COAGULEN-CIBA OMITTED FROM N. N. R.
Report of the Council on Pharmacy and Chemistry
The Council has authorized publication of the following report announcing the deletion of Coagulen-Ciba from New and Nonofficial Remedies.
W. A. Puckner, Secretary.
Coagulen-Ciba, a product of the Society of Chemical Industry, Basle, Switzerland, was admitted to New and Nonofficial Remedies in 1915. It is stated to be an extract prepared from blood platelets and to contain thromboplastic substances (cytozym, thrombokinase, thrombozym) mixed with lactose. Extensive clinical reports appeared to justify its acceptance for New and Nonofficial Remedies with Fibrin Ferments and Thromboplastic substances.
In 1918, Dr. Arthur D. Hirschfelder reported to the Council that of a number of specimens of Coagulen-Ciba examined by him, failed to accelerate the coagulation time of blood.
In view of Dr. Hirschfelder’s findings, the Therapeutic Research Committee of the Council invited Dr. P. J. Hanzlik to undertake an exhaustive investigation of thromboplastic substances, the Council, in the meantime temporarily retaining Coagulen in New and Nonofficial Remedies until the investigation was completed.
The following report on the eligibility of Coagulen-Ciba was made to the Council by Dr. Hanzlik:
Object: To test the claims of thromboplastic and hemostatic activities.
Claims: Coagulen is alleged to be a “physiological styptic prepared from the natural coagulants of animal food contained in the blood platelets. It has the characteristics of a lipoid.” (If cephalin is meant it is difficult to understand why platelets should be selected in preference to other abundantly supplied organs such as brains).
“Coagulen is indicated in all cases of external and internal hemorrhage due to a deficiency of the coagulating power of the blood: epistaxis, hemophilia, hemorrhage from gastric or duodenal ulcer, melaena neonatorum, hemorrhage from the gums, the lungs, the bladder, the uterus, hemorrhage during or after operations (turbinectomy, tonsillectomy). It has also been used as a prophylactic before operations, likely to produce severe hemorrhage.”
“In cases of true hemophilia one application of 5 grains of coagulen usually suffices to control the hemorrhage.” “In gastric and intestinal hemorrhage the internal administration of coagulen will be found effective.” “In bonegrafting, plastic surgery, dentistry and nose and throat surgery the application of a 10 per cent. solution of Coagulen will be found to be of valuable assistance in controlling hemorrhage and oozing.”
“It is a non-toxic and non-irritating powder to which a certain amount of sugar has been added, with a view to ensuring its prompt solution in water or physiological sodium chloride solution.”
Description: “Coagulen is a yellowish granular powder with but slight odor, a sweet taste and is readily soluble in water or a normal salt solution.” The dry Coagulen obtained corresponds to the description claimed. Old specimens show the presence of dark brown particles. Coagulen is marketed in 3 forms: (1) as dry powder containing lactose, which, it is claimed, facilitates solution in water; (2) as 3 per cent. sterile solution in ampoules;[137] (3) tablets.
Methods of Study: The alleged thromboplastic activity was tested by the method of Howell and a modification of this method by Fenger as described in “New and Nonofficial Remedies.” In the Howell method dog or cat blood is used, while beef blood at body temperature is used in Fenger’s method. In other respects the methods are essentially the same. Briefly these consist of noting the acceleration of coagulation time in a mixture of equal parts of serum and the thromboplastic agent to which about an equal part of oxalate plasma is added. Under these conditions cephalin causes clotting in about 1 minute or even less as compared with 20 to 30 minutes or more of the control.
The effects were compared with freshly prepared cephalin and other thromboplastic agents, using saline (0.9 per cent. NaCl) as control. The effect of different concentrations was also studied.
The literature of the manufacturers claims that Coagulen is harmless. This was tested by making intravenous and subcutaneous injections into guinea-pigs, using saline and cephalin as controls.
Bloods of 4 different species were used, namely, cat, dog, beef and human. Dog’s peptonized blood and plasma were also tried.
The 15 different tests that were made in vitro were carried out with 3 different samples of fresh dry Coagulen (from manufacturer), 2 old samples (one from Council on Pharmacy and Chemistry and one of our own), 3 fresh specimens of sterile solution in ampoules (from manufacturer), one old specimen and 4 small ampoules (Council on Pharmacy and Chemistry).
The tablets were not tested since these are made from dry Coagulen and the results would hardly be expected to show anything different.
Results: The results obtained may be briefly summarized as follows: (1) 0.1 per cent. to 5 per cent. Coagulen did not accelerate the coagulation time of blood and oxalate plasmas in the majority of tests any more than the controls of saline, while 0.1 per cent. cephalin was found to shorten the coagulation time from 1⁄3 to 1⁄2.
(2) There was no difference between the behavior of old and fresh specimens.
(3) No acceleration of coagulation in vitro was observed even with the highest concentrations tried, namely 25 and 50 per cent.
(4) Irrigations made with fresh dry coagulen in solution and sterile solution in ampoules on superficial bleeding from the foot-pads of 3 normal and peptonized dogs and local application to hemorrhages from dissected femoral arteries and bone and liver wounds of 3 dogs showed that coagulen was no more active than normal saline.
Toxicity: Subcutaneous and intravenous injections of different doses of Coagulen solutions (fresh ampoules) and dry Coagulen in solution in 8 guinea-pigs produced definite anaphylactoid symptoms with injury to the circulatory and respiratory systems as indicated by cardiac dilatation, abdominal congestion and pulmonary hemorrhages, congestion, distention and sometimes thrombi. On the other hand, the control animals injected with saline and cephalin remained practically unharmed.
Conclusions: The results obtained justify the following conclusions:
(1) Coagulen is entirely inactive as a thromboplastic and hemostatic agent.
(2) Coagulen is distinctly injurious when injected systemically.
(3) The claims of hemostatic efficiency and harmlessness for Coagulen by the manufacturer appear exaggerated and unjustified.
Recommendations: Because of its uncertain composition, the possible dangers when injected systemically, and its inactivity as a thromboplastic and hemostatic agent when tested by several different methods, Coagulen merits no recognition as a therapeutic agent for inclusion in New and Nonofficial Remedies.
The detail evidences used as the basis of this brief report concerning Coagulen will be published shortly in the Journal of Pharmacology,[138] together with the results with other thromboplastic agents.
The preceding report was sent to the American agent for the Society of Chemical Industry, Sept. 8, 1919.
In reply the American agent, Ciba Co., Inc., on March 22, 1920, sent the Council “some additional clinical reports on the use of Coagulen-Ciba in the treatment of Hemorrhages supporting our claims of the merits of Coagulen-Ciba.”
The material submitted by the Ciba Co., contains no objective evidence for or against the efficiency of Coagulen-Ciba but merely opinions. As a rule these opinions are favorable though conditional and hedging and quite unconvincing. Nothing was submitted to offset or challenge the findings of Dr. Hanzlik’s report.
Since the evidence indicates that Coagulen-Ciba has little, if any, efficacy as a hemostatic, the Council directed its omission from New and Nonofficial Remedies.—(From Reports of Council on Pharmacy and Chemistry, 1920, p. 53.)