HOLADIN AND BILE SALT MIXTURES

Holadin and Bile Salts-Fairchild; Capsules of Bile Salts, Succinate of Soda and Phenol­phthalein-Fairchild; Capsules of Holadin, Bile Salts and Phenol­phthalein-Fairchild; Capsules of Holadin, Succinate of Soda and Bile Salts-Fairchild.

Report of the Council on Pharmacy and Chemistry

To explain the omission from New and Non­official Remedies of certain mixtures, the Council has authorized publication of the matter which appears below.

W. A. Puckner, Secretary.

The Council holds that complex mixtures of remedial agents are from every point of view inimical to therapeutic progress and therefore to the public welfare. They are especially objectionable because it is impossible accurately to determine the effects which follow the simultaneous administration of a number of drugs having dissimilar actions, and because the practice of prescribing such mixtures tends to discourage careful consideration of the special needs of individual patients without which there can be no rational drug therapy. On the contrary, with the use of such mixtures, therapeutic treatment becomes haphazard and mere guesswork.

The Council, appreciating that long established customs cannot be changed at once, has applied Rule 10 concerning the recognition of mixtures with the greatest leniency compatible with consistency. When there has been a reasonable doubt concerning the value of a mixture it has frequently directed that Rule 10 should not apply, pending further clinical trial of such mixture.

In no instance has subsequent experience shown that a strict interpretation of the rule would have worked hardship or injustice. The Council feels that there is no longer any warrant for the admission of complex mixtures to New and Non­official Remedies or for the retention of any that have been admitted unless definite evidence of the therapeutic value of such combinations is available. In accordance with this decision, several mixtures now described in New and Non­official Remedies will be omitted as soon as the three year period for which articles are accepted has expired.

The following preparations are included in New and Non­official Remedies, 1918:

Holadin and Bile Salts-Fairchild.—A mixture of holadin, 5 parts, with bile salts-Fairchild, 1 part, put up in 3 grain capsules.

Capsules of Bile Salts, Succinate of Soda and Phenol­phthalein.—Each capsule contains bile salts-Fairchild, 0.065 Gm. (1 grain); sodium succinate exsiccated, 0.2 Gm. (3 grains), and phenol­phthalein, 0.03 Gm. (1⁄2 grain).

Capsules of Holadin, Bile Salts and Phenol­phthalein.—Each capsule contains holadin, 0.13 Gm. (2 grains); bile salts-Fairchild, 0.03 Gm. (1⁄2 grain), and phenol­phthalein, 0.065 Gm. (1 grain).

Capsules of Holadin, Succinate of Soda and Bile Salts.—Each capsule contains holadin, 0.20 Gm. (3 grains); sodium succinate exsiccated, 0.20 Gm. (3 grains), and bile salts-Fairchild, 0.03 Gm. (1⁄2 grain).

Oxbile has long been credited with a cholagogue action, which, however, has probably been greatly overestimated. When pure bile salts were placed on the market some years ago, they and their compounds were admitted to N. N. R.

Holadin is said to represent all the constituents of the pancreas and to possess great potency in respect to the several enzymes, trypsin, amylopsin, lipase, and the milk-curdling ferment.

It is not clear when such a substance is indicated thera­peutically. While it may be useful when there is a deficiency of pancreatin and gastric secretion, it should be used alone.

It is also quite possible that bile salts may have a distinct, though limited, field of usefulness when there is a deficiency of biliary secretion; but the bile salts are best administered alone, or in combination with such laxatives as may be deemed necessary by the physician while keeping in mind the fact that different patients show the widest difference in their reaction to laxatives, making combinations of these agents in fixed proportion irrational.

Phenol­phthalein was popularized by nostrum makers; and while it has some therapeutic value, this has been greatly overestimated, and it should be used only in amounts deemed necessary for each patient, preferably alone.

Succinate of sodium was introduced as a saline cathartic, with the claim that it exerts an antiseptic action on the biliary passages and gallbladder. There is no satisfactory evidence to substantiate this claim.

The Council maintains a liberal attitude toward new preparations, but it feels that it is impossible to determine the value of the several constituents of such complex mixtures when used as such; it holds that these mixtures are superfluous and that the several substances of which they are composed should be used singly or at most with greater attention to the individual requirements of the patient than is possible when these fixed mixtures are prescribed.

Despite the fact that these mixtures have been in use for more than nine years, there is no satisfactory evidence that they possess any advantage over the simple laxatives or the preparations of bile or pancreatic extract. They are therefore held to be in conflict with Rule 10, and the Council has directed that they be not included in N. N. R. after Dec. 31, 1918.

Having adopted the preceding report, the Council, in accordance with its regular procedure, submitted this to Fairchild Bros. and Foster for comment.

The following reply was received:

We are entirely at variance with you in the arbitrary conclusion expressed concerning the inimical influence of mixtures on therapeutic progress, the practice of medicine and the public welfare.

If the combinations of Holadin and Bile Salts, etc., in capsules, were ever properly within the scope of New and Non­official Remedies, they should be retained. If, however, complex mixtures are to be held as, a priori, unworthy of consideration, the rejection of all would naturally be a logical proceeding.

We believe that the particular combination of Holadin and Bile Salts etc., have been clearly in the line of therapeutic progress—a natural evolution, improvement and development.

For many years combinations of pancreatic extract and ox gall had naturally suggested themselves.

When we realized the fact that the bile salts were quite clearly the active principles of the bile, and that they must necessarily exist in greatly varying percentages in the official inspissated or ox gall, and also because these ox gall products of pharmacy were of extremely varying density, even from that of treacle to resin—and of other objectionable character, we undertook to prepare bile salts.

These combinations are now further justified in view of physiological considerations, the simultaneous secretion of the pancreas and bile, and the state of our knowledge of the function of bile salts, and as co-ferments, promoting and supplementing the pancreas enzymes.

The question suggested as to whether the cholagogic action of ox gall (and bile salts) has been overestimated seems to us no clear purport. The bile salts are obviously employed as the means of administering and thus realizing whatever properties this secretion may have in medicine, of which the cholagogic action is by no means the only consideration.

As for phenol­phthalein, which is credited with purely laxative properties, we are at a loss to see any bearing in the remark that phenol­phthalein was popularized by nostrum makers. We cannot see that the physician’s or chemist’s estimate of phenol­phthalein, its properties and uses, can be in the least degree influenced one way or the other by the statement that “phenol­phthalein has been popularized by nostrum makers.”

The phenol­phthalein and succinate of soda combinations were originally both prescribed, and we have simply placed them at the service of the physician without other exploitation of them than that designed to call attention to their use in the conditions indicated.

These combinations are offered in a form which may be administered by the mouth with the best promise of introducing the substance more directly in the intestinal tract during the digestion period or at such interval after or prior to, the digestion period, as would best, in the judgment of the physician, meet the indications.

These particular combinations are especially desirable in these “fixed forms” since they are stable and reliable resources at the command of the physicians, the enzymes retaining their stability and potency without material deterioration for many years, and they naturally possess the advantages which are obviously due to the character of the particular pancreas and bile products used in the combinations.

Furthermore, the hygroscopic and soluble organic substances in admixture cannot ex­tem­por­aneously be so prepared in sealed capsules as to be readily available under the practical requirements of prescribing and dispensing. And we do not believe that those who practice medicine will be in accord with your view that the pancreas substance should necessarily be administered alone, or the bile substance alone.

It now appears that these combinations are to be dropped from New and Non­official Remedies in consequence of the view, so stated, that in clinical experience “for more than nine years there is no satisfactory evidence that they possess any advantage over the simple laxatives or preparations of bile or pancreatic extract.”

In reply to this we would simply make the following comment:

During these “nine years” these combinations have inevitably been put to an informing clinical trial, because of the fact that they have been employed with success in disorders of the pancreas and bile functions and often in chronic and serious cases where the clinical conditions were obvious and unmistakable.

The reports of these cases come to us from physicians widely separated and each of his own independent initiative. It would seem gratuitous, to say the least, to state that the observers are “disinterested,” since it is quite clear that there is no other interest than that of the practitioner and his patient.

It is not a case of a new drug or combinations of new remedies, but simply resources which, upon well grounded reasons, both from a theoretical and material standpoint, justify clinical trial, and with results which would seem from any ordinary human standpoint to be satisfactory clinical evidence.

As to the interpretation of competent clinical evidence by the Council, we would, in view of the circumstances and without comment, ask to embody in this text this rule:

“Clinical Evidence.”—“To be acceptable, the clinical evidence must offer objective data with such citation of authority as will enable the Council to confirm the facts and establish the scientific value of the conclusions drawn. Clinical data are worthless when the author is not cited. The facts on which claims with regard to the value of a remedy are based must have been rendered accessible for investigation and confirmation by disinterested observers, either through publication or through the records of a hospital or other institution.”

To discredit these combinations would seem to us not only unjustified, but sterile of any real advancement in medicine, or of anything in the way of helpfulness to the patient in the class of cases in which these products have been resorted to with benefit; this on no other ground really than the opinion “that they have no advantage over the simple preparations themselves.”

Naturally we shall continue to prepare these products and shall continue to take such action as we deem best to bring them to the attention of the physician, for the conduct of our business must remain in the hands of those who are personally responsible for it.

And it is now forty years since we took up this line of work and with the declared intention of devoting ourselves to the applied science of the digestive ferments and “to their development and practical application in every useful purpose in medicine.”

We have been consistently in sympathy with the fundamental purpose of the Council, which must first rest upon fact as to the character of the products offered as medicinal agents. The weight of evidence justifies the position that these particular products rationally should be, and as a matter of fact are, of important special service in the utilization of these organic secretions in medicine.

As explained in the preceding report, the Council holds that complex mixtures of remedial agents are from every point of view inimical to therapeutic progress and therefore to the public welfare. They are especially objectionable because it is impossible to determine accurately the effects which follow the simultaneous administration of a number of drugs having dissimilar actions, and because such a practice tends strongly to discourage careful consideration of the special needs of individual patients without which there can be no therapeutic progress. On the contrary, with their use, therapeutic treatment becomes haphazard and mere guesswork.

The dismissal of the holadin and bile salts mixtures does not involve the question of the usefulness of holadin or of bile salts alone; on the contrary, the possible usefulness of these preparations is admitted in the report. It is the combination of holadin, bile salts, sodium succinate and phenol­phthalein to which objection is made.

The statement of Fairchild Bros. and Foster that “these combinations are now further justified in view of physiological considerations” is somewhat misleading. It is true that bile and the pancreatic secretion cooperate in intestinal digestion, but there is no evidence that in every case in which there is a deficiency of one of these secretions there is also a deficiency of the other, and it is an axiom of scientific therapeutics that no drug or remedial agent should be administered except to fill a definite want. Otherwise the practice of therapeutics becomes mere empiricism.

The properties of phenol­phthalein are not in the least influenced by the manner of its introduction, as Messrs. Fairchild Bros. and Foster emphasize; but the important fact in this connection is that the popular conception of their actions is greatly influenced by the mode of introduction, and phenol­phthalein has been widely advertised in a variety of conditions, so that the popular notion concerning it is not that of scientific therapeutics.

In short, the entire argument of Messrs. Fairchild Bros. and Foster concerning the exploitation of these preparations may be summed up by saying that they have been used by clinicians who believe that good results have followed their use, and that the firm will therefore continue to supply the demand. The tendency of some to use anything brought to their notice, and the readiness of manufacturers to market anything that physicians will use, presents the greatest obstacle to therapeutic progress. There was never a nostrum so irrational or worthless that honest but undiscriminating clinicians could not be found who reported wonderful results from its use.

According to Fairchild Bros. and Foster, these holadin and bile salts mixtures have been in use for some nine years. Yet the Council is not aware of any investigation of their merits that meets the requirements of scientific research.

The Council is not acquainted with a single clinical investigation of their action under conditions which afford satisfactory evidence of their therapeutic value.

It is obviously wholly insufficient for a clinician to report that the use of a mixture was followed by good results. The fallacy of such arguments was demonstrated long ago. He must make a comparison of the results obtained with the remedial agent with those obtained in as nearly similar conditions as possible except for the use of the agent. We are not aware that any such study of the mixtures in question has been made. It is in the last degree irrational to hold that because bile salts are the active constituents of bile, therefore such complex mixtures as these are necessary.—(From Reports of Council on Pharmacy and Chemistry, 1918, p. 59)

LIQUOR SANTAIVA, S. & D., OMITTED FROM N. N. R.

Report of the Council on Pharmacy and Chemistry

The following report explaining the omission from New and Non­official Remedies of Liquor Santaiva, S. & D., has been authorized for publication.

W. A. Puckner, Secretary.

So far the Council has applied Rule 10 concerning the recognition of mixtures with the greatest leniency compatible with consistency. When there has been a reasonable doubt concerning the value of a mixture, it has frequently directed that Rule 10 should not apply, pending further clinical trial of such mixture.

In no instance has subsequent experience shown that a strict interpretation of the rule would have worked hardship or injustice. The Council feels that there is no longer any warrant for the admission of complex mixtures to New and Non­official Remedies or for the retention of any that have been admitted, unless definite evidence of the therapeutic value of such combinations is available.

The Council being engaged in the annual revision of New and Non­official Remedies, the referee in charge of santal preparations reported that the three year period of acceptance had expired for Liquor Santaiva (Sharp & Dohme).

The referee held that Liquor Santaiva, S. & D., declared to be a solution of santal oil and copaiba with aromatic oils, in a mixture of alcohol and water, is plainly in conflict with the current interpretation of Rule 10, because there was no sound evidence to indicate that any useful end is gained by the simultaneous administration of santal oil and copaiba in any proportion, and that so, of course, there is no evidence of the special advantage in the fixed proportions represented by the mixture. He pointed out that the formula is essentially a survival of the discredited shotgun gonorrhea mixtures and therefore recommended that its acceptance be not continued.

The Council agreed to the recommendation of the referee and directed that Liquor Santaiva, S. & D., be omitted from New and Non­official Remedies.—(From Reports of Council on Pharmacy and Chemistry, 1918, p. 66)