COMPARATIVE SYMPTOMS RESULTING FROM THE USE OF SEVERAL OILY SUSPENSIONS OF RED MERCURIC IODID (MERCURY BINIODID)

Report of Dr. H. N. Cole [D]

At the request of Prof. Torald Sollmann of the Council on Pharmacy and Chemistry of the American Medical Association, we made a comparative study of several oily preparations of red mercuric iodid for intramuscular injections in syphilis.

The information, concerning the preparations submitted to the investigators, was as follows:

OILY SOLUTION OF RED MERCURIC IODID

“It is desired to ascertain whether there is any difference between three preparations, each containing 1 per cent. of mercuric iodid, as to pain, discomfort, induration, etc. The preparations will be labeled “1,” “2” and “3.” They will be sterile.

“One of these preparations will be a plain solution in oil; another will contain, in addition, 2.5 per cent. of guaiacol; the third will be a proprietary preparation containing the guaiacol.

“It is also desirable to know how the oily solution compares with the plain watery solution; but this is of secondary importance.”

The preparations all had the same appearance. The patients were taken indiscriminately, and we attempted to keep them on the injections as long as possible, in order to compare symptoms. Owing, however, to discharge from hospital, symptoms of mercury intoxication, etc., we were unable in all cases to give a thorough trial with each preparation.

In all, eleven patients were treated and seventy-one injections given—by which time our experimental supply was exhausted.

In each case the drug was given intramuscularly in the buttocks and the patients carefully observed for subjective symptoms of pain and for objective symptoms of swelling, induration, abscess formation, etc. The details are given in Table 1.

As will be noted, in several of the cases the patients were more or less confused and gave rather indefinite and conflicting answers. In attempting to compare the results from the different drugs, by careful tabulation one finds that symptoms were more marked with the respective sample as follows:

Preparation 1 was worse than Preparation 2 or 3 in six cases.
Preparation 2 was worse than Preparation 1 in two cases.
Preparation 2 was worse than Preparation 3 in five cases.
Preparation 3 was worse than Preparations 2 or 1 in one case.

TABLE 1.—DETAILS OF INVESTIGATION BY DR. COLE*

Case	Age	Sex†	Date	Prepara- tion	Dose, Grain	Symptoms
Case	Age	Sex†	Date	Prepara- tion	Dose, Grain	Induration—Pain	Objective
1	25	♂M	6/11/16	2	¹⁄₅	None	Still painful
			6/12/16	1	¹⁄₄	None	None
			6/13/16	2	¹⁄₅	None	Quite painful
			6/14/16	2	¹⁄₄	Hurt for some time	Very tender
			6/16/16	2	¹⁄₅	Hurt for some time	Very tender
			6/17/16	3	¹⁄₅	Not so painful	Less tender than with Preparation 2. Can sit on area; as needle prick is only place that it hurts
			6/18/16	3	¹⁄₅	Not so painful
			Discontinued (salivation)
			6/22/16	2	¹⁄₄	Hurt, but not so long	Slight induration and slight tenderness
			6/24/16	2	¹⁄₄	Hurt, but not so long	Pain “dead stinging” lasts 1 hour
			6/25/16	1	¹⁄₄	Not so bad	About the same
2	32	♂M	6/24/16	2	¹⁄₄	Some pain	No induration
2	32	♂M	6/25/16	1	¹⁄₄	More pain	Slight induration
3	..	♂M	6/12/16	1	¹⁄₅	No symptoms	Painful
			6/13/16	2	¹⁄₄	No symptoms	Painful
			6/14/16	2	¹⁄₄	Says the last two have hurt the more	Painful
			6/16/16	Arseno- benzol		Says the last two have hurt the more
			6/17/16	3	¹⁄₅	More pain than previously	Small painful area
			6/17/16	3	¹⁄₅
			6/18/16	3	¹⁄₅	Not so much pain: in fact, patient says he is over it in a very short while; complained of last one	Some induration at site of injections
			6/19/16	3	¹⁄₅
			6/20/16	3	¹⁄₄
			6/21/16	3	¹⁄₄
			6/22/16	2	¹⁄₄	Some pain	Considerable tenderness now after so many injections
			6/24/16	2	¹⁄₄	Not so much as previously
			6/25/16	1	¹⁄₄
4	36	♂M	6/22/16	2	¹⁄₄	No pain	No tenderness
			6/24/16	2	¹⁄₄	Some pain	Some tenderness
			6/25/16	1	¹⁄₄	Could not sleep at night	Some tenderness; slight induration
5	32	♂M	6/20/16	3	20 minims	Some pain	No induration
			6/21/16	3	25 minims	Some pain
			6/23/16	2	¹⁄₄	Worse pain	No induration
			6/24/16	2	¹⁄₄	Worse pain
			6/25/16	1	¹⁄₄	Worse than any	Slight tenderness
6	20	♂M	6/ 8/16	1	¹⁄₆	Very little
			6/10/16	1	¹⁄₅	Very little
			6/13/16	1	¹⁄₄	Very little
			6/14/16	2	¹⁄₄	Bothered more than others
			6/17/16	2	¹⁄₅	Quite a little pain	Still some soreness
			6/18/16	2	¹⁄₅	Quite a little pain	Still some soreness
			6/19/16	3	¹⁄₄	Considerably less pain than with Preparation 2	Very little tenderness
			6/20/16	3	¹⁄₄	Considerably less pain than with Preparation 2
			6/21/16	3	¹⁄₄
7	30	♂M	6/12/16	1	¹⁄₅	Little pain	None
			6/13/16	2	¹⁄₄	No pain
			6/14/16	2	¹⁄₅	Some pain
			6/16/16	Arseno- benzol
			6/17/16	3	¹⁄₅	Not so much	No tenderness
			6/18/16	3	¹⁄₅	Not so much	No tenderness
			6/19/16	3	¹⁄₅	Very little pain	Only slight amount of induration
			6/20/16	3	¹⁄₄
			6/21/16	3	¹⁄₄
			6/22/16	2	¹⁄₄	Some pain	Some little induration
			6/24/16	2	¹⁄₄	Considerable pain	Some induration
			6/25/16	1	¹⁄₄	“Fine”	Slight induration
8	28	♂MM	6/13/16	2	¹⁄₅	Little pain	Little pain afterward
8	28	♂MM	6/15/16	2	¹⁄₅	Little pain	Little pain afterward
9	28	♀M	6/17/16	2	¹⁄₅	Some complaint of pain. Fairly severe	Very little induration
			6/18/16	2	¹⁄₅	Some complaint of pain. Fairly severe
			6/19/16	3	¹⁄₅	Some pain; says these have hurt very much less than others	Very slight induration
			6/20/16	3	¹⁄₄
			6/21/16	3	¹⁄₄
10	37	♂M	6/12/16	1	¹⁄₅	No symptoms	None
			6/13/16	1	¹⁄₄	No symptoms	None
			6/14/16	1	¹⁄₅	No symptoms	None
			6/15/16	3	¹⁄₅	No symptoms	None
			6/16/16	Arseno- benzol
			6/17/16	3	¹⁄₅	“Much less pain than biniodid or grey oil”	None
			6/18/16	3	¹⁄₅	No complaint	None
			6/19/16	3	¹⁄₅	Says he is over it in one hour	Some induration at site of injection
			6/20/16	3	¹⁄₄	Says he is over it in one hour
			6/21/16	3	¹⁄₄
11	30	♀M	6/11/16	1	20 minims	Considerable; not so much	Considerable pain and tenderness on palpation over area
			6/12/16	2	20 minims	Considerable; not so much	Considerable pain and tenderness on palpation over area
			6/13/16	1	25 minims	Not much pain	Indurated area at pt. of each. Painful
			6/14/16	1	25 minims	Not much pain	Slight induration

* The diagnosis in Case 5 was primary syphilis, and in the other cases, secondary syphilis.

† In this column, ♂M indicates male, and ♀F female. In no case did Wassermann become negative.

The criticism may be raised that the number of cases and of injections is too small to permit the drawing of any just conclusions. Even should we grant it, the statistics certainly do not prove any marked superiority of any one of the preparations over the others. We wish to thank Dr. Sollmann for advising and directing us in this work, and Drs. Bailey, Bernstein, Markus and Reycraft for assistance in carrying it out.

Report of Dr. Albert Keidel

Twenty cases were chosen at random from the syphilitic patients attending the clinic. They were given intramuscular injections of the three solutions, in amounts varying from 1 to 2 c.c., at intervals (in most instances) of two days. The injections were invariably made into the gluteal muscles, at depths of from 2 to 2¹⁄₂ inches, and ordinary care exercised to preserve asepsis. After injection the patient was allowed to depart, and the result was recorded at the succeeding visit. The result was determined from the patient’s statement and our examination. Some patients received injections of only one solution; some were treated with first one and later with another, and one patient received all three at different times. The solutions were never mixed for a single injection, of course.

TABLE 2.—REACTIONS IN TWENTY CASES REPORTED BY DR. KEIDEL

Preparation	Reactions				Number of Injections
					Number of Injections
	Severe	Mild	None	Undetermined
1	13	14	4	8	39
2	5	15	16	5	41
3	7	25	3	2	37
					——
					117

The solutions are understood to contain a 1 per cent. solution of red mercuric iodid in oil, two of them containing in addition 2.5 per cent. of guaiacol, one of these being a proprietary preparation. The solutions are designated as Preparations 1, 2 and 3, respectively, corresponding to the numbers on the labels of the bottles in which they were originally received. The local reactions are recorded as “severe” (S), “mild” (M), “none” (O) and “Undetermined” (U). By “severe” is meant very severe pain lasting for from several hours to several days; by “mild” is meant slight pain or numbness for several hours, or less than an hour; “none” indicates that there was no local reaction, and “undetermined,” that the patient has failed to return after the last injection.

In Table 3 all the details of the investigation are recorded. Under “Local Reaction,” the letters represent the type of reaction after each injection, in the order in which they were given; when two solutions were used in the same case, the letters represent the reactions following the solution opposite which they stand. In the fifth column the plus and minus symbols indicate the Wassermann reaction; plus indicates a completely positive, and minus a completely negative reaction. When there is only one sign, it refers to the reaction at the end of treatment; when there are two, to the reaction before and after. The seventh column shows the clinical result at the end of treatment; when no note is made, it means that there was no change noted. In the eighth column are noted any objective results observed at the time of examinations of the patients.

The injections were made and the result charted by Dr. E. L. Zimmermann, of my staff, under my directions and supervision.—(Abstracted in The Journal A. M. A., Feb. 24, 1917.)

TABLE 3.—DETAILS OF INVESTIGATION BY DR. KEIDEL

Case	No.	Prepar- ation	Local Reaction	Total Amount Solution Given, C.c.	Duration of Treatment	Effect on Wasser- mann	Type of Case	Result	General Remarks
1	3	2	OOO	3	6 da.	+	Latent
2	5	2	MOSMS	5.6	9 da.	+	Gummas	Marked improvement
3	7 3	1 2	MMM; others U UUU	9.5	3 mo.	– to +	Latent
4	1	2	U	0.75	...	+	Latent
5	4	1	SSSM	4.4	9 da.	–	Gummas		After 4th injection, developed diarrhea; melena
6	9	1	OOUMSOSMU	9.1	1 mo.	–	Latent
7	2	3	MM	3.8	2 da.	+	Latent		Well tolerated
8	7	2	OOOOMOU	9.6	17 da.	+ to +	Primary	Primary healed
9	4	1	SMMU	5.5	9 da.	+	Gumma	Improved
10	3	3	MSS	3	6 da.	+	Palmar syphilis; tertiary	Markedly improved
11	7	3	MSMMMMM	10.6	13 da.	+ to +	Latent
12	3 2	2 1	MMO SM	5.4	14 da.	+	Secondary (papular)	Rash disappearing	Developed toxic erythema on thighs. Cleared up on stopping HgCl₂ and under local treatment
13	10	3	MMMMMMMM MMU	12.6	20 da.	+ to +	Secondary (lichen syph.)	Rash not improved	Small induration following injection of 1.2 c.c.
14	6 2	2 1	OOMSMM SM	7.2	17 da.	+ to +	Old cerebro- spinal syphilis		Responded to doses of 1 c.c. with salivation; fever after injection of 1.2 c.c.
15	4	1	SOMS	4.2	7 da.	+ to +	Secondary (condylomas)	No improvement
16	9 2	3 2	OMOMMSMSO SO	10.4	12 da.	+	Secondary (pustular syph.)	Pustules dried up; head- ache and fever gone	Slight gingivitis following dose of 1.5 c.c.
17	5 2	1 2	SSMSU MS	13.3	18 da.	+ to +	Tertiary; aortitis	General condition im- proved
	2	3	MS
18	4	2	OOMM	9.5	13 da.	– to +	Latent
	2	1	MM					Markedly improved
19	2	3	MU	2.5	5 da.	+	Gumma
20	5 2	2 3	MMMMO MS	9	14 da.	+ to +	Latent	Marked general improvement	Small induration following No. 3

CORPORA LUTEA (SOLUBLE EXTRACT), PARKE, DAVIS & CO.

Report of the Council on Pharmacy and Chemistry

Following inquiries, the Council took up for consideration “Corpora Lutea (Soluble Extract),” marketed by Parke, Davis & Co. in the form of ampules and proposed for hypodermic administration. The report which appears below was submitted to the Council by a committee, and was adopted by the Council. Corpora Lutea (Soluble Extract) was declared inadmissible to New and Nonofficial Remedies, and publication of the report authorized.

W. A. Puckner, Secretary.

Corpora Lutea (Soluble Extract) has not been submitted by the manufacturer. The information of the referee is based, therefore, on the claims made in the trade package, and on the statements in the price list. These show that the product is essentially secret and claims made for the actions and uses of the preparation do not make clear the essentially experimental status of the article, and are therefore misleading.

Conflict with Rule 1.—No definite statement of composition appears beyond the indefinite claim that it is an aqueous solution of “soluble Corpora Lutea Extract,” each ampule corresponding to 0.2 Gm. of desiccated gland. How these soluble products are obtained, whether they represent all the water-soluble principles, or whether some have been eliminated, are questions that are not answered. Yet such information is essential to intelligent and scientific use, for, as there is no method of standardization, the method of preparation is the only mark of identity. For instance, we do not know at this time whether proteins have anything to do with the supposed value of corpora lutea. It is, therefore, essential to know whether or not the proteins have been eliminated.

Conflict with Rule 6.—The circular in the package advises the hypodermic use of this extract, not only in functional amenorrhea and the ordinary reflex consequences of physiologic or artificial menopause, but also in:

“ ‘neurasthenic’ symptoms during menstrual life”;

“sterility, not due to pyogenic infection or mechanical obstruction”;

“repeated abortions, not due to disease or mechanical factors”;

“hyperemesis in the early months of pregnancy.”

These are not stated merely as conditions in which various enthusiasts have tried corpus luteum, but as conditions “for which it will be found serviceable.”

It is not necessary to inform the medical profession that this statement is calculated to raise expectations which cannot possibly be fulfilled. Even the manufacturers seem to realize this; at least they speak somewhat indefinitely of “suitable cases,” “good judgment,” “real indications,” etc. But they proceed to nullify this warning—if it was intended as a warning—by their illustrations of unsuitable cases, for instance, “amenorrhea due to extreme anemia, dysmenorrhea due to cervical stenosis,” etc. Finally, they sum up the case:

“Therefore, additional emphasis on the necessity for the proper selection of cases is essential in order that this useful preparation may not be unjustly discredited.”

How these cases of sterility, abortions, etc., are to be selected is not revealed. In other words, the restriction is no more than a convenient device by which every improvement is to be attributed to the medicine, and every failure to the physician.

The referee recommends that Corpora Lutea (Soluble Extract), Parke, Davis & Co., be held ineligible to N. N. R., because it is a secret preparation advertised under extravagant claims.

[Editorial Comment.—Was it not in Weir Mitchell’s “Adventures of François” that the itinerant promised to pull teeth without any pain, if the patient would hold absolutely still? And, mirabile dictu, the ones who suffered were those who had not held absolutely still!]—(From The Journal A. M. A., April 7, 1917.)