Frederick D. Malkinson

Sulfone therapy in the treatment of leukocytoclastic vasculitis: Report of three cases

Dapsone therapy for leukocytoclastic (necrotizing) vasculitis has been little used, except for the variant forms of erythema elevatum diutinum and urticarial vasculitis. We report three patients with the common (palpable purpura) form of the disease, limited to the skin, and successfully treated with moderate doses of dapsone (100-150 mg daily). Although the natural course of leukocytoclastic vasculitis is highly unpredictable, the prompt disappearance of new lesion formation after initiation of treatment and the rapid recurrence of lesions after therapy is discontinued (both often within 4 to 8 days after the critical dose level is reached) reflect drug efficacy. We believe that dapsone deserves wider evaluation as a therapeutic agent for chronic or recurrent cases of the common form of leukocytoclastic vasculitis.

Topical or Systemic 16,16 Dm Prostaglandin E2 or WR-2721 (WR-1065) Protects Mice from Alopecia after Fractionated Irradiation

Our previous studies in mice demonstrated that systemic or topical 16,16 dm PGE2 protected against single dose radiation-induced hair loss. We have now investigated prostaglandin, or WR-2721, protection against murine alopecia produced by varying doses and schedules of fractionated radiation. On days one to eight after hair was plucked from the thighs of B6D2F1 mice, groups of 6 animals each were given daily exposures of 4.0 or 4.5 Gy for 5 days; 2.5, 3.5, 4.5 or 5.5 Gy for 10 days; or 2 Gy for 15 days. One hour before irradiation each mouse received 10 microgram 16,16 dm PGE2, either by subcutaneous injection into the neck or topical application, 8 mg WR-2721 by injection, or 0.3 mg WR-1065 by topical application. Three weeks later counts of regrowing hairs were recorded from excised skin samples. For the radioprotectors used, hair regrowth was increased 25-100% in the various radiation groups in comparison to irradiated-only control sites. In some studies with the radioprotector given systemically, WR-2721 afforded slightly greater radioprotection than 16,16 dm PGE2. The two compounds were essentially equally radioprotective in the topical application studies. Since both systemic and topical applications of the agents tested enhanced hair regrowth following radiation, we conclude that clinical use of these compounds may provide some protection of hair follicles, and perhaps other tissues, lying within a radiation therapy field.

Ionizing radiation induces early, sustained increases in collagen biosynthesis: a 48-week study in mouse skin and skin fibroblast cultures.

Groups of 10 CF1 female mice, irradiated to the thorax with a dual-head 137Cs gamma-RAY source, received single doses of 0, 5, 10, 15, or 25 Gy. One to forty-eight weeks later collagen synthesis was measured in minced skin specimens incubated in medium containing [3H]proline and then assayed for radioactive hydroxyproline. A progressive, generally dose-dependent increase in collagen biosynthesis, up to 50% above control sites, was found 1, 4, and 12 weeks after radiation exposure. These changes showed further small fluctuations at 12-36 weeks, increasing again at the 48-week interval. At the same times throughout the study fibroblasts were cultured from skin explants. Following the second subculture, these cells were also incubated in medium containing [3H]proline, and collagen synthesis was again determined by [3H]hydroxyproline assay. At all radiation dose levels studied, collagen production increased threefold by 12 weeks postradiation and remained elevated for the 48-week duration of the study. In vitro radiation dose response differences were not observed.

EFFECTS OF HYDROXYUREA AND RADIATION ON HAIR MATRIX CELLS

Investigations were undertaken in CF1 mice to study the effects of hydroxyurea (HU) on hair matrix cell kinetics, and to assess the effects of combined administration of HU and irradiation on induction of temporary alopecia. HU 100 mg/kg was administered intraperitoneally and each animal received tritiated thymidine 0·5 μCi/g 30 min before biopsy. Serial biopsies were taken up to 48 hr after drug administration. Autoradiographs of anagen follicle squashes revealed sharp reductions in mitotic and labeling indices within 30 min. Depressed mitotic indices of 0·6–0·9% at 1–4 hr returned to normal (2·3%) after 6 hr, followed by cyclic mitotic ‘overshoot’, and were preceded by parallel changes in the labeling indices. HU‐induced cellular damage was most marked 4 hr after HU injection, with almost complete recovery from injury observed at the 24 hr interval.

RADIATION INJURY AND RECOVERY IN ANAGEN AND TELOGEN RODENT HAIRS.

Reduced incorporation of isotope-labeled compounds was studied to assess postirradiation damage and recovery in growing (anagen) and resting (telogen) rodent hairs. Reduced uptake of

MODIFICATION OF RADIATION RESPONSES OF TISSUE BY COLCHICINE

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Radiobiology of the Skin

Several recent reviews have described the effects of various chemical and physical agents in modifying radiation responses in normal tissues and tumors (1–3) . The observation that irradiation induces profound morphologic changes in animal and human hairs (4, 5) has provided a useful experimental device for the screening of such agents in rodents (6). At any given time areas of skin in rats and mice can be found in which most of the hair follicles are in the resting phase of the hair cycle. These telogen hair follicles are mitotically inactive and are insensitive to radiation (4). If the resting hair is disturbed by plucking, its follicle becomes active and a growing (anagen) hair is formed which is highly radiosensitive. When anagen hairs are irradiated, dysplastic changes in the shafts and atrophy of the bulbs occur, the number of hairs affected being proportionate to the dose of radiation sustained. Recent experiments in rats and mice have shown that anagen hairs also undergo profound atrophic and dysp...

Cysteamine protection of x-ray-induced dysplasia in mouse hair.

This chapter reviews the general effects of ionizing radiation at the cellular level, radiobiological reactions in the skin, and many of the specific changes induced by ionizing radiation in the various cellular components of the skin. The principal features of radioprotection and radiosensitization, as well as some specific agents that induce these efffects, are discussed. The investigative use of proliferative and nonproliferative hair cell populations as biological indicator systems to help elucidate the more universal cellular efffects of radiation alone, or combined with certain pharmacologic, physical, or biological agents, is stressed.

PERSISTENT IMPAIRMENT OF HAIR GROWTH AFTER SINGLE LARGE DOSES OF X-RAYS.

Cysteamine reduces the incidence of radiation-induced dysplasia in the growing hairs of mice. The dose reduction factor of about 1.5 is comparable to the protection afforded by cysteamine in other radiobiological studies. The administration of cysteamine immediately after x ray exposure results in slightly increased hair dysplasia. (auth)

Perspectives: Panel Discussion

Telogen mouse hairs treated with single doses of 2000 to 2500 rads showed persistent impairment of postirradiation growth as measured by determinations of overall hair length. Reductions in length of surviving hairs, compared to contralateral controls, averaged 27% for the hairs newly grown postirradiation. Subsequent hair generations showed no significant recovery: reductions in length of hairs from the same treatment sites averaged 33% 10 months after irradiation. Cyclic regrowth of hair in these areas was also unusually slow: after plucking, hair density was not fully restored in irradiated areas for 4 weeks or longer in contrast to the normal replacement time of 2 1/2 weeks observed in plucked control sites. This change was demonstrable up to 14 months postirradiation. Exposure of telogen hairs to a somewhat smaller dose of 1500 rads resulted in a 12% reduction of length in the generation of hairs growing immediately postirradiation, followed by complete recovery in the subsequent cycle of hair growth...