ALLANTOIN -- ITS PROPERTIES AND USES By A.M. POSNER, B.Sc., Ph.D. THE FOLLOWING is a critical survey of the literature dealing with the therapeutic and cell proliferant action of allantoin (glyoxyl-diureide). HISTORICAL The use of infusions of the common comfrey root to promote healing has been known for several hundred years. Macalister in 1912 • reported his observations on the healing power of this substance and in addition submitted some of the root to chemical analysis. Amongst other substances isolated was allantoin, which was present to the extent of 0.8 per cent. Macalister then successfully treated three refractory nicers with a solution of synthetic allantoin. Many other cases of a similar nature were also reported. • The apparent beneficial effects of maggots growing in open wounds has also been known for a long time, and Baer,, during and immediately after the First World War, developed a maggot therapy for the treatment of refractory wound infections. Robinson, • in a critical examination of maggot therapy, showed thai amongst other substances produced by the maggots was allantoin. He was able to obtain successful healing of severe osteomyelitis cases using allantoin however, the rate of healing was not so rapid as when maggots were used. Robinson and Norwood' demonstrated by dissection and culturing tech- niques that pyogenic bacteria are destroyed in the alimentary tract of the maggot. Thus bacteria taken in by the feeding maggot will be destroyed. They also showed' that the extract derived from maggots had no effect on bacteria cultures. It is possible that some of the active principle was destroyed during the maceration process. Livingston,, 8 treated 415 cases of osteomyelitis, ulcers and similar conditions with living maggots and maggot extract, and 605 cases by extract only. From 60 to 100 per cent of the cases showed clinical improvement through growth stimulation and a pathogenic bacterial inhibition. The maggot extract was shown to contain sulphydryl groups, allantoin, calcium, cysteine, glutathione and embryonic growth-promoting substances. Maggot therapy exhibits the following features. 1. Thorough surgical removal of diseased area. 2. The wound is actively sterihsed by the maggots, which physically remove micro-organisms by ingestion. 3. The proteolytic activity of the maggot enzymes breaks down the 58

ALLANTOIN•ITS PROPERTIES AND USES $9 wound discharges and sloughs into end-products, which are then consumed by the maggots. 4. The therapeutic active principle of maggots stimulates rapid growth. The beneficial effects (1) to (3) listed above can only be given by maggots themselves, while (4) could be given by allantoin. Thus, it is not difficult to see why maggot therapy does not necessarily equal allantoin therapy. ALLANTOIN THERAPY The synthetic allantoin has been mainly used in the form of a saturated solution (0.5 per cent at normal temperatures) or in the form of an ointment (2 to 5 per cent in a greaseless base).9 Almost all cases treated were those suffering from severe ulcers, suppura- tive wounds and osteomyelitis, and considerable success was claimed, although adequate testing and controls have not been carried out. •o,,,•,•s,• • CELL PROLIFERANT ACTION OF ALLANTOIN Most of the observations on the cell proliferant action of allantoin are qualitative in character, since they generally relate to the healing of wounds. Attempts to demonstrate the cell proliferant action of allantoin using the methods of tissue culture have not met with significant success.•', •' Allantoin does not normally play an important role in human meta- bolism, and occurs only to a small extent in human urine. However, it occurs in much higher concentrations in the allantoic fluid and in the urine of pregnant women. It is the normal end-product of purine metabolism in many animals, e.g., dogs, and again occurs in higher concentrations in the allantoic fluid. This association of allantoin and pregnant animals has again led to the inference that allantoin is closely associated with cell proliferation." Robinson has suggested that allantoin actually re-enters the cell nucleus. It has been suggested that one of the functions of allantoin is to cause phagocytosis. Berthelot and Bertrand •' reported that allantoin could cause leucocytosis in guinea pigs, while Macalister •9 showed that oral administra- tion of allantoin could increase the leucocyte count from 5 to 15 per cent. The successes he obtained with allantoin in the treatment of pneumonia were attributed to the increase in leucocytosis. THE CHEMISTRY OF ALLANTOIN Allantoin may be obtained by the alkaline oxidation of uric acid in the cold. It is a white, crystalline substance, m.p. 238 ø C., and is soluble to the extent of 0.6 per cent in cold water, 0.2 per cent in alcohol and insoluble in ether. It is appreciably soluble in hot water and alcohol. It is readily