Drugs used on the skin

J. P. Nater

14

drugs used on the skin

GENERAL Incidence o f contact sensitivity to locally applied drugs The incidence of contact sensitivity to 12 topically applied drugs in the relation to the frequency with which they are used in Warsaw was studied by Rudzki and Zakrzewski(1R). For this purpose 200,000 pharmaceutical prescriptions filled in 16Warsaw pharmacies were analysed. The ratio of sensitive subjects to the number of prescriptions of each drug was calculated. This 'index of sensitization' was calculated on the basis of prescribed ointments, creams and pastes etco (Table 1). The high ratio of sensitization to Balsam of Peru is attributed to the use of suppositories. In the case of coal tar the high sensitization index may be due to non-specific irritation. In another study, Ebner (59 C) reports that Balsam of Peru was the most frequently encountered contact allergen in children and young persons.

TOPICAL CORTICOSTEROIDS One of the main topics in dermatological literature during the past years has been the discussion of the side effects of topically used corticosteroids(6 R, 7 R, 70 R, 92R). Table 1. Incidence of contact sensitivity to 12 topically applied drugs Sensitization index Balsam of Peru Benzocaine Coal tar Ichthyol Mercuric chloride Vioform Neomycin sulphate Sulphanilamide Eucerin Chtoramphenicol Lanolin Oxytetracycline

1 2 3 4 5 6 7 8 9-12 9-12 9-12 9-12

This is understandable in view of the fact that at the moment some 50% of dermatological prescriptions contain topical steroids. Problems are complicated by the introduction of ever more potent topical steroid compounds, the potency of which is increased by a factor of at least 100 by the use of polythene occlusion. A general survey of the systematic and local side effects of topically applied steroids has been given in SED VIII. Hornstein et al. (6 R) tried to evaluate statistically the incidence of local side effects due to prolonged external use of corticosteroids. Among 7,978 patients attending a university clinic, local side effects could be noted in 75 (= 0.94%). These effects were found among patients with perioral and rosacea-like dermatitis (25.8%), eczema (2.4%), mycoid infections, psoriasis, rosacea, acne vulgaris, herpes simplex, lupus erythematodes, lichen ruber planus and alopecia areata. The adverse reactions consisted in decreasing frequency of teleangiectasis, skin atrophy, hypertrichosis lanuginosa, striae and miliaria. It is not quite clear, what this author means by 'perioral dermatitis treated with corticosteroids'; perioral dermatitis is more generally known as a side effect caused by local application of corticosteroids. Deakin(70 R) points out that topical corticosteroids have 3 main actions in the skin: (1) they suppress inflammation and allergic reactions, (2) they produce prolonged vasoconstriction, and (3) they have an antimitotic effect. The vasoconstriction more or less parallels their clinical effectiveness. Marks et al. (71) described a method of assaying the potency of topical corticosteroid preparations by studying the antimitotic activity on the skin of hairless mice. Briggs and Briggs (72) report on the induction of skin enzymes metabolizing carcinogenic hydrocarbons by topical corticosteroids. They consider that an increase occurs in epidermal aryl hydrocarbon hydroxylase (AHH) activity in human subjects who use topical corticosteroid therapy. This enzyme

Drugs used on the skin

is intimately involved in hydrocarbon carcinogenesis; such patients may thus be at increased risk of skin cancer from hydrocarbons with which they come in contact, for example foods, petroleum products or even ointment bases! Corticosteroids may of course furthermore be procarcinogenic by virtue of their suppression of the immunological defense mechanism. Deakins (70 R) points out that the face is the most common site of corticosteroid side effects. Two clinical entities may be produced: a rosacea-like syndrome and perioral dermatitis. Four patients with perioral dermatitis were reported in Japan (83C). All had had topical applications of fluorinated corticosteroids. Application of a non-fluorinated hydrocortisone ointment in one case was followed by an exacerbation. Abnormal facial pigmentation associated with the prolonged use of topical corticosteroids is a third, not widely recognized side effect in the face. Six patients in which this phenomenon could be noted have been reported by Allen and H u n t e r ( 9 1 c ) . It has also been pointed o u t ( 7 0 R) that although potent corticosteroid creams may appear to improve the lesions of solar type malignancies, they actually produce epidermal atrophy with a diffuse spread of the malignant lesion into surrounding tissue, the borderline being ill defined. Furthermore the skin is rendered very fragile in surgery. For these reasons, topical steroids should not be used as a treatment for solar damage. Cunliffe et al. (69 C) describe 3 patients with extensive skin disease and liver failure. Two were treated with large amounts of topical steroids and one with a small oral dose of betamethasone. The third patient had constitutional eczema and had taken oral betamethasone 1 mg/day for 6 months. The former two patients developed acute adrenal insuffiency when they failed to apply the steroid for several days. All 3 patients developed a septic necrosis of either the femoral head or the talus. This report emphasizes the fact that the hazards of steroid therapy may be increased in patients with hepatic failure. A previously unrecognized pharmacological event, i.e. acute tolerance to the vasoconstrictive action of topically applied glucocorticosteroids in human skin, has been reported by du Vivier and Staughton (8c).

125 After a rest period of a few days, the initial vasoconstrictive effect can again be produced. It will disappear once more if topical steroid treatment is resumed. The phenomenon of acute tolerance known as tachyphylaxis may in the opinion of the authors explain a not-infrequent patient complaint that their responsiveness to new corticosteroids, although often marked at first, diminishes with constant usage. Johnson (73 C) conducted an interesting experiment in which he proved that in a number of skin conditions simple protective applications are quite effective, and that the use of topical corticosteroids is superfluous. Especially those conditions which are characterized by dryness, scaling and cracking o f the skin, and in which environmental aspects are likely to be involved, responded well. These were xeroderma, winter (asteatotic) eczema and atopic eczema with dryness and cracking. Simple preparations are especially recommended by this author in skin conditions the cause of which is clearly traumatic in the sense that everyday activities associated with work, the home and leisure, unavoidably have a traumatic component. Benign intracranial h y p e r t e n s i o n a f t e r w i t h d r a w a l o f topical steroids in an i n f a n t The development of benign intracranial hypertension in an infant after stopping potent topical steroid treatment was reported by Roussounis (106c). In this case treatment had been limited to the napkin area. The author suggests that the napkin acted as an occlusive dressing.

PHOTOTHERAPY OF PSORIASIS COAL TAR Tar is obtained by destructive distillation of various materials. Since such destructive distillation may produce carcinogenic hydrocarbons Hirohata et al. (44) have attempted to identify such compounds and to test their carcinogenicity on laboratory animals, The authors demonstrated the carcinogenicity of severe tar-containing skin drugs such as Pityrol, Glyteer, Metashol and, to a lesser degree, Pinetar. As for the results of the chemical analysis, a substantial amount of polycyclic aromatic hydrocarbons and, in particular, of benzo(a)pyrene was identified. The contact of benzo(a)pyrene agreed well with the degree of carcinogenic activity

J. P. Nater

126 o b s e r v e d in a n i m a l e x p e r i m e n t s . T h e a u t h o r s stress t h a t t h e c a r c i n o g e n i c i t y of t a r - c o n t a i n ing drugs in m a n is difficult to assess. P h o t o t h e r a p y o f psoriasis c o n s i s t i n g of daffy a p p l i c a t i o n of c r u d e coal tar comb i n e d w i t h ultraviolet r a d i a t i o n is c o m m o n l y r e f e r r e d t o as t h e G o e c k e r m a n t r e a t m e n t . T h e p r o g r a m e m p l o y e d consists o f totalb o d y a p p l i c a t i o n o f 2 - 5 % crude coal t a r in p e t r o l a t u m in c o m b i n a t i o n w i t h u l t r a v i o l e t exposure. T h e coal t a r is applied t o t h e entire b o d y , f r o m t h e n e c k d o w n w a r d s , w i t h the e x c e p t i o n o f t h e i n t e r t r i g i n o u s areas such as axfflae, a n t e c u b i t a l fossae, a n d groin. S o m e p a t i e n t s will t o l e r a t e ( a n d even req u e s t ) a p p l i c a t i o n to t h e face, b u t the c h a n c e o f t a r c o n j u n c t i v i t i s is great. T h e r e are, a c c o r d i n g to Mitchell Sams ( 6 2 R ) , few c o m p l i c a t i o n s w i t h t h i s f o r m o f t h e r a p y . Folliculitis is t h e m o s t c o m m o n , a n d occurs w i t h greater f r e q u e n c y w h e n

Table 2.

using t h e h i g h e r t a r c o n c e n t r a t i o n s (5%) a n d w h e n c o m b i n i n g t a r w i t h salicylic acid (usually 2 - 5 % ) , p a r t i c u l a r l y w h e n tar cont a c t s t h e i n t e r t r i g i n o u s area. A n o t h e r comm o n a n d m i n o r c o m p l i c a t i o n is a n i r r i t a t i o n in t h e i n t e r t r i g i n o u s areas. A n i n f r e q u e n t p r o b l e m is n a u s e a b y the o d o r o f tar. M i t c h ell Sams w a r n s against t h e use o f tar a n d ultraviolet i r r a d i a t i o n in p a t i e n t s w i t h exfoliative a n d p u s t u l a r psoriasis. PSORALENS A l t h o u g h t h e psoralens are c o m m o n l y used orally, t h e i r d e r m a t o l o g i c a l i m p o r t a n c e justifies t h e i r b e i n g dealt w i t h in this chapter. T h e d e v e l o p m e n t of p s o r a l e n s for oral use in d e r m a t o l o g y is s u m m a r i z e d in Table 2, derived f r o m F i t z p a t r i c k ( 6 3 R ) . A l t h o u g h p s o r a l e n s have b e e n used for a b o u t 25 years for t h e t r e a t m e n t of vitiligo a n d m o r e r e c e n t l y for t h e t r e a t m e n t o f

Research and development o f psoralens in medicine and biology, 194 7 - 1 9 75

Psoralen

Period

CliniCal use

Clinical research

Relevant biological research

I. 8-Methoxypsoralen (Methoxsalen)

1947-1960

Treatment of vitiligo by oral ( 1 0 20 mg) and topical 8MOP (1%)

Increased skin pigmentation with sun + 8-MOP (1955). Increased sun tolerance (1959).

Relation of structure and photoactivity of psoralens (1956 1960). Synthesis of psoralens (1956-1960). Lethal effect on bacteria, fungi in vitro (1958). Action spectra 3 4 0 360 nm. in vitro and in vivo (1959-1960).

II. 4,5,8-Tri1960-1969 methylpsoralen (Trioxsalen)

Treatment of vitiligo with oral ( 1 0 - 2 0 mg) TMP (19621966)

Increased oral dose 8MOP and TMP in treatment of vitiligo (40 mg) (1966)

Mechanism of psoralen photosensitization: free-radical studies. Synthesis of trimethylpsoralen (1960-1964). Inactivation of DNA viruses (1965). Photobinding of psoralens to DNA in vitro, 1966; and in vivo, 1968.

Ill. Photo1970-1975 chemotherapy with 8-MOP and TMP

Oral TMP safe and effective for vitiligo

Inhibition of DNA synthesis by topical 8-MOP and UVA (1970-1972). Topical use of 8-MOP in treatment of psoriasis (1972-1973). Development of high-intensity UVA system ( 1 9 7 2 1973). Photochemotherapy of psoriasis and vitiligo with oral 8-MOP and UVA (1974).

Normal DNA repair of psoralen photoadducts is demonstrated (1972). Absorption and metabolism of psoralens (1973-1974).

8-MOP = 8-methoxypsoralen; TMP = trimethylpsoralen

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psoriasis, very little is, according to Pathak (64 R) known about the in vivo metabolism of orally administered psoralens. The penetration, permeation and resorption of radioactively labelled 8-methoxypsoralen in the human skin, using different carriers, was investigated by Kammerau et al. (74). Side e f f e c t s o f p s o r a l e n - U V A ( P U V A ) treatment

This treatment normally results in pigmentation and redness of healthy skin areas. These effects may result from a single application and cannot be avoided entirely when treating psoriasis. The erythema is a manifestation of the phototoxic property of psoralens in the presence of UVA. Excess of drug or light may lead to painful blistering reactions (65R). This is also the case in patients treated with locally applied psoralens. During treatment sunlight and solaria should be avoided. Seven patients out of a group of 40, treated orally with psoralen, experienced intense pruritis at the beginning of therapy, and 2 patients had a Koebner reaction (67c). During the period of UVA treatment neither steroids nor tar preparations should be applied to the skin. Other drugs possibly causing phototoxic or photoallergic reactions should not be used. Simple skin protective measures, e.g. the use of indifferent creams, should be encouraged (75 R). Eyes

Cloud e t a t (76, 77) reported cataracts in albino mice exposed to high doses of 8methoxypsoralen (8-MOP) and UV light. The photosensitizing effect of 8-MOP in the eyes of laboratory animals was also studied by Freeman and Troll (78). It appeared that guinea pigs were more susceptible to photosensitizing injury with 8-MOP than were rabbits. Experimental data suggest that this is due to a difference in penetration of 8-MOP in the eye. The injury was limited to the cornea, anterior chamber, iris and the anterior part of the lens, i.e. anatomical sites of long-wave ultraviolet absorption. Though no evidence of comparable effects in man has apparently been reported so far, Warin and Carruthers (79) consider it wise to screen all prospective patients for cataracts and perhaps exclude any patient with lens damage. Regular ophthalmic assessment and the

wearing of sunglasses during PUVA treatment is considered mandatory. Liver

In a study in 1959 of 27 patients with vitiligo treated with 8-MOP, 2 patients were reported to have abnormal bromsulphophthalein retention values. Pre-treatment values, however, were not available (82c). In 6 out of a group of 40 psoriasis patients treated with PUVA, serum transaminase activity was increased slightly; 3 of them had taken alcohol during treatment (67c). According to the authors patients should, until this is further studied, be advised not to take alcohol while receiving 8-MOP. In some patients the oral administration of psoralen may lead to nausea (65R). C h r o m o s o m a l damage and malignancy

It is known that prolonged doses of longwave UV light may cause fibrosarcomas and squamous carcinomas in albino mice (80, 81). In experiments in which Chinese hamster cells in culture were exposed to graded doses of long-wave UV light in the presence of 34.4/ag psoralen per ml of culture medium, extensive chromosomal damage was noted (68c). According to the authors somatic chromosome damage of this magnitude may result, after clonal selection, in later malignancy. A cytogenic study showed that 8-MOP and UVA treatment of lymphocytes in vitro gives rise to chromosomal aberrations (67c). In a combined in vivo and in vitro study where lymphocytes had been isolated from a patient 2 hours after intake of 6 0 - 8 0 mg 8-MOP and then irradiated with therapeutic UVA doses, a significant increase in chromosomal aberration was found. When chromosome analysis was performed on the patient whilst 8-MOP treatment was temporarily withdrawn and when the 13~mphocytes were not irradiated in vitro no increased frequency of chromosomal aberration was found on comparison with a group of psoriatic patients receiving dithranol t h e r a p y ( 6 7 c ) . Hoffman et aL (75 C) stress the need for adequate instruction of every patient before commencing PUVA treatment. Pregnancy is a contra-indication and conception during the period of treatment should be avoided. Urbach(66 R) warns against the casual use of PUVA treatment. There is, in his view, only a narrow margin between the

128 amount of energy required for therapeutic benefit and the amount that may produce injury. In all cases the possibility of chronic damage must be weighed carefully against the therapeutic benefits of PUVA in psoriasis (65R). Studies on the possible repair of DNA photodamaged by furocoumarins have been recently reported by Chandra et al. (99). It appeared that a post-irradiation dark recovery is possible, both in Saccharomyces cerevisiae cells and in guinea pig skin. It should be noted that the recorded side effects of 8-MOP are all reported after systemic use in animal experiments. It is clear, however, that further studies, e.g. on the side effects of local application during a longer period of time, are necessary. LOCAL AND SYSTEMIC SIDE EFFECTS OF OTHER ANTIPSORIATICS

6-A minonicotinamide Topical application of a 1.5% aqueous solution of 6-aminonicotinamide for four weeks resulted in substantial improvement or complete cleaning of plaques of psoriasis in 27 out of 34 patients (5c). Moderate to marked dermatitis occurred in 4 patients, and severe itching without dermatitis, requiring cessation of treatment, was found in one of the 4 patients with dermatitis; 3 were subsequently able to tolerate 1.0% or 0.5% solutions and were judged to have primary irritant dermatitis. Apparent hypersensitivity occurred in only one patient. In addition to these 5 patients with severe cutaneous side effects 3 others developed mild erythema, itching and dryness which were, however, not severe enough to interfere with treatment. The toxic hazards of 6-aminonicotinamide to the central nervous system are discussed. Vitamin A acid (retinoic acid) Vitamin A acid has within the last few years become an interesting drug for topical application. It is used by many physicians in the treatment of ache vulgaris. Its use in psoriasis is still a matter of dispute. Skin irritation seems to remain a limiting factor. There is also increasing interest in the oral administration of this drug e.g. in cases of psoriasis, ichthyosiform dermatosis, psoriasis, leukoplakia, acne and carcinoma. This treatment is, however, still in the experimental stage. The therapeutic possibilities of

J. P. Nater

vitamin A acid were discussed extensively at an international symposium held in Flims, Switzerland, in 1975 (84R). System ic adm in istra tio n Two derivatives of retinoic acid (13-cis-~retinoic acid and retinoic acid ethylamide) were orally administered to 26 hospitalized patients with widespread psoriasis (85 C). After 3 weeks, 15 of the 26 patients were improved, though none of them cleared completely. A common side effect (after 13-cis@retinoic acid only) was exfoliative cheilitis. In a few cases headaches, diarrhoea, vomiting, and increases in sedimentation rates, transaminases and serum lipids were noted. Schimpf(86 C) treated a group of 33 psoriasis patients with the vitamin A acid derivative Ro 1 0 - 9 3 5 9 (ethyl-all-trans-9(4methoxy-2, 3,6-trimethylphe nyl)-3,7-dimethyl-2,4,6,8-non-atetraenoate). Furthermore 13 patients with keratoses were treated systemically with Ro 1 0 - 9 3 5 9 ; the period of treatment varied from 28 days to 9 months. In the group of psoriasis patients various side effects were noted; 24 of 33 cases complained of dry, cracked lips, in 4 out 33 cases transient nose bleedings occurred, 4 cases complained of a dry nasal and buccal mucosa and in 1 case dental bleeding occurred; conjunctivitis was noted in 1 patient. In 3 female cases the medication had to be stopped on account of diffuse hair loss; one of these patients also complained of frontal headaches. In another case minor trauma (tennis playing) gave rise to painful loosening of the horny layer of the skin of the fight hand and the soles of the feet. In one other case bleeding from traumatically exposed skin areas occurred. Side effects noted by Sti~ttgen(87 R) after oral vitamin A acid therapy are listed in Table 3. Local reactions (see also SED VIII) Primary irritant effects The therapeutic value of locally applied retinoic acid in psoriasis is disputed. It appears that relatively high concentrations are necessary to obtain a satisfactory therapeutic effect. Irritation from these high concentrations remains a troublesome side effect. Kaidbey et al. (88c), in a study of the effect of topically applied retinoic acid with steroid ointment, described a patient who inadvertently transferred the 0.3% retinoic

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Drugs used on the skin

acid solution to the scrotum. An irritant dermatitis developed which took 4 days to subside. Care must thus be taken to avoid drug contact on areas that are easily irritated. Contact allergic reactions

T w o cases of contact allergic reactions to locally applied retinoic acid were reported by J o r d a n et al. (10C). Two volunteers were

found to be allergic to retinoic acid at the beginning of a predictive test designed to compare the skin irritation p o t e n t i a l of various acne formulations. The patch testing procedures reported by the authors eliminate the possibility o f a response due to irritation and the leukocyte migration inhibition test supports the existence o f a true cell-mediated response.

SYSTEMIC SIDE E F F E C T S O F D R U G S U S E D ON THE SKIN PHOTODYNAM1C INACTIVATION IN RECURRENT HERPES SIMPLEX VIRUS INFECTIONS E x p e r i m e n t s have revealed that in vitro herpes simplex virus could be inactivated by exposure to heterocyclic dyes and light. A n u m b e r of investigators r e p o r t e d , that ' p h o t o d y n a m i c inactivation' is effective in the t r e a t m e n t of orolabial and genital herpes simplex virus infections in man. However, Taylor and D o h e r t y ( 1 0 1 C) and R o o m e et al. (102 C) were unable to d e m o n s t r a t e an effect of p h o t o d y n a m i c inactivation in the course of genital herpes virus infection. Myers et al. (103 c ) evaluated the efficiency of p h o t o d y n a m i c inactivation with neutral red and light in a placebo-controlled study of 170 episodes of recurrent virus infections in 96 patients. The t r e a t m e n t appeared to have no significant effect on the resolution of herpetic lesions or on the f r e q u e n c y of subsequent recurrences, e x c e p t for orolabial lesions, in which an effect on the rate of subsequent recurrences was observed. The authors advise that the routine use o f neutral red and light in patients with recurrent herpes simplex virus infections should be discontinued. In addition, the d e m o n s t r a t i o n , that p h o t o d y n a m i c a l l y inactivated herpes simplex virus can induce neoplastic transform a t i o n of m a m m a l i a n cells in vitro, and that cells transformed in this m a n n e r have oncogenic properties in vivo (104, 105) suggest

that this form of therapy m a y not be free of hazard. GENTAMICIN Gillette et al. (97 r) examined the sensitivity to gentamicin of Pseudomonas aeruginosa obtained f r o m clinical specimens of 3 different hospitals. One was a general hospital, the other two were specialized in ENT and skin diseases. Their results show a striking increase in resistance at the specialized hospitals as compared with the general one. The difference is attributed to the use of gentamicin in locally applied preparations. This report is another serious warning against the undiscriminated use of this important antibiotic for local application. The same warning must be given against the local application of n e o m y c i n . Outbreaks of infection caused by neomycin-resistant staphylococci have been reported in a surgical ward, in which patients' noses and wounds were treated with sprays containing n e o m y c i n and its analogues (98c). Sensitization, of course, is another, equally i m p o r t a n t hazard (see

Table 3.

Undesired sMe efJects after oral vitamin

A acid*

Side effect

Frequency

Dryness of lips Headache Flush Dryness of skin Feeling of tiredness Bulb-pressure sensitivity Lack of appetite Increase of thirst Nausea Pruritus increased Pruritus diminished Dizziness Increased perspiration Petechial eruptions Dandruff Oedema of the face (100 200 mg) Chahges in the psychological state (100-200 rag) Dryness of the mucous membrane of the nose Alopecia diffusa Unconsciousness with complete reversibility after 4 days 100 rag/ daily (200 mg)

24 23 22 15 13 11 11 9 8 7 4 6 6 5 4 3 3 3 2 2

* 50-200 mg daily/4 weeks in 30 patients; same season and food

130 also SED VIII, pp. 3 4 9 - 3 5 1 ) . In our opinion the use o f gentamicin should be restricted to treatment of life-threatening infections. NEOMYCIN

After laryngectomy and neck dissection for an extensive carcinoma of the epiglottis a 2 by 2 cm pyocyaneus-infected wound was treated daily with neomycin sulphate solution. A total of 3 0 g was given over 3 months, during which time the patient became deaf. No other antibiotic was administered and the author believes neomycin caused the deafness (2c). AMPICILLIN

A patch test with ampicillin 5% in vaseline resulted in one patient in an anaphylactic reaction and an urticarial eruption. The reaction commenced one and a half hours after the application. Clinical treatment with intravenous and intramuscular prednisolone was necessary (9c). POVIDONE-IODINE

Two patients, one with a 75% burn, the second with a 35% burn, were treated topically with povidone-iodine (Betadine). In both patients severe metabolic acidosis developed which could not be attributed to sepsis, hypervolaemia, renal failure, lactic acidaemia etc. (3c). The acidosis associated with the 75% burn required large amounts of sodium bicarbonate to maintain pH at 7.35 and a serum bicarbonate c o n c e n t r a t i o n of 15 mmol/1 (mEq/l); serum iodine was 48,000 gg/dl (normal 4 - 8 . 5 #g/dl). Acidosis in the second patient was not as severe, and serum iodine concentration reached 17,600 #g/dl. Haemodialysis was very effective in reducing serum iodine concentration. According to the authors, the acidosis could have been caused by absorption of the iodine or the acidic povidone-iodine. Until the aetiology of the acidosis and renal damage is more clear, iodophors should not be used topically for burns greater than 20% of the body surface or in the presence of renal failure. ETHYLENEDIAMINE

A patient may develop a cutaneous reaction from a systemic medication because of prior contact sensitization, Petrozzi and Shore (24 c) present a case in which the administration of aminophylline led to a gen-

J. P. Nater

eralized exfoliative erythrodermia because of previous sensitization to ethylenediamine hydrochloride. The patient was apparently sensitized to ethylenediamine hydrochloride, which is a preservative in an antibiotic cream (Mycolog). Exposure to aminophylline suppositories led to the described systemic reaction. SEX H O R M O N E S

Thirty men (aged 1 7 - 3 7 y e a r s ) with alopecia androgenetica were treated with local application of a hair lotion containing 0.05 g% dienoestroldiacetate (4c). Urine oestrone levels were measured before treatment and after 3 and 6 months of treatment. The results were compared with those of a normal control group. Statistically significant differences could not be noted, and clinically no side effects could be observed. In an addendum, however, the authors mention the development of a hazelnut-sized thickening of the left mamma of one of the patients, 7 months after the commencement of treatment. It may be noted that the occurrence of side effects, namely pigmentation and gynaecomastia, following the application of stilboestrol-containing hair lotions in children has been reported previously (33c; see also SED VIII).

LOCAL SIDE EFFECTS OF DRUGS USED ON THE SKIN HY D R O Q U I N O N E

The use of the monobenzylether of hydroquinone as a skin lightener has been prohibited by the South African Government after a disastrous epidemic of patchy leukomelanoderma, reported by Dogliotti et al. (1 lC). Bentley-Phillips and Bayles (12 c) report the results of a 6 year investigation on the cutaneous side effects of topically applied hydroquinone, which is now used instead. A group of 840 volunteers of various race groups took part in this trial. Hyperpigmentary reactions of a delayed type without preceding erythema and contact-type erythema progressing to hyperpigmentation were the most frequently seen adverse effects. The latter reaction was, according to the authors, a post-inflammatory type of hyperpigmentation. The former is explained by the binding of hydroquinone to keratin and subsequent oxidation to a brown tint, as

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Drugs used on the skin

described by Fitzpatrick e t al. (13R). Without further applications both types of hyperpigmentation disappear gradually. It is concluded that 3% hydroquinone is the optimal strength for local use, irrespective of the base or the colour of the user's skin. 4-1SOPROPYLCATECHOL

A cream containing 1% 4-isopropylcatechol was applied topically to the hyperpigmented lesions of 29 patients with melasma, freckles or caf~-au-lait spots. The bleaching effect on melasmas was very satisfactory in all patients, but contact dermatitis developed in 3 patients and a reticular hyperpigmentation with areas of depigmented spots could be noted in one case. Freckles and caf~-au-lait spots did not bleach (14c).

contact dermatitis due to contact with elecamphane. This medicinal herb is apparently widely used in the Soviet Union for self treatment of skin ailments. CANTHARIDIN

Local application of cantharidin and salicylic acid is used for treatment of resistant plantar and periungual warts. Two patients seen by Dilaimy(61 C) developed a severe reaction with oedema, redness and tenderness accompanied by lymphangitis. The reaction started about 30 hours after therapy. According to the author this reaction is not uncommon and has also been seen after using cantharidin alone. UREA

EPINEPHRINE

Allergic reactions to epinephrine with positive patch tests have been reported by Colldahl and Fagerberg(51 c) and Gibbs (52c). Circulating antibodies have been demonstrated by Aronson and Jamamoto (53c). Recently Alani and Alani (54 c) described a case of sensitivity to epinephrine eyedrops; the patient showed positive allergic patch test reactions to the chloride solution of epinephrine, and furthermore reacted unexpectedly positive to diisopropyl fluorophosphate (DFP). There was no history of contact with pesticides of the organophosphate group, which would explain this sensitivity to be of the cross-sensitivity type. FLUOROURACIL

B u r n e t t ( 6 0 C) describes 4 p a t i e n t s who developed prolonged telangiectasia and herpes labialis after topical fluorouracil therapy. SALICYLIC ACID

Rudzki and Koslowska (58 C) report 5 patients with allergic reactions to salicylic acid. In 4 cases the source of salicylic acid was 2% salicylic acid in spirit. Three patients themselves noticed that the use of this preparation was responsible for the reactions. In none of the patients did aspirin cause exacerbation or relapses of the dermatitis. ELECAMPHANE (ALANTOLACTONE) From the USSR, Piyankova and Nugman o v a ( 3 8 c) have described cases of allergic

The epidermis thins in response to shortterm contact with urea. Results of extensive enzymological and autoradiographical studies suggest that urea plays a role in processes involved in epidermal proliferation (28). After long-term exposure of the skin to urea, lasting more than 2, 4 or 6 weeks, no further thinning occurred. There was also no tendency for atrophy to develop during this period. The authors make this assertion on the basis of biometrical, autoradiographical and cytophotometric data. It is, however, according to the authors, likely that a reduction in the number of cells synthesizing DNA is not the only change in epidermal proliferation leading to the measured epidermal thinning. The authors postulate that urea could also alter factors regulating either cell entry into DNA synthesis, the synthetic process itself or both. Frederiksson and Gip (27 R) conducted 2 randomized double-blind studies to evaluate the effects of 2 creams containing urea in the management of dry skin in atopic patients. Aquacare HP cream and Calmurid cream both contain 10% urea; the base properties are, however, different. The former cream is described as a moisturizing emulsion containing multisterols, phospholipids and fatty diols with a pH of about 6. Calmurid cream contains betaine and a high content of lactic acid with a pH of about 3. Side effects characterized as burning sensations upon application of the Calmurid cream were experienced by 13 out of 60 patients. This is thought to be due to the lower pH of the product. No side effects were noted with Aquacare HP.

132 IDOXURIDINE Four cases of proved allergic contact dermatitis caused by idoxuridine after application to the eye and skin for ophthalmic and genital herpes simplex infections were reported by Amon e t al. (48c). Patch tests were performed with 0.5%, 1% and 5% idoxuridine in a proprietary ointment base or dimethylacetamide. Cross reactions to brominated and chlorinated (but not to fluorinated) pyrimidine analogues could be noted. In another report the authors mention 2 more cases (49c), whilst Osmundsen ( 5 0c) has earlier reported 2 cases. Simpson (89 c) reports the clinical results of an uncontrolled double-blind random selection of 50 consecutive patients with attacks of herpes zoster who were treated with idoxuridine. Two concentrations (5% and 40%) in DMSO were used. Two patients developed an acute sensitization dermatitis. One was not patchtested, the other showed positive patch test reactions to 1% and 5%idoxuridine in DMSO. There was no reaction to DMSO alone. A stinging or burning sensation of the skin was experienced by 29 patients. Three patients complained of an unpleasant garlicky taste during treatment. In discussing various reports on patients allergic to a drug of apparently low sensitizing potential, all published within approximately one year, Amon et al. (48 c) list 2 possible causes for this increased frequency. In the first place the authors have been experiencing an epidemic of herpes progenitalis, which must have led to an increase of the applications of idoxuridine to the skin. In the second place the medication was applied as a solution of 5 - 4 0 % idoxuridine, (a concentration many times greater than that employed in standard ophthalmic preparations) in vehicles known to be excellent skin penetrants. Green and Staal (94 r) point out, that halogenated pyrimidines such as idoxuridine are myelosuppressive, radiosensitizing and potentially mutagenic compounds (see also 95, 96). In cases in which it is used on the eye, absorption of this drug is minimal. Application on the skin, however, may result in greater penetration. In addition to this, Green and Staal draw the attention to other possible undesirable side effects from the use of this drug such as enhanced susceptibility of resistant cell types to infection by cytomegalovirus and adenoviruses, enhanced replication of many other RNA and DNA

J. P. Nater

viruses and induction of infectious virus production in cells with integrated viral genpines, including viruses associated with human and animal neoplasia. OXYPHENBUTAZONE AND PHENYLBUTAZONE A case of contact sensitivity to Tanderil cream (oxyphenbutazone) with cross-sensitivity to Butazolidine (phenylbutazone) was reported by Krook (32c). Patch tests were performed in a concentration of 1% in petrolatum. The same author observed 2 cases of contact sensitivity to Butazolidine cream. These patients did not show cross-sensitivity to Tanderil. ANTISEPTICS SEPSO Sepso is the brand name of an alcoholic liquid introduced to replace S p i r i t u s i o d i concentratus. According to Heine and Zschunke (34 c ) allergic contact dermatitis to Sepso may occasionally develop, as may be proved by open patch testing. In 5 patients patch tests were performed with the individual ingredients: aluminium hydrochloride, ammonium thiocyanate, iron trichloride, camphor, salicylic acid and ethanol. All patients reacted positively to Sepso but only one reacted to an ingredient, namely ammonium thiocyanate (2%aq.). The authors suggest that patch tests with combinations of ingredients may offer a solution to this problem. DIETHYLTOLUAMIDE Contact urticaria comprises a wheal-andflare response occurring on the application of chemicals to intact skin. Maibach and Johnson (39 c) report on a patient who developed contact urticaria after contact with an insect repellent. Open patch tests were performed with several commercial brands of insect repellents. Only diethyltoluamide produced a positive wheal-and-flare response within 20 minutes after application. A positive passive transfer suggested that this case was due to an immunological response (immediate hypersensitivity). HEXOMEDINE (HEXAMIDINE) Hexomedine is used as a local disinfectant. The active substance is the di-isethionate salt of diamidino-4,4e-diphenoxy-l,6-

133

Drugs used on the skin

hexane, also called hexamidine. A case of contact allergic eczema with a positive patch test to a 0.15% solution of hexamidine in water was reported by Van Ketel (35c). A patch test with the related compound chlorhexidine was negative. MERCURY Pigmentation of the nails may occur after therapeutic use of mercurial preparations (40c). It may occur following administration of mercury by mouth, inunction or by inhalation, as well as after local application of lotions or ointments containing bichloride of mercury or ammoniated mercury. Exposure to the sun seems to initiate or accelerate the colour changes. Wtister e t al. (41 c) report a case of mercury poisoning caused by the bleaching of freckles. Apart from loss of weight, stomatitis, emotional disturbances, hearing and sensory loss the patient showed loss of hair and finger nail discolourations. The mercury contact of the finger nails was 1720 mg/1. The urinary level of mercury after dimercaprol injection was 1.97 rag/l, about 400 times above the upper limit of normal (0.005 mg/1). The authors warn against the uncontrolled external use of mercury-containing preparations for cosmetic purposes. The same warning comes from Summa (93c), who reports 2 cases of chronic mercury poisoning. Both patients had used skin creams containing mercury in various strengths (3-50%). These creams are commerciaUy available in Western Germany, usually in 20 g tins, as skin whiteners or skin care preparations. According to the regulation in force in that country, preparations containing not more than 5% Hg in the form of white precipitate can freely be obtained without prescriptions in drugstores and apparently also in shops dealing in cosmetics. Most customers were found to be dark-skinned foreigners. In one case, application on the skin of a total amount of 1 2 - 1 5 g Hg in the form of white precipitate during one year sufficed to cause symptoms of mercury poisoning. MERCUROCHROME (MERBROMIN) A patient has been reported who developed an erythematous, oedematous and vesicular eruption over the entire skin surface within a few hours after application of mercurochrome to injuries of the foot and the wrist (42c). The eruption was complicat-

ed by facial and laryngeal oedema. Treatment in the Intensive Care Unit was necessary. A patch test with Mercromina, which contains a 2% aqueous solution of the sodium salt of dibromohydroxy mercuric resorcinaphthalene had to be removed after 24 hours. Starting from the patch test the patient developed erythrodermia and laryngeal oedema; treatment with adrenaline and glucocorticoids in the Intensive Care Unit was again necessary. This was the third similar case seen by the author. In view of the serious generalized reaction observed, the author recommends the use of low concentrations in patch testing, especially if sensitivity to other mercurials has previously been detected. BENZYL BENZOATE Wranicz and Czernielewski (43 c) report on a 78-year-old female patient who was treated for scabies with Novoscabin, a drug which contains 30% benzyl benzoate. She developed an erythematous-bullous eruption on the sites to which the drug had been applied. The clinical picture corresponded with that of contact dermatitis. In the further course of the disease a generalized crop of urticarial-erythematous-bullous lesions resembling dermatitis herpetiformis appeared. Immunologically the presence of circulating antibodies and of antibodies bound to the basement membrane could be demonstrated. The authors discuss the possibility of provoking pemphigoid by topical application of Novoscabin.

VEHICLE CONSTITUENTS Hypersensitivity reactions to ingredients of vehicles has been discussed by Hannuksela e t al. (15R). The authors point out that the concentration of the various ingredients may be so low that epicutaneous tests with the preparation originally used remain negative. The authors report the results of a three-year survey of patch tests with vehicle constituents. Their findings are summarized in Table 4. LANOLIN The literature pertaining to lanolin hypersensitivity has recently been critically reviewed by Clark (16R), in view of the fact that this subject has become more prominent in the medical literature. The author

134

J. P. Nater

points out that most work has been concerned with relatively small groups of patients. The results, as far as the incidence o f lanolin allergy is concerned, cannot be equated to the overall general situation. Using recent data relating to 8.25 x 10 s p o p u l a t i o n in 3 E u r o p e a n countries, the incidence of specific lanolin allergy amongst the general p o p u l a t i o n is estimated by the author to be no m o r e than 9 - 7 per 106 and p r o b a b l y considerably less. STEARYL ALCOHOL (IOCTADECANOL) PROPYLENE GLYCOL HEXANTRIOL Eight cases o f c o n t a c t allergic reactions to Topsym o i n t m e n t were analysed by Pevny and Uhlich (17 C) and patch tests were p e r f o r m e d with constituents o f the vehicle. In 5 cases, positive patch tests were obtained to stearyl alcohol, 5 to p r o p y l e n e glycol and 3 to hexantriol. Patch tests with polyethylene glycol were negative in all cases. C o n t a c t allergic reactions to hexantriol have not been r e p o r t e d previously in the literature. SORBITAN MONOLAURATE A f t e r one week of t r e a t m e n t of an unexplained skin ailment w i t h A l p h a d e r m a patient developed a severe bullous e r u p t i o n with oedema. Patch tests with the constituents o f Alphaderm revealed a positive allergic reaction to sorbitan monolaurate, used as an emulsifier in the preparation. The patch Table 4.

test c o n c e n t r a t i o n was 5% in aqueous solution. Control tests remained negative (18c).

ANTIOXIDANTS NORDIHYDROGUAIARETIC ACID Nordihydroguaiaretic acid ( N D G A ) is used as an a n t i o x i d a n t in topical products. Jorgensen and Hjorth (22 c) described 2 cases of contact dermatitis. Cosmea lanolin cream containing 0.1% N D G A sensitized the first patient. The second patient was sensitized while preparing vitamin A D tablets at a pharmaceutical factory. B o t h patients reacted positively to N D G A 2% pet. RoedPetersen and Hjorth (23 c) r e p o r t e d 6 cases of contact sensitivity to N D G A since 1971. Three patients were sensitized by the abovem e n t i o n e d lanolin cream, the c o m p o s i t i o n of which has now been changed. In three patients the source of N D G A could not be traced. BUTYLATED HYDROXYANISOLE (BHA) BUTYLATED HYDROXYTOLUENE (BHT) Meneghini et al. (19 R) p e r f o r m e d patch tests w i t h n u m e r o u s constituents of topical medicaments, including additives. A m o n g 360 consecutive patients t h e y f o u n d one positive reaction to BHA 5% pet. and no reactions to BHT 5% pet. Cfinical data were n o t provided. Degreef and Verhoeve (20 c) observed one case of c o n t a c t sensitivity to BHA,

Allergic reactions to ingredients o f vehicles

Substance

Concentration %

Tested No.

Positive No.

Positive %

Balsam of Peru Perfume Thiomersal Formaldehyde Wool alcohols Lanolin Lanette N Sorbic acid Atlas G 2162 Atlas G 1441 Arlacel 83 Span 60 + 80 Parabens Hexachlorophene Triethanolamine stearate Tween 40 + 80 Propylene glycol Irgasan DP 300

25.0 3.0 0.1 2.0 30.0 as is 20.0 2.5 20.0 20.0 20.0 5.0 + 5.0 15.0 1.0 5.0 5.0 + 5.0 2.0 1.0

4,097 1,823 1,823 3,041 2,538 2,538 486 606 486 412 486 486 4,097 1,796 412 412 880 1,796

177 66 37 54 31 14 7 5 4 2 2 2 14 6 1 1 2 1

4.3 3.6 2.0 1.8 1.2 0.6 1.4 0.8 0.8 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.2 0.1

135

Drugs u s e d on the skin

probably caused by the use of an antimycotic cream containing 0.005% BHA. Patch tests were positive to BHA 5% pet. and to the active ingredient in the cream (miconazole nitrate 2% pet.). Roed-Petersen and H j o r t h ( 2 1 C) patch tested a total of 112 patients with BHA 2% pet. and BHT 2% pet. Two patients were positive to both, one to BHA only and one to BHT only. In 2 cases the positive patch tests were relevant, since both patients remained asymptomatic when antioxidants were avoided in food. Both had acute flares of vesicular eczema in the fingers after oral administration of small amounts. PROPELLANTS F R E O N 11 F R E O N 12 ( D I C H L O R O D I F L U O R O M E T H A N E ) ETHYLCHLORIDE (CHLOROETHANE)

Three patients with an acute eczema in the axiUae after the use of deodorant spray were investigated by van K e t e l ( 2 5 c ) . All 3 patients reacted positively to (open) patch tests with the propellant Freon 11 (trichloromonofluoromethane). One patient also reacted to Freon 12 (dichlorodifluoromethane). Of the other 2 patients one developed an eczematous eruption after ethylchloride had been sprayed onto the skin prior to taking a biopsy. Patch tests with ethyl chloride were performed on the other 2 patients and found to be positive. The author discusses the possibility of the existence of crosssensitization between the different compounds tested. ANTIPERSPIRANTS According to Agren-Jonsson and Magnussen (29 C) most cases of allergic axillary dermatitis seen at the Department of Dermatology of Lund (Sweden) developed after the use of Ercotina Derm (Ercoril Lotion). This antiperspirant and deodorant contains propantheline bromide 5% and trichlorocarbanilide (TCC) 0.25% in a vehicle consisting of propylene glycol 90% and water 4.75%. The sensitizer could be demonstrated in 12 of 14 patients with positive patch test reactions to the product. Eleven were positive to propantheline bromide, 3 to TCC and one to propylene glycol. Patch tests with propylene glycol were positive in one patient in

concentrations of 0.01%, 0.1% en 1%. Tile authors point out that propylene glycol is a weak sensitizer but also a potential irritant when applied under occlusion. The application of antiperspirant (containing propylene glycol 90%) may well have caused irritant reactions, which may have promoted sensitization to the other ingredients of the antiperspirant. I R G A S A N DP 3 0 0

Allergic contact dermatitis caused by Irgasan DP 300 in 2 persons was reported by Roed-Petersen e t al. (36c). One patient was sensitized by Irgasan 0.2% in a deodorant foot powder and the other by a deodorant stick containing 0.12% Irgasan. Patch tests were performed with Irgasan DP 300 in a concentration of 2% in petrolatum. Another case caused by a deodorant/antiperspirant spray 'Body mist' has been reported by Hindson (37 c). D I B U T Y L P t t T H A L A T E IN A N ANTIPERSPIRANT

Dibutyl phthalate is used as a plasticizer, as an insect repellant and also for the impregnation of clothing material. A case of allergic sensitivity to dibutyl phthalate conrained in an antiperspirant was reported by Calnan (30c). The patch test concentration was 5% dibutyl phthalate in petrolatum. A similar case was reported by Sneddon (31c).

MISCELLANEOUS AGENTS PERFUME

Collins and Mitchell (55 r) stress the difficulties in the search for the cause of allergic reactions to perfumes, which may contain as many as 50 ingredients. Fisher and Dooms-Goossens (56 R) point out that an ingredient of a perfume which is a sensitizer may become hypoallergenic by interacting with other ingredients during the ageing process of the perfume; thus a patient with an exquisite allergic sensitivity to cinnamic aldehyde may tolerate 2 perfumes containing cinnamic aldehyde without acquiring a dermatitis. There are several theories as to why cinnamic aldehyde can become a nonsensitizer in a perfume mixture. According to Fisher and Dooms-Goossens, testing with a mature perfume may for such reasons be much more significant than testing with individual ingredients.

136 A case of contact dermatitis due to the perfume Albert Verley E 1991 ( 3 8 - 4 2 0 ) in mycolog cream was reported by Coskey and Bryan(26c). Patch tests with other ingredients were negative. CINNAMON

Apart from its usage in bakery, cooking, confectionery, toothpastes and dentifrices, perfumes, cosmetics and on toothpicks, oil of cinnamon may be incorporated in proprietary medicines. Calnan (57 C) reported 6 patients with an allergic contact dermatitis from the use of a proprietary antiseptic ointment (TCP ointment), containing oil of cinnamon. Three were positive and three negative to balsam of Peru. Two of the latter cases and one other also reacted to cinnamic aldehyde. HEPARINO1D

Sch6ne (90 C) reports the results of the clinical assessment of a high concentrated heparinoid ointment/gel (Hirudoid 40,000 Salbe/Gel). In one case out of 513 treated patients a contact allergic reaction could be noted. Patch testing revealed the cause to be the heparinoid constituent of the ointment.

ACCIDENTAL CONTACTS

J. P. Nater

PHENOXYBENZAMINE HYDROCHLORIDE A woman laboratory technician developed acute allergic eczematous contact dermatitis of the hands and face, after contact with phenoxybenzamine hydrochloride (46c). Patch tests with phenoxybenzamine 1% in aqua, carried out after the clinical dermatitis had subsided, were positive. This was followed by recurrence of the dermatitis at the original sites. Sensitization to this chemical was produced in guinea pigs. Crosssensitivity to related compounds may be due to the chloroethylamine moiety of the molecule. No cross-sensitivity was observed to the dichlorodiethylamine compound, although nitrogen mustard is known to be capable of contact sensitization. PIPERAZINE A 55-year-old man developed respiratory symptoms on patch testing with piperazine (47c). The patient had worked some years before in a factory where piperazine and ethylenediamine were processed. After 2 months work in this factory he developed eczema of the hands, arms, face and penis. A patch test with piperazine 1% in water 3 years later was strongly positive and led furthermore to the above-mentioned respiratory symptoms. The reaction to ethylenediamine was negative.

NEMACTIL DECENTAN (PERPHENAZ1NE)

Camarasa (45 c) reports a case of chronic dermatitis of the lips and of the thumb and index finger of the right hand. The patient was a male psychiatric nurse who with these fingers picked up the pills which he gave to the patients. Patch test reactions were positive to: (1) Nemactil Rhodia or 8909 RP, i.e. cyano-3-(hydroxy-4-piperidine)-3-propyl10-phenothiazine; (2) Decentan Merck, i.e. 1 ( 2-hydroxyethyl)-4(3-chloro-10-phenothiazinyl) propyl-piperazine.

MISCELLANEOUS Contact dermatitis due to formaldehyde has been reported previously in renal dialysis units (see SED VIII). Another cause of dermatitis in haemodialysis units has been described by Penneys et al. (94c). An outbreak of dermatitis among patients in such a unit was traced to various thiuram compounds, probably leaching out of the components of the hemodialysis apparatus.

REFERENCES 1. Rudzki, E. and Zakrzewski, Z. (1975): Incidence of contact sensitivity to topically applied drugs as compared with the frequency of their prescription. Contact Dermatitis, 1,249. 2. Quante, M. (1976): Taubheit mit lokaler Neomycinapplikation. HNO (Bed.), 24, 127. 3. Pietsch, J. and Meakins, J. L. (1976): Complications of povidone-iodine absorption in topically treated burn patients. Lancet, H, 280.

4. Orfanos, C. E. and Wtistner, H. (1975): Penetration und Nebenwirkungen lokaler 0strogenApplikation bei Alopecia androgenetica. Hautarzt, 26, 367. 5. Zackheim, H. S. (1975): Treatment of psoriasis with 6-aminonicotinamide. Arch. Derm., 111, 880. 6. Hornstein, O.P., Wilsch, L. and Scheiber, W. (1975): Hautsch~iden durch prolongierte externe

Drugs used on the skin Kor tikosteroidanwendung. Einc statistischc H~iufigkeitsanalyse. Therapiewoche, 25, 4905. 7. Lee,& S. and Rapp, Y. (1975): The modern topical steroid. Int. J. Derm., 14, 412. 8. Du Vivier, A. and Staughton, R. B. (1975): Tachyphylaxis to the action of topically applied corticosteroids. Arch. Derm., 111, 581. 9. Pietzcker, F. and Kuncr, V. (1975): Anaphylaxie nach epicutanem Ampicillin-Test. Z. Hautkr., 50, 437. 10. Jordan, W.P., Higgins, M. and Dvorak, J. (1975): Allergic contact dermatitis to All-transretinoic acid; cpicutaneous and leukocyte migration inhibition testing. Contact Dermatitis, 1, 306. 11. Dogliotti, M., Caro, I., Hartdegen, R. G. and Whiting, D.A. (1974): Leucomclanoderma in blacks. S. Afr. med. J., 48, 1555. 12. Bentley-Phillips, B. and Bayles, A. H. (1975): Cutaneous reactions to topical application of hydroquinone. S. Afr. reed. J., 49, 1391. 13. Fitzpatrick, T.B., Arndt, K.A., l{l Mofty, A.M. and Pathak, M.A. (t966): Hydroquinone and psoralens in the therapy of hypermetanosis and vitiligo. Arch. Derm., 93, 589. 14. Dong Gil Byun, Young Hoe Kim, Yang Ja Park and Soon Bok Lee (1975): Treatment of hyperpigmented disease with 4-isopropylcaterhal (Korean). Korean J. Dermatol., 13, 5. 15. Hannuksela, M., Kousa, M. and Piril/i, V. (1976): Allergy to ingredients of vehicles. Contact Dermatitis, 2, 105. 16. Clark, E. W. (1975): Estimation of the general incidence of specific lanolin allergy. J. Soc. Cosmet. Chem., 26,323. 17. Pevny, J. and Uhlich, M. (1975): Allergic gegen Bestandteile medizinischer and kosmetischer Externa. Hautarzt, 26, 1252. 18. Finn, O. A. and Forsyth, A. (1975): Contact dermatitis due to Sorbitan monolaureate. Contact Dermatitis, 1, 318. 19. Meneghini, C. L., Rantuccio, F. and Lomuto, M. (1971): Additives, vehicles and active drugs of topical medicaments as causes of delayed-type allergic dermatitis. Dermatologica, 143, 137. 20. Degreef, H. and Verhoeve, L. (1975): Contact Dermatitis to miconazole nitrate. Contact Dermatitis, 1,269. 21. Roed-Peterson, J. and Hjorth, N. (1976): Contact dermatitis from antioxidants. Brit. J. Derm., 94, 233. 22. Jbrgensen, G. and Hjorth, N. (1970): Dermatitis from nordihydroguaiaretic acid, an antioxydant in fats. Contact Dermatitis Newsletter, no. 7., 151. 23. Roed-Peterson J. and Hjorth, N. (1976): Contact dermatitis from antioxydants. Hidden sensitizers in topical medications and foods. Brit. J. Derm., 94, 233. 24. Petrozzi, J.W. and Shore, R.N. (1976): Generalized exfoliative dermatitis from ethylenediamine. Arch. Derm., 112, 525.

137 25. Van Ketel, W. G. (1976): Allergic contact dermatitis from propellants in deodorant sprays in combination with allcrgy to ethyl chloride. C~)ntact Dermatitis, 2, 115. 26. Coskey, R.J. and Bryan, lt.G. (1975): Contact dermatitis dtlc to perfume in mycolog cream. Arch. Derm., 111, 131. 27. Frederiksson, T. and Gip, k. (1975): Urea creams in the treatment of dry skin and hand dermatitis. Int. J. Derm. {Philad.), 14,442. 28. Wohlrab, W. and B6hm, W. (1975): I:pidcrmisreaktion nach Langzcitcinwirkuug yon llarnstoff. Dermatologica, 15l, 149. 29. Agren-Jonsson, S. and Magnussen, B. (19761: Sensitization to propantheline bromide, trichlorocarbanilide and propylcne glycol in an antipcrspirant. Contact Dermatitis, 2, 79. 30. Calnan, C. D. (1975): Dil)utylphthalate. Contact Dermatitis, 1,388. 31. Sneddon, J.B. (1972): l)crmatitis from dibutyl phtalate in an aerosol antiperspirant and deodorant. O)ntact Dermatitis /Vewsletter, 12, 308. 32. Krook, G. (1975): Contact sensitivity to oxyphenbutazone (Tanderil) and cross-sensitivity to phenylbutazone (Butazolidine). Cow,tact Dermatitis, 1,385. 33. Stoppelman, M. R. tt. and van Valkenburg, R. A. (1955): Pigmcntatics cn gyneacomastie ten gevolgc van bet gebruik van stilboestrol bevattend haarwater bij kinderen. Ned. T. Geneesk., 99, 3925. 34. Heine, A. and Zschunke, E. (1976): Contact dermatitis to Sepso. Contact Dermatitis, 2, 60. 35. Van Ketek W. G. (1975): Allergic contact eczema by Hexomedine. Contact Dermatitis, 1, 332. 36. Rocd-Peterson, J., Auken, G. and Hjorth, N. (1975): Contact sensitivity to lrgasan DP 300. Contact Dermatitis, 1,293. 37. Hindson, T. C. (1975): lrgason D.P. 300 in a deodorant. Contact Dermatitis, 1,328. 38. Piyankova, Z.P. and Nugmanova, M. L. (1975): Dermatitis duc to elecampanc (Russian). Vegtn. Derm. Vener., 51/12, 52. 39. Maibach, H.l. and Johnson, lt. L. (1975): Contact urticaria syndrome. Arch. Derm., 111. 726. 40. Butterworth, T. and Strean, L. P. (1963): Mcrcureal pigmentation of nails. Arch. Derm., ~'~'. 107. 41. Wtistner, H. Orfanos, C.E., Steinbach. If., K~iferstein, H. and Herpers, H. (1975): Nagelverf'arbung und Haarausfall. Leitsymptome einer Quecksilbervergiftung dutch kosmetische Bleichmittel. Dtsch. reed. Wschr., 100, 1694. 42. Camarasa, G. (1976): Contact dermatitis from mercurochrome. Contact Dermatitis, 2, 120. 43. Wranicz, A. and Czernielewski, A. (1974): Pemfigoid sprowokowany nowoskabina. Preg. Derm., 61,693. 44. Hirohata, T., Masuda, Y., tlorie, A. and Kuratsune, M. (1973): Carcinogenicity of tar contain-

J. P. Nater

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