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THYMOL AS AN ANTHELMINTHIC
349
Notes, Comments
and
all fear of thymol ; and secondly, that while in safety thymol seemed superior to all other efficient anthelminthics, in efficacy it was distinctly inferior to oil of chenopodium, carbon tetrachloride and tetrachlorethylene, the last in dosage not exceeding 2 to 3 c.cm.-a view hardly borne out by the conclusions of Maplestone 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 human life and human happiness at stake that the immediate future should see a serious effort made, by unprejudiced and independent medical workers, to add to acceptable and controlled evidence regarding the real value and safety of hookworm-killing drugs " (Lane 1935). Maplestone and Mukerji, writing from the School of Tropical Medicine, Calcutta, where both necators and ancylostomes are met with, have since, in self-imposed limiting conditions, treated three series of patients, each numbering 25, with thymol, with tetrachlorethylene and with tetrachlorethylene combined with oil of chenopodium ; and they have put tetrachlorethylene in the first place on grounds of safety, efficiency, cheapness and ease of administration. Tetrachlorethyleme.—These writers, after experiments on cats (1934) and many years practical experience in treatment of man, give tetrachlorethylene in dosage of 4 c.cm. After experiments on 116 animals of varying species, Lamson, Robbins and Ward (1929) wrote of tetrachlorethylene, " The degree of absorption varies greatly with the species." What is the evidence that experiments on cats may confidently be transferred to man ? In determining the safety of anthelminthics in man it is numbers of treatments that matter (Maurice Hall advised 100,000) and not the years over which a series was spread. Maplestone and Mukerji (1929) treated 28 persons with 3 c.cm. of this drug in soft capsules with a cure rate of 16-7%. Some years later they came on a stored box of these capsules collapsed and empty, and suggested (1937) that evaporation had already begun before they used them in their test. But they could have noticed nothing amiss with these soft capsules during their test and indeed they reported the actual giving of 3 c.cm. of the drug from opened capsules. Even if they merely concluded that these still contained the full amount of the drug they are faced with Ashford’s opinion, which they clearly value highly, that its dose should not exceed 2 or 3 c.cm. ; the capsules could hardly have lost a third of their contents without obvious shrinkage and if they had not lost so much their contents would have been within his advised dosage. In the same paper (1937) they reported on 81 persons whom they were able to follow up after giving them 4 c.cm. of the drug ; there was a cure of 61-7%, near cure bringing the figure up to 75-3 %. In 1940, again using an adult dose of 4 c.cm., they cured 36% of 25 patients (near cures bring the percentage to 88) and brought away 99-1 % of the total bag of necators and 96-1 % of that of ancylostomes. Do these small numbers give significant results ? They seem significantly different. Tetrachlorethylene and oil of chenopodium.—When, to their adopted dose of 4 c.cm. of tetrachlorethylene, Maplestone and Mukerji (1940) added 1 c.cm. of oil of chenopodium of B.P. strength, they reduced worm removals. These were only 38-3 % in place of 99-1 % with tetrachlorethylene for necators, and 23.9 % in place of 96-1 % for ancylostomes. In 1933 this dosage had unwormed 62 % of 50 patients in one treatment. In the 25 patients reported in 1940 the rate was 48 "/’0. The figures are discrepant ; and two proved anthelminthic drugs taken together gave poorer results than one taken alone. Thymol.-The widely accepted dose of thymol is gr. 60 (4 g.). In no case did Maplestone and Mukerji give as much, saying that they had not reduced the dose to decry its value but that they were guided by Ashford’s widely based opinion (to which they give no reference) that for safety the dose of thymol must be carefully regulated, and they were dealing with underweight adults. Just before his death Ashford summed up his great experience of thymol by saying (1933) that the adult dose was 4 g. but was frequently lowered for women. He added, first, that after the administration of over a million doses without fatalities in the days when rum, a solvent of thymol, was plentiful, he had lost almost
Mukerji themselves. When I analysed (1929) all reports on deaths after thymol that I could trace I noted that the lesions and symptoms differed in all with the exception of two brothers who died after
excursion together into the hardly have been due directly to thymol. This and my experience of 50,000 treatments of Indians in their homes without anxiety, in a normal adult male dose of gr. 60, suggests that there could have been found in Calcutta 25 Indian patients to whom could be given in hospital without undue anxiety the full dose that has been taken without a death in such great numbers elsewhere. Further, after two such treatments to Maplestone and Mukerji’s 25 patients, 80-5% of the total collection of necators was got away, while for ancyIn Egypt, lostomes the figure was 0-2 % (3 of 1328). where ancylostomes seem to be the only form of hookworm reported, thymol has been widely given and esteemed. A drug which at this cure-rate would need 500 treatments for unworming could not have held for so many years the repute that thymol did in Egypt and
woods ; such deaths
an
can
elsewhere. DISCUSSION
The millions of doses of thymol that have been given are a measure of its risk. As to anthelminthic value Maplestone and Mukerji have reported on some hundreds with tetrachlorethylene. Their discrepant results do not lead to the conclusion that these hold generally. Unfortunately the matter cannot rest there. In its review of Conybeare’s " Textbook of Medical Treatment " the Indian Medical Gazette (1939, 74, 638) says : " The chapter on tropical diseases is left in the experienced hands of Dr. Greig. Most of the treatment he advocates is sound and up to date, an exception being that he gives preference to thymol in the treatment of ankylostomiasis, for the very poor reason that a particular worker who has had considerable experience in the treatment of this infection considers it the best treatment. He does not mention that this particular worker retired from the tropics 20 years ago and has obstinately refused to see that since his day, more effective, more safely administered and cheaper drugs have been introduced." Is it suggested that personal experience with each anthelminthic drug is necessary for right conclusions as to the grading of them all ?P For over ten years it has been my duty to read all that is written all over the world on helminthic and anthelminthic matters, in a singularly complete collection made by the staff of the Bureau of Tropical Diseases. Further, when I collected the cited evidence for the value of hookworm-killing drugs I did so with an open mind, and was surprised that on it I still had to put thymol first. I think there was, and still is, reasonable evidence that the drug’s position is where Ashford put it-that it is the safest of all efficient anthelminthics. 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. —
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MODERN ANÆSTHESIA IN his Honyman Gillespie lecture in Edinburgh last week Dr. John Gillies described some of the changes in anaesthetic practice which have taken place since the last war, at the end of which a vigorous fight was still going on between the supporters of chloroform and of ether, with nitrous oxide and oxygen just fighting for recognition. Ether won that struggle on account of its lower toxicity. But now still less toxic drugs are coming forward-cyclopropane, ethylene and divinyl ether. A mixture of nitrous oxide and oxygen with ether is perhaps the favourite anaesthetic, partly but not wholly_ on
Notes, Comments
and
all fear of thymol ; and secondly, that while in safety thymol seemed superior to all other efficient anthelminthics, in efficacy it was distinctly inferior to oil of chenopodium, carbon tetrachloride and tetrachlorethylene, the last in dosage not exceeding 2 to 3 c.cm.-a view hardly borne out by the conclusions of Maplestone 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 human life and human happiness at stake that the immediate future should see a serious effort made, by unprejudiced and independent medical workers, to add to acceptable and controlled evidence regarding the real value and safety of hookworm-killing drugs " (Lane 1935). Maplestone and Mukerji, writing from the School of Tropical Medicine, Calcutta, where both necators and ancylostomes are met with, have since, in self-imposed limiting conditions, treated three series of patients, each numbering 25, with thymol, with tetrachlorethylene and with tetrachlorethylene combined with oil of chenopodium ; and they have put tetrachlorethylene in the first place on grounds of safety, efficiency, cheapness and ease of administration. Tetrachlorethyleme.—These writers, after experiments on cats (1934) and many years practical experience in treatment of man, give tetrachlorethylene in dosage of 4 c.cm. After experiments on 116 animals of varying species, Lamson, Robbins and Ward (1929) wrote of tetrachlorethylene, " The degree of absorption varies greatly with the species." What is the evidence that experiments on cats may confidently be transferred to man ? In determining the safety of anthelminthics in man it is numbers of treatments that matter (Maurice Hall advised 100,000) and not the years over which a series was spread. Maplestone and Mukerji (1929) treated 28 persons with 3 c.cm. of this drug in soft capsules with a cure rate of 16-7%. Some years later they came on a stored box of these capsules collapsed and empty, and suggested (1937) that evaporation had already begun before they used them in their test. But they could have noticed nothing amiss with these soft capsules during their test and indeed they reported the actual giving of 3 c.cm. of the drug from opened capsules. Even if they merely concluded that these still contained the full amount of the drug they are faced with Ashford’s opinion, which they clearly value highly, that its dose should not exceed 2 or 3 c.cm. ; the capsules could hardly have lost a third of their contents without obvious shrinkage and if they had not lost so much their contents would have been within his advised dosage. In the same paper (1937) they reported on 81 persons whom they were able to follow up after giving them 4 c.cm. of the drug ; there was a cure of 61-7%, near cure bringing the figure up to 75-3 %. In 1940, again using an adult dose of 4 c.cm., they cured 36% of 25 patients (near cures bring the percentage to 88) and brought away 99-1 % of the total bag of necators and 96-1 % of that of ancylostomes. Do these small numbers give significant results ? They seem significantly different. Tetrachlorethylene and oil of chenopodium.—When, to their adopted dose of 4 c.cm. of tetrachlorethylene, Maplestone and Mukerji (1940) added 1 c.cm. of oil of chenopodium of B.P. strength, they reduced worm removals. These were only 38-3 % in place of 99-1 % with tetrachlorethylene for necators, and 23.9 % in place of 96-1 % for ancylostomes. In 1933 this dosage had unwormed 62 % of 50 patients in one treatment. In the 25 patients reported in 1940 the rate was 48 "/’0. The figures are discrepant ; and two proved anthelminthic drugs taken together gave poorer results than one taken alone. Thymol.-The widely accepted dose of thymol is gr. 60 (4 g.). In no case did Maplestone and Mukerji give as much, saying that they had not reduced the dose to decry its value but that they were guided by Ashford’s widely based opinion (to which they give no reference) that for safety the dose of thymol must be carefully regulated, and they were dealing with underweight adults. Just before his death Ashford summed up his great experience of thymol by saying (1933) that the adult dose was 4 g. but was frequently lowered for women. He added, first, that after the administration of over a million doses without fatalities in the days when rum, a solvent of thymol, was plentiful, he had lost almost
Mukerji themselves. When I analysed (1929) all reports on deaths after thymol that I could trace I noted that the lesions and symptoms differed in all with the exception of two brothers who died after
excursion together into the hardly have been due directly to thymol. This and my experience of 50,000 treatments of Indians in their homes without anxiety, in a normal adult male dose of gr. 60, suggests that there could have been found in Calcutta 25 Indian patients to whom could be given in hospital without undue anxiety the full dose that has been taken without a death in such great numbers elsewhere. Further, after two such treatments to Maplestone and Mukerji’s 25 patients, 80-5% of the total collection of necators was got away, while for ancyIn Egypt, lostomes the figure was 0-2 % (3 of 1328). where ancylostomes seem to be the only form of hookworm reported, thymol has been widely given and esteemed. A drug which at this cure-rate would need 500 treatments for unworming could not have held for so many years the repute that thymol did in Egypt and
woods ; such deaths
an
can
elsewhere. DISCUSSION
The millions of doses of thymol that have been given are a measure of its risk. As to anthelminthic value Maplestone and Mukerji have reported on some hundreds with tetrachlorethylene. Their discrepant results do not lead to the conclusion that these hold generally. Unfortunately the matter cannot rest there. In its review of Conybeare’s " Textbook of Medical Treatment " the Indian Medical Gazette (1939, 74, 638) says : " The chapter on tropical diseases is left in the experienced hands of Dr. Greig. Most of the treatment he advocates is sound and up to date, an exception being that he gives preference to thymol in the treatment of ankylostomiasis, for the very poor reason that a particular worker who has had considerable experience in the treatment of this infection considers it the best treatment. He does not mention that this particular worker retired from the tropics 20 years ago and has obstinately refused to see that since his day, more effective, more safely administered and cheaper drugs have been introduced." Is it suggested that personal experience with each anthelminthic drug is necessary for right conclusions as to the grading of them all ?P For over ten years it has been my duty to read all that is written all over the world on helminthic and anthelminthic matters, in a singularly complete collection made by the staff of the Bureau of Tropical Diseases. Further, when I collected the cited evidence for the value of hookworm-killing drugs I did so with an open mind, and was surprised that on it I still had to put thymol first. I think there was, and still is, reasonable evidence that the drug’s position is where Ashford put it-that it is the safest of all efficient anthelminthics. 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 last week Dr. John Gillies described some of the changes in anaesthetic practice which have taken place since the last war, at the end of which a vigorous fight was still going on between the supporters of chloroform and of ether, with nitrous oxide and oxygen just fighting for recognition. Ether won that struggle on account of its lower toxicity. But now still less toxic drugs are coming forward-cyclopropane, ethylene and divinyl ether. A mixture of nitrous oxide and oxygen with ether is perhaps the favourite anaesthetic, partly but not wholly_ on