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Drugs used on the skin
J.P. Nater and A.C. de Groot
15
Drugs used on the skin
ANTIPSORIATIC AGENTS
PUVA therapy, skin carcinomata and mutagenicity
Retinoic acid (Tretinoin) Retinoic acid may enhance the cancerinducing effects of the sun on the skin, according to preliminary results of a study in animals. Although the t u m o u r findings are only preliminary, they are of such concern that the American Academy of Dermatology, in a letter to its members, has advised them that patients being treated with this drug should minimize their exposure to sunlight or UV lamps. In addition patients who have a family history of sunlight-induced skin cancer or who show an unusual susceptibility to skin damage from sunlight should be particularly cautious when using retinoic acid (1R). Retinoic acid Ro 1 0 - 9 3 5 9 (Tigason) was administered orally to a group of 32 psoriatic patients. The following side effects were noted (2c): Scaling of palms and hands, thinning of the skin, itching, warm sensation, cheilitis, sweating, dryness of mucosa. Alopecia (noticed in 10 patients and prevailing in females), onychocryptosis (five cases) and onychomadesis (four cases) tend to appear suddenly; these complications thereafter run a chronic course and are a source of worry to the patient but if treatment is withdrawn they prove to be reversible.
Methotrexate A review of 248 patients with psoriasis who had been treated with methotrexate for periods of 1 - 9 years in doses up to 25 mg weekly (3 c ) has shown that in 69% of this group side effects were noted, principally nausea, fatigue, oral blisters, stomach ache, headache and vomiting (all >10%). There was no evidence of nephrotoxicity. Basal pulmonary infiltrates developed in six patients. Post-treatment liver biopsies showed fibrosis/cirrhosis in +_ 9% of the patients.
In April 1979 Stern et al. (4 C) published in the United States a 2.1-year prospective study o f 1 3 7 3 patients who had been given oral 8-methoxypsoralen p h o t o c h e m o t h e r a p y for psoriasis. The study revealed 30 patient5 with skin carcinomata - 12 having basal celi carcinoma, 15 s q u a m o u s cell carcinoma and 3 both types. The observed incidence oJ cutaneous carcinoma was 2. 63 times that expected for an age, sex and geographically m a t c h e d population. The relative risk to patients with a history o f ionizing radiation was 3. 63. Patients with a previous cutaneous carcinoma had a relative risk o f 10.22. A higher than e x p e c t e d proportion o f squam o u s cell carcinomas and an excess o f squam o u s cell carcinomas in areas n o t exposed to sun were seen. The authors o f this study concluded that 'new patients with k n o w n histories o f ionizing-radiation exposure or o f skin tumours should be given 8-methoxypsoralen photoc h e m o t h e r a p y only i f they understand the risks and have disabling psoriasis untreatable by other means.' The possibility that P U V A treatment might prove to be carcinogenic has been a source o f concern for s o m e time (SEDA-3, 133), especially in the case o f patients who have earlier been treated for their skin condition with k n o w n carcinogens; S E D A - 2 (p. 134) drew attention to a case in which multiple basal cell carcinoma developed following P U V A treatment but with a prior history o f arsenic treatment for vitiligo. In an editorial c o m m e n t a r y on Stern's report, Epstein (45 R ) has emphasized s o m e particular aspects o f the m o s t recent findings: 'Stern and his colleagues observed a reversal to the ratio o f squamous cell carcinomas to basal cell carcinomas, squamous cell carcinomas becoming relatively more frequent and occurring on parts o f the body not usually exposed to the sun. The sun is primarily stimulus of skin cancer in Caucasians.
105
Drugs used on the skin Thus the reversal o f the ratio o f the alteration o f anatomic distribution strongly supports the role o f photoehemotherapy in the causation o f these cancers. How may we compare this problem with those presented by treatment with coal tar and shortrange ultraviolet radiation? Both coal tar and ultraviolet radiation in the short range are carcinogenic. However, they have not resulted in noteworthy skin cancer formation despite usage for over 50years. In contrast, psoralens are non-carcinogenic, and long-range ultraviolet radiation is a weak carcinogen, i f carcinogenic at all. Combination treatment with oral psoralens and long-range radiation had not resulted in tumour formation in laboratory animals. However, the topical and intraperitoneal administration o f psoralens, followed by long-range radiation, does produce cutaneous cancer in animals. The problem may reside in the fact that the majority o f patients require maintenance psoralen photochemotherapy at relatively short intervals, since relapses commonly occur soon after cessation o f treatment. In contrast, coal tar and short-range ultraviolet radiation are usually used for short periods separated by long intervals. Stern et al. note that patients who have received ionizing radiation or who have already had skin cancers are at even greater risk. Since these patients generally have extensive psoriasis, the previous use o f coal tar and short-range radiation, corticosteroids and anti-metaboHtes may also be a factor, although Stern et al. did not find a relation with these other therapeutic factors.' In the m e a n t i m e , discussion as to a n o t h e r p o t e n t i a l risk o f P U V A t r e a t m e n t , n a m e l y m u t a g e n i c i t y , has c o n t i n u e d . Bridges (46 R ) has p u t the q u e s t i o n as to w h e t h e r o n e s h o u l d use a c y t o t o x i c a n d g e n o t o x i c c o m b i n a t i o n o f d r u g a n d radiation w h e n the condition being treated is n o t malignant. The evid e n c e t h a t psoralens react with D N A in the p r e s e n c e o f ultraviolet light is n o w overwhelming, a n d P U V A can be regarded as an established carcinogen a t least in animals. P U V A , as this a u t h o r p o i n t s out, has been associated with DATA damage in l y m p h o cytes, b u t gene m u t a t i o n s have also been f o u n d in p a t i e n t s n o t so treated, w h i c h suggests either t h a t psoriasis i t s e l f p r e d i s p o s e s to m u t a t i o n s or, more likely, that o t h e r t r e a t m e n t s which may have been given are also mutagenic. In this latter respect, Bridges p o i n t s o u t that 'one s h o u l d t h i n k hard bef o r e preven ring the u tiliza tion o f a po ten tially h a z a r d o u s t h e r a p e u t i c regimen s i m p l y because the risk f r o m its c o m p e t i t o r s has been less well investigated and d e f i n e d . ' I t m a y be borne in m i n d in this connection t h a t c h r o m o s o m a l a b n o r m a l i t i e s were
also p r e s e n t in the case r e p o r t e d b y Wagner (5 r see below). A l t h o u g h f u r t h e r e v i d e n c e b o t h on carcin o g e n i e i t y and m u t a g e n i e i t y is certain to emerge, the data c u r r e n t l y available underline o n c e m o r e the n e e d f o r caution a n d reticence in the use o f this t r e a t m e n t . I t s h o u l d be used o n l y in a l i m i t e d n u m b e r o f centres f r o m which p a t i e n t s can be carefully c o n t r o l l e d a n d f o l l o w e d u p ; f o r the p r e s e n t this t r e a t m e n t s h o u l d c o n t i n u e to be regarded as e x p e r i m e n t a l .
PUVA: other effects Preleukaemia A psoriatic patient treated with PUVA for 30 weeks developed refractory anaemia which required several blood transfusions. The bone marrow showed an excess of myeloblasts, abnormal chromosomes and abnormal culture growth on agar. The development of this condition known as preleukaemia may be coincidental. The suspicion of a causal relationship with psoralen can only be supported with future observations (5c).
Bullous eruptions Subepidermal bullae have been noted, not infrequently, in psoriasis patients undergoing PUVA or Goeckermann therapy. The exact pathogenesis is unknown. In a recent study among 24 psoriatic patients treated with PUVA, five developed buUae (6c). Direct and indirect immunofluorescence studies supported the diagnosis of buUous pemphigoid in one patient. In the others, the blisters were a p h o t o t o x i c acral eruption. Granuloma annulare The aetiology and pathogenesis of annular granulorna is as yet unknown. Dorval e t al. (7 c ) have reported a case in which typical granuloma developed in a psoriatic patient during PUVA treatment and the authors try (somewhat unconvincingly) to'associate these findings. Nail pigmentation Four patients are reported to have developed nail pigmentation while on oral 8-methoxypsoralen therapy for vitiligo (8c). Although other possible causes for this phenomenon were not excluded, the authors believe it to be attributable to 8-MOP. Photo-onycholysis Photo-onycholysis caused by tetracyclines is well known. Cases pro-
106 yoked by oral 8-MOP in combination with UVA radiation are less well known, but cases have been reported by Orlonne and Baran (9c), Rau et al. (10 c) and Zala et al. ( l l e ) . Freckling In three patients undergoing systemic p h o t o c h e m o t h e r a p y with 8-MOP a profuse freckling of the skin was observed ( 12 c).
LOCAL ANAESTHETICS
Lidocaine Contact allergy to hdocaine seems to be rare and only few reports have been published (3 c, 1 4 c - 1 6 c ) . ' R e c e n t l y Fregert e t al. (17 c ) have described two cases in which a patch test to lidocaine 1% in water gave positive reactions. These patients also reacted to chemically-related anaesthetics of the amide type (one to bupivacaine, mepivacaine and prilocaine and the other to mepivacaine only). Patch tests with 1% cinchocaine in water gave positive reactions in both cases. As this compound is a chemically non-related anaesthetic of the ester type, however, cross-sensitivity was considered to be unlikely. 6-Methylcoumarin 6-Methylcoumarin is a synthetic fragrance widely used in cosmetics. A case of severe photocontact allergic reactions developing after application of two sunscreens has been reported (18 c).
J. P. Nater and A. C. de Groot
Oxyphenbutazone Oxyphenbutazone is a h y d r o x y l a t e d metabolite of phenylbutazone and is regarded as its active product (24c). A case of contact sensitivity to Tanderil cream (oxyphenbutazone) with cross-sensitivity to Butazolidine (phenylbutazone) has been reported by Krook (25c). Patch tests were performed in a concentration of 1% in petrolatum. The same author observed two cases of contact sensitivity to phenylbutazone without cross-sensitivity to oxyphenbutazone and concludes that oxyphenbutazone may induce cross-sensitivity to phenylbutazone, but phenylbutazone does not induce cross-sensitivity to oxyphenbutazone. Vooys and van K e t e l ( 2 4 C) support this conclusion, although in their patient who reacted both to oxyphenbutazone and phenylbutazone, primary sensitization to oxyphenbutazone could not be ascertained.
Phenylbutazone Contact sensitivity to phenylbutazone has been observed by several author s (21 c, 25 c, 26c). Positive patch tests to phenylbutazone were obtained with 0.5%, 1% and 5% in petrolatum. In no instance where oxyphenbutazone was also tested (23 c, 25 c) was cross-sensitivity observed (see also oxyphenbutazone). MISCELLANEOUS AGENTS
ANTIRHEUMATIC DRUGS The topical use of anti-inflammatory and antirheumatic agents on the skin is increasing. Some of the more widely used are bufexamac (p-butoxyphenylacetohydroxamic acid), oxyphenbutazone and phenylbutazone.
Bufexamac p-Butoxyphenylacetohydroxamic acid is a non-steroid anti-inflammatory agent. Several cases of contact allergy to this drug have been described ( 1 9 c - 2 3 c ) . Patch tests are performed with bufexamac 5% in petrolatum.
Mechloretharnine hydrochloride (nitrogen mustard, chlormethine) In two patients with mycosis fungoides multiple cutaneous squamous cell carcinomas were observed by Kravitz and McDonald (27c). They strongly believe that in their patients long-term application of topical nitrogen mustard could be held responsible for the development of these malignancies. However, both patients had previously had other local therapy and systemic chemotherapy, and the authors admit that predisposing or cumulative effects of this treatment cannot be discounted. An increased frequency of actinic keratoses and squamous cell carcinomas in patients with mycosis fungoides was also observed
107
Drugs used on the skin
by Vonderheid (28 C) and the question was raised whether topical nitrogen mustard could have augmented pre-carcinogenic solar damage. Du Vivier et al.(29 C) found the prevalence of epithelial cancer in 202 patients with mycosis fungoides and the S~zary syndrome to be 10.5%. In about 60% of these, the malignancies developed de novo after nitrogen mustard therapy. According to the authors the findings indicate that nitrogen mustard may function as a carcinogen or a co-carcinogen.
Suppression of contact sensitivity to nitrogen mustard Contact dermatitis as a complication of topical treatment with nitrogen mustard is well known. In five cases of mycosis fungoides the contact sensitivity to nitrogen mustard diminished during treatment with PUVA (30c). The possibility of a spontaneous diminution has to be considered, but the authors of this paper claim (from unpublished observations) that an unchanged reactivity has been observed in cases not treated with PUVA.
in a pharmaceutical firm who developed eczema when working with the substance. Positive patch tests with an aqueous solution of alprenolol in the dilutions 10, 5, 2.5 and 1.25 mg/ml were found. Two of the patients showed a cross-sensitivity to metroprolol. In some individuals complaining of conjunctivitis, rhinitis or asthmalike symptoms intradermal skin tests were carried out, with negative results. These symptoms were not considered to be allergic in nature. Allergic contact dermatitis does not seem to have been recorded in patients or hospital staff handling commercially available alprenolol tablets or injections.
Clioquinol Allergic contact dermatitis to clioquinol was reviewed in SED 8 ( 2 7 6 , 2 8 3 - 1 8 7 ) . The local application may also cause primary irritant dermatitis. According to Kero et al. (44 C) the concentration of clioquinol is the main factor in such a reaction. The crystal size did not affect the appearance of irritant dermatitis.
Silver sulphadiazine VEHICLES In a series of 314 burn injury patients treated with silver sulphadiazine the incidence of drug reactions was 1.3% (43c). In another group of 156 patients who had been treated with maphenide (sulphamyIon) the incidence of drug reactions was, according to this same author, 5.1%.
Dinitrochlorobenzene (see also p. 108) 2,4-Dinitrochlorobenzene (DNCB), a potent sensitizer, is widely used for testing cell-mediated i m m u n i t y in patients with malignant diseases (31R). Recently DNCB has been used for treating patients with alopecia areata(32c). In some patients with grey hair, a yellow discolouration of the hair was noticed after repeated application of DNCB.
Alprenolol Contact eczema produced by alpreno1ol, a beta-adrenergic blocking agent, has been reported by Ekenvall and Forsbeck(33C). They described 14employees
Petrolatum Grimalt and Romaguera (34 c) have described a psoriatic patient in whom treatment with salicylic acid 3% in petrolatum provoked an eczematous and exudative reaction at all the sites treated. Patch tests with standard allergens gave positive reactions to all tests, with the exception of turpentine, bisphenol A and creosote, the vehicle for which was lanette wax. For the other allergens the vehicle was yellow soft paraffin. Patch tests with pure white and yellow soft paraffin showed strongly positive reactions to both.
SYSTEMIC REACTIONS Untoward systemic reactions to topically applied medicaments are reviewed at length in SED 9. Two types of adverse systemic reactions have been observed: (a) immediate hypersensitivity reactions, and (b) toxic effects.
108 Immediate hypersensitivity reactions have been reported after topical application of mechlorethamine hydrochloride (35R), neomycin sulphate (36C), bacitracin (37c), penicillin (38 c ) and Milian's solution (39c). The literature on this subject was recently reviewed by Pascher (40g). Recent reports of toxic effects to systemically used podophyllin and silver sulphadiazine are discussed below.
Podophyllin Absorption of podophyllum resin may lead to severe peripheral neuropathy, acute confusional states, vomiting, coma and death (SEDVIII, 341). Recently Stoehr et al. (41 c ) have described a case in which absorption of podophyllin led to bone marrow depression with leukopenia and thrombopenia. A 15-year-old girl was painted with podophyllin 20% in benzoin tincture over the entire perineal area because of condylomata acuminata. Soon afterwards the patient complained of dizziness, nausea, vomiting and right-sided abdominal pain. The treatment was repeated the next morning and afternoon. Afterwards, she was noted to be lethargic. The next morning she had tachycardia (130/min.), fever (38~ and tachypnoea (40/min.), and shortly afterwards she was in pre-coma. Neurological findings were normal except for her mental status. Serum enzyme values were greatly elevated (SGOT 220 IU; LDH 2184 IU; CPK 3850 IU; AF 262 IU). The patient improved clinically during the next two days. Four days after the initial dose of podophyllin a marked decrease in leukocyte and platelet count was noted. Leukocyte count was 900/mm 3 (on admission 8000]mm 3) on the fifth day and platelet count 3750 mm 3 on the 10th day (platelet count not available on admission, 73,600 on the 14th day after the initial dose of podophyllin). The granulocytopenia and thrombocytopenia were attributed to the marrow toxicity of podophyllin; the marrow aspirate was in accordance with this hypothesis.
Silver sulphadiazine Transient leukopenia following application of silver sulphadiazine cream in nine patients with thermal injury has been reported (42c). The maximum depression of the white blood cell count occurred on the second or third day after the burn and ranged from 3100 to 3500/mm 3. White blood counts on admission had ranged from 6500 to 37,600/mm a . In four patients silver sul-
J. P. Nater and A. C. de Groot
phadiazine application was discontinued because of the development of leukopenia. In each instance the white blood cell count returned to within normal limits within 4 8 - 7 2 hours. In five other patients the leukocyte count also returned to within normal limits within two or three days despite continuation of the drug. As other causes for neutropenia had not been excluded and the study was uncontrolled, the causal relationship between silver sulphadiazine and neutropenia cannot be considered to have been convincingly demonstrated by these cases.
N o t e added in p r o o f
2,4-Dinitrochlorobenzene (DNCB) Nineteen patients suffering from atopecia areata were treated weekly on the head with solutions of DNCB (acetone) in concentrations ranging from 0.01 to 1% by de G r o o t et al. (47c). The following side effects were noted: itching (19), dermatitis of the trunk and extremities (3), pompholyx (1), spreading dermatitis (1), secondary infection (2), painful lymph nodes (3) and oedema of the face and the neck (2). One patient complained of headache lasting three days after the application of DNCB and another of hypersalivation immediately following treatment. In a female patient, the clinical picture of contact dermatitis to a pair of her shoes developed during treatment; the responsible allergen could not be demonstrated. In seven of 19 patients a contact allergy to cignoline (dithranol), which was used concomitantly as an alternative treatment, developed during the trial. Similar observations concerning side effects caused by DNCB-applications were made by de Prost e t al. (48c). In addition to generalized dermatitis, lymphadenopathy, oedema and pompholyx, they noted an urticarial exanthema in two out of 16 patients and general symptoms including fever, arthralgia and insomnia in three patients. In one patient the development of contact allergy to nickel during DNCB treatment was recorded; this, together with the observations of de Groot e t al. mentioned above, indicates that this therapeutic regime may predispose patients to the development of o t h e r contact allergies.
Drugs used on the skin REFERENCES
1. FDA Bulletin (1978): Retinoic acid and sun caused skin cancer. August-September, 26. 2. Viglioglia, P. A. and Barclay, A. (1978): Oral retinoids and psoriasis. Dermatologica (Basel), 157/Suppl. 1, 32. 3. Nyfors, A. (1978): Benefits and adverse drug experiences during long-term methotrexate treatment of 248 psoriatics. Dan. reed. Bull., 25,208. 4. Stern, R.S., Thibudeau, L.A., Kleinerman, R. A., Parrish, J. A. and Fitzpatrick, Th. B. (1979): Risk of cutaneous carcinoma in patients treated with oral methoxsalen photochemotherapy for psoriasis. New Engl. J. Med., 300, 809. 5. Wagner, J., Manthorpe, R., Philip, P. and Frost, F. (1978): Preleukemia (haemopoietic dysplasia) developing in a patient with psoriasis treated with 8-methoxypsoralen and ultraviolet light. Scand. J. Haematol., 21,299. 6. Robinson, J.K., Baughman, R.D. and Provost, T. T. (1975): Bullous pemphigoid induced by Puva therapy. Brit. J. Derm., 99, 709. 7. Dorval, J.C., Leroy, J.P. and Mass~, R. (1979): Granulomes annulaires diss~min~s apr~s Puva th6rapie. Ann. Derm. Venereol. (Paris), 106, 79. 8. Naik, R. P. C. and Singh, G. (1979): Nail pigmentation due to oral 8-methoxypsoralen. Brit. J. Derm., 100, 229. 9. Orlonne, J.P. and Baran, R. (1978): Photoonycholyse induite par la photochimioth~rapie orale. Ann. Derm. Venereol. (Paris), 105, 887. 10. Rau, R.C., Flowers, F.P. and Barrett, J. L. (1978): Photo-onycholysis secondary to psoralen use. Arch. Derm., 114, 448. 11. Zala, L., Omar, A. and Krebs, A. (1977): Photo-onycholysis induced by 8-methoxypsoralen. Dermatologica (Basel), 154,203. 12. Bleehen, S.S. (1978): Freckles induced by Puva treatment. Brit. J. Derm., 99/Suppl. 16, 20. 13. Burry, J. H., Kirk, J., Reid, J.C. and Turner, T. (1973): Environmental dermatitis: Patch tests in 1,000 cases of allergic contact dermatitis. Med. J. Aust., 2, 681. 14. Wozniak, K.D. and L~ibbe, D. (1974): Zur Diagnostik yon Arzneimittel. Intoleranzreaktionen der Haut. Derm. Mschr., 160,451. 15. Roed-Petersen, J. (1976): Contact sensitivity to metaoxedrine. Contact Dermatitis, 2, 235. 16. Turner, T. W. (1977): Contact dermatitis to lignocaine. Contact Dermatitis, 3, 210. 17. Fregert, S., Tegner, E. and Trelin, I. (1979): Contact allergy to lidocaine. Contact Dermatitis, 5, 185. 18. Kaidbey, K. H. and Kligman, A. D. (1978): Contact photo allergy to 6-methylcoumarin in proprietary sunscreens. Arch. Derm., 114, 1709. 19. Smeenk, G. (1973): Contact allergy to bufexamac. Dermatologica {Basel}, 14 7, 334. 20. Sneddon, I. B. (1974): Contact dermatitis to bufexamac (Parfenac). Contact Dermatitis Newsletter, No. 16, 519.
10 ~) 21. Lachapelle, J. M. (1975): Contact sensitivity to bufexamac. Contact Dermatitis, 1, 261. 22. Van Hecke, E. (1973): Allergy to bufexamac. Arch. belg. Dermatol., 29, 301. 23. Meneghini, C.L. and Angelini, G. (1979~. Contact allergy to antirlleumatic drug.~. CoJztact Dermatitis, 5, 197. 24. Vooys, R. C. and van Ketel, W. G. (1977): Allergic drug eruption from pyrazohme compounds. Contact Dermatitis, 3, 57. 25. Krook, G. (1975): Contact sensitivity to ox,.~phenbutazone (Tanderil) and cross-sensitivity to phenylbutazone (Butazolidine). Contact Dermatitis, 1,385. 26. Thormann, J. and Kaaber, K. (1978): Contact sensitivity to phenylbutazone ointment (Buh~z~lidine). Contact Dermatitis, 4,235. 27. Kravitz, P.H. and McDonald, C.J. (t978): Topical nitrogen mustard induced carcinogenesis. Acta derm.-venereol. (Stockh.), 58, 421. 28. Vonderheid, E.C., van Scott, E. J., Johnson, W.C., Grekin, D.A. and Asbelt, S.O. (1977): Topical chemotherapy and immunotherapy of mycosis fungoides. Arch. Derm., 113, 459. 29. Du Vivier, A., Vonderheid, E.C., van Scott, E. J. and Urbach, F. (1978): Mycosis fungoides, nitrogen mustard and skin cancer. Brit. J. Derm., 99, 61. 30. Volden, G., Molen, C. and Thomse, K. (1978): Puva-induced suppression of contact sensitivity to mustine hydrochloride in mycosis fungoides. Brit. meal. J., 3, 865. 31. Bleumink, E., Nater, J.P., Schraffordt Koops, H. and The, T. H. (1974): A standard method for DNCB sensitization testing in patients with neoplasms. Cancer, 33, 911. 32. Happle, R., Cebulla, K. and EchternachtHapple, K. (1978): Dinitrochlorobenzene therapy for alopecia areata. Arch. Derm., 114, 1629. 33. Ekenvall, L. and Forsbeck, M. (1978): Contact eczema produced by a beta-adrenergic blocking agent (alprenolol). Contact Dermatitis, 4, 190. 34. Grimalt, F. and Romaguera, C. (1978): Sensitivity to petrolatum. Contact Dermatitis, 4, 377. 35. Daughters, D., Zackheim, H. and Maibach, H. (1973): Urticaria and anaphylactoid reactions. Arch. Derm., 107, 429. 36. Pippen, R. (1966): Anaphylactic reaction after chymacort ointment. Brit. reed. J., 1, 1176. 37. Roupe, G. and Stannegard, O. (1969): Anaphylactic shock elicited by topical administration of bacitracin. Arch. Derm., 100, 450. 38. Maucher, O.M. (1972): 'Anaphylaktische' Reaktionen beim Epicutantest. Hautarzt, 23, 109. 39. Francois, A., Henin, P., Carli Basset, C. and Ginies, G. (1970): Anaphylactic shock following application of Milian's solution. Bull. Soc. franf. Dermatol. Syphilol., 77, 834. 40. Pascher, F. (1978): Systemic reactions to topically applied drugs. Int. J. Derm., 1 7, 768.
110 41. Stoehr, G.P., Peterson, A.L. and Taylor, W. J. (1978): Systemic complications of local podophyllin therapy. Ann. intern. Med., 89, 362. 42. Jarrett, F., Ellerbe, S. and Demling, R. (1978): Acute leukopenia during topical burn therapy with silver sulfadiazine. Amer. J. Surg., 135, 818. 43. Pegg, S.P., Ramsay, K., Meldrum, L. and Laundy, M. (1979): Clinical comparison of maphenide silver sulphadiazine. Scand. J. Plast. Reconstr. Surg., 13, 95. 44. Kero, M., Hannuksela, M. and Sothman, A. (1979): Primary irritant dermatitis from topical clioquinol. Contact Dermatitis, 5, 115.
J. P. Nater and A. C. de Groot 45. Epstein, J. P. (1979): Risks and benefits of the treatment of psoriasis. New Engl. J. Med., 300, 852. 46. Bridges, B. A. (1978): PUVA and carcinogenicity. Clin. exp. Dermatol., 3, 349. 47. De Groot, A.C., Nater, J.P. and de Jong, M. C. J. M. (1979): De behandeling van alopecia areata met 2,4-dinitrochloorbenzeen (to be published). 48. De Prost, Y., Paquez, F.-R. and Touraine, R. (1979): Traitement de la pelade par applications locales de DNCB. Ann. Dermat.-V~ndreol. (Paris], 106,437.
15
Drugs used on the skin
ANTIPSORIATIC AGENTS
PUVA therapy, skin carcinomata and mutagenicity
Retinoic acid (Tretinoin) Retinoic acid may enhance the cancerinducing effects of the sun on the skin, according to preliminary results of a study in animals. Although the t u m o u r findings are only preliminary, they are of such concern that the American Academy of Dermatology, in a letter to its members, has advised them that patients being treated with this drug should minimize their exposure to sunlight or UV lamps. In addition patients who have a family history of sunlight-induced skin cancer or who show an unusual susceptibility to skin damage from sunlight should be particularly cautious when using retinoic acid (1R). Retinoic acid Ro 1 0 - 9 3 5 9 (Tigason) was administered orally to a group of 32 psoriatic patients. The following side effects were noted (2c): Scaling of palms and hands, thinning of the skin, itching, warm sensation, cheilitis, sweating, dryness of mucosa. Alopecia (noticed in 10 patients and prevailing in females), onychocryptosis (five cases) and onychomadesis (four cases) tend to appear suddenly; these complications thereafter run a chronic course and are a source of worry to the patient but if treatment is withdrawn they prove to be reversible.
Methotrexate A review of 248 patients with psoriasis who had been treated with methotrexate for periods of 1 - 9 years in doses up to 25 mg weekly (3 c ) has shown that in 69% of this group side effects were noted, principally nausea, fatigue, oral blisters, stomach ache, headache and vomiting (all >10%). There was no evidence of nephrotoxicity. Basal pulmonary infiltrates developed in six patients. Post-treatment liver biopsies showed fibrosis/cirrhosis in +_ 9% of the patients.
In April 1979 Stern et al. (4 C) published in the United States a 2.1-year prospective study o f 1 3 7 3 patients who had been given oral 8-methoxypsoralen p h o t o c h e m o t h e r a p y for psoriasis. The study revealed 30 patient5 with skin carcinomata - 12 having basal celi carcinoma, 15 s q u a m o u s cell carcinoma and 3 both types. The observed incidence oJ cutaneous carcinoma was 2. 63 times that expected for an age, sex and geographically m a t c h e d population. The relative risk to patients with a history o f ionizing radiation was 3. 63. Patients with a previous cutaneous carcinoma had a relative risk o f 10.22. A higher than e x p e c t e d proportion o f squam o u s cell carcinomas and an excess o f squam o u s cell carcinomas in areas n o t exposed to sun were seen. The authors o f this study concluded that 'new patients with k n o w n histories o f ionizing-radiation exposure or o f skin tumours should be given 8-methoxypsoralen photoc h e m o t h e r a p y only i f they understand the risks and have disabling psoriasis untreatable by other means.' The possibility that P U V A treatment might prove to be carcinogenic has been a source o f concern for s o m e time (SEDA-3, 133), especially in the case o f patients who have earlier been treated for their skin condition with k n o w n carcinogens; S E D A - 2 (p. 134) drew attention to a case in which multiple basal cell carcinoma developed following P U V A treatment but with a prior history o f arsenic treatment for vitiligo. In an editorial c o m m e n t a r y on Stern's report, Epstein (45 R ) has emphasized s o m e particular aspects o f the m o s t recent findings: 'Stern and his colleagues observed a reversal to the ratio o f squamous cell carcinomas to basal cell carcinomas, squamous cell carcinomas becoming relatively more frequent and occurring on parts o f the body not usually exposed to the sun. The sun is primarily stimulus of skin cancer in Caucasians.
105
Drugs used on the skin Thus the reversal o f the ratio o f the alteration o f anatomic distribution strongly supports the role o f photoehemotherapy in the causation o f these cancers. How may we compare this problem with those presented by treatment with coal tar and shortrange ultraviolet radiation? Both coal tar and ultraviolet radiation in the short range are carcinogenic. However, they have not resulted in noteworthy skin cancer formation despite usage for over 50years. In contrast, psoralens are non-carcinogenic, and long-range ultraviolet radiation is a weak carcinogen, i f carcinogenic at all. Combination treatment with oral psoralens and long-range radiation had not resulted in tumour formation in laboratory animals. However, the topical and intraperitoneal administration o f psoralens, followed by long-range radiation, does produce cutaneous cancer in animals. The problem may reside in the fact that the majority o f patients require maintenance psoralen photochemotherapy at relatively short intervals, since relapses commonly occur soon after cessation o f treatment. In contrast, coal tar and short-range ultraviolet radiation are usually used for short periods separated by long intervals. Stern et al. note that patients who have received ionizing radiation or who have already had skin cancers are at even greater risk. Since these patients generally have extensive psoriasis, the previous use o f coal tar and short-range radiation, corticosteroids and anti-metaboHtes may also be a factor, although Stern et al. did not find a relation with these other therapeutic factors.' In the m e a n t i m e , discussion as to a n o t h e r p o t e n t i a l risk o f P U V A t r e a t m e n t , n a m e l y m u t a g e n i c i t y , has c o n t i n u e d . Bridges (46 R ) has p u t the q u e s t i o n as to w h e t h e r o n e s h o u l d use a c y t o t o x i c a n d g e n o t o x i c c o m b i n a t i o n o f d r u g a n d radiation w h e n the condition being treated is n o t malignant. The evid e n c e t h a t psoralens react with D N A in the p r e s e n c e o f ultraviolet light is n o w overwhelming, a n d P U V A can be regarded as an established carcinogen a t least in animals. P U V A , as this a u t h o r p o i n t s out, has been associated with DATA damage in l y m p h o cytes, b u t gene m u t a t i o n s have also been f o u n d in p a t i e n t s n o t so treated, w h i c h suggests either t h a t psoriasis i t s e l f p r e d i s p o s e s to m u t a t i o n s or, more likely, that o t h e r t r e a t m e n t s which may have been given are also mutagenic. In this latter respect, Bridges p o i n t s o u t that 'one s h o u l d t h i n k hard bef o r e preven ring the u tiliza tion o f a po ten tially h a z a r d o u s t h e r a p e u t i c regimen s i m p l y because the risk f r o m its c o m p e t i t o r s has been less well investigated and d e f i n e d . ' I t m a y be borne in m i n d in this connection t h a t c h r o m o s o m a l a b n o r m a l i t i e s were
also p r e s e n t in the case r e p o r t e d b y Wagner (5 r see below). A l t h o u g h f u r t h e r e v i d e n c e b o t h on carcin o g e n i e i t y and m u t a g e n i e i t y is certain to emerge, the data c u r r e n t l y available underline o n c e m o r e the n e e d f o r caution a n d reticence in the use o f this t r e a t m e n t . I t s h o u l d be used o n l y in a l i m i t e d n u m b e r o f centres f r o m which p a t i e n t s can be carefully c o n t r o l l e d a n d f o l l o w e d u p ; f o r the p r e s e n t this t r e a t m e n t s h o u l d c o n t i n u e to be regarded as e x p e r i m e n t a l .
PUVA: other effects Preleukaemia A psoriatic patient treated with PUVA for 30 weeks developed refractory anaemia which required several blood transfusions. The bone marrow showed an excess of myeloblasts, abnormal chromosomes and abnormal culture growth on agar. The development of this condition known as preleukaemia may be coincidental. The suspicion of a causal relationship with psoralen can only be supported with future observations (5c).
Bullous eruptions Subepidermal bullae have been noted, not infrequently, in psoriasis patients undergoing PUVA or Goeckermann therapy. The exact pathogenesis is unknown. In a recent study among 24 psoriatic patients treated with PUVA, five developed buUae (6c). Direct and indirect immunofluorescence studies supported the diagnosis of buUous pemphigoid in one patient. In the others, the blisters were a p h o t o t o x i c acral eruption. Granuloma annulare The aetiology and pathogenesis of annular granulorna is as yet unknown. Dorval e t al. (7 c ) have reported a case in which typical granuloma developed in a psoriatic patient during PUVA treatment and the authors try (somewhat unconvincingly) to'associate these findings. Nail pigmentation Four patients are reported to have developed nail pigmentation while on oral 8-methoxypsoralen therapy for vitiligo (8c). Although other possible causes for this phenomenon were not excluded, the authors believe it to be attributable to 8-MOP. Photo-onycholysis Photo-onycholysis caused by tetracyclines is well known. Cases pro-
106 yoked by oral 8-MOP in combination with UVA radiation are less well known, but cases have been reported by Orlonne and Baran (9c), Rau et al. (10 c) and Zala et al. ( l l e ) . Freckling In three patients undergoing systemic p h o t o c h e m o t h e r a p y with 8-MOP a profuse freckling of the skin was observed ( 12 c).
LOCAL ANAESTHETICS
Lidocaine Contact allergy to hdocaine seems to be rare and only few reports have been published (3 c, 1 4 c - 1 6 c ) . ' R e c e n t l y Fregert e t al. (17 c ) have described two cases in which a patch test to lidocaine 1% in water gave positive reactions. These patients also reacted to chemically-related anaesthetics of the amide type (one to bupivacaine, mepivacaine and prilocaine and the other to mepivacaine only). Patch tests with 1% cinchocaine in water gave positive reactions in both cases. As this compound is a chemically non-related anaesthetic of the ester type, however, cross-sensitivity was considered to be unlikely. 6-Methylcoumarin 6-Methylcoumarin is a synthetic fragrance widely used in cosmetics. A case of severe photocontact allergic reactions developing after application of two sunscreens has been reported (18 c).
J. P. Nater and A. C. de Groot
Oxyphenbutazone Oxyphenbutazone is a h y d r o x y l a t e d metabolite of phenylbutazone and is regarded as its active product (24c). A case of contact sensitivity to Tanderil cream (oxyphenbutazone) with cross-sensitivity to Butazolidine (phenylbutazone) has been reported by Krook (25c). Patch tests were performed in a concentration of 1% in petrolatum. The same author observed two cases of contact sensitivity to phenylbutazone without cross-sensitivity to oxyphenbutazone and concludes that oxyphenbutazone may induce cross-sensitivity to phenylbutazone, but phenylbutazone does not induce cross-sensitivity to oxyphenbutazone. Vooys and van K e t e l ( 2 4 C) support this conclusion, although in their patient who reacted both to oxyphenbutazone and phenylbutazone, primary sensitization to oxyphenbutazone could not be ascertained.
Phenylbutazone Contact sensitivity to phenylbutazone has been observed by several author s (21 c, 25 c, 26c). Positive patch tests to phenylbutazone were obtained with 0.5%, 1% and 5% in petrolatum. In no instance where oxyphenbutazone was also tested (23 c, 25 c) was cross-sensitivity observed (see also oxyphenbutazone). MISCELLANEOUS AGENTS
ANTIRHEUMATIC DRUGS The topical use of anti-inflammatory and antirheumatic agents on the skin is increasing. Some of the more widely used are bufexamac (p-butoxyphenylacetohydroxamic acid), oxyphenbutazone and phenylbutazone.
Bufexamac p-Butoxyphenylacetohydroxamic acid is a non-steroid anti-inflammatory agent. Several cases of contact allergy to this drug have been described ( 1 9 c - 2 3 c ) . Patch tests are performed with bufexamac 5% in petrolatum.
Mechloretharnine hydrochloride (nitrogen mustard, chlormethine) In two patients with mycosis fungoides multiple cutaneous squamous cell carcinomas were observed by Kravitz and McDonald (27c). They strongly believe that in their patients long-term application of topical nitrogen mustard could be held responsible for the development of these malignancies. However, both patients had previously had other local therapy and systemic chemotherapy, and the authors admit that predisposing or cumulative effects of this treatment cannot be discounted. An increased frequency of actinic keratoses and squamous cell carcinomas in patients with mycosis fungoides was also observed
107
Drugs used on the skin
by Vonderheid (28 C) and the question was raised whether topical nitrogen mustard could have augmented pre-carcinogenic solar damage. Du Vivier et al.(29 C) found the prevalence of epithelial cancer in 202 patients with mycosis fungoides and the S~zary syndrome to be 10.5%. In about 60% of these, the malignancies developed de novo after nitrogen mustard therapy. According to the authors the findings indicate that nitrogen mustard may function as a carcinogen or a co-carcinogen.
Suppression of contact sensitivity to nitrogen mustard Contact dermatitis as a complication of topical treatment with nitrogen mustard is well known. In five cases of mycosis fungoides the contact sensitivity to nitrogen mustard diminished during treatment with PUVA (30c). The possibility of a spontaneous diminution has to be considered, but the authors of this paper claim (from unpublished observations) that an unchanged reactivity has been observed in cases not treated with PUVA.
in a pharmaceutical firm who developed eczema when working with the substance. Positive patch tests with an aqueous solution of alprenolol in the dilutions 10, 5, 2.5 and 1.25 mg/ml were found. Two of the patients showed a cross-sensitivity to metroprolol. In some individuals complaining of conjunctivitis, rhinitis or asthmalike symptoms intradermal skin tests were carried out, with negative results. These symptoms were not considered to be allergic in nature. Allergic contact dermatitis does not seem to have been recorded in patients or hospital staff handling commercially available alprenolol tablets or injections.
Clioquinol Allergic contact dermatitis to clioquinol was reviewed in SED 8 ( 2 7 6 , 2 8 3 - 1 8 7 ) . The local application may also cause primary irritant dermatitis. According to Kero et al. (44 C) the concentration of clioquinol is the main factor in such a reaction. The crystal size did not affect the appearance of irritant dermatitis.
Silver sulphadiazine VEHICLES In a series of 314 burn injury patients treated with silver sulphadiazine the incidence of drug reactions was 1.3% (43c). In another group of 156 patients who had been treated with maphenide (sulphamyIon) the incidence of drug reactions was, according to this same author, 5.1%.
Dinitrochlorobenzene (see also p. 108) 2,4-Dinitrochlorobenzene (DNCB), a potent sensitizer, is widely used for testing cell-mediated i m m u n i t y in patients with malignant diseases (31R). Recently DNCB has been used for treating patients with alopecia areata(32c). In some patients with grey hair, a yellow discolouration of the hair was noticed after repeated application of DNCB.
Alprenolol Contact eczema produced by alpreno1ol, a beta-adrenergic blocking agent, has been reported by Ekenvall and Forsbeck(33C). They described 14employees
Petrolatum Grimalt and Romaguera (34 c) have described a psoriatic patient in whom treatment with salicylic acid 3% in petrolatum provoked an eczematous and exudative reaction at all the sites treated. Patch tests with standard allergens gave positive reactions to all tests, with the exception of turpentine, bisphenol A and creosote, the vehicle for which was lanette wax. For the other allergens the vehicle was yellow soft paraffin. Patch tests with pure white and yellow soft paraffin showed strongly positive reactions to both.
SYSTEMIC REACTIONS Untoward systemic reactions to topically applied medicaments are reviewed at length in SED 9. Two types of adverse systemic reactions have been observed: (a) immediate hypersensitivity reactions, and (b) toxic effects.
108 Immediate hypersensitivity reactions have been reported after topical application of mechlorethamine hydrochloride (35R), neomycin sulphate (36C), bacitracin (37c), penicillin (38 c ) and Milian's solution (39c). The literature on this subject was recently reviewed by Pascher (40g). Recent reports of toxic effects to systemically used podophyllin and silver sulphadiazine are discussed below.
Podophyllin Absorption of podophyllum resin may lead to severe peripheral neuropathy, acute confusional states, vomiting, coma and death (SEDVIII, 341). Recently Stoehr et al. (41 c ) have described a case in which absorption of podophyllin led to bone marrow depression with leukopenia and thrombopenia. A 15-year-old girl was painted with podophyllin 20% in benzoin tincture over the entire perineal area because of condylomata acuminata. Soon afterwards the patient complained of dizziness, nausea, vomiting and right-sided abdominal pain. The treatment was repeated the next morning and afternoon. Afterwards, she was noted to be lethargic. The next morning she had tachycardia (130/min.), fever (38~ and tachypnoea (40/min.), and shortly afterwards she was in pre-coma. Neurological findings were normal except for her mental status. Serum enzyme values were greatly elevated (SGOT 220 IU; LDH 2184 IU; CPK 3850 IU; AF 262 IU). The patient improved clinically during the next two days. Four days after the initial dose of podophyllin a marked decrease in leukocyte and platelet count was noted. Leukocyte count was 900/mm 3 (on admission 8000]mm 3) on the fifth day and platelet count 3750 mm 3 on the 10th day (platelet count not available on admission, 73,600 on the 14th day after the initial dose of podophyllin). The granulocytopenia and thrombocytopenia were attributed to the marrow toxicity of podophyllin; the marrow aspirate was in accordance with this hypothesis.
Silver sulphadiazine Transient leukopenia following application of silver sulphadiazine cream in nine patients with thermal injury has been reported (42c). The maximum depression of the white blood cell count occurred on the second or third day after the burn and ranged from 3100 to 3500/mm 3. White blood counts on admission had ranged from 6500 to 37,600/mm a . In four patients silver sul-
J. P. Nater and A. C. de Groot
phadiazine application was discontinued because of the development of leukopenia. In each instance the white blood cell count returned to within normal limits within 4 8 - 7 2 hours. In five other patients the leukocyte count also returned to within normal limits within two or three days despite continuation of the drug. As other causes for neutropenia had not been excluded and the study was uncontrolled, the causal relationship between silver sulphadiazine and neutropenia cannot be considered to have been convincingly demonstrated by these cases.
N o t e added in p r o o f
2,4-Dinitrochlorobenzene (DNCB) Nineteen patients suffering from atopecia areata were treated weekly on the head with solutions of DNCB (acetone) in concentrations ranging from 0.01 to 1% by de G r o o t et al. (47c). The following side effects were noted: itching (19), dermatitis of the trunk and extremities (3), pompholyx (1), spreading dermatitis (1), secondary infection (2), painful lymph nodes (3) and oedema of the face and the neck (2). One patient complained of headache lasting three days after the application of DNCB and another of hypersalivation immediately following treatment. In a female patient, the clinical picture of contact dermatitis to a pair of her shoes developed during treatment; the responsible allergen could not be demonstrated. In seven of 19 patients a contact allergy to cignoline (dithranol), which was used concomitantly as an alternative treatment, developed during the trial. Similar observations concerning side effects caused by DNCB-applications were made by de Prost e t al. (48c). In addition to generalized dermatitis, lymphadenopathy, oedema and pompholyx, they noted an urticarial exanthema in two out of 16 patients and general symptoms including fever, arthralgia and insomnia in three patients. In one patient the development of contact allergy to nickel during DNCB treatment was recorded; this, together with the observations of de Groot e t al. mentioned above, indicates that this therapeutic regime may predispose patients to the development of o t h e r contact allergies.
Drugs used on the skin REFERENCES
1. FDA Bulletin (1978): Retinoic acid and sun caused skin cancer. August-September, 26. 2. Viglioglia, P. A. and Barclay, A. (1978): Oral retinoids and psoriasis. Dermatologica (Basel), 157/Suppl. 1, 32. 3. Nyfors, A. (1978): Benefits and adverse drug experiences during long-term methotrexate treatment of 248 psoriatics. Dan. reed. Bull., 25,208. 4. Stern, R.S., Thibudeau, L.A., Kleinerman, R. A., Parrish, J. A. and Fitzpatrick, Th. B. (1979): Risk of cutaneous carcinoma in patients treated with oral methoxsalen photochemotherapy for psoriasis. New Engl. J. Med., 300, 809. 5. Wagner, J., Manthorpe, R., Philip, P. and Frost, F. (1978): Preleukemia (haemopoietic dysplasia) developing in a patient with psoriasis treated with 8-methoxypsoralen and ultraviolet light. Scand. J. Haematol., 21,299. 6. Robinson, J.K., Baughman, R.D. and Provost, T. T. (1975): Bullous pemphigoid induced by Puva therapy. Brit. J. Derm., 99, 709. 7. Dorval, J.C., Leroy, J.P. and Mass~, R. (1979): Granulomes annulaires diss~min~s apr~s Puva th6rapie. Ann. Derm. Venereol. (Paris), 106, 79. 8. Naik, R. P. C. and Singh, G. (1979): Nail pigmentation due to oral 8-methoxypsoralen. Brit. J. Derm., 100, 229. 9. Orlonne, J.P. and Baran, R. (1978): Photoonycholyse induite par la photochimioth~rapie orale. Ann. Derm. Venereol. (Paris), 105, 887. 10. Rau, R.C., Flowers, F.P. and Barrett, J. L. (1978): Photo-onycholysis secondary to psoralen use. Arch. Derm., 114, 448. 11. Zala, L., Omar, A. and Krebs, A. (1977): Photo-onycholysis induced by 8-methoxypsoralen. Dermatologica (Basel), 154,203. 12. Bleehen, S.S. (1978): Freckles induced by Puva treatment. Brit. J. Derm., 99/Suppl. 16, 20. 13. Burry, J. H., Kirk, J., Reid, J.C. and Turner, T. (1973): Environmental dermatitis: Patch tests in 1,000 cases of allergic contact dermatitis. Med. J. Aust., 2, 681. 14. Wozniak, K.D. and L~ibbe, D. (1974): Zur Diagnostik yon Arzneimittel. Intoleranzreaktionen der Haut. Derm. Mschr., 160,451. 15. Roed-Petersen, J. (1976): Contact sensitivity to metaoxedrine. Contact Dermatitis, 2, 235. 16. Turner, T. W. (1977): Contact dermatitis to lignocaine. Contact Dermatitis, 3, 210. 17. Fregert, S., Tegner, E. and Trelin, I. (1979): Contact allergy to lidocaine. Contact Dermatitis, 5, 185. 18. Kaidbey, K. H. and Kligman, A. D. (1978): Contact photo allergy to 6-methylcoumarin in proprietary sunscreens. Arch. Derm., 114, 1709. 19. Smeenk, G. (1973): Contact allergy to bufexamac. Dermatologica {Basel}, 14 7, 334. 20. Sneddon, I. B. (1974): Contact dermatitis to bufexamac (Parfenac). Contact Dermatitis Newsletter, No. 16, 519.
10 ~) 21. Lachapelle, J. M. (1975): Contact sensitivity to bufexamac. Contact Dermatitis, 1, 261. 22. Van Hecke, E. (1973): Allergy to bufexamac. Arch. belg. Dermatol., 29, 301. 23. Meneghini, C.L. and Angelini, G. (1979~. Contact allergy to antirlleumatic drug.~. CoJztact Dermatitis, 5, 197. 24. Vooys, R. C. and van Ketel, W. G. (1977): Allergic drug eruption from pyrazohme compounds. Contact Dermatitis, 3, 57. 25. Krook, G. (1975): Contact sensitivity to ox,.~phenbutazone (Tanderil) and cross-sensitivity to phenylbutazone (Butazolidine). Contact Dermatitis, 1,385. 26. Thormann, J. and Kaaber, K. (1978): Contact sensitivity to phenylbutazone ointment (Buh~z~lidine). Contact Dermatitis, 4,235. 27. Kravitz, P.H. and McDonald, C.J. (t978): Topical nitrogen mustard induced carcinogenesis. Acta derm.-venereol. (Stockh.), 58, 421. 28. Vonderheid, E.C., van Scott, E. J., Johnson, W.C., Grekin, D.A. and Asbelt, S.O. (1977): Topical chemotherapy and immunotherapy of mycosis fungoides. Arch. Derm., 113, 459. 29. Du Vivier, A., Vonderheid, E.C., van Scott, E. J. and Urbach, F. (1978): Mycosis fungoides, nitrogen mustard and skin cancer. Brit. J. Derm., 99, 61. 30. Volden, G., Molen, C. and Thomse, K. (1978): Puva-induced suppression of contact sensitivity to mustine hydrochloride in mycosis fungoides. Brit. meal. J., 3, 865. 31. Bleumink, E., Nater, J.P., Schraffordt Koops, H. and The, T. H. (1974): A standard method for DNCB sensitization testing in patients with neoplasms. Cancer, 33, 911. 32. Happle, R., Cebulla, K. and EchternachtHapple, K. (1978): Dinitrochlorobenzene therapy for alopecia areata. Arch. Derm., 114, 1629. 33. Ekenvall, L. and Forsbeck, M. (1978): Contact eczema produced by a beta-adrenergic blocking agent (alprenolol). Contact Dermatitis, 4, 190. 34. Grimalt, F. and Romaguera, C. (1978): Sensitivity to petrolatum. Contact Dermatitis, 4, 377. 35. Daughters, D., Zackheim, H. and Maibach, H. (1973): Urticaria and anaphylactoid reactions. Arch. Derm., 107, 429. 36. Pippen, R. (1966): Anaphylactic reaction after chymacort ointment. Brit. reed. J., 1, 1176. 37. Roupe, G. and Stannegard, O. (1969): Anaphylactic shock elicited by topical administration of bacitracin. Arch. Derm., 100, 450. 38. Maucher, O.M. (1972): 'Anaphylaktische' Reaktionen beim Epicutantest. Hautarzt, 23, 109. 39. Francois, A., Henin, P., Carli Basset, C. and Ginies, G. (1970): Anaphylactic shock following application of Milian's solution. Bull. Soc. franf. Dermatol. Syphilol., 77, 834. 40. Pascher, F. (1978): Systemic reactions to topically applied drugs. Int. J. Derm., 1 7, 768.
110 41. Stoehr, G.P., Peterson, A.L. and Taylor, W. J. (1978): Systemic complications of local podophyllin therapy. Ann. intern. Med., 89, 362. 42. Jarrett, F., Ellerbe, S. and Demling, R. (1978): Acute leukopenia during topical burn therapy with silver sulfadiazine. Amer. J. Surg., 135, 818. 43. Pegg, S.P., Ramsay, K., Meldrum, L. and Laundy, M. (1979): Clinical comparison of maphenide silver sulphadiazine. Scand. J. Plast. Reconstr. Surg., 13, 95. 44. Kero, M., Hannuksela, M. and Sothman, A. (1979): Primary irritant dermatitis from topical clioquinol. Contact Dermatitis, 5, 115.
J. P. Nater and A. C. de Groot 45. Epstein, J. P. (1979): Risks and benefits of the treatment of psoriasis. New Engl. J. Med., 300, 852. 46. Bridges, B. A. (1978): PUVA and carcinogenicity. Clin. exp. Dermatol., 3, 349. 47. De Groot, A.C., Nater, J.P. and de Jong, M. C. J. M. (1979): De behandeling van alopecia areata met 2,4-dinitrochloorbenzeen (to be published). 48. De Prost, Y., Paquez, F.-R. and Touraine, R. (1979): Traitement de la pelade par applications locales de DNCB. Ann. Dermat.-V~ndreol. (Paris], 106,437.