TRIMETHOL
Report of the Council on Pharmacy and Chemistry
Trimethol is the trade name for a substance said to be trimethyl-methoxy-phenol of the formula C6H(CH3)3(OCH3).OH—1:2:4:5:6, originated by J. T. Ainslie Walker. It is sold as a nontoxic germicide, having a Rideal-Walker phenol-coefficient of 40, even in the intestinal canal. It is described as insoluble in water and not to be decomposed in the alimentary tract, and to be excreted unchanged in the feces.
Trimethol itself is not obtainable. Pharmaceutical preparations—Trimethol Syrup, Trimethol Capsules and Trimethol Tablets, said to contain Trimethol—are prepared by The Walker-Leeming Laboratories and sold by Thos. Leeming and Co., New York.
Trimethol preparations are advertised for use in all conditions dependent on intestinal putrefaction. The advertising claims made are very extensive and some of them give to “Trimethol” the scope of a panacea. For example:
“Physicians are constantly reporting cases where Trimethol has been especially efficient, and describing conditions (until recently not associated with intestinal infection) which have been distinctly benefited by its use. This would seem to bear out the contentions of Charcot and Metchnikoff that 90% of all human ailments have their origin in intestinal infection.
“The careful practitioner, when in doubt, will bear this in mind, now that we have a really efficient and non-toxic intestinal germicide—not a mere antiseptic.”
The Walker-Leeming Laboratories have not formally requested the Council to consider the Trimethol preparations, though in a personal letter to a member of the Council J. T. Ainslie Walker invited an investigation of his compound.
For the investigation of Trimethol and its preparation the Council secured the aid of a bacteriologist who has given much attention to the study of the intestinal flora. The Walker-Leeming Laboratories and J. T. Ainslie Walker were both asked to submit details of experimental studies and also to furnish a supply of the pure “Trimethol.” But the only data sent that had any definiteness set forth the bacterial counts made of plate cultures of stools of one patient before and after the administration of Trimethol Capsules.
REFUSE TO FURNISH TRIMETHOL
The request for the pure substance was refused, on the grounds that the substance was not used in the undiluted form. The failure to furnish the chemical substance claimed as the essential constituent of the Trimethol preparations is to be deprecated if indeed it has not greater significance. At least it made it impossible for the Council’s expert to express his results in terms of absolute Trimethol of established composition. The data obtained apply only to the market preparations claimed to contain Trimethol. So far as the investigation and report go, “Trimethol” is a hypothetical substance.
Clinical or animal tests of the asserted intestinal antiseptics have hitherto given equivocal results because it is impossible, on the one hand, to predict the course of any intestinal infection, or, on the other hand, to determine what effect, if any, was produced by administration of the medicament. It therefore seemed unwise to undertake this line of investigation until the more direct laboratory bacteriologic methods had been exhausted. Consequently the investigator checked, in the first place, the phenol coefficient of one of the Trimethol preparations and then also determined its “penetrability” coefficient. Although by both methods Trimethol was found to be a germicide, the results did not indicate any remarkable potency or other properties suggesting that the drug possessed special therapeutic value. From the results obtained it appeared inadvisable to proceed further with the work until more definite evidence of the nature and of the value of the substance should be at hand. The report of the bacteriologic investigation follows:
THE BACTERIOLOGIST’S REPORT
“I have made no attempt to study the effects of internal administration of Trimethol on the intestinal flora. The methods available at the present time of enumerating the numbers of viable bacteria in the feces are probably not accurate within 100 per cent. and the precision of such determinations is equally variable. The physiologic factors involved are so complex that they would appear to make a really valuable assay a question of many months’ careful study. If it were possible to administer known amounts of Trimethol, as such, the problem might be worth while; inasmuch as the available reactive substance is not at present quantitatively assayable, this phase of the investigation barely seems practicable.
“ ‘Trimethol Syrup,’ as such, appears to be about 10 per cent. as efficient in its germicidal value as carbolic acid. If the assay, 3⁄4 m. Trimethol per drm. (as the label indicates), is correct, the substance would appear to possess germicidal merit provided enough could be administered, if it is not influenced by passage through the stomach.
“A package containing four four-ounce bottles labeled ‘Trimethol, A Non-Toxic Germicide SYRUP Representing 3⁄4 m. Trimethol per drm., Alcohol 11⁄2 per cent.’ was received at the laboratory Dec. 15, 1916. Later a smaller package containing, according to the label, 100 Trimethol tablets, each 5 gr., representing 11⁄4 m. Trimethol, was received. The tablets were apparently chocolate coated.
“Two separate series of tests were made upon the syrup. (a) Phenol coefficient, using the method outlined in Bulletin No. 82, Hygienic Laboratory, Method of Standardizing Disinfectants With and Without Organic Matter. (b) A Penetrability coefficient by the method of Kendall and Edwards, Journal of Infectious Diseases, 8, 250.
“The former method compares the viability of naked germs in a 1 per cent. carbolic acid solution as a standard, with various dilutions of the germicide to be tested. The latter measures the relative diffusibility and germicidal power of carbolic acid and various dilutions of the germicide to be tested upon Bacillus coli suspended in 1.2 per cent. agar which is molded in cylinders of one centimeter diameter after infection with the organism.
“The first method—phenol coefficient—possesses advantages and disadvantages which are well known and need no mention here. It is worthy of notice, however, that as the death rate of the bacteria increases during the progress of the test, it becomes increasingly difficult to maintain a uniform suspension of living organisms so that each loopful removed shall exactly represent the developmental potentiality of the residual organisms.
“The second method theoretically covers the possibility because all the organisms are immobilized and are exposed to the germicide in direct proportion to its diffusibility until the center of the agar mass is reached, where the residual viable bacteria are presumably located. Inasmuch as the penetrability of an intestinal mass is involved in a discussion of intestinal germicides, the propriety of utilizing this ‘penetrability coefficient’ in this connection is obvious, in spite of its patent shortcomings.
“It is unnecessary to discuss the technique—the standard broth mentioned in the Hygienic Bulletin, a temperature of 70 F., a standard 4 mm. loop and careful attention to dilutions (using distilled water) were all observed. The various dilutions of Trimethol Syrup were made with accurate volumetric pipettes, measuring flasks and distilled water was used as a diluent.
“The results of several determinations, using Trimethol Syrup from three separate bottles, were in sufficient accord to warrant the statement that a dilution of 1⁄10 of Trimethol Syrup was equivalent to a 1⁄100 dilution of carbolic acid, using Bacillus typhosus as the test organism. Both solutions—the Trimethol and phenol—killed the organism in the interval between 71⁄2 minutes and 10 minutes’ exposure. That is to say, our observations indicate that under standard conditions as defined above, a 10 per cent. solution of Trimethol Syrup is equivalent in germicidal powers, as defined by the phenol coefficient to a 1 per cent. solution of phenol. Naturally, no predictions can be drawn from these observations indicative of the value as an intestinal germicide of Trimethol itself.
“The Penetrability coefficient resulted as follows: A 5 per cent. solution of phenol killed Bacillus coli, suspended uniformly throughout a cylinder of 1.2 per cent. agar in the interval between 60 and 90 minutes. A 1 per cent. solution of phenol killed the same organisms under the same conditions in the interval between two and one half and three hours. An undiluted solution of Trimethol Syrup killed the organisms in the interval between two and one half and three hours. A 10 per cent. solution (nine volumes of distilled water to one volume of Trimethol Syrup) failed to kill the organisms in four hours. It would appear that undiluted Trimethol Syrup has the same combined penetrability and germicidal value as a 1 per cent. phenol solution.
“The Phenol coefficient: A 10 per cent. solution of Trimethol Syrup in distilled water (nine volumes of distilled water to one volume of Trimethol Syrup) possesses the same germicidal power as a 1 per cent. solution of carbolic acid. This coefficient takes no cognizance of the actual amount of Trimethol as such—it merely indicates the relative germicidal power of the Trimethol Syrup as sold.”
The preceding report shows that Trimethol Syrup has a phenol coefficient of 1⁄10, and, assuming Trimethol Syrup contains the amount of Trimethol declared, the substance Trimethol would have a phenol coefficient of 81⁄3 instead of 40, as is claimed. According to Kendall and Edwards’ method, the penetrability-germicidal value of the syrup is equal to a 1 per cent. solution of phenol.
WALKER’S REPLY TO CRITICISM
The report of the bacteriologist was submitted to The Walker-Leeming Laboratories for comment. The following reply was received from J. T. Ainslie Walker:
(May 22, 1917) “In reply to your letter of the 15th inst., which has just been placed before me on my return to town, I have to inform you that the potent constituent of Trimethol Tablets and Trimethol Syrup is not fully available as a bactericide until it comes in contact with the pancreatic fluid.
“As you will see from the enclosed extracts from clinical reports, the therapeutic value of Trimethol has been well established.
“As regards penetrability, no claim has ever been made for Trimethol in this connection; and, as I pointed out in my original paper (American Medicine, September, 1914), when referring to the independent tests made by Dr. Frederick Sondern, ‘No attempt was made to determine the bacterial content of the solid particles, as in the opinion of the writer sterilization of the interior of these particles is not only absolutely impossible, but wholly unnecessary. The fact of the fluid contents of the canal being sterile may be taken to indicate that the exterior of all solid particles is in a like condition, and therefore harmless. It is the organisms in the fluid portions only that produce the deadly effects through the chemical substances they secrete; those in the interior of the solid portions (i. e., as evacuated) may be disregarded, as they are not available for good or evil.’
“I must confess to no little surprise on learning that your investigator is still using the Hygienic Laboratory method of determining phenol coefficients. I would respectfully suggest that you call his attention to the critical comparison of the Hygienic Laboratory and R.-W. Tests, which he will find in the enclosed reprint from the New York Medical Journal of March 11, 1916: ‘Instead of being an improvement upon the standard R.-W. Test, the so-called Hygienic Laboratory Method is so defective as to be wholly unreliable, and incapable of furnishing results of any scientific or practical value whatever.’ ”
As to the statement that the potent constituent of Trimethol Tablets and Trimethol Syrup is not fully available as a bactericide until it comes in contact with the pancreatic fluid, attention is called to a leaflet, which accompanies each bottle of Trimethol Syrup, that reads:
“Trimethol is insoluble in water, but when properly emulsified has a Rideal-Walker co-efficient of 40; that is to say, it is 40 times more efficient as a germicide than phenol (pure carbolic acid).”
The Trimethol Syrup which was used in the investigation, when mixed with water produced an almost perfectly transparent solution, which justifies the assumption that the proper physical conditions were observed and that this objection is not well founded.
As regards the relation of pancreatic fluid to bactericidal availability of Trimethol, there is little to say, other than that the published statements in the advertising accompanying the packages make no mention of this point. It would be interesting to know what, if any, relation the pancreatic fluid has to this substance, in view of the statement that it “has a Rideal-Walker coefficient of 40.”
The Trimethol “literature” does not throw light on the question, What is the germicidal value of Trimethol Syrup as compared with phenol? The only available method of determining the germicidal value of a liquid disinfectant is to make a direct comparison of the substance in question with phenol under similar conditions. Given parallel conditions, not obviously prejudicial to the substance tested in contrast to the standard solution, the results are comparable, and furnish a basis for estimating the relative germicidal power of the two substances. In the investigation, Trimethol Syrup and phenol were thus compared.
As regards the contention that the bacteria within fecal masses are harmless, this may be granted. But it must also be admitted that these intestinal masses are constantly being reformed so that buried micro-organisms do not remain in the interior. For this reason, the determination of the penetrability coefficient of a germicide is pertinent.
Regarding the respective merits of the old Rideal-Walker and the newer U. S. Hygienic Laboratory method of determining the phenol coefficient, the Rideal-Walker method was found to possess certain drawbacks, and in an attempt to overcome these the “Lancet Method” was evolved; this method in turn was improved in the U. S. Hygienic Laboratory and led to the United States Public Health Service Hygienic Laboratory method for the determination of the phenol coefficient of disinfectants (published in Hygienic Laboratory Bulletin 82). In 1913 this method was formally adopted by the Council for the valuation of disinfectants or germicides of the phenol type, and the method is now in general use for this purpose in the United States.[119] In this connection Hiss and Zinsser may be quoted (Ed. 2, page 80): “The most precise method of standardizing disinfectants is that now in use in the United States Public Health Service.” Stitt, director of the United States Naval Medical Schools, in his Practical Bacteriology, Blood Work and Parasitology (Ed. 4, page 473) says: “In the United States disinfectants are rated according to the Hygienic Laboratory Phenol Coefficient.”
The Council adopted the recommendation of the Committee on Pharmacology to the effect that the claims made for Trimethol are unsupported by acceptable evidence. Accordingly, Trimethol and the pharmaceutical preparations said to contain it—Trimethol Syrup, Trimethol Capsules, and Trimethol Tablets—were held ineligible for New and Nonofficial Remedies.—(From The Journal A. M. A., Aug. 11, 1917.)