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HISTORICAL ASPECTS OF AND OTHER FUROCOUMARINS* THOMAS B. FITZPATRICK, M.D., Ph.D. AND M. A. PATHAK, B.Sc. (Hons.), M.Sc. (Tech.)

Some of man's earliest research efforts werewritten by Be thold Laufer, (5) a drug by the concerned with attempts to restore the normalname pu-ku-c (bu-kut-tsi) which had been skin color to scattered, pigment-less areas con-identified as Psoralea corylifolia by the Maci sidered to be leprosy, although most of whichcollaborator in the Kai Pao pen Tscao (A.D. were probably . In the Indian sacred book968—976) of the Sung period, is mentioned as a Atharva Veda, which dates back to 1400 B.C. ortreatment of leukoderma. The author comments earlier, the "cure" of leprosy and leukodermathat the plant name Bwa-ku-Si or Ba-ku-c, (vitiligo) with certain black seeds together withpopularly but erroneously written as po ku c, Bringartga(Eeclipta prostata), Indravaruni,is not of Chinese but Indian origin. It resembles (Coloc path), and turmeric (Curcuma longa)the Sanskrit, Va-ku-ci, (Vasuchika) which is has been described in detail. The importance ofPsoratea corylifolia and which had been used the problem is illustrated by the following odeby the Hindus in the Ayurvedic system of medi- to one of the plants used, described in thecine. This plant contains a photodynamically Atharva Veda (1, 2). active furocoumarin, . Another important plant, , a weed Born by night art thou, 0 plant, found in the Nile Valley, has been employed for Dark, black, sable, do thou, centuries as a "cure" for leukoderma. Ibn El That art rich in color, stain Bitar, who lived in the thirteenth century, gave a This leprosy and white gray spots. description of the usefulness of this plant for Even color is the name of thy mother, leukoderma in his famous book, "Mofradat El- Even color is the name of thy father. Adwiya" (6). This plant was used by "Ben- Thon 0 plant producest even color Shocib" a Berberian tribe in the Northwestern Render this (spot) to even color. African desert. The plant alluded to is not precisely known, but The modern period of psoralen research began when one reads other ancient Indian medicalin 1938 when Kuske investigated "phytophoto- literature such as A.stanga-Hridaya Samhitadermatitis", a bullous eruption appearing on the by Vagbhata, or edicine, a large Germanareas of the skin which have been in contact encyclopedia of Indo-Iranian studies (3), it wouldwith certain plants and subsequently exposed to appear that the most widely used plant was Bava-sunlight (7). He obtained pure compounds by chee, a species containing psoralen. extraction of oil of bergamot (), mas- In the Bower manuscript translated by A. F.terwort or Peucedenum ostruthium (oxypeucede- R. Hoernele (4) which deals with manuscriptnm), and figs (ficusin or psoralen). remains of Buddhist literature found in Eastern Extensive research on psoralens began in Turkestan and the studies of medicine in ancient1941 in the laboratories of Fahmy and his India (about 200 A.D.), the cure of leukodermagroup at the University of Cairo, Egypt. Fahmy with the plant known as "Vasuchika" (said to beobserved that some Egyptian herb doctors were an old form of Bavachee or Psoralea corytijolia)using a gray-green powder called "Atrillal" for has been distinctly mentioned. In "Sino-Iranica"the treatment of vitiligo. It was distributed through only one or two dealers who would not *Fromthe Division of Dermatology, Univer-reveal its nature. Fahmy later ascertained that sity of Oregon Medical School, Portland, Oregon. Presented at the Brook Lodge Invitational"Atrillal" powder was obtained from the fruits Symposium on the Psoralens, sponsored by Theof a weed growing along the Nile delta called Upjohn Company, Kalamazoo, Michigan, March 27—25, 1958. Ammi majus L. Fahmy and Abu-Shady in 1947 229 230 THEJOURNAL OF INVESTIGATIVE DERMATOLOGY isolated three crystalline compounds which theyvitiligo skin following treatment (16). In addition, believed were the active ingredients of the crude36 normal persons claimed increased tanning and powder (8). These were found to be furocou-decreased sunburn while using 20 mg. of methox- marins and were named from the plant fromsalen daily. Because of the testimonial type of which they were obtained (Ammi majus L.):evidence, it was decided to carry out controlled ammoidin, ammidin and majudin. This was anstudies of the apparent augmented tanning and unfortunate selection of names for two of theincreased solar tolerance following oral methox- compounds had already been known. Ammoidin,salen. The results of earlier controlled experi- or 8-methoxypsoralen, had been isolated in 1911ments have been reported (17). Meanwhile, from a different plant source (9) and synthesizedMusajo (1955) in Italy had reported the relative in 1933 by Spath (10). Majudin, or 5-methoxy-activity of many furocoumarins and psoralen, was a well-known constituent of oil ofderivatives applied topically to human skin (18). bergamot which had long been used in the per- It became apparent that methoxsalen or one fume industry. of the furocoumarins might possibly be de- Fahmy then engaged an excellent young Egyp-veloped as an oral drug to increase the tolerance tian dermatologist, El Mofty, to carry out aof human skin to sunlight. Because of the im- clinical trial of the three compounds in the treat-portant basic and clinical implications of this ment of vitiligo. The results were encouraginghypothesis, a fairly extensive research effort (11), and shortly afterward two of the com-was begun in a few medical centers on the bo- pounds, 8-methoxypsoralen and 8-isoamylene-tanical sources of furocoumarins, their mecha- oxypsoralen, were marketed by an Egyptiannism of action, their toxicity in animals and firm in Cairo. This firm distributed tablets andman, the development of high intensity, mono- a topical liquid containing the two drugs. Con-chromatic sources, and the effect of firmation of El Mofty's results were reported infurocoumarins on the incidence of solar or ultra- France (12, 13). However, some difficulty wasviolet-induced skin cancer in man and mice. As a encountered in introducing the drugs into theresult, considerable information is now available United States, and only one pharmaceuticalon some of the phases mentioned above, although firm started clinical trials of 8-methoxypsoralenmany aspects remain to be clarified. (generic name, methoxsalen) in this country. The notion that an orally ingested compound In 1951, Pinkus began a study of topical methox-could alter the tolerance of man to solar radiation salen in the treatment of vitiligo (14). Lerner,appears to be following the pattern of hypothe- Denton and Fitzpatrick (1952) at the Universityses which, according to William James, pass of Michigan used the drug orally in nine vitiligothrough three classic stages: patients with moderate success (15). In the First, a new hypothesis is attacked as absurd; course of this study, a curious effect was noted in Second, it is admitted to be true but obvious two of the vitiligo patients. These patients, whoand insignificant; were brothers engaged in farming, noted that they Finally, it is seen to be so important that its were able to tolerate sunlight on the vitiligoadversaries claim that they themselves dis- areas much better than before the treatment.covered it. In addition, three albinos, who were then given The furocoumarin hypothesis is at present in methoxsalen, commented on an increased toler-the first of these stages with symptoms of the ance to sunlight. Fitzpatrick and Lerner (1954)second stage having begun in a few quarters. had the opportunity to treat a physician's wife REFERENCES with vitiligo at the University of Oregon Med- 1. BLOOMFIELD, M.: Sacred Books of the East; ical School in November, 1952. The patient Hymns of Atharva-Veda, Vol. XLII, Claren- declared that ingestion of methoxsalen before don Press, Oxford, 1897. 2. WHITNEY, W. D.: Atharva-Veda SamhitS exposure to sunlight substantially enhanced the (translation and notes), Harvard Oriental tanning response of her normal-appearing skin. Series, Vol. 7, Lanman, Harvard Uni. Press. Cambridge, Mass. 1905. From 1952—54, Fitzpatrick and Lerner used 3. JOLLY, J.: Medicine. K. J. Trtibner, Strass- methoxsalen orally in the treatment of 110 burg, 1901. 4. HOEENLE, A. F. R.: Studies in Medicine of vitiligo patients and extended the testimonial- Ancient India. Bower Manuscript. Calcutta, type evidence of increased sun tolerance of Government Printing, India, 1893—1912. HISTORICAL ASPECTS OF FUROCOIJMARINS 231

5. LAUFER, B.: Sino-Iranica, Anthropological 12. Sini, E.AND BOURGE0I5-GAVARDIN, J.:The Series. Vol. XV, No. 3 Field Museum of treatment of vitiligo with Ammimajus Lmn. Natural History, Chicago. 1874. J.Invest. Dermat., 18: 391, 1952. 6.IBNEL, BITAR. Mofradat El-Adwiya, 11: 4 13. Sins, E., BoURGEoIsSPINA55E, J.ANDPLANAT, (cited by Fahmy, I. R., Quart. J. Pharm. P.:Dyschromies et vitiligo, Expansion sei- and Pharmacol., 20: 291, 1947). entifique française, Paris, 1957. 7. Kusxa, H.: Experimentelle Untersuehungen 14. KELLY,E.W.,JR., AND PINKU5, H.:Local zur Photosensibilisierung der Haut dureh applicationof 8-methoxypsoralen in vitiligo. pflanzliehe Wirkstoffe. Arch. f. Dermat. u. J. Invest. Dermat., 25: 453, 1955. Syph., 178: 112, 1938. 15. LEaNER, A. B., DENTON, C. H. AND FITZPAT- 8. FAIIMY, I.R. ANDABU-SHADY, H.:Pharma- RICK, T. B.: Clinical and experimental cognosticalstudy and isolation of crystal- studies with 8-methoxypsoralen in vitiligo. line constituent, Ammoidin. Quart. J. J.Invest. Dermat., 20: 299, 1953. Pharm.and Pharmacol. 20: 231, 1947. 16. FITZPATRICK,T.B., ANDLERNER, A.B.: 9.Tuoais, H.: The constitution of xanthotoxin (Unpublisheddata). andits relationship to bergapten. Ber., 44: 17. FITZPATRICK, T.B., HOPKINS,C. E., BLICK- 3325,1911. EN5TAFF, D.B.AND SWIFT, S.: Augmented 10.SPATII,E.ANDHOLZEN, H.:Plant fish poisons, pigmentation and other responses of normal part 5,Constitution of . Ber., human skin to solar radiation following oral 66:1137, 1933. administration of 8-methoxypsoralen. J. 11.E. MOFTY, A.M.: A preliminary clinical re- Invest. Dermat., 25: 187, 1955. port on the treatment of leukoderma with18. MusAjo, L.: Interessanti Proprieta Della Ammi mejus Linn.J.Roy. Egyptian M. A. Furneoumarine Naturali. II Farmaeo, Vol. 31:651, 1948. X, No. 8.1, 1955.