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Notes, Comments and Abstracts

THYMOL AS AN ANTHELMINTHIC

BY CLAYTON LANE, M.D. Lond.LIEUT.-COL. I.M.S. (RETD.)

FIVE years ago I wrote " There is so much of humanlife and human happiness at stake that the immediatefuture should see a serious effort made, by unprejudicedand independent medical workers, to add to acceptableand controlled evidence regarding the real value andsafety of hookworm-killing drugs " (Lane 1935).Maplestone and Mukerji, writing from the School ofTropical Medicine, Calcutta, where both necators andancylostomes are met with, have since, in self-imposedlimiting conditions, treated three series of patients, eachnumbering 25, with thymol, with tetrachlorethylene andwith tetrachlorethylene combined with oil of cheno-

podium ; and they have put tetrachlorethylene in thefirst place on grounds of safety, efficiency, cheapness andease of administration.

Tetrachlorethyleme.—These writers, after experimentson cats (1934) and many years practical experience intreatment of man, give tetrachlorethylene in dosage of4 c.cm. After experiments on 116 animals of varyingspecies, Lamson, Robbins and Ward (1929) wrote oftetrachlorethylene, " The degree of absorption variesgreatly with the species." What is the evidence thatexperiments on cats may confidently be transferred toman ? In determining the safety of anthelminthics inman it is numbers of treatments that matter (MauriceHall advised 100,000) and not the years over which aseries was spread. Maplestone and Mukerji (1929)treated 28 persons with 3 c.cm. of this drug in softcapsules with a cure rate of 16-7%. Some years laterthey came on a stored box of these capsules collapsed andempty, and suggested (1937) that evaporation hadalready begun before they used them in their test. Butthey could have noticed nothing amiss with these softcapsules during their test and indeed they reported theactual giving of 3 c.cm. of the drug from opened capsules.Even if they merely concluded that these still containedthe full amount of the drug they are faced with Ashford’sopinion, which they clearly value highly, that its doseshould not exceed 2 or 3 c.cm. ; the capsules could hardlyhave lost a third of their contents without obvious shrink-age and if they had not lost so much their contents wouldhave been within his advised dosage. In the same paper(1937) they reported on 81 persons whom they were ableto follow up after giving them 4 c.cm. of the drug ; therewas a cure of 61-7%, near cure bringing the figure up to75-3 %. In 1940, again using an adult dose of 4 c.cm.,they cured 36% of 25 patients (near cures bring the per-centage to 88) and brought away 99-1 % of the total bagof necators and 96-1 % of that of ancylostomes. Do thesesmall numbers give significant results ? They seemsignificantly different.

Tetrachlorethylene and oil of chenopodium.—When, totheir adopted dose of 4 c.cm. of tetrachlorethylene,Maplestone and Mukerji (1940) added 1 c.cm. of oil ofchenopodium of B.P. strength, they reduced worm re-movals. These were only 38-3 % in place of 99-1 % withtetrachlorethylene for necators, and 23.9 % in place of96-1 % for ancylostomes. In 1933 this dosage hadunwormed 62 % of 50 patients in one treatment. In the25 patients reported in 1940 the rate was 48 "/’0. Thefigures are discrepant ; and two proved anthelminthicdrugs taken together gave poorer results than one takenalone. -

Thymol.-The widely accepted dose of thymol is gr. 60(4 g.). In no case did Maplestone and Mukerji give asmuch, saying that they had not reduced the dose todecry its value but that they were guided by Ashford’swidely based opinion (to which they give no reference)that for safety the dose of thymol must be carefullyregulated, and they were dealing with underweightadults. Just before his death Ashford summed up hisgreat experience of thymol by saying (1933) that theadult dose was 4 g. but was frequently lowered forwomen. He added, first, that after the administrationof over a million doses without fatalities in the days whenrum, a solvent of thymol, was plentiful, he had lost almost

all fear of thymol ; and secondly, that while in safetythymol seemed superior to all other efficient anthelmin-thics, in efficacy it was distinctly inferior to oil of cheno-podium, carbon tetrachloride and tetrachlorethylene,the last in dosage not exceeding 2 to 3 c.cm.-a viewhardly borne out by the conclusions of Maplestone andMukerji themselves.When I analysed (1929) all reports on deaths after

thymol that I could trace I noted that the lesions andsymptoms differed in all with the exception of twobrothers who died after an excursion together into thewoods ; such deaths can hardly have been due directlyto thymol. This and my experience of 50,000 treatmentsof Indians in their homes without anxiety, in a normaladult male dose of gr. 60, suggests that there could havebeen found in Calcutta 25 Indian patients to whom couldbe given in hospital without undue anxiety the full dosethat has been taken without a death in such greatnumbers elsewhere. Further, after two such treatmentsto Maplestone and Mukerji’s 25 patients, 80-5% of thetotal collection of necators was got away, while for ancy-lostomes the figure was 0-2 % (3 of 1328). In Egypt,where ancylostomes seem to be the only form of hook-worm reported, thymol has been widely given andesteemed. A drug which at this cure-rate would need500 treatments for unworming could not have held forso many years the repute that thymol did in Egypt andelsewhere.

DISCUSSION

The millions of doses of thymol that have been givenare a measure of its risk. As to anthelminthic valueMaplestone and Mukerji have reported on some hundredswith tetrachlorethylene. Their discrepant results do notlead to the conclusion that these hold generally.

Unfortunately the matter cannot rest there. In itsreview of Conybeare’s " Textbook of Medical Treat-ment " the Indian Medical Gazette (1939, 74, 638) says :" The chapter on tropical diseases is left in the experi-enced hands of Dr. Greig. Most of the treatment headvocates is sound and up to date, an exception beingthat he gives preference to thymol in the treatment ofankylostomiasis, for the very poor reason that a parti-cular worker who has had considerable experience in thetreatment of this infection considers it the best treatment.He does not mention that this particular worker retiredfrom the tropics 20 years ago and has obstinately refusedto see that since his day, more effective, more safelyadministered and cheaper drugs have been introduced."Is it suggested that personal experience with eachanthelminthic drug is necessary for right conclusions asto the grading of them all ? P For over ten years it hasbeen my duty to read all that is written all over the worldon helminthic and anthelminthic matters, in a singularlycomplete collection made by the staff of the Bureau ofTropical Diseases. Further, when I collected the citedevidence for the value of hookworm-killing drugs I didso with an open mind, and was surprised that on it I stillhad to put thymol first. I think there was, and still is,reasonable evidence that the drug’s position is whereAshford put it-that it is the safest of all efficientanthelminthics.

REFERENCES

Ashford, B. K. (1933) Section on duodenal parasites in E. L.Kellogg’s The Duodenum.

Lamson, P. D., Robbins, B. H. and Ward, C. B. (1929) Amer. J.Hyg. 9, 430.

Lane, Clayton (1929) Hookworm Infection, London.— (1935) Lancet, 1, 1459.

Maplestone, P. A. and Mukerji, A. K. (1929) Ind. med. Gaz. 64, 424.— — (1933) Ibid, 68, 617.— — (1937) Ibid, 72, 650.— — (1940) Ibid, 75, 193.

MODERN ANÆSTHESIA

IN his Honyman Gillespie lecture in Edinburgh lastweek Dr. John Gillies described some of the changes inanaesthetic practice which have taken place since the lastwar, at the end of which a vigorous fight was still goingon between the supporters of chloroform and of ether,with nitrous oxide and oxygen just fighting for recogni-tion. Ether won that struggle on account of its lowertoxicity. But now still less toxic drugs are comingforward-cyclopropane, ethylene and divinyl ether. Amixture of nitrous oxide and oxygen with ether is perhapsthe favourite anaesthetic, partly but not wholly_ on

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account of its cheapness. Ethylene, which has now beenused for some years, has a higher specific anaestheticvalue than nitrous oxide because of its greater lipoidsolubility, but cyclopropane is ousting it. Cyclopropanehas the advantage of being used with a high concentrationof oxygen-15% of cyclopropane to 85% of oxygen-whereas with nitrous oxide the proportions are reversed.Though expensive in bulk, so little is used with modernapparatus that the cost per operation is low. It isinflammable and explosive and must be used carefullyin the presence of the cautery ; the danger is lessenedby using the closed-circuit method. It is suitable for

patients of all ages. A great advance has also takenplace in premedication ; formerly atropine alone wasgiven, but atropine raises the threshold of anaesthesia.Today the purpose of premedication is to lower themetabolic rate and the threshold of anaesthesia by dimin-ishing emotional excitement. Morphine and hyoscineare satisfactory, and should be given in the proportionmorphine 25 : hyoscine 1. Avertin per rectum is widelyused especially for nervous patients ; Luminal gr. perstone of body-weight is also useful. Endotracheal admin-istration is becoming more popular, especially now that asatisfactorily wide tube can be passed into the larynxwithout a direct-vision laryngoscope. It enables theface to be completely covered with sterile towels,which has obvious advantages in operations on thehead and neck. The closed-circuit method enables auniform level of anaesthesia to be maintained with aminimum expenditure of anæsthetic—nitrous oxide,ether or cyclopropane. Experience is necessary ingiving intravenous anaesthetics, of which pentothalsodium is perhaps the most satisfactory. Drugs of thistype probably should not be used with sulphanilamide ;and they are also expensive. Respiratory depressioncan be counteracted bv picrotoxin. For continuedanaesthesia by this method the intravenous drip can

be used. The technique of spinal anaesthesia is moreeasily acquired than that of inhalation or intravenousanaesthesia. Dr. Gillies believes that procaine andNeocaine are the most satisfactory spinal anaesthetics,and that they can be used with advantage with verylight nitrous oxide or cyclopropane anaesthesia. So farin this war burns and lacerated wounds have beencommon, and in these the anaesthetic must not increasethe shock. Regional nerve-block is valuable, but spinalanaesthesia may cause a dangerous fall in blood-pressure,and should not be used unless the systolic pressure isabove 100 mm. Hg and shock very slight. For casualtywork the anaesthetic of choice is nitrous oxide and

oxygen or cyclopropane ; and Dr. Gillies advised thatchloroform and ether should be avoided as far as possible.

THE INFLEXIBLE CHEESE-MAKER

IT is always a little humbling to realise what a vastbody of technical knowledge goes to supply our everydaywants. Our shoes, our ships, and even our sealing-wax,only come our way because in each case a large quietbody of people is fantastically expert about detail.Cheese is a mundane enough substance, one of the oldestforms of food, but it still has its secrets and busy studentslabour to hunt them out. At the National Institute forResearch in Dairying (Annual Report, 1939) they havebeen conducting psycho-physical investigations to findout what makes the skilled cheese-maker so good at hisjob. It seems that cheese-makers, in the exercise oftheir craft, squeeze their cheeses-a sport which has hadpractical uses ever since Jack the Giant Killer turnedit to good account. The cheese-maker, when hesqueezes, is attempting to form a judgment on thequality of the cheese, and that judgment is probablybased, among other things, on its firmness, springinessor elasticity. Mr. G. W. Scott Blair, Ph.D., and MissValda Coppen of the chemistry department of theinstitute, have reported experiments 1 in which variouspeople-some of them cheese-makers and some not-were asked to form judgments on the firmness andelasticity, not of cheeses, but of substances in whichthese qualities could be exactly measured. The investi-gators would have liked to use cheese for the experimentsbut cheese, as they point out, changes its physical

1. Proc. roy. Soc. B. 1939, 128, 109; and Brit. J. Psychol. July, 1940,p. 61.

properties too rapidly and "it is not easy to obtainhomogeneous samples of any size." They had to devisean ingenious material made up from rubber solution,vaseline and plasticine, and the cheese-makers—allexcept one-pointed out that this was not at all thesame thing as cheese. ,

Twenty people were chosen to compare the firmnessof 8 samples of this synthetic material on a number ofdifferent days. They were asked to put the samples onthe bench in order of firmness using any method theyliked, short of tearing them in pieces. The caution mayhave been necessary ; the observers had found al-ready that after about six tests subjects began toshow signs of boredom. Their results are pleasantlyunexpected ; in the early stages of the experiment thetrained cheese-makers were slightly superior to the restbut as time went on they became inferior. Routineanalytical chemists, inexperienced in this type of testing,were very good at it and quickly excelled the cheese-makers. Other types of scientific training did not seemto influence either the success of the subject, his learningpower or the consistency of his results ; nor did sex.Only one of the cheese-makers approached the experi-ment in anything like a scientific spirit ; she expectedher previous experience to help her and it did ; herpowers of testing improved during the experiment. Theinvestigators attribute the failure of most cheese-makersto hold their own in the experiment to their mentalattitude. In the early stages the novelty of the testsand an open mind helped them to get good results, butlater the apparent purposelessness of the experimentcaused them to lose interest, especially as the wholething seemed to them to have been copied, and badlycopied at that, from their usual purposeful activities.Dr. Scott Blair and his colleague found that " howevermuch the expert may be urged to base his judgments ofcheese on the results of handling alone, he invariablyfinds great difficulty in keeping these judgments distinctfrom those derived from other senses." And who canblame him ? It is rather like asking a doctor to basehis opinion of the patient on the results of using astethoscope alone. The cheese-maker uses his eyes andnose as well as his hands and, being strictly practical,cannot see the point of analysing one sensation apartfrom the others. Yet to evaluate even one of theunconscious observations which form the basis of skilledjudgment is instructive. Psychology badly needs a

foundation of accurate experimental work of this kind.

THE MYSTERY OF GOUT

GOUT still attacks a few distinguished personages but itis not as common as it was and even uric acid has lostits force as a seller of patent medicines. Neverthelessthe disease is still with us and there is plenty of work yetto be done on its aetiology and cure. K. Brochner-Mortensen (Medicine, May, 1940, p. 161) has performed auseful service in reviewing what is known of the concen-tration of uric acid in the blood and its excretion in theurine. On reading his article one cannot help beingstruck by the fact that, as so often happens, advances inknowledge of this subject have originated either from animproved analytical technique or from some discoveryin an adjacent field of science. Thus the article tracesout the way in which our knowledge of the concentrationand variations of uric acid in the blood have become moreand more exact as methods for its determination havebecome more perfect ; and how the study of its excretionhas profited from all the work which has been done in thelast twenty years on other functions of the kidney. Thearticle is informative, easily written and well documented,but it reveals our lamentable ignorance of uric-acidmetabolism. The cause of gout remains one of theunsolved mysteries of medicine. One cannot helpwondering whether the problem will be solved by adoctor, a colloid chemist or an accident. Possibly allthree may have to collaborate.

MESSRS. ALLEN & HANBURYS have submitted a sounddeadener consisting of a malleable plug made fromspecially prepared fibrous clay which can be softenedbetween the fingers and pressed into the ear. It isdesigned to exclude noise and protect the ear drums.The price is Is. per pair.