158

New Methods with A.C.T.H. and CortisoneTHE supply of A.C.T.H. and cortisone, though

increasing greatly, cannot keep pace with the demand.A.C.T.H. is now being recovered commercially from thepituitary glands of cattle, pigs, sheep, and even whales ;and no doubt seals, silver foxes, horses, the largerpoultry, and other animals commonly slaughtered enmasse will be pressed into service in this cause.

Similarly, cortisone is being made out of bile steroidsfrom several different animals, and many plants arebeing investigated for intermediate-stage steroids ;the Mexican wild yam, the tomato, and even thecommon potato contain substances with the funda-mental phenanthrene-ring structure, and the chemistshave established methods for converting some of theseto compounds more nearly related to adrenal steroids. 1 2Nevertheless, at present our best hope of making thesehormones more widely available lies in improvedmethods of administration.

Future generations, it is said, will be horrified atthe way we waste coal. This black substance contains

up to 50% of precious organic chemicals whose

potential value to mankind is daily squandered in thedomestic hearth and in the boilers of steam engines toprovide a meagre amount of heat. Likewise, theconventional intramuscular method of administeringA.C.T.H. is extremely wasteful, for it realises only asmall proportion of the hormone’s usefulness. Follow-

ing the pioneer work of SAYERS 3 and of GORDON,4workers in this country 5 and in the U.S.A.6 haveshown that A.C.T.H. by intravenous drip is safe and ismore effective than the usual intramuscular injection.THORN and his colleagues have found that althougha single 20 mg. dose of A.C.T.H. is without effect if

injected rapidly into a vein, the same amount given byintravenous infusion over a period of up to 48 hourswill’ cause maximal adrenal stimulation. Indeed,these workers may not have reached the limit of themethod ; possibly, for example, 20 mg. over 72 hourswould still give maximal stimulation. This findingwas to be expected from the work of Li and his

colleagues, who showed that both blood 8 and muscle 9contain substances which rapidly inactivate A.C.T.H.Thus with any method other than continuous infusionadrenal stimulation is only transitory. The efficiencyof A.C.T.H. can be increased twentyfold or more by theintravenous-infusion method ; and initial fears thatintravenous administration of this protein substancefrom a different animal would lead to catastropheshave not so far been realised. In addition, THORNet al. point out that A.C.T.H. by this route provides afar more reliable test of adrenal cortical function thandoes the conventional " Thorn test," in which 25 mg.of A.C.T.H. is given intramuscularly. Furthermore,cases apparently refractory to intramuscular A.C.T.H.1. New York Times, July 7, 1951.2. Rosenkranz, G., Djerassi, C., Yashin, R., Pataki, J. Nature,

Lond. 1951, 168, 28.3. Sayers, G., Burns, T. W., Tyler, F. H., Jager, B. V., Schwartz,

T. B., Smith, E. C., Samuels, L. T., Davenport, H. W. J.clin. Endocrinol. 1949, 9, 593.

4. Gordon, E. S., Kelsey, C., Meyer, E. S. Proceedings of theSecond Clinical A.C.T.H. Conference (Ed. J. R. Mote). Phil-adelphia, 1951.

5. Jelliffe, A. M., Stewart, P. B., Beaumont, G. E. Lancet, 1951,i, 1261.

6. Renold, A. E., Forsham, P. H., Maisterrena, S., Thorn, G. W.New Engl. J. Med. 1951, 244, 796.

7. Mandel, W., Singer, M. J., Gudmundson, H. R., Meister, L.Modern, F. W. S. J. Amer. med. Ass. 1951, 146, 546.

8. Greenspan, F. S., Li, C. H., Evans, H. M. Endocrinology, 1950,46, 261.

9. Cited by W. Mandel et al. (footnote 7).

have responded to this method. The success of thismethod naturally causes one to wonder why " depot

"

preparations of A.C.T.H., or long-acting A.C.T.H.

preparations, have not been found more suitable forambulant patients. Such preparations 10 have givenfairly promising results, but their usefulness has so farbeen limited by the local reaction at the injection site.Another economy is promised by the " local "

administration of cortisone. If cortisone in highconcentration can be brought into contact with thediseased tissues it may give benefits without side-effects, and only a small amount will be required.Thus, cortisone has been used successfully by sub.conjunctival injection in diseases of the anteriorsegment of the eye,11 and in eye-drops for con-

junctivitis ; it has been used in a spray for allergicrhinitis 12 ; it has also been used in an ointment forpsoriasis, and by intra-articular injection for rheuma.toid arthritis. These investigations have yielded nooutstanding results except in the ophthalmic cases;and clinically it seems that if a large enough dose isgiven cortisone is more effective when applied to thebody as a whole. Furthermore, absorption from thelocal area may well be quite rapid ; in mice, applicationof cortisone ointment produces an eosinopenia withina few hours, suggesting a rapid systemic effect. 13It must also be remembered that the natural steroid

predominantly released from the human adrenal

glands under the influence of A.C.T.H. is not cortisonebut compound F.14 Although these two apparentlyhave somewhat similar actions when given by intra-muscular injection the effects are not quite the same;and possibly some of the effects of cortisone dependon its conversicn in the body to compound F, whichprobably does not have the same effect locally. Muchfurther work remains to be done before local applica-tion of these hormones becomes a reliable method oftreatment.

Smokers Beware !NEARLY a year has passed since we drew attention 15

to an American inquiry by WYNDER and GRAHAM, 16who concluded that the " excessive and prolonged useof tobacco, especially cigarettes, seems to be an

important factor in the induction of bronchiogeniccarcinoma." Since then DOLL and BRADFORD HILL 17have published a preliminary report on an investiga-tion planned in 1947 " to determine whether patientswith carcinoma of the lung differed materially fromother persons in respect of their smoking habits orin some other way which might be related to theatmospheric pollution theory." Their basic lung-cancer material consisted of 709 cases clinicallydiagnosed in London hospitals. In 489 of these the

diagnosis was confirmed by necropsy, biopsy, or

exploratory operation. This group was matched by709 non-cancer cases, selected as of the same sexand age, and usually in the same hospital at or aboutthe same time. A comparison was also made with637 cases of cancer of the stomach or large bowel.The definition of a smoker was " a person who had10. Wolfson, W. J., Thompson, B. E., Cohn C. J. clin. Endocrinol.

1950, 10, 836.11. Koff, R., Rome, S., Kaspe, R., Commons, R. R., Button, R.,

Starr, R. J. Amer. med. Ass. 1950, 144, 1259.12. Bordley, J. E. Bull. Johns Hopk. Hosp. 1950, 87, 415.13. Spiers, R. S. Science, 1951, 113, 621.14. Conn, J. W., Louis, L. H., Fajans, S. S. Ibid, p. 713.15. Lancet, 1950, ii, 257.16. Wynder, E. L., Graham, E. A. J. Amer. med. Ass. 1950, 143, 329.17. Doll, R., Hill, A. B. Brit. med. J. 1950, ii, 739.

LEADING ARTICLES

159ANNOTATIONS

smoked as much as one cigarette a day for as longas one year," but great care was taken to assess alsothe amount of smoking indulged in. This was done byrecording the amount smoked immediately before theonset of the illness which brought the patient intohospital or, if the patient had given up smoking beforethen, by recording the amount smoked immediatelybefore giving it up. It was found that few lung-cancer patients were non-smokers (0’3%), and thatamong the smokers with lung cancer a relatively highproportion fell in the heavier-smoking categories.The differences between these patients and those ofthe control groups were all statistically significant.Cigarette smoking was more closely related than

pipe smoking to carcinoma of the lung ; but, sur-

prisingly, no association was found with inhaling. Itwas also concluded that the risk of developing car-cinoma of the lung is the same in both men andwomen, apart from the influence of smoking, thoughDOLL and BRADFORD HILL emphasised that thisobservation was based on a small number of cases.

By and large these conclusions are in close accord withthose of the American workers, who thought, however,that inhalation might be the cause of the danger ofcigarette smoking.

Recently, Sir ERNEST KENNAWAY, F.R.S.; and hiscolleagues 18 have sought to enlarge the field of inquiryin several ways. They had already estimated thearsenic content of 15 brands of cigarettes, 19 and theyhave now brought the number up to 27. The results

show, on the whole, a gradation from the arsenic-richAmerican type smoked in Western Europe to thearsenic-poor Turkish type smoked in the East, withan intermediate type in the mid-European zone. Ifarsenic in tobacco smoke were the responsible carcino-gen a low incidence of lung cancer would be expectedin those countries where mainly Turkish tobacco issmoked. But the available data do not suggest thatthis is the case, and KENNAWAY concludes that thearsenic content of tobacco does not provide a simpleexplanation for the association between tobacco

smoking and this form of cancer. An answer wasthen sought in the relation between the amount oftobacco smoked in different European countries andthe prevalence of lung cancer at different periods,and it was concluded that the disease has increased

more-rapidly than-the use of tobacco. A complicatingfactor is that when the population of a country con-sumes more tobacco, there is no means of knowinghow much of this increase is due to the initiation ofnew smokers and how much to the increased use oftobacco by those who smoke already. Finally, newdata were collected on the necropsy incidence of

pulmonary cancer in Britain, and a striking increasewas demonstrated.

KENNAWAY and his colleagues have collected a vastamount of information from all -over Europe. Theyhave frankly pointed out the deficiencies of the avail-able statistics ; and they remark that " the study ofthe relation between the national consumption oftobacco and the national incidence of cancer of thelung has scarcely begun." Such a study must dependfirst and foremost on accurate diagnosis of thedisease-a condition not yet fulfilled in this or anyother European country. It must also depend on a true18. Daff, M. E., Doll, R., Kennaway, E. L. Brit. J. Cancer, 1951, 5, 1.19. Daff, M. E., Kennaway, E. L. Ibid, 1950, 4, 173.

estimation of its incidence ; and this condition is

hardly likely to be fulfilled from hospital statisticsat a time of reorganisation of the hospital services,including the setting up of thoracic-surgery units atspecial centres. Furthermore, who can foretell whatdifference examination by mass radiography will maketo the statistical incidence of pulmonary cancer ?The elucidation of this problem should, however,surely be possible by well-planned experimentalinvestigation.

Annotations

REMUNERATION: A FURTHER STEP

THE Conference of Local Medical Committees held a

special meeting last week to discuss the progress ofnegotiations on general practitioners’ remuneration, anda recommendation from the General Medical ServicesCommittee that the profession should call on the Ministerof Health to refer to arbitration the determination of the

proper size of the central pool. 1Before settling down to debate this recommendation,

the conference placed on record :" its profound disappointment and dismay that, after pro-longed and detailed negotiations, and the fullest cooperationby the General Medical Services Committee in every type ofenquiry, the Minister of Health, and the Secretary of Statefor Scotland, have refused to examine the practitioners’ claimon its’merits, and have made it clear that any new moneyfor general practitioners must be paid from whatever remainsafter the costs of all other parts of the Service have been met."The conference regretted also " the suggestion that theremuneration of doctors should be dependent in anyway on the reduction of cost of prescribing." There

appeared to be general agreement that the GeneralMedical Services Committee had acted correctly inrejecting the conditional offer of :E2 million ; no voicewas raised to advocate the acceptance of this sum evenas an interim payment. The conference felt strongly thatthey had a sound case for asking appreciably more thanthis, and a case that they would have no hesitation insubmitting to arbitration. Lancashire, it is true, proposedthat, rather than ask the Minister to refer the case toarbitration, the conference should forthwith instruct theG.M.S.C. to obtain practitioners’ resignations, and toplace these in the hands of executive councils on Sept. 29 ;but it became clear that Lancashire was suggesting thiscourse in the belief that it was the only one that wouldassuredly produce the independent inquiry that waswanted. Lancashire argued that once the resignationswere handed in, a dispute would automatically.arise, which, before the resignations could take effect,would have to pass for adjudication to the industrialcourt. Ultimately the conference voted in favour of

accepting the advice of the G.M.S.C., and of giving theMinister the opportunity of himself referring the case toarbitration. But Lancashire’s arguments had sufficientlyimpressed the delegates for a further instruction to begiven to the G.M.S.C. that" unless a suitable form of arbitration is agreed by September25 steps shall be taken immediately, to put into operation themachinery for obtaining the resignations of the generalpractitioners in the National Health Service, and placing themin the hands of the Executive Councils."

Having thus clearly defined their attitude to the mainproblem, the conference went on to debate the secondrecommendation of the G.M.S.C. that" once the proper size of the Central Pool has been determined

by arbitration, the General Medical Services Committee beauthorised to resume discussions with the Minister in order toapply a form of distribution which is in accordance with therecommendations of the Spens Committee, and which will

1. See Lancet, 1951, i, 1311.