatient who has becom sensitized to one drugshould tolerate another. For example, a patientwho has become sensitized to sulphonamide mightwell be sensitive to other drugs of this group.Thus, a patient known to be sensitive to a drug,even though it be the first choice for a particularinfection, should be treated with a drug belongingto a different chemical group. This is one of thegreat advantages of having more than one drug forthe treatment of a given infection.

Disturbances in Baoterial FloraAmong the toxic effects which sometimes

accompany chemotherapy are those which may bedue to the indiscriminate destruction of com-mensals as well as pathogenic micro-organisms.It is sometimes desirable to sterilize the alimentarytract, as, for example, before operations on thebowel which might contaminate the peritoneum,but there is evidence which suggests that glossitis,angular stomatitis, and inflammation in the rectumand vagina, may often be due to the upheaval inbacterial ecology produced by chemotherapy; thisleads to the unusual predominance of such in-sensitive ,organisms as B. coli and monilia suchas Candida albicans. Some of the changes, e.g.angular stomatitis have been attributed to de-ficiency of vitamin B complex, e.g. ariboflavinosis,but administration of vitamin B does not alwaysprevent or relieve these complications, and theabnormal flora might well act directly to causesuch changes.The flatulence and looseness of the bowels

which occur with chloramphenicol and aureo-mycin may also be due to alterations in the flora ofthe alimentary tract, but direct irritation by thedrugs might sometimes cause diarrhoea in the sameway as it may produce vomiting.The future of chemotherapy is difflcult to fore-

cast, but some of the long-term problems arebeginning to be revealed. The gradual develop-ment of drug-resistance of certain bacterial

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species is a striking illustration of the adaptivepower of living organisms to their environmentand how far this process will eventually nullify thebenefits which chemotherapy has provided, or howfar the dislocations of bacterial ecology will perhapsprove harmful to man, are questions which noone can answer. On the hopeful side there are ofcourse the possibilities of gaining control of in-fections due to viruses and a beginning has beenmade in this field with the introduction of chloram-phenicol and aureomycin.

In conclusion, one might recall how all thefundamental factors involved in modern chemo-therapy were outlined, and in many casesthoroughly studied, 'by Ehrlich in the early years*of this century. His practical achievements wereperhaps less important than his establishment ofthe principles of the subject. His ' chemo-receptor' theory, with the recognition of ' para-sitotropic ' and ' organotropic ' effects of drugs,led to the introduction of what is now called thechemotherapeutic index, which Ehrlich defined asthe ratio between the ' dosis toxicata' and the'dosis tolerata.' According to Ehrlich the aim of

chemotherapy is to produce ' Therapia sterilisansmagna,' that is, cure with one large sterilizing doseof the drug. This can now be done with penicillinin acute gonorrhoea, but is not yet attainable withother infections.

Ehrlich was particularly interested in the dis-tribution of drugs in the body, and indeed hisearliest work dealt with the selective uptake ofdyes by different tissues. Throughout his life heworked with dyes, and all the important drugswhich he discovered were coloured substanceswhich had a selective affinity for pathogenicparasites. Much of his work consisted of studiesin the synthesis of dyestuffs in the test tube andthe testing of their staining properties on cottonthreads. Martha Marquardt, who was Ehrlich'ssecretary for many years, tells us in her book' Paul Ehrlich' that he loved bright colours, 'thesight of a bunch of gay colours would make himquite ecstatic.' It is thus perhaps not too fancifulto say that the structure of modern chemotherapyhas been built on foundations which were createdfrom a highly developed responsiveness to colourin a scientist who happened to be a genius.

NOTES

PETHIDINE INANAESTHESIA

The increasing popularity of pethidine topotentiate nitrous oxide-oxygen anaesthesia andallow it to be used in major surgery, has promptedBurroughs Wellcome & Co. to issue a specialstrength of' Wellcome' brand Injection of Pethi-dine Hydrochloride for this purpose. The newstrength is i per cent. and is additional to the5 per cent. strength. It is issued in rubber-cappedbottles of 25 cc. (4/6 subject). In order to avoidconfusion between the two strengths, each packwill be suitably over-printed in red figures. Inaddition, the new product will bear a black rubbercap as a contrast to the yellow one used on theexisting 5 per cent. solution. The advantages ofthe I per cent. solution in anaesthesia are that itcan be measured easily to an accuracy of I mgm..that dilutions are not required and that risk ofthrombosis is reduced to a minimum.

CHOLlNVEL-THE V. L. CHOLINE SYRUPAn agreeable liquid preparation of choline

dihydrogen citrate. This has the same therapeuticaction as choline chloride, but is without thedisagreeable flavour. It is being used for con-ditions associated with disordered hepatic func-tion, including fatty liver and cirrhosis, and isunder clinical trial for atheroma, including casesof corona:ry occlusion.

Prepared in a io per cent. solution, one or twvosmall teaspoons provide 0.35 to 0.7 g. Thisconcentration allows a daily dose of i to 3 g.,which is that being employed for most conditions.

It is recommended to be given with or aftermeals to prevent toxic effects such as abnormallowering of blood pressure, but much largerdoses than those mentioned have been given forprolonged periods without any ill-effects, and it isthought that the dangers of toxicity may havebeen over-emphasised. Available in bottles of6 fluid ounces.

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