Allantoin

ALLANTOIN A NEW GRANULATION TISSUE STIMULATING SUBSTANCE WITH ESPECIAL EMPHASIS ON ALLANTOIN IN OINTMENT FORM* FREDERICK R. GREENBAUM D.SC. PHILADELPHIA, PA.

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HE story of the deveiopment of this new tissue promoting substance, aIIantoin, seems to answer in the affirmative the question, “Does man know by instinct what wiII cure his iIIs?” It is an interesting fact that for centuries European peasants have been heaIing uIcers with the root of a plant caIIed comfrey, which is rich in aIIantoin. Of course, they did not know this pIant contained aIIantoin. They discovered empiricaIIy the heaIing virtues of comfrey. During recent years, the use of Iarva or maggot therapy has enjoyed increasing popularity in the treatment of chronic suppurative Iesions of soft tissue and bone, particularIy serviceabIe in osteomyeiitis. CIinicaI and laboratory studies indicate that the chief advantages of the maggot Iies in the abiIity of the Iarva to serve as efficient scavengers without destroying Iiving tissue. Ambrose Pare’ in 1652 observed unusuaIIy rapid healing in suppurating wounds in which bIow&es had deposited their eggs. Larrey2 in 1829 observed that wounds infested with maggots heaIed rapidly. MaIgaigne3 in 1847 made an observation concerning the action of maggots in the treatment of compound fractures. SimiIar observations were made during the CiviI War by Keen and Zacharias4 who stated that maggots exerted a heaIing influence on infected wounds. However, it remained for Baer5 of Johns Hopkins MedicaI SchooI, to make the first deIiberate therapeutic appIication of this principle, with such results that this method of treatment has become an accepted procedure and numerous reports have appeared in medica Iiterature ampIy confirming his resuhs. The characteristics of treatment are rapidity of heaIing and increase of

heaIthy granulation tissue. Buchman and BIair,6 and Buchmannr reported particuIarIy on the effective way in which maggots remove necrotic tissue and reduce wound infection. Myers and Czaja,* and Robinson and Norwood aIso reported how maggots aid indirectIy in the healing process. WeiI and his co-workerslO reported success with this method. The unusua1 progress of heaIing, however, sometimes in stubborn cases of Iong standing, has indicated that in addition, maggots secrete a substance into the wound which directIy stimulates the heaIing process, a theory frequentIy expressed in the Iiterature.” Simmons12 showed that maggots excrete a bactericida1 substance particuIarIy potent to StaphyIococcus aureus, Streptococcus hemoIyticus and CIostridium WeIchii. This accounts in part for the gratifying resuIts obtained in such infections under maggot therapy. Ferguson and McLaughIinr3 reported favorabIe resuIts with maggot therapy in 13 cases of OsteomyeIitis, 8 carbuncIes, 6 sloughing ulcers of the Ieg, 7 cases of gangrene and 13 other lesions of soft tissue. RecentIy Ayres and his co-workers14 demonstrated the appIicabiIity of maggot therapy in dermatologic conditions involving chronic uIcerative or granuIomatous processes, such as amebic uIceration of the skin, coccidioda1 granuIoma and spreading uIcerative and gangrenous infections of the abdominal waI1, occasionally following appendectomy. There are obvious disadvantages, however, in the maggot treatment of wounds: I. The possibIe hazard of introducing additional infection into the wound with the maggots; 2. The frequent rev&ion of patients to this form of therapy;

* From the Research Laboratories of The National Drug Company, PhiIadeIphia, Pa, Presented before the Medicinal Division of the Meeting of The American Chemical Society, Pittsburgh, September 7-12, 1936.

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tions are that aIIantoin and possibIy some of its reIated substances, are more than waste products. They may be normaIIy present in the nucIear structure of the ceI1. Twenty-four years ago, in 1912, MacaIister’6 found aIIantoin a very efficient ceI1 proIiferant. He tried pure aIIantoin soIution in the treatment of chronic uIcers. He aIso used it internaIIy in the treatment of gastric and duodena1 uIcers, with success. To MacaIister beIongs priority in the discovery of the,therapeutic vaIue of aIIantoin, but his work was soon forgotten and it is due to the untiring efforts of Robinson, who showed that aIIantoin is present in the excretions of maggots and that it is responsibIe for the heaIing action. AIIantoin, formerIy a rare Iaboratory chemica1 and hardIy avaiIabIe on the American market, was synthesized in our Iaboratories in ApriI, 1935, by the oxidaFIG. I. Case I. After treatment, anterior view. tion of uric acid,l’ obtaining beautifu1 crystaIs of aIIantoin with a meIting point of 4. The high cost of maggots; z~g.4~c. The theoretica nitrogen content 5. The diffrcuhy in readiIy securing is 35.45 per cent; we found 35.39 per cent steriIe maggots for appIication. and 35.25 per cent, and in another batch ALLANTOIN, AN ACTIVE PRINCIPLE OF THE 35.31 per cent. EXCRETIONS OF MAGGOTS At first a 0.5 per cent soIution was used Robinson,15 of the Bureau of Entobut we found when this soIution was moIogy, United States Department of placed in the ice box, crystaIs of aIIantoin AgricuIture, has undertaken an investigawere precipitated, whiIe a 0.4 per cent tion to determine the heaIing principIe soIution remains cIear in the ice box. contained in the excretion of maggots. AIIantoin is an inert substance and does He demonstrated that aIIantoin was found not possess bactericida1 vaIue. It was in the crystaIs obtained from the excrebelieved, however, that bactericida1 action tions of maggots. Further experiments of an aIIantoin soIution is highIy desirabIe. have estabhshed that aIIantoin possesses It is necessary to at first kiI1 the organisms heaIing action upon chronic non-healing before any healing action may be obtained. wounds with edamatous, indoIent tissues Therefore, 0.5 per cent of chIorbutano1 is lining the wounds and discharging pus, added to the 0.4 per cent aIIantoin soIution. particuIarIy when poor in circuIation. This appears to exert sufficient antiseptic AIIantoin is a crystalline substance of action to destroy the organisms present the composition (C4H6N403) a gIyoxyIin the wounds. diureid and an oxidation product of uric AIIantoin soIution shouId be poured acid. It is the principa1 termina1 product into the wound and the wound then packed of purin metabolism in animals lower than with gauze saturated with the soIution, man and man-Iike apes. It is regarded as and shouId be kept constantIy moist. It an excretory materia1, resuIting from the occurred to us that a more convenient and metaboIism of the ceI1 nucleus; it is also suitabIe form for appIying aIIantoin wouId widely distributed among pIants. In its be in an ointment. After experiments with new roIe as a stimuIator of tissue growth, grease base and greaseless base ointments, where deveIopment is inactive, the indicathe non-grease base was found more 3. The extreme discomfort feIt by the patient due to the activity of the maggots in the wounds;

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A FIG. 2. Case 1. After treatment,

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3 A, posteroIateraI

FIG. 3. Case 11. A, before treatment;

view; B, IateraI view.

B, after treatment.

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A

FIG. 4. Case III. A, before treatment;

A

FIG. 5. Case IV. A, before treatment;

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B B, after treatment.

B

B, after treatment.

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desirabIe. The greaseIess ointment possesses distinct advantages because: I. The ointment base itseIf promotes

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used. CIinicaI experience shows that a greaseIess base ointment containing 2 per cent aIIantoin is entireIy sufficient. Higher

6. Case v. After treatment.

healing; 2. The ointment insures a constant supply of aIIantoin brought directIy and remaining in contact with the desired area; 3. Longer continued effect is obtained; 4. Obviates the necessity of frequent appIication of aIIantoin. After numerous experiments with various types of bases, we found that stearic acid with triethanoIamine is a very satisfactory base for the greaseIess type of aIIantoin ointment. This type of ointment offers another advantage over the solution. In the soIution onIy 0.4 per cent of aIIantoin is avaiIabIe, as the maximum soIubiIity of ahantoin in water at room temperature is 0.6 per cent, whiIe by chemicaI.dispersion of from 2 per cent to 5 per cent of alIantoin is incorporated in the ointment base, by dissoIving aIIantoin in hot water (solubiIity about IO per cent of aIIantoin in aImost boiIing water). The soIution is brought to 706c. GIycerin and triethanoIamine are dissoIved in the soIution and finahy by mixing it with meIted stearic acid, this procedure produces a very fine and veIvety-Iike ointment containing 2 per cent of aIIantoin in a uniform colIoida1 dispersion in the ointment. As an antiseptic, 0.5 per cent of chIorbutano1 was

concentrations of aIIantoin up to 5 per cent, however, may be suppIied in ointment if deemed

desirabIe.

CLINICAL

INVESTIGATIONS

CASE I. A miner sustained an extensive injury from a crushing bIow whiIe working in a mine. There was a perforation in the inguina1 region. He was treated at the Ohio State Industrial Commission, of Logan, Ohio. The Wassermann test and the sputum were negative. With the constant application of gauze saturated with aIIantoin soIution and aIIantoin ointment this Iesion was compIeteIy heaIed after a few months treatment (Figs. I, zA and B). A young man, nineteen years of CASE II. age, was burned in a forest fire over eIeven years previousIy. The injury heaIed but broke down at various times over the site of the original burn. In December, 1934, he feI1 over a wheeIbarrow and reopened the scar. He was treated at the C.C.C. camp without success and was then transferred to the Waiter Reed Hospital. For the next eighteen months every type of treatment was applied, incIuding two different attempts at skin grafting. The resuIt of one graft is shown in Figure 3A. During this time the injury showed signs of heaIing onIy to break down again. On June 12, 1936 the treatment was changed to aIIantoin ointment. Three days Iater there

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was remarkable improvement and IiIIing in of the injury. June 25, 1936, the record shows that the uIcer is heahng and the attending physician remarks that there was more progress in two weeks than in the previous eighteen months. On August 26, 1936 the condition was practicahy heaIed. (Fig. 3B.) CASE III. Another patient was hospitahzed March, 1936, with uIcers on the right and Ieft arms and Iegs, diagnosed as tubercuIous. They a11 responded to x-ray therapy except one uIcer on right Ieg, which did not improve with any type of treatment (Fig. 4A). Treatment with aIIantoin ointment was started on June I I, 1936, folIowed by improvement during the past six weeks (Fig. 4B). In spite of the diagnosis of tubercuIosis the treatment is progressing favorabIy. CASE IV. A man in the SpringfieId City HospitaI, Springfield, Ohio, had tubercuIosis of the Ieg with no bone invoIvement, andidefinite infection of the hips. The patient couId not rotate his Iegs. After treatment with aIIantoin there is now about 5” rotation. The IateraI and anterior views in the x-ray picture taken March 12, 1936, (Fig. 5A) show the infection invoIving the Iower half of the femur and the upper third of the tibia and IibuIa. After the use of aIIantoin soIution and ointment, which was started ApriI I, 1936, the infection in the femur practicaIIy cIeared and the infection in the tibia and IibuIa is considerably reduced (Fig. 5B). CASE v. A maIe butcher, seventy-six years of age, an inmate of an Old Men’s Home in PhiIadeIphia, was a diabetic and was given insulin treatment for four months. Diabetic gangrene deveIoped on the right foot. The great toe sIoughed off at the first joint, foIlowed by the infection of the entire foot with Iymphatic infection reaching to the knee for which an amputation above the first third of the femur was made at the Presbyterian Hospital. The patient returned to the Home after three weeks with the entire stump unheaIed and with deep 0verIapping Aaps. The wound was treated twice daiIy with ahantoin ointment with exceIIent resuIts obtained in the compIete heaIing of the stump (Fig. 6). The Bureau of EntomoIogy of the United States Department of Agriculture have obtained encouraging results with allantoin ointment under a considerabIe variety of uses.

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One of the hospitak in Washington, reported the use of aIIantoin ointment in a series of 15 to 20 cases of chronic ulcer and repoi-t the product has a large place in the treatment of chronic uIcer, especiaIIy of the Iower limb. The benebt resuIting in many of these cases has been marked. Another report regarding the therapeutic value of alIantoin ointment stated that it seems to possess great value in the stirnuIation of granuIations, cleaning up of uIcers and heIping in the formation of new skin. In MinneapoIis, it was asserted that “it very definiteIy stimuIated granuIating tissue as we11 as hastening the absorption of slough.” The foIIowing case report was received from CoIumbus, Ohio : On October 8, 1928, Mr. C. during the course of his reguIar empIoyment sustained .a;.crushing injury to his Ieft Ieg and a&e. Once that time the Ieg has never heaIed and, he has .been under continuous treatment. On January ‘16; 1936, there were three uIcers on h’iG’Ieg. .The Iarger one was about two and one haIf inches in diameter. These uIcers which have been sIowIy decreasing in size, showed marked. Improvement. At the present time the two smaIIer ones are entireIy heaIed and the larger one is about the size of a fifty cent piece. It was noted in connection with this treatment, that the uIcers became very sensitive soon after the first treatment and the tissues to take on a more heaIthy appearance. AIIantoin ointment has been successfuIIy used in the treatment of “x-ray burns.” It is indicated after a11 surgica1 operations, when desired healing does not occur. In the treatment of carbuncIe and of mastoid conditions, a1Iantoin ointment has demonstrated definite vaIue. We have a report on a case of varicose ulcer of sixteen years duration. “Four smaI1 uIcers of one to two inches in diameter and one Iarger uIcer of about ten inches in Iength and about half way around the other medication faiIed to Ieg. Every produce resuIts. With allantoin ointment the uIcer is filling up with new granulations and is getting smaller in size.” These reports demonstrate definitely the cIinica1 vaIue of aIIantoin ointment,

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and show we are dealing with a remarkabIe drug of great promise and wide possibihties in the treatment of infected or slow heaIing wounds. ReaIizing the cIinica1 possibiIities of aIIantoin, we are studying the action of vegetabIe mucin obtained from okra, combined with aIIantoin, in coIIoida1 dispersion, for the treatment of coIitis and gastric, peptic and duodena1 uIcers. AIIantoin with vegetabIe mucin combines the mechanica coating action of the powdered okra on the Iining of the stomach, with the healing action of allantoin on the inffamed mucosa of the stomach. The previous work of MacaIiste9 and BramweIll* shows that muciIaginous infusion of the comfrey root, reinforced with saturated soIution of aIIantoin, produced improvement in certain stomach conditions. AIIantoin may be used successfuIly in a surgical dusting powder and further study aIong this Iine is in progress. The incorporation of alIantoin in a watersoIubIe base, such as tragacanth, in the form of a jeIIy, makes the heaIing properties of aIIantoin accessible in the fIeId of sinus treatment for the ear, nose and throat diseases. SUMMARY

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A brief historica account is given of the maggot therapy in OsteomyeIitis, chronic or varicose uIcer, pruritus ani and vuIva, burns and wounds that refuse to hea1. 2. The importance of the discovery of aIlantoin as an active principIe of the excretions of maggots by Robinson is emphasized. 3. The deveIopment of aIIantoin products, such as the 0.4 per cent aIlantoin soIution and the 2 per cent aIlantoin ointment, has been brought to a successfu1 issue. 4. The cIinica1 evaIuation of alIantoin soIution 0.4 per cent and particularly aIIantoin ointment 2 per cent is briefly shown. REFERENCES I. PAR& AMBROSE. Les oeuvres d’Ambroise Ed. 2, 1579. Les Oeuvres d’Ambroise A. Lyon, Pierre Rigaud, 1652: Translation

Pare, Par& from

12.

13.

I 4.

I

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the Latin by Theo. Johnson, London, CIark, IO: 249, 11: 277, 1679. Singer: Selections from the Works of Ambroise Par&, 1924, p. 218. LARREY, D. J. Observations on Wounds and Their Complications by ErysipeIas, Gangrene and Tetanus. TransIated from the French bv E. F. Rivinus: PhiIadeIphia, Key, Mielke andaBiddIe 1832, p. 34: Des vers ou Iarves de Ia mouche bIeue Chez Gabon, Paris, Clin. C&r., r-51 (Nov.) 1829. MALGAIGNE, J. F. Treatise on Fractures (and Luxations) under the heading of “Treatment of CompIicated Fractures,” I : 271, line 22, concerning maggots, Paris, 1847. ZACHARIAS. In Keen, Text Book on Surgery, PhiIa., 1918. BAER, W. S. SacroiIiac joint, arthritis deformans, viable antiseptic in chronic osteomyelitis. Proc. Znternat. Assemb. Inter-State Post-Grad. M. A. Nortb America (1929) 5: 371, 1930. The treatment of chronic osteomyeIitis with the maggot (the Iarvae of the blowfly). Jour. Bone and Joint Surg., 13: 438 (JuIy) 1931. BUCHMAN, Jos. Maggots and their use in the treatment of chronic osteomveIitis. Surg., Gvnec. and Obst., 15: 177, 1932. ” BUCHMAN. Jos. The rationaIe of the Treatment of chronic osteomyeIitis with specia1 reference to maggot therapy. Ann. Surg., 9: 251, 1934. MYERS, JACOB and CZAJA, L. M. The maggot treatment of osteomyelitis. Illinois Med. Jour., 60: 124, 1931. ROBINSON, WM. and NORWOOD. V. H. The role of surgica1 maggots in the disinfection of osteomyelitis and other infected wounds. Jour. Bone and Joint Surg., 15: 4.09 (April) 1933. WEIL, G. C., SIMON, R. J. and SWEADNER, W. R. A bioIogica1, bacterioIogica1 and cIinica1 study of IarvaI or maggot therapy in the treatment of acute and chronic pyogenic infections. Am. Jour. Surg., 19: 36, 1933. ROBINSON, WM. Literature reIating in the use of maggots in the treatment of suipurative infections. U. S. Deoartment of AnricuIture. Bureau of EntomoIog;, Circular Z?. 310 (Revised) June, 1934. SIMMONS, S. W. A bactericida1 principie in excretions of surgical maggots which destroy important etioIogica1 agent of pyogenic infections. Jour. Bacterial., 30: 253 (Sept.) 1935. FERGUSON,L. K. and MCLAUGHLIN, C. W. Maggot Therapy. Am. Jour. Surg., 29: 72-84 (JuIy) 1935. AYRES. S. JR., ANDERSON, N. P. and TAYLOR, G. M. piactice. Ma&ot therapy in- dermatoIogic Arch. Dermat. and Syph., 33: 21-30 (Jan.) 1936. ROBINSON, WM. StimuIation of heaIing in nonhealing wounds by aIIantoin occurring in maggot secretions and of wide bioIogica1 distribution. Jour. Bone and Joint Surg., 17: 267-271 (April),

1935. 16. MACALISTER, C. J. A new ceI1 proIiferant: its clinical appIication in the treatment of ulcers. Britisb Med. Jour. I: IO, 1912. 17. HARTMAN, W. W., MOFFETT, E. W. and BICKEY, J. D. Organic Synthesis, New York, John Wiley & Son, Inc., 1933, p. I. 18. BRAMWELL, WM. The new ceI1 proliferant. A note on the Symphytum offrcinale of common comfrey. Brit. Med. Jour.. I: 12. . 1912. _