Photosensitization caused by ibuprofen Thomas Bergner, MD, and Bernhard Przybilla, MD Mfmchen, Federal Republic of Germany Several nonsteroid antiinflammatory drugs (e.g., benoxaprofen, carprofen, and piroxicam) are known to induce photosensitivity reactions, but this has not yet been documented for ibuprofen. We observed a photosensitivity reaction in a patient treated with an oral ibuprofen preparation. This patient had a lowered minimal erythema dose for UVA but not for UVB after oral administration of ibuprofen. Results of a photopatch test with the drug were negative. In vitro UVA irradiation of human erythrocytes in the presence of ibuprofen caused ultraviolet dose-dependent phototoxic hemolysis. (J AM ACAD DERMATOL 1992;26:114-6.)
Photosensitization is an adverse effect of numerous nonsteroidal antiinflammatory drugs 1-10 but has not yet been well documented for ibuprofen. 10, II We observed a patient who had a photosensitivity reaction to ibuprofen. CASE REPORT A 41-year-old woman with rheumatoid arthritis was treated with 600 mg of ibuprofen three times daily. A few days after the first administration of the drug, she noticed itchy lesions on areas of sun-exposed skin. She continued to take ibuprofen, and her skin lesions persisted despite topical corticosteroid therapy. Three months after the onset, a physical examination revealed relatively sharply defined, slightly indurated red plaques on her face and the backs of her hands. Routine laboratory tests (blood cell count, liver enzymes, and electrolytes), as well as screening tests for porphyrins, yielded normal results. Rheumatoid factor was positive, the antinuclear antibody titer was 1:640, but antibodies to extractable nuclear antigen, to Ro, and to double-stranded DNA were not demonstrable.
From the Dermatologische Klinik und Poliklinik der Ludwig-Maximilians-Universitat Mtinchen. Presented in part at the Forty-sixth Annual Meeting of the American Academy of Allergy and Immunology, Baltimore, Md., March 2328, 1990. Reprint requests: Thomas Bergner, MD, Dermatologische Klinik der Universitat Munchen, Frauenlobstrasse 9-11, D-8000 Mtinchen 2, Federal Republic of Germany.
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Test procedures UV sources. Irradiation was performed with several lamps. Photopatch testing. TL 40 W /091ight bulbs were used (Philips MMizin Systeme GMBH, Hamburg, F.R.G.) that emitted mainly in the range of 31 0 to 450 nm (maximum at approximately 355 nm). UVA irradiance at a distance of 20 cm (used at testing) was 8,4 mW/cm2; UVB irradiance was 0.25 mW/cm 2• Photoprovocation testing. For UVA, a UVASUN 5000 lamp (Mutzhas, Miinchen, F.R.G.) was used that emitted at 320 to 460 nm (maximum at approximately 375nm). UVAirradianceata distance of 40 em (used at testing) was 37 illW/cm 2. For DVB, TL 20 W /12 light bulbs were used (Philips Medizin Systeme GmbH, Hamburg, F.R.G.) with a main emission between 275 nm and 365 nm (maximum at approximately 315 nm). DVB irradiance was 1.0 mW/cm2 at a distance of 40 cm (used at testing); UVA irradiance was 0.3 m W/ cm2. Photohemolysis test. UVASUN 5000, TL 40 W /09, and TL 40 W /12 lightbulbs were used. Dosimetry. UVA and DYB intensity and dose were measured by an integrating instrument (Centra-UV, Osram, Miinchen, F.R.G.). Testing. Photopatch testing. On day 0, a standard photopatch test series and part of a pulverized ibuprofen tablet (moistened with tap water) were applied in duplicate on the patient's upper back. On day I, one test series was irradiated with 10 joules/cm2 UVA (TL 09). Test reactions were read on days 2 and 3. Photoprovocation testing. The minimal erythema doses (MEDs) for DVB (TL 12) and UVA (UVASUN 5000) were determined before and during the administration of ibuprofen tablets. On the patient's lower back, skin areas measuring 2.5 cm 2 were exposed to incremental doses of
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Photosensitization caused by ibuprofen 115
UVB (0, 14,20,28,40,56,80, and 113 millijoulesjcm2 ) or UVA (0, 5, 7, 10, 14,20,28, and 40 joulesjcm2), respectively. The MED was defined as the lowest dose that caused a homogeneous, sharply defined erythema 24 ± 2 hours after exposure. Photohemolysis test. Testing was done as previously described. 12 Suspensions of human erythrocytes or correspondingly prepared erythrocyte-free samples were incubated with ibuprofen (Serva Feinbiochemica GmbH & Co., Heidelberg, F.R.G.) of 10-5, 10-4, or 10-3 moljL. Both substance-free erythrocyte samples (blanks), as well as samples containing ibuprofen, were exposed to 0, 10, 20,25,40,50, or 100 joulesJcm2 UVA (from UVASUN 5000 or TL 09 lamps) or to 0, 100,200,400,800, or 1600 millijoulesjcm2 UVB (from a TL 12 lamp). By exposure of erythrocytes to distilled water, 100% hemolysis was obtained. Hemolysis was determined by reading the absorbance at 550 nm with an MR 700 Microplate reader (Dynatech Deutschland GmbH, Denkendorf, F.R.G.). Hemolysis was calculated on the basis of the absorbance data according to the formula: (Test sample) - (blank) . (erythrocyte-free sample) % HemolysIs::::; 100 X (100% Hemolysis)-(blank) RESULTS
Photopatch testing With the exception of presumably phototoxic reactions to two compounds of the standard series (5% tiaprofenic acid and 1% promethazine), no positive results were obtained.
Oral photoprovocation testing MEDs for UVB and UVA were determined both during the administration of ibuprofen tablets and when ibuprofen was not administered. Ibuprofen had been taken until day 0 (the first day of testing) and then again from day 14 to day 17 (the reexposure period) at a dosage of 600 mg three times daily. Irradiation was performed on days 0, 14, 17, 22, and 29. After ibuprofen tablets were administered for approximately 3 months or 3 days (day or day 17), respectively, the MEDs for UVA were 7 or 14 joules/cm2. After 14, 5, or 12 days without medication, the MEDs for UVA were 40, 14, or greater than 40 joules/cm2. The MED for UVB was 56 millijoules/cm2 at each assessment. The reactions after MED testing of either UV quality were those of a typical sunburn.
°
Photohemolysis test Without irradiation, ibuprofen did not cause hemolysis. At a concentration of 10-3 mol/L, there were dose-dependent phototoxic effects after exposure to the UVASUN 5000 lamp as well as to the TL 09 light bulbs; maximum photohemolysis was 100% or 95.1 %, respectively. A phototoxic effect at lower ibuprofen concentrations was demonstrable only at 10-4 mol/L after irradiation with 100 joules/cm2 ofUVA (from a UVASUN 5000 lamp) (photohemolysis 84.5%). Radiation rich in UVB (from TL 12 light bulbs) did not cause significant hemolysis. DISCUSSION
The nonsteroid antiinflammatory drug ibuprofen, a substituted phenylalkanoic acid, belongs to the group of propionic acid derivatives,13, 14 among which several compounds have marked photosensitizing properties. 3 Although various adverse effects to ibuprofen have been well documented, a photodependent reaction has not been definitely demonstrated previously. Our patient had a clear history of developing skin lesions that were confined to sun-exposed areas in association with the administration of ibuprofen. Photosensitization was proved by photoprovocation testing. We can not decide whether the reaction in our patient was phototoxic or photoallergic. Because of the rarity of photoreactions to ibuprofen, a photoallergic reaction might be presumed. However, the morphologic result of the reactions to phototesting was that of a sunburn. Unfortunately, the patient would not permit a biopsy to be performed, which would have helped distinguish between a phototoxic or photoallergic mechanism. REFERENCES 1. Widener H, Littman B. Ibuprofen-induced meningitis
2. 3. 4. 5. 6.
in systemic lupus erythematosus. JAMA 1978;239: 1062-4. Harber Le. Current status of mammalian and human models for predicting drug photosensitivity. J Invest DermatoI1981;77:65-70. Bailin PL, Matkaluk RM. Cutaneous reactions to antirheumatic drugs. Clin Rheumatic Dis 1982;8:493-516. Stern RS, Bigby M. An expanded profile of cutaneous reactions to nonsteroidal anti-inflammatory drugs. lAMA 1984;252:143 3-7. Ljunggren B. Propionic acid-derived nonsteroidal antiinflammatory drugs are phototoxic in vitro. Photoderrnatol 1985;2:3-9. Ljunggren B, Lundberg K. In vitro phototoxicity of non-
116 Bergner and Przybilla steroidal anti-inflammatory drugs evaluated by the mouse tail technique. PhotodermatoI1985;2:377-82. 7. Przybilla B, Ring J, Schwab V, Galosi A, Dorn M, BraunFalco O. Photosensibilisierende Eigenschaften nichtsteroidaler Antirheumatika im Photopatchtest. Hautarzt 1987; 38:18-25. 8. Przybilla B, Schwab-Przybilla V, Ruzicka T, Ring J. Phatotoxicity of non-steroidal antiinflammatory drugs demonstrated in vitro by a phota-basophil-histamine-release test. PhotodermatolI987;4:73-8. 9. Kaidbey KH, Mitchell FN. Photosensitizing potential of certain nonsteroidal anti-inflammatory agents. Arch DermatolI989;125:783-6.
Journal of the American Academy of Dermatology 10. Kochevar IE. Phototoxicity of nonsteroidal anti-inflammatory drugs. Arch Dermatol1989;125:824-6. 11. Kantor TG. Ibuprofen. Ann Intern Moo 1979;91:877-82. 12. Przybilla B, Georgii A, Bergner T, Ring J. Demonstration of quinolone phototoxicity in vitro. Dermatologica 1990; 181:98-103. 13. Bigby M, Stern R. Cutaneous reactions to nonsteroidal antiinflammatory drugs. J AM ACAD DERMATOL 1985;12: 866-76. 14. Albert KS, Gernaat eM. The pharmacokinetics of ibuprofen. Am J Med 1984;77:40-5.
BOUND VOLUMES AVAILABLE TO SUBSCRIBERS Bound volumes of the JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY are available to subscribers (only) for the 1992 issues from the Publisher at a cost of $66.00 for domestic, $88.62 for Canadian, and $84.00 for international for volume 26 (January-June) and volume 27 (July-December). Shipping charges are included. Each bound volume contains a subject and author index and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mosby-Year Book, Inc., Subscription Services, 11830 Westline Industrial Dr., 81. Louis, MO 63146-3318. USA: phone (800) 325-4177, ext. 4351; (314) 453-4351. Subscriptions must be inforee to qualify. Bound volumes are not available in place of a regular journal subscription.
Photosensitization is an adverse effect of numerous nonsteroidal antiinflammatory drugs 1-10 but has not yet been well documented for ibuprofen. 10, II We observed a patient who had a photosensitivity reaction to ibuprofen. CASE REPORT A 41-year-old woman with rheumatoid arthritis was treated with 600 mg of ibuprofen three times daily. A few days after the first administration of the drug, she noticed itchy lesions on areas of sun-exposed skin. She continued to take ibuprofen, and her skin lesions persisted despite topical corticosteroid therapy. Three months after the onset, a physical examination revealed relatively sharply defined, slightly indurated red plaques on her face and the backs of her hands. Routine laboratory tests (blood cell count, liver enzymes, and electrolytes), as well as screening tests for porphyrins, yielded normal results. Rheumatoid factor was positive, the antinuclear antibody titer was 1:640, but antibodies to extractable nuclear antigen, to Ro, and to double-stranded DNA were not demonstrable.
From the Dermatologische Klinik und Poliklinik der Ludwig-Maximilians-Universitat Mtinchen. Presented in part at the Forty-sixth Annual Meeting of the American Academy of Allergy and Immunology, Baltimore, Md., March 2328, 1990. Reprint requests: Thomas Bergner, MD, Dermatologische Klinik der Universitat Munchen, Frauenlobstrasse 9-11, D-8000 Mtinchen 2, Federal Republic of Germany.
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Test procedures UV sources. Irradiation was performed with several lamps. Photopatch testing. TL 40 W /091ight bulbs were used (Philips MMizin Systeme GMBH, Hamburg, F.R.G.) that emitted mainly in the range of 31 0 to 450 nm (maximum at approximately 355 nm). UVA irradiance at a distance of 20 cm (used at testing) was 8,4 mW/cm2; UVB irradiance was 0.25 mW/cm 2• Photoprovocation testing. For UVA, a UVASUN 5000 lamp (Mutzhas, Miinchen, F.R.G.) was used that emitted at 320 to 460 nm (maximum at approximately 375nm). UVAirradianceata distance of 40 em (used at testing) was 37 illW/cm 2. For DVB, TL 20 W /12 light bulbs were used (Philips Medizin Systeme GmbH, Hamburg, F.R.G.) with a main emission between 275 nm and 365 nm (maximum at approximately 315 nm). DVB irradiance was 1.0 mW/cm2 at a distance of 40 cm (used at testing); UVA irradiance was 0.3 m W/ cm2. Photohemolysis test. UVASUN 5000, TL 40 W /09, and TL 40 W /12 lightbulbs were used. Dosimetry. UVA and DYB intensity and dose were measured by an integrating instrument (Centra-UV, Osram, Miinchen, F.R.G.). Testing. Photopatch testing. On day 0, a standard photopatch test series and part of a pulverized ibuprofen tablet (moistened with tap water) were applied in duplicate on the patient's upper back. On day I, one test series was irradiated with 10 joules/cm2 UVA (TL 09). Test reactions were read on days 2 and 3. Photoprovocation testing. The minimal erythema doses (MEDs) for DVB (TL 12) and UVA (UVASUN 5000) were determined before and during the administration of ibuprofen tablets. On the patient's lower back, skin areas measuring 2.5 cm 2 were exposed to incremental doses of
Volume 26 Number 1 January 1992
Photosensitization caused by ibuprofen 115
UVB (0, 14,20,28,40,56,80, and 113 millijoulesjcm2 ) or UVA (0, 5, 7, 10, 14,20,28, and 40 joulesjcm2), respectively. The MED was defined as the lowest dose that caused a homogeneous, sharply defined erythema 24 ± 2 hours after exposure. Photohemolysis test. Testing was done as previously described. 12 Suspensions of human erythrocytes or correspondingly prepared erythrocyte-free samples were incubated with ibuprofen (Serva Feinbiochemica GmbH & Co., Heidelberg, F.R.G.) of 10-5, 10-4, or 10-3 moljL. Both substance-free erythrocyte samples (blanks), as well as samples containing ibuprofen, were exposed to 0, 10, 20,25,40,50, or 100 joulesJcm2 UVA (from UVASUN 5000 or TL 09 lamps) or to 0, 100,200,400,800, or 1600 millijoulesjcm2 UVB (from a TL 12 lamp). By exposure of erythrocytes to distilled water, 100% hemolysis was obtained. Hemolysis was determined by reading the absorbance at 550 nm with an MR 700 Microplate reader (Dynatech Deutschland GmbH, Denkendorf, F.R.G.). Hemolysis was calculated on the basis of the absorbance data according to the formula: (Test sample) - (blank) . (erythrocyte-free sample) % HemolysIs::::; 100 X (100% Hemolysis)-(blank) RESULTS
Photopatch testing With the exception of presumably phototoxic reactions to two compounds of the standard series (5% tiaprofenic acid and 1% promethazine), no positive results were obtained.
Oral photoprovocation testing MEDs for UVB and UVA were determined both during the administration of ibuprofen tablets and when ibuprofen was not administered. Ibuprofen had been taken until day 0 (the first day of testing) and then again from day 14 to day 17 (the reexposure period) at a dosage of 600 mg three times daily. Irradiation was performed on days 0, 14, 17, 22, and 29. After ibuprofen tablets were administered for approximately 3 months or 3 days (day or day 17), respectively, the MEDs for UVA were 7 or 14 joules/cm2. After 14, 5, or 12 days without medication, the MEDs for UVA were 40, 14, or greater than 40 joules/cm2. The MED for UVB was 56 millijoules/cm2 at each assessment. The reactions after MED testing of either UV quality were those of a typical sunburn.
°
Photohemolysis test Without irradiation, ibuprofen did not cause hemolysis. At a concentration of 10-3 mol/L, there were dose-dependent phototoxic effects after exposure to the UVASUN 5000 lamp as well as to the TL 09 light bulbs; maximum photohemolysis was 100% or 95.1 %, respectively. A phototoxic effect at lower ibuprofen concentrations was demonstrable only at 10-4 mol/L after irradiation with 100 joules/cm2 ofUVA (from a UVASUN 5000 lamp) (photohemolysis 84.5%). Radiation rich in UVB (from TL 12 light bulbs) did not cause significant hemolysis. DISCUSSION
The nonsteroid antiinflammatory drug ibuprofen, a substituted phenylalkanoic acid, belongs to the group of propionic acid derivatives,13, 14 among which several compounds have marked photosensitizing properties. 3 Although various adverse effects to ibuprofen have been well documented, a photodependent reaction has not been definitely demonstrated previously. Our patient had a clear history of developing skin lesions that were confined to sun-exposed areas in association with the administration of ibuprofen. Photosensitization was proved by photoprovocation testing. We can not decide whether the reaction in our patient was phototoxic or photoallergic. Because of the rarity of photoreactions to ibuprofen, a photoallergic reaction might be presumed. However, the morphologic result of the reactions to phototesting was that of a sunburn. Unfortunately, the patient would not permit a biopsy to be performed, which would have helped distinguish between a phototoxic or photoallergic mechanism. REFERENCES 1. Widener H, Littman B. Ibuprofen-induced meningitis
2. 3. 4. 5. 6.
in systemic lupus erythematosus. JAMA 1978;239: 1062-4. Harber Le. Current status of mammalian and human models for predicting drug photosensitivity. J Invest DermatoI1981;77:65-70. Bailin PL, Matkaluk RM. Cutaneous reactions to antirheumatic drugs. Clin Rheumatic Dis 1982;8:493-516. Stern RS, Bigby M. An expanded profile of cutaneous reactions to nonsteroidal anti-inflammatory drugs. lAMA 1984;252:143 3-7. Ljunggren B. Propionic acid-derived nonsteroidal antiinflammatory drugs are phototoxic in vitro. Photoderrnatol 1985;2:3-9. Ljunggren B, Lundberg K. In vitro phototoxicity of non-
116 Bergner and Przybilla steroidal anti-inflammatory drugs evaluated by the mouse tail technique. PhotodermatoI1985;2:377-82. 7. Przybilla B, Ring J, Schwab V, Galosi A, Dorn M, BraunFalco O. Photosensibilisierende Eigenschaften nichtsteroidaler Antirheumatika im Photopatchtest. Hautarzt 1987; 38:18-25. 8. Przybilla B, Schwab-Przybilla V, Ruzicka T, Ring J. Phatotoxicity of non-steroidal antiinflammatory drugs demonstrated in vitro by a phota-basophil-histamine-release test. PhotodermatolI987;4:73-8. 9. Kaidbey KH, Mitchell FN. Photosensitizing potential of certain nonsteroidal anti-inflammatory agents. Arch DermatolI989;125:783-6.
Journal of the American Academy of Dermatology 10. Kochevar IE. Phototoxicity of nonsteroidal anti-inflammatory drugs. Arch Dermatol1989;125:824-6. 11. Kantor TG. Ibuprofen. Ann Intern Moo 1979;91:877-82. 12. Przybilla B, Georgii A, Bergner T, Ring J. Demonstration of quinolone phototoxicity in vitro. Dermatologica 1990; 181:98-103. 13. Bigby M, Stern R. Cutaneous reactions to nonsteroidal antiinflammatory drugs. J AM ACAD DERMATOL 1985;12: 866-76. 14. Albert KS, Gernaat eM. The pharmacokinetics of ibuprofen. Am J Med 1984;77:40-5.
BOUND VOLUMES AVAILABLE TO SUBSCRIBERS Bound volumes of the JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY are available to subscribers (only) for the 1992 issues from the Publisher at a cost of $66.00 for domestic, $88.62 for Canadian, and $84.00 for international for volume 26 (January-June) and volume 27 (July-December). Shipping charges are included. Each bound volume contains a subject and author index and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mosby-Year Book, Inc., Subscription Services, 11830 Westline Industrial Dr., 81. Louis, MO 63146-3318. USA: phone (800) 325-4177, ext. 4351; (314) 453-4351. Subscriptions must be inforee to qualify. Bound volumes are not available in place of a regular journal subscription.
