Chapter XXV: Appendix (6)

According to the statements of the Balsamea Co., Syrup Leptinol is prepared from the root of a species of Leptotaenia (a plant belonging to the parsnip family) which grows in Nevada and which has heretofore not been used in medicine. The manufacturer states that the botanists who have been consulted have been unable to agree on the botanical classification of the plant. The dried root of this unclassified species of Leptotaenia is extracted with alcohol and from the extract so obtained the syrup is made, but no information has been furnished to show how the alcohol-soluble material is incorporated in the syrup. Further, the manufacturer has not announced tests whereby the identity and uniformity of the finished preparation may be determined.

A booklet contains the following:

“The species of Leptotaenia from which LEPTINOL is produced was
first used in medicine by Dr. E. T. Krebs, who, after thorough
laboratory investigation and clinical application over a period
of several months, which resulted in the perfecting of LEPTINOL,
prescribed the preparation for Influenza during the epidemic of
that disease in 1918 with remarkably good results. Since this first
use, LEPTINOL has been exhaustively tested by clinicians in private
practice and in hospitals in the treatment of Pneumonia, Influenza
Bronchitis, etc., and has been universally endorsed.”

In a circular letter it is asserted that the use of “Leptinol” during the “influenza epidemic” of 1918-1919 “demonstrated its almost specific action in respiratory affections”; that “during this epidemic it proved to be five times as efficacious as any other treatment in pneumonia ...”; and that “it is now as firmly fixed in the mind of many doctors for respiratory diseases as quinine is for malaria and the salicylates for rheumatism.”

In the booklet it is further stated that the therapeutic action of the preparation is primarily that of a “stimulating expectorant” and secondarily as a “sedative expectorant”; that “its antiseptic action in the respiratory tract is prompt”; that it “is an effectual cardiac tonic where the tone of the heart muscle is impaired by fever”; that “in acute pulmonary conditions it effectively improves the respiratory action and allays cerebral irritation due to fever and toxins”; that it acts “as a vital stimulant and nerve sedative”; that “it stimulates the excretion of acid by the skin and in fever it has a strongly diaphoretic and antipyretic action without depressing the circulation or the central nervous system”; that it is “mildly diuretic” and “slightly augments the biliary flow” and that “it increases the gastric and intestinal secretions and allays intestinal fermentation.”

No evidence has been presented to the Council which shows that Syrup Leptinol has the actions ascribed to it. The reports of clinical trial are little more than chance observations and lack all control. This applies also to the following, stated to be a quotation from the report of the Tonopah Mines Hospital Association:

“In the spring of 1919 a recurrence of the Influenza epidemic of
the previous winter was experienced. During the first period of
this second epidemic, prior to April 15th, there were treated one
hundred sixteen cases of Influenza, fourteen of which developed
Influenzal Pneumonia, with six deaths. The Pneumonia was of the
very virulent type which prevails in this high altitude.... After
April 15th, when the clinical use of Leptinol was inaugurated,
three hundred and sixty-eight cases of Influenza were treated
and not a single case developed Pneumonia. Twenty-two cases of
Influenzal Pneumonia were received and treated with LEPTINOL, with
a consequent one hundred per cent. recovery....

“In the cases where LEPTINOL was used the treatment was the same
as had been previously followed, as to diet, fresh air, etc., but
the medication was confined to LEPTINOL. Syrup LEPTINOL was started
immediately in one-dram doses at one-hour intervals, in cases with
high temperatures, and this was continued until temperature and
pulse subsided. It was then used in one-dram doses at three-hour
intervals as recovery progressed. On admission to the hospital,
calomel in 1/4 grain doses, was given at fifteen minute intervals
for eight doses. The last calomel was followed in six hours by 1/2
ounce Magnesium Sulphate in saturated solution. The second day 1/10
grain of calomel was given at one-hour intervals for ten doses....”

Medical journals are replete with reports of remarkable results obtained with the most varied forms of treatment instituted at the time that the “influenza epidemic” had been reached. In these cases it is more than probable that the lessened virulence of the causative factor of the disease, the gradually established resistance of those stricken with it in the latter period and the improved management resulting from experience deserve the credit for the successful outcome of the treatment, rather than the particular form of medication employed.

The report of the Tonopah Mines Hospital Association directly implies that Syrup Leptinol prevents the development of pneumonia in practically all cases of influenza in which it would develop and that it entirely abolishes the mortality of that disease. However, it is well known that innumerable remedies have been recommended as specifics in the treatment of pneumonia on the basis of the treatment of a limited number of cases which recovered, and that eventually these asserted specifics have been discarded as of little value. In the present instance, the recovery of twenty-two cases in succession afford _prima facie_ evidence that those cases were not the virulent type of pneumonia in which the death rate is very high under any methods of treatment. While no effort appears to have been made to determine the nature of the infecting organism, the records show fairly conclusively that they belonged to those causing the milder type of pneumonia.

The Council finds Syrup Leptinol (formerly Syrup Balsamea) inadmissible to New and Nonofficial Remedies because: (1) the information in regard to composition does not state the amount of potent ingredient, nor permit the determination of its identity and uniformity; (2) the recommendation for its use in such infectious diseases as pneumonia and epidemic influenza is unwarranted and its claimed therapeutic efficacy in other diseases is without satisfactory supporting evidence; and (3) the recommendations for its use which appear on the label and the circular wrapped with the trade package constitute an indirect advertisement to the public.

The Council accepts the explanation of the manufacturer that he has been unable to obtain a satisfactory classification of the plant from which Syrup Leptinol is made. It would be undesirable to exclude from therapeutic use a valuable drug simply because its botanical character has not been determined or because an exhaustive chemical examination had so far not been made. However, in the absence of such information the manufacturer should give full information with regard to the preparation or standardization of his remedy and the therapeutic claims made for it should be accompanied by indisputable, thoroughly controlled clinical evidence. In the case of Syrup Leptinol, there is no satisfactory evidence available showing that the preparation has any value in the treatment of epidemic influenza, pneumonia, whooping cough, etc. While it is probable that a balsamic syrup, such as Syrup Leptinol, has palliative properties in coughs, such action does not at all justify the claim that it is useful in the contagious diseases for which it is proposed. The Council cannot recognize a syrup presenting an unknown plant in uncertain proportions which is recommended in a variety of dangerous contagious diseases in which it ultimately may be harmful, even though in early stages of these diseases it may serve to allay some of the milder symptoms.

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 7-1/2 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 1-1/2 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 2-1/2 c.c. of light, clear, amber colored, thick, sticky fluid, having a distinct caramel odor. Reaction _p_↓{H} = 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 citrate 0.06 Gm.
Sodium cacodylate 0.06 Gm.
Sodium glycerophosphate 0.1 Gm.
Chloretone 0.005 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]

[134] Iron Citrate Green, The Journal A. M. A., Jan. 12, 1917, p. 135; Reports Council Pharm. and Chem., 1916, p. 42.

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._)

[135] Glycerophosphates, The Journal A. M. A., Sept. 30, 1916, p. 1033; Reports Council Pharm. and Chem., 1916, p. 32. Sodium glycerophosphates. Reports Council Pharm. and Chem., 1916, p. 52.

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 Maximal
Germicidal Not Germicidal
Concentrations Concentrations

Typhoid Bacilli in Bouillon:
Chlorlyptus (Exp. 3) 10%, 2 to 4 hours 10% for 1 hour
5% for 2 hours
Eucalyptus oil (Exp. 1) 5% within 5 minutes No 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, No data
sometimes
Eucalyptus oil No data No data
Phenol (Exps. 9 and 10) 1%, almost at once, No data

Staphylococci in Pus:
Chlorlyptus (Exp. 11) 10% for 1 hour 10% for 1/2 hour
5% for 2 hours
Eucalyptus oil No data No data
Phenol No data No data

Staphylococci in Human Blood Serum:
Chlorlyptus (Exp. 12) 5% in 1 hour 1% in 1 hour
Eucalyptus oil No data No 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:

====================================================
Chlorlyptus Results

Exp. 19, No. 1 None Survived
Exp. 20, No. 1 None Died
Exp. 19, No. 2 At once Died
Exp. 19, No. 3 After 24 hours Survived
Exp. 20, No. 2 After 18 hours Died
Exp. 20, No. 3 After 24 hours Died
----------------------------------------------------

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:

==================================================================
Survived Chlorlyptus Eucalyptus 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. (1-1/2 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 Maximal
Fatal Dose Survived Dose
C.c. per Kg. 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, hypodermic 1/5 : 1
Rivas guinea-pig, peritoneal 1/3 : 1
Rivas guinea-pig, pleural 1/4 : 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.

[136] Barker and Rowntree (Bull. Johns Hopkins Hospital =29=:215, 221 [Oct.] 1918) obtained the following results with eucalyptus oil:

Cat, hypodermic; survived 3 c.c. per kg.; killed by 5.5 c.c. per kg.

Cat, intraperitoneal; killed by 5 c.c. per kg.

Dog, hypodermic; survived 1.3 c.c. per kg.

They quote from Browning that the following doses, c.c. per kilogram, are not fatal: frogs, 0.5; rabbits, 1 to 5; guinea-pigs, 1.

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

======================================================================
Chlorinated Chlorinated
Chlorlyptus Eucalyptol-Abbot Eucalyptol-Squibb

Odor Acrid Like eucalyptus Like eucalyptus

Density and Dark brown; Light yellow; Colorless;
color viscous, mobile; lighter mobile; lighter
heavier than water than water
than water

AgNO₃ added Heavy ppt. Slight turbidity Clear
to alcoholic
solution

Equal parts Gives free Gives free iodin No free iodin
with KI iodin slowly, in 4 hours; in 4 hours
solution noticeable not much
in 1/2 hour

Equal parts Much iodin Small amount of No free iodin
with 10% KI, immediately free iodin in in 3 hours
10% KIO₃  few numbers;
solution does not
noticeably
increase

Equal parts Some blackening; Reddish mixture; Same
with conc. odor of HCl no HCl;
H₂SO₄ eucalyptol odor

Alcohol KI No iodin Same Same as Abbott
liberated product

Heating Decomposes and Apparently does not
boils at decompose; some
103-105 C.; gas given off
then higher when T=80; the
fraction comes liquid distilled
over at 178 C.; at 173 C.; the
distillate has distillate did
sharp odor, is not have much
acid, but frees odor; no HCl
very little gas detected;
I₂ from KI;  no I₂ from
distillation KI; distillate
not completed 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 Neutral between five
slightly acid to litmus after ten minutes; and ten minutes
taste almost gone in two minutes

Gums, a few drops between cheeks and gums: Neutral between ten
Five per cent. still strongly acid in and fifteen minutes
twelve minutes; distinctly acid in
seventeen minutes. One per cent. still
strongly acid in twenty-one minutes
---------------------------------------------------------------------

CHLORLYPTUS: REACTION (LITMUS PAPER) ON CONTACT WITH TISSUE

======================================================================
Serial When Quantity, Time Blue Symptoms or
No. Animal Injected C.c. of Death Litmus Toxicity

1 Rat Pleura 1 1/2 hour Remains blue None; killed;
pleura not
congested;
lung spec. =
21; slight
congestion
2 Rat Pleura <1 1 hour Remains blue Negative
3 Rat Pleura 1 23 min. Remains blue Almost at once
bad gasping
respiration
and died in
23 m.; heart
distend.;
possibly
injection
penetrated
lung
Peritoneum 1 23 min. Turns red
4 Rabbit Pleura 1 .... ...... Died
overnight
5 Dog Pleura 1 1/4 hour Remains blue
20 m. p. m.
Peritoneum 1 1/4 hour Remains blue
20 m. p. m.
6 Dog Pleura 1 3 min. Remains blue
45 m. p. m.
Peritoneum 1 3 min. Remains blue
45 m. p. m.
7 Dog Pleura 1 20 min. Remains blue
20 m. p. m.
Peritoneum 1 20 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