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35_623_652 05.11.2005 11:22 Uhr Seite 623

Chapter 35 Topical Drugs 35 Francisco M. Brandão, An Goossens, Antonella Tosti

Contents habits. Prescribing habits are changing, 35.1 Incidence and Prevalence ...... 623 and some medicaments that were common 20–30 years ago,such as sulfonamides,penicillin,and 35.2 Factors Predisposing , have now been replaced by other al- to Medicament Contact Dermatitis ...... 624 lergenic drugs, such as anti-inflamma- 35.3 Clinical Patterns of Contact Reactions . . . . 624 tory drugs (NSAID), and . 35.3.1 Irritant Contact Dermatitis ...... 624 The real incidence of adverse reactions to topical 35.3.2 Contact Urticaria ...... 625 medicaments is not known, and most of the data 35.3.3 Other Important Clinical Patterns ...... 625 about prevalence are quite old. Bandmann et al. [1] 35.3.4 Allergic Contact Dermatitis ...... 626 found that 14% of 4,000 patients tested in several Eu- 35.4 Allergens ...... 627 ropean countries were allergic to medicaments.Blon- 35.4.1 Local ...... 627 deel et al. [2] found a much higher incidence – 54.6%. 35.4.2 and ...... 627 Still, in Belgium [3], 17% of 2,025 patients were aller- 35.4.3 Antivirals ...... 629 gic to the ingredients of pharmaceutical products, 35.4.4 Antimycotics ...... 629 while in Italy, in the 1980s [4], about 20.5% of 8,230 35.4.5 Corticosteroids ...... 630 patients were allergic to topical drugs. In Sweden, 35.4.6 Antihistamines ...... 632 40% of all recorded allergic reactions were due to 35.4.7 Nonsteroidal Anti-Inflammatory Drugs . . . 632 medicaments [5], which was equivalent to an annual 35.4.8 Ingredients of the Vehicles ...... 634 incidence of 43/100,000. More recently, in Singapore 35.4.9 Other Allergens ...... 635 [6], 22.5% of patients tested at a contact dermatitis 35.4.10 Transdermal Therapeutic Systems ...... 636 clinic had medicament sensitivity.A more recent sur- 35.5 Sites at Risk ...... 637 vey in Italy (1984–1993) disclosed a prevalence of 35.5.1 Ophthalmic Preparations ...... 637 13.2% in patients with nonoccupational allergic con- 35.5.2 Vulval and Perianal Dermatoses ...... 638 tact dermatitis [7], while in Portugal, over a 6-year 35.5.3 Stasis Dermatitis and Leg Ulcer Patients . . . 638 period (1998–2003), 18.0% of all patch-tested pa- 35.6 Systemic Contact Dermatitis ...... 639 tients were sensitized to medicaments (Table 1). Such 35.7 Diagnosis and Prognosis ...... 640 a high figure may be due to the existence and use of several topical still containing 35.8 Appendix: Allergens in Medicaments compounds, , and other common sensitiz- (pet. petrolatum, aq. aqueous, eth. , o.o. oil) ...... 641

References ...... 644 Table 1. Incidence of medicament contact allergy in Portugal, 1998–2003 (data from the Portuguese Contact Dermatitis Group) Year Total patients Patch tests positive % 35.1 Incidence and Prevalence patch tested to medicaments

Cutaneous adverse drug reactions are usually an iat- 1998 4,154 740 17.8 1999 3,990 755 18.9 rogenic disease induced in patients. More rarely, they 2000 3,625 675 18.6 are an occupational disease, either in health care per- 2001 3,361 635 18.9 sonnel or in pharmaceutical industry employees. 2002 2,681 490 18.3 The incidence of topical reactions to drugs varies 2003 2,849 426 14.9 from one area to another, and from one country to Total 20,660 3,721 18.0 another, depending on local prescribing and self- 35_623_652 05.11.2005 11:22 Uhr Seite 624

624 Francisco M. Brandão, An Goossens, Antonella Tosti

ers. However, there is a trend of these figures to de- cidence of medicament allergy [3, 4]. In addition, pa- crease in future. tients with otitis externa, eye problems, perianal and These differences are due not only to geographic vulval dermatoses, and chronic hand and foot der- differences, but also to the type of patient selection – matitis are known to frequently develop secondary leg ulcer patients, anogenital dermatitis, for example medicament allergy. – and to the specific interests of some investigators.A In other chronic dermatological conditions, how- prevalence of allergic reactions to medicaments of ever,such as atopic dermatitis and psoriasis,this pos- about 15%, excluding leg ulcers or other high-risk pa- sibly increased contact allergy seems to be an open tients,seems a realistic figure to be expected in a con- question. In atopic patients, the defective T-cell pop- tact dermatitis clinic. However, this figure does not ulation and the difficulty in sensitizing patients to include other clinical entities, such as irritant contact dinitrochlorobenzene (DNCB) would suggest that dermatitis or contact urticaria, among others. these patients would not develop allergic contact der- matitis as often as nonatopic individuals [10]. This seems to be confirmed in some reports [11, 12], al- Core Message though others consider that atopic patients become sensitized to topical medicaments at least as often as í A prevalence of up to 15% of allergic nonatopic patients [13–15]. contact dermatitis to topical medicaments It has also been suggested that psoriatic patients is, probably, a realistic figure in most are not easily sensitized [16, 17], and that sensitiza- contact clinics. tion could be associated with certain localizations (palmoplantar and flexural [18]), although this could not be confirmed by other authors [19, 20]. Sensitiza- tion was found to be equal in other patients, especial- ly to antipsoriatic medicaments [21–24], although 35.2 Factors Predisposing seemingly less to corticosteroids [19, 25]. to Medicament Contact Dermatitis

Many factors may contribute, in various ways, to cu- Core Message taneous drug sensitization. The environment, on the whole, must be considered to be the more important í The use of medicaments under occlusion 35 contributing factor, although there is some individu- or in folds increases its absorption and al predisposition, which mainly depends on genetic allergenic potential. It is not unanimous factors. The intrinsic sensitizing potential of each if atopic and psoriatic patients really drug is by far the most important factor (see Chap.3), do sensitize more or less to topical although sometimes impurities, contaminants, and medicaments. degradation of products may be the allergenic mate- rial [4].Moreover,compound allergy [8] and quench- ing phenomena [9] may interfere with this intrinsic capacity. However, many of the more potent aller- gens, such as sulfonamides and penicillin, have now 35.3 Clinical Patterns of Contact Reactions been almost banished from our prescribing habits and from the market; on the other hand, some weak Allergic contact dermatitis is by far the more com- sensitizers, such as neomycin, are so widely used that mon and more important clinical entity caused by several new cases are seen every year. topical drugs. However, other pathological clinical The use of medicaments in high concentrations entities, through direct cutaneous aggression, by im- or in vehicles that increase skin penetration favors munoallergic mechanisms, or by local or systemic their irritant and sensitizing capacities. The same ap- pharmacological effects, may be caused by medica- plies when medications are used in folds, under oc- ments (Table 2) [26–29]. clusive dressings or in transdermal devices, both of which lead to a much greater skin absorption and, thus, increase the probability of developing contact 35.3.1 Irritant Contact Dermatitis allergy. Damage to the skin barrier is another very impor- There are several medicaments that can irritate the tant factor favoring sensitization. Leg ulcer and stasis skin [26,30] (Table 3).Most are well-known mildly ir- dermatitis patients are known to have a very high in- ritant drugs, and their irritancy is usually expected, 35_623_652 05.11.2005 11:22 Uhr Seite 625

Topical Drugs Chapter 35 625

Table 2. Clinical patterns of eruptions caused by topical medic- repeated contact, the skin becomes dry, erythema- aments [26–29] tous, and scaly, with pruritus or burning sensation, Allergic contact dermatitis usually confined to the application area [26]. If ap- Irritant contact dermatitis plied for a longer time, in higher concentrations, or Photoallergic contact dermatitis in occluded areas, they may cause acute irritant con- Phototoxic contact dermatitis tact dermatitis with edema, erythema, vesicles, or Contact urticaria bullae that may be difficult to differentiate from al- Photocontact urticaria Dermographism lergic contact dermatitis. Airborne allergic contact dermatitis Airborne irritant contact dermatitis predominates Airborne irritant contact dermatitis in exposed areas, but, as opposed to photosensitive Airborne photoallergic contact dermatitis dermatitis, it does not spare areas such as the upper Airborne phototoxic contact dermatitis eyelids, retroauricular folds, or submental area. Erythema-multiforme-like eruptions Lichenoid contact dermatitis The subjective irritant sensation of “stinging” may Purpuric contact dermatitis be immediate or delayed, and may be caused by sev- Skin necrosis eral drugs (see Chap. 15). Dyschromia Pustular contact dermatitis Lymphomatoid contact dermatitis 35.3.2 Contact Urticaria /folliculitis/rosacea Granulomatous eruption Interactions with cutaneous microbial flora Since the first reports [31], the contact urticaria syn- Pharmacological local effects drome (CUS) has been frequently studied. It includes Systemic side-effects the localized cutaneous forms (immunological and nonimmunological), as well as a broad spectrum of noncutaneous involvement (generalized urticaria, Table 3. Topical drugs that can induce irritant contact derma- asthma, and anaphylaxis). The list of medicaments titis (adapted from [26, 30]) causing immunological contact urticaria (ICU) or nonimmunological contact urticaria (NICU) is very Oxidizing agents , benzoyl long (Table 4) [32–37] (see also Chap. 5). Chlorprom- peroxide, cantharidin, hypochlorite, azine has been reported as causing photocontact ur- permanganate, , , ticaria [38]. povidone-iodine Denaturing agents Formaldehyde, mercuric drugs Salicylic , compounds, 35.3.3 Other Important Clinical Patterns resorcinol, pyrogallol Organic solvents , , Topical medicaments may cause other noneczema- ethyl ether, chloroform, tous contact reactions (see Chap. 21). Erythema-mul- Antineoplastic drugs Carmustine, mechlorethamine, tiforme-like eruptions or urticarial papular and 5-fluorouracil plaque eruption may be caused by several drugs Other compounds Quaternary ammonium com- [26–28, 39–41] (Table 5). This eruption is usually pre- pounds, tar, dithranol, thimerosal, ceded by an eczematous allergic reaction, which be- gentian violet, brilliant green, , mercurial com- comes urticarial, disseminates after a few days, and pounds, , , persists longer than the initial reaction. nonsteroidal anti-inflammatory Skin necrosis induced by medicaments is a rare drugs, , calcipotriol, urea, event. Gentian violet and brilliant green may cause α and other -hydroxy necrosis, especially when applied in the genital area , dimethylsulfoxide, , monobenzone, podophyllotoxin, [42]. Quaternary ammonium compounds in high selenium sulfide, methyl nicotinate concentration [43], dichlorhexidine, 5-fluorouracil, phenol, and povidone iodine have also been incrimi- nated as causing skin necrosis [26, 44]. Purpuric reactions may be due to proflavine [45] and sometimes desired, as part of their therapeutic and [46]. antibio- action – tretinoin, benzoyl peroxide, 5-fluorouracil, tics can cause lichenoid reactions [47], as can mercu- dithranol, sulfur compounds, and others. The first ry in dental amalgams; its removal sometimes im- contact usually does not produce any visual altera- proves the oral lesions [48, 49]. Mercury salts may al- tion or abnormal subjective sensation.However,after so cause either hyper- or hypopigmentation [50]. 35_623_652 05.11.2005 11:22 Uhr Seite 626

626 Francisco M. Brandão, An Goossens, Antonella Tosti

Table 4. Topical drugs that can induce immunological contact Table 5. Topical drugs inducing erythema-multiforme-like urticaria (ICU) and nonimmunological contact urticaria (NI- eruptions [26–28, 39–41] CU) [32–37] Ethylenediamine NICU ICU Pyrrolnitrin Sulfonamides IDU Alcohols Alcohols /sodium benzoate Antibiotics Mephenesin Nifuroxime Ampicillin Mafenide Scopolamine hydrobromide Proflavine Mechlorethamine Capsaicin Cephalosporins Povidone iodine DMSO Chloramphenicol DNCB Formaldehyde Clioquinol Neomycin Diphenylcyclopropenone Nicotinic acid esters Sorbic acid/sorbates Mezlocillin Vitamin E Tar extracts Neomycin Tincture of benzoin Penicillin Rifamycin fungal, viral, or parasitic diseases, they can mask and Aescin Benzocaine aggravate the pre-existing disease, leading, for exam- ple, to “tinea incognito” or converting common sca- Carboxymethyl cellulose bies into the “Norwegian” type. Benzophenone Long-term application of potent corticosteroids to Phenothiazines the whole skin promotes skin absorption of large Promethazine Chlorpromazine amounts of the drug, which may induce Cushing’s Levomeprazine syndrome [53]. Nonsteroidal anti-inflam- The percutaneous absorption of other drugs can matory drugs rarely provoke toxic systemic effects. The degree of absorption depends on the physicochemical proper- ties of the substance, the use of occlusive dressings, Ketoprofen the vehicle in which the substance is incorporated, the drug concentration, the site of application, age, Propoxyphen butazone temperature, and the integrity of the skin barrier 35 Mechlorethamine [26]. Boric acid, carmustine, , gentami- cin, hexachlorphene, , , mercurial propionate compounds, phenol, salicylic acid, and selenium sul- fide [26] represent some of the drugs that have been Polysorbate 60 noted to cause systemic toxicity. Parabens Cetyl Nicotine Core Message Pilocarpine Polyvinyl pyrrolidone í Beyond allergic contact dermatitis, topical drugs may induce several other clinical patterns, like irritant dermatitis, contact The effects of the application of topical cortico- urticaria, erythema multiforme, skin , mainly potent fluorinated steroids, over necrosis, purpuric and lichenoid reactions, long periods are well known. Women with a sebor- hyper and hypopigmentation, and others. rheic diathesis, using steroids on the face, may devel- op acneiform or rosaceiform eruptions, perioral der- matitis, or hypertrichosis, leading to so-called topical drug addiction [51].On the face,as well as in other ar- eas, they induce cutaneous atrophy, telangiectasia, 35.3.4 Allergic Contact Dermatitis purpura, ecchymoses (which evolve into pseudostel- lariae scars), susceptibility to minor trauma, striae Most contact reactions to medicaments are of the al- distensae, and vellus hair growth [26, 52]. When ap- lergic type, whether by direct contact, or an airborne plied on skin , mainly tinea, but also other or photoallergic mechanism. They usually arise as a 35_623_652 05.11.2005 11:22 Uhr Seite 627

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complication of a pre-existing, possibly eczematous, [57,58], or pruritus vulvae [59], but occupational cas- dermatosis. es have been reported [60]. Nowadays, they have The clinical picture is usually an acute dermatitis largely been replaced by anesthetics of other groups. – erythema, edema, papules, and vesicles, sometimes They may cross-react with other components of the with exudation and scaling, and always accompanied para-group, especially with p-phenylenediamine. by intense pruritus. When a previous dermatosis is Dibucaine (), a derivative, is being treated, aggravation of the picture may suggest currently more frequently used in such medica- superimposed sensitization. However, particularly if ments. It can also cause allergic contact dermatitis the sensitization is due to a or to an in- [55, 61–64] and systemic contact dermatitis [65]. gredient of a corticosteroid , this acute picture The amide derivative group, lidocaine (lignocaine, is usually mild or absent due to the anti-inflammato- xylocaine), (Marcaine), ry properties of the . In these circumstances, if (Carbocaine), and (Citanest), are less po- the dermatosis does not improve, despite correct tent sensitizers. However, as they are now more often treatment, a secondary contact allergy should be sus- used than p-aminobenzoic esters, there have been pected. several cases of sensitization reported. Since the first In patients with stasis dermatitis and/or leg ul- descriptions [66, 67], many other cases of allergy to cers, or other chronic eczemas, it is not rare to see lidocaine have been reported [68, 69], mainly from dissemination of the eczema (hematogenous route – Australia [68], where there are several over-the- systemic contact dermatitis) to the other leg at first, counter products containing lidocaine. It cross- then to the entire integument, leading sometimes to reacts with mepivacaine and less often with bupiva- erythroderma; this is mainly seen in older patients caine and prilocaine [68]. Contact sensitization to with long-standing eczemas. Sometimes, there is prilocaine is rare [70], and it has been primarily in- scant local symptomatology, and the first acute duced by EMLA cream [71, 72]; in none of these cases symptoms are seen at a distance, usually by ectopic was there cross-reaction with lidocaine. dissemination (on the face,for example).In our expe- Several other, mainly local, anesthetics, including rience, elderly patients with eyelid dermatitis should , (proparacaine) [73], oxy- arouse the suspicion of allergy to topical drugs ap- buprocaine (in ophthalmic preparations) [74], pro- plied on the lower limbs, i.e., NSAID and venotropic pipocaine, (pramoxine), , cy- drugs. clomethycaine, propanidid (intravenous ), Airborne [54] and photoallergic contact derma- diclonine hydrochloride [26, 55], and butylaminob- titis have a similar clinical expression – acute or sub- enzoate [75] have been reported as sensitizers. acute dermatitis on exposed areas. They differ from toxic dermatitis because they have a more polymor- phic clinical picture, not precisely limited to exposed Core Message areas. However, as stated with the irritant type, there are some locations spared in photodermatitis, which í Benzocaine and other p-aminobenzoic may be affected in the airborne type, such as the derivatives may cross-react with compo- upper eyelids, under the chin, behind the ears, the nents of the para-group, but are less used back of the neck, or even the scalp. nowadays. Dibucaine and lidocaine and derivatives, which are more often used, are less potent sensitizers, but several cases 35.4 Allergens of allergic contact dermatitis have been reported. Topical medicaments include active principles and ingredients of the vehicles, many of which are found in cosmetics. Most substances in a medicament may, at some point, induce cutaneous sensitization. 35.4.2 Antibiotics and Antimicrobials

35.4.1 Local Anesthetics Antibiotics and other antimicrobials and that are used on the skin may cause contact allergy. The esters of p-aminobenzoic acid (PABA), benzo- Their sensitizing capacity is quite variable, depend- caine, (Novocaine),and amethocaine (tetra- ing not only on their intrinsic potential, but also on caine) are allergenic topical anesthetics [55, 56]. They percutaneous penetration, site of application, and were often used to treat pruritus ani, frequency of prescription and use. 35_623_652 05.11.2005 11:22 Uhr Seite 628

628 Francisco M. Brandão, An Goossens, Antonella Tosti

Aminoglycoside antibiotics, especially neomycin, tartrate, virginiamycin, and form the most important group of topical antibiotics. are mainly of veterinary use.Veterinary surgeons and Neomycin, which is included in the standard series, farmers are those usually affected [84, 85]. Virgini- has a wide range of use and is rarely used systemical- amycin can cross-react with . ly. It is often combined with topical corticosteroids, Bacitracin causes contact urticaria [86] and con- not only for use on the skin, but also in many eye and tact allergy, especially in leg ulcers/stasis dermatitis ear preparations (Fig. 1). This association may mask patients [87–91]. The concomitance of reactions to the neomycin sensitization, due to the corticosteroid both neomycin and [88, 91] is not due to anti-inflammatory activity. In most statistics, neo- cross-reaction, but to their frequent association in mycin appears as the leading allergenic medicament topical medicaments [92]. Contact allergy to chlo- [1, 3, 4, 76–79]. Gentamicin is less often used and ramphenicol is uncommon and is usually due to the seems to be less allergenic than neomycin [77,78, 80], use of eye preparations [77,93].As with other antimi- with which it may cross-react [76, 81]. Other less fre- crobials, allergy to sodium fusidate seems to occur quently used are mainly found in especially in leg ulcer patients [79, 90, 94]. Tetracy- ophthalmic and ear preparations, or sensitize clines [95], clindamycin [96] (which may cross-react through occupational medical or veterinary contact with lincomycin), and [97] are generally – streptomycin, , kanamycin, paromomy- rare sensitizers. base is a weak sensi- cin, , , , framycetin tizer [98], but its salts (sulfate, stearate, and ethylsuc- (neomycin B, soframycin). With the exception of cinate) may more readily induce contact allergy [99]. streptomycin, aminoglycosides often cross-react [76, In the past, penicillin became a frequent sensitizer 78, 81–83]. in some countries [1], but nowadays, it is hardly used topically. Semi-synthetic penicillins and derivatives – ampicillin, amoxycillin, pivampicillin, cloxacillin, and cephalosporins (first, second, or third genera- tion) – can cause either allergic contact dermatitis [100–104] or contact urticaria [105, 106] in health care personnel, pharmaceutical industry workers, veterinary surgeons, or farmers. Having been one of the major sensitizers some decades ago [1, 4], topical sulfonamides are now very 35 little used in skin products. They are still present in ophthalmic preparations (sulfathiazole and sulfacet- amide) and vaginal (sulfathiazole), but re- ports of sensitization are scarce. Sulfanilamide-con- taining powders and creams may,however, be a prob- a lem in leg ulcer patients [89], and mafenide (4-ho- mosulphanilamide) can still be a common in some countries [107]. sulfadiazine, marketed in some countries for use on , seems to be almost nonallergenic and does not cross-react with other sulfonamides [108]. is a local used in oint- ment or lubricated dressings for wounds and burns. It is a well known sensitizer that can induce very se- vere reactions in some patients [76, 109]. Clioquinol (Vioform) and (Sterosan) are usually combined with corticosteroids in topical prepara- tions. They are weak sensitizers and may cross-react, clioquinol being the more important of the two aller- gens [79, 110]. b One of the most extensively used local antiseptics in the present day is povidone iodine. Besides skin ir- Fig. 1a, b. Allergic contact dermatitis from neomycin in eye- ritation and necrosis,there have been a few reports of drops (a) and associated with severe conjunctivitis (b) (cour- contact allergy [89, 111] and contact urticaria [36]. tesy of P.J. Frosch) Thimerosal () contains two sensitizing 35_623_652 05.11.2005 11:22 Uhr Seite 629

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moieties, mercury and thiosalicylic acid [112]. It is used in merthiolate tincture, and as a in vaccines, toxoids, contact lens solutions, and other eye preparations. The relevance of a positive patch test to thimerosal is usually very difficult to establish. Most cases seem to be due either to vaccines or to ophthalmic products [113–115]. Patients sensitized to the thiosalicylic moiety of thimerosal are at risk of developing photosensitization to [112,116]. Other mercury compounds include and phenylmercury salts. Merbromin (mercurochrome) had wide use in Portugal, Spain, and certain other countries, but its use has now almost been aban- doned; it may cause anaphylaxis [117]. Quaternary Fig. 2. Acute allergic contact dermatitis from tromantadine ammonium compounds are widely used antiseptics HCl and ,and can cause irritation and necro- sis, as well as contact sensitization [118]. Triphenylmethane dyes include gentian violet ridine [131] are mainly used in ophthalmologic prep- (pyoctanin), brilliant green, malachite green, methyl arations. green, rosaniline, chrysoidine, and . They are rare sensitizers [119, 120]. Core Message

Core Message í Acyclovir is a weak allergen. Patients sensitized to this antiviral may develop í Neomycin is still a frequent allergen and systemic contact dermatitis if administered may cross-react with most aminoglyco- valaciclovir, ganciclovir, or famciclovir. sides, with the exception of streptomycin. Penicillin and sulfonamides are, currently, rare sensitizers. Bacitracin can cause im- mediate and delayed reactions and, often, reacts simultaneously with neomycin and 35.4.4 Antimycotics polymyxin B. Most antimycotics can cause contact allergy, among them are hydroxyquinoline, [132] and its derivatives,pyrrolnitrin, [133],tolnaf- tate [134], [135], and [136, 137], as 35.4.3 Antivirals well as several derivatives, for which con- tact and cross-allergic reactions have been missed Tromantadine hydrochloride and acyclovir are the because of problems with the correct choice of vehi- two most widely prescribed antiviral drugs. Troman- cle for patch testing [138]. An extensive study on the tadine is a potent sensitizer,with several cases of con- sensitizing capacity (in guinea pigs) of tact allergy reported [121–123]. It usually causes a [139, 140], – mostly used in agriculture [140] very severe acute exudative eczema around the lips, – and [141] was performed by Hausen et al. characteristically in patients who have already used and they could demonstrate that imidazoles, the tromantadine several times for treatment of recur- most commonly used antimycotics, have only very rent herpes simplex (Fig. 2). Acyclovir, although weak sensitization properties compared to,for exam- much more extensively used, is a weak sensitizer ple, naftifine [139]. The most frequently reported [124, 125]. Some of the cases of contact dermatitis imidazoles having caused allergic contact dermatitis from Zovirax cream are probably due to compound [see 138–140 for a review] are the substances most allergy [126].Patients with allergic contact dermatitis commonly used, i.e., , econazole, isocona- to acyclovir may develop systemic contact dermatitis zole – which may provoke pustular contact derma- to valaciclovir, ganciclovir, and famciclovir [127–129], titis [142] – and [143] (probably due to its the only valid alternatives being foscarnet and ci- use at a 28% concentration in a nail solution) (Fig. 3). dofovir [129]. Idoxuridine (IDU) [123, 130] and triflu- , which is only marketed in the Far East, 35_623_652 05.11.2005 11:22 Uhr Seite 630

630 Francisco M. Brandão, An Goossens, Antonella Tosti

phenylethylimidazoles (miconazole, econazole, , , and tioconazole). Systemic contact dermatitis may occur with antimycotics.

35.4.5 Corticosteroids

Contact allergy to corticosteroids is now a well estab- lished phenomenon, and cases from all over the world have been reported in the literature. The inci- Fig. 3. Paronychia due to allergic contact dermatitis from tio- dence of the reactions observed, however, varies and conazole nail solution (courtesy of O. Bordalo) depends on several factors, such as the nature and amount of corticosteroids used in each country, pre- scription habits, the awareness among the medical profession of the importance of corticosteroid sensi- seems to be a strong allergen, both clinically and ex- tivity, the selection of the patients and their referral perimentally [see 140 for a review]. , to test centers, the routine testing of screening agents considered to be an unusual allergen [144], but re- for corticosteroid sensitivity, as well as of all the cor- ported as an occupational allergen in a nurse [145], ticosteroids used by the patient, and the test and sulconazole, ketoconazole, , – reading methods used (see [162, 163] for a review, which showed a moderate sensitizing capacity [140] [164, 165]). – enilconazole,and [138,146] have been Patients with contact allergy to corticosteroids less frequently reported as causes of contact allergy. generally present with a chronic dermatitis that is Cross-sensitivity has been reported mainly within not exacerbated by, but fails to respond to, cortico- the group of the phenylmethylimidazoles, for exam- steroid therapy.Indeed,the allergenic and simultane- ple, between miconazole, econazole, and isoconazole, ous anti-inflammatory effects of topical corticoster- as well as sulconazole, and also between isoconazole oids cause a nonspecific self-supporting eczematous 35 and tioconazole [138,147],but not ketoconazole.They condition, which is rarely recognized as a potentially do not seem to cross-react with the phenylmethyli- iatrogenic sensitivity [162–164]. midazoles, i.e., clotrimazole, bifonazole, and crocon- Although infrequent relative to the large scale of , for which cross-reactions between them may their use, allergic reactions may also arise to the cor- [148], but not necessarily [149], occur. The more re- ticosteroids administered by inhalation in the treat- cent reports concern [150–152] (with ment of or bronchial asthma [162–164]. Gen- possible cross-reactivity with econazole and sulcona- eralized reactions may, of course, also occur after zole [150]), lanoconazole [152–156] – all from Japan – systemic administration (oral, intravenous, intra-ar- and (cross-reactivity to miconazole ticular). The lesions may manifest themselves mainly and econazole) [157]. as eczema, exanthema, purpura, urticaria, and so on Drug eruptions after systemic administration [163, 166, 167], with type IV or delayed hypersensitiv- have been described, such as immediate reactions to ity [168] being much more common than type I or ketoconazole [158, 159], systemic reactions to nystatin immediate hypersensitivity [169, 170]. – also in lozenges [160] – and a generalized exan- In general, corticosteroid-sensitive patients react thematous pustulosis (confirmed by a positive patch upon patch testing to several corticosteroids. This test result) to [161]. may,in part,be because most of them have used large numbers of corticosteroids and would, thus, be vul- Core Message nerable to concomitant sensitization. However, irref- utable proof for the existence of cross-reactions is provided by reactions to substances to which the pa- í The imidazoles are not strong sensitizers, tient has never been exposed. Studies in this regard but as they are very extensively used, can have practical consequences for the identifica- several cases have been described. tion of screening agents and for advice regarding the Cross-reaction between them has been topical and systemic corticosteroids that the corti- reported mainly within the group of costeroid-sensitive patient can safely use. Our earlier 35_623_652 05.11.2005 11:22 Uhr Seite 631

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Table 6. The new classification of corticosteroids based on cross-reaction patterns

Characteristics of the group Typical members Possible cross-reactions with corticosteroids outside the group

Group A No methyl substitution on , acetate, D2 group labile steroids: C16, no side chain on C17, , , , possibly short side chain , pivalate hydrocortisone-17-butyrate, on C21 methylprednisolone aceponate,

Group B Cis diol or ketal function on (R-isomer), , – C16 and C17, possibly a side , acetonide, chain on C21 acetonide

Group C Methyl substitution on C16, , – no side chain on C17, possibly flumethasone pivalate, halomethasone a side chain on C21

Group D1 Methyl substitution on C16 Betamethasone, dipropionate, – (so far halogenation on the betamethasone-17-valerate, basic structure), side-chain , ester on C17, and often also propionate, momethasone furoate on C21

Group D2 No methyl substitution on C16 Hydrocortisone aceponate, Budesonide S-isomer, (up to now no halogenation of , Group A corticosteroids the four-ring structure), side- hydrocortisone-17-butyrate, chain ester on C17, possibly a methylprednisolone aceponate, side chain on C21 prednicarbate

studies led us to suggest four groups of cross-react- which the metabolized prednisolone [173] and meth- ing molecules [171], which, in the light of new find- ylprednisolone [174] belong. This mechanism might ings [172], were subclassified as regards to the ester- also account for cross-reactions that have been ob- type corticosteroids (Table 6). served between hydrocortisone and hydrocortisone- Indeed, when testing Group D molecules, contact- 17-butyrate (our own data and [175]), the latter being allergic reactions are frequently observed with sub- able to be converted to hydrocortisone-21-butyrate, stances such as hydrocortisone-17-butyrate, -acepo- which is rapidly hydrolyzed to form hydrocortisone nate, and -buteprate, as well as methylprednisolone [176]. However, individual skin metabolization char- aceponate and prednicarbate, rather than with mole- acteristics certainly influence the cross-sensitivity cules as betamethasone and its esters, such as valer- patterns observed [172, 177]. ate and dipropionate, valerate, diflora- Thus,not only the molecular configuration,but al- sone diacetate, clobetasol propionate, so other factors, such as the presence of certain sub- butyrate, and also the newer furoate stituents, the role of which is still being discussed and (now classified as Group and more than one site of immune recognition might D1). The former esters can be classified as the more be involved [177], the solubility in the vehicle used, sensitizing D2 corticosteroid molecules. They are the patch-test conditions [178], and the skin penetra- “pro-drug”corticosteroids that, because of their high tion [177] seem to be critical for the allergenic and lipophilicity, easily penetrate the skin, where they the cross-reaction potential of individual corticos- break down into the corresponding structures with teroids. the hydroxyl group at the C21 and/or C17 positions. As most contact allergies are missed if corticoster- As regards the influence of the skin metabolization of oids are not routinely tested, it has been recommend- corticosteroids, patch test results have shown [172] ed [179] to add (0.1% pet.) that, for instance, positive reactions to “labile” mole- (screening agent for Group A) [180, 181] and budeso- cules such as prednicarbate and methylprednisolone nide (0.01% pet.) (screening agent for acetonides and aceponate correlate significantly with reactions ob- the labile esters [182]) to the standard series, al- tained with Group A corticosteroids (P<0.01), to though a uniform agreement on the patch-test con- 35_623_652 05.11.2005 11:22 Uhr Seite 632

632 Francisco M. Brandão, An Goossens, Antonella Tosti

centration has not been achieved, with some authors 35.4.7 Nonsteroidal Anti-Inflammatory favoring lower [183, 184] and others higher [185, 186] Drugs patch-test concentrations. Should a corticosteroid sensitivity be detected, more extensive corticosteroid series should be test- Topical nonsteroidal anti-inflammatory drugs ed, if possible, to determine cross-reactivity patterns, (NSAIDs) have been introduced to the market in the so that appropriate advice for the future can be given past few decades for the treatment of soft trau- both for local and for systemic corticosteroid therapy ma, inflammatory and musculoskeletal disorders, [187]. and some inflammatory skin diseases as an alterna- tive to topical corticosteroids. They have the advan- tage of being simple to apply, of having low systemic Core Message absorption, and of avoiding the well known systemic side-effects [198, 199]. However, they do cause fre- í Allergic contact dermatitis to corticoster- quent local side effects, which led to the withdrawal oids is more common than previously of some of these substances from the market – be- judged, and should be suspected whenever noxaprofen, , and, in some countries, phe- a chronic dermatitis is exacerbated by or nylbutazone and [198]. does not respond to local corticosteroid They belong to eight different groups [198]: salicy- therapy. Four groups of cross-reacting lates, pyrazolone derivatives, p-aminophenol deriva- molecules have been proposed. It has been tives, and , arylacanoic acid, recommended that budesonide and tixo- tolmetins, arylpropionic acid derivatives, and oxi- cortol pivalate should be added to the stan- cans. Cutaneous side effects include skin irritation, dard series as screening agents for corti- phototoxicity, contact urticaria, erythema-multi- costeroid allergy. forme-like eruptions, and, mainly, allergic and pho- toallergic contact dermatitis. Since many of these compounds may also be used systemically, the pos- sibility of the development of systemic contact der- matitis, in patients topically sensitized, must always 35.4.6 Antihistamines be borne in mind [200–202]. With the exception of pyrazolones and bufexa- 35 Topical antihistamines are mainly used for their anti- mac, which are used in northern European countries, pruritic properties. However, their sensitizing capac- most of the reports in the literature were coming ity greatly exceeds their beneficial effects. Beyond from the Mediterranean area. This could partially be that, oral antihistamines or chemically related sub- explained by the former extensive use of these drugs stances may induce systemic contact dermatitis in in these countries and also by the higher UV radi- patients topically sensitized. Thus, they are now be- ance in southern Europe, contributing to the devel- coming less frequently used [188]. opment of photosensitization [203]. However, they (which belongs to the ethanolamine group) can are currently used in many other countries. cause allergic [189] and photoallergic contact derma- Arylpropionic acid derivatives,mainly ketoprofen, titis [190], chorpheniramine is a sensitizer, either in are responsible for the great majority of cases of al- topical application [62] or in eye drops [191],and pro- lergy and photoallergy reported to date (Fig. 4 a, b). methazine and chlorpromazine (which are phenothi- Since the first reports [204, 205] to the present day azines) are well known sensitizers and photosensitiz- [206–209], several dozen cases have been published. ers. Promethazine cream still exists in some Europe- Cross-reactivity of ketoprofen with other drugs of an countries, including Portugal, and several cases of the same group is controversial.Although cross-reac- allergy and photoallergy are seen every year. Chlor- tivities have been reported for [210], flu- promazine, which is now much less employed, previ- biprofen [211, 212], and suprofen [201, 213], they were ously sensitized mainly health care personnel han- not found by Le Coz et al. [207], who regarded them dling this medicament and pharmaceutical industry as concomitant reactions. These authors suggested workers [192]. that benzophenone is the sensitizing moiety of keto- More recently, , a tricyclic antidepressive profen, which could explain the almost constant drug with activity, has been widely cross-reaction with [202, 214] and used for pruritus relief. Some cases of allergic and with unsubstituted benzophenone, and the frequent systemic contact dermatitis have been reported cross-reaction with fenofibrate [202, 215] and other [193–197]. monosubstituted benzophenones, such as oxyben- zone [202, 203, 216, 217]. 35_623_652 05.11.2005 11:22 Uhr Seite 633

Topical Drugs Chapter 35 633

profen [201], [220, 221], and tiaprofenic acid [207]. is a new arylpropionic acid derivative NSAID that induces photoallergic contact dermatitis and cross-reacts with ketoprofen [222, 223]. From the other groups, some emphasis should be given to etofenamate, which can cause contact der- matitis [224, 225], contact urticaria [226], and photo- contact allergy [227, 228], and to bufexamac. This is widely used in some northern countries as an alter- native to topical corticosteroids. Bufexamac seems to have a high sensitizing capacity [229–231] (Fig. 5), and may cause erythema-multiforme-like eruptions [39].Although it has been suggested that it should be added to the standard series in some countries [231], because of the high rate of sensitization and the seri- ous clinical pictures of bufexamac allergy, the use of this drug should be critically reassessed [232]. Diclof- enac, which is now being used for the treatment of actinic keratoses, and have also been re- ported as sensitizers [233, 234]. hydrochloride is mainly a photoal- a lergen [235]. Piroxicam is usually a systemic photo- sensitizer in patients allergic to the thiosalicylic acid moiety of thimerosal [116, 236], but it also can sensi- tize and photosensitize topically [218].

b

Fig. 4a, b. Photoallergic contact dermatitis from ketoprofen (a). Positive photopatch test to ketoprofen and related materi- als (b) (courtesy of A. Dooms-Goossens)

Ibuproxam is another arylpropionic acid deriva- tive which sensitizes mainly by contact [214, 218]. Iso- lated reports of allergy or photoallergy to other Fig. 5. Allergic contact dermatitis from bufexamac in a patient NSAIDs of this group include [219], su- with atopic dermatitis (courtesy of PJ Frosch) 35_623_652 05.11.2005 11:22 Uhr Seite 634

634 Francisco M. Brandão, An Goossens, Antonella Tosti

Indomethacin [237] and the pyrazolone deriva- matitis, as well as NICU and subjective or sensory ir- tives are now less often used, but can cause allergic ritation [253, 254]. PPG patch test reactions are often contact dermatitis [200, 238] and erythema-multi- difficult to evaluate and reports of contact allergy in forme-like reactions [40]. , not ex- the literature must, therefore, be interpreted with actly an NSAID, is a muscle relaxant that was report- caution. Cases of allergy to PPG in corticosteroid ed as a contact allergen [239] and photoallergen creams, EEC electrodes and gel, and other creams [240]. have been reported [255–258]. Polyethylene glycols (PEG) are the condensation products of glycols with ethylene oxide, with variable molecular weight Core Message (200–6,000 Da), depending on the condensation de- gree. Their sensitizing capacity is higher for lower í Nonsteroidal anti-inflammatory drugs molecular weights [259]. Emulsifiers and emollients, (NSAIDs) are very widely used and are like long-chain aliphatic fatty alcohols – lauryl, my- frequent sensitizers. Ketoprofen induces ristyl, oleyl, cetyl, and stearyl alcohols – may sensi- allergic and photoallergic contact derma- tize, especially in leg ulcer patients [260]. Oleyl alco- titis and cross-reacts with arylpropionic hol seems to be the stronger sensitizer [261]. Contact acid derivatives, tiaprofenic acid, as well sensitivity to other emulsifiers, like sorbitan sesquio- as with benzophenone, oxybenzone, and leate (Arlacel 83), sorbitan stearate and oleate (Span fenofibrate. Bufexamac is strongly allergen- 60 and 80), and polysorbates (Tween 40 and 80) has ic and its use should, probably, be discon- also been reported [262, 263]. tinued. Parabens are the most widely used , either in cosmetics or in topical medicaments. There are four esters (methyl, ethyl, propyl, and butyl), which are used in combination, mainly methyl and propyl esters, in concentrations up to 0.1–0.3%. Some 35.4.8 Ingredients of the Vehicles decades ago, they were used in much higher concen- trations (up to 5%), but in the currently used concen- Active products are incorporated in vehicles, which trations, the benefits largely exceed the risks of sensi- may contain several different substances, with differ- tization, which remains at about 0.5–1% of all patch- ent purposes – preservatives, emollients, emulsifiers, tested patients [264–266]. The paraben paradox is 35 , antioxidants, perfumes – which may al- well known [267] – patients sensitized topically so induce contact allergy. through medicaments can tolerate cosmetics pre- Sensitization to white and yellow petrolatum is served with parabens. rare [241–243], but white petrolatum, which is purer Sorbic acid, which induces NICU and contact al- than yellow petrolatum, seems to be less allergenic lergy [268], chlorocresol [269], and nonoxynols [270] [4]. Lanolin is a from sheep fleece are other preservatives reported as causes of contact and consists of a complex mixture of sterols (wool allergy. wax alcohols), fatty alcohols, and fatty acids, whose Formaldehyde and formaldehyde releasers, isothi- composition varies from time to time and from place azolinones, and methyldibromoglutaronitrile, as well to place [244].It is an important sensitizer in patients as a few other preservatives are mainly used in cos- with long-standing eczemas, especially in leg ulcer metics (see Chap. 30). patients, in whom it is usually one of the main aller- gens. However, it seems to be a very weak allergen Core Message when used on noneczematous skin or in cosmetics [244–247]. The allergen fraction resides mainly in the wool wax alcohols.Therefore,30% wool wax alco- í Lanolin is an important allergen in hols in petrolatum is the recommended concentra- patients with stasis dermatitis and leg tion for patch testing. Acetylated lanolin [248, 249], ulcers, but it rarely induces allergy when dewaxed lanolin, hydrogenated lanolin [250], and a used in noneczematous skin or in cosmet- purified anhydrous lanolin [251] have been claimed ics. Similarly, parabens may be safely used to cause less sensitization, although they may reduce in cosmetics, but can induce sensitization the effectiveness of lanolin as an excipient [252]. in patients with long-standing eczemas. Propylene glycol (PPG) is a viscous hygroscopic liquid. It may cause irritant and allergic contact der- 35_623_652 05.11.2005 11:22 Uhr Seite 635

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35.4.9 Other Allergens [290], salicylic acid [291], like [292], and [293], resorcinol [294], ethanol [295], and benzoyl peroxide, mainly Several other topical drugs, either in therapeutic or when used for leg ulcer treatment [296]. occupational use, may sensitize. Psoriatic patients Topical traditional Chinese medicaments are may become topically sensitized, which can aggra- largely sold as over-the-counter products, not only in vate and possibly be, in some cases, a trigger factor the Far East, but also in Asian communities in some for their skin disease [21].Although extensively used, European countries and in the USA. The components corticosteroids rarely seem to sensitize these patients usually include terpenes, salicylates, and essential oil [19, 25], but two cases have been reported by Heule et extracts [297]. They may irritate [298] and sensitize al. [21]. More often, tars [21, 25], dithranol [25, 271, [297, 299, 300] (Fig. 7). Colophony, fragrance, and 272], calcipotriol [273–276], and tacalcitol [277] are myrrh seem to be rather frequent allergens in these the main offenders. From the recently introduced preparations [300–303]. Four patients who reacted to topical immunomodulators, a case of allergic contact five Chinese medicaments were also allergic to fra- dermatitis to tacrolimus has been reported [278], but grance mix, and three to Myroxylon pereirae (balsam no known cases from pimecrolimus. of Peru), which strongly suggests cross-sensitization Antineoplastic drugs may induce contact urticaria with the plant extracts contained in these medica- (cisplatin [279] and mechlorethamine [280]) and ments [297]. In a study conducted in Taiwan, 30 pa- allergic contact dermatitis {5-fluorouracil [281], tients were tested with 27 traditional Chinese crude (Fig. 6), mitomycin C [282], mechlorethamine [283], drugs and other selected material. Fifteen out of the and azathioprine [284]}. 30 patients reacted to at least one of 23 crude drugs; Other possible allergenic topical drugs include seven were positive to Myroxylon Pereirae resin and proflavine [77], [285] (which can also pho- six to colophony, which was a much higher incidence tosensitize [286] and cause pigmentation [287]),met- than in the patients without contact dermatitis to ronidazole [288], retinoic acid [289], zinc pyrithione Chinese medicaments [304].

Fig. 6. Severe infected allergic contact dermatitis from fluoro- Fig. 7. Allergic contact dermatitis from tea-tree oil used by the ointment used for the treatment of actinic keratoses patient to treat seborrheic keratosis (courtesy of PJ Frosch) (courtesy of PJ Frosch) 35_623_652 05.11.2005 11:22 Uhr Seite 636

636 Francisco M. Brandão, An Goossens, Antonella Tosti

Core Message Core Message

í Traditional Chinese medicaments can í The occlusion these systems provoke induce sensitization. They contain several predisposes to inducing hypersensitivity. different chemical products, with colopho- Several different drugs have been reported ny, fragrances, and myrrh being the main to cause allergy – scopolamine, clonidine, sensitizers. nitroglycerin, , norethisterone, nicotine, and testosterone.

35.4.10 Transdermal Therapeutic Systems 35.5 Sites at Risk

These therapeutic devices were introduced to the Several skin sites, for one reason or another, may be market more than two decades ago, and an increas- at special risk of developing contact sensitization. ing number of drugs are being used this way. They They are usually sites where skin conditions are have made possible effective rate-controlled transcu- prone to be chronic and,for that reason,many topical taneous administration of the drugs. In addition, medicaments are applied over the course of time. gastro-intestinal absorption and first-pass hepatic Besides that, particular anatomical and pathological is avoided and an improved compliance, conditions, or special application methods, can in- with decreased administration cycle, is obtained. crease skin penetration, which also increases the sen- However, they also have some disadvantages. The ef- sitizing capacity of pharmaceutical products. In this fect of occlusion for 1–7 days may induce miliaria and short review, we will consider three special sites and irritant contact dermatitis, and these conditions pre- pathological conditions – ophthalmic preparations, dispose to inducing hypersensitivity to one or more anogenital dermatoses and stasis dermatitis, and leg components [305, 306]. ulcers. There are now reports of allergy to six different transdermal therapeutic systems. Contact allergy may be due to a component of the adhesive layer – 35.5.1 Ophthalmic Preparations 35 ethanol, hydroxypropyl cellulose, polyisobutylene, methacrylates – or, more commonly,to the drug itself Such medicaments are quite a common cause of con- – scopolamine [307], clonidine [308, 309], nitroglyce- tact sensitization [93, 319–321]. Patients with glauco- rin [310, 311] (Fig. 8), estradiol [312–315], and nore- ma who are chronically treated with several ophthal- thisterone [314], nicotine [316], and testosterone [317, mic drugs are likely to become sensitized [322]. 318]. Symptoms may be limited to the eye (allergic contact conjunctivitis) or may involve the periocular skin and the eyelids. Allergic contact conjunctivitis often goes undiagnosed, since it usually occurs in patients who are already affected by ocular inflammation due to other causes, and its clinical features are not spe- cific. Clinical examination reveals pronounced vaso- dilatation and chemosis of the conjunctiva. Watery discharge and papillary response can be present.Pos- sible complications include punctate keratitis and corneal opacities. Patch tests should be carried out with the eye preparations used by the patient and their individual ingredients (Table 7). Patch testing only the prepara- tions may give false-negative results, especially when the responsible allergen is a preservative. The diag- nosis of allergic contact conjunctivitis may be con- Fig. 8. Allergic contact dermatitis to a transdermal device con- firmed by a provocative test with the responsible eye taining nitroglycerin (courtesy of O Bordalo) preparation. 35_623_652 05.11.2005 11:22 Uhr Seite 637

Topical Drugs Chapter 35 637

Table 7. Substances reported to have caused contact allergy in ophthalmics (modified from [93, 319–321, 323])

Preservatives Antiviral drugs Idoxiuridine Trifluridine Chlorhexidine gluconate β-interferon Cetalkonium chloride Phenylmercuric nitrate Antihistaminics Sorbic acid Chlorpheniramine Thimerosal Sodium cromoglycate Amlexanox Beta-blockers N-Acyl-aspartyl glutamic acid (NAAGA-DCI) Befunolol Ketotifen Betaxolol Carteolol Anesthetics Levobunolol Benzocaine Metipranol Procaine Metoprolol 1-Pentbutol Proxymetacaine Timolol Proparacaine Mydriatics Atropine Enzymatic cleaners Cyclopentolate Papain Dipivalyl-epinephrine Tegobetaine L7 Homatropine Others Scopolamine Apraclonidine Tropicamide Boric acid Brominidine Antibiotics D-Penicillamine Bacitracin Diclofenac Chloramphenicol Dorzolamide Gentamicin Echothiopate iodine Kanamycin e-Aminocaproic acid Neomycin Pilocarpine Polymyxin B Prednisolone Resorcinol Penicillin Rubidium iodide Sulfathiazole Tolazoline Cefradine Tobramycin

Both preservatives and active ingredients may blocking agents, mydriatics, antibiotics, antiviral produce contact sensitization. Preservatives are cer- drugs, antihistamines, anti-inflammatory drugs, cor- tainly the most important sensitizers in eye drops, ticosteroids, and anesthetics [93, 319–321, 323]. and since each preservative is contained in a large number of ophthalmic preparations, not only does allergic conjunctivitis due to these compounds fre- 35.5.2 Vulval and Perianal Dermatoses quently go undetected, but it can actually be pro- longed by the very eye drops that are prescribed to Patients with chronic vulval dermatoses, mainly relieve the patient’s ocular discomfort. Thimerosal pruritus vulvae, lichen sclerosus, and lichen simplex sensitization is probably the main allergological chronicus, frequently apply several topical prepara- problem in eye drop users, as it is also in contact lens tions that may contribute to maintain, prolong, and wearers [115]. Preservative-free monodose eye drops aggravate the local symptomatology. Vulval skin is are now available for the most important ophthalmic hyper-reactive to local irritants [324], which, in con- ingredients. junction with the local conditions – occlusion and Active ingredients of the ophthalmic products that high temperature – and an increased permeability of may cause sensitization include beta-adrenergic vulvovaginal mucosa compared to that of keratinized 35_623_652 05.11.2005 11:22 Uhr Seite 638

638 Francisco M. Brandão, An Goossens, Antonella Tosti

skin [325], are factors that predispose to inducing í sensitization. Contact allergy incidence in these pa- Lanolin: despite all the polemics around its tients is high (29–58%) [59, 326–328] and is higher in sensitizing capacity [94, 244–246], lanolin re- patients with simultaneous anogenital dermatoses mains a constant finding as one of the main [64, 329]. sensitizers in these patients í Fragrances and topical medicaments are the main Antibiotics and other chemotherapeutic relevant allergens. Among topical drugs, antibiotics, agents: neomycin, bacitracin, polymyxin B, particularly neomycin, local anesthetics, corticoster- chloramphenicol, nitrofurazone, clioquinol, oids [330], antiseptics, and preservatives should be sodium fusidate í highlighted. Corticosteroids [346] (Fig. 9) í Patients with pruritus ani and hemorrhoids are Preservatives and antiseptics: parabens, ben- submitted to the same local and general conditions, zalkonium chloride, , povidone io- as well as to the application of multiple topical drugs. dine, benzoyl peroxide í Therefore, allergic contact eczema is frequently seen Emollients and emulsifiers: cetearyl alcohol in these patients [64, 329]. Local anesthetics are, by (Lanette O), Lanette N, and Lanette E, sorbitan far, the more common allergens [57, 58, 64, 331–333], sesquioleate and others [260, 347, 348] but several other topical drugs or components of me- dicaments have been reported as contact allergens in In the last two decades, new wound dressings, such as this area – [334], [335], hydrocolloids, hydrogels, alginates, and polyurethane sodium metabisulfite [336], glyceryl trinitrate [337], foams, have been used with increasing frequency. [338], trimebutine [339], and bufexamac They are generally well tolerated, but can occasional- [232]. This induced a generalized eruption,“baboon- ly cause irritant contact dermatitis. Some recent pub- syndrome”-like, similar to the one induced by 5-ami- lications report allergic contact dermatitis from nosalicylic acid enemas [340]. components of these dressings, mainly from hydro- colloids. Pentalin (pentaerythritol ester of hydrogen- ated rosin), a tackifying agent that usually cross- Core Message reacts with colophony, and Vistanex (polyisobuty- lene), another tackifier, are the main allergens re- í A hyperreactive skin mucosa, in conjunc- ported [349–353]. PPG proved to be the sensitizer in tion with local conditions like occlusion 35 and high temperature, and an increased permeability are factors that predispose to sensitization in these patients. Local anesthetics are the more common aller- gens, but antibiotics, corticosteroids, anti- septics, and preservatives should not be forgotten.

35.5.3 Stasis Dermatitis and Leg Ulcer Patients

Stasis dermatitis and leg ulcer patients have a well known increased risk of becoming sensitized. The long course of these pathological conditions, the damage to the skin barrier, and the use of occlusive bandages promoting skin penetration are all factors that favor polysensitization. There is usually a very high incidence of medicament contact allergy in these patients, varying in different series from 58% to 86% [3, 4, 89, 90, 94, 341–345]. The more important allergen groups are the fol- Fig. 9. Allergic contact dermatitis from methylprednisolone lowing: aceponate in a patient with leg ulcer (courtesy of O Bordalo) 35_623_652 05.11.2005 11:22 Uhr Seite 639

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three patients allergic to hydrogels [344]. Carboxy- Systemic contact dermatitis may assume several methyl cellulose in a hydrocolloid dressing induced a different clinical cutaneous manifestations, which, in generalized urticarial rash [35]. some severe cases, may be accompanied by general symptomatology, like fever, malaise, headache, nau- sea, vomiting,diarrhea, or even syncope [26,354,355]: Core Message

í Flare-up of previous eczema or patch-test í A high percentage of stasis dermatitis reaction sites. and leg ulcer patients are contact allergic í Vesicular hand eczema, with or without to several topical drugs – lanolin, topical erythema, localized to the palms, volar antibiotics, corticosteroids, and emulsifiers aspects, and sides of the fingers. are the main allergens. Some components í Generalized maculopapular rash – this is the of recent wound dressings may rarely commonest eruption, which may become more sensitize. severe and lead to erythroderma [356] (Fig. 10). í Erythema multiforme, purpura, vasculitis. í Generalized acute exanthematic pustulosis [161]. í Urticaria and anaphylaxis. 35.6 Systemic Contact Dermatitis í The “baboon syndrome” [357]: this well recog- nized syndrome has a characteristic distribu- tion pattern, with diffuse pink or dark violet This very important matter is dealt with in much erythema of the buttocks and inner thighs, like more detail elsewhere in this textbook (Chap.16).It is an inverted triangle or V-shaped; sometimes, an inflammatory skin disease that may develop from the axilla are also involved. Several drugs may the systemic administration of a substance in pa- cause the baboon syndrome, particularly ampi- tients topically sensitized to it or to a chemically re- cillin, erythromycin, other antibiotics, and mer- lated substance [354]. The route of administration cury. may be oral, rectal, vaginal, parenteral, intra-articular, by inhalation, or through percutaneous penetration. Drugs are, by far, the most frequent causes of Mercury may induce other exanthematic reactions, systemic contact dermatitis, and because of the pos- such as mercury exanthema – a diffuse symmetrical sibility of severe generalized reactions, one should al- erythema predominantly of major flexures [358, 359] ways bear this clinical entity in mind. The more impor- – and even acute generalized exanthematic pustulo- tant drugs and chemically related substances that may sis. These eruptions, which are currently much less cause systemic contact dermatitis are listed in Table 8. common than some years ago, were usually due to

Fig. 10. Systemic reaction to an in- jection of methylpredniso- lone in a patient previously sensitized by a topical prep- aration containing the same corticosteroid (courtesy of A. Dooms-Goossens) 35_623_652 05.11.2005 11:22 Uhr Seite 640

640 Francisco M. Brandão, An Goossens, Antonella Tosti

Table 8. Drugs and chemically related substances that may cause systemic contact dermatitis [26, 354–359]

Topical drugs Substances (groups) that can induce systemic contact dermatitis

Acyclovir Acyclovir Antimycotic imidazoles Antimycotic imidazoles, Benzocaine Para-amino compounds Captopril Captopril Chloramphenicol Chloramphenicol Cinchocaine Cinchocaine Clonidine Clonidine Corticosteroids Corticosteroids Diphenhydramine Diphenhydramine Doxepin Doxepin Estradiol Estradiol Ethyl alcohol Alcohol-containing medicaments and beverages Ethylenediamine Ethylenediamine antihistamines (hydroxyzine), aminophylline Famciclovir Acyclovir 5-Fluorouracil 5-Fluorouracil Gentamycin Neomycin and other aminoglycoside antibiotics Halogenated hydroxyquinolines Vioform, chlorquinaldol Iodine Iodides, iodinated organic compounds Mercury compounds Mercury compounds (organic and inorganic) Acetyl salicylic acid Mitomycin C Mitomycin C Neomycin Aminoglycoside antibiotics, except streptomycin Nitroglycerin Nitroglycerin Nonsteroidal anti-inflammatory drugs Nonsteroidal anti-inflammatory drugs Norfloxacin Clioquinol Nystatin Nystatin Parabens Parabens Penicillin/semi-synthetic penicillins Penicillin/semi-synthetic penicillins Phenothiazines Phenothiazines (antihistamines and other) Propylene glycol Propylene glycol (in foods) 35 Pseudoephedrine Ephedrine, phenylephrine Sorbic acid Sorbic acid, sorbates Sulfonamides Sulfonamides, sulfonylureas, para-amino compounds Terbinafine Terbinafine Thimerosal Thimerosal, piroxicam Valaciclovir Acyclovir Vitamin B6 Vitamin B6 Vitamins B1/C Vitamins B1/C

the inhalation of mercury vapors resulting from 35.7 Diagnosis and Prognosis broken thermometers and, less often, following den- tal treatments. Correct diagnosis of the many cutaneous drug reac- Core Message tions is not always an easy task. Nonallergic reactions are, in most cases, diagnosed on a presumptive basis, according to the clinical history and course, with ref- í Several topical medicaments can induce erence to the available literature. The evaluation of systemic contact dermatitis in sensitized immediate reactions (ICU/NICU) should follow the patients, if administered by other routes. test procedures suggested by Amin et al. [33]. Other Multiple different clinical patterns may allergic noneczematous patterns, like erythema mul- be seen, with the “baboon syndrome” being tiforme, purpura, or lymphomatoid reactions, may a well recognized manifestation that can be diagnosed by patch tests, although patch test reac- be provoked by several medicaments. tions are usually eczematous, not reproducing the clinical features. 35_623_652 05.11.2005 11:22 Uhr Seite 641

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In cases of suspected allergic contact dermatitis, 35.8 Appendix: Allergens in Medicaments besides the history and the whole clinical picture, (pet. petrolatum, aq. aqueous, patch tests are of utmost importance. The patient eth. ethanol, o.o. olive oil) must be tested with all and every medicament that he has applied, as well as all the active principles and other suspected substances. This may prove rather difficult in many instances because patients may of- 1. Anesthetics ten use many different medicaments and, in cases of a. Amethocaine (tetracaine) – 1% pet. ectopic dermatitis, the offending drugs may be disre- b. Amylocaine – 5% pet. garded. c. Benzamine lactate – 1% pet. Several difficulties arise in testing these patients: d. Benzocaine – 5% pet. e. Bupivacaine – 1% pet. f. Butacaine – 5% pet. í Some allergenic drugs are also irritants or, at g. Butethamine – 5% pet. least, marginal irritants – propylene glycol, h. Butyl aminobenzoate – 5% pet. dithranol, calcipotriol, 5-fluorouracil, some i. – 1% pet. , and others. Patch test inter- j. Dibucaine (cinchocaine) – 5% pet. pretation may be quite difficult and false-posi- k. Diperocaine – 1% pet. tive reactions may be misinterpreted. l. Lidocaine – 5% pet. í Most commercial medicaments have a com- m. Mepivacaine – 1% pet. plex composition. False-negative reactions n. – 1% pet. may be expected from the whole medicament, o. Oxybuprocaine – 1% pet. if the allergenic substance is used at a low p. – 3% pet. concentration in the final product. q. Pramocaine – 1% pet. í The possibility of testing all the components r. Prilocaine – 5% pet. of a commercial product depends largely on s. Procaine – 1% pet. the manufacturer’s goodwill. This may make t. Propanidid – 5% pet. the identification of individual allergens im- u. Proparacaine (proxymetacaine) – 2% pet. possible. v. Propipocaine – 1% pet. í Contact allergy to some medicaments may be due to compound allergy [8, 126]. Here, again, 2. Antibiotics the identification of the allergenic substance a. Ampicillin – 5% pet. may prove a hard task. b. Amikacin – 20% pet. í Correct concentrations and vehicles for patch c. Azidamfenicol – 2% pet. testing have not yet been determined for d. Bacitracin – 20% pet. many drugs, which can lead to false-posi- e. Cephalosporins – 5%–20% aq. or pet. tive/negative reactions. In the case of a posi- f. Chloramphenicol – 5% pet. tive reaction to an uncommon allergen, the g. Clindamycin – 1% aq. use of serial dilutions and patch tests in con- h. Erythromycin base – 1% pet. trols is mandatory. i. Erythromycin salts – 1% pet. í In polysensitized patients, the occurrence of j. Framycetin – 20% pet. an excited skin syndrome must not be over- k. Gentamicin – 20% pet. looked. l. Kanamycin – 10% pet. m. Lincomycin – 1% aq. Patients with medicament contact allergy usually n. Mafenide – 10% pet. have a good prognosis. However, in some circum- o. Mupirocin – 10% pet. stances, there is a high propensity for relapse – in pa- p. Neomycin – 20% pet. tients with long-standing eczemas, this is a rather q. – 10% pet. common phenomenon due to possible cross-reac- r. Penicillin (benzyl) – 10.000 U/g pet. tions with other drugs, the difficulty in completely s. Polymyxin B – 3% pet. avoiding some allergens, like lanolin, or the possibil- t. Pristinamycin – 5% pet. ity of systemic contact dermatitis. u. Ribostamycin – 20% pet. v. Rifamycin – 2.5% pet. w. Sisomicin – 20% pet. x. Sodium fusidate – 2% pet. 35_623_652 05.11.2005 11:22 Uhr Seite 642

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y. Spiramycin – 10% pet f. Naftifine – 5% eth. z. Streptomycin – 2.5% pet. g. Nystatin – 2% pet. aa. Sulfonamides – 5% pet. h. Pecilocin – 1% pet. ab. – 3% pet. i. Pyrrolnitrin – 1% pet. ac. – 5% pet. j. – 1% pet. ad. Tobramycin – 20% pet. k. Undecylenic acid – 2% pet. ae. Tylosin tartrate – 5% pet. af. Virginiamycin – 5% pet. 6. Antihistamines a. Amlexanox – 1% pet. 3. Antivirals b. – 1% pet. a. Acyclovir – 5% pet. c. Chlorpheniramine – 5% pet. b. Famciclovir – 10% aq. d. Chlorpromazine – 0.1% pet. c. Ganciclovir – 20% aq. e. Diphenhydramine – 1% pet. d. Idoxuridine – 1% pet. f. Doxepin – 5% pet. e. Trifluridine – 5% pet. g. Ketotifen – 0.7% aq. f. Tromantadine – 1% pet. h. Promethazine – 1% pet. g. Valaciclovir – 10% aq. i. Pyrilamine – 2% pet. j. Sodium cromoglycate – 2% aq. 4. Antiseptics/antibacterials k. – 1% pet. a. Ammoniated mercury – 1% pet. b. Chlorquinaldol – 5% pet. 7. Antineoplastic drugs c. Clioquinol – 5% pet. a. Azathioprine – 1% pet d. Cycloheximide – 1% pet. b. Chlorambucil – 2% pet. e. Ethacridine – 2% pet. c. Fluorouracil – 1% pet. f. Merbromin – 2% aq. or pet. d. Mechlorethamine – 0.02% aq g. Mercuric chloride – 0.1% pet. e. Mitomycin C – 0.1% pet. h. Nitrofurazone – 1% pet. i. Phenylmercuric salts – 0.05% pet. (ace- 8. tate, borate, nitrate) a. Benzyl benzoate – 5% pet. j. Povidone iodine – 10% aq. b. Crotamiton – 3% pet. k. Proflavine HCl – 1% pet. c. Mesulfen – 5% pet. l. Triphenylmethane dyes – 2% aq. d. Metronidazole – 1% pet. m. Thimerosal – 0.1% pet. 5. Antimycotics 9. NSAIDs a. Amorolfine – 1% pet. a. Aceclofenac – 1% pet. b. Chlorphenesin – 1% pet. b. Benzydamine – 5% pet. c. Dibenzthione – 3% pet. c. Bufexamac – 5% pet. d. – 1% pet. d. – 5% pet. e. Imidazoles e. Cinnoxicam – 1% pet. – bifonazole – 1% eth. f. Dexketoprofen – 1% pet. – clotrimazole – 1% eth. g. Diclofenac – 1% pet. – croconazole – 1% eth. h. Etofenamate – 2% pet. – econazole – 1% eth. i. – 5% pet. – enilconazole – 1% eth. j. – 5% pet. – fenticonazole – 1% eth. k. – 1% pet. – isoconazole – 1% eth. l. – 5% pet. – ketoconazole – 1% eth. m. Ibuprofen – 5% pet. – lanoconazole – 1% eth. n. Ibuproxam – 2.5% pet. – miconazole – 1% eth. o. Indomethacin – 5% pet. – neticonazole – 1% eth. p. Ketoprofen – 2.5% pet. – oxiconazole – 1% eth. q. – 1% pet. – sertaconazole – 1% eth. r. – 1% pet. – sulconazole – 1% eth. s. – 5% pet. – tioconazole – 1% eth. t. Oxyphenbutazone – 1% pet. 35_623_652 05.11.2005 11:22 Uhr Seite 643

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u. Phenylbutazone – 1% pet. d. Levobunolol – 1% aq. v. Piketoprofen – 2.5% pet. e. Metipranolol – 2% aq. w. Piroxicam – 1% pet. f. Metopronolol – 3% aq. x. Sulindac – 1% pet. g. 1-Pentbutolol – 2% aq. y. Suprofen – 0.1% pet. h. Timolol – 0.5% aq. z. – 1% pet. aa. Tiaprofenic acid – 1% pet. 13. Mydriatics ab. Thiocolchicoside – 1% pet. a. Atropine – 1% pet. b. Cyclopentolate – 0.5% aq. 10. Antipsoriatic drugs c. Dipivalyl-epinephrine – 1% aq. a. Calcipotriol – 2 µg/ml eth. d. Homatropine – 1% aq. b. Dithranol – 0.02% pet. e. Phenylephrine –10% aq. c. Tacalcitol – 2 µg/ml eth. f. Scopolamine – 0.25% aq. d. Tars (coal tar) – 5% pet. g. Tropicamide – 1% pet.

11. Corticosteroids 14. Preservatives/antioxidants a. dipropionate – 1% eth. a. Benzyl alcohol – 1% pet. b. Amcinonide – 0.1% eth. b. Bithionol – 1% pet. c. Betamethasone dipropionate – 1% eth c. Butylated hydroxyanisol – 2% pet. d. Betamethasone-17-valerate – 1% eth. d. Butylated hydroxytoluene – 2% pet. e. Budesonide – 0.1% pet. e. Chloroacetamide – 0.2% pet. f. Clobetasol propionate – 1% eth. f. Chlorhexidine gluconate – 0.5% aq. g. Clobetasone butyrate – 1% eth. g. Chlorocresol – 1% pet. h. Cloprednol – 1% eth. h. – 1% pet. i. Desonide – 1% eth. i. Dichlorophene – 1% pet. j. Desoxymethasone – 1% eth. j. Ethyl alcohol – 10% aq. k. – 1% eth. k. Nonoxynols – 5% aq. l. Dexamethasone phosphate – 1% eth. l. Nordihydroguaiaretic acid – 2% pet. m. diacetate – 1% eth. m. Quaternary ammonium compounds – n. Diflucortolone pivalate – 1% eth. 0.1% aq. o. Fludrocortisone acetate – 1% eth. n. Propyl gallate – 1% pet. p. Flumethasone acetate – 1% eth. o. Sorbic acid – 2% pet. q. – 1% eth. p. Alpha-tocopherol – 10% pet. r. – 1% eth. q. – 1% pet. s. – 1% eth. r. – 1% pet. t. Fluticasone propionate – 1% eth. s. Zinc pyrithione – 1% pet. u. – 1% eth. v. Halomethasone – 1% eth. 15. Vehicle ingredients w. Hydrocortisone – 1% eth. a. Amerchol L-101 – 50% pet. x. Hydrocortisone aceponate – 1% eth. b. Carbowaxes – as is y. – 1% eth. c. Castor oil – as is z. Hydrocortisone buteprate – 1% eth. d. Cetyl alcohol – 5% pet. aa. Hydrocortisone-17-butyrate – 1% eth. e. Cetearyl alcohol – 20% pet. ab. Methylprednisolone aceponate – 1% eth. f. Ethyl sebacate – 2% eth. ac. Methylprednisolone acetate. – 1% eth. g. Ethylenediamine – 1% pet. ad. Mometasone furoate – 1% eth. h. Eucerin – as is ae. Prednicarbate – 1% eth. i. Lanette E – 20% pet. af. Prednisolone – 1% eth. j. Lanette N – 20% pet. ag. Tixocortol pivalate – 1% pet. k. Lanolin – as is ah. – 1% eth. l. Myristyl alcohol – 5% pet. 12. β-Blockers m. Oleyl alcohol – 30% pet. a. Befulenol – 1% aq. n. Petrolatum – as is b. Betaxolol – 1% aq. o. Polyethylene glycols – pure c. Carteolol – 1% aq p. Polysorbate [20, 40, 80] – 5% pet. 35_623_652 05.11.2005 11:22 Uhr Seite 644

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q. Propylene glycol – 5% aq. References r. Sesame oil – as is s. Sodium lauryl sulfate – 0.1% aq. 1. Bandmann HJ, Calnan CD, Cronin E, Fregert S, Hjorth N, Magnusson B, Maibach HI, Malten E, Meneghini CL, Piri- t. Sorbitan laureate – 5% aq. la V,Wilkinson DS (1972) Dermatitis from applied medic- u. Sorbitan oleate – 5% aq. aments. Arch Dermatol 106 : 335–337 v. Sorbitan palmitate – 5% aq. 2. Blondeel A, Oleffe J, Achten G (1978) Contact allergy in w. Sorbitan sesquioleate – 20% pet. 330 patients. Contact Dermatitis 4 : 270–276 x. Stearyl alcohol – 30% pet. 3. Dooms-Goossens A (1982) Allergic contact dermatitis to ingredients used in topically applied pharmaceutical y. Triethanolamine – 2.5% pet. products and cosmetics. Katholieke Universitat Leuven, z. Wool wax alcohols – 30% pet. Leuven, Belgium 4. Angelini G, Vena GA, Meneghini CL (1985) Allergic con- 16. Miscellaneous tact dermatitis to some medicaments. Contact Dermatitis a. Allantoin – 0.5% aq. 12 : 263–269 5. Edman B, Moller H (1986) Medicament contact allergy. b. e-Aminocaproic acid – 1% aq. Derm Beruf Umwelt 34 : 139–143 c. Benzoyl peroxide – 1% pet 6. Goh CL (1989) Contact sensitivity to topical medica- d. Boric acid – 10% pet. ments. Int J Dermatol 28 : 25–28 e. Clonidine – 1% pet. 7. Sertoli A, Francalanci S, Acciai MC, Gola M (1999) Epi- f. Cocamidopropyl betaine – 1% aq. demiological survey of contact dermatitis in Italy (1984–1993) by GIRDCA (Gruppo Italiano Ricerca Der- g. Dexpanthenol – 50% aq. matiti da Contatto e Ambientali). Am J Contact Dermat h. Echothiopate iodine – 1% aq. 10 : 18–30 i. Ephedrine – 1% pet. 8. Smeenk G, Kerckoffs HP, Schreurs PH (1987) Contact al- j. Epinephrine – 1% aq. lergy to a reaction product in Hirudoid cream: an exam- ple of compound allergy. Br J Dermatol 116 : 223–231 k. Estradiol – 2% eth. 9. Fisher AA, Dooms-Goossens A (1976) The effect of per- l. Ichthammol – 10% pet. fume “ageing” on the allergenicity of individual perfume m. Methyl salicylate – 2% pet. ingredients. Contact Dermatitis 2 : 155–159 n. Minoxidil – 5%: 20% PPG/aq. 10. Beltrani VS (1996) Clinical manifestations of atopic der- o. Monobenzylether hydroquinone – 1% pet. matitis. In: Leung DYM (ed) Atopic dermatitis: from pathogenesis to treatment. Springer, Berlin Heidelberg p. Nicotine – 10% pet. New York, p 24 q. Nitroglycerin – 1% pet. 11. Jones HE, Lewis CW, McMarlin SL (1973) Allergic con- r. Norethisterone acetate – 1% eth. tact dermatitis in atopic patients. Arch Dermatol 107 : 35 s. Papain – 1% pet. 217–222 12. Angelini G, Meneghini CL (1977) Contact and bacterial t. D-Penicillamine – 1% aq. allergy in children with atopic dermatitis. Contact Der- u. Pilocarpine – 1% pet. matitis 3 : 163–167 v. Resorcinol – 1% pet. 13. Lammintausta K, Kalimo K, Fagerlund VL (1992) Patch w. Retinoic acid – 0.005% pet. test reactions in atopic patients. Contact Dermatitis 26 : x. Rubidium iodide – 1% pet. 234–240 y. Salicylic acid – 1% pet. 14. Klas PA, Corey G, Storrs FJ, Chan SC, Hanifin JM (1996) Allergic and irritant patch test reactions in atopic disease. z. Scopolamine hydrobromide – 0.25% aq. Contact Dermatitis 34 : 121–124 aa. Tacrolimus – 2.5% eth. 15. Giordano-Labadie F, Rance F, Pellegrin F, Bazex J, Dutau ab. Testosterone propionate – 1% eth. G, Schwarze HP (1999) Frequency of contact allergy in ac. Thioxolone – 0.5% eth. children with atopic dermatitis: results of a prospective study of 137 cases. Contact Dermatitis 40 : 192–195 ad. Tolazoline – 10% aq. 16. Fedler R, Stromer K (1993) Nickel sensitivity in atopic, ae. Triethanolamine polypeptide oleate con- psoriatics and healthy subjects. Contact Dermatitis 29 : densate – 25% o.o. 65–69 17. Henseler T, Christophers E (1995) Disease concomitance in psoriasis. J Am Acad Dermatol 32 : 982–986 18. Fransson J, Storgards A, Hammer H (1985) Palmoplantar lesions in psoriatic patients and their relation to inverse psoriasis, tinea and contact allergy. Acta Derm Venereol (Stockh) 65 : 218–223 19. Fleming CJ, Burden AD (1997) Contact allergy in psoria- sis. Contact Dermatitis 36 : 274–276 20. Stinco G, Frattasio A, De Francesco V,Bragadin G, Patrone P (1999) Frequency of delayed-type hypersensitivity to contact allergens in psoriatic patients. Contact Derma- titis 40 : 323–324 35_623_652 05.11.2005 11:22 Uhr Seite 645

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110. Agner T, Menné T (1993) Sensitivity to clioquinol and 133. Cooper SM, Shaw S (1999) Contact allergy to nystatin: an chlorquinaldol in the quinoline mix. Contact Dermatitis unusual allergen. Contact Dermatitis 41 : 120 29 : 163 134. Gonzalez Perez R, Aguirre A, Oleaga JM, Eizaguirre X, 111. Marks JG (1982) Allergic contact dermatitis to povidone Diaz Perez JL (1995) Allergic contact dermatitis from tol- iodine. J Am Acad Dermatol 6 : 473–475 naftate. Contact Dermatitis 32 : 173 112. Gonçalo M, Figueiredo A, Gonçalo S (1996) Hypersensi- 135. Willa-Craps C, Wyss M, Elsner P (1995) Allergic contact tivity to thimerosal: the sensitizing moiety. Contact Der- dermatitis from naftifine. Contact Dermatitis 32 : 369–370 matitis 34 : 201–203 136. Kramer K, Paul E (1996) Contact dermatitis from amorol- 113. Moller H (1980) Why thimerosal allergy? Int J Dermatol fine-containing cream and nail lacquer. Contact Derma- 19 : 29 titis 34:145 114. 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Umebayashi Y, Ito S (2001) Allergic contact dermatitis 155–157 due to lanoconazole and neticonazole. Contact Derma- 130. van Ketel WG (1977) Allergy to idoxuridine eyedrops. titis 44 : 48–49 Contact Dermatitis 3 : 106–107 153. Tanaka N, Kawada A, Hiruma M, Tajima S, Ishibashi A 131. Millan-Parrilla F, de la Cuadra J (1990) Allergic contact (1996) Contact dermatitis from lanoconazole. Contact dermatitis from trifluoridine in eye drops. Contact Der- Dermatitis 35 : 256–257 matitis 22 : 289 154. Nakano R, Miyoshi H, Kanzaki T (1996) Allergic con- 132. Anguita JL, Escutia B, Mari JI, de la Cuadra J, Aliaga A tact dermatitis from lanoconazole. Contact Dermatitis (2002) Allergic contact dermatitis from undecylenic acid 35 : 63 in a common nail solution. Contact Dermatitis 155. Umebayashi Y (1999) Three cases of contact dermatitis 46 : 109 due to lanoconazole. Environ Dermatol (Jpn) 6 : 122 35_623_652 05.11.2005 11:22 Uhr Seite 648

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156. Soga F, Katoh N, Kishimoto S (2004) Contact dermatitis 179. Isaksson M, Brandao FM, Bruze M, Goossens A (2000) due to lanoconazole, cetyl alcohol and diethyl sebacate in Recommendation to include budesonide and tixocortol lanoconazole cream. Contact Dermatitis 50 : 49–50 pivalate in the European standard series. Contact Derma- 157. Goday JJ, Yanguas I, Aguirre A, Ilardia R, Soloeta S (1995) titis 43:41–42 Allergic contact dermatitis from sertaconazole with cross 180. Wilkinson SM, English JSC (1991) Hydrocortisone sensi- sensitivity to miconazole and econazole. Contact Derma- tivity: a prospective study of the value of tixocortol piva- titis 32 : 370–371 late and hydrocortisone acetate as patch test markers. 158. van Ketel WG (1983) An allergic eruption probably caused Contact Dermatitis 25 : 132–133 by ketoconazole. Contact Dermatitis 9 : 113 181. Lauerma AI, Tarvainen K, Forström L, Reitamo S (1993) 159. van Dijke CPH, Veerman FR, Haverkamp HC (1983) Contact hypersensitivity to hydrocortisone-free alcohol Anaphylactic reactions to ketoconazole. Br Med J 287 : in patients with allergic patch test reactions to tixocortol 1673 pivalate. Contact Dermatitis 28 : 10–14 160. Cooper SM, Reed J, Shaw S (1999) Systemic reaction to 182. Lepoittevin J-P, Drieghe J, Dooms-Goossens A (1995) nystatin. Contact Dermatitis 41 : 345–346 Studies in patients with corticosteroid contact allergy. 161. Kempinaire A, de Raeve L, Merckx M, de Coninck A, Bau- Understanding cross-reactivity among different steroids. wens M, Roseeuw D (1997) Terbinafine-induced acute Arch Dermatol 131 : 31–37 generalized exanthematous pustulosis confirmed by a 183. Isaksson M, Bruze M, Björkner B, Hindsén M, Svensson positive patch test result. J Am Acad Dermatol 37 : 653–655 L (1999) The benefit of patch testing with a corticos- 162. Matura M, Goossens A (2000) Contact allergy to corti- teroid at a low concentration. Am J Contact Dermat 10 : costeroids. Allergy 55 : 698–704 31–33 163. Scheuer E, Warshaw E (2003) Allergy to corticosteroids: 184. Isaksson M, Andersen KE, Brandao FM, Bruynzeel DP, update and review of epidemiology, clinical characteris- Bruze M, Diepgen T, Ducombs G, Frosch PJ, Goossens A, tics and structural cross-reactivity. Am J Contact Dermat Lahti A, Menné T,Seidenari S, Tosti A,Wahlberg J,Wilkin- 14: 179–187 son JD (2000) Patch testing with budesonide in serial di- 164. Corazza M, Mantovani C, Maranini C, Bacilieri S,Virgili A lutions.A multicentre study of the EECDRG. Contact Der- (2000) Contact sensitization to corticosteroids: increased matitis 42 : 352–354 risk in long term dermatoses. Eur J Dermatol 10 : 533–535 185. Wilkinson SM, Beck MH (2000) Patch testing for corti- 165. Keegel T, Saunders H, Milne R, Sajjachareonpong P, costeroids using high and low concentrations. Contact Fletcher A, Nixon R (2004) Topical corticosteroid allergy Dermatitis 42 : 350–351 in an urban Australian centre. Contact Dermatitis 50 : 186. Chowdhury MMU, Statham BN, Sansom JE, Foulds IS, 6–14 English JSC, Podmore P, Bourke J, Orton D, Ormerod AD 166. Uter W (1990) Allergische reaktionen auf glukokorticoide (2002) Patch testing for corticosteroid allergy with low (Allergic reaction to , in German). Derm and high concentrations of tixocortol pivalate and budes- Beruf Umwelt 38 : 75–90 onide. Contact Dermatitis 46 : 311–312 167. Lauerma AI, Reitamo S (1994) Allergic reactions to topical 187. Bircher AJ, Levy F, Langauer S, Lepoittevin J-P (1995) and systemic corticosteroids. Eur J Dermatol 5 : 354–358 Contact allergy to topical corticosteroids and systemic 168. Whitmore SE (1995) Delayed systemic allergic reactions contact dermatitis from prednisolone with tolerance 35 to corticosteroids. Contact Dermatitis 32 : 193–198 of triamcinolone. Acta Derm Venereol (Stockh) 75 : 169. Butani L (2002) Corticosteroid-induced hypersensitivity 490–493 reaction. Ann Allergy Asthma Immunol 89 : 439–445 188. Goossens A, Linsen G (1998) Contact allergy to antihista- 170. Karsh J,Yang W (2003) An anaphylactic reaction to intra- mines is not common. Contact Dermatitis 39 : 38 articular triamcinolone: a case report and review of the 189. Heine A (1996) Diphenhydramine: a forgotten allergen? literature. Ann Allergy Asthma Immunol 90 : 254–258 Contact Dermatitis 35 : 311–312 171. Coopman S, Degreef H, Dooms-Goossens A (1989) Iden- 190. Yamada S,Tanaka K, Kawahara Y,Inada M, Ohata Y (1998) tification of cross-reaction patterns in allergic contact Photoallergic contact dermatitis due to diphenhydra- dermatitis from topical corticosteroids. Br J Dermatol mine hydrochloride. Contact Dermatitis 38 : 282 121 : 27–34 191. Parente G, Pazzaglia M,Vincenzi C, Tosti A (1999) Contact 172. Goossens A, Matura M, Degreef H (2000) Reactions to dermatitis from pheniramine maleate in eye drops. Con- corticosteroids: some new aspects regarding cross-sensi- tact Dermatitis 40 : 338 tivity. Cutis 65 : 43–45 192. Calnan CD, Frain-Nell W, Cuthbert JW (1962) Occupa- 173. Barth J, Lehr KH, Derendorf H, Möllmann HW, Höhler T, tional dermatitis from chlorpromazine. Trans St John Hochhaus G (1993) Studies on the pharmacokinetics and Derm Soc 48 : 49 metabolism of prednicarbate after cutaneous and oral 193. Greenberg JH (1995) Allergic contact dermatitis from administration. Skin Pharmacol 6 : 179–186 topical doxepin. Contact Dermatitis 33 : 281 174. Töpert M, Olivar A, Optiz D (1990) New developments in 194. Taylor JS, Praditsuwan P, Handel D, Kuffner G (1996) corticosteroid research. J Dermatol Treat 1(Suppl 3) : Allergic contact dermatitis from doxepin cream. One- S5–S9 year patch test clinic experience. Arch Dermatol 132 : 175. Wilkinson SM, Hollis S, Beck MH (1995) Reaktionen auf 515–518 andere Kortikosteroide bei Patienten mit allergischer 195. Bilbao I, Aguirre A, Vicente JM, Raton JA, Zabala R, Diaz Kontaktdermatitis infolge Hydrocortison. Z Haut Gesch- Perez JL (1996) Allergic contact dermatitis due to 5% dox- lechtskr 70 : 368–372 epin cream. Contact Dermatitis 35 : 254–255 176. Täuber U (1994) Dermatocorticosteroids: structure, ac- 196. Buckley DA (2000) Contact allergy to doxepin. Contact tivity, pharmacokinetics. Eur J Dermatol 4 : 419–429 Dermatitis 43 : 231–232 177. Wilkinson SM (2000) Corticosteroid cross-reactions: an 197. Horn HM, Tidman MJ, Aldridge RD (2001) Allergic con- alternative view. Contact Dermatitis 42 : 59–63 tact dermatitis due to doxepin cream in a patient with 178. Isaksson M, Bruze M (2003) Corticosteroid cross-reactiv- dystrophic epidermolysis bullosa. Contact Dermatitis 45 : ity. Contact Dermatitis 49 : 53–54 115 35_623_652 05.11.2005 11:22 Uhr Seite 649

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198. Ophaswongse S, Maibach HI (1993) Topical nonsteroidal 217. Kawada A,Aragane Y,Asai M, Tezuka T (2001) Simultane- antiinflammatory drugs: allergic and photoallergic con- ous photocontact sensitivity to ketoprofen and oxyben- tact dermatitis and phototoxicity. Contact Dermatitis 29 : zone. Contact Dermatitis 44 : 370 57–64 218. Pigatto PD, Mozzanica N, Bigardi AS, Legori A, Valsecchi 199. Achten B, Bourlond A, Haven E, Lapière CM, Piérard G, R, Cusano F, Tosti A, Guarrera M, Balato N, Sertoli A Reynaers H (1973) Étude du bufexamac crème et du bu- (1993) Topical NSAID allergic contact dermatitis. Italian fexamac onguent dans le traitement de diverses derma- experience. Contact Dermatitis 29 : 39–41 toses (Bufexamac cream and ointment for the treatment of 219. Valsecchi R, Cainelli T (1985) Contact dermatitis from various dermatoses, in French). Dermatologica 146 : 1–7 ibuprofen. Contact Dermatitis 12 : 286–287 200. Pigatto PD, Riboldi A, Morelli M, Altomare GF, Polenghi 220. Navarro LA, Jorro G, Morales LC, Pelaez A (1995) Allergic MM (1985) Allergic contact dermatitis from oxyphenbu- contact dermatitis due to piketoprofen. Contact Derma- tazone. Contact Dermatitis 12 : 236–237 titis 32:181 201. Kurumaji Y, Ohshiro Y, Miyamoto C, Keong CH, Katoh T, 221. Goday JJ, Oleaga M, Gonzalez M, del Pozo JDP,Fonseca E Nishioka K (1991) Allergic photocontact dermatitis due to (2000) Photoallergic contact dermatitis from piketo- suprofen. Contact Dermatitis 25 : 218–223 profen. Contact Dermatitis 43 : 115 202. Bagheri H, Lhiaubet V,Montrastuc JL, Chouini-Lalanne N 222. Valenzuela N, Puig L, Barnadas MA, Alomar A (2002) (2000) Photosensitivity to ketoprofen: mechanisms and Photocontact dermatitis due to dexketoprofen. Contact pharmacoepidemiological data. Drug Saf 22 : 339–349 Dermatitis 47 : 237 203. Horn HM, Humphreys F,Aldridge RD (1998) Contact der- 223. Cuerda E, Goday JJ, del Pozo JDP, Garcia J, Peña C, Fon- matitis and prolonged photosensitivity induced by keto- seca E (2003) Photocontact dermatitis due to dexketo- profen and associated with sensitivity to benzophenone- profen. Contact Dermatitis 48 : 283–284 3. Contact Dermatitis 38 : 353–354 224. Vanhee J, Gevers D, Dooms-Goossens A (1981) Contact 204. Valsecchi R, Falghieri G, Cainelli T (1983) Contact derma- dermatitis from an antirheumatic gel containing etofena- titis from ketoprofen. Contact Dermatitis 9 : 163–164 mate. Contact Dermatitis 7 : 50–51 205. Alomar A (1985) Ketoprofen photodermatitis. Contact 225. Hergueta JP, Ortiz FJ, Iglesias L (1994) Allergic contact Dermatitis 12 : 112–113 dermatitis from etofenamate: report of 9 cases. Contact 206. Adamski H, Benkalfate L, Delaval Y, Ollivier I, le Jean S, Dermatitis 31 : 60–62 Toubel G, le Hir-Garreau I, Chevrant-Breton J (1998) Pho- 226. Piñol J, Carapeto FJ (1984) Contact urticaria to etofena- todermatitis from non-steroidal anti-inflammatory mate. Contact Dermatitis 11 : 132–133 drugs. Contact Dermatitis 38 : 171–174 227. Montoro J, Rodriguez-Serna M, Liñara JJ, Ferre MA, San- 207. le Coz CJ, Bottlaender A, Scrivener JN, Santinelli F,Cribier chez-Motilla JM (1997) Photoallergic contact dermatitis B, Heid E, Grosshans E (1998) Photocontact dermatitis due to flufenamic acid and etofenamate. Contact Derma- from ketoprofen and tiaprofenic acid: cross-reactivity titis 37 : 139–140 study in 12 consecutive patients. Contact Dermatitis 38 : 228. Sanchez-Perez J, Sanchez TS, Garcia-Diez A (2001) Com- 245–252 bined contact and photocontact allergic dermatitis to 208. Durieu C, Marguery MC, Giordany-Labadie F, Journe F, etofenamate in flogoprofen gel. Am J Contact Dermat 12 : Loche F, Bazex J (2001) Allergies de contact photoaggra- 215–216 vées et photoallergies de contact au ketoprofène: 19 cas. 229. 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Proske S, Uter W, Schnuch A, Hartschuh W (2003) Severe tact allergy to ketoprofen: clinical and experimental allergic contact dermatitis with generalized spread due to study. Contact Dermatitis 23 : 336–340 bufexamac presenting as the “baboon”syndrome (in Ger- 212. Kawada A,Aragane Y,Maeda A,Yudate T,Tezuka T (2000) man). Dtsch Med Wochenschr 128 : 545–547 Contact dermatitis due to flurbiprofen. Contact Derma- 233. Kerr OA, Kavanagh G, Horn H (2002) Allergic contact titis 42:167–168 dermatitis from topical diclofenac in Solaraze gel. Con- 213. Sugiyiama M, Nakada T, Hosaka H, Sueki H, Iijima M tact Dermatitis 47 : 175 (2001) Photocontact dermatitis to ketoprofen. Am J Con- 234. Goday JJ, Garcia GM, Martinez W, del Pozo J, Fonseca E tact Dermat 12 : 180–181 (2001) Photoallergic contact dermatitis from aceclofenac. 214. Pigatto PD, Bigardi A, Legori A, Valsecchi R, Picardo M Contact Dermatitis 45 : 170 (1996) Cross-reactions in patch testing and photopatch 235. 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239. Foti C, Cassano N, Mazzarella F, Bonamonte D, Vena GA 263. Tosti A, Guerra L, Morelli R, Bardazzi F (1990) Prevalence (1997) Contact allergy to thiocolchicoside. Contact Der- and source of sensitization to emulsifiers: a clinical study. matitis 37:134 Contact Dermatitis 23 : 68–72 240. Foti C, Vena GA, Angelini G (1992) Photocontact allergy 264. Menné T,Hjorth N (1988) Routine patch testing with par- due to thiocolchicoside. Contact Dermatitis 27 : 201–202 aben esters. Contact Dermatitis 19 : 189–191 241. Grimalt F, Romaguera C (1978) Sensitivity to petrolatum. 265. Goossens A, Claes L, Drieghe J (1998) Antimicrobials: Contact Dermatitis 4 : 377 preservatives, antiseptics and disinfectants. Contact Der- 242. Dooms-Goossens A, Degreef H (1980) Sensitization to matitis 39 : 133–134 yellow petrolatum used as a vehicle for patch testing. 266. Wilkinson JD, Shaw S,Andersen KA, Brandao FM, Bruyn- Contact Dermatitis 6 : 146–147 zeel DP,Bruze M, Camarasa JMG, Diepgen T,Ducombs G, 243. Conti A, Manzini BM, Schiavi ME, Motolese A (1995) Sen- Frosch PJ, Goossens A, Lachapelle J-M, Lahti A, Menné T, sitization to white petrolatum used as vehicle for patch Seidenari S, Tosti A, Wahlberg JE (2002) Monitoring lev- testing. Contact Dermatitis 33 : 201–202 els of preservative sensitivity in Europe. A 10-year over- 244. Andersen KE, Maibach HI (1983) Drugs used topically. view (1991–2000). Contact Dermatitis 46 : 207–210 In: de Weck AL, Bundgaard H (eds) Allergic reactions 267. Fisher AA (1973) The paraben paradox. Cutis 12 : 830–832 to drugs. Springer, Berlin Heidelberg New York, pp 268. Ramsing DW, Menné T (1993) Contact sensitivity to sor- 313–372 bic acid. Contact Dermatitis 28 : 124–125 245. Kligman AM (1983) Lanolin allergy: crisis or comedy? 269. Oleffe JA, Blondeel A, de Connick A (1979) Allergy to Contact Dermatitis 9 : 99–107 chlorocresol and propylene glycol in a steroid cream. 246. Kligman AM (1998) The myth of lanolin allergy. Contact Contact Dermatitis 5 : 53–54 Dermatitis 39 : 103–107 270. Dooms-Goossens A, Deveylder H, de Alam AG, Lacha- 247. Wakelin SH, Smith H, White IR, Rycroft RJG, McFadden pelle JM, Tennstedt D, Degreef H (1989) Contact sensitiv- JP (2001) A retrospective analysis of contact allergy to ity to nonoxynols as a cause of intolerance to antiseptic lanolin. Br J Dermatol 145 : 28–31 preparations. J Am Acad Dermatol 21 : 723–727 248. Clark EW, Blondeel A, Cronin E, Oleffe JA, Wilkinson DS 271. de Groot AC, Nater JP (1981) Contact allergy to dithranol. (1981) Lanolin of reduced sensitizing potential. Contact Contact Dermatitis 7 : 5–8 Dermatitis 7 : 80–83 272. Chadha V, Shenoi SD (1999) Allergic contact dermatitis 249. Schlossman ML, McCarthy JP (1979) Lanolin and deriva- from dithranol. Contact Dermatitis 41 : 166 tives chemistry: relationship to allergic contact derma- 273. Zollner TM, Ochsendorf FR, Hensel O, Thaci D, Diehl S, titis. Contact Dermatitis 5 : 65–72 Kalveram CM, Boehncke W-H, Wolter M, Kaufmann R 250. Oleffe JA, Blondeel A, Boschmans S (1978) Patch testing (1997) Delayed-type reactivity to calcipotriol without with lanolin. Contact Dermatitis 4 : 233–247 cross-sensitization to tacalcitol. Contact Dermatitis 37 : 251. Edman B, Moller H (1989) Testing a purified lanolin prep- 251 aration by a randomized procedure. Contact Dermatitis 274. Frosch PJ, Rustemeyer T (1999) Contact allergy to calci- 20 : 287–290 potriol does exist. Report of an unequivocal case and re- 252. Rietschel RL, Fowler JF (1995) Dermatitis to preserva- view of the literature. Contact Dermatitis 40 : 66–71 tives and other additives in cosmetics and medications. 275. Krayenbühl BH, Elsner P (1999) Allergic and irritant con- 35 In: Rietschel RL, Fowler JF (eds) Fisher’s contact derma- tact dermatitis from calcipotriol. Am J Contact Dermat titis. Williams and Wilkins, Baltimore, Md, pp 257–329 10 : 78–80 253. Hannuksela M, Pirila V, Salo OP (1975) Skin reactions to 276. Park YK, Lee JH, Chung WJ (2002) Allergic contact der- propylene glycol. Contact Dermatitis 1 : 112–116 matitis from calcipotriol. Acta Derm Venereol (Stockh) 254. Funk JO, Maibach HI (1994) Propylene glycol dermatitis: 82 : 71–72 re-evaluation of an old problem. Contact Dermatitis 31 : 277. Kimura K, Katayama I, Nishioka K (1995) Allergic contact 236–241 dermatitis from tacalcitol. Contact Dermatitis 33 : 255. Fowler JF (1993) Contact allergy to propylene glycol in 441–442 topical corticosteroids. Am J Contact Dermat 4 : 37 278. Shaw DW, Eichenfield LF, Shainhouse T, Maibach HI 256. Uter W, Schwanitz HJ (1996) Contact dermatitis from (2004) Allergic contact dermatitis from tacrolimus. J Am propylene glycol in ECG electrode gel. Contact Derma- Acad Dermatol 50 : 962–965 titis 34 : 230–231 279. Schena D, Barba A, Costa G (1996) Occupational contact 257. Connolly M, Buckley DA (2004) Contact dermatitis from urticaria to cisplatin. Contact Dermatitis 34 : 220–221 propylene glycol in ECG electrodes, complicated by me- 280. Daughters D, Zackheim H, Maibach HI (1973) Urticaria dicament allergy. Contact Dermatitis 50 : 42 and anaphylactoid reactions after topical applications of 258. Farrar CW,Bell HK, King CM (2003) Allergic contact der- mechlorethamine. Arch Dermatol 107 : 429–430 matitis from propylene glycol in Efudix cream. Contact 281. Anderson LL, Welch ML, Grabski WJ (1997) Allergic con- Dermatitis 48 : 345 tact dermatitis and reactivation phenomenon from - 259. Bajaj AK, Gupta SC, Chatterjee AK, Singh KG (1990) Con- tophoresis of 5-fluorouracil. J Am Acad Dermatol 36 : tact sensitivity to polyethylene glycols. Contact Derma- 478–479 titis 22 : 291–292 282. Valsecchi R, Imberti G, Cainelli T (1991) Mitomycin C 260. Pasche-Koo F, Piletta PA, Hunziker N, Hauser C (1994) contact dermatitis. Contact Dermatitis 24 : 70–71 High sensitization rate to emulsifiers in patients with 283. Vonderheid EC, van Scott EJ, Johnson WC, Grekin DA, chronic leg ulcers. Contact Dermatitis 31 : 226–228 Asbell SO (1977) Topical chemotherapy and immunother- 261. Tosti A, Vicenzi C, Guerra L, Andrisano E (1996) Contact apy of mycosis fungoides: intermediate-term results. dermatitis from fatty alcohols. Contact Dermatitis 35 : Arch Dermatol 113 : 454–462 287–289 284. Burden A, Beck MH (1992) Contact hypersensitivity to 262. Hannuksela M, Kousa M, Pirilä V (1976) Contact sensitiv- azathioprine. Contact Dermatitis 27 : 329–330 ity to emulsifiers. Contact Dermatitis 2 : 201–204 35_623_652 05.11.2005 11:22 Uhr Seite 651

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285. Suzuki K, Suzuki M, Akamatsu H, Matsungaga K (2002) 309. Prisant LM (2002) Transdermal clonidine skin reactions. Allergic contact dermatitis from minoxidil: study of the J Clin Hypertens (Greenwich) 4 : 136–138 cross-reaction to minoxidil. Am J Contact Dermat 13 : 310. Torres V,Lopes JC, Leite L (1992) Allergic contact derma- 45–46 titis from nitroglycerin and estradiol transdermal thera- 286. Tosti A, Bardazzi F, de Padova MP, Caponeni GM, Melino peutic systems. Contact Dermatitis 26 : 53–54 M, Veronesi S (1985) Contact dermatitis to minoxidil. 311. Perez-Calderon R, Gonzalo-Garijo MA, Rodriguez-Neva- Contact Dermatitis 13 : 275–276 do I (2002) Generalized allergic contact dermatitis from 287. Trattner A, David M (2002) Pigmented contact dermatitis nitroglycerin in a transdermal therapeutic system. Con- from topical minoxidil 5%. Contact Dermatitis 46 : 246 tact Dermatitis 46 : 203 288. Vicenzi C, Lucente P,Ricci C, Tosti A (1997) Facial contact 312. Boehncke W-H, Gall H (1996) Type IV hypersensitivity to dermatitis to metronidazole. Contact Dermatitis 36 : topical estradiol in a patient tolerant to it orally. Contact 116–117 Dermatitis 35 : 187–188 289. Balato N, Patruno C, Lembo G, Cuccurullo FM, Ayala F 313. Gonçalo M, Oliveira HS, Monteiro C, Clerins I, Figueiredo (1995) Allergic contact dermatitis from retinoic acid. A (1999) Allergic and systemic contact dermatitis from Contact Dermatitis 332 : 51 estradiol. Contact Dermatitis 40 : 58–59 290. Pereira F, Fernandes C, Dias M, Lacerda MH (1995) Aller- 314. Koch P (2001) Allergic contact dermatitis from estradiol gic contact dermatitis from zinc pyrithione. Contact Der- and norethisterone acetate in a transdermal hormonal matitis 33 : 131 patch. Contact Dermatitis 44 : 112–113 291. Goh CL, Ng SK (1986) Contact sensitivity to salicylic acid. 315. Corazza M, Mantovani L, Montanari A, Virgili A (2002) Contact Dermatitis 14 : 114 Allergic contact dermatitis from transdermal estradiol 292. Baptista A, Barros MA (1992) Contact dermatitis to crot- and systemic contact dermatitis from oral estradiol. A amiton. Contact Dermatitis 27 : 59 case report. J Reprod Med 47 : 507–509 293. Meneghini CL, Vena GA, Angelini G (1982) Contact der- 316. Farm G (1993) Contact allergy to nicotine from a nicotine matitis to scabicides. Contact Dermatitis 8 : 285–286 patch. Contact Dermatitis 29 : 214–215 294. Fisher AA (1982) Resorcinol – a rare sensitizer. Cutis 29 : 317. Buckley DA, Wilkinson SM, Higgins EM (1998) Contact 331 allergy to a testosterone patch. Contact Dermatitis 39 : 295. Okazawa H, Aihara M, Nagatani T, Nakajima H (1998) Al- 91–92 lergic contact dermatitis due to ethyl alcohol. Contact 318. Shouls J, Shum KW, Gadour M, Gawkrodger DJ (2001) Dermatitis 38 : 233 Contact allergy to testosterone in an androgen patch: 296. Agathos M, Bandmann HJ (1984) Benzoyl peroxide con- control of symptoms by pre-application of topical corti- tact allergy in leg ulcer patients. Contact Dermatitis 11 : costeroid. Contact Dermatitis 45 : 124–125 316–317 319. Herbst RA, Maibach HI (1991) Contact dermatitis caused 297. Leow YH, Ng SK, Wong WK, Goh CL (1995) Contact aller- by allergy to ophthalmic drugs and contact lens solu- gic potential of topical traditional Chinese medicaments tions. Contact Dermatitis 25 : 305–312 in Singapore. Am J Contact Dermat 6 : 4–8 320. Herbst RA, Maibach HI (1992) Contact dermatitis caused 298. Lee TY, Lam TH (1988) Irritant contact dermatitis due to by allergy to ophthalmics: an update. Contact Dermatitis a Chinese herbal Lu-Shen-Wan. Contact Der- 27 : 335–336 matitis 18 : 213–218 321. Herbst RA, Maibach HI (1997) Allergic contact dermatitis 299. Lee TY,Lam TH (1991) Contact dermatitis due to Chinese from ophthalmics: update 1997. Contact Dermatitis 37 : orthopaedic tincture, Zheng Gu Shui. Contact Dermatitis 252–253 24:64–65 322. Manni G, Centofanti M, Sacchetti M, Oddone F, Bonini S, 300. Barbaud A, Mougeolle JM, Tang JQ,Protois JC (1991) Con- Parravano M, Bucci MG (2004) Demographic and clinical tact allergy to colophony in Chinese Musk and Tiger- factors associated with the development of brimonidine Bone Plaster. Contact Dermatitis 25 : 324–326 tartrate 0.2%-induced ocular allergy. J Glaucoma 13 : 301. Koh D, Lee BL, Ong HY,Ong CN (1997) Colophony in top- 163–167 ical traditional Chinese medicaments. Contact Derma- 323. Friedlaender MH (1995) A review of the causes and treat- titis 37:243 ment of bacterial and allergic conjunctivitis. Clin Ther 302. Lee TY, Lam TH (1993) Myrrh is the putative allergen in 17 : 800–810 bonesetter’s herbs dermatitis. Contact Dermatitis 29 : 279 324. Britz MB, Maibach HI (1979) cutaneous vulvar re- 303. Li L-F,Wang J (2002) Patch testing in allergic contact der- activity to irritants. Contact Dermatitis 5 : 375–377 matitis caused by topical Chinese herbal medicine. Con- 325. Farage MA, Bjerke DL, Mahony C, Blackburn KL, Ger- tact Dermatitis 47 : 166–168 berick GF (2003) Quantitative risk assessment for the 304. Chen HH, Sun CC, Tseng MP, Hsu CJ (2003) A patch test induction of allergy contact dermatitis: uncertainty factors study of 27 crude drugs commonly used in Chinese topi- for mucosal exposure. Contact Dermatitis 49 : 140–147 cal medicaments. Contact Dermatitis 49 : 8–14 326. Marren P,Wojnarowska F, Powell SM (1982) Allergic con- 305. Holdiness MR (1989) A review of contact dermatitis asso- tact dermatitis and vulvar dermatoses. Br J Dermatol 126 : ciated with transdermal therapeutic systems. Contact 52–56 Dermatitis 20 : 3–9 327. Virgili A, Corazza M, Bacilieri S, Califano A (1997) Con- 306. Hogan DJ, Maibach HI (1990) Adverse dermatologic reac- tact sensitivity in vulvar lichen simplex chronicus. Con- tions to transdermal drug delivery systems. J Am Acad tact Dermatitis 37 : 296–297 Dermatol 22 : 811–814 328. Lewis FM, Shah M, Gawkrodger DJ (1997) Contact sensi- 307. Gordon DR, Shupak A, Doweck I, Spitzer O (1989) Aller- tivity in pruritus vulvae: patch test results and clinical gic contact dermatitis by transdermal hyoscine. Br Med J outcome. Am J Contact Dermat 8 : 137–140 298 : 1220–1221 329. Goldsmith PC, Rycroft RJG, White IR, Ridley CM, Neill 308. Corazza M, Mantovani L, Virgili A, Strumia R (1995) Al- SM, McFadden JP (1997) Contact sensitivity in women lergic contact dermatitis from a clonidine transdermal with anogenital dermatoses. Contact Dermatitis 36 : delivery system. Contact Dermatitis 32 : 246 174–175 35_623_652 05.11.2005 11:22 Uhr Seite 652

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330. Chow ET (2001) Multiple corticosteroid allergies. Austra- 346. Wilkinson SM (1994) Hypersensitivity to topical corti- las J Dermatol 42 : 62–63 costeroids. Clin Exp Dermatol 19 : 1–11 331. Black RJ, Dawson TAJ, Strang WC (1990) Contact sensitiv- 347. Keilig W (1983) Kontaktallergie auf cetylstearyl alkohol ity to lignocaine and prilocaine. Contact Dermatitis 23 : (Lanette O) als therapeutisches problem bei stauungsder- 117–118 matitis und ulcus cruris (Contact allergy to cetylsteary- 332. Urrutia I, Jauregui I, Gamboa P, Gonzalez G, Antepara I lalcohol (Lanette O) as a therapeutic problem in stasis (1998) Photocontact dermatitis from cinchocaine (dibu- dermatitis and leg ulcer, in German). Derm Beruf Umwelt caine). Contact Dermatitis 39 : 139–140 31 : 50–54 333. Lee AY (1998) Allergic contact dermatitis from dibucaine 348. Mallon E, Powell SM (1994) Sorbitan sesquioleate: a po- in Proctosedyl ointment without cross-reaction. Contact tential allergen in leg ulcer patients. Contact Dermatitis Dermatitis 39 : 261 30 : 180–181 334. Corbett JR (1985) Allergic contact dermatitis to Trimo- 349. Mallon E, Powell SM (1994) Allergic contact dermatitis vate. Contact Dermatitis 13 : 281 from Granuflex hydrocolloid dressing. Contact Derma- 335. Valsecchi R, Imberti GL, Cainelli T (1990) Nifuratel con- titis 30 : 110–111 tact dermatitis. Contact Dermatitis 23 : 187 350. Schliz M, Rauterberg A, Weiss J (1996) Allergic contact 336. Sanchez-Perez J, Abajo P, Córdoba S, Garcia-Diez A dermatitis from hydrocolloid dressings. Contact Derma- (2000) Allergic contact dermatitis from sodium metabis- titis 34 : 146–147 ulfite in an antihemorrhoidal cream. Contact Dermatitis 351. Molin L, Stymne S, Stark HU, Eriksson IL (1996) Allergic 42 : 176–177 contact dermatitis induced by tackifying agents in hydro- 337. McKenna KE (2000) Allergic contact dermatitis from colloid dressings. J Eur Acad Dermatol Venereol 7(Suppl glyceryl trinitrate ointment. Contact Dermatitis 42 : 246 2) : S142–S143 338. Tanaka S, Otsuki T,Matsumoto Y,Hayakawa R, Sugiura M 352. Sasseville D, Tennstedt D, Lachapelle JM (1997) Allergic (2001) Allergic contact dermatitis from enoxolone. Con- contact dermatitis from hydrocolloid dressings. Am J tact Dermatitis 44 : 192 Contact Dermat 8 : 236–238 339. Reyes JJ, Fariña MC (2001) Allergic contact dermatitis 353. Downs AMR, Sharp LA, Sansom JE (1999) Pentaerythri- due to trimebutine. Contact Dermatitis 45 : 164 tol-esterified gum rosin as a sensitizer in Granuflex hy- 340. Gallo R, Parodi A (2002) Baboon syndrome from 5-ami- drocolloid dressing. Contact Dermatitis 41 : 162–163 nosalicylic acid. Contact Dermatitis 46 : 110 354. Menné T,Veien N, Sjolin K-E, Maibach HI (1994) System- 341. Pecegueiro M Brandão FM (1983) Alergia de contacto em ic contact dermatitis. Am J Contact Dermat 5 : 1–12 doentes com úlcera de perna (contact allergy in patients 355. Rietschel RL, Fowler JF (1995) Systemic contact-type der- with leg ulcers, in Portuguese). Trab Soc Port Dermatol matitis. In: Rietschel RL, Fowler JF (eds) Fisher’s contact Venereol XLI : 37–46 dermatitis. Williams and Wilkins, Baltimore, Md., 342. Schupp DL, Winkelmann RK (1988) The role of patch pp 114–129 testing in stasis dermatitis. Cutis 42 : 528–530 356. Guin JD, Phillips D (1989) Erythroderma from systemic 343. Wilson CL, Cameron J, Powell SM, Cherry G, Ryan TJ contact dermatitis: a complication of systemic gentami- (1991) High incidence of contact dermatitis in leg-ulcer cin in a patient with contact allergy to neomycin. Cutis patients – implications for management. Clin Exp Der- 43 : 564–567 35 matol 16 : 250–253 357. Andersen KE, Hjorth N, Menné T (1984) The baboon syn- 344. Gallenkemper G, Rabe E, Bauer R (1998) Contact sensiti- drome: systemically-induced allergic contact dermatitis. zation in chronic venous insufficiency: modern wound Contact Dermatitis 10 : 97–100 dressings. Contact Dermatitis 38 : 274–278 358. Nakayama H, Niki F,Shono M, Hada S (1983) Mercury ex- 345. Machet L, Couhe C, Perrinaud A, Hoarau C, Lorette G, anthema. Contact Dermatitis 9 : 411–417 Vaillant L (2004) A high prevalence of sensitization still 359. Bártolo E, Brandão FM (1988) Mercury exanthema. Con- persists in leg ulcer patients: a retrospective series of 106 tact Dermatitis 18 : 172 patients tested between 2001 and 2002 and a meta-analy- sis of 1975–2003 data. Br J Dermatol 150 : 929–935