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Dermatological drugs and cosmetics
A.C. de Groot and J.P. Nater
15
Dermatological drugs and cosmetics
Kathon | CG, an important 'new' contact allergen 'Kathon' is the proprietary name for a family o f microbiocides and preservatives containing, as active ingredients, a mixture o f 5-chloro-2methyl-4-isothiazolin-3-one ( CTFA name methylchloroisothiazolinone, CAS no. 2617255-4) and 2-methyl-4-isothiazolin-3-one ( CTFA name methylisothiazolinone, CAS no. 2682-20-4) in an approximate ratio o f 3:1, respectively, with MgClz ( +_9 % ) and M g ( N 0 3 ) 2 (+_16%) present as stabilizers. Several formulations are commercially available under the names Kathon 886 M W , Kathon WT, Kathon L X and Kathon CG from Rohm and Haas, Philadelphia, USA. Besides Rohm and Haas, other firms market these isothiazolinones under various trade names ( lCR). This biocide is an effective preservative for toiletries, cosmetics, and household cleaning products. It is also used as a biocide for swimming-pool water and in various industrial applications such as cooling-tower water, metalworking fluids, latex emulsions, and for slime control in paper mills. One o f the Kathon formulations, Kathon CG ( CG = Cosmetic Grade) has in recent years become a very popular preservative with the cosmetic industry. At the present time Kathon CG is not permitted in the EEC in any pharmaceutical or dermatological application, nor as a food additive, nor for internal use by humans. However, Kathon CG at a maximum concentration o f 50 p.p.m, active ingredients (hereafter referred to as "a.i. ') has been given provisional clearance for use as a cosmetic and toiletry preservative in the EEC (Council Directive 82/368/EEC, May 17, 1982). Kathon CG has been used in cosmetics and toiletries f o r 11 years in Europe, and for 6 years in the United States (2c~). The manufacturers estimate that in 1980 it was used in 55,000 Side Effects of Drugs Annual 11 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1987
tons o f cosmetic products in Europe, and in 20,000 tons in the United States (3), and its application in cosmetic products has increased enormously since then. Kathon CG has been shown to be effective at very low concentrations in controlling microbial growth over a wide spectrum o f bacteria, yeasts and fungi. The manufacturer recommends levels o f 0.02-0.1% by weight (3-15 p.p.m, a.i.) in products such as shampoos and hair conditioners, hair and body gels, bubble baths, skin creams and skin lotions (2cR). Kathon CG as supplied is a strong irritant. The levels advised by the manufacturer (3-15 p.p.m, a.i.) are far below levels which will irritate the skin. Data from the manufacturer suggest the highest non-irritant concentration o f an aqueous solution o f Kathon CG to be 100 p.p.m, a.i. 21-Day cumulative irritancy assays confirmed this; there was evidence that Kathon CG in higher concentrations o f 200 p.p.m, a.i. may produce irritation (4). Single diagnostic patch tests at levels o f up to 100 p.p.m, a.i. produced f e w irritant responses, and this was suggested to be a useful concentration for patch testing in ~liagnostic studies. However, the authors o f a Swedish study (1 c~) conclude from the data obtained in their investigation that levels o f up to 300 p.p.m, a.i. in water are not irritant at diagnostic patch-testing. Studies both in guinea-pigs (modified Buehler technique) (5) and man (4; Kathon CG product information sheet, Rohm & Haas, Philadelphia, USA, 1983) demonstrated that Kathon CG has a dosedependent potential for inducing contact allergic reactions. Two case-reports (2 cR, 6 c) and 4 epidemiological studies (1 c~, 7~, 8~R, 9cr) on contact allergic reactions to Kathon CG have been published. When tested with Kathon CG I00 p.p.m, a.i., prevalence rates o f sensitization hi patients seen for routine testing were 1.4% ha a Dutch study (8~R), 1.9% in a Swedish study (lC~), and 0.8% in a Danish stud.v (9c'). When tested with the higher (but apparent(v ramirritant) concentration o f 300 p.p.m, a.i.. 43
135
Dermatological drugs and cosmetics Chapter 15 o f 976 patients routinely patch-tested reacted to Kathon CG (4.4%) (lCa). O f 179 patients suspected to suffer from cosmetic allergy 6 (3.4%) reacted to Kathon CG tested at 150 p.p.m. (7r In a study not yet published (at the time of writing) o f 7866 patients tested with Kathon CG 100 p.p.m, a.i. in a water patch-test system, conducted in conjunction with members o f the ICDRG, the prevalence rate o f sensitization was found to be 0.51% ( Bji~rkner et al, cited in R e f 10). Bj6rkner et al (I ce) have provided data which suggest that the actual prevalence rate may be higher; in their study o f 34 patients who had reacted to Kathon CG 300 p.p.m, a.i. only 17 (50%) also reacted to I00 p.p.m, on serial dilution testing. Thus, these authors feel that 50% o f allergic individuals may be overlooked when a test concentration o f 100 p.p.m, a.i. is used. Nevertheless, they also use patch-test concentrations lower than 250 p.p.m, because o f an unacceptably high risk ( +_1%) o f patch-test sensitization when test concentrations o f 250 or 300 p.p.m, a.i. are used. From these data it appears that, at least in some countries like Sweden and The Netherlands, contact allergy to Kathon CG has become common among patients suffering from dermatitis. It is very difficult, however, to trace the cause o f the sensitization, as the preservative is so widely used. In the Swedish study (11) commercial products used in daily life by patients with contact allergy to Kathon CG were tested for its presence. For each patient, one or many o f the products proved to contain Kathon CG! It is equally difficult to determine the relevance o f the observed contact allergy to Kathon CG. The demonstration o f Kathon CG in one or more products used by the patient does not necessarily imply a role o f Kathon CG in this product for the development and/or persistence o f the patient's actual dermatitis. Eighteen human volunteers who had developed delayed contact hypersensitivity to the isothiazolinone mixture through exaggerated, repeated, occlusive exposure, used one or more rinse-off products containing Kathon CG 4-6 p.p.m, a.i. for 3-6 weeks without experiencing allergic reactions (12). Use tests involving daily application o f a Kathon CG (8.6 p.p.m, a.i.) containing cosmetic lotion in the elbow flexure for 5 days were negative in all 11 patients tested, who were previously shown to be allergic to Kathon CG (9c'). On the other hand, o f 13 Kathon CG allergic patients who applied a cream containing Kathon CG 15 p.p.m, a.i., 7 (54%) developed a mild dermatitis, whereas control tests using the
same cream without Kathon CG remained negative in these patients (lCR). In one reporI, the relevance o f the observed patch-test reaction to Kathon CG was clearly demonstrated (2cR). It was convincingly shown that one patient had become sensitized to a moisturizing cream containing Kathon CG 12 p.p.m, a.i. Provocative testing with the cream and Kathon CG 15 p.p.m, was positive, and after discontinuation o f the incriminated cosmetic the dermatitis cleared. I f indeed a postulated no-effect level exists under which Kathon CG can be used without concern about the development o f clinically significant delayed contact dermatitis (9 c', 12), this level must be lower than 12 p.p.m, a.i. Further studies using various bases and concentrations for Kathon CG seem to be warranted. The occurrence o f sensitization to the preservative must be monitored by Contact Dermatitis Groups in various countries. Use tests should be included. We therefore recommend that Kathon CG 100 p.p.m, a.i. in water be included in the European Standard Series, which is tested routinely in patients suffering from dermatitis, to assess its significance.
Photochemotherapy ( P U V A ) (SED-IO, 254; S E D A - 8 , 152; S E D A - 9 , 130; S E D A - I O , 125)
Antinuclear antibodies (13 cR)
Antinuclear antibodies (ANA) were looked for in patients receiving PUVA therapy. During PUVA treatment ANA appeared in 34 of 100 patients. Of 8 patients who had A N A prior to PUVA, a significant increase in ANA titer was noted in 4. A statistically significant difference was noted when the first and last A N A tests for each patient were compared. No such difference was seen in control patients. All PUVAtreated patients developing A N A were evaluated clinically and with laboratory screening for signs of systemic disease. Only 1 patient, who developed A N A with a nucleolar staining pattern, showed symptoms consistent with a collagen vascular disease. The results of this report indicate that PUVA therapy has the capacity t o induce ANA. The mechanism for this is not clear and the clinical importance is also obscure. As long as a possible relationship between PUVAinduced A N A and the development of a connective-tissue disease has not been ruled out, monitoring of ANA in PUVA patients is advisable.
136 The development of systemic lupus erythematosus (SLE), SLE-like syndrome and scleroderma-like changes during PUVA therapy has been reported previously (SEDA-10, 126).
Disseminated superficial actinic porokeratosis (SED-IO, 255) A patient with chronic psoriasis treated with PUVA developed lesions clinically and histologically characteristic of disseminated superficial actinic porokeratosis (DSAP). The association of these lesions with exposure to artificial or natural UV light has been emphasized previously. Although DSAP has been reported to occur in dark-skinned individuals, it is usually seen in sun-exposed areas of fair-skinned persons. Thus, the authors feel that DSAP may represent a PUVA-induced cutaneous side effect (14cr). Among its many known effects, PUVA is associated with immunosuppression. Immunosuppression has been proposed as an etiology of porokeratosis (15), and it has been suggested (16) that PUVA-induced immunosuppression may allow the proliferation of latent abnormal clones of epidermal cells, thereby producing the porokeratosis (17). Drug fever (18c) After several uneventful PUVA treatments, a 61-year-old female developed a fever reaching 39.5~ 3 hours after a treatment session on 2 occasions. Both times, the body temperature spontaneously returned to normal after 8-10 hours. Apart from an accelerated erythrocyte sedimentation rate (47 mm/h) the clinical and laboratory examinations did not reveal any other pathological changes. After cessation of treatment, the fever did not recur. Provocation tests with UV-A alone and methoxsalen alone were negative, but 2 hours after receiving 40 mg methoxsalen with 3 J/cm 2 UV-A irradiation, she developed a temperature of 39.2~ with dyspnea. The drug fever was felt to be an allergic phenomenon caused by a product of methoxsalen, transformed by UV-A irradiation. Interaction between methoxsalen and phenytoin (19c) A patient with epilepsy and psoriasis taking phenytoin was treated with PUVA therapy with no effect at all. The PUVA treatment failure was demonstrated to be due to abnormally low serum levels of methoxsalen during phenytoin therapy. Normal serum levels of methoxsalen were observed after phenytoin was discontinued. The effect may be due to induction of the hepatic enzyme system by
Chapter 15 A.C. de Groot and J.P. Nater phenytoin, leading to increased metabolism of methoxsalen. Other drugs inducing hepatic enzymes might also interfere with psoralen metabolism, and thereby influence the result of PUVA therapy. ORAL RETINOIDS (SED-IO, 255, 717)
Etretinate (SEDA-8, 152, 347; SEDA-9, 134;
SEDA-IO, 123) Cholestatic jaundice (SED-IO, 257; SEDA-IO, 124; 20cR) A slight, transient elevation of liver enzyme concentrations can be observed in some etretinate-treated patients. Cases of overt hepatotoxicity have also been observed (SED-10,257). Mild cholestasis was noted infrequently. A first case of etretinate-induced cholestatic jaundice has been reported (20cR): A 58-year-old man with psoriasis vulgaris was treated with etretinate 1 mg/kg/d. At the end of the 12th day the patient gradually started complaining of pruritus, dark urine and acholic stools. Alkaline phosphatase was 420 U/l, ~-glutamyl transpeptidase 380 U/l; other liver enzymes were only slightly elevated. The patient became jaundiced with a bilirubin level up to 400 ~mol/l. The histological findings were compatible with non-specific reactive hepatitis with cholestasis. Liver function tests returned to normal values 4 weeks after treatment was discontinued.
Diffuse hyperostosis (21 c) Hyperostosis due to isotretinoin has been reported several times (SED- 10, 257,;SEDA-9, 132). In contrast, etretinate has only twice been linked to diffuse skeletal hyperostosis (21 c, 22c). This discrepancy may only reflect the more widespread use of isotretinoin, especially in the United States. Long-term studies are required to define the magnitude of this problem; to establish whether it can be reduced by intermittent rather than continuous therapy, and to determine the prognosis for patients with retinoid hyperostosis (21c). Hair disorders (23c, 24c, 25c) It is wellrecognized that etretinate therapy may cause accelerated hair growth and a dose-dependent telogen effluvium. At high dosage, hair loss may be severe and may be associated with dystrophy of hair roots. Kinking of the hair has been associated with isotretinoin therapy (26r This side effect, also described as 'unruly hair' has now also been
Dermatological drugs and cosmetics Chapter15 observed in etretinate-treated patients (23c, 25c). The hair becomes diffusely dry, curly and unruly. Onset can occur within weeks of commencing etretinate and the process is dose-dependent and reversible. The mechanism for the production of such hair is as yet unclear. Possibilities include interference with the kinetics of the inner root sheath, thereby influencing keratinization. Alternatively, the drying effect of the retinoid therapy in an individual with previously waxy hair might also produce 'wooly' hair. Skin fragility (27cR) Skin thinning and increased skin fragility are well-recognized side effects of retinoid therapy. A patient with severe erythrodermic psoriasis and histologically proven alcoholic cirrhosis was treated with etretinate 25 mg 3 times daily. After 3 years the patient was admitted because of circumferential ulceration of his lower legs which had slowly developed over the preceding 6 months. The skin became increasingly smooth and shiny, and hair fall and nail loss were noted. Superficial erosions developed over pressure areas such as hips and spine. After discontinuation of treatment small superficial blisters, some hemorrhagic, developed repeatedly at sites of trauma. Six months later plasma levels of etretinate were still as high as 180 ng/ml (therapeutic'range 100-700 ng/ml). The electron-microscopic features of keratinocyte separation and degeneration, and the presence of fine granular material have been described previously in etretinate-treated patients, and these probably contributed to the clinical finding of blistering. The pronounced cutaneous side effects described occurred while the patient was taking etretinate in standard dosage, and almost certainly resulted from excessive accumulation of the drug due to impaired excretion by preexisting liver disease. At present, the use of etretinate in patients with liver disease is contraindicated.
Palmoplantar eruption (28c') Of 32 patients treated with etretinate 1 mg/kg/d for psoriasis, 5 developed a palmoplantar eruption several clays after starting therapy; the palms and soles had previously been unaffected. The lesions were red discrete papules 3-4 mm in diameter, with small scales; in 2 patients there were also minute pustules. Bacterial and fungal smears and cultures from the pustules were negative. A punch biopsy did not reveal any abnormal findings apart from mild dilation of the capillaries in the dermis. The lesions disap-
137 peared completely in all patients 5-35 days leaving colarette desquamation. The authors suggest that this palmoplantar eruption is caused by etretinate. The eruption subsided spontaneously within some weeks, which may explain why it has not been recorded previously, despite the fact that it occurred in 5 of 32 patients in this study.
Isotretinoin (13-cis-retinoic acid) (SED-IO, 256; SEDA-8, 345; SEDA-9, 132, 134; SEDA-IO, 124) Exercise-induced bronchoconstriction (29c) A 20-year-old middle-distance runner with acne conglobata related a history of atopic dermatitis and hay fever, but not asthma. He was prescribed isotretinoin and within 3-4 weeks noted the development of exercise-induced wheezing. Upon cessation of isotretinoin, the problem was alleviated, but after restarting isotretinoin he again noted the recurrence of wheezing when he ran. Cooling of the airway and respiratory water loss are the factors causing exercise-induced asthma in susceptible individuals, and it was hypothesized that the isotretinoin produced significant dryness of the respiratory passages to cause exercise-induced asthma in an atopic individual.
Acne fulminans (30c', 31c, 32c)
Acne fulminans is a rare complication of severe acne. The syndrome includes severe ulcerating cystic acne, fever and arthralgia. Other documented features include microscopic hematuria, an increased erythrocyte sedimentation rate and white cell count, anemia, myalgia, and rarely erythema nodosum (30cr). Two patients treated with isotretinoin 1 mg/kg/d developed signs of acne fulminans and erythema nodosum (30cr). A platelet aggregation test for circulating IgG immune complexes yielded positive results on 2 occasions at 1/160 dilution (normal
Chapter 15 A.C. de Groot and J.P. Nater
138
Osteoma cuffs (SEDA-IO, 124; 33c) Osteoma cutis is a rare sequel to chronic, severe, scarring acne. A patient was observed who presented with a mild form of this disease which was stable for a number of years. Following a successful course of treatment with isotretinoin she developed florid and severe osteoma curls of her face (33c). Isotretinoin has been noted to cause calcinosis in rats, and ossification disorders such as premature closure of epiphyses (SED-10, 257), skeletal hyperostosis (34c) and nasal bone osteophytosis (SEDA-10, 124) have been documented. Osteoma curls is generally considered an osteoid metaplasia resulting from chronic inflammation. It was suggested (33 c) that in predisposed individuals isotretinoin may exacerbate the condition. Adverse ocular reactions (35R) Ocular findings are among the more frequent side effects in patients taking isotretinoin, the most common being blepharoconjunctivitis. In a review article (35 x) 237 cases of adverse ocular reactions possibly associated with isotretinoin were evaluated. Of the 237 patients, 121 were extensively monitored by the manufacturer during a 2-year period. Seventy-eight other cases were previously reported in the Table 1. Possible adverse ocular effects associated with isotretinoin exposure in 236 patients Adverse effects Eyelids Blepharoconjunctivitis or meibomianitis Photodermatitis Cornea Corneal opacities Dry eyes Contact-lens intolerance Optic nerve Papilledema or pseudotumor cerebri Optic neuritis (9.) Congenital abnormalities Microphthalmos Orbital hypertelorism Optic nerve hypoplasia Cortical blindness Others Blurred vision Myopia Decreased dark adaptation (36c, 37c)* Ocular inflammation (.9) (uveitis, scleritis, retinitis, ophthalmitis, iritis)
No. of patients 88 6 12 47 19 18 3 5 2 4 1 39 5 3 7
*Also observed in 2 of 5 patients treated with fenretinide, another synthetic retinoid (38cr).
literature, and the remaining 38 cases consisted of 7 reported to the FDA and 31 reported to the US National Registry of Drug Induced Ocular Side Effects. The results are shown in Table 1. Ocular side effects secondary to isotretinoin are generally benign in nature and reversible on reduction or cessation of drug therapy. However, papilledema demands discontinuation of the drug. Corneal opacities should be monitored closely. Although they do not usually interfere with vision, prudence indicates discontinuation of isotretinoin or reduction of the dosage when corneal opacities develop (35~). CONTACT A L L E R G Y (SED-IO, 257, 266; SEDA-9, 135; SEDA-IO, 126) Every year 'new' allergens (i.e. chemicals which previously had not caused contact allergy) are being described in the literature. These allergens and updated information on chemicals which were already known to be sensitizers are presented in Table 2 (topical drugs) and Table 3 (cosmetic ingredients). SYSTEMIC SIDE EFFECTS OF TOPICAL DRUGS
Clindamycin phosphate and pseudomembranous colitis (SED-IO, 270; SEDA-8, 160) Topical clindamycin is regarded as a safe and effective agent for the treatment of acne vulgaris. It is estimated that about 4-5% of topically applied clindamycin hydrochloride is absorbed percutaneously (SEDA-8, 160); several cases of clindamycin-related diarrhea have been reported (SED-10, 270), including 1 case ofpseudomembranous colitis (71Cr). Topical clindamycin phosphate seems to be less readily absorbed. Using a sensitive radioimmunoassay (72ca), it was found that less than 1% of a 20-rag dose (1 ml twice daily; 0.25 mg/kg/d) of clindamycin phosphate was absorbed, reaching peak serum levels of only 1.7 ng/ml. In addition, 42 human subjects receiving topical clindamycin phosphate were studied (73), but significant changes in stool flora, diarrhea, and measurable clindamycin absorption were not detected. Nevertheless, a case of pseudomembranous colitis thought to be caused by topical clindamycin phosphate has now been reported (72cx). The patient had 2 episodes of pseudomembranous colitis. Assays for Clostridium di~cile toxin were positive, and the patient was ultimately cured by oral vancomycin hydro-
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141
Minoxidil (SEDA-IO, 128)
Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) is a potent vasodilator effective in Psychosis due to transdermally administered severe hypertension irrespective of the cause. scopolamine (SEDA-8, 161; 74c') Toxic psy- Hypertrichosis occurs in approximately 70% of chosis after oral or subcutaneous administra- patients taking oral minoxidil, usually within 2 tion of scopolamine and other anticholinergic months of the start of therapy. Although this agents has been well-documented. Transder- increased hair growth may be generalized, it real scopolamine is widely used for the preven- most often occurs on the face and extremities. tion of motion sickness. There have been some In addition, isolated case-reports have been reports of toxic psychosis associated with the published of hair growth in areas of male product (75c~). A further case has been docupattern baldness in patients treated with oral mented (74cr): minoxidil. Because of this side effect, topical minoxidil has been used for the treatment of A 62-year-old woman had a 3-day history of alopecia areata (78cr-80 c~) and alopecia androagitation, aggressive behavior, confusion, disorienta- genetica (80cr-82c~) with some success. tion, incoherent speech and repetitive picking at the Local side effects of therapy with topical air. When examined, the patient was incontinent of minoxidil (usually in an alcohol-propylene urine, scratched at her arms, and talked incoherently. glycol base) have included dryness, irritation, Her pupils were moderately dilated and reacted pruritus (81cr), contact allergy (53 c, 54c), slowly; horizontal nystagmus was also present. Screening for amphetamines, barbiturates, alcohol photocontact allergy (54c) and possibly comeand hallucinogens gave negative results. The patient dones (83c). This last observation has been was not taking any medications, but she had been disputed (84c). Minoxidil is poorly absorbed using a scopolamine-containing transdermal during a through the skin (< 4%) (85Cr); blood levels of sea voyage. Toxic psychosis due to anticholinergic minoxidil are far less than 10% of the mean poisoning was considered, and physostigmine 1 mg minoxidil blood level present 2 hours after oral i.m. was given twice with a 1-hour interval. Within 189 ingestion of a 5.0 mg pill, the lowest dose for hours after she received the first dose the patient was the treatment of hypertension (80cr). Nevertheless confused, and within 3 hours she was oriented, less, in 7 of 30 non-hypertensive patients alert, and acting appropriately. treated with 3% minoxidil solution twice daily a 'significant' decrease in blood pressure was Topical corticosteroids and avascular necrosis of noted (86c). Also, 4 patients treated with the hips (76c') Although osteoporosis and minoxidil solution showed increased hair osteonecrosis are well-known complications of growth outside the area of drug application, long-term therapy with systemic corticoste- which suggests a systemic effect (81cr). The roids, few disorders of bone attributable to sudden death of a patient on topical minoxidil topical corticosteroid therapy have been docu- (87 ~) was probably not drug-related but due to mented. One report described avascular necro- cardiovascular disease and hypertension. sis of bone in 2 chronic alcoholics who applied Nevertheless, in patients who are known to be large amounts of undiluted topical fluorinated hypertensive and who are also receiving other steroids for 3-4 years for extensive psoriasis antihypertensive medication extra caution is (77c). Hogan et al (76c) describe a 5 l-year-old warranted when topical minoxidil is used (88). man with extensive psoriasis who, after apply- Some authors do not prescribe topical minoxiing on average 60 grams of clobetasol propion- dii at all to patients who are on other ate ointment per week, developed severe bilat- antihypertensive medication (88). eral hip discomfort. A radiographic survey revealed osteonecrosis of both femoral heads, and striking vertebral osteopenia. Corticoster- MISCELLANEOUS oid therapy and alcoholism are the commonest factors associated with the development of Comedogenieity of white petrolatum (89c) A osteonecrosis. The patient had a history of 21-year-old woman presented with comedones alcohol abuse 10 years previously which, and papulopustular acne sharply limited to the according to the authors, did not cause the right side of her face. The patient had been osteonecrosis, but may have rendered the rubbing white petrolatum into the right cheek patient more susceptible to systemic complica- for about 15 minutes each night because of tions of topical corticosteroid therapy. Bell's palsy. As the Bell's palsy cleared, the
142
Chapter 15 A.C. de Groot and J.P. Nater
patient began noticing blackheads on her right cheek, then pimples and pustules. White petrolatum (Vaseline| ) was formerly thought to be non-comedogenic and safe to use in acne-prone skin. However, this case suggests that pleomorphic acne vulgaris may be caused by white petrolatum when applied with sufficient vigor and frequency.
Nicotinic acid and acanthosis nigricans
(90c')
A 16-month-old girl was treated with topical nicotinic acid on her head and neck for alopecia. The dose applied approximated 1 gram of nicotinic acid per week. After 4 months hair started to regrow. However, at the same time a brownish hyperpigmentation with hyperkeratosis developed on the neck; the lesions were most pronounced in the cutaneous folds. A clinical diagnosis of acanthosis nigricans was made. Other possible etiologies of the disease were eliminated. The patient had also been treated with carbon dioxide snow and betamethasone dipropionate cream, but the eruption was ascribed to nicotinic acid, as orally applied nicotinic acid has previously been linked with acanthosis nigricans. Possible mechanisms were suggested including epidermal stimulation due to vasodilatation, interference with lipid metabolism involved in epidermal differentiation and the role of nicotinic acid coenzyme in various metabolic processes. Two months after the nicotinic-acidcontaining lotion had been discontinued all signs of acanthosis nigricans disappeared while regrowth of hair continued. Lymphedema due to 5-fluorouracil (SED-IO, 271; SEDA-IO, 131) A 68-year-old woman continued treatment with 5% 5-fluorouracil cream for 4 weeks because of multiple actinic keratoses on her face despite a considerable reaction of edema, erythema and crusting (91c). Six weeks after completion of treatment her skin had returned to normal with the exception of a mild lymphedema on her left cheek; the swelling was unchanged when she was re-examined 1 month later. The patient declined further investigation, and other possible causes could not be excluded; nevertheless, the lymphedema was ascribed to the severe reaction to the fluorouracil cream,
Contact allergy to cosmetics
(92cR)
A prospective study o f cosmetic reactions was performed by members o f the North American
Contact Dermatitis Group during a period of 64 months. The results o f the first period of the study have been reported previously ( SED A- 7, 160). In the 64-month period, from an estimated 281,100 patients seen, 13,216 contact dermatitis cases were observed, including 713 patients with cosmetic-related reactions. Cosmetic-related reactions therefore represented 0.3% of the total patient population and 5.4% of all patients with contact dermatitis. An important finding was that half the patients and physicians were initially unaware that a cosmetic was responsible for the dermatitis. The dermatitis was usually caused by contact allergy (more than 80%), less often by irritation (about 15%), and rarely by other factors such as photosensitivity. The body sites most frequently affected were the face (37%), the skin around the eyes Table 4. Product categories: frequency of reactions Product category
Skin-care products Hair preparations (including colors) Facial makeup Nail preparations Fragrance products Personal cleanlinessproducts Shaving preparations Eye-makeup products Suntan/sunscreen products Miscellaneous~Not specified
Products causing reaction (n = 713) No.
%
203 172
28 24
75 55 49 43 28 27 10 51
11 8 7 6 4 4 1 7
Table 5. Cosmetic ingredients responsible for cutaneous reactions (n=536) Ingredients
No. of cutaneous reactions
%
Fragrances,fragrance materials Preservatives p-Phenylenediamine Lanolin (derivatives) Glyceryl monothioglycolate Propylene glycol Toluenesulfonamide/ Formaldehyde resin Sunscreens and other UV absorbers Acrylate or methacrylate Others
161
30
149 41 29 25 25 23
28 8 5 5 5 4
20
4
9 56
2 10
Dermatological drugs and cosmetics Chapter 15 (12%), theforearm (12%), and the axilla (6%). The cosmetic products most frequently causing contact dermatitis were skin-care products, hair preparations, facial makeup, and nail preparations (Table 4). The types o f ingredients most often recorded as causing cutaneous reactions were fragrances, preservatives, and p-phenylenediamine (Table 5). The fragrance ingredients most frequently identified as causing cutaneous allergy were cinnamic alcohol, hydroxycitronellal, musk am-
143
brette, isoeugenol, geraniol, cinnamal, coumarin, and eugenol. The preservatives most frequently causing cosmetic allergy were quaternium-15 (44% o f all cases o f preservative allergy), imidazolidinyl urea (14%), parabens (13%), 2bromo-2-nitropropane-l,3-diol (11%), and formaldehyde (11%). It was estimated that the frequency o f adverse reactions to cosmetics leading to dermatologic consultation approximates 210 per million products used.
REFERENCES 1. Bjfrkner B, Bruze M, Dahlquist I e t al (1986) Contact allergy to the preservative Kathon | CG. Contact Derm., 14, 85. 2. De Groot AC, Liem DH, Weyland JW (1985) Kathon | CG: cosmetic allergy and patch test sensitization. Contact Derm., 12, 76. 3. Wright C, Gingold E, Venitt S e t al (1983) Mutagenic activity of Kathon, an industrial biocide and cosmetics preservative containing 5-chloro-2methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one. Mutat. Res., 119, 35. 4. Maibach HI (1985) Diagnostic patch test concentration for Kathon CG. Contact Derm., 13, 242. 5. Chart PK, Baldwin RC, Parsons RD et al (1983) Kathon biocide: manifestation of, delayed contact dermatitis in guinea pigs is dependent on the concentration for induction and challenge. J. Invest.
Dermatol., 81, 409. 6.
Foussereau J, Br/indle I, Boujnah-Khouadja A (1984) Allergisches Kontaktekzem durch Isothiazolin-3-on Derivate. Dermatosen, 32, 208. 7. De Groot AC, Liem DH, Nater JP et al (1985) Patch tests with fragrance materials and preservafives. Contact Derm., 12, 87. 8. De Groot AC, Bos JD, Jagtman BA et al (1986) Contact allergy to preservatives (2). Contact Derm., 15, 218. 9. Hjorth N, Roed-Petersen J (1986) Patch test sensitivity to Kathon | CG. Contact Derm., 14, 155. 10. Lewis PG (1986) Contact allergy to the preservative Kathon | CG (Letter to Editor). Contact Derm., 14, 198. 11. Bjrrkner B, Bruze M, Dahlquist I e t al (1986) Contact allergy to the preservative Kathon | CG. (Letter to Editor). Contact Derm., 14, 199. 12. Weaver JE, Cardin CW, Maibach HI (1985) Dose-response assessments of Kathon | biocide (1). Diagnostic use and diagnostic threshold patch testing with sensitized humans. Contact Derm., 12, 141. 13. Bruze M, Ljunggren B (1985) Antinuclear antibodies appearing during PUVA therapy. Acta
Derm.- VenereoL, 65, 3 I. 14. Hazen PG, Carney JF, Walker AE et al (1985) Disseminated superficial actinic porokeratosis: ap-
pearance associated with photochemotherapy for psoriasis. J. Am. Acad. Dermatol., 12, 1077. 15. Lederman JS, Sober AJ, Lederman GS (1985) Immunosuppression - an etiology of porokeratosis? J. Am. Acad. DermatoL, 13, 75. 16. Lederman JS, Sober AJ, Lederman GS (1986) Psoralens and ultraviolet A, immunosuppression, and porokeratosis (Letter to Editor). J. Am. Acad. DermatoL, 14, 284. 17. Reed RJ, Leone P (1970) Porokeratosis: a mutant clonal keratosis of the epidermis. I. Histogenesis. Arch. Dermatol., 101, 340. 18. Toth Kasa I, Dobozy A (1985) Drug fever caused by PUVA treatment. Acta. Derm.-Venereol., 65, 557. 19. Staberg B, Hueg B (1985) Interaction between 8-methoxypsoralen and phenytoin: consequence for PUVA therapy. Acta Derm.-Venereol., 65, 553. 20. Gavish D, Katz M, Gottehrer N et al (1985) Cholestatic jaundice, an unusual side effect of etretinate. J. Am. Acad. DermatoL, 13, 669. 21. Burge S, Ryan T (1985) Diffuse hyperostosis associated with etretinate. Lancet, 2, 397. 22. Smitt JHS, De Mari F (1984) A serious side effect of etretinate (Tigason). Clin. Exp. DermatoL, 9, 554. 23. Graham RM, James MP, Ferguson DJP et al (1985) Acquired kinking of the hair associated with etretinate therapy. Clin. Exp. Dermatol., 10, 426. 24. Mortimer PS (1985) Unruly hair. Br. J. Dermatol., 113, 467. 25. Hays SB, Camisa C (1985) Acquired pili torti in two patients treated with synthetic retinoids. Cutis, 35, 466. 26. Shalita AR, Cunningham W J, Leyden JJ et al (1983) Isotretinoin treatment of acne and related disorders: an update. J. Am. Acad. Dermatol., 9, 629. 27. Neild VS, Moss RF, Marsden RA et al (1985) Retinoid-induced skin fragility in a patient with hepatic disease. Clin. Exp. Dermatol., 10, 459. 28. David M, Ginzburg A, Hodak E et al (1986) Palmoplantar eruption associated with etretinate therapy. Acta Derm.-Venereol., 66, 87. 29. Fisher DA (1985) Exercise-induced broncho-
144 constriction related to isotretinoin therapy (Letter to Editor). J. Am. Acad. Derrnatol., 13, 524. 30. Kellett JK, Beck MH, Chalmers RIG (1985) Erythema nodosum and circulating immune complexes in acne fulminans after treatment with isotretinoin. Br. Med. J., 290, 820. 31. Huston NR, Mules R (1985) Acne fulminans with severe myalgia precipitated by isotretinoin therapy (Letter to Editor). N Z Med. J., 36, 821. 32. Stary A (1986) Acne conglobata: ungew6hnlicher Verlauf unter 13-ct~-Retins~uretherapie. Hautarzt, 37, 28. 33. Brodkin RH, Abbey AA (1985) Osteoma cutis: a case of probable exacerbation following treatment of severe acne with isotretinoin. Dermatologica, 170, 210. 34. Kilcoyne RF, Cope R, Cunningham W e t al (1986) Minimal spinal hyperostosis with low-dose isotretinoin therapy. Invest. Radiol., 21, 41. 35. Fraunfelder FT, LaBraico JM, Meyer SM (1985) Adverse ocular reactions possibly associated with isotretinoin. Am. J. Ophthalmol., 100, 534. 36. Weleber RG, Denman ST, Cunningham WC et al (1985) Abnormal night vision, dark adaptation and electrophysiologic responses associated with isotretinoin therapy for acne. Clin. Res., 33, 158. 37. Denman S, Weleber R, Hanifin JM et al (1986) Abnormal night vision and altered dark adaptometry in patients treated with isotretinoin for acne (Letter to Editor). J. Am. Acad. Dermatol., 14, 692. 38. Kaiser-Kupfer MI, Peck GL, Caruso RC et al (1986) Abnormal retinal function associated with fenretinide, a synthetic retinoid. Arch. Ophthalmol., 104, 69. 39. Meding B, Dahlberg E (1986) Contact allergy to budesonide in a nasal spray. Contact Derm., 14, 253. 40. Santucci B, Picardo M, Cristaudo A (1985) Contact dermatitis due to Centelase ~. Contact Derm., 12, 39. 41. Bechgaard E, Ploug E, Hjorth N (1985) Contact sensitivity to chlorhexidine? Contact Derm., 13, 53. 42. Lasthein Andersen B, Brandrup F (1985) Contact dermatitis from chlorhexidine. Contact Derm., 13, 307. 43. Myatt AE, Beck MH (1985) Contact sensitivity to parachlorometaxylenol (PCMX). Clin. Exp. Dermatol., 10, 491. 44. Burns DA (1986) Allergic contact sensitivity to chlorphenesin. Contact Derm., 14, 246. 45. Grattan CEH, Kennedy CTC (1985) Allergic contact dermatitis to transdermal clonidine. Contact Derm., 12, 225. 46. Kalb RE, Grossman ME (1985) Contact dermatitis to clotrimazole. Cutis, 36, 240. 47. De Groot AC, Conemans J (1986) Allergic urticarial rash from oral codeine. Contact Derm., 14, 209. 48. Gollhausen R, Przybilla B, Ring J (1985) Contact allergy to dexpanthenol. Contact Derm., 12, 38. 49. Lang E, Goos M (1985) Kontaktallergie gegen
Chapter 15 A.C. de Groot and J.P. Nater das perkutan wirksame Antirheumatikum Etofenamat. Aktuel. Dermatol., 11, 99. 50. Pinol J, Navarro M, Carapeto FJ (1985) Allergic contact dermatitis to etophenamate. Contact Derm., 13, 193. 51. Valsecchi R, Cainelli T (1985) Contact dermatitis from ibuprofen. Contact Derm., 12, 286. 52. Westphal H-J, Kaben U (1986) Iatrogene 8Methoxypsoralen Sensibilisierung. Aktuel, Dermatol., 12, 10. 53. Degreef H, Hendrickx I, Dooms-Goossens A (1985) Allergic contact dermatitis to minoxidil. Contact Derm., 13, 194. 54. Tosti A, Bardazzi F, De Padova MP et al (1985) Contact dermatitis to minoxidil. Contact Derm., 13, 275. 55. Lang E, Goos M (1985) Combined allergy to tolnaftate and nystatin. Contact Derm., 12, 182. 56. Figueiredo A, Goncalo S, Freitas JD (1985) Contact sensitivity to pyrazolone compounds. Contact Derm., 13, 271. 57. Milpied B, Van Wassenhove L, Larousse C et al (1986) Contact dermatitis from rifamycin. Contact Derm., 14, 252. 58. Trozak DJ (1985) Delayed hypersensitivity to scopolamine delivered by a transdermal device. J. Am. Acad. Dermatol., 13, 247. 59. Romaguera C, Grimalt F, Vilaplana J (1986) Contact dermatitis by Timolol. Contact Derm., 14, 248. 60. Frosch PJ, Olbert D, Weickel R (1985) Contact allergy to tolazoline. Contact Derm., 13, 272. 61. Balato N, Lembo G, Nappa P et al (1985) Allergic cheilitis to azulene. Contact Derm., 13, 39. 62. Hausen BM (1986) Zahnpasta-Allergie durch L-Carvon. Aktuel. Dermatol., 12, 23. 63. Koch SE, Mathias T, Maibach HI (1985) Chloracetamide: an unusual cause of cosmetic dermatitis (Letter to Editor). Arch. Dermatol., 121, 172. 64. English, JSC, White IR (1985) Dermatitis from D&C Red no. 36. Contact Derm., 13, 335. 65. Kantor GR, Taylor JS, Ratz JL et al (1985) Acute allergic contact dermatitis from diazolidinyl urea (Germall II) in a hair gel. J. Am. Acad. Dermatol., 13, 116. 66. Ormerod AD, Main RA (1985) Sensitisation to 'sensitive teeth' toothpaste. Contact Derm., 13, 192. 67. Ippen H (1985) Labilin| - a little-known contact allergen. Contact Derm., 13, 200. 68. Ayala F, Lembo G, Nappa P e t al (1985) Contact dermatitis from propolis. Contact Derm., 12, 181. 69. Gollhausen R, Przybilla B, Ring J (1986) Contact allergy to C.I. Solvent Red 3. Contact Derm., 14, 123. 70. Whittington CV (1985) Elicitation of contact lens allergy to thimerosal by eye cream. Contact Derm., 13, 186. 71. Milstone EB, McDonald AJ, Scholhamer CF (1981) Pseudomembranous colitis after topical application of clindamycin. Arch. Dermatol., 117, 154.
Dermatological drugs and cosmetics
Chapter 15
72. Parry MF, Rha C-K (1986) Pseudomembranous colitis caused by topical clindamycin phosphate. Arch. Dermatol., 122, 583. 73. Borglund E, Hagermark O, Nord CE (1984) Impact of topical clindamycin and systemic tetracycline on the skin and colon microflora in patients with ache vulgaris. Scand. ,L Infect. Dis., 43, Suppl 76. 74. MacEwan GW, Remick" RA, Noone JA (1985) Psychosis due to transdermally administered scopolamine. Can. Med. Assoc. J., 133, 431. 75. Rodysill KJ, Warren JB (1983) Transdermal scopolamine and toxic psychosis. Ann. Intern. Med., 98, 561. 76. Hogan DJ, Sibley JT, Lane PR (1986) Avascular necrosis of the hips following longterm use of clobetasol propionate. (Letter to Editor). J. Am. Acad. Dermatol., 14, 515. 77. Cunliffe WJ, Burton JL, Hold G e t al (1975) Hazards of steroid therapy in hepatic failure. Br. J. DermatoL, 93, 183. 78. Weiss VC, West DP, Fu TS et al (1984) Alopecia areata treated with topical minoxidil. Arch. Dermatol., 120, 457. 79. Frentz G (1985) Topical minoxidil for extended areate alopecia. Acta Derm.-Venereol., 65, 172. 80. Vanderveen EE, Ellis CN, Kang S e t al (1984) Topical minoxidil for hair regrowth. J. Am. Acad. Dermatol., 11, 416. 81. Olsen EA, Weiner MS, Delong ER et al (1985) Topical minoxidil in early male pattern baldness. J. Am. Acad. Dermatol., 13, 185.
145 82. De Villez RL (1985) Topical minoxidil therapy in hereditary androgenetic alopecia. Arch. Dermatol., 121, 197. 83. Baral J (1985) Scalp comedones after topical minoxidil. (Letter to Editor). J. Am. Acad. Dermatol., 13, 1051. 84. Olsen EA (1985) Scalp comedones after topical minoxidil: reply (Letter to Editor). J. Am. Acad. Dermatol., 13, 1051. 85. Franz TJ (1985) Percutaneous absorption of minoxidil in man. Arch. Dermatol., 121, 203. 86. Ranchoff RE, Bergfeld WF (1985) Topical minoxidil reduces blood pressure (Letter to Editor). J. Am. Acad. DermatoL, 12, 586. 87. Baral J (1985) Minoxidil and sudden death (Letter to Editor). J. Am. Acad. Dermatol., 13, 297. 88. Vanderveen EE (1985) Minoxidil and sudden death: reply (Letter to Editor). J. Am. Acad. Dermatol., 13, 298. 89. Frankel EB (1985) Aene secondary to white petrolatum use. (Letter to Editor). Arch. Dermatol., 121, 589. 90. Pascal J (1984) Acanthosis nigricans induced by topical nicotinic acid. Ann. Derm.-Venereol., 111, 739. 91. Friedman SJ, Su WPD, Doyle JA (1985) Reaction to topical fluorouracil of secondary lymphedema (Letter to Editor). Arch. Dermatol., 121, 1484. 92. Adams RM, Maibach HI (1985) A five-year study of cosmetic reactions. J. Am. Acad. Dermatol., 13, 1062.
15
Dermatological drugs and cosmetics
Kathon | CG, an important 'new' contact allergen 'Kathon' is the proprietary name for a family o f microbiocides and preservatives containing, as active ingredients, a mixture o f 5-chloro-2methyl-4-isothiazolin-3-one ( CTFA name methylchloroisothiazolinone, CAS no. 2617255-4) and 2-methyl-4-isothiazolin-3-one ( CTFA name methylisothiazolinone, CAS no. 2682-20-4) in an approximate ratio o f 3:1, respectively, with MgClz ( +_9 % ) and M g ( N 0 3 ) 2 (+_16%) present as stabilizers. Several formulations are commercially available under the names Kathon 886 M W , Kathon WT, Kathon L X and Kathon CG from Rohm and Haas, Philadelphia, USA. Besides Rohm and Haas, other firms market these isothiazolinones under various trade names ( lCR). This biocide is an effective preservative for toiletries, cosmetics, and household cleaning products. It is also used as a biocide for swimming-pool water and in various industrial applications such as cooling-tower water, metalworking fluids, latex emulsions, and for slime control in paper mills. One o f the Kathon formulations, Kathon CG ( CG = Cosmetic Grade) has in recent years become a very popular preservative with the cosmetic industry. At the present time Kathon CG is not permitted in the EEC in any pharmaceutical or dermatological application, nor as a food additive, nor for internal use by humans. However, Kathon CG at a maximum concentration o f 50 p.p.m, active ingredients (hereafter referred to as "a.i. ') has been given provisional clearance for use as a cosmetic and toiletry preservative in the EEC (Council Directive 82/368/EEC, May 17, 1982). Kathon CG has been used in cosmetics and toiletries f o r 11 years in Europe, and for 6 years in the United States (2c~). The manufacturers estimate that in 1980 it was used in 55,000 Side Effects of Drugs Annual 11 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1987
tons o f cosmetic products in Europe, and in 20,000 tons in the United States (3), and its application in cosmetic products has increased enormously since then. Kathon CG has been shown to be effective at very low concentrations in controlling microbial growth over a wide spectrum o f bacteria, yeasts and fungi. The manufacturer recommends levels o f 0.02-0.1% by weight (3-15 p.p.m, a.i.) in products such as shampoos and hair conditioners, hair and body gels, bubble baths, skin creams and skin lotions (2cR). Kathon CG as supplied is a strong irritant. The levels advised by the manufacturer (3-15 p.p.m, a.i.) are far below levels which will irritate the skin. Data from the manufacturer suggest the highest non-irritant concentration o f an aqueous solution o f Kathon CG to be 100 p.p.m, a.i. 21-Day cumulative irritancy assays confirmed this; there was evidence that Kathon CG in higher concentrations o f 200 p.p.m, a.i. may produce irritation (4). Single diagnostic patch tests at levels o f up to 100 p.p.m, a.i. produced f e w irritant responses, and this was suggested to be a useful concentration for patch testing in ~liagnostic studies. However, the authors o f a Swedish study (1 c~) conclude from the data obtained in their investigation that levels o f up to 300 p.p.m, a.i. in water are not irritant at diagnostic patch-testing. Studies both in guinea-pigs (modified Buehler technique) (5) and man (4; Kathon CG product information sheet, Rohm & Haas, Philadelphia, USA, 1983) demonstrated that Kathon CG has a dosedependent potential for inducing contact allergic reactions. Two case-reports (2 cR, 6 c) and 4 epidemiological studies (1 c~, 7~, 8~R, 9cr) on contact allergic reactions to Kathon CG have been published. When tested with Kathon CG I00 p.p.m, a.i., prevalence rates o f sensitization hi patients seen for routine testing were 1.4% ha a Dutch study (8~R), 1.9% in a Swedish study (lC~), and 0.8% in a Danish stud.v (9c'). When tested with the higher (but apparent(v ramirritant) concentration o f 300 p.p.m, a.i.. 43
135
Dermatological drugs and cosmetics Chapter 15 o f 976 patients routinely patch-tested reacted to Kathon CG (4.4%) (lCa). O f 179 patients suspected to suffer from cosmetic allergy 6 (3.4%) reacted to Kathon CG tested at 150 p.p.m. (7r In a study not yet published (at the time of writing) o f 7866 patients tested with Kathon CG 100 p.p.m, a.i. in a water patch-test system, conducted in conjunction with members o f the ICDRG, the prevalence rate o f sensitization was found to be 0.51% ( Bji~rkner et al, cited in R e f 10). Bj6rkner et al (I ce) have provided data which suggest that the actual prevalence rate may be higher; in their study o f 34 patients who had reacted to Kathon CG 300 p.p.m, a.i. only 17 (50%) also reacted to I00 p.p.m, on serial dilution testing. Thus, these authors feel that 50% o f allergic individuals may be overlooked when a test concentration o f 100 p.p.m, a.i. is used. Nevertheless, they also use patch-test concentrations lower than 250 p.p.m, because o f an unacceptably high risk ( +_1%) o f patch-test sensitization when test concentrations o f 250 or 300 p.p.m, a.i. are used. From these data it appears that, at least in some countries like Sweden and The Netherlands, contact allergy to Kathon CG has become common among patients suffering from dermatitis. It is very difficult, however, to trace the cause o f the sensitization, as the preservative is so widely used. In the Swedish study (11) commercial products used in daily life by patients with contact allergy to Kathon CG were tested for its presence. For each patient, one or many o f the products proved to contain Kathon CG! It is equally difficult to determine the relevance o f the observed contact allergy to Kathon CG. The demonstration o f Kathon CG in one or more products used by the patient does not necessarily imply a role o f Kathon CG in this product for the development and/or persistence o f the patient's actual dermatitis. Eighteen human volunteers who had developed delayed contact hypersensitivity to the isothiazolinone mixture through exaggerated, repeated, occlusive exposure, used one or more rinse-off products containing Kathon CG 4-6 p.p.m, a.i. for 3-6 weeks without experiencing allergic reactions (12). Use tests involving daily application o f a Kathon CG (8.6 p.p.m, a.i.) containing cosmetic lotion in the elbow flexure for 5 days were negative in all 11 patients tested, who were previously shown to be allergic to Kathon CG (9c'). On the other hand, o f 13 Kathon CG allergic patients who applied a cream containing Kathon CG 15 p.p.m, a.i., 7 (54%) developed a mild dermatitis, whereas control tests using the
same cream without Kathon CG remained negative in these patients (lCR). In one reporI, the relevance o f the observed patch-test reaction to Kathon CG was clearly demonstrated (2cR). It was convincingly shown that one patient had become sensitized to a moisturizing cream containing Kathon CG 12 p.p.m, a.i. Provocative testing with the cream and Kathon CG 15 p.p.m, was positive, and after discontinuation o f the incriminated cosmetic the dermatitis cleared. I f indeed a postulated no-effect level exists under which Kathon CG can be used without concern about the development o f clinically significant delayed contact dermatitis (9 c', 12), this level must be lower than 12 p.p.m, a.i. Further studies using various bases and concentrations for Kathon CG seem to be warranted. The occurrence o f sensitization to the preservative must be monitored by Contact Dermatitis Groups in various countries. Use tests should be included. We therefore recommend that Kathon CG 100 p.p.m, a.i. in water be included in the European Standard Series, which is tested routinely in patients suffering from dermatitis, to assess its significance.
Photochemotherapy ( P U V A ) (SED-IO, 254; S E D A - 8 , 152; S E D A - 9 , 130; S E D A - I O , 125)
Antinuclear antibodies (13 cR)
Antinuclear antibodies (ANA) were looked for in patients receiving PUVA therapy. During PUVA treatment ANA appeared in 34 of 100 patients. Of 8 patients who had A N A prior to PUVA, a significant increase in ANA titer was noted in 4. A statistically significant difference was noted when the first and last A N A tests for each patient were compared. No such difference was seen in control patients. All PUVAtreated patients developing A N A were evaluated clinically and with laboratory screening for signs of systemic disease. Only 1 patient, who developed A N A with a nucleolar staining pattern, showed symptoms consistent with a collagen vascular disease. The results of this report indicate that PUVA therapy has the capacity t o induce ANA. The mechanism for this is not clear and the clinical importance is also obscure. As long as a possible relationship between PUVAinduced A N A and the development of a connective-tissue disease has not been ruled out, monitoring of ANA in PUVA patients is advisable.
136 The development of systemic lupus erythematosus (SLE), SLE-like syndrome and scleroderma-like changes during PUVA therapy has been reported previously (SEDA-10, 126).
Disseminated superficial actinic porokeratosis (SED-IO, 255) A patient with chronic psoriasis treated with PUVA developed lesions clinically and histologically characteristic of disseminated superficial actinic porokeratosis (DSAP). The association of these lesions with exposure to artificial or natural UV light has been emphasized previously. Although DSAP has been reported to occur in dark-skinned individuals, it is usually seen in sun-exposed areas of fair-skinned persons. Thus, the authors feel that DSAP may represent a PUVA-induced cutaneous side effect (14cr). Among its many known effects, PUVA is associated with immunosuppression. Immunosuppression has been proposed as an etiology of porokeratosis (15), and it has been suggested (16) that PUVA-induced immunosuppression may allow the proliferation of latent abnormal clones of epidermal cells, thereby producing the porokeratosis (17). Drug fever (18c) After several uneventful PUVA treatments, a 61-year-old female developed a fever reaching 39.5~ 3 hours after a treatment session on 2 occasions. Both times, the body temperature spontaneously returned to normal after 8-10 hours. Apart from an accelerated erythrocyte sedimentation rate (47 mm/h) the clinical and laboratory examinations did not reveal any other pathological changes. After cessation of treatment, the fever did not recur. Provocation tests with UV-A alone and methoxsalen alone were negative, but 2 hours after receiving 40 mg methoxsalen with 3 J/cm 2 UV-A irradiation, she developed a temperature of 39.2~ with dyspnea. The drug fever was felt to be an allergic phenomenon caused by a product of methoxsalen, transformed by UV-A irradiation. Interaction between methoxsalen and phenytoin (19c) A patient with epilepsy and psoriasis taking phenytoin was treated with PUVA therapy with no effect at all. The PUVA treatment failure was demonstrated to be due to abnormally low serum levels of methoxsalen during phenytoin therapy. Normal serum levels of methoxsalen were observed after phenytoin was discontinued. The effect may be due to induction of the hepatic enzyme system by
Chapter 15 A.C. de Groot and J.P. Nater phenytoin, leading to increased metabolism of methoxsalen. Other drugs inducing hepatic enzymes might also interfere with psoralen metabolism, and thereby influence the result of PUVA therapy. ORAL RETINOIDS (SED-IO, 255, 717)
Etretinate (SEDA-8, 152, 347; SEDA-9, 134;
SEDA-IO, 123) Cholestatic jaundice (SED-IO, 257; SEDA-IO, 124; 20cR) A slight, transient elevation of liver enzyme concentrations can be observed in some etretinate-treated patients. Cases of overt hepatotoxicity have also been observed (SED-10,257). Mild cholestasis was noted infrequently. A first case of etretinate-induced cholestatic jaundice has been reported (20cR): A 58-year-old man with psoriasis vulgaris was treated with etretinate 1 mg/kg/d. At the end of the 12th day the patient gradually started complaining of pruritus, dark urine and acholic stools. Alkaline phosphatase was 420 U/l, ~-glutamyl transpeptidase 380 U/l; other liver enzymes were only slightly elevated. The patient became jaundiced with a bilirubin level up to 400 ~mol/l. The histological findings were compatible with non-specific reactive hepatitis with cholestasis. Liver function tests returned to normal values 4 weeks after treatment was discontinued.
Diffuse hyperostosis (21 c) Hyperostosis due to isotretinoin has been reported several times (SED- 10, 257,;SEDA-9, 132). In contrast, etretinate has only twice been linked to diffuse skeletal hyperostosis (21 c, 22c). This discrepancy may only reflect the more widespread use of isotretinoin, especially in the United States. Long-term studies are required to define the magnitude of this problem; to establish whether it can be reduced by intermittent rather than continuous therapy, and to determine the prognosis for patients with retinoid hyperostosis (21c). Hair disorders (23c, 24c, 25c) It is wellrecognized that etretinate therapy may cause accelerated hair growth and a dose-dependent telogen effluvium. At high dosage, hair loss may be severe and may be associated with dystrophy of hair roots. Kinking of the hair has been associated with isotretinoin therapy (26r This side effect, also described as 'unruly hair' has now also been
Dermatological drugs and cosmetics Chapter15 observed in etretinate-treated patients (23c, 25c). The hair becomes diffusely dry, curly and unruly. Onset can occur within weeks of commencing etretinate and the process is dose-dependent and reversible. The mechanism for the production of such hair is as yet unclear. Possibilities include interference with the kinetics of the inner root sheath, thereby influencing keratinization. Alternatively, the drying effect of the retinoid therapy in an individual with previously waxy hair might also produce 'wooly' hair. Skin fragility (27cR) Skin thinning and increased skin fragility are well-recognized side effects of retinoid therapy. A patient with severe erythrodermic psoriasis and histologically proven alcoholic cirrhosis was treated with etretinate 25 mg 3 times daily. After 3 years the patient was admitted because of circumferential ulceration of his lower legs which had slowly developed over the preceding 6 months. The skin became increasingly smooth and shiny, and hair fall and nail loss were noted. Superficial erosions developed over pressure areas such as hips and spine. After discontinuation of treatment small superficial blisters, some hemorrhagic, developed repeatedly at sites of trauma. Six months later plasma levels of etretinate were still as high as 180 ng/ml (therapeutic'range 100-700 ng/ml). The electron-microscopic features of keratinocyte separation and degeneration, and the presence of fine granular material have been described previously in etretinate-treated patients, and these probably contributed to the clinical finding of blistering. The pronounced cutaneous side effects described occurred while the patient was taking etretinate in standard dosage, and almost certainly resulted from excessive accumulation of the drug due to impaired excretion by preexisting liver disease. At present, the use of etretinate in patients with liver disease is contraindicated.
Palmoplantar eruption (28c') Of 32 patients treated with etretinate 1 mg/kg/d for psoriasis, 5 developed a palmoplantar eruption several clays after starting therapy; the palms and soles had previously been unaffected. The lesions were red discrete papules 3-4 mm in diameter, with small scales; in 2 patients there were also minute pustules. Bacterial and fungal smears and cultures from the pustules were negative. A punch biopsy did not reveal any abnormal findings apart from mild dilation of the capillaries in the dermis. The lesions disap-
137 peared completely in all patients 5-35 days leaving colarette desquamation. The authors suggest that this palmoplantar eruption is caused by etretinate. The eruption subsided spontaneously within some weeks, which may explain why it has not been recorded previously, despite the fact that it occurred in 5 of 32 patients in this study.
Isotretinoin (13-cis-retinoic acid) (SED-IO, 256; SEDA-8, 345; SEDA-9, 132, 134; SEDA-IO, 124) Exercise-induced bronchoconstriction (29c) A 20-year-old middle-distance runner with acne conglobata related a history of atopic dermatitis and hay fever, but not asthma. He was prescribed isotretinoin and within 3-4 weeks noted the development of exercise-induced wheezing. Upon cessation of isotretinoin, the problem was alleviated, but after restarting isotretinoin he again noted the recurrence of wheezing when he ran. Cooling of the airway and respiratory water loss are the factors causing exercise-induced asthma in susceptible individuals, and it was hypothesized that the isotretinoin produced significant dryness of the respiratory passages to cause exercise-induced asthma in an atopic individual.
Acne fulminans (30c', 31c, 32c)
Acne fulminans is a rare complication of severe acne. The syndrome includes severe ulcerating cystic acne, fever and arthralgia. Other documented features include microscopic hematuria, an increased erythrocyte sedimentation rate and white cell count, anemia, myalgia, and rarely erythema nodosum (30cr). Two patients treated with isotretinoin 1 mg/kg/d developed signs of acne fulminans and erythema nodosum (30cr). A platelet aggregation test for circulating IgG immune complexes yielded positive results on 2 occasions at 1/160 dilution (normal
Chapter 15 A.C. de Groot and J.P. Nater
138
Osteoma cuffs (SEDA-IO, 124; 33c) Osteoma cutis is a rare sequel to chronic, severe, scarring acne. A patient was observed who presented with a mild form of this disease which was stable for a number of years. Following a successful course of treatment with isotretinoin she developed florid and severe osteoma curls of her face (33c). Isotretinoin has been noted to cause calcinosis in rats, and ossification disorders such as premature closure of epiphyses (SED-10, 257), skeletal hyperostosis (34c) and nasal bone osteophytosis (SEDA-10, 124) have been documented. Osteoma curls is generally considered an osteoid metaplasia resulting from chronic inflammation. It was suggested (33 c) that in predisposed individuals isotretinoin may exacerbate the condition. Adverse ocular reactions (35R) Ocular findings are among the more frequent side effects in patients taking isotretinoin, the most common being blepharoconjunctivitis. In a review article (35 x) 237 cases of adverse ocular reactions possibly associated with isotretinoin were evaluated. Of the 237 patients, 121 were extensively monitored by the manufacturer during a 2-year period. Seventy-eight other cases were previously reported in the Table 1. Possible adverse ocular effects associated with isotretinoin exposure in 236 patients Adverse effects Eyelids Blepharoconjunctivitis or meibomianitis Photodermatitis Cornea Corneal opacities Dry eyes Contact-lens intolerance Optic nerve Papilledema or pseudotumor cerebri Optic neuritis (9.) Congenital abnormalities Microphthalmos Orbital hypertelorism Optic nerve hypoplasia Cortical blindness Others Blurred vision Myopia Decreased dark adaptation (36c, 37c)* Ocular inflammation (.9) (uveitis, scleritis, retinitis, ophthalmitis, iritis)
No. of patients 88 6 12 47 19 18 3 5 2 4 1 39 5 3 7
*Also observed in 2 of 5 patients treated with fenretinide, another synthetic retinoid (38cr).
literature, and the remaining 38 cases consisted of 7 reported to the FDA and 31 reported to the US National Registry of Drug Induced Ocular Side Effects. The results are shown in Table 1. Ocular side effects secondary to isotretinoin are generally benign in nature and reversible on reduction or cessation of drug therapy. However, papilledema demands discontinuation of the drug. Corneal opacities should be monitored closely. Although they do not usually interfere with vision, prudence indicates discontinuation of isotretinoin or reduction of the dosage when corneal opacities develop (35~). CONTACT A L L E R G Y (SED-IO, 257, 266; SEDA-9, 135; SEDA-IO, 126) Every year 'new' allergens (i.e. chemicals which previously had not caused contact allergy) are being described in the literature. These allergens and updated information on chemicals which were already known to be sensitizers are presented in Table 2 (topical drugs) and Table 3 (cosmetic ingredients). SYSTEMIC SIDE EFFECTS OF TOPICAL DRUGS
Clindamycin phosphate and pseudomembranous colitis (SED-IO, 270; SEDA-8, 160) Topical clindamycin is regarded as a safe and effective agent for the treatment of acne vulgaris. It is estimated that about 4-5% of topically applied clindamycin hydrochloride is absorbed percutaneously (SEDA-8, 160); several cases of clindamycin-related diarrhea have been reported (SED-10, 270), including 1 case ofpseudomembranous colitis (71Cr). Topical clindamycin phosphate seems to be less readily absorbed. Using a sensitive radioimmunoassay (72ca), it was found that less than 1% of a 20-rag dose (1 ml twice daily; 0.25 mg/kg/d) of clindamycin phosphate was absorbed, reaching peak serum levels of only 1.7 ng/ml. In addition, 42 human subjects receiving topical clindamycin phosphate were studied (73), but significant changes in stool flora, diarrhea, and measurable clindamycin absorption were not detected. Nevertheless, a case of pseudomembranous colitis thought to be caused by topical clindamycin phosphate has now been reported (72cx). The patient had 2 episodes of pseudomembranous colitis. Assays for Clostridium di~cile toxin were positive, and the patient was ultimately cured by oral vancomycin hydro-
Dermatological drugs and cosmetics Chapter 15
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Dermatological drugs and cosmetics Chapter15 chloride and the withdrawal of topical clindamycin phosphate therapy.
141
Minoxidil (SEDA-IO, 128)
Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) is a potent vasodilator effective in Psychosis due to transdermally administered severe hypertension irrespective of the cause. scopolamine (SEDA-8, 161; 74c') Toxic psy- Hypertrichosis occurs in approximately 70% of chosis after oral or subcutaneous administra- patients taking oral minoxidil, usually within 2 tion of scopolamine and other anticholinergic months of the start of therapy. Although this agents has been well-documented. Transder- increased hair growth may be generalized, it real scopolamine is widely used for the preven- most often occurs on the face and extremities. tion of motion sickness. There have been some In addition, isolated case-reports have been reports of toxic psychosis associated with the published of hair growth in areas of male product (75c~). A further case has been docupattern baldness in patients treated with oral mented (74cr): minoxidil. Because of this side effect, topical minoxidil has been used for the treatment of A 62-year-old woman had a 3-day history of alopecia areata (78cr-80 c~) and alopecia androagitation, aggressive behavior, confusion, disorienta- genetica (80cr-82c~) with some success. tion, incoherent speech and repetitive picking at the Local side effects of therapy with topical air. When examined, the patient was incontinent of minoxidil (usually in an alcohol-propylene urine, scratched at her arms, and talked incoherently. glycol base) have included dryness, irritation, Her pupils were moderately dilated and reacted pruritus (81cr), contact allergy (53 c, 54c), slowly; horizontal nystagmus was also present. Screening for amphetamines, barbiturates, alcohol photocontact allergy (54c) and possibly comeand hallucinogens gave negative results. The patient dones (83c). This last observation has been was not taking any medications, but she had been disputed (84c). Minoxidil is poorly absorbed using a scopolamine-containing transdermal during a through the skin (< 4%) (85Cr); blood levels of sea voyage. Toxic psychosis due to anticholinergic minoxidil are far less than 10% of the mean poisoning was considered, and physostigmine 1 mg minoxidil blood level present 2 hours after oral i.m. was given twice with a 1-hour interval. Within 189 ingestion of a 5.0 mg pill, the lowest dose for hours after she received the first dose the patient was the treatment of hypertension (80cr). Nevertheless confused, and within 3 hours she was oriented, less, in 7 of 30 non-hypertensive patients alert, and acting appropriately. treated with 3% minoxidil solution twice daily a 'significant' decrease in blood pressure was Topical corticosteroids and avascular necrosis of noted (86c). Also, 4 patients treated with the hips (76c') Although osteoporosis and minoxidil solution showed increased hair osteonecrosis are well-known complications of growth outside the area of drug application, long-term therapy with systemic corticoste- which suggests a systemic effect (81cr). The roids, few disorders of bone attributable to sudden death of a patient on topical minoxidil topical corticosteroid therapy have been docu- (87 ~) was probably not drug-related but due to mented. One report described avascular necro- cardiovascular disease and hypertension. sis of bone in 2 chronic alcoholics who applied Nevertheless, in patients who are known to be large amounts of undiluted topical fluorinated hypertensive and who are also receiving other steroids for 3-4 years for extensive psoriasis antihypertensive medication extra caution is (77c). Hogan et al (76c) describe a 5 l-year-old warranted when topical minoxidil is used (88). man with extensive psoriasis who, after apply- Some authors do not prescribe topical minoxiing on average 60 grams of clobetasol propion- dii at all to patients who are on other ate ointment per week, developed severe bilat- antihypertensive medication (88). eral hip discomfort. A radiographic survey revealed osteonecrosis of both femoral heads, and striking vertebral osteopenia. Corticoster- MISCELLANEOUS oid therapy and alcoholism are the commonest factors associated with the development of Comedogenieity of white petrolatum (89c) A osteonecrosis. The patient had a history of 21-year-old woman presented with comedones alcohol abuse 10 years previously which, and papulopustular acne sharply limited to the according to the authors, did not cause the right side of her face. The patient had been osteonecrosis, but may have rendered the rubbing white petrolatum into the right cheek patient more susceptible to systemic complica- for about 15 minutes each night because of tions of topical corticosteroid therapy. Bell's palsy. As the Bell's palsy cleared, the
142
Chapter 15 A.C. de Groot and J.P. Nater
patient began noticing blackheads on her right cheek, then pimples and pustules. White petrolatum (Vaseline| ) was formerly thought to be non-comedogenic and safe to use in acne-prone skin. However, this case suggests that pleomorphic acne vulgaris may be caused by white petrolatum when applied with sufficient vigor and frequency.
Nicotinic acid and acanthosis nigricans
(90c')
A 16-month-old girl was treated with topical nicotinic acid on her head and neck for alopecia. The dose applied approximated 1 gram of nicotinic acid per week. After 4 months hair started to regrow. However, at the same time a brownish hyperpigmentation with hyperkeratosis developed on the neck; the lesions were most pronounced in the cutaneous folds. A clinical diagnosis of acanthosis nigricans was made. Other possible etiologies of the disease were eliminated. The patient had also been treated with carbon dioxide snow and betamethasone dipropionate cream, but the eruption was ascribed to nicotinic acid, as orally applied nicotinic acid has previously been linked with acanthosis nigricans. Possible mechanisms were suggested including epidermal stimulation due to vasodilatation, interference with lipid metabolism involved in epidermal differentiation and the role of nicotinic acid coenzyme in various metabolic processes. Two months after the nicotinic-acidcontaining lotion had been discontinued all signs of acanthosis nigricans disappeared while regrowth of hair continued. Lymphedema due to 5-fluorouracil (SED-IO, 271; SEDA-IO, 131) A 68-year-old woman continued treatment with 5% 5-fluorouracil cream for 4 weeks because of multiple actinic keratoses on her face despite a considerable reaction of edema, erythema and crusting (91c). Six weeks after completion of treatment her skin had returned to normal with the exception of a mild lymphedema on her left cheek; the swelling was unchanged when she was re-examined 1 month later. The patient declined further investigation, and other possible causes could not be excluded; nevertheless, the lymphedema was ascribed to the severe reaction to the fluorouracil cream,
Contact allergy to cosmetics
(92cR)
A prospective study o f cosmetic reactions was performed by members o f the North American
Contact Dermatitis Group during a period of 64 months. The results o f the first period of the study have been reported previously ( SED A- 7, 160). In the 64-month period, from an estimated 281,100 patients seen, 13,216 contact dermatitis cases were observed, including 713 patients with cosmetic-related reactions. Cosmetic-related reactions therefore represented 0.3% of the total patient population and 5.4% of all patients with contact dermatitis. An important finding was that half the patients and physicians were initially unaware that a cosmetic was responsible for the dermatitis. The dermatitis was usually caused by contact allergy (more than 80%), less often by irritation (about 15%), and rarely by other factors such as photosensitivity. The body sites most frequently affected were the face (37%), the skin around the eyes Table 4. Product categories: frequency of reactions Product category
Skin-care products Hair preparations (including colors) Facial makeup Nail preparations Fragrance products Personal cleanlinessproducts Shaving preparations Eye-makeup products Suntan/sunscreen products Miscellaneous~Not specified
Products causing reaction (n = 713) No.
%
203 172
28 24
75 55 49 43 28 27 10 51
11 8 7 6 4 4 1 7
Table 5. Cosmetic ingredients responsible for cutaneous reactions (n=536) Ingredients
No. of cutaneous reactions
%
Fragrances,fragrance materials Preservatives p-Phenylenediamine Lanolin (derivatives) Glyceryl monothioglycolate Propylene glycol Toluenesulfonamide/ Formaldehyde resin Sunscreens and other UV absorbers Acrylate or methacrylate Others
161
30
149 41 29 25 25 23
28 8 5 5 5 4
20
4
9 56
2 10
Dermatological drugs and cosmetics Chapter 15 (12%), theforearm (12%), and the axilla (6%). The cosmetic products most frequently causing contact dermatitis were skin-care products, hair preparations, facial makeup, and nail preparations (Table 4). The types o f ingredients most often recorded as causing cutaneous reactions were fragrances, preservatives, and p-phenylenediamine (Table 5). The fragrance ingredients most frequently identified as causing cutaneous allergy were cinnamic alcohol, hydroxycitronellal, musk am-
143
brette, isoeugenol, geraniol, cinnamal, coumarin, and eugenol. The preservatives most frequently causing cosmetic allergy were quaternium-15 (44% o f all cases o f preservative allergy), imidazolidinyl urea (14%), parabens (13%), 2bromo-2-nitropropane-l,3-diol (11%), and formaldehyde (11%). It was estimated that the frequency o f adverse reactions to cosmetics leading to dermatologic consultation approximates 210 per million products used.
REFERENCES 1. Bjfrkner B, Bruze M, Dahlquist I e t al (1986) Contact allergy to the preservative Kathon | CG. Contact Derm., 14, 85. 2. De Groot AC, Liem DH, Weyland JW (1985) Kathon | CG: cosmetic allergy and patch test sensitization. Contact Derm., 12, 76. 3. Wright C, Gingold E, Venitt S e t al (1983) Mutagenic activity of Kathon, an industrial biocide and cosmetics preservative containing 5-chloro-2methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one. Mutat. Res., 119, 35. 4. Maibach HI (1985) Diagnostic patch test concentration for Kathon CG. Contact Derm., 13, 242. 5. Chart PK, Baldwin RC, Parsons RD et al (1983) Kathon biocide: manifestation of, delayed contact dermatitis in guinea pigs is dependent on the concentration for induction and challenge. J. Invest.
Dermatol., 81, 409. 6.
Foussereau J, Br/indle I, Boujnah-Khouadja A (1984) Allergisches Kontaktekzem durch Isothiazolin-3-on Derivate. Dermatosen, 32, 208. 7. De Groot AC, Liem DH, Nater JP et al (1985) Patch tests with fragrance materials and preservafives. Contact Derm., 12, 87. 8. De Groot AC, Bos JD, Jagtman BA et al (1986) Contact allergy to preservatives (2). Contact Derm., 15, 218. 9. Hjorth N, Roed-Petersen J (1986) Patch test sensitivity to Kathon | CG. Contact Derm., 14, 155. 10. Lewis PG (1986) Contact allergy to the preservative Kathon | CG (Letter to Editor). Contact Derm., 14, 198. 11. Bjrrkner B, Bruze M, Dahlquist I e t al (1986) Contact allergy to the preservative Kathon | CG. (Letter to Editor). Contact Derm., 14, 199. 12. Weaver JE, Cardin CW, Maibach HI (1985) Dose-response assessments of Kathon | biocide (1). Diagnostic use and diagnostic threshold patch testing with sensitized humans. Contact Derm., 12, 141. 13. Bruze M, Ljunggren B (1985) Antinuclear antibodies appearing during PUVA therapy. Acta
Derm.- VenereoL, 65, 3 I. 14. Hazen PG, Carney JF, Walker AE et al (1985) Disseminated superficial actinic porokeratosis: ap-
pearance associated with photochemotherapy for psoriasis. J. Am. Acad. Dermatol., 12, 1077. 15. Lederman JS, Sober AJ, Lederman GS (1985) Immunosuppression - an etiology of porokeratosis? J. Am. Acad. DermatoL, 13, 75. 16. Lederman JS, Sober AJ, Lederman GS (1986) Psoralens and ultraviolet A, immunosuppression, and porokeratosis (Letter to Editor). J. Am. Acad. DermatoL, 14, 284. 17. Reed RJ, Leone P (1970) Porokeratosis: a mutant clonal keratosis of the epidermis. I. Histogenesis. Arch. Dermatol., 101, 340. 18. Toth Kasa I, Dobozy A (1985) Drug fever caused by PUVA treatment. Acta. Derm.-Venereol., 65, 557. 19. Staberg B, Hueg B (1985) Interaction between 8-methoxypsoralen and phenytoin: consequence for PUVA therapy. Acta Derm.-Venereol., 65, 553. 20. Gavish D, Katz M, Gottehrer N et al (1985) Cholestatic jaundice, an unusual side effect of etretinate. J. Am. Acad. DermatoL, 13, 669. 21. Burge S, Ryan T (1985) Diffuse hyperostosis associated with etretinate. Lancet, 2, 397. 22. Smitt JHS, De Mari F (1984) A serious side effect of etretinate (Tigason). Clin. Exp. DermatoL, 9, 554. 23. Graham RM, James MP, Ferguson DJP et al (1985) Acquired kinking of the hair associated with etretinate therapy. Clin. Exp. Dermatol., 10, 426. 24. Mortimer PS (1985) Unruly hair. Br. J. Dermatol., 113, 467. 25. Hays SB, Camisa C (1985) Acquired pili torti in two patients treated with synthetic retinoids. Cutis, 35, 466. 26. Shalita AR, Cunningham W J, Leyden JJ et al (1983) Isotretinoin treatment of acne and related disorders: an update. J. Am. Acad. Dermatol., 9, 629. 27. Neild VS, Moss RF, Marsden RA et al (1985) Retinoid-induced skin fragility in a patient with hepatic disease. Clin. Exp. Dermatol., 10, 459. 28. David M, Ginzburg A, Hodak E et al (1986) Palmoplantar eruption associated with etretinate therapy. Acta Derm.-Venereol., 66, 87. 29. Fisher DA (1985) Exercise-induced broncho-
144 constriction related to isotretinoin therapy (Letter to Editor). J. Am. Acad. Derrnatol., 13, 524. 30. Kellett JK, Beck MH, Chalmers RIG (1985) Erythema nodosum and circulating immune complexes in acne fulminans after treatment with isotretinoin. Br. Med. J., 290, 820. 31. Huston NR, Mules R (1985) Acne fulminans with severe myalgia precipitated by isotretinoin therapy (Letter to Editor). N Z Med. J., 36, 821. 32. Stary A (1986) Acne conglobata: ungew6hnlicher Verlauf unter 13-ct~-Retins~uretherapie. Hautarzt, 37, 28. 33. Brodkin RH, Abbey AA (1985) Osteoma cutis: a case of probable exacerbation following treatment of severe acne with isotretinoin. Dermatologica, 170, 210. 34. Kilcoyne RF, Cope R, Cunningham W e t al (1986) Minimal spinal hyperostosis with low-dose isotretinoin therapy. Invest. Radiol., 21, 41. 35. Fraunfelder FT, LaBraico JM, Meyer SM (1985) Adverse ocular reactions possibly associated with isotretinoin. Am. J. Ophthalmol., 100, 534. 36. Weleber RG, Denman ST, Cunningham WC et al (1985) Abnormal night vision, dark adaptation and electrophysiologic responses associated with isotretinoin therapy for acne. Clin. Res., 33, 158. 37. Denman S, Weleber R, Hanifin JM et al (1986) Abnormal night vision and altered dark adaptometry in patients treated with isotretinoin for acne (Letter to Editor). J. Am. Acad. Dermatol., 14, 692. 38. Kaiser-Kupfer MI, Peck GL, Caruso RC et al (1986) Abnormal retinal function associated with fenretinide, a synthetic retinoid. Arch. Ophthalmol., 104, 69. 39. Meding B, Dahlberg E (1986) Contact allergy to budesonide in a nasal spray. Contact Derm., 14, 253. 40. Santucci B, Picardo M, Cristaudo A (1985) Contact dermatitis due to Centelase ~. Contact Derm., 12, 39. 41. Bechgaard E, Ploug E, Hjorth N (1985) Contact sensitivity to chlorhexidine? Contact Derm., 13, 53. 42. Lasthein Andersen B, Brandrup F (1985) Contact dermatitis from chlorhexidine. Contact Derm., 13, 307. 43. Myatt AE, Beck MH (1985) Contact sensitivity to parachlorometaxylenol (PCMX). Clin. Exp. Dermatol., 10, 491. 44. Burns DA (1986) Allergic contact sensitivity to chlorphenesin. Contact Derm., 14, 246. 45. Grattan CEH, Kennedy CTC (1985) Allergic contact dermatitis to transdermal clonidine. Contact Derm., 12, 225. 46. Kalb RE, Grossman ME (1985) Contact dermatitis to clotrimazole. Cutis, 36, 240. 47. De Groot AC, Conemans J (1986) Allergic urticarial rash from oral codeine. Contact Derm., 14, 209. 48. Gollhausen R, Przybilla B, Ring J (1985) Contact allergy to dexpanthenol. Contact Derm., 12, 38. 49. Lang E, Goos M (1985) Kontaktallergie gegen
Chapter 15 A.C. de Groot and J.P. Nater das perkutan wirksame Antirheumatikum Etofenamat. Aktuel. Dermatol., 11, 99. 50. Pinol J, Navarro M, Carapeto FJ (1985) Allergic contact dermatitis to etophenamate. Contact Derm., 13, 193. 51. Valsecchi R, Cainelli T (1985) Contact dermatitis from ibuprofen. Contact Derm., 12, 286. 52. Westphal H-J, Kaben U (1986) Iatrogene 8Methoxypsoralen Sensibilisierung. Aktuel, Dermatol., 12, 10. 53. Degreef H, Hendrickx I, Dooms-Goossens A (1985) Allergic contact dermatitis to minoxidil. Contact Derm., 13, 194. 54. Tosti A, Bardazzi F, De Padova MP et al (1985) Contact dermatitis to minoxidil. Contact Derm., 13, 275. 55. Lang E, Goos M (1985) Combined allergy to tolnaftate and nystatin. Contact Derm., 12, 182. 56. Figueiredo A, Goncalo S, Freitas JD (1985) Contact sensitivity to pyrazolone compounds. Contact Derm., 13, 271. 57. Milpied B, Van Wassenhove L, Larousse C et al (1986) Contact dermatitis from rifamycin. Contact Derm., 14, 252. 58. Trozak DJ (1985) Delayed hypersensitivity to scopolamine delivered by a transdermal device. J. Am. Acad. Dermatol., 13, 247. 59. Romaguera C, Grimalt F, Vilaplana J (1986) Contact dermatitis by Timolol. Contact Derm., 14, 248. 60. Frosch PJ, Olbert D, Weickel R (1985) Contact allergy to tolazoline. Contact Derm., 13, 272. 61. Balato N, Lembo G, Nappa P et al (1985) Allergic cheilitis to azulene. Contact Derm., 13, 39. 62. Hausen BM (1986) Zahnpasta-Allergie durch L-Carvon. Aktuel. Dermatol., 12, 23. 63. Koch SE, Mathias T, Maibach HI (1985) Chloracetamide: an unusual cause of cosmetic dermatitis (Letter to Editor). Arch. Dermatol., 121, 172. 64. English, JSC, White IR (1985) Dermatitis from D&C Red no. 36. Contact Derm., 13, 335. 65. Kantor GR, Taylor JS, Ratz JL et al (1985) Acute allergic contact dermatitis from diazolidinyl urea (Germall II) in a hair gel. J. Am. Acad. Dermatol., 13, 116. 66. Ormerod AD, Main RA (1985) Sensitisation to 'sensitive teeth' toothpaste. Contact Derm., 13, 192. 67. Ippen H (1985) Labilin| - a little-known contact allergen. Contact Derm., 13, 200. 68. Ayala F, Lembo G, Nappa P e t al (1985) Contact dermatitis from propolis. Contact Derm., 12, 181. 69. Gollhausen R, Przybilla B, Ring J (1986) Contact allergy to C.I. Solvent Red 3. Contact Derm., 14, 123. 70. Whittington CV (1985) Elicitation of contact lens allergy to thimerosal by eye cream. Contact Derm., 13, 186. 71. Milstone EB, McDonald AJ, Scholhamer CF (1981) Pseudomembranous colitis after topical application of clindamycin. Arch. Dermatol., 117, 154.
Dermatological drugs and cosmetics
Chapter 15
72. Parry MF, Rha C-K (1986) Pseudomembranous colitis caused by topical clindamycin phosphate. Arch. Dermatol., 122, 583. 73. Borglund E, Hagermark O, Nord CE (1984) Impact of topical clindamycin and systemic tetracycline on the skin and colon microflora in patients with ache vulgaris. Scand. ,L Infect. Dis., 43, Suppl 76. 74. MacEwan GW, Remick" RA, Noone JA (1985) Psychosis due to transdermally administered scopolamine. Can. Med. Assoc. J., 133, 431. 75. Rodysill KJ, Warren JB (1983) Transdermal scopolamine and toxic psychosis. Ann. Intern. Med., 98, 561. 76. Hogan DJ, Sibley JT, Lane PR (1986) Avascular necrosis of the hips following longterm use of clobetasol propionate. (Letter to Editor). J. Am. Acad. Dermatol., 14, 515. 77. Cunliffe WJ, Burton JL, Hold G e t al (1975) Hazards of steroid therapy in hepatic failure. Br. J. DermatoL, 93, 183. 78. Weiss VC, West DP, Fu TS et al (1984) Alopecia areata treated with topical minoxidil. Arch. Dermatol., 120, 457. 79. Frentz G (1985) Topical minoxidil for extended areate alopecia. Acta Derm.-Venereol., 65, 172. 80. Vanderveen EE, Ellis CN, Kang S e t al (1984) Topical minoxidil for hair regrowth. J. Am. Acad. Dermatol., 11, 416. 81. Olsen EA, Weiner MS, Delong ER et al (1985) Topical minoxidil in early male pattern baldness. J. Am. Acad. Dermatol., 13, 185.
145 82. De Villez RL (1985) Topical minoxidil therapy in hereditary androgenetic alopecia. Arch. Dermatol., 121, 197. 83. Baral J (1985) Scalp comedones after topical minoxidil. (Letter to Editor). J. Am. Acad. Dermatol., 13, 1051. 84. Olsen EA (1985) Scalp comedones after topical minoxidil: reply (Letter to Editor). J. Am. Acad. Dermatol., 13, 1051. 85. Franz TJ (1985) Percutaneous absorption of minoxidil in man. Arch. Dermatol., 121, 203. 86. Ranchoff RE, Bergfeld WF (1985) Topical minoxidil reduces blood pressure (Letter to Editor). J. Am. Acad. DermatoL, 12, 586. 87. Baral J (1985) Minoxidil and sudden death (Letter to Editor). J. Am. Acad. Dermatol., 13, 297. 88. Vanderveen EE (1985) Minoxidil and sudden death: reply (Letter to Editor). J. Am. Acad. Dermatol., 13, 298. 89. Frankel EB (1985) Aene secondary to white petrolatum use. (Letter to Editor). Arch. Dermatol., 121, 589. 90. Pascal J (1984) Acanthosis nigricans induced by topical nicotinic acid. Ann. Derm.-Venereol., 111, 739. 91. Friedman SJ, Su WPD, Doyle JA (1985) Reaction to topical fluorouracil of secondary lymphedema (Letter to Editor). Arch. Dermatol., 121, 1484. 92. Adams RM, Maibach HI (1985) A five-year study of cosmetic reactions. J. Am. Acad. Dermatol., 13, 1062.