: hydrox yurea 2 = A bs trac t= Low er le g ulc ers as s oc iate d w ith long - te rm hydrox y ure a the rapy Sang Yeop Lee, M.D., Hyun A Oh

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1 : hydrox yurea 2 = A bs trac t= Low er le g ulc ers as s oc iate d w ith long - te rm hydrox y ure a the rapy Sang Yeop Lee, M.D., Hyun A Oh, M.D., Ku Lee, M.D., Hun Mo Ryu, M.D., Kyung Hee Lee, M.D. and Myung Soo Hyun, M.D. Department of Internal M edicine, Y eung N am University College of M edicine, T aegu, K orea Hydroxyurea is an antineoplastic agent with selective cytotoxicity for cells in the DNA synthesizing phase, or S phase, of the cell cycle. It is commonly used in the treatment of myeloproliferative disorders, e.g., chronic myelogenous leukemia, essential thrombocythemia and polycythemia vera. Its major adverse reactions are reversible and dose dependent marrow suppression and gastroenteric disturbances. Cutaneous side effects such as erythema, hyperpigmentation, lichen planus- like dermatitis, nail discoloration and alopecia, atropy of the skin occur, especially with long- term treatment. Painful leg ulcers in association with hydroxyurea have only rarely been reported. The ulcers were usually extremely painful and typically located near the malleoli but were occasionally found over the tibia, on the dorsal aspect of the feet, calves, knees, heels, and hands. Any minor trauma could precipitate skin breakdown and ulceration and these ulcers tended to heal slowly. No consistent correlation between the dose or duration of hydroxyurea therapy and the occurrence of ulcers. Complete wound healing was achieved by simply discontinuing treatment with hydroxyurea. We describe 2 patients who developed spontaneous painful lower leg ulcers during long- term hydroxyurea therapy for a myeloproliferative disorder(chronic myelogenous leukemia and essential thrombo cythemia). All ulcers were painful and typically located both lateral malleoli. T hese ulcers healed only after hydroxyurea was withdrawn and with conservative therapy including manual debridement and occlusive dressing.(korean J Med 59: , 2000) Key Word : Hydroxyurea; Myeloproliferative disorders; Leg ulcer Hydroxyurea ribonucleotide deoxyribonucleotide ribonucleotide reductase RNA DNA S- 1-3).,, 4-6), 7), 8), 10). : : :, 317-1, ( ) lsyksy@chollian.net

Korean Journal of Medicine : Vol. 59, No. 4, 2000.,,.,,,,,,,,,, 2). hydroxyurea,,,,, 2, 11-14) 15-21). Hydroxyurea 1 2.,,,,,. hydroxyurea 3 6 6 6 2.

8 gm/dl, 9,900/, 1,531,000/, 53%, 11%, 6%, 7%, 1%, 13%, 10%. T P 6.1 g/dl, LDH 684 U/L. pseudomonas aeruginosa, (Figure 3).

2 Korean Journal of Medicine : Vol. 59, No. 4, 2000.,,.,,,,,,,,,, 2). hydroxyurea,,,,, 2, 11-14) 15-21). Hydroxyurea 1 2.,,,,,. hydroxyurea hydroxyurea g/d hydroxyurea. hydroxyurea,,.. 130/80 mmhg, 36.8, 70 /, 20 /.,, 4 2 cm, 1 1 cm (Figure 1),, gm/dl, 9,900/, 1,531,000/, 53%, 11%, 6%, 7%, 1%, 13%, 10%. T P 6.1 g/dl, LDH 684 U/L. pseudomonas aeruginosa, (Figure 3). Figure 1A Figure 1B Figure 1. Ulceration on the both lateral malleolus of a patient receiving hydroxyurea therapy because of chronic myelogenous leukemia

Sang Yeop Lee, et al : Lower leg ulcers associated with long- term hydroxyurea therapy Figure 2A Figure 2B Figure

thrombocythemia., hydroxyurea cytarabine 200 mg/d 21. 2. 2 74 93 1,063,000/.,,.,.. 6 6 hydroxyurea 1.0 2.

Histology of a skin biopsy specimen from the border of a hydrxyurea- induced ulcer.

3 Sang Yeop Lee, et al : Lower leg ulcers associated with long- term hydroxyurea therapy Figure 2A Figure 2B Figure 2. Ulceration on the both lateral malleolus of a patient receiving hydroxyurea therapy because of essential thrombocythemia., hydroxyurea cytarabine 200 mg/d ,063,000/.,,., hydroxyurea g/d (Figure 2). 1,194,000/, 1 1 cm, 4 2 cm.. Hydroxyurea. 2,487,000/ Figure 3. Histology of a skin biopsy specimen from the border of a hydrxyurea- induced ulcer. Bed of ulcer shows a few necrotic keratinocytes, polymorphous inflammatory cell infiltrate.(hematoxylin- eosin stain; 100) g/d 1. Hydroxyurea 1860 Dressler Stein )

4 : ). 48 DNA. Hydroxyurea RNA ribonucleotide reductase DNA. Ribonucleotide reductase ribonucleotide deoxyribonucleotide M1 M2 2. Hydroxyurea M2 tyrosyl free radical ribonucleotide reductase S- 1-3). Leavell Yarbro24) hydroxyurea DNA Klem25) hydroxyurea DNA thymidine. Hydroxyurea,, g/d 4-6)., 7), 8, 9), 10).. 2 5,,..,,,,,,,,,, 2). hydroxyurea,,,,, 2, 11-14) 15-21) Kennedy 11) hydroxyurea Montefusco 15) hydroxyurea (8.5%) hydroxyurea hydroxyurea. Nguyen 16) 1 hydroxyurea 4 hydroxyurea. Best 18) 2 15 hydroxyurea (64%).,,, Kato 21) 9 hydroxyurea g/d 17 37,,,,,.. 15, 21) (Figure 3). hydroxyurea.,,, 18). 15, 21). hydroxyurea. hydroxyurea, (cytocidal) (cytostatic). (hyperviscosity) (livedoid vasculitis)

5 5 : hydroxyurea 2 26, 27). hydroxyurea., hydroxyurea. hydroxyurea hydroxyurea 1.0 g. hydroxyurea. hydroxyurea 1 g 1 2.,,,,,. hydroxyurea.,,,,,. Hydroxyurea hydroxyurea. hydroxyurea hydroxyurea. RE F E R E N C E S 1) Young CW, Schochetman G, Karnowski DA. Hydroxyurea- induced inhibition of deoxyribonucleotide synthesis. Cancer Res 27: , ) Boyd AS, Neldner KH. Hydroxyurea therapy. J Am Acad Dermatol 25: , ) Yarbro JW. M echanism of action of hydroxyurea. Semin Oncol 19(3 Suppl 9):1-10, ) Kennedy BJ. Hydroxyurea therapy in chronic myelogenous leukemia. Cancer 29: , ) Cortelazzo S, Finazzi G, Ruggeri M, Vestri O, Galli M, Rodeghiero F, Barbui T. Hydroxyuea for patients with essential thrombocythemia and high risk of thrombosis. N Engl J M ed 332: , ) Sharon R, Tatarsky I, Ben- Arieh Y. T reatment of polycythemia vera with hydroxyurea. Cancer 57: , ) Willbanks OL, Fogelman MJ. Gastrointestinal melanosarcoma. Am J Surg 120: , ) Moschella SL. Chemotherapy of psoriasis: ten years of experiance. Int J Dermatol 15: , ) Layton AM, Sheehan- Dare RA, Goodfield MJD, Cotterill JA. Hydroxyurea in the management of therapy resistant psoriasis. Br J Dermatol 121: , ) Goldberg MA, Brugnara C, Dover GJ, Schapira L, Charache S, Bunn HF. T reatment of sickle cell anemia with hydroxyurea and erythropoietin. N Engl J M ed 323: , ) Kennedy BJ, Smith LR, Goltz RW. Skin changes secondary to hydroxyurea therapy. A rch Dermatol 111: , ) Renfro L, Kamino H, Raphael B, Moy J, Sanchez M. Ulcerative lichen planus- like dermatitis associated with hydroxyurea. J Am A cad Dermatol 24: , ) Daoud MS, Gibson LE, Pittelknow MR. Hydroxyurea dermopathy. A unique lichenoid eruption complicating long- term therapy with hydroxyurea. J Am Acad Dermatol 36: , ) Radaelli F, Calori R, Faccini P, Maiolo AT. Early cutaneous lesions secondary to hydroxyurea therapy. Am J Hematol 58:82-83, ) Montefusco E, Alimena G, Gastaldi R, Carlesimo OA, Valesini G, Madelli F. Unusual dermatologic toxicity of long term therapy with hydroxyurea in chronic myelogenous leukemia. T umori 72: , ) Nguyen T V, Margolis DJ. Hydroxyurea and lower leg ulcers. Cutis 52: , ) Cox C, Nowicki D, Young R. Hydroxyurea- related

6 Korean Journal of Medicine : Vol. 59, No. 4, 2000 ankle ulcers in patients with myelopro liferative disorders: A case report and review of the literature. Ann Plast Surg 39: , ) Best PJ, Daoud MS, Pittelkow MR, Petitt RM. Hydroxyurea- induced leg ulceration in 14 patients. Ann Intern M ed 128:29-32, ) Wirth K, Schoepf E, Mertelsmann R, Lindemann A. Leg ulceration with thrombocytosis : healing of ulceration associated with treatment of the raised platelet count. B r J Dermatol 138: , ) Weinlich G, Schuler G, Greil R, Kofler H, Fritsch P. Leg ulcers associated with long term hydroxyurea therapy. J Am Acad Dermatol 39: , ) Kato N, Kimura K, Yasukawa K, Yoshida K. Hydroxyurea- related leg ulcer in patient with chronic myelogenous leukemia: A case report and review of the literature. J Dermatol 26:56-62, ) Reilly HC, Falco E, Myron SA, Philips FS, Stock CC. Sarcoma 180 screening data. Cancer Res 23: , ) Rosten M. Hydroxyurea: A new antimetabolite in the treatment for psoriasis. Br J Dermatol 85: , ) Leavell UW, Yarbro JW. T reatment of psoriasis by hydroxyurea. South M ed J 64: ) Klem EB. Effect of antipsoriasis drugs and metabolic inhibitors on the growth of epidermal cells in culture. J Invest Dermatol 70:27-32, ) Stevens DM, Shupack CB, Javid J, Silber R. Ulcers of the leg in thalassemia. Arch Dermatol 113: , ) Rustin MH, Bunker CB, Dowd PM. Chronic leg ulceration with livedoid vasculitis and response to oral ketanserin. Br J Dermatol 120: ,

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract