Volume 1 / Part 1 — FOREWORD (continued 10)
Reading edition
Concerning the composition of the plant from which Syrup Leptinol is prepared, the Balsamea Company states that it contains “Alkaloids, acids, glucosides, volatile and fixed oils, gums and resins.” This information is valueless, since no information is given concerning the character, amounts or pharmacologic action of the ingredients. Further, it is unreliable as far as the presence of alkaloids is concerned since the A. M. A. Chemical Laboratory has been unable to find any alkaloids in the specimen of the crude drug furnished by the manufacturers.
In accordance with its regular procedure, the Council submitted the preceding statement to the manufacturer.
In reply the Balsamea Company stated that it is more than ever of the belief that Syrup Leptinol is deserving of recognition by the Council, basing this opinion on further clinical experience with it in the treatment of influenza.
The manufacturer stated that the use of the words “Leptinol” and “Syrup Leptinol” interchangeably was due to an oversight and promised to limit the use of the word “Leptinol” to an alcoholic extract of the plant.
Concerning the method of preparation of this alcoholic extract and the amount used in the preparation of Syrup Leptinol the Balsamea Company replied as follows:
“The alcoholic extract of the Leptotaenia, which we have termed ‘Leptinol’ is a preparation of definite and uniform strength, as determined by two methods: (a) the gravity test using the U. S. Hydrometer Scale for spirits, by which Leptinol registers 52 degrees at 60 degrees F., and (b) by gentle evaporation of the alcohol content and the measuring of the active constituents, which measures twenty-five per cent. by weight.
“The alcoholic extract ‘Leptinol’ is glycerinated in a machine, using one part of the alcoholic concentration to four parts of glycerin. This is then added to eleven parts of a heavy syrup, containing 71⁄2 pounds of sugar to the gallon of syrup, and thoroughly mixed in an agitating machine. Leptinol is the sole active ingredient of Syrup Leptinol. Syrup Leptinol is a preparation of uniform strength. It is far more uniform in strength than most of the syrups of the U. S. P. made from fluid extracts which are made from crude drugs which are not uniform in strength.”
This claim cannot be allowed as meeting the conflict with Rule 1. It is well known that plants vary in their composition at different times of the year; under different conditions of cultivation and growth; and under other conditions; hence the claim that alcoholic extracts of equal specific gravity insure uniformity of composition in active principles must be considered entirely illogical, especially since the exact nature of the active principles, if any be present, is unknown. If these are known their nature should be stated and tests for their identity be given. If they are unknown it is manifestly misleading to state that the preparation is of uniform strength.
It is evident that the Council cannot approve of the use of a preparation of unknown composition without satisfactory evidence of its value, especially when it is recommended in a variety of serious infectious diseases such as influenza and pneumonia. The mere fact that a small number of patients who have received the drug recover is no evidence of its curative value, and until carefully controlled clinical tests of the preparation are made, it is not entitled to the consideration of physicians.—(From The Journal A. M. A., June 5, 1920.)
FORMITOL TABLETS, II
Report of the Council on Pharmacy and Chemistry
The Council has authorized publication of the following supplementary report on Formitol Tablets.
W. A. Puckner, Secretary.
In the Council report (The Journal A. M. A., Oct. 4, 1919, p. 1077) on the ineffectiveness of lozenges claimed either to contain formaldehyd or to liberate formaldehyd in the mouth, the composition of Formitol Tablets of the E. L. Patch Co. was briefly discussed in the following terms:
“The A. M. A. Chemical Laboratory reported that Formitol Tablets contained formaldehyd (or paraformaldehyd), an ammonium compound, and some hexamethylenamin. It is probable that the formaldehyd (or paraformaldehyd) was produced by the decomposition of hexamethylenamin originally present in the tablets but decomposed by long contact with the acid.”
At the time this report was published, the label and the advertising matter contained but vague and indefinite statements with regard to the composition of Formitol Tablets. In the October, 1919, issue of Patchwork, the house organ of the E. L. Patch Co., it was denied that these tablets contain hexamethylenamin since none had ever been used in their manufacture. It was also claimed that the company had a “printed sheet giving the formula of these tablets.”
The Council advised the E. L. Patch Co. that it desires to publish only facts about the products which it examines and that if the report on Formitol Tablets was inaccurate in any way the Council would want to correct any error it might have unintentionally made. As the Formitol advertising in the files of the Council contained no information as to the composition of the tablets, the firm was also requested to send the printed sheet giving the “formula.”
When this printed “formula” came it was found to be a sheet used by the E. L. Patch Co. for the purpose of giving its salesmen information regarding Formitol tablets, to be passed on to the physician. This printed sheet conveyed the information that Formitol Tablets contain ammonium chlorid, benzoic acid, citric acid, guaiac, hyoscyamus, menthol, paraformaldehyd and tannic acid, but it gave no information in regard to the amount of any of the ingredients except that it declared that each tablet represents the equivalent of 10 minims of a 1 per cent. formaldehyd solution.
Because of the nonquantitative, and, therefore meaningless printed “formula” and because, also, of its complexity, it was thought desirable to make a more complete analysis of Formitol Tablets. Experience has shown that frequently the real formula of a thing is quite different from the alleged formula published by the manufacturer. The details of the laboratory’s later analysis will appear in the Annual Reports of the Chemical Laboratory or may be had on request.
The result of the laboratory’s additional experimental work, especially when taken in connection with investigations made elsewhere on the interaction of formaldehyd and ammonium chlorid justifies the conclusion that Formitol Tablets do contain some hexamethylenamin, even though the amount may be very small. As the E. L. Patch Co. declare that no hexamethylenamin is put into Formitol Tablets the conclusion drawn in the Council’s original report to the effect that the formaldehyd probably was formed by the decomposition of hexamethylenamin was evidently an error. The hexamethylenamin present is doubtless produced by the action of the paraformaldehyd on the ammonium chlorid present.
The analysis also showed that more than 78 per cent. of the weight of Formitol Tablets was made up of sugars and about 16.5 per cent. was starch and other material, some of which was talcum or similar material. This means that about 94 per cent. of the total weight of the tablets is sugar and starch, neither of which is mentioned in the printed “formula.” The significance of this is apparent when it is considered that there are eight ingredients listed in the “formula” for which therapeutic effects are claimed. Since a tablet weighs about 13.5 grains, the combined weight of all the claimed active ingredients is less than 1 grain per tablet!
The amount of ammonium chlorid found, as indicated by the total nitrogen, was not more than 1.0 per cent. or about 1⁄8 grain per tablet. The amount of benzoic acid found was 0.34 per cent. or 1⁄25 grain per tablet. Yet these two drugs are said to exert their peculiar expectorant action. (The U. S. P. lozenge of ammonium chlorid contains 11⁄2 grains ammonium chlorid or twelve times the amount of this drug in a Formitol Tablet.)
The tannic acid contained in the tablets could not be determined with accuracy but it was much less than 1 per cent. (or 1⁄8 grain per tablet) yet it is said to add valuable astringent qualities to Formitol Tablets! (The U. S. P. lozenge of tannic acid contains 1 grain of tannic acid.)
The quantity of guaiac (as resin) is but a fraction of 1 per cent. Yet it is said to impart to Formitol Tablets “stimulant resolvent” properties and it is intimated that there is sufficient to be of value in “cases of abscess of the throat and inflammation of the tissues.”
The total acidity indicates the presence of about 2 per cent. of citric acid or 1⁄4 grain per tablet. Yet this amount is said to be “antiseptic” and “aids in the general results.”
While the presence of the drug hyoscyamus (henbane) was not positively identified by microscopic examination, alkaloids were present.
The manufacturers claim that the tablets contain menthol yet only a suggestion of menthol could be obtained from the odor. However, the odor of methyl salicylate—a constituent not declared in the “formula”—predominated throughout the operations of analysis.
Formitol Tablets furnish a good illustration of some well established but often ignored truths:
1. “Formulas” that are nonquantitative are valueless or worse than valueless.
2. The fact that a manufacturer puts certain drugs in a mixture, is no proof that these drugs are there when the mixture reaches the patient. The physician must be assured that they are there when he prescribes them.
3. Complex mixtures should be avoided. It is absurd to expect, as is claimed in the case of Formitol Tablets, anodyne, antiseptic, astringent, expectorant, and resolvent action all at the same time.—(From The Journal A. M. A., June 19, 1920.)
SUKRO-SERUM AND APHLEGMATOL
Report of the Council on Pharmacy and Chemistry
Two years ago, American newspapers contained accounts of an alleged cure for pulmonary tuberculosis “discovered” by Prof. Domenico Lo Monaco of Rome, Italy. At that time no reference to the “cure” could be found in medical journals which had come from Italy and other European countries (The Journal A. M. A., July 13, 1918, p. 142). Later, reports were published of experiments carried out in Italy, according to which the intramuscular injection of solutions of sugar (saccharose—cane sugar) diminished pulmonary secretion and was of considerable value in the treatment of tuberculosis (The Journal A. M. A., Sept. 28, 1918, p. 1083). On the whole the reports of the trial of what has been called the Italian Sugar Cure for Consumption have been unfavorable. At a meeting in Paris in October, 1918, Drs. Louis Rénon and Mignot reported that they had found that the disease in guinea-pigs was not modified by the treatment and with humans the results were also negative (Paris Letter, The Journal A. M. A., Nov. 23, 1918, p. 1760).
In view of the exploitation of this treatment in the United States by the Anglo-French Drug Co., which offers “Sukro-Serum,” and by G. Giambalvo & Co., which sells “Aphlegmatol,” and because of inquiries received, the Council has authorized publication of the statement which follows.
W. A. Puckner, Secretary.
A circular issued by the Anglo-French Drug Co., describes “Sukro-Serum” as a “Sterilized Solution of lacto-gluco-saccharose.” By reading the circular to the end, however, one learns that “Sukro-Serum” is not a “serum” in the ordinary sense but apparently it is a solution of ordinary sugar (sucrose). “Sukro-Serum is a sterilized, specially prepared solution of Saccharose.”
Sukro-Serum has been advertised (N. Y. Med. Jour., Sept. 6, 1919) as an “INTRAMUSCULAR INJECTION FOR TUBERCULOSIS” “... ready for use in cases of Pulmonary and general Tuberculosis” with the assertion that “It is quite certain that in the near future Sukro-Serum will be largely used and its value fully recognized.” The circular received from the Anglo-French Drug Co. contains quotations from an article by Professor Lo Monaco in the British Medical Journal (Aug. 24, 1918) setting forth the merits of intramuscular injections of sucrose in tuberculosis. It is recommended that “Néocaine-Surrénine” (which the Anglo-French Drug Co. supplies) be used for the control of pain when Sukro-Serum is injected.
The circular enclosed with a package of “Aphlegmatol,” purchased from G. Giambalvo & Co., contained the following with reference to the composition of this preparation:
“A solution of Hydrats of Carbon After the formula of Prof. D. Lo Monaco, Director of the Institut of Physiological Chemistry of the University of Rome. Contents: Sucrose (C12H22O11) Glucose and Galactose (C6H12O6).”
The package contained ampules of thin, fragile, brown colored glass, containing approximately 21⁄2 c.c. of light, clear, amber colored, thick, sticky fluid, having a distinct caramel odor. Reaction pH = 5.0. A reducing substance (probably glucose) amounting to 7.4 per cent. was found by using Benedict’s method for estimating glucose quantitatively; after hydrolysis with hydrochloric acid, 55.5 per cent. glucose was found. There was no reaction for albumin. No attempt was made to identify the sugars, as it seemed probable that in the preparation caramel had been produced.
The circular which accompanied the package of Aphlegmatol contained the following information (spelling and composition as in original) about its use and effects:
To be emploied where a large bronchial secretion is present in the respiratory branches disease. The secretion will diminish and, in non complicated cases, it will completely disappear.
Fever, cough, hemottisis, night perspiration, vomiting and difficulty of breathing are, in the meantime, diminuished.
Aphlegmatol acts also as a riconstituent, being itself a nurrishing composition, improves the digestive function of the body and increases the arterial pressure.
5 c.c. (2 Phials) of Aphlegmatol per day must be injected intramuscularly in the Gluteus.
If the patient wishes two injections may be made, one at the right immediately followed by a second one at the left.
The cure must not be interrupted untill sometime after expectoration has disappeared, which result may be obtained only after fifty or sixty days, in the meantime the patient must be controlled by his home physician, especialy when thermal elevation of the body takes place.
Improvement will be manifested on or about the tenth day of the first injection.
In the advertising circular, which is apparently intended for general distribution, much the same information is given as in the sheet enclosed with the ampules, except that in the directions we find: “If the injections are painful—especially in cases where patients are very emaciated—physicians are advised to inject together with Aphlegmatol, as an anesthetic, a vial with 1 c.c. solution of Stovain at 3%.” The advertising for Aphlegmatol contains many misspelled words and appears to be the work of those ignorant of the English language.
Tuberculosis is a widespread disease and a majority of the uninformed are only too willing and ready to try such a “cure.” The preparations appear to be nothing more than concentrated solutions of sugar. It is probable that a small amount of the cane sugar might be inverted to glucose and fructose, but experiments have shown that cane sugar subcutaneously administered in the small amounts used in this instance is largely excreted in the urine unchanged. Less is known about galactose, but the evidence available would indicate that galactose is largely excreted in the urine unchanged when given subcutaneously. Glucose would be absorbed as such, and in the amounts under consideration, used by the system much the same as when given by mouth.—(From The Journal A. M. A., Aug. 21, 1920.)
SUPSALVS NOT ADMITTED TO N. N. R.
Report of the Council on Pharmacy and Chemistry
The Council has authorized publication of the following report declaring Supsalvs (Anglo-French Drug Company) inadmissible to New and Nonofficial Remedies.
W. A. Puckner, Secretary.
Supsalvs are advertised by the Anglo-French Drug Company as “stable suppositories of ‘606’ (of French manufacture)” with the claim that by the rectal administration of these suppositories the effects of arsphenamine may be obtained. The asserted efficacy of Supsalvs medication is based in part on the claim that for these suppositories an excipient was found which mixes with the cocoa butter base “to form an assimilable emulsion.”
“The active principle and the vehicle being bound to one another, the mucous membrane is able to absorb both simultaneously and progressively in the form of an organic emulsion.”
As no information was furnished the Council by the Anglo-French Drug Company on the origin or quality of the arsphenamine used in the preparation of Supsalvs or the character of the vehicle which was “bound” to the arsphenamine in such a way as to permit the absorption of this combination in the form of an “organic emulsion,” the firm was requested to furnish: (1) Evidence that the arsphenamine used in Supsalvs complies with the N. N. R. standards and that deterioration of it does not occur in the preparation of the suppositories or on keeping. (2) The identity of the ingredients composing the suppository.
The Anglo-French Drug Company did not supply the requested evidence and consequently the Council judged the preparation on the basis of the information received from the company, and that contained in the available advertising and circulars. It found Supsalvs inadmissible to New and Nonofficial Remedies, first because the quality of the medicament contained in the suppositories has not been established, and second because the claimed efficacy of this preparation as a means of securing the effects of arsphenamine lacks substantiating proof.
During the past few years some French physicians have reported favorably on the intrarectal administration of arsphenamine. Boyd and Joseph at Panama published (The Journal, Aug. 17, 1918, p. 521) an enthusiastic report on intrarectal injection of arsphenamine but did not refer to its use in the form of suppositories. In a comprehensive report, on the “Treatment of Syphilis” (Quarterly Journal of Medicine, July, 1917) L. W. Harrison stated that arsphenamine (Salvarsan) in the shape of an enema is definitely less effective than intravenously and that “Neisser and the vast majority of workers can see no value in the rectal method.” Schamberg and Hirschler (A Safe and Efficient Intensive Method of Treating Syphilis, Therapeutic Gazette, November, 1919, p. 761) have given a rather thorough trial of this method; the results were most disappointing: “A certain or rather uncertain amount of arsphenamine is absorbed into the blood, but the quantity is obviously too small to be at all comparable in its effect with the intravenous administration. Our conclusions are that the rectal administration of arsphenamine or neoarsphenamine is an extremely feeble method of administering these drugs.”
The report of the Special Committee on the Manufacture, Biological History and Clinical Administration of Salvarsan and Other Substances of the British National Health Insurance Medical Research Committee contains the following: “The rectal method of administration, either in the form of solution or as suppositories, has been advocated by a few observers mainly for cases in which there is difficulty in the adoption of the intravenous method. The experiments made by Mills at Rochester Row show that three enemata of ‘606’ (0.6 Gm. in each) on successive days failed to produce any effect on the spironemes in the lesions. The general opinion of experienced workers is that the rectal method is ineffective, and in this view the Committee concur.”—(From The Journal A. M. A., Oct. 30, 1920.)
HYPODERMIC SOLUTION NO. 13, IRON, ARSENIC AND PHOSPHORUS COMPOUND NOT ACCEPTED FOR N. N. R.
Report of the Council on Pharmacy and Chemistry
The Council has authorized publication of the following report.
W. A. Puckner, Secretary.
Hypodermic Solution No. 13, Iron, Arsenic and Phosphorus Compound (Burdick-Abel Laboratory) is said to contain in each c.c.:
Ferrous citrate0.06 Gm.
Sodium cacodylate0.06 Gm.
Sodium glycerophosphate0.1 Gm.
Chloretone0.005 Gm.
The preparation is advertised as “the old reliable hematinic” which is “indicated in all forms of anemia, where both red and white cells are low.” It is for hypodermic or intramuscular administration. The product is inadmissible to New and Nonofficial Remedies because:
1. It does not contain ferrous citrate as claimed. Instead the iron is in the ferric condition, apparently in the form of the unofficial and unstandardized “iron citrate green” for which there is no evidence of superiority over the official iron and ammonium citrate.134
2. Its name gives no information on the form in which the iron, the arsenic and the phosphorus occur therein. The term “arsenic” does not indicate whether the mild cacodylate or the potent arsenous oxid is being administered nor does the term “phosphorus” tell the physician that he is administering the practically inert sodium glycerophosphate.135—(From The Journal A. M. A., Nov. 13, 1920.)
PARATHESIN NOT ADMITTED TO N. N. R.
Report of the Council on Pharmacy and Chemistry
The Council has authorized publication of the following report.
W. A. Puckner, Secretary.
The local anesthetic ethyl paraminobenzoate was first introduced as “Anesthesin” or “Anæsthesin.” Ethyl paraminobenzoate is not patented in the United States and it may be manufactured, therefore, by any firm which chooses to do so. In order that a common name by which to designate the drug might be available, the Council coined the name “Benzocaine,” as being short and easily remembered, but yet suggestive of its composition and character (“benzo” to indicate its derivation from benzoic acid and “caine” to indicate its cocaine-like properties). As the term “anesthesin” had become a common name for the drug, the Council recognized this as a synonym for benzocaine.
One of the accepted brands for benzocaine is “Anesthesin,” manufactured by the H. A. Metz Laboratories, Inc. (see New and Nonofficial Remedies, 1920, p. 33). However, on April 19, 1920, the Metz Laboratories requested that its product be recognized under the designation of “Parathesin.” As the use of one substance under several names causes confusion and retards rational therapeutics, the Council’s rules provide against the recognition of proprietary names for nonproprietary, established drugs. In view of this and because the legitimate interests of the manufacturer may be safeguarded by appending his name or initials to the common name, benzocaine or anesthesin, the Council voted not to recognize the designation “Parathesin.”—(From The Journal A. M. A., Nov. 13, 1920.)
CHLORLYPTUS
Report of the Council on Pharmacy and Chemistry
The condensed report on Chlorlyptus which follows and also a complete detailed report was sent to the proprietor, Jan. 9, 1920. In reply he requested that publication be postponed pending the submission of further clinical evidence. As after nine months this evidence had not been received the Council has authorized publication of its report.
W. A. Puckner, Secretary.
Chlorlyptus is manufactured by Chas. A. Weeks, trading as the Weeks Chemical Company, Philadelphia. It is prepared by chlorinating eucalyptus oil until it has bound 30 per cent. of chlorin, the chlorin being in relatively stable combination. It is claimed that Chlorlyptus is a new “chlorinated antiseptic,” highly efficient as a wound antiseptic and at the same time nonirritant and nontoxic. Chlorlyptus is offered for use in the treatment of local infections of all types, as well as of burns, and also as an antiseptic in the alimentary and genito-urinary tracts.
The claims were based largely on reports of investigations made by Philip B. Hawk and his collaborators. These reports the referee of the committee in charge of Chlorlyptus considered incomplete and unconvincing. Being advised of this Mr. Weeks caused further investigations to be made. Some of the information was checked and extended by the A. M. A. Chemical Laboratory and by the referee.
The laboratory side of the investigation may now be considered as complete. The results show that Chlorlyptus is a feeble antiseptic of the aromatic oil type, considerably weaker than eucalyptus oil, both as to therapeutic and toxic qualities. The chlorin contained in it is bound too firmly to have any action; in fact, the chlorination appears to have accomplished nothing more than a considerable destruction or weakening of the eucalyptus oil. As far as the referee can judge, this object could have been accomplished just as effectively by diluting ordinary eucalyptus oil with some indifferent solvent.
The manufacturer of Chlorlyptus contends that if the experimental findings are against his product, it should be judged by the clinical data. The clinical evidence, however, is not decisive. It shows that wounds healed and infections were prevented or successfully combated in cases in which Chlorlyptus was used in combination with good surgery, but it does not show how much of the result was due to the surgery and how much, if any, to the use of Chlorlyptus. Even if it were granted as probable that the Chlorlyptus contributed to the favorable outcome, it would still be a question whether it equals other established antiseptics, or whether it possesses any material advantages over diluted eucalyptus oil. Until these points are established the clinical reports cannot offset the unfavorable results of the laboratory investigation.
The manufacturer has endeavored to obtain more convincing clinical reports, but the lack of success in this direction during the past nine months gives little encouragement that acceptable clinical evidence will be available within a reasonable time.
Believing that the information which has been obtained should be made available to the profession, the Council authorized publication of this statement and also of the detailed report. The Council voted not to accept Chlorlyptus for New and Nonofficial Remedies because of the unfavorable results of the laboratory investigation, but with the agreement that the product would receive further consideration should more convincing clinical data become available.
I. DETAILED REPORTS
Summarized Reports
CHEMICAL NATURE OF CHLORLYPTUS
Chlorlyptus is prepared by chlorinating eucalyptus oil until it has bound 30 per cent. of chlorin. “Chlorlyptol” is prepared in an analogous manner from eucalyptol. There has been some confusion as to the composition; but the principal constituent is now stated to be “a dichloride of eucalyptus oil,” to which the formula C10H16OCl2 has been assigned. It differs from the “chlorinated eucalyptus oil,” as ordinarily used for making dichloramin-T solutions, and which contains only 2⁄3 per cent. of chlorin.
AVAILABILITY OF CHLORIN IN CHLORLYPTUS
The chlorin content of chlorlyptus is almost entirely firmly bound, and therefore not “available,” in contrast to the group of so-called chlorinated antiseptics (i. e., the hypochlorite and chloramin type). For instance, it does not directly liberate iodin from iodid. It contains a very small quantity of free hydrochloric acid, or perhaps some acid esters, and liberates a little more on prolonged contact with water; but the total quantity liberated under reasonable conditions is very small. According to Hawk’s data, they correspond only to 1⁄8 per cent. HCl even after standing with water overnight and to only 1⁄5 per cent. of HCl after two weeks. The referee has shown that this quantity of acid has no therapeutic significance.
The “bound” chlorin of chlorlyptus, being chemically inactive, would have no more practical significance than the bound chlorin in common salt. The “ozone” said to be used during the preparation, to expel the HCl, has also practically disappeared, to judge by the slowness with which iodin is liberated from potassium iodid.
ACID FORMATION
Some constituents of chlorlyptus hydrolyze slowly and to a slight degree with the liberation of a trace of free hydrochloric acid. According to the data of Hawk’s report, the free acidity, in term of HCl, is 1⁄12 per cent. On standing with water over night, this increases to 1⁄8 per cent.
On this basis, Hawk proposed a theory that the claimed antiseptic effects of chlorlyptus are due to the continuous liberation of hydrochloric acid.
Experiments by the referee show this to be untenable. The traces of acid are neutralized and absorbed by the tissues so rapidly that an acid reaction is not maintained. These experiments are described in the appendix.
They were submitted to the manufacturers, who in the name of Mr. Weeks (May 9, 1919) concede this conclusion and state that “there is no doubt that the referee’s statements as to action in mouth, contact with living tissue and improbability that the acidity is effectively antiseptic is correct, and I am willing to accept the referee’s statement as conclusive in this respect.”
BACTERIAL CULTURE EXPERIMENTS
Mr. Weeks submitted a statement by Hawk to the effect that chlorlyptus has a phenol coefficient of 2.6, determined by the standard Hygienic Laboratory procedure.
He also quotes Rockefeller War Hospital that chlorlyptus kills Staphylococcus aureus in concentra of 1 dram: 1 gallon (about 1:1,000), but not in more dilute solutions.
More recently, he presented a more comprehensive report by Rivas, which is reproduced in the appendix. The essential results are tabulated herewith. This tabulation shows that chlorlyptus fails to kill the organisms after an hour’s exposure of the following concentrations:
Typhoid in bouillon, 10 per cent. of chlorlyptus. Staphylococci in pus, 5 per cent. of chlorlyptus. Staphylococci in serum, 1 per cent. of chlorlyptus.
It seems to the referee that a substance that is ineffective with an hour’s exposure to these concentrations is not at all likely to kill or check bacteria under clinical conditions. In other words, it is not an antiseptic in the ordinary sense.
The referee is not impressed by the superior power attributed by Rivas to chlorlyptus in the presence of pus. Inefficiency of 10 per cent. for one-half hour or of 5 per cent. for two hours seems a failure rather than a success. The referee also notes the absence of any data as to the relative efficiency of chlorlyptus against staphylococci in pus and in bouillon. The data on serum indicate that chlorlyptus is much weaker than phenol and show that it is less effective in the presence of pus than in other mediums.
The referee fails to grasp the bearing of the oil experiments on any clinical condition. Moreover, the inconstant results mentioned by Rivas suggest the possibility that the incorporation of the bacteria in oil may have prevented their effective distribution in the culture medium. If any significance is to be attached to these experiments, they should be checked by controls, without antiseptics.
SUMMARY OF RIVAS’ IN VITRO EXPERIMENTS
Minimal Germicidal ConcentrationsMaximal Not Germicidal Concentrations
Typhoid Bacilli in Bouillon:
Chlorlyptus (Exp. 3)10%, 2 to 4 hours10% for 1 hour
5% for 2 hours
Eucalyptus oil (Exp. 1) 5% within 5 minutesNo data
Phenol (Exp. 5) 1% within 10 min.No data
Streptococci and Staphylococci in Olive Oil:
Chlorlyptus (Exps. 7 and 8) 1%, almost at once, sometimesNo data
Eucalyptus oilNo dataNo data
Phenol (Exps. 9 and 10) 1%, almost at once,No data
Staphylococci in Pus:
Chlorlyptus (Exp. 11)10% for 1 hour10% for 1⁄2 hour
5% for 2 hours
Eucalyptus oilNo dataNo data
PhenolNo dataNo data
Staphylococci in Human Blood Serum:
Chlorlyptus (Exp. 12) 5% in 1 hour 1% in 1 hour
Eucalyptus oilNo dataNo data
Phenol 5% almost at once 1% in 1 hour
INFECTION EXPERIMENTS IN VIVO
Dr. Rivas reports two series of experiments, in each of which three guinea-pigs received staphylococcus suspensions in the peritoneum. One guinea-pig in each series was left untreated; the others received injections of chlorlyptus into the peritoneum at various intervals.
The following results were obtained:
ChlorlyptusResults
Exp. 19, No. 1NoneSurvived
Exp. 20, No. 1NoneDied
Exp. 19, No. 2At onceDied
Exp. 19, No. 3After 24 hoursSurvived
Exp. 20, No. 2After 18 hoursDied
Exp. 20, No. 3After 24 hoursDied
This shows mortalities of: 1 in 2, i. e., 50 per cent., without chlorlyptus. 3 in 4, i. e., 75 per cent., with chlorlyptus.
It is doubtful whether so small a series of experiments on so variable a phenomenon as is infection should receive any serious consideration. So far as they go, they would indicate that chlorlyptus is useless or worse.
TOXICITY
The referee determined the acute toxicity of chlorlyptus by hypodermic injection of oily solutions into white rats. Comparative experiments were made with ordinary eucalyptus oil. The details are given in the appendix. The end-results may be summarized as follows:
SurvivedChlorlyptusEucalyptus Oil
1.56 c.c.
3.75 c.c.
5.00 c.c.
6.25 c.c.1.25 c.c.
8.65 c.c.2.5 c.c. (3 days)
Died (in days)12.5 c.c. (1 day)3.75 c.c. (3 days)
12.5 c.c. (1 day)5.00 c.c. (3 days)
18.75 c.c. (1 day) 6.25 c.c. (11⁄2 days)
M. F. D.8.75 to 12.5 c.c. per kg.1.25 to 2.5 c.c. per kg.
Fatality.—The doses are calculated for cubic centimeters of the undiluted drugs per kilogram of rat.
Dr. Rivas reports a series of toxicity experiments on guinea-pigs. Assuming a uniform weight of 400 gm. per animal, his results (details in appendix) may be summarized as:
Minimal Fatal Dose C.c. per Kg.Maximal Survived Dose C.c. per Kg.
Chlorlyptus, peritoneal (Exp. 14)7.5 c.c.5.0 c.c.
Chlorlyptus, pleural (Exp. 15)5.0 c.c.2.5 c.c.
Eucalyptus oil, peritoneal (Exp. 16)2.5 c.c.No Data
Eucalyptus oil, pleural (Exp. 16)1.25 c.c.No Data
Dichloramin-T, peritoneal (Exp. 16)1.25 c.c.No Data
The comparative toxicity in the various series is therefore approximately as follows:
Chlorlyptus:Eucalyptus
Referee, rats, hypodermic1⁄5:1
Rivas guinea-pig, peritoneal1⁄3:1
Rivas guinea-pig, pleural1⁄4:1
Evidently, the toxicity of chlorlyptus is about one-fourth of that of eucalyptus oil. The difference is considerable, but not fundamental. Moreover, the symptoms of chlorlyptus resemble the characteristics of eucalyptus oil.
According to the tabulation of Barker and Rowntree,136 the mean fatal dose of eucalyptus oil for man, in the twenty-nine clinical cases reported in the literature, is about 20 c.c. If the toxicity ratio of the two substances were the same as for the rat experiments (a rather hazardous assumption), the fatal dose of chlorlyptus for man would be about 80 c.c.
IRRITATION
Rivas’s Experiment 14 shows that chlorlyptus gives very definite irritation, apparently similar to that produced in Experiment 16 by eucalyptus oil in one-fourth the dose.
Incidentally, the referee may add from personal experience that the “chlorlyptus oil, 5 per cent. Cl” is markedly irritating in the nostrils, although marked “non-irritating” on the label.
II. APPENDIX: SPECIAL REPORTS
A. COMPARISON OF CHLORLYPTUS WITH CHLORINATED EUCALYPTOL
From the Chemical Laboratory of the American Medical Association
According to the label, “Chlorlyptus” is a “Synthatized Chlorinated Oil of Eucalyptos, with Acid Reaction, containing approximately 30 per cent. Chlorine and possesses excellent Germicidal Properties, when made under our special process.” It is manufactured by the Weeks Chemical Company, Philadelphia, Pa. This product was submitted to the Council on Pharmacy and Chemistry by the manufacturers, and in turn the Laboratory was asked to examine it with the idea of comparing it with the nonproprietary brands of “chlorinated eucalyptol” (used as a solvent for dichloramine-T; see New and Nonofficial Remedies, 1919, p. 70). In the submission, certain tests were described, most of which were followed. Among the statements given under the chemical properties of chlorlyptus are:
“On distillation, chlorlyptus begins to boil at about 100 C. The temperature rises as the distillation continues, accompanied by the decomposition of the chlorlyptus and the evolution of hydrochloric acid and chlorine.”
“When brought into contact with water, chlorlyptus undergoes a process of hydrolysis ...”
Notwithstanding the foregoing the statement is made on the label that chlorlyptus “is a Stable Compound, not affected by heat, light or water.”
The following comparisons of chlorlyptus, chlorinated eucalyptol-Abbott and chlorinated eucalyptol-Squibb were made:
Chlorlyptus is a viscous, dark brown liquid, with an acrid odor and having a specific gravity of 1.2098. Chlorinated eucalyptol-Abbott is a mobile, light yellow liquid, with a eucalyptus odor, having a specific gravity of 0.9317. Chlorinated eucalyptol-Squibb is a mobile, colorless liquid, and its specific gravity is 0.9303.
An alcoholic solution of silver nitrate added to an alcoholic solution of chlorlyptus yields a heavy precipitate of silver chloride. In the case of the Abbott chlorinated eucalyptol a slight turbidity is caused by this test; the Squibb product shows no reaction.
A 10 per cent. solution of potassium iodide is overlaid with an equal volume of chlorlyptus. Iodine is slowly liberated, being noticeable in one-half hour. With chlorinated eucalyptol-Abbott, a trace of free iodine is discernible after four hours, while with chlorinated eucalyptol-Squibb there is no free iodine present. When the respective products are shaken with an alcoholic solution of potassium iodide, no iodine is immediately liberated, thus showing the absence of “active chlorine” (difference from the hypochlorite derivatives).
When chlorlyptus is dissolved in concentrated sulphuric acid, some blackening occurs and the odor of hydrogen chloride is very noticeable. Both the Abbott and Squibb brands of chlorinated eucalyptol give a reddish mixture, with no perceptible evolution of hydrogen chloride, and still retain the characteristic eucalyptol odor.
On heating, chlorlyptus decomposes and begins to boil at from 103 to 105 C. Then a higher fraction comes over at 178 C. The distillate has a sharp odor, is acid, and frees very little iodine from potassium iodide. Chlorinated eucalyptol-Abbott does not seem to decompose. Some gaseous substance is given off at 80 C, but the liquid distills at 173 C. The distillate has no acid odor, is neutral, and liberates no iodine from potassium iodide. (In both cases the distillation was not carried to completion, approximately only about half of the volume being distilled over.)
PRELIMINARY TESTS ON CHLORLYPTUS AND CHLORINATED EUCALYPTOL
Chlorlyptus Chlorinated Eucalyptol-Abbot Chlorinated Eucalyptol-Squibb
Odor Acrid Like eucalyptus Like eucalyptus
Density and color Dark brown; viscous, heavier than water Light yellow; mobile; lighter than water Colorless; mobile; lighter than water
AgNO3 added to alcoholic solution Heavy ppt. Slight turbidity Clear
Equal parts with KI solution Gives free iodin slowly, noticeable in 1⁄2 hour Gives free iodin in 4 hours; not much No free iodin in 4 hours
Equal parts with 10% KI, 10% KIO3 solution Much iodin immediately Small amount of free iodin in few numbers; does not noticeably increase No free iodin in 3 hours
Equal parts with conc. H2SO4 Some blackening; odor of HCl Reddish mixture; no HCl; eucalyptol odor Same
Alcohol KI No iodin liberated Same Same as Abbott product
Heating Decomposes and boils at 103–105 C.; then higher fraction comes over at 178 C.; distillate has sharp odor, is acid, but frees very little I2 from KI; distillation not completed Apparently does not decompose; some gas given off when T=80; the liquid distilled at 173 C.; the distillate did not have much odor; no HCl gas detected; no I2 from KI; distillate was neutral (distillation not completed)
The addition of chlorlyptus to a mixture of 10 per cent. potassium iodide, 10 per cent. potassium iodate solution, brings about the liberation of iodine, increasing perceptibly on standing. This shows that the hydrogen chloride is gradually split off, and in time will cause a solution having a considerable degree of acidity. When this test is carried out on chlorinated eucalyptol-Abbott, a small amount of iodine is liberated in a few minutes but does not increase, showing a slight initial acidity without further hydrolysis. Chlorinated eucalyptol-Squibb yields no free iodine after standing three hours.
When the chlorine content of chlorlyptus is determined according to the method of Carius, the amount is found to be 29.6 per cent. (The manufacturers give a method of determining chlorine by Hunter’s fusion method. It is believed that in this method hydrogen chloride may be lost, and this opinion is substantiated by the firm’s statement, “Chlorlyptus analyzed in this manner shows approximately 25 per cent. of chlorine.”) The chlorine content of chlorinated eucalyptol-Abbott is found to be 0.67 per cent., and that of the Squibb brand to be 0.62 per cent. (about one-fiftieth as much as in chlorlyptus).
To sum up: Chlorlyptus differs from chlorinated eucalyptol in odor, color, density, in reaction to silver nitrate, potassium iodide, sulphuric acid and the aqueous solution of potassium iodate and potassium iodide. The distillation of the two products occurs differently. Chlorlyptus contains nearly 30 per cent. of chlorine, which is approximately fifty times as much as in chlorinated eucalyptol. Thus it appears to have considerable chlorine in the negative form (Cl-) which may be relatively easily split off as hydrogen chloride.
B. THE PERSISTENCE OF THE ACID
Reaction of Chlorlyptus in the Body
BY THE REFEREE
This “chlorinated ozonized eucalyptus oil” is distinctly acid to litmus paper. It is claimed that further quantities of acid are liberated on contact with water. This is credited with producing a continuous acid reaction on the surface of tissues to which the oil may be applied and this in turn is stated to be antiseptic or germicidal.
This theoretical speculation does not take into account the large quantity of reserve alkali in the body by which it combats attempts to alter its normal reaction. It is therefore not convincing, unless it is supported by direct evidence.
In the absence of such data on the part of the promoters of the preparation, experiments were made to determine whether the oil preserves its acid reaction in contact with mucous and serous membranes. The answers were clearly in the negative.
In the mouth, the reaction becomes neutral within ten or fifteen minutes; in the pleura and peritoneum within half an hour, and probably in much shorter periods.
More detailed data follow:
SERIES A: BEHAVIOR IN THE MOUTH; HOMO
Experiment.—Chlorlyptus and to less extent Chlorlyptus Oil, are acid to litmus. They are applied:
(a) Drop to litmus paper and this to gums. (b) Several drops directly to tongue. (c) Same to gums. The reaction to litmus paper is tried from time to time.
Results.—(a) Applied to gums on litmus paper:
Chlorlyptus: Red color becomes gradually feebler and does not spread on the paper. Chlorlyptus Oil: Turns blue in a few minutes.
(b) Dropped on tongue:
Chlorlyptus: Acid taste at once. Does not increase, but on contrary, becomes less. Litmus applied after ten minutes: not acid. Litmus applied after five minutes: distinctly acid.
(c) Dropped on inside of cheek:
Chlorlyptus, 1⁄3 c.c.: After six minutes, litmus very red. After ten minutes, faintly red. After fifteen minutes, blue. Chlorlyptus Oil, 1 c.c. After three minutes, faintly red. After eight minutes, neutral.
Conclusions.—On contact with living tissues, the acid of chlorlyptus is rapidly neutralized and absorbed.
The surface is neutral within ten or fifteen minutes.
It is therefore very improbable that the acidity is effectively antiseptic.
A comparison of chlorlyptus with dilute acetic acid shows that the chlorlyptus does not maintain the acidity even as well as 1 per cent. acetic acid.
Acetic Acid Chlorlyptus
Tongue, a drop of 5 per cent.; still slightly acid to litmus after ten minutes; taste almost gone in two minutes Neutral between five and ten minutes
Gums, a few drops between cheeks and gums: Five per cent. still strongly acid in twelve minutes; distinctly acid in seventeen minutes. One per cent. still strongly acid in twenty-one minutes Neutral between ten and fifteen minutes
CHLORLYPTUS: REACTION (LITMUS PAPER) ON CONTACT WITH TISSUE
Serial No.AnimalWhen InjectedQuantity, C.c.Time of DeathBlue LitmusSymptoms or Toxicity
1RatPleura11⁄2 hourRemains blueNone; killed; pleura not congested; lung spec. = 21; slight congestion
2RatPleuraLess than 11 hourRemains blueNegative
3RatPleura123 min.Remains blueAlmost at once bad gasping respiration and died in 23 m.; heart distend.; possibly injection penetrated lung
Peritoneum123 min.Turns red
4RabbitPleura1................Died overnight
5DogPleura11⁄4 hourRemains blue 20 m. p. m.
Peritoneum11⁄4 hourRemains blue 20 m. p. m.
6DogPleura13 min.Remains blue 45 m. p. m.
Peritoneum13 min.Remains blue 45 m. p. m.
7DogPleura120 min.Remains blue 20 m. p. m.
Peritoneum120 min.Remains blue 20 m. p. m.
SERIES B: SEROUS MEMBRANES
In these experiments, 1 c.c. of chlorlyptus was injected into the pleura or peritoneum. After a stated time, the animal was killed, and the reaction of the pleural or peritoneal surface was tested with blue litmus paper. The results are shown in the table.
C. TOXICITY EXPERIMENTS
By the Referee
TECHNIC
White rats were injected hypodermically with chlorlyptus or with eucalyptus oil, diluted with olive oil in the ratio of 1:4. The larger doses were divided between two or more sites of injection.
DETAILED PROTOCOLS
Hypodermic injections in white rats. Drugs diluted with 3 parts of olive oil. Doses are given as cubic centimeters of pure drug per kilogram of rat.
A. EUCALYPTUS SERIES
Experiment 1.—1.25 c.c.; injected VII.9.19: Active; walks about. No depression at any time. VII.10.19. Appears normal.
Experiment 2.—2.5 c.c.; injected VI.30.19: Quiet—not very depressed, reflexes good (six hours). VII.1.19—Active—reflexes good, eats moderately. VII.2.19—Animal acts normal—eats moderately, reflexes good; active (a.m.). Later in day, depressed. VII.4.19—Died during night of VII.3.19.
Experiment 3.—3.75 c.c.; injected VI.24.19: Quiet; depressed; pain reflex diminished. Animal lay on ventral surface, not supported by legs. Will get on to feet very sluggishly if turned on side (twenty-four hours). Does not eat. VI.26.19—Depressed slightly; pain reflex present. VI.27.19—Fairly active; eats a little. VI.28.19—Depressed. Died during night of VI.29.19 (three days).
Experiment 4.—5 c.c.; injected VI.24.19: Quiet; markedly depressed (one hour). Does not get on feet when turned on side; ataxia well marked. Slight watery secretion in eyes. Reflexes diminished. Does not eat (twenty-four hours). VI.26.19—Heart slowed and arrhythmic. Animal lies on side. Unable to walk; markedly depressed. VI.27.19—Lies on side; does not eat. Died during night of VI.27.19 (three days).
Experiment 5.—6.25 c.c.; injected VI.24.19: Quiet; very markedly depressed. Heart and respiration greatly slowed. Lies on side; tears in eyes; does not eat (twenty-four hours). VI.25.19—Temperature subnormal; cold to touch; tail stiffened and straight. Died during night of VI.25.19 (one and one-half days). Postmortem: Lungs congested. Liver pale in color. Spleen very dark red. Kidneys normal. Other organs normal.
B. CHLORLYPTUS EXPERIMENTS
Experiment 1.—1.56 c.c.; injected VI.24.19: Rather restless for an hour. Active during next four hours and following twenty-four. Eats well, reflexes good. Acts normal on VII.1.19 and since VI.26.19.
Experiment 2.—3.75 c.c.; injected VI.24.19: More quiet; active during next twenty-four hours. Reflex all right. Eats well; normal VII.1.19, since VI.26.19.
Experiment 3.—5 c.c.; injected VI.24.19: Quiet; defecation in four hours. Rather quiet for six hours. Eats well. Reflexes good; normal VII.1.19, since VI.26.19.
Experiment 4.—6.25 c.c.; injected VI.24.19: Quiet and breathing labored in four hours; active after twenty-four hours. Eats well. Somewhat depressed on VI.26.19; pain reflex present. On VI.26.19, eats well and fairly active. Active and eats, VI.27.19. Appears normal, VII.1.19.
Experiment 5.—8.75 c.c.; injected VI.30.19: Rather quiet during next two hours. Morning of VII.1.19, lies on stomach; quiet; does not eat very much. Pain reflexes good. VII.2.19, still depressed; does not eat. Appears normal, VII.3.19.
Experiment 6.—12.5 c.c.; injected VI.25.19: Quiet, but reflexes good; more quiet and depressed after several hours. Some loss of oil from wound. Died night of VI.25.19 (one day). Tail stiff. Temperature low. Postmortem: Lungs markedly congested. Spleen and liver dark red. One kidney congested. Other viscera normal.
Experiment 7.—12.5 c.c.; injected VII.9.19: Quiet for one-half hour; 1.5 hours twitching of muscles of whole body, lies on side, ataxia present. Died night of VII.9.19 (one day).
Experiment 8.—18.75 c.c.; injected VI.25.19: Quiet; reflexes good (three hours). Some loss of oil. Depressed and turns on side (six hours). Died night of VI.25.19 (one day). Postmortem: Lungs congested. Spleen and liver very dark red. Right kidney much darker red. Viscera normal.
D. REPORT OF DR. D. RIVAS
The following are the results of experiments conducted by me, during the past four months, on the germicidal action of chlorlyptus (chlorinated oil of eucalyptus, principal constituent C10H17OCl2) in vitro and in vivo, and comparison also with carbolic acid, oil of eucalyptus and dichloramine in test for irritation and toxicity.
Germicidal Action.—Based on the results obtained, chlorlyptus when used in a 5 per cent. paraffin oil solution was found to be a mild germicidal against typhoid B, streptococcus and staphylococcus when these organisms were suspended in ordinary bouillon culture or sterile salt solutions.
The germicidal action was found stronger when these micro-organisms were suspended in a sterile oily or lipoid substance, such as olive oil. The results of these experiments were not constant, owing probably to the imperfect suspension of the bacteria. Thus, while in some of the experiments chlorlyptus in 1 per cent. oil solution destroyed these micro-organisms, in other cases the same strength solution failed to give same result in same time.
The increased germicidal action of chlorlyptus on bacterial suspensions in olive oil may be accounted for by the fact that chlorlyptus is soluble in olive oil and not an admixture, as in the case of paraffin oil.
Chlorlyptus is not a coagulant, as are germicides of the phenol or hypochlorite types, and the germicidal action is therefore not strictly comparable.
The germicidal action of chlorlyptus oil solution, on pathogenic bacteria, on streptococcus and staphylococcus, suspended in pus, was found to be stronger than when these micro-organisms were suspended in ordinary bouillon culture or sterile salt solution. In one of the experiments, similar results were obtained when these micro-organisms were suspended in olive oil, chlorlyptus showing marked germicidal action.
Irritation and Toxicity.—The irritating action was found to be relatively mild in tests on laboratory animals. Thus, from 0.5 to 1 c.c. of chlorlyptus in paraffin oil 5 per cent. solution, injected into peritoneal or pleural cavities of guinea-pigs weighing 400 gm. was found to be without any appreciable disturbance in the health of the animal, and in some cases the injection of as much as 2 c.c. did not kill the animal.
Therapeutic Action.—Guinea-pigs were inoculated with purulent material containing streptococcus, staphylococcus and B. coli in peritoneal and pleural cavities respectively, and after six hours 1 c.c. of chlorlyptus 5 per cent. in paraffin oil solution was injected. Other infected animals were similarly treated twenty-four hours after inoculation, and another series forty-eight hours after inoculation. In some of these cases the animals died from shock but in a clearly defined series in which the injection of 1 c.c. of the chlorlyptus solution was made in the peritoneum of the guinea-pigs twenty-four hours after the inoculation, the animals lived. The control animal, inoculated with the purulent material and not treated with chlorlyptus oil solution, died.
In consideration that the injection of chlorlyptus oil solution [sic, referee] were made [? referee] in the peritoneal cavity this substance is apt to affect the vital organs in the abdominal cavity. It is my belief that in case of wall abscess of chronic inflammation, by limiting the action of chlorlyptus to the infected area, preventing at the same time the infection of the vital organs, chlorlyptus, because of its non-irritating quality, can be used effectively as an antiseptic.
CONCLUSIONS
1. Chlorlyptus is a mild and relatively nonirritating antiseptic of marked action on pus and suppuration.
2. When bacteria were suspended in olive oil or in pus, chlorlyptus showed marked germicidal action.
3. Chlorlyptus can be injected into the peritoneum or the pleural cavities of guinea-pigs in the proportion of 1 c.c. per 400 gm. of body weight without detriment to the animal.
4. Chlorlyptus in 5 per cent. oil solution (taking Clause 3 as comparison) can perhaps be injected in man as an antiseptic agent when there is a walled-in abscess in the peritoneum or pleural cavity where there is drainage, in the proportion of 0.5 to 1 c.c. per pound of body weight with good result.
REPORT ON THE GERMICIDAL ACTION OF CHLORLYPTUS ON PATHOGENIC BACTERIA IN VITRO AND IN VIVO
Experiment 1.—The germicidal action of eucalyptus oil.—Typhoid bacillus was destroyed in less than five minutes when exposed to the action of a 5 per cent. suspension of oil of eucalyptus. The exposure for four hours in a 5 per cent. suspension of chlorlyptus in paraffin oil was without effect on typhoid bacillus. It requires an exposure of two to four hours in a 10 per cent. suspension of chlorlyptus in paraffin oil to destroy typhoid bacillus.
Experiment 2.—Bacilliary action of chlorlyptus on the growth of pathogenic bacteria.—Typhoid and anthrax bacilli were selected for the experiment. Two series of five tubes each were made. The culture medium used was nutrient bouillon. Chlorlyptus was added in the following proportions: Tube 1, 1:10; Tube 2, 1:100; Tube 3, 1:1,000; Tube 4, 1:10,000, and Tube 5, 1:100,000. One series was inoculated with typhoid bacillus. All tubes were incubated for three days at 37 C. Chlorlyptus inhibited the growth of typhoid bacillus when added to the bouillon in the proportions of 1:10. The growth of anthrax bacillus was inhibited by chlorlyptus when it was added in the proportions of 1:10, 1:100 and 1:1,000, as shown in the accompanying table. [The table was not submitted.—Ed.] In one instance the growth was markedly inhibited by chlorlyptus when added in the proportion of 1:10,000.
Experiment 3.—Germicidal action of chlorlyptus on typhoid bacillus.—Bouillon cultures of typhoid bacillus forty-eight hours old, and a suspension of forty-eight-hour agar cultures of typhoid bacillus in sterile salt solution were used for the experiment. Chlorlyptus was added in the proportion of 1:1,000; 1:1,500; 1:100; 2 per cent.; 3 per cent.; 4 per cent.; 5 per cent. and 10 per cent., respectively. Inoculations were made in trypsinized peptone bouillon after the addition of chlorlyptus at different intervals, namely: at once, after five minutes, after ten minutes, after fifteen minutes, after thirty minutes, after one hour and after two hours, and tubes incubated at 37 C. for forty-eight hours. Result: Growth was shown in all tubes except those in which chlorlyptus was added in the proportion of 10 per cent. and after the action of the antiseptic for two hours or longer.
Experiment 4.—Inhibitory action of chlorlyptus in the growth of typhoid bacillus.—Chlorlyptus was added to sterile bouillon in the proportion of 1:100, 1:1,000, 1:10,000 and 1:100,000, and incubated for forty-eight hours at 37 C. to eliminate any possible contamination of the bouillon during the manipulations. All tubes were found sterile and inoculated with typhoid bacillus. Result: All tubes were found sterile again after being inoculated with typhoid bacillus and incubated at 37 C. for forty-eight hours, which shows chlorlyptus inhibited and the growth of typhoid bacillus in bouillon when this antiseptic was added in the proportions of 1:100 to 1:100,000. Remarks: In another experiment made, chlorlyptus showed a weaker inhibitory action on the growth of typhoid bacillus.
Experiment 5.—Germicidal action of carbolic acid.—The technic was the same as that outlined in Experiment 1. except that carbolic acid was used instead of chlorlyptus. Result: Carbolic acid showed a distinct germicidal action on typhoid bacillus in the proportions of 1 per cent. in ten minutes.
Experiment 6.—Action of nitrogen gas on the growth of typhoid bacillus in bouillon and nutrient agar when chlorlyptus was added to this culture medium.—Chlorlyptus was added to the bouillon in the proportions of 1:100, 1:1,000, 1:10,000 and 1:100,000, as outlined in Experiment 2; also to agar kept melted at 45 C. Tubes were inoculated with typhoid bacillus; plates were made of the inoculated agar tubes; all plates and tubes were incubated at 37 C. for forty-eight hours in an atmosphere of nitrogen gas. Duplicate experiments were made with cultures of typhoid bacillus as above in bouillon and agar plates containing the same amount of chlorlyptus and incubated at 37 C. in ordinary atmosphere as control. Result: Nitrogen gas did not show any appreciable increase of the germicidal action of typhoid bacillus when grown in medium containing chlorlyptus. Growth was about the same in cultures supplied with nitrogen gas as in those growing in ordinary atmosphere.
Experiment 7.—Germicidal action of chlorlyptus on pyogenic bacteria suspended in an oily medium.—Experiment with streptococcus: Cultures of streptococcus in blood agar three days old were suspended in olive oil (sterile), and chlorlyptus was added in the proportions of 1, 5 and 10 per cent. and inoculated in trypsinized bouillon at different intervals, namely: at once, after five minutes, after ten minutes, after fifteen minutes, after thirty minutes, and after one hour. Tubes were incubated at 37 C. for forty-eight hours. Result: All tubes remained sterile. The germicidal action of chlorlyptus on streptococcus suspended in oil was almost at once and with certainty after five minutes when added in the proportion of 1, 5 and 10 per cent.
Experiment 8.—Germicidal action of chlorlyptus on staphylococcus, suspended in sterile olive oil.—The technic employed was the same as in Experiment 5, except that a culture of staphylococcus was used. Result: All tubes remained sterile. The germicidal action of chlorlyptus was almost at once in the proportions of 1, 5 and 10 per cent. Remarks: By repeating this experiment the result showed some variations. The discrepancy was probably due to an imperfect suspension of the micro-organism in the oil.
Experiment 9.—Germicidal action of carbolic acid on streptococcus suspended in olive oil.—The technic employed was the same as in Experiment 5, except that carbolic acid was used instead of chlorlyptus. Result: The germicidal action of carbolic acid of streptococcus suspended in olive oil was almost at once in the proportions of 1, 5 and 10.
Experiment 10.—Germicidal action of chlorlyptus on staphylococcus.—The technic employed was the same as in Experiment 6 except that the carbolic acid was used instead of chlorlyptus. Result: The germicidal action of carbolic acid on staphylococcus suspended in olive oil was almost at once, in proportions of 1, 5 and 10 per cent.
Experiment 11.—Germicidal action of chlorlyptus on pyogenic bacteria suspended in pus.—Chlorlyptus was added to sterile pus in the proportions of 1, 5 and 10 per cent., and then inoculated with staphylococcus and cultures were made in bouillon at once, after five minutes, after ten minutes, after fifteen minutes, after thirty minutes, after one hour and after two hours, respectively, and tubes incubated for forty-eight hours at 37 C. Result: Growth was shown in all tubes except those inoculated from tubes in which chlorlyptus was added in the proportions of 10 per cent. after one hour.
Experiment 12.—Germicidal action of chlorlyptus on streptococcus suspended in sterile human blood serum.—Staphylococcus culture in agar forty-eight hours old was suspended in sterile human blood serum, and to the suspension chlorlyptus 5 per cent. in paraffin oil was added in the proportions of 1, 5 and 10 per cent. Inoculations were made at intervals, at once, after five minutes, after ten minutes, after fifteen minutes and after one hour in trypsinized bouillon. Tubes were incubated at 37 C. for forty-eight hours. Result: Chlorlyptus showed inhibitory action on the growth of staphylococcus in the strength of 10 per cent., but did not produce complete sterilization. Similar results were shown with the 5 per cent., and in the 1 per cent. chlorlyptus did not show any inhibitory action at all.
Experiment 13.—Germicidal action of carbolic acid on staphylococcus suspended in human blood serum (sterile).—The technic employed was the same as in Experiment 10 except that carbolic acid was used instead of chlorlyptus. Result: Carbolic acid produced a complete sterilization in the strength of 10 per cent. almost at once, and with certainty after five minutes. Similar results were produced with the 5 per cent. The 1 per cent. carbolic acid did not show any appreciable germicidal action on staphylococcus.
Experiment 14.—Toxic and irritant action of chlorlyptus.—Six normal guinea-pigs were used for the experiment. Guinea-Pig 1 was injected peritoneally with 1 c.c. of chlorlyptus, Guinea-Pig 2 with 2 c.c. of chlorlyptus, Guinea-Pig 3 with 3 c.c. of chlorlyptus, Guinea-Pig 4 with 4 c.c. and Guinea-Pig 5 with 5 c.c. 5 per cent. respectively. Guinea-Pig 6 was used as a control and not injected. Result: Guinea-Pigs 1 and 2 did not show any appreciable disturbance. Guinea-Pig 3 was sick for four days, after which it gradually recovered but it became sick again after one week and died ten days after the injection. Guinea-Pig 4 died over night. Guinea-Pig 5 died six hours after injection. Guinea-Pig 5 was injected at 11:30 with 5 c.c. chlorlyptus. Ten minutes after the injection it was lying relaxed, respiration and heart normal, conjunctive reflex present. One hour after the injection the animal seemed to present symptoms resembling those of narcosis: respiration and heart were normal. After four hours there was no change in the condition of the guinea-pig except that the respiration was irregular. Five and a half hours after it showed prostration with irregular respiration and heart action. Six hours after injection the animal was dead. Autopsy: The peritoneum showed a congestion and a fibrinous exudation, amount of liquid increased, some part of which was probably chlorlyptus unabsorbed. Spleen about normal, liver congested, kidney about normal, suprarenal glands about normal, lungs normal, pleural cavity obtained no exudation, heart soft, flabby and congested.
Experiment 15.—Toxic and irritant action of chlorlyptus when injected into the pleural cavity.—Six normal guinea-pigs used for the experiment. Chlorlyptus was injected in the pleural cavity as follows: Guinea-Pig 1, 0.5 c.c.; Guinea-Pig 2, 1 c.c.; Guinea-Pig 3, 2 c.c.; Guinea-Pig 4, 3 c.c., and Guinea-Pig 5, 4 c.c. Guinea-Pig 6 was used as a control. Result: Guinea-Pigs 1 and 2 recovered about four hours after injection. Guinea-Pig 3 died three days after and Guinea-Pigs 4 and 5 four and two hours after, respectively. Conclusions: Guinea-pigs weighing on the average of 400 gm. may be injected peritoneally with one or two c.c. or intrapleurally with 0.5 to 1 c.c. of chlorlyptus without having fatal results from the injection.
Experiment 16.—Toxic and irritant action of eucalyptus oil.—Three normal guinea-pigs were used for the experiment. Guinea-Pig 1 was injected with 1 c.c. of oil of eucalyptus in the peritoneum, and Guinea-Pig 2 with 0.5 c.c. in the pleural cavity. Guinea-Pig 3 was used as a control. Result: Guinea-Pig 1 died about three hours after injection, and Guinea-Pig 2 about two hours after the injection. Autopsy: Both guinea-pigs showed marked congestion and a moderate degree of exudate in the peritoneum.
Experiment 17.—Toxic and virulent action of eucalyptus.—Three normal guinea-pigs were selected for the experiment, as in Experiment 16. The injection was made in the pleural cavity. Guinea-Pig 1 was injected with 0.5 c.c. and Guinea-Pig 2 with 1 c.c. of eucalyptus oil. Result: Guinea-Pig 1 died the following day, and Guinea-Pig 2 one hour after the injection.
Experiment 18.—Toxic and irritant action of dichloramin-T, 0.5 per cent. in chlorcozane.—One guinea-pig was used for each experiment. Guinea-Pig 1 was injected with 0.5 c.c. and Guinea-Pig 2 with 1 c.c. of dichloramin-T peritoneally. Result: Both animals became restless immediately after the injection, and died twelve hours after of acute hemorrhagic peritonitis.
Experiment 19.—Effect of chlorlyptus on staphylococcus suspended in salt solution and one of that solution injected into the peritoneum of the guinea-pig.—Three guinea-pigs were used for the experiment. Guinea-Pig 1 was injected with 0.5 c.c. of staphylococcus suspension as control. Guinea-Pig 2 was given the same, and immediately after received 1 c.c. of chlorlyptus. Guinea-Pig 3 was injected with the same amount, and chlorlyptus was injected twenty-four hours after injection. Results: Guinea-Pig 1 was sick and weak with loss of appetite for some days, but gradually recovered. Guinea-Pig 2 died over night. Autopsy: There was a large amount of exudate in the peritoneal cavity, irritation of the intestine, and other signs of acute inflammation. A moderate degree of congestion; spleen not enlarged; liver showed cloudy swelling and fibrinous exudate; lungs and heart about normal except for a moderate degree of congestion but no exudate. Guinea-Pig 3 was sick for some days, but recovered gradually one week after.
Experiment 20.—Effect of chlorlyptus in vivo on staphylococcus.—The experiment was conducted in the same way as in Experiment 17, but 2 c.c. were used instead of 1 c.c. Result: Guinea-Pig 1 was injected with 2 c.c. staphylococcus suspension and died over night. Autopsy showed that the animal died of acute peritonitis. The peritoneum showed some fibrinous exudate and mesenteric vessels. Guinea-Pig 2 was injected with 2 c.c. of staphylococcus, and eighteen hours after was injected with 1 c.c. of chlorlyptus. The animal died two weeks after injection. Guinea-Pig 3 was injected with 2 c.c. staphylococcus suspension, and twenty-four hours after with 1 c.c. of chlorlyptus. The Guinea-Pig died ten days after. Autopsy revealed bronchopneumonia of the left lung and acute miliary abscess in the liver.
—(From The Journal A. M. A., Nov. 27, 1920, with additions.)
AQUAZONE (OXYGEN WATER)
Report of the Council on Pharmacy and Chemistry
Aquazone is stated by the Aquazone Laboratories, Inc., Los Angeles, California, to be a supersaturated solution of oxygen in water, carrying approximately five and one-half times as much dissolved oxygen as ordinary water. In an advertising booklet, it is suggested that Aquazone is of value in the treatment of influenza, pneumonia, typhoid, Bright’s disease and kindred disorders. It was also stated therein that in the treatment of fevers it lowers the temperature, and that the administration of three bottles of Aquazone (representing 0.033 gm.—11⁄2 grain—of oxygen) is of value for “preventive and tonic purposes.”
The evidence which the Aquazone Laboratories submitted did not show that the effects were other than those which might be obtained from the administration of ordinary potable water. The Council declared Aquazone inadmissible to New and Nonofficial Remedies, because the therapeutic claims made for it were unwarranted, and because its use is irrational for the reason that oxygen given by stomach in this way is of little or no value.—(Abstracted from Reports of Council on Pharmacy and Chemistry, 1920, p. 50.)
COAGULEN-CIBA OMITTED FROM N. N. R.
Report of the Council on Pharmacy and Chemistry
The Council has authorized publication of the following report announcing the deletion of Coagulen-Ciba from New and Nonofficial Remedies.
W. A. Puckner, Secretary.
Coagulen-Ciba, a product of the Society of Chemical Industry, Basle, Switzerland, was admitted to New and Nonofficial Remedies in 1915. It is stated to be an extract prepared from blood platelets and to contain thromboplastic substances (cytozym, thrombokinase, thrombozym) mixed with lactose. Extensive clinical reports appeared to justify its acceptance for New and Nonofficial Remedies with Fibrin Ferments and Thromboplastic substances.
In 1918, Dr. Arthur D. Hirschfelder reported to the Council that of a number of specimens of Coagulen-Ciba examined by him, failed to accelerate the coagulation time of blood.
In view of Dr. Hirschfelder’s findings, the Therapeutic Research Committee of the Council invited Dr. P. J. Hanzlik to undertake an exhaustive investigation of thromboplastic substances, the Council, in the meantime temporarily retaining Coagulen in New and Nonofficial Remedies until the investigation was completed.
The following report on the eligibility of Coagulen-Ciba was made to the Council by Dr. Hanzlik:
Object: To test the claims of thromboplastic and hemostatic activities.
Claims: Coagulen is alleged to be a “physiological styptic prepared from the natural coagulants of animal food contained in the blood platelets. It has the characteristics of a lipoid.” (If cephalin is meant it is difficult to understand why platelets should be selected in preference to other abundantly supplied organs such as brains).
“Coagulen is indicated in all cases of external and internal hemorrhage due to a deficiency of the coagulating power of the blood: epistaxis, hemophilia, hemorrhage from gastric or duodenal ulcer, melaena neonatorum, hemorrhage from the gums, the lungs, the bladder, the uterus, hemorrhage during or after operations (turbinectomy, tonsillectomy). It has also been used as a prophylactic before operations, likely to produce severe hemorrhage.”
“In cases of true hemophilia one application of 5 grains of coagulen usually suffices to control the hemorrhage.” “In gastric and intestinal hemorrhage the internal administration of coagulen will be found effective.” “In bonegrafting, plastic surgery, dentistry and nose and throat surgery the application of a 10 per cent. solution of Coagulen will be found to be of valuable assistance in controlling hemorrhage and oozing.”
“It is a non-toxic and non-irritating powder to which a certain amount of sugar has been added, with a view to ensuring its prompt solution in water or physiological sodium chloride solution.”
Description: “Coagulen is a yellowish granular powder with but slight odor, a sweet taste and is readily soluble in water or a normal salt solution.” The dry Coagulen obtained corresponds to the description claimed. Old specimens show the presence of dark brown particles. Coagulen is marketed in 3 forms: (1) as dry powder containing lactose, which, it is claimed, facilitates solution in water; (2) as 3 per cent. sterile solution in ampoules;137 (3) tablets.
Methods of Study: The alleged thromboplastic activity was tested by the method of Howell and a modification of this method by Fenger as described in “New and Nonofficial Remedies.” In the Howell method dog or cat blood is used, while beef blood at body temperature is used in Fenger’s method. In other respects the methods are essentially the same. Briefly these consist of noting the acceleration of coagulation time in a mixture of equal parts of serum and the thromboplastic agent to which about an equal part of oxalate plasma is added. Under these conditions cephalin causes clotting in about 1 minute or even less as compared with 20 to 30 minutes or more of the control.
The effects were compared with freshly prepared cephalin and other thromboplastic agents, using saline (0.9 per cent. NaCl) as control. The effect of different concentrations was also studied.
The literature of the manufacturers claims that Coagulen is harmless. This was tested by making intravenous and subcutaneous injections into guinea-pigs, using saline and cephalin as controls.
Bloods of 4 different species were used, namely, cat, dog, beef and human. Dog’s peptonized blood and plasma were also tried.
The 15 different tests that were made in vitro were carried out with 3 different samples of fresh dry Coagulen (from manufacturer), 2 old samples (one from Council on Pharmacy and Chemistry and one of our own), 3 fresh specimens of sterile solution in ampoules (from manufacturer), one old specimen and 4 small ampoules (Council on Pharmacy and Chemistry).
The tablets were not tested since these are made from dry Coagulen and the results would hardly be expected to show anything different.
Results: The results obtained may be briefly summarized as follows: (1) 0.1 per cent. to 5 per cent. Coagulen did not accelerate the coagulation time of blood and oxalate plasmas in the majority of tests any more than the controls of saline, while 0.1 per cent. cephalin was found to shorten the coagulation time from 1⁄3 to 1⁄2.
(2) There was no difference between the behavior of old and fresh specimens.
(3) No acceleration of coagulation in vitro was observed even with the highest concentrations tried, namely 25 and 50 per cent.
(4) Irrigations made with fresh dry coagulen in solution and sterile solution in ampoules on superficial bleeding from the foot-pads of 3 normal and peptonized dogs and local application to hemorrhages from dissected femoral arteries and bone and liver wounds of 3 dogs showed that coagulen was no more active than normal saline.
Toxicity: Subcutaneous and intravenous injections of different doses of Coagulen solutions (fresh ampoules) and dry Coagulen in solution in 8 guinea-pigs produced definite anaphylactoid symptoms with injury to the circulatory and respiratory systems as indicated by cardiac dilatation, abdominal congestion and pulmonary hemorrhages, congestion, distention and sometimes thrombi. On the other hand, the control animals injected with saline and cephalin remained practically unharmed.
Conclusions: The results obtained justify the following conclusions: (1) Coagulen is entirely inactive as a thromboplastic and hemostatic agent. (2) Coagulen is distinctly injurious when injected systemically. (3) The claims of hemostatic efficiency and harmlessness for Coagulen by the manufacturer appear exaggerated and unjustified.
Recommendations: Because of its uncertain composition, the possible dangers when injected systemically, and its inactivity as a thromboplastic and hemostatic agent when tested by several different methods, Coagulen merits no recognition as a therapeutic agent for inclusion in New and Nonofficial Remedies.
The detail evidences used as the basis of this brief report concerning Coagulen will be published shortly in the Journal of Pharmacology,138 together with the results with other thromboplastic agents.
The preceding report was sent to the American agent for the Society of Chemical Industry, Sept. 8, 1919.
In reply the American agent, Ciba Co., Inc., on March 22, 1920, sent the Council “some additional clinical reports on the use of Coagulen-Ciba in the treatment of Hemorrhages supporting our claims of the merits of Coagulen-Ciba.”
The material submitted by the Ciba Co., contains no objective evidence for or against the efficiency of Coagulen-Ciba but merely opinions. As a rule these opinions are favorable though conditional and hedging and quite unconvincing. Nothing was submitted to offset or challenge the findings of Dr. Hanzlik’s report.
Since the evidence indicates that Coagulen-Ciba has little, if any, efficacy as a hemostatic, the Council directed its omission from New and Nonofficial Remedies.—(From Reports of Council on Pharmacy and Chemistry, 1920, p. 53.)
FERRIC CACODYLATE OMITTED FROM NEW AND NONOFFICIAL REMEDIES
Report of the Council on Pharmacy and Chemistry
The Council has authorized publication of the report which appears below, explaining the omission of ferric cacodylate from New and Nonofficial Remedies.
W. A. Puckner, Secretary.
Iron cacodylate, the ferric salt of cacodylic acid, was admitted to New and Nonofficial Remedies in 1917. It is required to contain from 39.7 to 44.9 per cent. of arsenic (As).
The following statement of the action, uses and dosage of iron cacodylate appears in the 1920 edition of New and Nonofficial Remedies:
“Actions and Uses.—Ferric Cacodylate has the properties of iron salts and of arsenic. Its use has been proposed in conditions in which the effects of iron and the mild arsenic action of cacodylates is desired.
“Dosage.—from 0.015 to 0.1 Gm. (1⁄4 to 11⁄2 grains).”
The period for which the iron cacodylate preparations now in New and Nonofficial Remedies were accepted coming to an end with the close of 1920, the Council decided to determine if sufficient evidence for the value of ferric cacodylate has accumulated to warrant its continued recognition. The following is the report of the referee of the Committee on Therapeutics to whom the matter was assigned:
“As far as the Referee knows, the only claim that Iron Cacodylate has as a therapeutic agent is that it forms a convenient method for the administration of Iron and Cacodylate (while there is no reason why a drug should not be given by mouth, usually intramuscularly, and apparently it has recently been given intravenously). The effects to be expected from its use are those of iron and arsenic.
“Granted that iron and arsenic are valuable therapeutic agents, Iron Cacodylate is not a satisfactory preparation in which to administer these drugs for the following reasons:
“1. It would appear that Cacodylates are not the best form in which to administer arsenic. Cacodylates in therapeutic doses exert but a feeble action. Small quantities may be reduced to cacodyl (CH2)4As2, and varying amounts to inorganic arsenic. The amount transformed to arsenic is apparently unknown and probably varies in different individuals. On these grounds alone the use of the cacodylates where an arsenic effect is desired seems dubious.
“2. The amounts of iron and cacodylates contained in the doses recommended are small when compared with the usual doses of either iron or cacodylate. The amount of iron in the Iron Cacodylate preparations is small, about .0036 gram per dose, while the preparations admitted to ‘Useful Drugs’ contain much larger amounts per dose recommended. The list follows:
Massa Ferri CarbonatesFe per dose .042 gm.
Pilulae Ferri Carbonates" .058 gm.
Tinctura Ferri Chloride" .022 gm.
Ferri et Ammonii Citrae" .042 gm.
“The approximate amount of arsenic in Iron Cacodylate in the commonly recommended doses varies from .012 gm. to 0.024 gm., while the amount of arsenic in Sodium Cacodylate in the recommended doses varies between .021 and .35 gms. It would seem that a much more rational method of administration of these two drugs would be separately, in which case a better control over the dosage is possible.
“3. The Referee has been unable to secure reliable clinical evidence that Iron Cacodylate is a serviceable preparation. A search of the available literature for the past fifteen years has been made, also Drs. Edsall, Longcope, Stengel, Hoover, Phillips and Miller have been consulted. These physicians know nothing of its use.
“4. In view of the above, it appears to the Referee that Iron Cacodylate is an irrational and useless method of the administration of iron and arsenic.”
The Council adopted the report of the referee and directed that iron cacodylate be omitted from the 1921 edition of New and Nonofficial Remedies.—(From Reports of Council on Pharmacy and Chemistry, 1920, p. 62.)
LIBRADOL
Report of the Council on Pharmacy and Chemistry
The Council has authorized for publication the following report which explains why Libradol was found ineligible for New and Nonofficial Remedies.
W. A. Puckner, Secretary.
Libradol is manufactured by Lloyd Bros., Cincinnati. According to a circular (a “readily removable” label) which accompanies the trade package, its “uses” are: “In colds, croup and acute bronchitis. In local congestions; in lung trouble, in acute inflammations of this or any other organ, especially if pain or soreness be present. In lumbago, sciatica, or in rheumatic pains of the joints or muscles. Applied to the forehead, it induces sleep.”
Libradol is offered in two forms, “Libradol Mild” for infants and supersensitive persons which is said to be “destitute of drug energy” and Libradol “Regular” which is “highly medicated,” the “constituents” being “DRACONTIUM, SANGUINARIA, CEPHAELIS, MELALEUCA, LOBELIA, LAURUS, CAPSICUM, TOBACCO.”
According to a circular, “The sanitary plasma Libradol” is a “homogeneous, highly medicated, and exceedingly potent compound, in plastic form,” which “carries the energies of its drug constituents and the high antiseptic qualities of Laurus Camphora and Melaleuca.” It is stated: “The Drug Influence of Libradol is necessarily different from that of any known single member of the Materia Medica. But yet, no mystery either in medicine or of pharmacy is claimed as a part of its composition or process of manufacture. It is a thing peculiar to itself, the result of the study of the drugs from which it is derived and compounded. These drugs may be studied at leisure by whoever cares to do so....”
The following information bearing on the composition of Libradol was furnished by Lloyd Brothers in response to a request from the Council to aid in the consideration of the preparation:
“ ‘Compound Lobelia Powder’ has been, since 1852, official in the American Dispensatory, in the first edition of which (1852) its formula is given, as follows:
“ ‘Take of Lobelia, in powder, twelve ounces; Bloodroot and Skunk Cabbage, in powder, of each, six ounces; Ipecacuanha, eight ounces; Capsicus, in powder, two ounces. Mix them.’
“This preparation came increasingly into demand with the Eclectic profession, the principal use for which it was first employed (as an emetic), being finally displaced by its local application in bronchial pneumonia troubles, when sprinkled on a greased cloth and applied to the chest.”
“In 1898, Dr. Finley Ellingwood petitioned Lloyd Brothers to make for him, in plasma form, ready for application, a compound carrying the ingredients of the old ‘Compound Lobelia Powder,’ strengthened by the addition of Melaleuca leucadendron, Laurus camphora and Nicotiana tabacum. Experiments not very encouraging in a pharmaceutical sense were made, and it was not until repeated requests had been made that a product was at last satisfactorily prepared and forwarded to Dr. Ellingwood (1900), with no thought other than that of serving him personally in his practice. This product he used and commended to his professional friends, and under his commendation it came into professional demand.”
An examination of the information submitted by Lloyd Brothers showed Libradol to be in conflict with the principles and rules that govern in the acceptance of articles for New and Nonofficial Remedies as follows:
Composition (Rule 1).—The information which has been received gives little idea of the actual composition of the preparation; for example, the statement that Libradol “carries the energies of its drug constituents and the high antiseptic qualities of Laurus Camphora and Melaleuca” gives no indication as to the part or parts of the Laurus Camphora or Melaleuca employed. If the statement is correct, that Libradol “is a homogeneous, highly medicated, and exceedingly potent compound,” it is essential that the several potent ingredients be stated clearly and not merely hinted at by their qualities. Other conflicts with Rule 1 might be enumerated, but the foregoing citations state the direct conflict; and this has not been removed, although an inquiry was sent to Lloyd Brothers for a statement of the amount of each potent ingredient in a given quantity of Libradol.
Indirect Advertising (Rule 4).—The recommendation for the use of Libradol in the treatment of colds, bronchitis, lumbago, sciatica and rheumatic pains, which accompanies the trade package, is prone to lead the public to depend on it in cases where definite treatment is imperative.
Unwarranted Therapeutic Claims (Rule 6).—Libradol is recommended in a great variety of conditions and is especially claimed not only to relieve pain, but to remove the cause of pain. This is explained as follows: “In the study of the physiological action of many drugs, it was found that the constituent remedies in this combination exercised a most salutary influence, not only upon the sensibility of the nerves involved, but upon the capillary circulation within the diseased area, the muscular structures therein included, and, subsequently, upon the course of the advancement of the congestive and inflammatory processes, and upon secretion, exudation, adhesion, induration, hypertrophy, suppuration and excretion.”
Granting, for the sake of argument, that carefully controlled experimental clinical evidence were available to substantiate this statement with reference to a single case of pain, the statement would be misleading when considered as a general explanation of the preparation’s relieving pain by removing the cause of pain when taken in connection with the conditions for which it is recommended and in which pain is even a minor symptom. Still, if pain were relieved in these cases by removing the cause, the patient would be cured of the conditions which give rise to the pain, and these include: “Acute pain in the chest;... acute inflammation in the chest;... persistent local pain;...” (This might be interpreted as including tuberculosis; pneumonia; cancer, and appendicitis.) “lumbago; sciatica; articular rheumatism” (gonorrheal infections?).
Name (Rule 8).—The name, derived from Dolar and Liber, suggests the claimed action of the preparation (the relief of pain) rather than the drugs said to be presented by it.
Irrational Composition (Rule 10).—It is quite possible that Libradol will relieve pain in certain instances and that the drug constituents present in Libradol “Regular” make this more effective than “Libradol Mild” which is “destitute of drug energy”; this, however, is no justification for the use by physicians of a cataplasm containing or made from skunk cabbage, bloodroot, ipecac, melaleuca (oil of cajeput?), lobelia, laurus comphora (camphor?), capsicum and tobacco. The combination is thoroughly irrational and a reminder of a past century. Further, the Council knows of no evidence to support the following claims:
“As a stimulant Capsicum has the power of neutralizing depressant remedies like Lobelia and Tobacco.”
“Our association of its desirable constituents with those of Lobelia, in connection with the modifying influence of Capsicum, Melaleuca, and Laurus Camphora, permits a more free use in Libradol than would be possible were it to be employed alone.”
“Capsicum, Melaleuca, and Laurus Camphora in Libradol tend to counteract the excessive relaxative and depressant effects of Lobelia.”
“The great value of Melaleuca in Libradol is its quality of modifying and controlling the action of the associated energetic constituents of the drugs Tobacco and Lobelia, which reduce congestion and inflammation, but which would, unsupported, be too depressant.”
Libradol is inadmissible to New and Nonofficial Remedies because its composition is complex, irrational and semi-secret, and because its name and the unwarranted therapeutic recommendations made for it will lead to its ill-advised use.—(From Reports of Council on Pharmacy and Chemistry, 1920, p. 65.)
HELMITOL OMITTED FROM N. N. R.
Report of the Council on Pharmacy and Chemistry
Helmitol is hexamethylenamin methylencitrate. It was introduced with the claim that it was superior to hexamethylenamin—which acts in acid fluids only—in that it is equally efficient whether the urine is alkaline or acid.
In 1918 The Bayer Company, which then marketed the product in the United States, was notified that the Council questioned the claims made for Helmitol and desired evidence to substantiate them. In 1919 the same notification was sent the Winthrop Chemical Company, which in the meantime had secured control of the product. Pending the submission of the evidence, the Council continued the acceptance of Helmitol for New and Nonofficial Remedies with the statement that the actions and uses of hexamethylenamin anhydromethylencitrate were those of hexamethylenamin.
W. A. Puckner, Secretary.
The following report on Helmitol was made by the referee in charge of hexamethylenamin compounds and preparations, adopted by the Council and sent the Winthrop Chemical Company:
“Helmitol is a compound of anhydromethylencitric acid and hexamethylenamin. It was introduced with the claim that it would be antiseptic even in alkaline urine. The Council did not entirely trust the evidence, but continued to list Helmitol in N. N. R., merely as a salt of hexamethylenamin, until satisfactory data should become available. These have now been furnished by Hanzlik (Journal of Urology 4:145) who has shown that:
“1. The alkalinity required to split off formaldehyd from anhydromethylencitric acid is greater than exists in the urine, even in advanced ammoniacal fermentation.
“2. Even if any formaldehyd were liberated in ammoniacal fermentation, it would at once become inactive by combining with ammonia.
“3. Urine after the administration of anhydromethylencitric acid actually putrefies readily.
“4. Less than 5 per cent. of the anhydromethylencitric radical reaches the urine, the remainder being destroyed in the body.
“The only reason for the existence of Helmitol was this claim of antiseptic action in alkaline and putrefying urines. Since this has been disproved, there remains no reason for retaining Helmitol in N. N. R.; on the contrary, its retention would only tend to continue the fallacy on which it is based.
“It is, therefore, recommended that Helmitol be no longer listed with New and Nonofficial Remedies, and that this report be published, after the usual submission to the manufacturers.”
In accordance with the recommendation of the report, the Council has directed the omission of Helmitol from New and Nonofficial Remedies and has authorized the publication of this report.—(From The Journal A. M. A., Jan. 22, 1921.)
SPIROCIDE NOT ADMITTED TO N. N. R.
Report of the Council on Pharmacy and Chemistry
The Council has authorized publication of the following report.
W. A. Puckner, Secretary.
“Spirocide” (The Spirocide Corporation of New York) is advertised as a new and successful treatment of syphilis by fumigation and inhalation. According to the information presented to the Council, Spirocide is a mechanical mixture of metallic mercury 25 per cent., copper sulphate 25 per cent., cypress cones 20 per cent., henna 20 per cent., nut gall 5 per cent., and dried pomegranate 5 per cent. It is supplied in the form of greenish-gray tablets weighing about 10 gm. each, and containing, therefore, about 2.5 gm. (about 38 grains) of mercury. It is sold in packages of six tablets.
The following directions for its use are contained in a pamphlet recently distributed:
“Spirocide is administered by means of fumigation and inhalation. The patient is disrobed to the waist and placed in a light chair, preferably with arms. A pastil or tablet of Spirocide is placed on a small plate, or open receptacle, after being ignited by holding in a gas or alcohol flame for a minute or so until it begins to smoulder. The plate with the burning Spirocide is then placed on the floor between the patient’s feet or just under the chair. A small shelf or platform between the lower rounds of the chair is an excellent location for the plate containing the burning mass. When all is in position a sheet should be thrown over the patient and arranged to enclose the whole. The patient should breathe naturally and inhale the vapor, which will rise and fill the canopy surrounding him. The treatment will require 15 to 30 minutes, or until the Spirocide is burned up. The patient may complain at first of a slight choking sensation, and there may be some tendency to cough. This can be removed by raising the sheet long enough to let in a little clear air. The eyes should be closed or lightly bandaged to avoid smarting.”
Experiments conducted in the A. M. A. Chemical Laboratory show that Spirocide, when ignited, burns slowly with consequent volatilization of mercury. The several organic constituents serve as fuel and the copper sulphate possibly acts as a regulator of the combustion. During the burning process the cypress cones, henna, etc., are consumed but most, if not all, the copper remains behind, the mercury only being vaporized. It is asserted in the advertising pamphlet that Spirocide is indicated in all stages of syphilis, primary, secondary and tertiary, and in all its complications or sequelae. In these varying conditions one tablet daily or every other day is recommended until six treatments have been taken, though it is stated that “occasionally, depending on the severity or the duration of the disease, it may be wise to give nine treatments, the last three at intervals of two, three or more days.”
Some of the results which it is claimed are obtained with Spirocide are:
“At the completion of this course of treatment with Spirocide, all signs or evidences of syphilis are removed, and in ten days to three months all Wassermann tests prove negative. Any further treatments than the original course of fumigations are rarely needed. Wassermann’s will be found uniformly negative after a period which, according to the patient, may vary from ten days to three months. These results have been obtained in cases in which Salvarsan and kindred preparations have been employed without the slightest benefit.”
In a letter to the Council the “scientific observer” of the Spirocide Corporation declared:
“We do not claim that the vaporization method is new. We do claim, however, that this combination of mercury produces more rapid volatilization, certain absorption and undoubted effect than any form of mercury administered by any method known to science without the usual danger. That this is so we are willing to prove by comparison with other methods both by ourselves and many observers scattered over the United States....”
To determine the validity of the claims made for Spirocide, the Corporation was asked to present the evidence which it offered. In reply, the corporation’s “scientific observer,” Dr. J. Lewengood, submitted 83 case reports from a number of different observers, including those from military hospitals and a state institution, and also a reprint of an article published by him in the New York Medical Journal, Feb. 21, 1920, wherein were reported eight cases which received “Spirocide Treatment.” In no case were controls with other methods of mercury administration carried out.
This material the Council sent to two recognized syphilographers for an opinion. One of the consultants reported that of the 83 cases, 20 dealt with patients who had also received arsphenamin medication and, therefore, these 20 cases could not be considered as evidence concerning the value of Spirocide. As to the remaining cases, he found on the whole that the history and data furnished were far from sufficient to warrant the claims made. In many of the cases emphasis was laid on the Wassermann test, as though this test were the only thing to be considered in a case of syphilis. He pointed out that in one case the reaction changed from negative to strongly positive after six treatments and that in several cases the phenomena reported cannot be explained by anything else than a desire to get a negative blood test. For example, one case had Spirocide treatment and a Wassermann, 1 plus, 55 days after; the author then reports that 19 days later the reaction had become negative and, therefore, the change must be due to Spirocide. In several of the cases reported it is even questionable if the patients were syphilitic. The consultant concluded that the evidence submitted by the Spirocide Corporation failed to prove the claims made for Spirocide. He pointed out on the other hand that patients readily become salivated from the use of Spirocide, often after 8 or 10 treatments.
The second consultant replied that in his opinion the claim that Spirocide produces more “undoubted effect than any form of mercury administered by any method known to science without the usual danger,” was not substantiated. He believed that it was not as effective as some other methods, that the dosage is not as exact, and, therefore, it is not as free from danger when the drug is pushed.
The Council’s two consultants were also asked whether or not, in their opinion, the administration of mercury by inhalation is a method which the Council should endorse to the extent of recognizing a preparation based on this principle. This inquiry was also sent to the members of the editorial board of the Archives of Dermatology and Syphilology. Five replies were received. One advised a thorough study of the different methods of administering mercury by inhalation. The other four were opposed to such recognition on the ground that as the dosage is not exact the effects, therefore, are not certain.
In consideration of the opinions expressed by its consultants, the Council declared Spirocide inadmissible to New and Nonofficial Remedies because (1) the claims made for it are unproved and unwarranted, (2) the routine use of an inexact method for the administration of mercury is detrimental to sound therapy and (3) the name is not descriptive of its composition, thus failing to remind the physician who uses these pastils that he is administering metallic mercury.—(From The Journal A. M. A., Jan. 22, 1921.)
DIGIFOLIN-CIBA NOT ADMITTED TO N. N. R.
Report of the Council on Pharmacy and Chemistry
The Council has authorized the publication of the following report, declaring Digifolin-Ciba inadmissible to New and Nonofficial Remedies.
W. A. Puckner, Secretary.
Digifolin-Ciba is a product of the Society of Chemical Industry of Basle, Switzerland. It is marketed in the United States by the Ciba Company, 91 Barclay Street, New York City. It is claimed that Digifolin-Ciba is “a preparation of digitalis leaves that has been freed from the useless and harmful principles such as Digitonin (saponin), coloring and inert matter, etc., but does contain all the really valuable, therapeutically active constituents of the leaves, namely: digitoxin and digitalein in their natural proportions.” There is no evidence that digifolin contains all of the glucosides of digitalis as they exist in the leaf, and it is extremely improbable that this is the case because one cannot remove saponin without altering the other active principles of digitalis.
The Ciba Company sends out the following pamphlets relating to Digifolin:
“ ‘Concerning Digifolin-Ciba, A New Preparation of Digitalis,’ by C. Hartung, M.D., Ph.D. Extracts from the work ‘Ueber Digifolin, Ein Neues Digitalis-Praeparat’ in the Munich Medical Weekly, No. 36, page 1944, 1912.”
“ ‘Digitoxin Contents of Digifolin-Ciba,’ by C. Hartung, M.D., Ph.D., Basle, Switzerland. Reprints from the Pharmaceutical Post, 1913. No. 34, page 357. No. 40, page 431.”
“ ‘Pharmacological Tests of Digitalis,’ by M. J. Chevalier, Chef Des Travaux Pratiques de Pharmacologie et Matiere Medicale, Faculte De Medecine De Paris. Report Presented to the Societe de Therapeutique at Their Meeting, May 28, 1913.”
In the reprint “Concerning Digifolin, ‘Ciba.’ ” Hartung lays stress on the presence of harmful and inert substances present in the leaf and galenical preparations with the direct or implied statement that digifolin has an advantage in that these are absent from it. This is misleading. It is true that Boehm whom Hartung cites, found saponin to be irritating, but Boehm states that it required 100 mg. per kilogram of body weight to induce vomiting after its oral administration. Furthermore, saponin is present in traces only in infusion of digitalis, so that the therapeutic dose contains a wholly negligible amount of it.
The following occurs in “Pharmacological Tests of Digitalis,” by M. J. Chevalier:
“Hartung’s Digifolin merits our attention, especially because it seems to possess all the pharmacodynamic properties of galenic preparations of digitalis without showing any of their disadvantages.”
This claim scarcely needs comment, since it is well established that the chief “disadvantages” of digitalis are inherent in the principles which produce the desired effects of digitalis and may be avoided to a large extent by a carefully regulated dosage of any digitalis preparation. In short, the advertising for Digifolin asserts that this digitalis preparation has all the advantages of digitalis itself, but none of its disadvantages. This claim has been refuted so frequently that manufacturers must be aware that it is untenable. Further the claims now made for Digifolin are essentially those made nearly four years ago at which time the attention of the American agent was called to their unwarranted character.
The Council declared Digifolin-Ciba inadmissible to New and Nonofficial Remedies because the therapeutic claims advanced for it are misleading and unwarranted.—(From The Journal A. M. A., April 2, 1921.)