- Email: [email protected]
14 Dermatological drugs, topical agents, and cosmetics
Sandra R. Knowles, Gavin Wong, and Neil H. Shear
14
Dermatological drugs, topical agents, and cosmetics
Botulinum toxin A (SED-15, 551; SEDA-27, 161; SEDA-28, 168) Botulinum toxin A is used for the treatment of facial rhytides (for example, lateral orbital wrinkles, lower eyelid wrinkles, nasolabial lines) by producing weakness or paralysis of the associated muscles, and in the treatment of hyperhidrosis. Transient adverse effects, such as temporary bruising, discomfort, incomplete muscle paralysis, or headache, can occur (1R , 2M , 3C ). A meta-analysis showed that about 25% of patients who receive botulinum toxin A report mild to moderate adverse events, compared with 15% of patients who receive placebo. Focal weakness was the only adverse event that occurred significantly more often with botulinum toxin A than control (2M ). In a randomized study of patients with moderate or severe glabellar lines, blepharoptosis occurred in 3.2% of patients (3C ).
Calcipotriol
(SED-15, 594; SEDA-28,
• An 85-year-old woman presented with anorexia, oliguria, and acute renal insufficiency 19 days after starting to take calcipotriol (4A ). She also had raised calcium and sodium concentrations.
Colophony Colophony is another term for rosin, a resin that is obtained when turpentine is prepared from dead pine wood. It is used to make waxes and varnishes and for coating the strings of bows used to play stringed musical instruments. Colophony, or its chemically modified forms, is also found in permanent color markers. Skin Contact dermatitis due to acrylates in ultraviolet curing ink has been described (5c ), but there has only been one report of contact allergic dermatitis caused by a permanent marker. In that case, a dye (Solvent Yellow 146, BioDiagnostics Ltd, UK) was the causative agent (6A ). There has now been a case of allergic contact dermatitis due to the colophony analogue abitol as a component of a permanent marker, Edding 3000.
169) Endocrine Calcipotriol, a biologically active form of vitamin D3, is usually well-tolerated, although it can cause local irritation in up to 30% of patients. Topical calcipotriol in recommended dosages has rarely been associated with hypercalcemia. Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29014-7 © 2007 Elsevier B.V. All rights reserved.
156
• A 28-year-old woman developed skin lesions on her right thigh 24 hours after liposuction, the fifth episode of liposuction that the patient had undergone (7A ). A blue permanent marker (Edding 3000, Edding International GmbH) was used to outline the area at each site of liposuction. Pruritic, erythematous, and infiltrated plaques, with vesicles and papular spread, developed on these lines within a few days. The manufacturers provided information about the components of Edding 3000, rosin (colophony), colorants, and organic solvents. Epicutaneous tests were carried out with the suspected agent, the permanent marker (Edding 3000), in three different colors: blue, red, and black, all of which were positive at 48 hours (++) and 96 hours (+++).
Dermatological drugs, topical agents, and cosmetics
The patient did not have a positive patch test reaction to colophony in the standard series, but had a positive reaction with a modified product of colophony, abitol. The incidence of allergic reactions to colophony has increased to such an extent that in most countries it has become one of the 10 most important sources of sensitization. However, the use of only one type of colophony for patch tests in the standard series does not address all aspects of the problem. There are three complicating factors: • colophony has been replaced in recent years by its chemically modified forms; • modified colophony products commonly cause stronger sensitization reactions than unmodified ones do; • cross-reactions between modified and unmodified products are not the rule. The question therefore arises as to whether testing is being conducted with the right material, which raises the suspicion that the real number of cases of colophony allergy is much higher than is commonly thought.
Patch testing was performed with the SIDAPA (Societa Italiana di Dermatologia Allergologica e Professionale) standard series and the patient’s emollient cream. Readings at D2 and D3 were negative, except for a mild erythematous edematous (+) reaction to the emollient cream. The cream was withdrawn and the patient improved within 3 weeks. An open application test with the cream in the antecubital fossa was positive within 3 days and 6 months after resolution of his dermatitis, the patient was patch tested again. Readings performed at days 2, 3, and 4 showed a delayed but clearly positive erythematous edematous reaction to VP-eicosene copolymer 10% in petrolatum (+ at D4), plus a weak erythematous reaction to disodium stearoyl glutamate 30%. (at D4). The cream reacted positively (+/+) at D3 and D4.
Although p-phenylenediamine (PPD) and toluene-2,5-diamine are the most frequently reported hair dye allergens, allergic contact dermatitis from direct dyes for hair coloration is unusual. Two patients with a history of PPD allergic contact dermatitis had positive patch tests to HC Yellow 7,4 amino-3-nitrophenol and HC Red B54 in hair dyes (9A ).
Finasteride CONTACT ALLERGENS VP-eicosene copolymer VP-eicosene copolymer, also known as Ganex® V-220 F, is a film-former and waterproofing agent that belongs to the family of co-polymers of vinylpyrrolidone and long-chain α-olefins. These polymers are used as emulsifiers and dispersants in non-aqueous systems, desensitizers/wax dispersants in melt-cast explosives, dye dispersants for candles and shoe polish, and water-resistant film-formers in wood coatings. Skin VP-eicosene copolymer has been identified as a contact allergen in an emollient formulation widely prescribed by dermatologists as a treatment for dry skin. • A 59-year-old non-atopic man with a 6-month history of xerosis and pruritus of the hands, lower arms, and legs was given an emollient cream (Lipikar Baume® La Roche-Posay, France) for daily application (8A ). Within a month he developed itchy vesicular dermatitis of the limbs.
157
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(SEDA-28, 169)
Sensory systems Finasteride has not previously been associated with the development of cataracts. • A 43-year-old man who had been taking finasteride 1 mg/day for 3 years to treat androgenetic alopecia developed failing vision in both eyes and was found to have anterior subcapsular opacities of both lenses (10A ). There was no family history of early onset cataract.
Sexual function The main adverse effects associated with finasteride are loss of libido, erectile dysfunction, and reduced ejaculate volume. In clinical trials 4.4% of patients treated with finasteride and 2.2% of patients taking placebo experience sexual adverse effects. However, recent evidence suggests that sexual adverse effects are less common in practice. In multicenter study of 186 patients with androgenetic alopecia sexual adverse effects occurred in under 0.5% of subjects (11C ). Reproductive system Gynecomastia has not previously been reported with finasteride.
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• A 23-year-old man who was taking finasteride 1 mg/day for 2 months for androgenetic alopecia developed painful enlargement of his right breast (12A ). Treatment was withdrawn and resolution occurred after 2 months.
• After 12 PUVA treatments a 51-year-old man developed painful hyperesthesia, which persisted despite cessation of bath PUVA (15A ). Gabapentin 300 mg qds produced a dramatic improvement in symptoms over a period of 2 weeks.
PHOTOCHEMOTHERAPY
VITAMIN A (RETINOIDS)
(SED-15, 2823; SEDA-28, 171)
(SED-15, 3653; SEDA-27, 159; SEDA-28, 171; for vitamin A carotenoids see Chapter 34)
Aminolevulinic acid Skin Contact allergy to 5-aminolaevulinic acid (ALA) has been rarely reported. The derivative ALA methylester is considered to be a more specific sensitizer of abnormal cells than ALA. • A patient developed acute eczema of the treated areas and itch and hyper-reactivity of the untreated skin after several photodynamic therapy treatments with both ALA and ALA methylester (13A ). Patch testing demonstrated a strong reaction to ALA methylester only.
PUVA Skin Systemic and topical psoralens plus ultraviolet A irradiation (PUVA therapy) are well established treatments for vitiligo. Adverse effects of PUVA therapy include non-melanoma skin cancer and PUVA-induced lentigines. Lentigines are common among PUVA-treated patients with psoriasis, but rare in patients with vitiligo. • A 22-year-old woman who had been treated with PUVA for 3 years for vitiligo developed extensive and widespread stellate and irregularly shaped black and brown lentigines in exposed and unexposed skin areas (14A ). The lesions were present in both vitiliginous and normal skin.
Severe skin pain is an uncommon complication of PUVA and is characterized by a persistent severe prickling or burning pain lasting from 15 minutes to several hours. Analgesics, antihistamines, and topical and oral glucocorticoids have generally been ineffective. Gabapentin is effective in relieving neuropathic pain and has now been tried in this condition.
Acitretin Cardiovascular Capillary leak syndrome with associated edema has been reported following acitretin therapy. • A 79-year-old man with extensive psoriasis and joint involvement was given acitretin 10 mg/day for 12 days (16A ). He developed myalgia and non-pitting edema associated with large hemorrhagic lesions, and weight gain of 13 kg. Laboratory values were normal, except for moderate hypoproteinemia and hypoalbuminemia, and raised creatine kinase, myoglobin, and aspartate transaminase. The clinical and laboratory findings were suggestive of capillary leak syndrome. Withdrawal of acitretin resulted in slow regression of the edema over 2 months.
Sensory systems Ocular adverse effects with systemic retinoids have been reported, especially keratoconjunctivitis sicca. A 32-year-old man noted reduced visual acuity after treatment with acitretin 30 mg/day for one year (17A ).
Isotretinoin Nervous system There have been two reports of Guillain–Barré syndrome after isotretinoin therapy (18A ). • A 31-year-old man developed paresthesia, influenza-like symptoms, and areflexic tetraparesis after 5 weeks of isotretinoin therapy. • A 13-year-old boy took isotretinoin for 3½ months and developed lethargy, headaches, and a flaccid areflexic tetraparesis requiring ventilatory support.
Both patients received intravenous immunoglobulin and were discharged from hospital after 3 months.
Dermatological drugs, topical agents, and cosmetics
A review of isotretinoin-associated intracranial hypertension identified 179 case reports (19c ). The mean time from the start of therapy to the diagnosis of intracranial hypertension was 2.3 months. Withdrawal of isotretinoin resulted in resolution of the symptoms within weeks. Musculoskeletal Short (4- to 5-month) courses of isotretinoin for recalcitrant acne in young adults can cause asymptomatic radiographic changes of hyperostosis of the anterior longitudinal and spinal ligaments. Bone mineral density was measured in the lumbar spine and hip in 217 adolescents who took isotretinoin for 16 to 20 weeks (20C ). There was no clinically significant effect on bone mineral density, and neither was hyperostosis observed.
Tretinoin (All-trans retinoic acid) Respiratory Tretinoin is used in the treatment of acute promyelocytic leukemia. The most important adverse effect is the retinoic acid syndrome, which is characterized by fever, respiratory distress, weight gain, and extensive infiltration of soft tissue by maturing leukemic cells. It has an incidence of up to 30% and a median onset of 7–10 days. Retinoic acid syndrome has now been reported starting immediately after just one dose (21A ). • A 42-year-old woman with acute promyelocytic leukemia was given daunorubicin, cytarabine, and tretinoin 40 mg. Within hours of the first dose
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she became confused with increasing shortness of breath over 2 days. On the third day she had deteriorated to a degree where she had to be intubated and given intravenous dexamethasone 20 mg. She recovered quickly.
The authors of this report subsequently searched the literature and confirmed that no other cases had previously been reported in which the retinoic acid syndrome had started after just one dose of tretinoin. Hematologic Hemophagocytic syndrome has been reported in a patient receiving tretinoin (22A ). • A 56-year-old woman with acute promyelocytic leukemia developed severe retinoic acid syndrome on day 17 with pancytopenia, hepatosplenomegaly, increased triglycerides, ferritin, and liver enzymes. Tretinoin was withdrawn. Dexamethasone, started on day 20, and high-dose immunoglobulins were ineffective. A bone marrow biopsy showed abundant macrophages and no evidence of leukemia. Tests for secondary hemophagocytic syndrome were negative.
Hemophagocytic syndrome (reactive or secondary) is a serious complication of malignancies. It results from inappropriate stimulation of macrophages in bone marrow and lymphoid organs, leading to phagocytosis of blood cells and production of high amounts of pro-inflammatory cytokines. The authors speculate that in this patient the syndrome could have been related to release of macrophagestimulating cytokines by leukemic cells during retinoic acid syndrome.
References 1. Klein A. Contraindications and complications with the use of botulinum toxin. Clin Dermatol 2004;22:66–75. 2. Carruthers A, Carruthers J, Lowe NJ, Menter A, Gibson J, Nordquist M, Mordaunt J. One-year, randomised, multicenter, two-period study of the safety and efficacy of repeated treatments with botulinum toxin type A in patients with glabellar lines. J Drug Assessment 2004;7:63–82.
3. Naumann M, Jankovic J. Safety of botulinum toxin type A: a systematic review and metaanalysis. Curr Med Res Opin 2004;20:981–90. 4. Kawahara C, Okada Y, Tanikawa T, Fukusima AH, Tanaka Y. Severe hypercalcemia and hypernatremia associated with calcipotriol for treatment of psoriasis. J Bone Miner Metab 2004;22:159–62.
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5. Whitfeld M, Freeman S. Allergic contact dermatitis to ultra violet cured inks. Australas J Dermatol 1991;31:65–8. 6. Komerichi P, Kern T, Aberer W, Kranke B. Contact dermatitis from Solvent Yellow 146 in a permanent marker. Contact Dermatitis 2001;44:256. 7. Martin-Garcia C, Salazar LC, Gonzales-Mendioca R, Hinojosa M, Sanchez-Cano H. Contact dermatitis due to Edding 3000. Allergy 2004;59:235–6. 8. Gallo R, Sacco D, Ghigliotti G. Allergic contact dermatitis from VP/eicosene copolymer (GanexR V-220) in an emollient cream. Contact Dermatitis 2004;50:261. 9. Sanchez-Perez J, Garcia del Rio I, Alvarez Ruiz S, Garcia Diez A. Allergic contact dermatitis from direct dyes for hair colouration in hairdressers’ clients. Contact Dermatitis 2004;50(4):261–2. 10. Chou S, Kao S, Hsu W. Propecia-associated bilaterial cataract. Clin Exp Ophthalmol 2004;32:106–8. 11. Tosti A, Pazzaglia M, Soli M, Rossi A, Rebora A, Atzori L, Barbareschi M, Benci M, Voudouris S, Vena GA. Evaluation of sexual function with an international index of erectile function in subjects taking finasteride for androgenetic alopecia. Arch Dermatol 2004;140:857–8. 12. Kim H, Kye K, Seo Y, Suhr K, Lee J, Park J. A case of unilateral idiopathic gynecomastia aggravated by low-dose finasteride. Korean J Dermatol 2004;42:643–5. 13. Wulf H, Philipsen P. Allergic contact dermatitis to 5-aminolaevulinic acid methylester but not to 5-aminolaevulinic acid after photodynamic therapy. Br J Dermatol 2004;150:143–5. 14. Naser M, Wollina U, El Okby M, El Shiemy S. Psoralen plus ultraviolet A irradiation-induced
lentigines arising in vitiligo: involvement of vitiliginous and normal appearing skin. Clin Exp Dermatol 2004;29:380–2. Zamiri M, Bilsland D. Treatment of bath PUVAinduced skin pain with gabapentin. Br J Dermatol 2004;150:516–7. Estival J, Dupin M, Kanitakis J, Combemale P. Capillary leak syndrome induced by acitretin. Br J Dermatol 2004;150:150–2. Lois N, White M. Acitretin-associated maculopathy. Arch Ophthalmol 2004;122:928–30. Pritchard J, Appleton R, Howard RRA. Guillain– Barré syndrome seen in users of isotretinoin. BMJ 2004;328:1537. Fraunfelder F, Fraunfelder F, Corbett J. Isotretinoin-associated intracranial hypertension. Ophthalmology 2004;111:1248–50. DiGiovanna JJ, Langman CB, Tschen EH, Jones T, Menter A, Lowe NJ, Eichenfield L, Hebert AA, Pariser D, Savin RP, Smith SR, Jarratt M, Rodriguez D, Chalker DK, Kempers S, Ling M, Rafal ES, Sullivan S, Kang S, Shah LP, Wu E, Newhouse J, Pak J, Eberhardt DR, Bryce GF, McLane JA, Ondovik M, Chin C, Khoo KC, Rich P. Effect of a single course of isotretinoin therapy on bone mineral density in adolescent patients with severe, recalcitrant, nodular acne. J Am Acad Dermatol 2004;51:709–17. Battistella M, Burry LD, Seki JT. Retinoic acid syndrome after one dose of all-trans retinoic acid. J Oncol Pharm Pract 2004;10:149–54. Garcia-Suarez J, Banas H, Krsnik I, De Miguel D, Reyes E, Burgaleta C. Hemophagocytic syndrome associated with retinoic acid syndrome in acute promyelocytic leukaemia. Am J Hematol 2004;76:172–5.
15. 16. 17. 18. 19. 20.
21. 22.
14
Dermatological drugs, topical agents, and cosmetics
Botulinum toxin A (SED-15, 551; SEDA-27, 161; SEDA-28, 168) Botulinum toxin A is used for the treatment of facial rhytides (for example, lateral orbital wrinkles, lower eyelid wrinkles, nasolabial lines) by producing weakness or paralysis of the associated muscles, and in the treatment of hyperhidrosis. Transient adverse effects, such as temporary bruising, discomfort, incomplete muscle paralysis, or headache, can occur (1R , 2M , 3C ). A meta-analysis showed that about 25% of patients who receive botulinum toxin A report mild to moderate adverse events, compared with 15% of patients who receive placebo. Focal weakness was the only adverse event that occurred significantly more often with botulinum toxin A than control (2M ). In a randomized study of patients with moderate or severe glabellar lines, blepharoptosis occurred in 3.2% of patients (3C ).
Calcipotriol
(SED-15, 594; SEDA-28,
• An 85-year-old woman presented with anorexia, oliguria, and acute renal insufficiency 19 days after starting to take calcipotriol (4A ). She also had raised calcium and sodium concentrations.
Colophony Colophony is another term for rosin, a resin that is obtained when turpentine is prepared from dead pine wood. It is used to make waxes and varnishes and for coating the strings of bows used to play stringed musical instruments. Colophony, or its chemically modified forms, is also found in permanent color markers. Skin Contact dermatitis due to acrylates in ultraviolet curing ink has been described (5c ), but there has only been one report of contact allergic dermatitis caused by a permanent marker. In that case, a dye (Solvent Yellow 146, BioDiagnostics Ltd, UK) was the causative agent (6A ). There has now been a case of allergic contact dermatitis due to the colophony analogue abitol as a component of a permanent marker, Edding 3000.
169) Endocrine Calcipotriol, a biologically active form of vitamin D3, is usually well-tolerated, although it can cause local irritation in up to 30% of patients. Topical calcipotriol in recommended dosages has rarely been associated with hypercalcemia. Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29014-7 © 2007 Elsevier B.V. All rights reserved.
156
• A 28-year-old woman developed skin lesions on her right thigh 24 hours after liposuction, the fifth episode of liposuction that the patient had undergone (7A ). A blue permanent marker (Edding 3000, Edding International GmbH) was used to outline the area at each site of liposuction. Pruritic, erythematous, and infiltrated plaques, with vesicles and papular spread, developed on these lines within a few days. The manufacturers provided information about the components of Edding 3000, rosin (colophony), colorants, and organic solvents. Epicutaneous tests were carried out with the suspected agent, the permanent marker (Edding 3000), in three different colors: blue, red, and black, all of which were positive at 48 hours (++) and 96 hours (+++).
Dermatological drugs, topical agents, and cosmetics
The patient did not have a positive patch test reaction to colophony in the standard series, but had a positive reaction with a modified product of colophony, abitol. The incidence of allergic reactions to colophony has increased to such an extent that in most countries it has become one of the 10 most important sources of sensitization. However, the use of only one type of colophony for patch tests in the standard series does not address all aspects of the problem. There are three complicating factors: • colophony has been replaced in recent years by its chemically modified forms; • modified colophony products commonly cause stronger sensitization reactions than unmodified ones do; • cross-reactions between modified and unmodified products are not the rule. The question therefore arises as to whether testing is being conducted with the right material, which raises the suspicion that the real number of cases of colophony allergy is much higher than is commonly thought.
Patch testing was performed with the SIDAPA (Societa Italiana di Dermatologia Allergologica e Professionale) standard series and the patient’s emollient cream. Readings at D2 and D3 were negative, except for a mild erythematous edematous (+) reaction to the emollient cream. The cream was withdrawn and the patient improved within 3 weeks. An open application test with the cream in the antecubital fossa was positive within 3 days and 6 months after resolution of his dermatitis, the patient was patch tested again. Readings performed at days 2, 3, and 4 showed a delayed but clearly positive erythematous edematous reaction to VP-eicosene copolymer 10% in petrolatum (+ at D4), plus a weak erythematous reaction to disodium stearoyl glutamate 30%. (at D4). The cream reacted positively (+/+) at D3 and D4.
Although p-phenylenediamine (PPD) and toluene-2,5-diamine are the most frequently reported hair dye allergens, allergic contact dermatitis from direct dyes for hair coloration is unusual. Two patients with a history of PPD allergic contact dermatitis had positive patch tests to HC Yellow 7,4 amino-3-nitrophenol and HC Red B54 in hair dyes (9A ).
Finasteride CONTACT ALLERGENS VP-eicosene copolymer VP-eicosene copolymer, also known as Ganex® V-220 F, is a film-former and waterproofing agent that belongs to the family of co-polymers of vinylpyrrolidone and long-chain α-olefins. These polymers are used as emulsifiers and dispersants in non-aqueous systems, desensitizers/wax dispersants in melt-cast explosives, dye dispersants for candles and shoe polish, and water-resistant film-formers in wood coatings. Skin VP-eicosene copolymer has been identified as a contact allergen in an emollient formulation widely prescribed by dermatologists as a treatment for dry skin. • A 59-year-old non-atopic man with a 6-month history of xerosis and pruritus of the hands, lower arms, and legs was given an emollient cream (Lipikar Baume® La Roche-Posay, France) for daily application (8A ). Within a month he developed itchy vesicular dermatitis of the limbs.
157
Chapter 14
(SEDA-28, 169)
Sensory systems Finasteride has not previously been associated with the development of cataracts. • A 43-year-old man who had been taking finasteride 1 mg/day for 3 years to treat androgenetic alopecia developed failing vision in both eyes and was found to have anterior subcapsular opacities of both lenses (10A ). There was no family history of early onset cataract.
Sexual function The main adverse effects associated with finasteride are loss of libido, erectile dysfunction, and reduced ejaculate volume. In clinical trials 4.4% of patients treated with finasteride and 2.2% of patients taking placebo experience sexual adverse effects. However, recent evidence suggests that sexual adverse effects are less common in practice. In multicenter study of 186 patients with androgenetic alopecia sexual adverse effects occurred in under 0.5% of subjects (11C ). Reproductive system Gynecomastia has not previously been reported with finasteride.
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• A 23-year-old man who was taking finasteride 1 mg/day for 2 months for androgenetic alopecia developed painful enlargement of his right breast (12A ). Treatment was withdrawn and resolution occurred after 2 months.
• After 12 PUVA treatments a 51-year-old man developed painful hyperesthesia, which persisted despite cessation of bath PUVA (15A ). Gabapentin 300 mg qds produced a dramatic improvement in symptoms over a period of 2 weeks.
PHOTOCHEMOTHERAPY
VITAMIN A (RETINOIDS)
(SED-15, 2823; SEDA-28, 171)
(SED-15, 3653; SEDA-27, 159; SEDA-28, 171; for vitamin A carotenoids see Chapter 34)
Aminolevulinic acid Skin Contact allergy to 5-aminolaevulinic acid (ALA) has been rarely reported. The derivative ALA methylester is considered to be a more specific sensitizer of abnormal cells than ALA. • A patient developed acute eczema of the treated areas and itch and hyper-reactivity of the untreated skin after several photodynamic therapy treatments with both ALA and ALA methylester (13A ). Patch testing demonstrated a strong reaction to ALA methylester only.
PUVA Skin Systemic and topical psoralens plus ultraviolet A irradiation (PUVA therapy) are well established treatments for vitiligo. Adverse effects of PUVA therapy include non-melanoma skin cancer and PUVA-induced lentigines. Lentigines are common among PUVA-treated patients with psoriasis, but rare in patients with vitiligo. • A 22-year-old woman who had been treated with PUVA for 3 years for vitiligo developed extensive and widespread stellate and irregularly shaped black and brown lentigines in exposed and unexposed skin areas (14A ). The lesions were present in both vitiliginous and normal skin.
Severe skin pain is an uncommon complication of PUVA and is characterized by a persistent severe prickling or burning pain lasting from 15 minutes to several hours. Analgesics, antihistamines, and topical and oral glucocorticoids have generally been ineffective. Gabapentin is effective in relieving neuropathic pain and has now been tried in this condition.
Acitretin Cardiovascular Capillary leak syndrome with associated edema has been reported following acitretin therapy. • A 79-year-old man with extensive psoriasis and joint involvement was given acitretin 10 mg/day for 12 days (16A ). He developed myalgia and non-pitting edema associated with large hemorrhagic lesions, and weight gain of 13 kg. Laboratory values were normal, except for moderate hypoproteinemia and hypoalbuminemia, and raised creatine kinase, myoglobin, and aspartate transaminase. The clinical and laboratory findings were suggestive of capillary leak syndrome. Withdrawal of acitretin resulted in slow regression of the edema over 2 months.
Sensory systems Ocular adverse effects with systemic retinoids have been reported, especially keratoconjunctivitis sicca. A 32-year-old man noted reduced visual acuity after treatment with acitretin 30 mg/day for one year (17A ).
Isotretinoin Nervous system There have been two reports of Guillain–Barré syndrome after isotretinoin therapy (18A ). • A 31-year-old man developed paresthesia, influenza-like symptoms, and areflexic tetraparesis after 5 weeks of isotretinoin therapy. • A 13-year-old boy took isotretinoin for 3½ months and developed lethargy, headaches, and a flaccid areflexic tetraparesis requiring ventilatory support.
Both patients received intravenous immunoglobulin and were discharged from hospital after 3 months.
Dermatological drugs, topical agents, and cosmetics
A review of isotretinoin-associated intracranial hypertension identified 179 case reports (19c ). The mean time from the start of therapy to the diagnosis of intracranial hypertension was 2.3 months. Withdrawal of isotretinoin resulted in resolution of the symptoms within weeks. Musculoskeletal Short (4- to 5-month) courses of isotretinoin for recalcitrant acne in young adults can cause asymptomatic radiographic changes of hyperostosis of the anterior longitudinal and spinal ligaments. Bone mineral density was measured in the lumbar spine and hip in 217 adolescents who took isotretinoin for 16 to 20 weeks (20C ). There was no clinically significant effect on bone mineral density, and neither was hyperostosis observed.
Tretinoin (All-trans retinoic acid) Respiratory Tretinoin is used in the treatment of acute promyelocytic leukemia. The most important adverse effect is the retinoic acid syndrome, which is characterized by fever, respiratory distress, weight gain, and extensive infiltration of soft tissue by maturing leukemic cells. It has an incidence of up to 30% and a median onset of 7–10 days. Retinoic acid syndrome has now been reported starting immediately after just one dose (21A ). • A 42-year-old woman with acute promyelocytic leukemia was given daunorubicin, cytarabine, and tretinoin 40 mg. Within hours of the first dose
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she became confused with increasing shortness of breath over 2 days. On the third day she had deteriorated to a degree where she had to be intubated and given intravenous dexamethasone 20 mg. She recovered quickly.
The authors of this report subsequently searched the literature and confirmed that no other cases had previously been reported in which the retinoic acid syndrome had started after just one dose of tretinoin. Hematologic Hemophagocytic syndrome has been reported in a patient receiving tretinoin (22A ). • A 56-year-old woman with acute promyelocytic leukemia developed severe retinoic acid syndrome on day 17 with pancytopenia, hepatosplenomegaly, increased triglycerides, ferritin, and liver enzymes. Tretinoin was withdrawn. Dexamethasone, started on day 20, and high-dose immunoglobulins were ineffective. A bone marrow biopsy showed abundant macrophages and no evidence of leukemia. Tests for secondary hemophagocytic syndrome were negative.
Hemophagocytic syndrome (reactive or secondary) is a serious complication of malignancies. It results from inappropriate stimulation of macrophages in bone marrow and lymphoid organs, leading to phagocytosis of blood cells and production of high amounts of pro-inflammatory cytokines. The authors speculate that in this patient the syndrome could have been related to release of macrophagestimulating cytokines by leukemic cells during retinoic acid syndrome.
References 1. Klein A. Contraindications and complications with the use of botulinum toxin. Clin Dermatol 2004;22:66–75. 2. Carruthers A, Carruthers J, Lowe NJ, Menter A, Gibson J, Nordquist M, Mordaunt J. One-year, randomised, multicenter, two-period study of the safety and efficacy of repeated treatments with botulinum toxin type A in patients with glabellar lines. J Drug Assessment 2004;7:63–82.
3. Naumann M, Jankovic J. Safety of botulinum toxin type A: a systematic review and metaanalysis. Curr Med Res Opin 2004;20:981–90. 4. Kawahara C, Okada Y, Tanikawa T, Fukusima AH, Tanaka Y. Severe hypercalcemia and hypernatremia associated with calcipotriol for treatment of psoriasis. J Bone Miner Metab 2004;22:159–62.
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Sandra R. Knowles, Gavin Wong, and Neil H. Shear
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15. 16. 17. 18. 19. 20.
21. 22.