TAKA-DIASTASE AND LIQUID TAKA-DIASTASE
Report of the Council on Pharmacy and Chemistry
Some time ago it was decided that a reexamination should be made of Taka-Diastase and Liquid Taka-Diastase, both of which had previously been rejected, to ascertain whether or not the preparations were in accord with the claims made for them by the manufacturers. Accordingly, the matter was referred to a committee of the Council, and an examination of specimens of these two preparations bought in the market was made. The referee’s report, which appears below, according to the usual procedure, and before final confirmation by the Council, was first submitted to the manufacturers of Taka-Diastase for comment. The report recommends that the rejection of Taka-Diastase and Liquid Taka-Diastase be allowed to stand, and that the report be published. Parke, Davis & Co., in their reply, which is given in full below, claim that the report is unjust concerning Liquid Taka-Diastase, because the period of activity of the preparation has been greatly prolonged by reducing the amount of alcohol from 18 per cent. to 10 per cent. and by adding glycerin. They reiterate their claims for the digestive power of Taka-Diastase, but admit that it will not reduce the stated amount of starch to the colorless end-point in ten minutes (the standard method for the valuation of diastase). They further state that they would change the word “digest” on the label to “liquefy.”
The conclusion of the report having been questioned, the entire matter was referred to a member of the Council’s staff of clinical consultants. His report, which, also, is given in full below, states that the material before him was sufficient to decide the matter, and no further tests were necessary. He concludes that the claims of the manufacturers regarding the strength and properties of the material are erroneous and exaggerated; that the literature still sent out by Parke, Davis & Co. is misleading; and that if substitution of the word “liquefy” for “digest” were endorsed by the Council confusion would result which would give an exaggerated and false value to Taka-Diastase. He therefore recommends that the report of the reinvestigation of Taka-Diastase be accepted by the Council and published.
This report of the second referee was referred to Parke, Davis & Co. with the request that they state more definitely the actual amylolytic strength of their preparations. To this they replied that they had no desire to discuss the subject further, or to make any additional statements.
In accordance with the second referee’s recommendations, the Council confirmed its provisional action and voted that the rejection of Taka-Diastase and Liquid Taka-Diastase be allowed to stand, and that the report which appears below be authorized for publication.
W. A. Puckner, Secretary.
REFEREE’S REPORT ON TAKA-DIASTASE AND LIQUID TAKA-DIASTASE
Following is the report of the committee to which was referred the reexamination of Taka-Diastase and Liquid Taka-Diastase:
Some time ago a comparison was made of the various methods proposed for the valuation of preparations claimed to have amylolytic power. This work was reported in The Journal,[22] and the method proposed for the testing of diastase preparations now appears in New and Nonofficial Remedies.[23] In view of the incorrect and exaggerated claims made for Taka-Diastase, the Council in 1908 was obliged to rescind its acceptance and to direct its omission from New and Nonofficial Remedies. The report contained the following reference to Taka-Diastase (Parke, Davis & Company), a product that had been accepted for inclusion with New and Nonofficial Remedies:
“The widest discrepancy between the values as claimed by the manufacturer and those found by actual tests seems to be shown in the case of Taka-Diastase. The liquid preparation has been tested a number of times in different samples and has always been found weak. Some samples, in fact, were quite inert. This ferment appears to lose strength very rapidly in solution, as the manufacturers now concede. The stability of the solid product is also far from satisfactory, and appears to be less than that of the ferment as marketed some years ago. The two samples examined recently were weak.”
More than three years have now elapsed since the publication of the Council’s findings regarding Taka-Diastase—sufficient time, it is believed, for the manufacturers to modify either their claims or the product itself, and thus again make it eligible for inclusion with New and Nonofficial Remedies. With this idea in mind new specimens of Taka-Diastase and Liquid Taka-Diastase were purchased from a Chicago drug house and the preparations reinvestigated. The following is the report of this reinvestigation.
REPORT OF THE REEXAMINATION
In our report on the diastase preparations three years ago, it was recommended that Taka-Diastase be removed from New and Nonofficial Remedies, because the examinations showed that it did not have the digestive strength claimed for it. This was true both for Taka-Diastase itself and for Liquid Taka-Diastase. So far as the latter was concerned, the starch-converting power was practically nil in those preparations which had been in the drug stores for some months.
During the last few weeks new tests have been carried out with several samples of the Taka-Diastase preparations and the results obtained are essentially the same as those obtained in the former examinations. The liquid preparation is still extremely weak in starch-converting power, while we found that Taka-Diastase itself would convert only 16.6 parts of pure anhydrous starch to the colorless end-point in ten minutes, as explained below.
In our method of experimentation we determine the weight of the diastase in question which will convert a given weight of starch in uniform paste to the so-called colorless end-point in ten minutes, that is to the point where it will no longer give any color reaction with a standard iodin solution. The standard starch weight in 50 c.c. always is 1 gm. or 1,000 mg. and to a series of flasks containing this amount of starch, maintained at a constant temperature of 40 C., the diastase dilutions are added. These diastase dilutions are made by dissolving small, accurately weighed amounts of the sample in some small, constant volume of water, usually 5 or 10 c.c. and they are then poured into the starch flasks at the right temperature, and agitated regularly.
Tests are made by taking a few drops from each flask and mixing with the iodin solution. The end-point is reached when a dilution is found which, at ten minutes from the mixing time, gives no color with the iodin reagent. The first set of tests is taken as a general guide, and quite accurate results may be obtained in a second set of dilutions.
We first used a sample of Taka-Diastase bought in the open market. It was found that 140 mg. were required to convert the gram of starch as explained. This is equivalent to a conversion of 7.14 parts of starch by 1 part of the Taka-Diastase.
A new, and possibly fresher, sample was then obtained and the test repeated. With this new sample it was found that 60 mg. were necessary to convert the gram of starch to the colorless end-point in ten minutes, from which it follows that 1 part of the ferment will convert 16.6 parts of starch to the colorless end-point in the same time. With a new sample of Liquid Taka-Diastase obtained simultaneously it was found that 3.5 c.c. were necessary to convert 1 gram of starch to the colorless end-point in ten minutes. As a fluidounce of this liquid is said to contain 20 grains of the solid it will be seen that the results approximately agree with those of the first sample of the solid, and that they are both very low.
In the earlier tests 16 parts of starch converted by 1 part of the ferment was the value found. These results are in close agreement with values reported by Sherman (Jour. Am. Chem. Soc., xxxii, 1073) for a sample of recent purchase. He found a conversion of 51 parts of starch to the colorless end-point in thirty minutes for one sample, while for another he found 66 parts, in the same time. It will be noted that our time limit is ten minutes. It is worthy of note that for a perfectly fresh and specially prepared sample furnished by Dr. Takamine, a conversion of 278 parts in thirty minutes was found by Sherman. Taking the time into consideration, it will be seen that the results are about the same for the market samples as those found by us and much lower than claimed, as well as much lower than for other makes of similar products. The difference in the behavior of fresh specially prepared Taka-Diastase and the market sample is very clearly shown. No one questions the fact that fresh laboratory samples of Taka-Diastase may show a moderate converting power on starch. But we have to deal with the activity of market samples only, and Sherman’s work and our own show the low digesting power of the product as physicians may secure it on the market.
The marked difference in activity between perfectly fresh and ordinary market samples of Taka-Diastase is very clearly shown also in a recent paper published by Wohlgemuth.[24] In the digestion of starch paste to the “dextrin” stage Wohlgemuth found in the commercial sample a strength approximately a hundred times less than that observed in a fresh sample sent him by Dr. Takamine.
Wohlgemuth’s results were obtained by a method not essentially different from ours, with this difference, however, that he digested through 24 hours in the cases reported, and carried the reaction to the “dextrin” stage only, in place of to a colorless end-point. Making the proper reductions, it is evident that the actual values found by him for the market samples bought in Germany are not greater than those reported by us.
The reference to the work of Sherman is made because, in a following paper in the same journal, he recommends the use of salt as an activator in finding the strength of certain diastase preparations. It is well known that dialyzed diastase preparations and starch of highest purity have but slight action on each other; a little salt increases the activity greatly, and also increases the activity of commercial diastase preparations. These facts Sherman utilizes in working out a method for valuation of commercial diastases. The facts were well known to us at the time of our former report, but it was not thought best to depart from the general method which had been in use by all analysts following the general scheme of Roberts. Quite recently, I. Bang has published a paper on the investigation of diastase (Biochem. Ztschr., xxxii, 417) in which he studies the behavior of sodium chlorid and other salts on the rapidity of starch conversion, and finds that a much smaller amount of salt than Sherman recommends brings the maximum increase.
The method employed in our former tests is a good comparative method, and this is all that may be claimed at present for any method. By adding salt to our starch solution the activity of Panase and other ferments is likewise greatly increased. For Panase, a preparation possessing rather high starch-converting power, we have recently found an increase of about 30 per cent. in the converting power, with salt present. Working to loss of blue color, merely, it is possible in this way to get a higher value than that claimed by the manufacturer. There is no practical gain in using the salt for our purpose as the methods are at best arbitrary, and the results only comparative.
Taking all the facts into consideration, it is recommended that the rejection of Taka-Diastase and Liquid Taka-Diastase be allowed to stand and that, in view of their extensive exploitation, this report be authorized for publication so that physicians may know the facts.
This report was referred to Parke, Davis & Co., and they made the following reply:
“The report submitted in your letter of the 23d is, we contend, erroneous and unjust: first, to our Liquid Taka-Diastase, because over three years ago we changed our formula, reducing the alcohol from 18 per cent. to 10 per cent., increasing the glycerin and thus prolonging greatly the period of activity.
“As for our regular Taka-Diastase, our claim is and has been for years simply that Taka-Diastase will digest or hydrolyze 150 times its weight of starch in ten minutes, under proper conditions. We do not claim, we do not permit our representatives to claim, that Taka-Diastase will completely transform starch, to the colorless end-point, into sugars. Taka-Diastase is used to supplement a deficiency of ptyalin and converts the starch into soluble material with great rapidity, thus giving the gastric fluid immediate access to the proteids.
“If in the enclosed labels the word ‘digest’ were replaced with the word ‘liquefy,’ the claim could not be assailed by the most carping critic. To save any possible question, we shall therefore make this change in our label, having it read: ‘Taka-Diastase will liquefy 150 times its weight of starch in ten minutes, under proper conditions.’ Is there the slightest question in your mind that this statement as just quoted is entirely correct and entirely supported by clinical experience?
“It is our conviction that Taka-Diastase has a very remarkable power to hydrolyze starch either in the test-tube or in the stomach, and that this property is of great utility in clinical work. We do not claim that its conversion of the starch into sugars is complete, to the colorless end-point of the Johnson test; and on this point we have been perfectly frank with the Council, as well as with every physician who has taken sufficient interest to inquire.”
In view of the above protest, the matter was submitted to a second referee, who reported as follows:
“Your referee on the matter of Taka-Diastase has made a careful investigation of the reports and correspondence submitted, and begs to make the following report:
“The question at issue, viz., whether Taka-Diastase should be included in New and Nonofficial Remedies, I believe, can be determined by the material before me, and further tests of the material are not necessary.
“The letter of the makers of Taka-Diastase admits that the early claims regarding the strength and properties of the material were erroneous and exaggerated. Since the product was once admitted to New and Nonofficial Remedies, it may be claimed that as the Council on Pharmacy and Chemistry must have been in error then, it may be now. Your referee does not consider this supposition worth discussing. The conclusion he draws is that the Council was too hasty in accepting the preparation, and that the incident shows how much better it would be in all cases to accept no remedy until sufficient time has been given for conclusive tests.
“The literature still sent out by Parke, Davis & Co. regarding Taka-Diastase is misleading and of a kind more appropriate for a nostrum than a standard chemical substance. What would we think if morphin, quinin or even heroin were advertised in the same way? I cite the statement, ‘Taka-Diastase digests starchy food with vigor and directness.’ It seems to the referee that the proposition to modify the label to indicate the amount of starch which is liquefied rather than the amount which is saccharified, in accordance with the Council’s standard, is bound to lead to confusion and to give an exaggerated and false value to Taka-Diastase.
“Your referee recommends that the report of the reinvestigation of Taka-Diastase which has been submitted to me, be made available to the medical profession, and that the rejection of Taka-Diastase and Liquid Taka-Diastase be allowed to stand.”
This report of the second referee was submitted to Parke, Davis & Co., with the request that they state more explicitly their claims regarding the activity of Taka-Diastase and Liquid Taka-Diastase, in order that, if they decided to revise their claims for the preparations, such revision of claims might be published along with the reports of the Council. They replied:
“Answering your note of the 15th instant: We have no desire to discuss further the subject of your letter of February 24, or to make any statement beyond that set forth in our letter to you of Dec. 27, 1911.”—(From The Journal A. M. A., July 6, 1912.)