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Dermatological drugs, topical agents, and cosmetics
A.E. Goossens and J.K. Aronson
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Dermatological drugs, topical agents, and cosmetics
COSMETICS Reviews of the 7th Amendment to the Cosmetics Directive (2003/15/EC) have been published (1R , 2R ). The Directive foresees the phasing out of animal experiments by 2009, by introducing bans on animal testing of cosmetics and on the marketing in the EU of cosmetics tested on animals. For toxicity studies relevant to humans the ban would apply by 2013, with a possible postponement in case of technical difficulties in the development of alternative methods. The Directive also requires an immediate marketing ban if alternative methods have already been validated by the European Centre for the Validation of Alternative Methods and adopted by the Community. The safety of various ingredients of cosmetics, including tert-butyl alcohol, polyacrylamide and acrylamide residues, and a wide variety of antioxidants have been reviewed on the basis of animal toxicology (3ER , 4ER , 5ER ). Observational studies The prevalence and characteristic of adverse cosmetic events have been studied using a questionnaire supplied by ten community pharmacies to 4373 customers in Naples (6c ). There were 2716 female and 812 male respondents, of whom 98.5% reported using cosmetics. There were 1507 adverse cosmetic events; 848 customers had had at least one adverse cosmetic events and 18% reported more than one event. There was a significantly higher prevalence of adverse cosmetic events in women (27 versus 17% in men). In 95.9% the event affected the skin and 4.1% were systemic. Side Effects of Drugs, Annual 30 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(08)00014-7 © 2008 Elsevier B.V. All rights reserved.
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Among cutaneous reactions, burning and itching were the most prominent and accounted for 36 and 33% respectively. The most frequently reported systemic event was headache (40%) followed by nausea (24%). The authors concluded that there is a sizeable problem and they advocated a system to report, collect, and evaluate adverse cosmetic events. Skin The role of contact allergy in rosacea has been investigated in a retrospective study of the results of patch tests in 361 of 76 697 patients with rosacea (7c ). There were positive reactions to nickel (II) sulfate in 9.3%, fragrance mix in 8.8%, thimerosal in 6.9%, Myroxylon pereirae resin in 5.9%, potassium dichromate in 4.6%, and propolis in 2.8%. Patients with rosacea had a significantly higher risk of contact allergy to propolis and contact allergy to nickel was significantly less frequent. Only 2/329 patients were positive to neomycin sulfate and 1/100 to gentamicin sulfate. Of 118 patients tested with their own products, three were tested to metronidazole, and one had a positive reaction. Immunologic Products brought in by 5911 patients were subjected to 34 082 single patch tests and assigned to 1 of 26 categories, based on the EU Classification Annex I to 76/768/EEC (8c ). The leave-on products most commonly tested were creams, emulsions, lotions, gels, and oils for the skin (3621 tested, 312 positive). The rinse-off products most commonly tested were bath and shower preparations (1333 tested, 71 positive). Positive reactions to the fragrance mix, Myroxylon pereirae resin, methyldibromoglutaronitrile, (chloro-)methylisothiazolinone, 2-bromo-2-nitropropane-1,3diole and other ingredients of cosmetics and toiletries were more common than in productnegative patients.
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In patch tests with a cosmetic and fragrance series in 50 patients of both sexes with clinically suspected cosmetic dermatitis for more than 1 year, most of whom were young adults aged 10–29 years, 33 reacted to one or more allergens (9c ). Fragrance components were most commonly implicated (in 52%) followed by preservatives (39%), paraphenylenediamine (21%), and cetrimide and tertiary butyl hydroquinone (12% each).
(FDA) and the Consumer Federation of America (CFA). The safety of cosmetics has been reviewed by the CIR, with particular emphasis on hair dyes (12R ).
Infection risk In an assessment of the risk of transmission of the BSE prion in cosmetics, the FDA has concluded that cosmetics that contain proteins derived from bovine sources might be sources of exposure and that the preferred way of preventing such transmission by cosmetics would be by avoiding the use of highrisk cattle-derived protein in their manufacture (10c ). The FDA has therefore prohibited the use of certain cattle materials in cosmetics and human foods, including the brain, skull, trigeminal ganglia, spinal cord, parts of the vertebral column and the transverse processes of the thoracic and lumbar vertebrae, tonsils, and distal ileum.
Gold Immunologic Of 49 respondents to a questionnaire that was sent to 102 gold-allergic patients, all but one were women (11c ). Most of the patients reported that their dermatitis had improved after patch testing, but most had avoided other allergens as well as gold. The authors concluded that avoidance of gold earrings did not appear to benefit patients with earlobe dermatitis, but that total avoidance of gold jewelry on the hands and wrists did seem to benefit a subgroup of patients with facial and eyelid dermatitis who wore powder, eye shadow, or foundation on affected areas.
Hair dyes The Cosmetic Ingredient Review (CIR) program was established in 1976 by the Cosmetics, Toiletry, and Fragrance Association, with the support of the Food and Drug Administration
Respiratory The causes of occupational asthma over 8 year have been studied in 47 hairdressers, mean age 25 (range 17–52) years, using responses to specific inhalation (13c ). In 24 patients with asthma it was attributed to persulfate salts in 21, permanent hair dyes in two, and latex in one. In 13 of these 24 patients with occupational rhinitis, it was due to persulfate salts in 11 and to paraphenylenediamine in two. Patients with persulfate-induced asthma had a long period of exposure to bleaching agents and a long latent period between the start of exposure and the onset of symptoms. Immunologic An interview-based study in a representative random sample (n = 4000) of the Danish population showed that allergic skin reactions to hair dyes was more common than expected from patch-test studies (14c ). In all, 18% of the male respondents and 75% of the female respondents had at some point dyed their hair, the median age at first exposure being 16 years. Adverse skin reactions to hair dyes compatible with allergic reactions were reported in 5.3% of individuals who had ever used a hair dye. Of these, only 16% had been in contact with health-care services after the reaction. Direct oxidative DNA damage and production of tumor necrosis factor alfa have been studied in 19 hairdressers with contact dermatitis of the hands who had been exposed to irritants and allergens, mainly hair dyes; 14 had allergic contact dermatitis and five had irritant contact dermatitis (15c ). The serum concentrations of TNF alfa in those with allergic contact dermatitis were significantly higher than in controls; the effect increased with increasing exposure. There was significant exposure-related DNA damage in those with irritant contact dermatitis. Genotoxicity/mutagenicity/carcinogenicity The members of a biopharmaceutical drug development services contract research organization, Covance Laboratories Ltd, have reviewed the guidelines of the European Scientific Committee on Cosmetics and Non-Food Products (SCCNFP) for testing hair dyes for genotoxic/
182 mutagenic/carcinogenic potential (16SR ). They have pointed out that the battery of six in vitro tests recommended in those guidelines differs substantially from the batteries of two or three in vitro tests recommended in other guidelines and suggested that potential genotoxic activity may effectively be determined by the use of a limited number of well-validated test systems that are capable of detecting induced gene mutations and structural and numerical chromosomal change, and that increasing the number of in vitro assays would merely reduce increase the number of false positives. They recommended the use of three assays, the bacterial gene mutation assay, the mammalian cell gene mutation assay (preferably the mouse lymphoma tk assay), and the in vitro micronucleus assay, combined with metabolic activation systems optimized for the individual chemical types. One could comment, however, that it a high rate of false positives in such testing would be preferable to a high rate of false negatives. Problems in testing include the fact that new compounds are formed on the scalp by reaction between the chemicals in hair dyes and that one component could mask the genotoxicity of another. Tumorigenicity The possible association between the personal use of hair dyes and nonHodgkin’s lymphoma, leukemia, multiple myeloma, and Hodgkin’s disease has been investigated in a case-control study in 2737 patients and 1779 controls (17C ). Among women, there was no association between ever using hair dyes and the risk of lymphopoietic malignancies. For permanent hair dyes, there was a slightly but non-significantly increased risk of lymphocytic leukemia (OR = 1.3; 95% CI = 0.8, 2.2) and of follicular subtypes of non-Hodgkin’s lymphoma (OR = 1.3; 95% CI = 0.8, 2.0). Women who used black hair dye colors were at an increased risk of leukemia (OR = 1.9; 95% CI = 1.0, 3.4), in particular chronic lymphocytic leukemia (OR = 3.0; 95% CI = 1.1, 7.5). In a case-control study of 112 white women with gliomas and 215 controls there was a 1.7fold increased risk of glioma among women who had ever used hair coloring products (95% CI = 1.0, 2.9; n = 62), and a 2.4-fold risk among those who had used permanent hair coloring products (OR = 2.4; 95% CI = 1.3, 4.5; n = 39) (18C ). For women with the most
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aggressive form of glioma, glioblastoma multiforme, the risk increased with duration of exposure to 4.9 (95% CI = 1.6, 15.7; n = 10) after 21 or more years of permanent hair coloring use. The risk was higher with earlier age at first use. There was no association with non-permanent (sometimes called temporary or semi-permanent) hair coloring products. Teratogenicity The relation between maternal hair dye use in pregnancy and the risk of neuroblastoma in their offspring has been studied in 538 mothers of children with neuroblastoma and 504 controls (19C ). The use of any hair dye in the month before and/or during pregnancy was associated with a moderately increased risk of neuroblastoma (adjusted OR = 1.6; 95% CI = 1.2, 2.2). Temporary hair dyes (OR = 2.0, CI = 1.1, 3.7) were more strongly associated with neuroblastoma than permanent hair dyes (OR = 1.4, CI = 1.0, 2.0). It is not known whether or how the risk is affected by the color and chemical composition of the dye and the method of application.
Aminophenols Immunologic Allergic contact dermatitis due to paraphenylenediamine after tattooing with black henna has been reviewed (20R ). Paraphenylenediamine (PPD) is the most common screening agent used to diagnose allergic contact dermatitis from oxidative hair dyes. However, testing with this allergen does not pick up all cases. Contact allergy to two frequently used hair dye chemicals has been described: 3-nitro-para-hydroxyethylaminophenol for the first time and 4-amino-3-nitrophenol for the second time (21A ). • A 50-year-old woman developed severe scalp dermatitis and vesicular hand eczema for the first time in her life. She had a +? reaction to paraphenylenediamine and to her own hair collected at day 3 after exposure to the hair dye that had elicited the reaction. Open exposure to the product (often advised on the packaging of such products) was negative both before and after the allergic reaction to the product.
This adverse reaction could only be explained by patch testing with the individual hair dye
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product ingredients and the positive reactions to the dyes present. Work is currently going on to establish a new screening patch-test series for hair-dye allergy.
native or chemically modified forms, hydrogenated, disproportionated, esterified, polymerized, as salts, or reacted with maleic anhydride or formaldehyde. It is used in the sizing of paper and paperboard, to make waxes and varnishes, for coating the strings of bows used to play stringed musical instruments, and in permanent color markers. Exposure can occur by contact with adhesive tapes, soaps, coatings on price labels, eye shadow, periodontal and surgical dressings, furniture polish, glues, musician’s rosin, printing inks, printing paper surfaces, rubber, and plastics. The main sensitizing components are abietic acid and abitol (a mixture of hydroabietyl alcohols).
Sodium stearoyl lactylate Immunologic Contact allergy to sodium stearoyl lactylate, an emulsifier commonly used in food (E481), has been reported as the cause of dermatitis, because of its presence in a cosmetic cream (22A ).
Nail cosmetics The adverse effects of nail cosmetics have been reviewed (23R ). Nail cosmetics are of three types: (1) coatings that harden on evaporation; (2) coatings that polymerize; and (3) stick-on nail dressings (synthetic covers). The adverse effects of the two first types consist of both local reactions and distant contact dermatitis. Nail enamels especially cause ectopic contact dermatitis, while polymerizing coatings and synthetic covers are more likely to cause local reactions, which can be severe. Systemic adverse effects and infections can also occur.
Corticosteroids, topical Immunologic Corticosteroids not infrequently cause contact allergy. In most cases the reaction is eczematous, but occasionally other types of skin reactions occur. A generalized exanthematous reaction with pustulosis (AGEP), a drug eruption that is in most cases caused by systemic medication, has been reported in association with topical application of a glucocorticoid (24A ).
Respiratory Some workers exposed to colophony during soldering can develop occupational asthma. Serum obtained from seven exposed symptomatic individuals, some with a likely diagnosis of occupational asthma, 10 exposed asymptomatic individuals, and 11 unexposed individuals was tested for specific IgE antibodies against a protein extract produced following in vitro challenge of mono-mac-6 cells with colophony extract (26c ). The serum from exposed symptomatic individuals showed increased binding of specific IgE antibodies to a range of colophony-cell protein conjugates compared with both the exposed asymptomatic and the non-exposed control populations. The authors concluded that they were able to assess sensitization to colophony by detecting specific IgE in colophony-exposed workers with a likely diagnosis of occupational asthma. Immunologic Contact dermatitis from colophony is common. Of 250 Iranian patients with a diagnosis of contact dermatitis and/or atopic dermatitis 126 (50%) had at least one positive patch test reaction and 23 (9.2%) had more than two positive reactions to a range of allergens (27c ). Colophony caused reactions in 13 cases (5.2%) and was the fifth most common allergen.
Minoxidil Colophony
(SEDA-29, 156)
Colophony (rosin) derives from pine resin, tall oil, and stump extracts (25R ). It is used in its
(SED-15, 2354; SEDA-27, 217;
SEDA-29, 215) Immunologic Allergic contact dermatitis has been reported in a 72-year-old woman during
184 treatment with topical minoxidil for alopecia (28A ).
PHOTOTHERAPY AND PHOTOCHEMOTHERAPY
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therapy. However, in 4294 Japanese patients who had been exposed to long-term PUVA therapy in Korea, Thailand, Egypt, and Tunisia, with a follow-up period of at least 5 years, the risk of non-melanoma skin cancer relative to general dermatology out-patients was 0.86 (CI = 0.36, 1.35) (35c ).
(SED-15, 2823; SEDA-28, 171; SEDA-29, 158)
Aminolevulinic acid
UVB
Nervous system Photodynamic therapy with topical 5-aminolevulinic acid generally causes few adverse effects, which are mild and transient, such as itching, stinging or burning pain (29c ), and slight to moderate edema and erythema (30c ), although pain during illumination can be problematic, for example in psoriasis (31c ). The pain occasionally persists for up to 24 hours and rarely for several days. The mechanism may be related to GABA receptors, by which ALA is transported into peripheral nerve endings, resulting in fiber stimulation (32R ). Cooling by fanning or water spray directed at the treatment site is effective. Topical anesthesia with local anesthetics is not, but cold-air anesthesia can help. A severe, acute, predominantly motor polyneuropathy, with signs of autonomic involvement, and skin changes followed aminolevulinic acid administration in an 82-year-old man (33A ). There were changes in heme metabolism and the authors interpreted this as a rare response to aminolevulinic resembling an acute attack of hepatic porphyria with neurological features.
Tumorigenicity UVB phototherapy is commonly used to treat psoriasis and other skin diseases. The risk of skin cancer associated with UVB phototherapy has been surveyed in a systematic review of 11 prospective and retrospective studies in about 3400 patients published from 1966 to June 2002 (36M ). Other than the most recent Finnish study, none showed an increased risk of skin cancer. In one of the studies there was an increased rate of genital tumors associated with UVB phototherapy. The incidence of skin cancer in 1380 adults in a long-term study of PUVA has been investigated in relation to UVB exposure (37c ). High UVB exposure (at least 300 treatments) was associated with a modest but significant increase in the risk of squamous cell carcinoma (adjusted incidence rate ratio = 1.37, 95% CI = 1.03, 1.83) and basal cell carcinoma (adjusted IRR = 1.45, 95% CI = 1.07, 1.96). Among patients with under 100 PUVA treatments, high exposure to UVB was significantly associated with a risk of squamous cell carcinoma (adjusted IRR = 2.75, 95% CI = 1.11, 6.84) and basal cell carcinoma (adjusted IRR = 3.00, 95% CI = 1.30, 6.91) on body sites typically exposed to UVB but not on chronically sun-exposed sites, which are typically covered during therapy.
Skin Photocontact urticaria has been attributed to topical aminolevulinic acid in a patient with unilesional mycosis fungoides (34A ). In a photopatch test black light and visible light irradiation after topical aminolevulinic acid provoked an urticarial reaction in the uninvolved skin, suggesting an allergic reaction.
SUNSCREENS Drometrizole trisiloxane
PUVA Tumorigenicity There is an increased incidence of skin cancer in Caucasians who have been treated with psoralen plus ultraviolet A
Immunologic Allergic contact dermatitis from drometrizole trisiloxane, a chemical UVA and UVB sunscreen agent used in cosmetic products, has been reported, with concomitant sensitivities to other sunscreens (38A ). Allergic
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reactions to drometrizole trisiloxane seem to be rare, but this could be due to lack of appropriate testing.
Musculoskeletal Retinoids can rarely cause hyperostosis when they are used in high dosages and over long periods. In one case exuberant enthesitis occurred in a 60-year-old man with psoriatic arthropathy who had taken acitretin 25 mg/day for 10 years (44A ).
VITAMIN A (RETINOIDS) (SED-15, 3653; SEDA-27, 159; SEDA-28, 171; SEDA-29, 158; for vitamin A carotenoids see Chapter 34) Teratogenicity Although the teratogenicity of oral retinoids is well known, it is not clear what the risks are with topical retinoids (adapalene and tretinoin). Although the results of two flawed epidemiological studies were reassuring, new cases of birth defects were subsequently reported in children exposed in utero to topical tretinoin. However, the epidemiological data are still scant and unconvincing, neither confirming the risk nor ruling it out completely. It has been suggested that it is best to avoid topical retinoids altogether in early pregnancy (39R ).
Acitretin Ear, nose, throat Dysphonia has been attributed to acitretin (40A ). • A 36-year-old woman, who had taken acitretin 20 mg/day for palmoplantar keratoderma for about 3 months, complained of dysphonia. She had bilateral vocal fold edema and congestion, consistent with vocal abuse. Reduction of the dose of acitretin to 10 mg/day did not produce and the acitretin was withdrawn. Within 5 days, her voice recovered spontaneously. Acitretin was reintroduced and 8 days later she was dysphonic. When the acitretin was withdrawn the dysphonia resolved.
Sensory systems Sudden bilateral symmetrical sensorineural hearing loss has been attributed to oral acitretin (41A ). Gastrointestinal Rectal bleeding has been attributed to acitretin in a patient with discoid lupus erythematosus (42A ). Skin Pseudoporphyria, with erosions and crusts on the backs of the hands and millium cysts, has been attributed to acitretin used to prevent cutaneous malignancies (43A ). The acitretin was not withdrawn and the skins symptoms varied in severity, worsening in the summer.
Adapalene See tazarotene.
Isotretinoin Ear, nose, throat Hoarseness, possibly caused by excess granulomatous tissue formation over nodules on the vocal cords, has been reported in a patient taking isotretinoin (45A ). • A 38-year-old woman with papulopustular acne took isotretinoin 30 mg/day (0.6 mg/kg) for 3 weeks and noticed mild hoarseness, which gradually worsened. After 5 months, isotretinoin was withdrawn; 2 weeks later the hoarseness started to improve and it disappeared completely after 6 weeks. As the woman was a teacher, vocal abuse could have been the origin of this adverse event.
Psychiatric The possible association of isotretinoin with depression, suicidal ideation, and attempted suicide is still controversial. A series of cases suggesting an association between exposure to isotretinoin and manic psychosis has been reported (46c ). Five young adults developed manic psychosis during 1 year in association with isotretinoin treatment, resulting in suicidality and progression to long-standing psychosis. Associated risk factors were a family and personal history of psychiatric morbidity. The cases were drawn from 500 soldiers who had been evaluated in a military specialist dermatology clinic for severe acne. Skin An acquired port wine stain has been reported in a patient taking isotretinoin (47A ). • An 18-year-old man with severe comedonal and pustular acne took isotretinoin 40 mg/day for 6 months and 6 weeks after the end of the course of treatment developed a large erythematous telangiectatic area on his left cheek and upper lip, consistent with an acquired port stain.
186 The mechanism by which isotretinoin could cause this adverse effect is not clear, but increased skin dryness might have been the main pathological change.
Tazarotene Tazarotene has been included in a review of treatments for psoriasis, including adalimumab, efalizumab, and infliximab, alefacept and etanercept, and pimecrolimus (48R ). Skin Tazarotene cream 0.05 and 0.1% and adapalene 0.1% cream and gel have been compared in 26 subjects (49c ). They were applied under occlusive dressings at randomized sites on the upper back for about 24 hours 4 times a week and for 72 hours once a week for 3 weeks. In all, 16 subjects stopped using one or more of the test products because of severe irritation scores; all but one of these were at sites treated with tazarotene. The mean 21-day cumulative irritancy scores for adapalene 0.1% cream and gel were significantly lower than those for tazarotene cream 0.05 and 0.1% and not higher than with the control product.
Tretinoin (all-trans retinoic acid, ATRA) Placebo-controlled studies There has been a 2-year placebo-controlled study of the efficacy and safety of tretinoin emollient cream 0.05% in 204 subjects with photodamaged facial skin, including histopathological assessment of safety and an analysis of markers of collagen deposition (50c ). Tretinoin produced significantly greater improvement than placebo in the signs of photodamage (fine and coarse wrinkling, mottled hyperpigmentation, lentigines, and sallowness), the overall severity of photodamage, and the investigators’ global assessment of response. Histological evaluation showed no increase in keratinocytic or melanocytic atypia, dermal elastosis, or untoward effects on the stratum corneum compared with placebo. Immunohistochemistry showed a significant increase relative to placebo in facial procollagen 1C terminal, a marker for procollagen synthesis, at month 12.
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VITAMIN D ANALOGUES, TOPICAL Calcipotriol
(SED-15, 594; SEDA-28, 169; SEDA-29, 156; for oral vitamin D analogues see Chapter 34)
Skin In three patients with psoriasis calcipotriol ointment resulted in severe eczematous eruptions, which resolved after withdrawal of calcipotriol and topical application of a glucocorticoid. Patch tests showed a strong reaction to calcipotriol; there was no crossreactivity to other vitamin D3 analogues, tacalcitol and calcitriol (51c ). Exacerbation of pustular psoriasis has been attributed to calcipotriol (52A ). • A 55-year-old Japanese man with generalized pustular psoriasis controlled by oral etretinate, oral ciclosporin, and topical beclometasone dipropionate was given calcipotriol ointment (Dovonex® ; 50 µg/g) instead of the steroid, and 2 weeks later became feverish, with numerous pustules on most of the body, a white blood cell count of 10.8 × 109 /l, and a CRP concentration of 263 mg/l, consistent with exacerbation of pustular psoriasis. The lesions were controlled within 2 weeks by withdrawing calcipotriol, restarting topical 0.025% beclometasone dipropionate ointment, and increasing the dose of oral ciclosporin to 5 mg/kg/day. During remission, 2 months later, calcipotriol ointment again caused exacerbation of the pustular psoriasis.
Nails In 24 patients (19 women and 5 men) with nail psoriasis calcipotriol ointment (50 µg/g), 14 patients improved significantly after 3 months and two were completely free of nail lesions after 5 months (53c ). There were adverse reactions in two patients: periungual irritation and inflammation in one, irritation, pruritus, and oozing in the other; these patients withdrew from the study.
Tacalcitol The efficacy and safety of tacalcitol have been reviewed (54R ). The adverse effects are uncommon and generally mild, and include local irritation and pruriginous or burning sensations.
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39. 40. 41.
42.
option for psoriasis? Results of a randomized, observer-blinded study. Br J Dermatol 2005;152(2):279–83. Alster TS, Tanzi EL, Welsh EC. Photorejuvenation of facial skin with topical 20% 5-aminolevulinic acid and intense pulsed light treatment: a split-face comparison study. J Drugs Dermatol 2005;4(1):35–8. Fransson J, Ros AM. Clinical and immunohistochemical evaluation of psoriatic plaques treated with topical 5-aminolaevulinic acid photodynamic therapy. Photodermatol Photoimmunol Photomed 2005;21(6):326–32. Wennberg AM. Pain, pain relief and other practical issues in photodynamic therapy. Australas J Dermatol 2005;46(Suppl):S3–4. Sylantiev C, Schoenfeld N, Mamet R, Groozman GB, Drory VE. Acute neuropathy mimicking porphyria induced by aminolevulinic acid during photodynamic therapy. Muscle Nerve 2005;31(3):390–3. Yokoyama S, Nakano H, Nishizawa A, Kaneko T, Harada K, Hanada K. A case of photocontact urticaria induced by photodynamic therapy with topical 5-aminolaevulinic acid. J Dermatol 2005;32(10):843–7. Murase JE, Lee EE, Koo J. Effect of ethnicity on the risk of developing nonmelanoma skin cancer following long-term PUVA therapy. Int J Dermatol 2005;44(12):1016–21. Lee E, Koo J, Berger T. UVB phototherapy and skin cancer risk: a review of the literature. Int J Dermatol 2005;44(5):355–60. Lim JL, Stern RS. High levels of ultraviolet B exposure increase the risk of non-melanoma skin cancer in psoralen and ultraviolet A-treated patients. J Invest Dermatol 2005;124(3):505–13. Hughes TM, Martin JA, Lewis VJ, Stone NM. Allergic contact dermatitis to drometrizole trisiloxane in a sunscreen with concomitant sensitivities to other sun screens. Contact Dermatitis 2005;52:226–7. Anonymous. Topical retinoids during pregnancy (continued). Prescrire Int 2005;14(77):100–1. Petitpain N, Pouaha J, Cosserat F, Gambier N, Truchetet F, Cuny JF. Recurrent dysphonia and acitretin. J Voice 2006;20(4):642–3. Mahasitthiwat V. A woman with sudden bilateral sensorineural hearing loss after treatment psoriasis with acitretin. J Med Assoc Thai 2005;88(Suppl 1):S79–81. Fairhurst DA, Clark SM. Rectal bleeding following acitretin therapy for discoid lupus erythematosus. Dermatology 2005;211(4):385.
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43. Martin Ezquerra G, Sola Casas M, Herrera Acosta E, Umbert Millet P. Pseudoporhyria secondary to acitretin. J Am Acad Dermatol 2005;53(1):169–71. 44. Fairhurst DA, Clark SM. Rectal bleeding following acitretin therapy for discoid lupus erythematosus. Dermatology 2005;211(4):385. 45. Busso CIM, Serrano RL. Hoarseness during isotretinoin therapy. J Am Acad Dermatol 2005;52:168. 46. Barak YAC, Wohl YBC, Greenberg YA, Dayan YBB, Friedman TB, Shoval GA, Knobler HAD. Affective psychosis following Accutane (isotretinoin) treatment. Int Clin Psychopharmacol 2005;20:39–41. 47. Hoque S, Holden C. Acquired port wine stain following oral isotretinoin. Clin Exp Dermatol 2005;30:587–8. 48. Saini R, Tutrone WD, Weinberg JM. Advances in therapy for psoriasis: an overview of infliximab, etanercept, efalizumab, alefacept, adalimumab, tazarotene, and pimecrolimus. Curr Pharm Design 2005;11:273–80. 49. Dosik JS, Homer K, Arsonnaud S. Cumulative irritation potential of adapalene 0.1% cream and gel compared with tazarotene cream 0.05 and 0.1%. Cutis 2005;75(5):289–93. 50. Kang S, Bergfeld W, Gottlieb AB, Hickman J, Humeniuk J, Kempers S, Lebwohl M, Lowe N, McMichael A, Milbauer J, Phillips T, Powers J, Rodriguez D, Savin R, Shavin J, Sherer D, Silvis N, Weinstein R, Weiss J, Hammerberg C, Fisher GJ, Nighland M, Grossman R, Nyirady J. Long-term efficacy and safety of tretinoin emollient cream 0.05% in the treatment of photodamaged facial skin: a two-year, randomized, placebo-controlled trial. Am J Clin Dermatol 2005;6:245–53. 51. Foti C, Carnimeo L, Bonamonte D, Conserva A, Casulli C, Angelini G. Tolerance to calcitriol and tacalcitol in three patients with allergic contact dermatitis to calcipotriol. J Drugs Dermatol 2005;4(6):756–9. 52. Tamiya H, Fukai K, Moriwaki K, Ishii M. Generalized pustular psoriasis precipitated by topical calcipotriol ointment. Int J Dermatol 2005;44(9):791–2. 53. Zakeri M, Valikhani M, Mortazavi H, Barzegari M. Topical calcipotriol therapy in nail psoriasis: a study of 24 cases. Dermatol Online J 2005;11(3):5. 54. Leone G, Pacifico A. Profile of clinical efficacy and safety of topical tacalcitol. Acta Biomed 2005;76(1):13–9.
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COSMETICS Reviews of the 7th Amendment to the Cosmetics Directive (2003/15/EC) have been published (1R , 2R ). The Directive foresees the phasing out of animal experiments by 2009, by introducing bans on animal testing of cosmetics and on the marketing in the EU of cosmetics tested on animals. For toxicity studies relevant to humans the ban would apply by 2013, with a possible postponement in case of technical difficulties in the development of alternative methods. The Directive also requires an immediate marketing ban if alternative methods have already been validated by the European Centre for the Validation of Alternative Methods and adopted by the Community. The safety of various ingredients of cosmetics, including tert-butyl alcohol, polyacrylamide and acrylamide residues, and a wide variety of antioxidants have been reviewed on the basis of animal toxicology (3ER , 4ER , 5ER ). Observational studies The prevalence and characteristic of adverse cosmetic events have been studied using a questionnaire supplied by ten community pharmacies to 4373 customers in Naples (6c ). There were 2716 female and 812 male respondents, of whom 98.5% reported using cosmetics. There were 1507 adverse cosmetic events; 848 customers had had at least one adverse cosmetic events and 18% reported more than one event. There was a significantly higher prevalence of adverse cosmetic events in women (27 versus 17% in men). In 95.9% the event affected the skin and 4.1% were systemic. Side Effects of Drugs, Annual 30 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(08)00014-7 © 2008 Elsevier B.V. All rights reserved.
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Among cutaneous reactions, burning and itching were the most prominent and accounted for 36 and 33% respectively. The most frequently reported systemic event was headache (40%) followed by nausea (24%). The authors concluded that there is a sizeable problem and they advocated a system to report, collect, and evaluate adverse cosmetic events. Skin The role of contact allergy in rosacea has been investigated in a retrospective study of the results of patch tests in 361 of 76 697 patients with rosacea (7c ). There were positive reactions to nickel (II) sulfate in 9.3%, fragrance mix in 8.8%, thimerosal in 6.9%, Myroxylon pereirae resin in 5.9%, potassium dichromate in 4.6%, and propolis in 2.8%. Patients with rosacea had a significantly higher risk of contact allergy to propolis and contact allergy to nickel was significantly less frequent. Only 2/329 patients were positive to neomycin sulfate and 1/100 to gentamicin sulfate. Of 118 patients tested with their own products, three were tested to metronidazole, and one had a positive reaction. Immunologic Products brought in by 5911 patients were subjected to 34 082 single patch tests and assigned to 1 of 26 categories, based on the EU Classification Annex I to 76/768/EEC (8c ). The leave-on products most commonly tested were creams, emulsions, lotions, gels, and oils for the skin (3621 tested, 312 positive). The rinse-off products most commonly tested were bath and shower preparations (1333 tested, 71 positive). Positive reactions to the fragrance mix, Myroxylon pereirae resin, methyldibromoglutaronitrile, (chloro-)methylisothiazolinone, 2-bromo-2-nitropropane-1,3diole and other ingredients of cosmetics and toiletries were more common than in productnegative patients.
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In patch tests with a cosmetic and fragrance series in 50 patients of both sexes with clinically suspected cosmetic dermatitis for more than 1 year, most of whom were young adults aged 10–29 years, 33 reacted to one or more allergens (9c ). Fragrance components were most commonly implicated (in 52%) followed by preservatives (39%), paraphenylenediamine (21%), and cetrimide and tertiary butyl hydroquinone (12% each).
(FDA) and the Consumer Federation of America (CFA). The safety of cosmetics has been reviewed by the CIR, with particular emphasis on hair dyes (12R ).
Infection risk In an assessment of the risk of transmission of the BSE prion in cosmetics, the FDA has concluded that cosmetics that contain proteins derived from bovine sources might be sources of exposure and that the preferred way of preventing such transmission by cosmetics would be by avoiding the use of highrisk cattle-derived protein in their manufacture (10c ). The FDA has therefore prohibited the use of certain cattle materials in cosmetics and human foods, including the brain, skull, trigeminal ganglia, spinal cord, parts of the vertebral column and the transverse processes of the thoracic and lumbar vertebrae, tonsils, and distal ileum.
Gold Immunologic Of 49 respondents to a questionnaire that was sent to 102 gold-allergic patients, all but one were women (11c ). Most of the patients reported that their dermatitis had improved after patch testing, but most had avoided other allergens as well as gold. The authors concluded that avoidance of gold earrings did not appear to benefit patients with earlobe dermatitis, but that total avoidance of gold jewelry on the hands and wrists did seem to benefit a subgroup of patients with facial and eyelid dermatitis who wore powder, eye shadow, or foundation on affected areas.
Hair dyes The Cosmetic Ingredient Review (CIR) program was established in 1976 by the Cosmetics, Toiletry, and Fragrance Association, with the support of the Food and Drug Administration
Respiratory The causes of occupational asthma over 8 year have been studied in 47 hairdressers, mean age 25 (range 17–52) years, using responses to specific inhalation (13c ). In 24 patients with asthma it was attributed to persulfate salts in 21, permanent hair dyes in two, and latex in one. In 13 of these 24 patients with occupational rhinitis, it was due to persulfate salts in 11 and to paraphenylenediamine in two. Patients with persulfate-induced asthma had a long period of exposure to bleaching agents and a long latent period between the start of exposure and the onset of symptoms. Immunologic An interview-based study in a representative random sample (n = 4000) of the Danish population showed that allergic skin reactions to hair dyes was more common than expected from patch-test studies (14c ). In all, 18% of the male respondents and 75% of the female respondents had at some point dyed their hair, the median age at first exposure being 16 years. Adverse skin reactions to hair dyes compatible with allergic reactions were reported in 5.3% of individuals who had ever used a hair dye. Of these, only 16% had been in contact with health-care services after the reaction. Direct oxidative DNA damage and production of tumor necrosis factor alfa have been studied in 19 hairdressers with contact dermatitis of the hands who had been exposed to irritants and allergens, mainly hair dyes; 14 had allergic contact dermatitis and five had irritant contact dermatitis (15c ). The serum concentrations of TNF alfa in those with allergic contact dermatitis were significantly higher than in controls; the effect increased with increasing exposure. There was significant exposure-related DNA damage in those with irritant contact dermatitis. Genotoxicity/mutagenicity/carcinogenicity The members of a biopharmaceutical drug development services contract research organization, Covance Laboratories Ltd, have reviewed the guidelines of the European Scientific Committee on Cosmetics and Non-Food Products (SCCNFP) for testing hair dyes for genotoxic/
182 mutagenic/carcinogenic potential (16SR ). They have pointed out that the battery of six in vitro tests recommended in those guidelines differs substantially from the batteries of two or three in vitro tests recommended in other guidelines and suggested that potential genotoxic activity may effectively be determined by the use of a limited number of well-validated test systems that are capable of detecting induced gene mutations and structural and numerical chromosomal change, and that increasing the number of in vitro assays would merely reduce increase the number of false positives. They recommended the use of three assays, the bacterial gene mutation assay, the mammalian cell gene mutation assay (preferably the mouse lymphoma tk assay), and the in vitro micronucleus assay, combined with metabolic activation systems optimized for the individual chemical types. One could comment, however, that it a high rate of false positives in such testing would be preferable to a high rate of false negatives. Problems in testing include the fact that new compounds are formed on the scalp by reaction between the chemicals in hair dyes and that one component could mask the genotoxicity of another. Tumorigenicity The possible association between the personal use of hair dyes and nonHodgkin’s lymphoma, leukemia, multiple myeloma, and Hodgkin’s disease has been investigated in a case-control study in 2737 patients and 1779 controls (17C ). Among women, there was no association between ever using hair dyes and the risk of lymphopoietic malignancies. For permanent hair dyes, there was a slightly but non-significantly increased risk of lymphocytic leukemia (OR = 1.3; 95% CI = 0.8, 2.2) and of follicular subtypes of non-Hodgkin’s lymphoma (OR = 1.3; 95% CI = 0.8, 2.0). Women who used black hair dye colors were at an increased risk of leukemia (OR = 1.9; 95% CI = 1.0, 3.4), in particular chronic lymphocytic leukemia (OR = 3.0; 95% CI = 1.1, 7.5). In a case-control study of 112 white women with gliomas and 215 controls there was a 1.7fold increased risk of glioma among women who had ever used hair coloring products (95% CI = 1.0, 2.9; n = 62), and a 2.4-fold risk among those who had used permanent hair coloring products (OR = 2.4; 95% CI = 1.3, 4.5; n = 39) (18C ). For women with the most
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aggressive form of glioma, glioblastoma multiforme, the risk increased with duration of exposure to 4.9 (95% CI = 1.6, 15.7; n = 10) after 21 or more years of permanent hair coloring use. The risk was higher with earlier age at first use. There was no association with non-permanent (sometimes called temporary or semi-permanent) hair coloring products. Teratogenicity The relation between maternal hair dye use in pregnancy and the risk of neuroblastoma in their offspring has been studied in 538 mothers of children with neuroblastoma and 504 controls (19C ). The use of any hair dye in the month before and/or during pregnancy was associated with a moderately increased risk of neuroblastoma (adjusted OR = 1.6; 95% CI = 1.2, 2.2). Temporary hair dyes (OR = 2.0, CI = 1.1, 3.7) were more strongly associated with neuroblastoma than permanent hair dyes (OR = 1.4, CI = 1.0, 2.0). It is not known whether or how the risk is affected by the color and chemical composition of the dye and the method of application.
Aminophenols Immunologic Allergic contact dermatitis due to paraphenylenediamine after tattooing with black henna has been reviewed (20R ). Paraphenylenediamine (PPD) is the most common screening agent used to diagnose allergic contact dermatitis from oxidative hair dyes. However, testing with this allergen does not pick up all cases. Contact allergy to two frequently used hair dye chemicals has been described: 3-nitro-para-hydroxyethylaminophenol for the first time and 4-amino-3-nitrophenol for the second time (21A ). • A 50-year-old woman developed severe scalp dermatitis and vesicular hand eczema for the first time in her life. She had a +? reaction to paraphenylenediamine and to her own hair collected at day 3 after exposure to the hair dye that had elicited the reaction. Open exposure to the product (often advised on the packaging of such products) was negative both before and after the allergic reaction to the product.
This adverse reaction could only be explained by patch testing with the individual hair dye
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product ingredients and the positive reactions to the dyes present. Work is currently going on to establish a new screening patch-test series for hair-dye allergy.
native or chemically modified forms, hydrogenated, disproportionated, esterified, polymerized, as salts, or reacted with maleic anhydride or formaldehyde. It is used in the sizing of paper and paperboard, to make waxes and varnishes, for coating the strings of bows used to play stringed musical instruments, and in permanent color markers. Exposure can occur by contact with adhesive tapes, soaps, coatings on price labels, eye shadow, periodontal and surgical dressings, furniture polish, glues, musician’s rosin, printing inks, printing paper surfaces, rubber, and plastics. The main sensitizing components are abietic acid and abitol (a mixture of hydroabietyl alcohols).
Sodium stearoyl lactylate Immunologic Contact allergy to sodium stearoyl lactylate, an emulsifier commonly used in food (E481), has been reported as the cause of dermatitis, because of its presence in a cosmetic cream (22A ).
Nail cosmetics The adverse effects of nail cosmetics have been reviewed (23R ). Nail cosmetics are of three types: (1) coatings that harden on evaporation; (2) coatings that polymerize; and (3) stick-on nail dressings (synthetic covers). The adverse effects of the two first types consist of both local reactions and distant contact dermatitis. Nail enamels especially cause ectopic contact dermatitis, while polymerizing coatings and synthetic covers are more likely to cause local reactions, which can be severe. Systemic adverse effects and infections can also occur.
Corticosteroids, topical Immunologic Corticosteroids not infrequently cause contact allergy. In most cases the reaction is eczematous, but occasionally other types of skin reactions occur. A generalized exanthematous reaction with pustulosis (AGEP), a drug eruption that is in most cases caused by systemic medication, has been reported in association with topical application of a glucocorticoid (24A ).
Respiratory Some workers exposed to colophony during soldering can develop occupational asthma. Serum obtained from seven exposed symptomatic individuals, some with a likely diagnosis of occupational asthma, 10 exposed asymptomatic individuals, and 11 unexposed individuals was tested for specific IgE antibodies against a protein extract produced following in vitro challenge of mono-mac-6 cells with colophony extract (26c ). The serum from exposed symptomatic individuals showed increased binding of specific IgE antibodies to a range of colophony-cell protein conjugates compared with both the exposed asymptomatic and the non-exposed control populations. The authors concluded that they were able to assess sensitization to colophony by detecting specific IgE in colophony-exposed workers with a likely diagnosis of occupational asthma. Immunologic Contact dermatitis from colophony is common. Of 250 Iranian patients with a diagnosis of contact dermatitis and/or atopic dermatitis 126 (50%) had at least one positive patch test reaction and 23 (9.2%) had more than two positive reactions to a range of allergens (27c ). Colophony caused reactions in 13 cases (5.2%) and was the fifth most common allergen.
Minoxidil Colophony
(SEDA-29, 156)
Colophony (rosin) derives from pine resin, tall oil, and stump extracts (25R ). It is used in its
(SED-15, 2354; SEDA-27, 217;
SEDA-29, 215) Immunologic Allergic contact dermatitis has been reported in a 72-year-old woman during
184 treatment with topical minoxidil for alopecia (28A ).
PHOTOTHERAPY AND PHOTOCHEMOTHERAPY
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therapy. However, in 4294 Japanese patients who had been exposed to long-term PUVA therapy in Korea, Thailand, Egypt, and Tunisia, with a follow-up period of at least 5 years, the risk of non-melanoma skin cancer relative to general dermatology out-patients was 0.86 (CI = 0.36, 1.35) (35c ).
(SED-15, 2823; SEDA-28, 171; SEDA-29, 158)
Aminolevulinic acid
UVB
Nervous system Photodynamic therapy with topical 5-aminolevulinic acid generally causes few adverse effects, which are mild and transient, such as itching, stinging or burning pain (29c ), and slight to moderate edema and erythema (30c ), although pain during illumination can be problematic, for example in psoriasis (31c ). The pain occasionally persists for up to 24 hours and rarely for several days. The mechanism may be related to GABA receptors, by which ALA is transported into peripheral nerve endings, resulting in fiber stimulation (32R ). Cooling by fanning or water spray directed at the treatment site is effective. Topical anesthesia with local anesthetics is not, but cold-air anesthesia can help. A severe, acute, predominantly motor polyneuropathy, with signs of autonomic involvement, and skin changes followed aminolevulinic acid administration in an 82-year-old man (33A ). There were changes in heme metabolism and the authors interpreted this as a rare response to aminolevulinic resembling an acute attack of hepatic porphyria with neurological features.
Tumorigenicity UVB phototherapy is commonly used to treat psoriasis and other skin diseases. The risk of skin cancer associated with UVB phototherapy has been surveyed in a systematic review of 11 prospective and retrospective studies in about 3400 patients published from 1966 to June 2002 (36M ). Other than the most recent Finnish study, none showed an increased risk of skin cancer. In one of the studies there was an increased rate of genital tumors associated with UVB phototherapy. The incidence of skin cancer in 1380 adults in a long-term study of PUVA has been investigated in relation to UVB exposure (37c ). High UVB exposure (at least 300 treatments) was associated with a modest but significant increase in the risk of squamous cell carcinoma (adjusted incidence rate ratio = 1.37, 95% CI = 1.03, 1.83) and basal cell carcinoma (adjusted IRR = 1.45, 95% CI = 1.07, 1.96). Among patients with under 100 PUVA treatments, high exposure to UVB was significantly associated with a risk of squamous cell carcinoma (adjusted IRR = 2.75, 95% CI = 1.11, 6.84) and basal cell carcinoma (adjusted IRR = 3.00, 95% CI = 1.30, 6.91) on body sites typically exposed to UVB but not on chronically sun-exposed sites, which are typically covered during therapy.
Skin Photocontact urticaria has been attributed to topical aminolevulinic acid in a patient with unilesional mycosis fungoides (34A ). In a photopatch test black light and visible light irradiation after topical aminolevulinic acid provoked an urticarial reaction in the uninvolved skin, suggesting an allergic reaction.
SUNSCREENS Drometrizole trisiloxane
PUVA Tumorigenicity There is an increased incidence of skin cancer in Caucasians who have been treated with psoralen plus ultraviolet A
Immunologic Allergic contact dermatitis from drometrizole trisiloxane, a chemical UVA and UVB sunscreen agent used in cosmetic products, has been reported, with concomitant sensitivities to other sunscreens (38A ). Allergic
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reactions to drometrizole trisiloxane seem to be rare, but this could be due to lack of appropriate testing.
Musculoskeletal Retinoids can rarely cause hyperostosis when they are used in high dosages and over long periods. In one case exuberant enthesitis occurred in a 60-year-old man with psoriatic arthropathy who had taken acitretin 25 mg/day for 10 years (44A ).
VITAMIN A (RETINOIDS) (SED-15, 3653; SEDA-27, 159; SEDA-28, 171; SEDA-29, 158; for vitamin A carotenoids see Chapter 34) Teratogenicity Although the teratogenicity of oral retinoids is well known, it is not clear what the risks are with topical retinoids (adapalene and tretinoin). Although the results of two flawed epidemiological studies were reassuring, new cases of birth defects were subsequently reported in children exposed in utero to topical tretinoin. However, the epidemiological data are still scant and unconvincing, neither confirming the risk nor ruling it out completely. It has been suggested that it is best to avoid topical retinoids altogether in early pregnancy (39R ).
Acitretin Ear, nose, throat Dysphonia has been attributed to acitretin (40A ). • A 36-year-old woman, who had taken acitretin 20 mg/day for palmoplantar keratoderma for about 3 months, complained of dysphonia. She had bilateral vocal fold edema and congestion, consistent with vocal abuse. Reduction of the dose of acitretin to 10 mg/day did not produce and the acitretin was withdrawn. Within 5 days, her voice recovered spontaneously. Acitretin was reintroduced and 8 days later she was dysphonic. When the acitretin was withdrawn the dysphonia resolved.
Sensory systems Sudden bilateral symmetrical sensorineural hearing loss has been attributed to oral acitretin (41A ). Gastrointestinal Rectal bleeding has been attributed to acitretin in a patient with discoid lupus erythematosus (42A ). Skin Pseudoporphyria, with erosions and crusts on the backs of the hands and millium cysts, has been attributed to acitretin used to prevent cutaneous malignancies (43A ). The acitretin was not withdrawn and the skins symptoms varied in severity, worsening in the summer.
Adapalene See tazarotene.
Isotretinoin Ear, nose, throat Hoarseness, possibly caused by excess granulomatous tissue formation over nodules on the vocal cords, has been reported in a patient taking isotretinoin (45A ). • A 38-year-old woman with papulopustular acne took isotretinoin 30 mg/day (0.6 mg/kg) for 3 weeks and noticed mild hoarseness, which gradually worsened. After 5 months, isotretinoin was withdrawn; 2 weeks later the hoarseness started to improve and it disappeared completely after 6 weeks. As the woman was a teacher, vocal abuse could have been the origin of this adverse event.
Psychiatric The possible association of isotretinoin with depression, suicidal ideation, and attempted suicide is still controversial. A series of cases suggesting an association between exposure to isotretinoin and manic psychosis has been reported (46c ). Five young adults developed manic psychosis during 1 year in association with isotretinoin treatment, resulting in suicidality and progression to long-standing psychosis. Associated risk factors were a family and personal history of psychiatric morbidity. The cases were drawn from 500 soldiers who had been evaluated in a military specialist dermatology clinic for severe acne. Skin An acquired port wine stain has been reported in a patient taking isotretinoin (47A ). • An 18-year-old man with severe comedonal and pustular acne took isotretinoin 40 mg/day for 6 months and 6 weeks after the end of the course of treatment developed a large erythematous telangiectatic area on his left cheek and upper lip, consistent with an acquired port stain.
186 The mechanism by which isotretinoin could cause this adverse effect is not clear, but increased skin dryness might have been the main pathological change.
Tazarotene Tazarotene has been included in a review of treatments for psoriasis, including adalimumab, efalizumab, and infliximab, alefacept and etanercept, and pimecrolimus (48R ). Skin Tazarotene cream 0.05 and 0.1% and adapalene 0.1% cream and gel have been compared in 26 subjects (49c ). They were applied under occlusive dressings at randomized sites on the upper back for about 24 hours 4 times a week and for 72 hours once a week for 3 weeks. In all, 16 subjects stopped using one or more of the test products because of severe irritation scores; all but one of these were at sites treated with tazarotene. The mean 21-day cumulative irritancy scores for adapalene 0.1% cream and gel were significantly lower than those for tazarotene cream 0.05 and 0.1% and not higher than with the control product.
Tretinoin (all-trans retinoic acid, ATRA) Placebo-controlled studies There has been a 2-year placebo-controlled study of the efficacy and safety of tretinoin emollient cream 0.05% in 204 subjects with photodamaged facial skin, including histopathological assessment of safety and an analysis of markers of collagen deposition (50c ). Tretinoin produced significantly greater improvement than placebo in the signs of photodamage (fine and coarse wrinkling, mottled hyperpigmentation, lentigines, and sallowness), the overall severity of photodamage, and the investigators’ global assessment of response. Histological evaluation showed no increase in keratinocytic or melanocytic atypia, dermal elastosis, or untoward effects on the stratum corneum compared with placebo. Immunohistochemistry showed a significant increase relative to placebo in facial procollagen 1C terminal, a marker for procollagen synthesis, at month 12.
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VITAMIN D ANALOGUES, TOPICAL Calcipotriol
(SED-15, 594; SEDA-28, 169; SEDA-29, 156; for oral vitamin D analogues see Chapter 34)
Skin In three patients with psoriasis calcipotriol ointment resulted in severe eczematous eruptions, which resolved after withdrawal of calcipotriol and topical application of a glucocorticoid. Patch tests showed a strong reaction to calcipotriol; there was no crossreactivity to other vitamin D3 analogues, tacalcitol and calcitriol (51c ). Exacerbation of pustular psoriasis has been attributed to calcipotriol (52A ). • A 55-year-old Japanese man with generalized pustular psoriasis controlled by oral etretinate, oral ciclosporin, and topical beclometasone dipropionate was given calcipotriol ointment (Dovonex® ; 50 µg/g) instead of the steroid, and 2 weeks later became feverish, with numerous pustules on most of the body, a white blood cell count of 10.8 × 109 /l, and a CRP concentration of 263 mg/l, consistent with exacerbation of pustular psoriasis. The lesions were controlled within 2 weeks by withdrawing calcipotriol, restarting topical 0.025% beclometasone dipropionate ointment, and increasing the dose of oral ciclosporin to 5 mg/kg/day. During remission, 2 months later, calcipotriol ointment again caused exacerbation of the pustular psoriasis.
Nails In 24 patients (19 women and 5 men) with nail psoriasis calcipotriol ointment (50 µg/g), 14 patients improved significantly after 3 months and two were completely free of nail lesions after 5 months (53c ). There were adverse reactions in two patients: periungual irritation and inflammation in one, irritation, pruritus, and oozing in the other; these patients withdrew from the study.
Tacalcitol The efficacy and safety of tacalcitol have been reviewed (54R ). The adverse effects are uncommon and generally mild, and include local irritation and pruriginous or burning sensations.
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