“... normal phenol serum—phenol with methyl blue dissolved in anaphylactic serum...”“... a combination of human or horse serum with Phenol and Methylene-blue, thereby forming a new chemico-biologic product which he termed Methyl-phenol Serum or, chemically, Chloride of Phenol Thionin Tetramethylene-Seric.”“Methyl-phenol Serum is a chemico-biological product in which Phenol is the chief factor. Each ampule of 10 c.c. contains the therapeutic equivalent of 0.5 gm. (7.5 grains) of Phenol.”
“... normal phenol serum—phenol with methyl blue dissolved in anaphylactic serum...”
“... a combination of human or horse serum with Phenol and Methylene-blue, thereby forming a new chemico-biologic product which he termed Methyl-phenol Serum or, chemically, Chloride of Phenol Thionin Tetramethylene-Seric.”
“Methyl-phenol Serum is a chemico-biological product in which Phenol is the chief factor. Each ampule of 10 c.c. contains the therapeutic equivalent of 0.5 gm. (7.5 grains) of Phenol.”
From the foregoing it appears that both preparations contain phenol and methylthionine chloride (methylene blue) and that the second does not contain methyl phenol (cresol) as the name would indicate.
No definite evidence for the value of these preparations is brought forward and even the manufacturer is constrained to caution, “We assume no responsibility for the therapeutic action of the serum....” On the other hand there are a great many statements in the papers of Cano and his colleagues to which exception must be taken. Of these, from among many similar, the following statements are to be cited and commented on:
“Accepting that the gonorrheal infection gives systemic toxemia from absorption of the toxins...”
“Accepting that the gonorrheal infection gives systemic toxemia from absorption of the toxins...”
It is the general opinion that in the majority of instances there is no systemic toxemia.
“The technique of intraprostatic injection, while less simple than that of the intravenous, is by no means so difficult or complicated as to place it exclusively in the category of the urologist.”
“The technique of intraprostatic injection, while less simple than that of the intravenous, is by no means so difficult or complicated as to place it exclusively in the category of the urologist.”
This obviously is an attempt to encourage the general use of these preparations and to minimize the necessity for careful study and special skill in their employment. It is most unwise for one to attempt intraprostatic injections unless he is specially trained in the technique of this procedure.
“This injection to be performed after the 5th or 6th intravenous injection of Methyl-phenol Serum....”
“This injection to be performed after the 5th or 6th intravenous injection of Methyl-phenol Serum....”
Intravenous injections have a place in sane therapy only when the medicament to be so administered is of known composition and when evidence is available which gives assurance that definite results shall follow its use. In the absence of these conditions it is manifestly unwise and even unexcusable to employ any medicament in this manner, and its repeated use is reprehensible.
“Intravenous injection of Methyl-phenol Serum alternating with intravenous injections of mercury should be given every 48 hours until infection is under control.”
“Intravenous injection of Methyl-phenol Serum alternating with intravenous injections of mercury should be given every 48 hours until infection is under control.”
This quotation further emphasizes that the treatment, as advised, carries with it a certain element of danger.
“Methylene blue prevents the phenol from exerting its usual action upon the red blood corpuscles, and ensures rapid elimination through healthy kidneys. It preserves the antiseptic power of the phenol and prevents the phenol from interfering with the chemico-biologicalfunction of the white and red blood cells. The serum component favors chemotaxis, it strengthens bodily defense, it prevents anaphylaxis even in debilitated patients, and it replaces the resistance which has been impaired by the demands that have already been made upon it.”
“Methylene blue prevents the phenol from exerting its usual action upon the red blood corpuscles, and ensures rapid elimination through healthy kidneys. It preserves the antiseptic power of the phenol and prevents the phenol from interfering with the chemico-biologicalfunction of the white and red blood cells. The serum component favors chemotaxis, it strengthens bodily defense, it prevents anaphylaxis even in debilitated patients, and it replaces the resistance which has been impaired by the demands that have already been made upon it.”
No evidence is submitted to substantiate these claims. It seems strange that phenol should lose its power and that this should be restored by the methylene blue.
“It has a refractory chemico-biological action, and exercises no vicious effect on the red blood corpuscles in the circulation, but, on the contrary, by its inoffensive presence, it wholly preserves all of the physiological properties of the blood.”
“It has a refractory chemico-biological action, and exercises no vicious effect on the red blood corpuscles in the circulation, but, on the contrary, by its inoffensive presence, it wholly preserves all of the physiological properties of the blood.”
What “a refractory chemico-biologic action” is, is not clear, but there is no evidence that this preparation has any action which might be defined as “refractory chemico-biological,” that its presence is inoffensive or that it wholly preserves all the physiologic properties of the blood.
“The treatment of gonorrhea by Cano’s theory... is firmly based upon chemico-biological facts and accepted authoritative theories and bears the same relation to gonorrhea that intravenous injections of arsenicals bear to syphilis.”
“The treatment of gonorrhea by Cano’s theory... is firmly based upon chemico-biological facts and accepted authoritative theories and bears the same relation to gonorrhea that intravenous injections of arsenicals bear to syphilis.”
Quite an exaggerated and unwarranted statement. In the same way, objection is taken to the following quotations:
“Phenol administered intravenously in combination with methylene blue, to protect the red-blood globule, undergoes no change, and preserves all of its actual antiseptic effect on the gonococcus and its toxins as though employed in the test tube.”“When thus introduced into the human body its elimination is unique, effective, antiseptic, germicidal, being completely and exclusively thrown off through the kidneys in a period varying from one-half to twelve hours without local injury or disturbance to the general economy.”“Combinations of phenol are unstable, but they do have the advantage of mitigating direct action on the cells and globules. It is also known that ordinary phenol has acoagulant actionon the albumins and anoxidizing poweron the tissues, which power, if permanent, produces gangrene. By virtue of this dual action it therefore acts as amodifier; by its oxidizing power on the germ it is germicidal, and prevents the growth of the gonococcus; and by its coagulant power on the toxins it relieves paragonococcal lesions (mono- and poly-arthritides) and affections of the serous organs (endo- and pericarditis, meningitis), and some definite systemic disturbances, the pathology of which is often confused with that of other infections.”“Lymphocytosis is often persistent in some individuals in whom the internal secretions and the processes of assimilation and disassimilation are deficient; and because of the lack of these the organic physiological ferments are insufficient for the mechanism of nutrition and the phenomena of hematopoiesis.”
“Phenol administered intravenously in combination with methylene blue, to protect the red-blood globule, undergoes no change, and preserves all of its actual antiseptic effect on the gonococcus and its toxins as though employed in the test tube.”
“When thus introduced into the human body its elimination is unique, effective, antiseptic, germicidal, being completely and exclusively thrown off through the kidneys in a period varying from one-half to twelve hours without local injury or disturbance to the general economy.”
“Combinations of phenol are unstable, but they do have the advantage of mitigating direct action on the cells and globules. It is also known that ordinary phenol has acoagulant actionon the albumins and anoxidizing poweron the tissues, which power, if permanent, produces gangrene. By virtue of this dual action it therefore acts as amodifier; by its oxidizing power on the germ it is germicidal, and prevents the growth of the gonococcus; and by its coagulant power on the toxins it relieves paragonococcal lesions (mono- and poly-arthritides) and affections of the serous organs (endo- and pericarditis, meningitis), and some definite systemic disturbances, the pathology of which is often confused with that of other infections.”
“Lymphocytosis is often persistent in some individuals in whom the internal secretions and the processes of assimilation and disassimilation are deficient; and because of the lack of these the organic physiological ferments are insufficient for the mechanism of nutrition and the phenomena of hematopoiesis.”
Until proof is available showing that phenol, administered intravenously in the quantities employed in Cano’s Normal Phenol Serum and Cano’s Methyl-Phenol Serum, acts as a germicide and methylthionine chloride (“methylene blue”) prevents the deleterious effects of phenol on the red blood corpuscles; that repeated intravenous injections of phenol and mercury are without danger; that there is no danger of anaphylaxis; that the physiologic properties of the blood are preserved by these medicaments; and, finally, that these preparations have an effect on gonorrhea and its complications, these substances Normal Phenol Serum (Cano) and Methyl-Phenol (Cano), are inadmissible to New and Nonofficial Remedies.
The following quotations taken from the circular are admissions that these preparations are not innocuous:
“That the economy will tolerate to a surprising degree substances directly introduced through the blood stream is now well known. By the intravenous injection of 10 c.c. of methyl-phenol serum we throw into the human body a massive dose of an alien substance. The immediate effect of this injection is upon the central nervous system. The recipient usually becomes either pale or suffused, he has a ringing in his ears, has a sensation of great altitude, and occasionally has a dryness of the fauces and a metallic or a garlic taste.”“In some patients secondary reactions occur in from one to four hours after injection. The phenomena we have observed in these secondary reactions are pronounced chill and rigor...”
“That the economy will tolerate to a surprising degree substances directly introduced through the blood stream is now well known. By the intravenous injection of 10 c.c. of methyl-phenol serum we throw into the human body a massive dose of an alien substance. The immediate effect of this injection is upon the central nervous system. The recipient usually becomes either pale or suffused, he has a ringing in his ears, has a sensation of great altitude, and occasionally has a dryness of the fauces and a metallic or a garlic taste.”
“In some patients secondary reactions occur in from one to four hours after injection. The phenomena we have observed in these secondary reactions are pronounced chill and rigor...”
There is no doubt that considerable harm may be done by the intravenous and by the intraprostatic administration of these preparations and until there is good evidence showing the therapeutic value of the treatment, the routine use of these preparations, except perhaps at hospitals in selected and well controlled and carefully guarded cases, is to be strongly discouraged.
When the foregoing statement was sent to the Mulford Company for comment, the firm submitted a letter from Dr. Perry Townsend to the Mulford Company in which he declared that the results obtained with the Cano preparations had been satisfactory and without untoward results. In this letter, Dr. Townsend proposed that a series of injections with these preparations be carried out under the observation of members of the Council and the supervision of Dr. Cano or himself.
The report of the Council, the letter from the Mulford Company and that of Dr. Townsend were sent to a number of urologists for their opinion concerning this whole matter. It was explained that the referee held that no reason had been presented which would warrant the Council to depart from its customary procedure, namely, to require that clinical evidence be submitted in the form of published reports which permit investigation and verification by independent observers but that, before making further recommendation to the Council, he desired the opinion of urologists of recognized standing concerning the report submitted to the Mulford Company. All replies received approved the Council’s position.
The following is one of the replies received:
Your letter in regard to Normal Phenol Serum (Cano) and Methyl-Phenol Serum (Cano) received. I wish to state that I have read the correspondence between the Council and H. K. Mulford Co. and in my opinion the referee and the Council are quite correct in their attitude in the matter. In my opinion I would emphasize the following:(1) There is absolutely nothing about the remedies directedspecificallyagainst the gonococcus and no evidence to show that any action against them is obtained. As we know there are certain states of normal serum which are highly toxic and any normal serum from another animal will produce disturbances in man when injected intravenously—particularly if repeated. The addition of substances to serum normal or otherwise is apt to and frequently does render that serum highly toxic! The substances added in the instances referred to—phenol and methylene blue are not in any way calculated to lessen the toxicity of serum. The element of danger existing in the indiscriminate use of serums intravenously is, in my opinion, increased by the addition of the substances mentioned, and it would be unwise to encourage the general use of any such remedies. Furthermore the products are condemned by the very evidence of the originators and their admissions are quite sufficient to deter anyone from using the products as they suggest.As to the intraprostatic injections with the serums it does not at all meet my views; although the introduction of serums by this route have been frequently advocated and I have personally carried this mode out I cannot allow the impression to go out that it could be done in a routine manner—nor that no ill results could follow—for I have seen otherwise. Furthermore from theoretical standpoint serums need not be given in this way.
Your letter in regard to Normal Phenol Serum (Cano) and Methyl-Phenol Serum (Cano) received. I wish to state that I have read the correspondence between the Council and H. K. Mulford Co. and in my opinion the referee and the Council are quite correct in their attitude in the matter. In my opinion I would emphasize the following:
(1) There is absolutely nothing about the remedies directedspecificallyagainst the gonococcus and no evidence to show that any action against them is obtained. As we know there are certain states of normal serum which are highly toxic and any normal serum from another animal will produce disturbances in man when injected intravenously—particularly if repeated. The addition of substances to serum normal or otherwise is apt to and frequently does render that serum highly toxic! The substances added in the instances referred to—phenol and methylene blue are not in any way calculated to lessen the toxicity of serum. The element of danger existing in the indiscriminate use of serums intravenously is, in my opinion, increased by the addition of the substances mentioned, and it would be unwise to encourage the general use of any such remedies. Furthermore the products are condemned by the very evidence of the originators and their admissions are quite sufficient to deter anyone from using the products as they suggest.
As to the intraprostatic injections with the serums it does not at all meet my views; although the introduction of serums by this route have been frequently advocated and I have personally carried this mode out I cannot allow the impression to go out that it could be done in a routine manner—nor that no ill results could follow—for I have seen otherwise. Furthermore from theoretical standpoint serums need not be given in this way.
In consideration of the opinion expressed by the Council’s consultants the referee recommended that Normal Phenol Serum (Cano) and Methyl-Phenol Serum (Cano) be declared ineligible for New and Nonofficial Remedies because of conflict with Rule 6 (unwarranted therapeutic claims) without considering possible conflicts with other rules, and that publication of the report be authorized.—(From Reports of Council on Pharmacy and Chemistry, 1919, p. 85.)
Soamin is the name under which the firm of Burroughs Wellcome and Company sells its brand of sodium arsanilate. The Council directed the omission of Soamin from New and Nonofficial Remedies and authorizedpublication of the report which appears below after the proprietors of the product had declined to withdraw or suitably revise the unwarranted therapeutic claims which it made.
W. A. Puckner, Secretary.
The proprietary brand “Soamin” of sodium arsanilate was admitted to New and Nonofficial Remedies several years ago at a time when the therapeutic value of arsanilic acid had not been definitely determined. Experience with this drug has shown that it is far more dangerous and also has a more limited field of usefulness than was at first recognized. The proprietors of the Soamin brand have continued to include in the list of conditions in which it “would seem” to be a “very effective agent” cerebrospinal meningitis and pellagra; in fact, meningitis is the first in the list of conditions mentioned, syphilis the second and pellagra third. In support of their belief in the efficacy of the remedy in meningitis, three reports, published from six to nine years ago, are quoted. In one of these it is stated that two patients “were cured”; in another report, seven of eight patients in whom the clinical, but not the microscopic, diagnosis of meningitis had been made were reported as having recovered; in the third report, fifty-six of ninety cases were reported cured; in this larger series of cases the author neglects to state the method of administration. The firm quotes but one paper (which is a very uncritical report) in regard to pellagra.
It seems to the Council that the evidence of value of sodium arsanilate in these conditions (which are now treated by more rational methods) is too slight to justify the emphasis laid on it by the firm, especially as sodium arsanilate is admittedly a dangerous agent, several cases of blindness having been reported from its use.
For these reasons it was voted to omit Soamin from New and Nonofficial Remedies.—(From Reports of Council on Pharmacy and Chemistry, 1919, p. 89.)
The Council has authorized publication of the following report.
W. A. Puckner, Secretary.
The consideration of the following “mixed” vaccines was requested by F. I. Lackenbach, San Francisco:
Special Bacterial Vaccine No. 2 (Staph-Strep. Bacterin) containing killedStaphylococcus albus,Staphylococcus aureusand streptococcus.Special Bacterial Vaccine No. 3 (Pneumo-Staph-Strep. Bacterin) containing killedStaphylococcus albus,Staphylococcus aureus, streptococcus and pneumococcus.Special Bacterial Vaccine No. 4 (Pneumo-Staph-Strep-Coli Bacterin) containing killedStaphylococcus albus,Staphylococcus aureus,Staphylococcus citreus,Bacillus coli, streptococcus and pneumococcus.Special Bacterial Vaccine No. 5 (Influenza Combined Bacterin) containing killedStaphylococcus albus,Staphylococcus aureus,Bacillus Friedländer,Bacillus influenzae,Micrococcus catarrhalis, streptococcus and pneumococcus.Special Bacterial Vaccine No. 11 (Pneumo-Strep. Bacterin) containing killed streptococcus and pneumococcus.Special Bacterial Vaccine No. 15 (Combined Whooping Cough Bacterin) containing killedBacillus pertussis,Staphylococcus albus,Staphylococcus aureus,Micrococcus catarrhalis,Bacillus influenzae, streptococcus and pneumococcus.Special Bacterial Vaccine No. 16 (Mixed Gonococcus Bacterin) containing killed gonococcus,Staphylococcus albus,Staphylococcus aureus,Bacillus coli,diphtheroid bacillus, streptococcus and pneumococcus.
Special Bacterial Vaccine No. 2 (Staph-Strep. Bacterin) containing killedStaphylococcus albus,Staphylococcus aureusand streptococcus.
Special Bacterial Vaccine No. 3 (Pneumo-Staph-Strep. Bacterin) containing killedStaphylococcus albus,Staphylococcus aureus, streptococcus and pneumococcus.
Special Bacterial Vaccine No. 4 (Pneumo-Staph-Strep-Coli Bacterin) containing killedStaphylococcus albus,Staphylococcus aureus,Staphylococcus citreus,Bacillus coli, streptococcus and pneumococcus.
Special Bacterial Vaccine No. 5 (Influenza Combined Bacterin) containing killedStaphylococcus albus,Staphylococcus aureus,Bacillus Friedländer,Bacillus influenzae,Micrococcus catarrhalis, streptococcus and pneumococcus.
Special Bacterial Vaccine No. 11 (Pneumo-Strep. Bacterin) containing killed streptococcus and pneumococcus.
Special Bacterial Vaccine No. 15 (Combined Whooping Cough Bacterin) containing killedBacillus pertussis,Staphylococcus albus,Staphylococcus aureus,Micrococcus catarrhalis,Bacillus influenzae, streptococcus and pneumococcus.
Special Bacterial Vaccine No. 16 (Mixed Gonococcus Bacterin) containing killed gonococcus,Staphylococcus albus,Staphylococcus aureus,Bacillus coli,diphtheroid bacillus, streptococcus and pneumococcus.
Mr. Lackenbach states that these bacterial mixtures were prepared for him by E. R. Squibb & Sons. Their sale in interstate commerce is permitted underthe license granted to the latter firm by the U. S. Treasury Department. However, no evidence of any kind was presented to the Council proving the therapeutic efficacy of the several mixed vaccines. As a mixture of two or more kinds of organisms is accepted for New and Nonofficial Remedies only if there is satisfactory evidence that its therapeutic use is rational, the Council declared the several vaccine mixtures ineligible for New and Nonofficial Remedies (Rule 10).—(From Reports of Council on Pharmacy and Chemistry, 1919, p. 90.)
The Council examined the available evidence for Somnoform, sold by Stratford-Cookson Company, successors to E. de Trey and Sons, and found the preparation inadmissible to New and Nonofficial Remedies. The Council authorized publication of the report which appears below.
W. A. Puckner, Secretary.
Somnoform is sold in the United States by Stratford-Cookson Company, successors to E. de Trey and Sons. According to the label on a package of Somnoform sent the Council.
“This mixture contains Chloride of Ethyl, 83 per cent.; Chloride of Methyl, 16 per cent.; Bromide of Ethyl, 1 per cent.”
“This mixture contains Chloride of Ethyl, 83 per cent.; Chloride of Methyl, 16 per cent.; Bromide of Ethyl, 1 per cent.”
Although Somnoform has been on the market for a long time, the published reports present no proof that it is superior to ethyl chlorid used alone. Moreover, the published reports and statistics do not necessarily apply to the Somnoform now sold for the reason that mixtures of varying composition have been sold as Somnoform in the past. Thus, when Somnoform was considered by the Council in 1909, it was claimed to be composed of chloride of ethyl, 60 per cent.; chloride of methyl, 35 per cent., and bromide of ethyl, 5 per cent. Federal chemists found, however, that it contained no bromide of ethyl (Notice of Judgment No. 571). It is a question, therefore, whether a given report applies to a mixture containing 5 per cent. bromide of ethyl, 1 per cent. of this substance, or none at all.
The present advertising booklet for Somnoform does not present acceptable evidence of the therapeutic value of the preparation. An ignorance concerning the elementary facts of physiology and pharmacology is evident in the second sentence: when having stated that “Somnoform is the result of several years of study and investigation by Dr. George Rolland, Dean of the Bordeau Dental School,” the pamphlet continues: “He sought an anesthetic which would enter, dwell in, and leave the body in the same manner that oxygen does....”
The claim as to the value of the 1 per cent. of ethyl bromide in the mixture is highly improbable; certainly no evidence in support of the claimed value of this constituent is available to the referee.
No evidence is submitted which proves the claim of superiority of Somnoform over similar preparations, asserted in the following:
“The peculiar manner in which the elements are combined is what makes Somnoform at once so efficient and so safe.”
“The peculiar manner in which the elements are combined is what makes Somnoform at once so efficient and so safe.”
The Council declared Somnoform inadmissible to New and Nonofficial Remedies because, in the absence of acceptable evidence showing its exceptional safety and value, the claims are unwarranted (Rule 6), and because the name of the mixture is not descriptive of its composition (Rule 8).—(From Reports of Council on Pharmacy and Chemistry, 1919, p. 90.)
The Council has authorized publication of the following report which declares Tablets Formothalates (Tailby-Nason Company, Boston, Mass.) ineligible for New and Nonofficial Remedies.
W. A. Puckner, Secretary.
Tablets Formothalates are sold by Tailby-Nason Company, Boston, Mass. On the label a formula is given: “Constituents: Acetanilid 2 gr.; phenolphthalein1⁄2gr. In a balanced combination with Hexamene [a name sometimes applied to hexamethylenamin] and Oil of Cinnamon. Indications: Influenza, Colds, Grippe, Headache, Neuralgia, Rheumatism.” The same formula is given in advertisements and in this advertisement it is claimed that they are “For Influenza and Grip” and if “given in the acute stage may avert a serious attack” (Boston M. & S. J., Oct. 3, 1918). The dose is given as one to two tablets at 6 p. m. and repeat at bedtimes.
The A. M. A. Chemical Laboratory reported that the tablets weigh an average of 0.4882 Gm., or 71⁄2grains; that theyhavethe odor and taste of cinnamon; and that they contain hexamethylenamin, are neutral and therefore give up no formaldehyde in the presence of water alone. The Laboratory further reported that they contain phenolphthalein and acetanilid. These tablets were directed to be taken internally and therefore their effect was not intended to be local.
The amount of hexamethylenamin was not determined, but in any case could not exceed 5 grains per tablet. It is evident that 4 grains of acetanilid and 10 grains of hexamethylenamin and 1 grain of phenolphthalein (in two tablets) “if given in the acute stage” of influenza would not “avert a serious attack,” as claimed in the advertisements.
The Council declared Tablets Formothalates inadmissible to New and Nonofficial Remedies.—(From Reports of Council on Pharmacy and Chemistry, 1919, p. 92.)
The Council has declared Triple Arsenates with Nuclein No. 1 and Triple Arsenates with Nuclein No. 2, tablets marketed by the Abbott Laboratories, inadmissible to New and Nonofficial Remedies because unwarranted therapeutic claims (Rule 6) are made for them and because they present an illogical combination of drugs (Rule 10). The publication of the following report has been authorized by the Council.
W. A. Puckner, Secretary.
The following claims are made for Triple Arsenates with Nuclein:
“Puts ‘pep’ and strength back into that patient recovering from Spanish Influenza, pneumonia, typhoid, or surgical operation. An extremely powerful reconstructive tonic. Try it for that ‘run down’ feeling.”
“Puts ‘pep’ and strength back into that patient recovering from Spanish Influenza, pneumonia, typhoid, or surgical operation. An extremely powerful reconstructive tonic. Try it for that ‘run down’ feeling.”
Triple Arsenates with Nuclein is said to contain “Strychnin Arsenate gr.1⁄128, Quinin Arsenate gr.1⁄64, Iron Arsenate gr.1⁄64, Nuclein Solution mins. 4.” A second preparation, of double strength—Triple Arsenates with Nuclein No. 2—is also advertised. The Council voted not to accept these preparations for New and Nonofficial Remedies on the following grounds:
The quantities of quinin, iron and nuclein in the doses represented in these mixtures are negligible; thus, one tablet of Triple Arsenates with Nuclein containing1⁄64grain of quinin arsenate contains only about1⁄90grain of anhydrous quinin; the tablet containing1⁄64grain of iron arsenate contains1⁄210grain of iron; 4 minims of the nuclein solution (assuming it to be the “Nuclein Solution-Abbott”) would contain but2⁄5of a grain of nuclein—a substance which even in large doses is of questionable therapeutic value. The amounts of iron and nuclein contained in doses of this preparation are insignificant in comparison with the amounts present in ordinary foods. The only substances present in even small therapeutic doses are strychnin and arsenic. The effects of arsenic and strychnin are very different and there are comparatively few conditions in which they should be prescribed at the same time. Hence a preparation containing these two in fixed proportions is illogical.—(From Reports of Council on Pharmacy and Chemistry, 1919, p. 92.)
The Council has adopted and authorized publication of the report which appears below. This report declares “Anti-Pneumococcic Oil” (a solution of camphor in oil sold by Eimer and Amend, New York) ineligible for New and Nonofficial Remedies because (1) the recommendations for its use in pneumonia are not warranted by the evidence, (2) the name is not descriptive of its composition but is therapeutically suggestive, and (3) the sale of a solution of camphor in oil under a name nondescriptive of its composition is unscientific and a hindrance to therapeutic progress.
W. A. Puckner, Secretary.
The Council having decided to consider Anti-Pneumococcic Oil (Eimer and Amend, New York), the preparation was assigned to the Committee on Therapeutics for report. The report that follows was made by a member of this committee:
According to the advertising, Anti-Pneumococcic Oil is a “twenty-five per cent. solution of camphor in a thin oil” which was “originated” by August Seibert, M.D. The following directions are given for its use:
“10 c.c. (150 minims) to every 100 pounds of body weight, to be injected hypodermically every eight to twelve hours in pneumococcic pneumonia, as soon after the initial chill as possible.”
“10 c.c. (150 minims) to every 100 pounds of body weight, to be injected hypodermically every eight to twelve hours in pneumococcic pneumonia, as soon after the initial chill as possible.”
It is claimed that the prescribed dose one hour before general anesthesia begins, “safeguards against postoperative pneumonia,” and, that “animals can so be immunized against later and otherwise fatal intravenous pneumococcic infection (Boehnke, Institute for Experimental Therapy, Frankfort).” The advice is given:
“In pneumococcic meningitis, endocarditis and pleuritis, 3% of salicylic acid should be added to this oil.”
“In pneumococcic meningitis, endocarditis and pleuritis, 3% of salicylic acid should be added to this oil.”
In an article by Seibert, “Camphor and Pneumococci” (Medical Record, April 20, 1912), a reprint of which is used to advertise Anti-Pneumococcic Oil, previous work (München, med. Wchnschr., No. 36, 1909) is mentioned as the starting point for the use of camphor in pneumonia. In this article, the author reports his first case, that of a young woman who entered St. Francis’ Hospital on the third day after the initial chill “with the symptoms of severe toxemia (unconscious, temperature 105.5 F., pulse 130, and respiration 40) and involvement of both lower lobes.” “Large doses of camphor,” 12 c.c. of a 20 per cent. solution, were injected hypodermically “every twelve hours, resulting ingradualimprovement and recovery by the fourth day, without a crisis.” Seibert reports success in its use in twenty-one cases, but gives no casehistories or protocols. He admits, however, that in four out of sixteen cases, following the first twenty-one so reported certain “limitations of this treatment were observed,” and a “sudden rise of temperature in two patients on the second and third days of treatment, respectively, proved to be due to pneumococcic nephritis, promptly subdued by appropriate doses of urotropin, while the camphor injections were continued and resulting in speedy recovery.” He further admits that empyema occurs, and states: “This proves that the camphor brought into the blood cannot prevent the as yet living organisms, constantly entering the blood current from the affected alveoli, from colonizing in the renal and pleural tissue.”
He reports, among thirty-seven patients treated in this manner, one death, that of a man 68 years old, weighing 200 pounds, with a fatty heart. Heart failure was the real cause of death. Seibert also reports some very incomplete experimental work; Dr. Hensel, assistant and pathologist of the German Hospital, found that “1⁄10,000part of camphor added to the usual culture media inhibited the growth of pneumococci, while the controls all thrived”; Dr. J. C. Welch, pathologist of the Lying-in Hospital, found that rabbits infected with lethal doses of pneumococcus cultures intravenously were saved by large doses of camphorated oil; fragmentary protocols are given. The assistant pathologist of St. Francis’ Hospital carried on the experimental work, adding salicylic acid to the camphor. No blood cultures are reported. The conclusion reached by Dr. Seibert is that salicylic acid up to 3 per cent., added to the camphorated oil, is effective in preventing pleural infection. In the article by Dr. Seibert, there appear most sketchy reports of cases, recovery being reported without crisis in from three to nine days.
The referee has made a careful search of the literature, with the following results: Boehnke (Berl. klin. Wchnschr.50:818, 1913), using white mice, failed to confirm the experiments reported in Seibert’s paper, unless camphorated oil were given before the pneumococci, and even then, he felt that the results were too irregular to be of great significance. When given with anti-pneumococcic serum, however, he felt that there was some benefit to be seen by the administration of camphor; his protocols, however, are not detailed. There is no report of blood cultures, etc.
Another worker, H. Leo (Deutsch. med. Wchnschr.39:690, 1913), reported that camphor water given intravenously prolonged the lives of thirty-eight rabbits inoculated with pneumococci. Here again there were no adequate protocols and very little evidence of careful experimental work appears.
In the literature of the past ten years, there appear sketchy clinical articles on the value of huge doses of camphor in pneumonia. Markevitch (Russk. Vrach, June 27, 1914; abstr.,The Journal, Dec. 5, 1914, p. 2081) treated 226 cases of pneumonia with 5 c.c. of camphorated oil hypodermically four times daily, at the same time giving digitalis (amount not stated), with a mortality of 6.6 per cent., whereas, in 322 cases untreated, there was a mortality of 13.3 per cent. He reports 133 grave cases; sixty-six received no camphor; 48 per cent. died. Of sixty-seven treated with camphor, only 22 per cent. died. He reports temperature falling by lysis when camphor is used, and comments on the symptomatic improvement following its use. With the great variation in the clinical course of pneumonia, the above figures, though suggestive, certainly need further support before the routine use of camphor as recommended by Seibert can be sanctioned.
Later articles found on the subject refer to it in a very cursory way, giving no protocols and no cases, and giving the referee the feeling that the conclusions were very impressionistic.
After a careful search of the literature, the referee concludes that: Huge doses of camphor, to 250 grains in twenty-four hours, may be given to man without serious results. No satisfactory evidence, however, appears that camphor has a specific germicidal action on pneumococci (similar to that of ethylhydrocuprein). The clinical evidence, as found in the literature, is certainly of very little value. It appears that the sale of a simple solution of camphor in oil under the guise of “Anti-Pneumococcic Oil” is to be deplored (a 20 per cent. solution of camphor in cottonseed oil is official in the U. S. Pharmacopeia as camphor liniment). It is recommended that the preparation be held inadmissible to New and Nonofficial Remedies because exaggerated therapeutic claims are advanced for it, and because the name is not descriptive of the composition, but is, instead, therapeutically suggestive.—(From The Journal A. M. A., Jan. 3, 1920.)
Dial “Ciba” has not been accepted for “New and Nonofficial Remedies” because, as the report which follows shows, unwarranted claims are made for the product. It is a definite new chemical compound which might be made eligible for N. N. R. if misleading therapeutic claims were eliminated. The Council directed that Dial “Ciba” be included with Articles Described but Not Accepted, so that physicians might be informed with regard to its character and properties.
W. A. Puckner, Secretary.
Dial “Ciba” is a hypnotic manufactured by the Society of Chemical Industry of Basle, Switzerland, and is sold in the United States by A. Klipstein and Company, Inc., New York. Chemically, Dial “Ciba” is diallylbarbituric acid and is, therefore, closely related to diethylbarbituric acid or barbital (“veronal”).
The claims made for Dial “Ciba” are (1), that the “allyl” group in its molecule makes it more readily decomposed by oxidizing agents than barbital, which contains the “ethyl” group; (2) that because of this ease of oxidation, it is more readily decomposed in the body and more rapidly and completely eliminated, and (3) that because of its alleged rapid elimination, it is devoid of the after effects of barbital and other hypnotics.
The Council took up the substance in February, 1918, and referred the matter to the referee in charge of barbital preparations. The referee considered unwarranted the claim that Dial “Ciba” did not have the after-effects of other hypnotics due to its alleged total decomposition in the body. The American agents, A. Klipstein and Company, were informed of the referee’s objections. Their attention was also called to the fact that, notwithstanding the claimed absence of after-effects in one part of the advertising, other parts of the same advertising admitted certain post-hypnotic effects of the product. It was pointed out also that while it was claimed in one of the advertising circulars that lowering of the blood pressure is never observed after administration of Dial “Ciba,” yet two of the authors quoted in the same circular definitely stated that a lowering of the blood pressure followed even small doses of the drug and these authors warn against this very danger in certain conditions.
A year later, a circular letter sent out by A. Klipstein and Company reiterated the claim that the asserted decomposition of Dial “Ciba” in the body prevents after-effects, the drug being still contrasted with barbital (“veronal”). In view of the reiteration of this highly improbable claim, the referee undertook to study the comparative action of Dial “Ciba” as compared with other hypnotics. It was found that the actions of Dial “Ciba” are not distinguishable, qualitatively,from those of barbital, there being no perceptible difference in the after-effects or in the nature of the side actions. In toxic doses, both caused profound depression with the temperature falling to that of the room (or about one degree above), the respiration being extraordinarily slow and shallow as one would expect with lowering of the temperature. There were also the same evidences of nausea that are so frequently seen after toxic doses of the various hypnotics of this group. In view of these results, the Council declared that it is unwarranted to claim freedom from after-effects for Dial “Ciba.”
The Council held that the following statement is unwarranted:
“The therapeutic field for Dial ‘Ciba,’ as shown by tests on rabbits, is just as broad as the field for Diethylbarbituric Acid.”
“The therapeutic field for Dial ‘Ciba,’ as shown by tests on rabbits, is just as broad as the field for Diethylbarbituric Acid.”
Tests on rabbits do not and cannot show the breadth of the therapeutic field for a hypnotic. The Council also declared the following statement improbable, and contrary to the evidence obtained by the referee:
“In dogs, the increase of dosage beyond the therapeutic dose to the point of death is decidedly in favor of Dial ‘Ciba,’ which required a larger dose [than diethylbarbituric acid] to produce death.”
“In dogs, the increase of dosage beyond the therapeutic dose to the point of death is decidedly in favor of Dial ‘Ciba,’ which required a larger dose [than diethylbarbituric acid] to produce death.”
The referee’s experiments on cats show that Dial “Ciba” is several times as toxic as hydrated chloral, and more than twice as toxic as diethylbarbituric acid (barbital).
Since the circular to which objection was made in 1918 was still being sent out in December, 1919, the Council held Dial “Ciba” inadmissible to N. N. R. and voted that report of its action in the matter be authorized for publication. The Council further directed that Dial “Ciba” be included with Articles Described but Not Accepted.—(From The Journal A. M. A., Jan. 24, 1920.)
Apothesine is a synthetic drug for producing local anesthesia, made by Parke, Davis & Company. In the fall of 1917 the Council wrote to Parke, Davis & Company offering its aid in establishing the identity, purity and therapeutic efficiency of this synthetic local anesthetic with the ultimate object of accepting the product for inclusion in New and Nonofficial Remedies should the facts warrant such acceptance. The Council’s letter was never acknowledged. After Apothesine was put on the market the Council desired to accept it for inclusion in New and Nonofficial Remedies but, unfortunately, was unable to do so because some of the claims made for the product were not justified by acceptable evidence. The manufacturers were notified of the Council’s desire to admit this product to N. N. R. and the wish was expressed that the company would either so modify its claims as to make the product acceptable under the Council’s rules or else would submit evidence to the Council in proof of the claims made and thus permit the Council to revise its conclusions. Parke, Davis & Company were, apparently, either unwilling or unable to submit evidence that would sustain their claims; neither did they offer to modify the claims themselves. The product, therefore, is ineligible to inclusion in New and Nonofficial Remedies; it will, however, be listed in the “Described But Not Accepted” department of New and Nonofficial Remedies. The report on Apothesine that follows has been authorized for publication.
W. A. Puckner, Secretary.
Apothesine, “the hydrochlorid of diethyl-amino-propyl-cinnamate,” is an efficient local anesthetic. It belongs to the procain rather than to the cocain type, that is, it belongs to that type which, while effective for injection anesthesia (especially when combined with epinephrin) is relatively inefficient when applied to mucous membranes. Apothesine may also be used for spinal anesthesia. Its absolute toxicity is less than that of cocain (as 20 is to 15, see table below) but about twice that of procain (as 20 is to 40, see table below). It is non-irritant, is easily soluble and makes a stable solution so that it may readily be sterilized.
The Council took exception to certain claims made by Parke, Davis & Company for their product on the ground that these claims were not supported by acceptable scientific evidence. One of the claims was that Apothesine is applicable in any case in which any other local anesthetic is used. This statement, made in many advertisements, is distinctly misleading as used. When applied to mucous membranes Apothesine is far inferior to cocain and to some other local anesthetics, yet the claim obviously suggests that Apothesine is an efficient substitute for any local anesthetic.
The manufacturers claimed, too, that Apothesine is as potent as cocain. The claim would lead the physician to think that Apothesine had the same anesthetic potency as cocain in solution of equal strength. This statement, so far as it refers to the drug when applied to mucous membranes, is not in accord with the facts and is true for injection anesthesia only when stronger solutions are used. The only support for the claim of equal efficiency appears to be the experiments with intracutaneous injections made by H. C.Hamilton130in Parke, Davis & Company’s laboratory. These differed considerably from the results of Sollmann.131A further series of experiments were made by Sollmann to compare still further the diverse results previously reported by him and Hamilton. The latest series, while showing considerable variations in the susceptibility of different skin areas, especially toward Apothesine, demonstrated in every case that the efficiency of Apothesine is unmistakably lower than that of cocain, being at best one half. The series also showed that the potency of Apothesine was never greater than procain and averaged considerably below it.
Another claim made for Apothesine which the Council holds is not supported by evidence is that of superior safety. This claim is made on the basis of hypodermic injections in guinea-pigs carried out in the laboratory of Parke, Davis & Company. Such experiments prove little because of the fact—well known to laboratory workers—that the use of rodents in toxicity tests made by injecting a drug into the subcutaneous tissues does not give a reliable index of the relative toxicity of such a drug for man. This is due partly to the peculiar resistance of rodents to poisons and partly to the great importance of the rate of absorption. The organism destroys most local anesthetics so rapidly that the rate of absorption is more important than the absolute dose. The absorption from hypodermic injections into guinea-pigs differs, of course, from that in clinical accidents, especially where the drug has been applied to mucous membranes. One cannot, therefore, reliably estimate the degree of clinical danger on animals.
It has been shown that when toxicity tests of local anesthetics are made on cats these animals seem to respond to the drugs in a manner more closely approximating humans and it is a suggestive fact that the more toxic of local anesthetics, as shown by tests on cats, have been found the most dangerous in clinical use. Theabsolutetoxicity of Apothesine has been measured byEggleston andHatcher132by the intravenous injection in cats. The fatal doses, in terms of milligrams per kilogram ranged as follows:
Alypin, Holocain10Beta Eucain12.5Cocain15Apothesine20Tropacocain20–25Stovain25–30Nirvanin30–35Procain40–45
Alypin, Holocain
Beta Eucain
Cocain
Apothesine
Tropacocain
Stovain
Nirvanin
Procain
Theabsolutetoxicity of Apothesine is, therefore, only a little lower than that of cocain, and is twice as great as that of procain. Theclinicaldangers cannot be predicted by either method, since clinical accidents depend, in most instances, on idiosyncrasies, or the technic of application.—(From The Journal A. M. A., Jan. 24, 1920.)
The Council has adopted and authorized publication of the report which appears below. This report declares “Eumictine” ineligible for New and Nonofficial Remedies because (1) it conflicts with Rule 10 in that it is unscientific, (2) it conflicts with Rule 6 in that it is sold under unwarranted therapeutic claims, (3) it conflicts with Rule 4 against indirect advertising to the public in that the name “Eumictine” is blown in the bottle for the obvious purpose of bringing the product to the attention of the public when it is prescribed in the original package, and (4) because the name is therapeutically suggestive and not in any way descriptive of its composition.
W. A. Puckner, Secretary.
Eumictine is a preparation from the laboratory of Maurice Le Prince, Paris, France, and is marketed in this country by George J. Wallau, Inc., New York. It is claimed that the product is “a balsamo-antiseptic preparation composed of Santalol, Salol, and Hexamethylene-Tetramine, in the form of gluten-coated capsules.” Nowhere in the advertising are the amounts of the ingredients given. According to the American agent, however, “each capsule is supposed to contain 20 centigrams of Santalol, 5 centigrams of Salol, 5 centigrams of Hexamethylene-Tetramine.”
Eumictine is advised “in treating genito-urinary diseases (urethritis, cystitis, prostatitis, pyelitis, etc.).” It is claimed to be “both an antiphlogistic modifying agent, a well-tolerated diuretic” which “may be administered for long periods without ill effects.”
The Council declares Eumictine ineligible for New and Nonofficial Remedies because it is exploited in conflict with the following rules:
It is unscientific (Rule 10). Eumictine is composed of hexamethylenamin, salol and sanalol in fixed proportions. Hexamethylenamin may serve a useful purpose in some forms of infection of the urinary tract, but neither it nor salol is of any considerable value in gonorrhea. It is now known that the balsamic preparations, formerly so widely used, do not have the curative effects in gonorrhea and associated conditions that used to be ascribed to them. To combine three substances, none of which has any distinct therapeutic value in the conditions for which Eumictine is proposed, does not enhance their value.There is nothing original in the combination used in Eumictine, or in the manner of dispensing it.
It is sold under unwarranted therapeutic claims (Rule 6). These claims are made not only for the components of Eumictine but for the combination itself. Though santalol has certain advantages over the somewhat variable oil of santal and other balsamic resins, it is not true that santalol “does not cause congestion of the renal epithelium” or that it does not “produce exanthema as do copaiba, cubebs, and the ordinary santal oil.” It is not true that salol is “devoid of toxicity.” Neither is it correct to say that salol “asepticizes and disinfects the bladder, the prostate and the urethra.” The claim that hexamethylenamin “is of value when any acute symptoms or tendency to inflammation subsist” is not justified. The claim that hexamethylenamin “renders soluble the uric acid and urates” is also without foundation. The following paragraph is characteristic of the claims made for Eumictine: