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Ciprofloxacin-induced phototoxicity in patients with cystic fibrosis
P2501
P2503
A PLACEBO-CONTROLLED EUROPEAN STUDY COMPARING MAL–PDT WITH CRYOTHERAPY AND 5-FLUOROURACIL IN PATIENTS WITH BOWEN’S DISEASE Colin Morton, MD, Department of Dermatology, Falkirk, Scotland; M. Horn, MD, University of Graz, Graz, Austria; J. Leman, MD, Department of Dermatology, Falkirk, Scotland; B. Tack, MD, Caen, France Background: Guidelines support topical photodynamic therapy (PDT) in treating certain nonmelanoma skin cancers, including Bowen’s disease. Methyl aminolevulinate (MAL) is a new topical agent, indicated in the treatment of actinic keratoses and basal cell carcinoma.
A TOPICAL ANTIOXIDANT SOLUTION CONTAINING VITAMIN C, VITAMIN E, AND FERULIC ACID PREVENTS ULTRAVIOLET RADIATION-INDUCED CASPASE-3 AND CASPASE-7 INDUCTION IN SKIN Sheldon Pinnell, MD, F.-Y. Lin, PhD, James M. Grichnik, MD, PhD, Duke University, Durham, NC, United States; J. E. Zielinski, PhD, Zielinski Research, San Diego, CA, United States New methods of photoprotection are necessary to prevent ultraviolet injury to skin resulting in skin cancer and photoaging changes. We have previously reported the photoprotective effect of topical application of 15% L-ascorbic acid and 1% atocopherol (J Am Acad Dermatol 2003;48:866). The solution provided 4-fold protection against ultraviolet irradiation and reduced cellular apoptosis measured as sunburn cells. The stability and photoprotection of 15% L-ascorbic acid and 1% atocopherol have been augmented by addition of 0.5% ferulic acid. This natural plant antioxidant increases the stability of L-ascorbic acid and doubles photoprotection of the solution against solar-simulated irradiation. In this study, we further explored the mechanism of antioxidant photoprotection by measuring caspase-3 and caspase-7 induction. Fifteen percent L-ascorbic acid, 1% a-tocopherol, or 15% L-ascorbic acid, 1% a-tocopherol, 0.5% ferulic acid antioxidant solutions were applied daily for 4 days to pig skin 0.5 mL to a 7.5- 3 10-cm patch. Antioxidant-treated and untreated skin was irradiated (4 minimal erythema doses) with a solar simulator fitted with a 295-nm band pass filter. Twenty-four hours later the irradiated skin was biopsied, frozen in liquid nitrogen, and shattered. Cell protein was extracted with detergents in the presence of protease inhibitors and electrophoresed in 12% sodium dodecyl sulfate--polyacrylamide gel, transferred to PVDF membranes and treated with rabbit anti-human cleaved caspase-3 or caspase-7 antibody. Densitometry of Western blots was performed using Kodak ID image analysis software. Levels of activated caspase-3 in control or vehicle-treated skin were 74% 6 32%; in skin treated with 15% Lascorbic acid and 1% a-tocopherol were 17% 6 16%; and in skin treated with 15% Lascorbic acid, 1% a-tocopherol, and 0.5% ferulic acid were 1.7% 6 2%. Corresponding levels of caspase-7 were 74 6 57, 20 6 0, and 1.2 6 1.4. All values are significant when compared with each other group (P \.01, two-tailed t test). Ferulic acid stabilizes an antioxidant solution of 15% L-ascorbic acid, 1% atocopherol and provides added photoprotection, resulting in reduced activation of caspase-3, its downstream product caspase-7, and subsequent apoptosis.
Objectives: To compare efficacy and safety of PDT using either MAL or placebo with cryotherapy and with 5-fluorouracil (5-FU). Methods: Two hundred twenty-five patients with 275 lesions were treated with either MAL-PDT (2 treatment sessions 1 week apart [n = 96]), placebo-PDT (n = 17), cryotherapy (n = 82), or 5-FU (n = 30). PDT was performed using 160 mg/g of MAL or placebo cream and a 3-hour application time with broadband red light (570-670 nm; total light dose, 75 J/cm2). Cryotherapy used liquid nitrogen spray, and the duration of the 5-FU treatment was 4 weeks. Lesion response and cosmetic outcome were assessed 3 and 12 months after the last treatment. Results: Three months after last treatment, 103 of 111 lesions (93%) treated with MAL-PDT, 4 of 19 lesions (21%) with placebo-PDT, 73 of 85 (86%) with cryotherapy, and 24 of 29 (83%) with 5-FU had responded completely. The 12-month recurrence rate was 15% for MAL-PDT, 24% for cryotherapy, and 21% for 5-FU. Overall cosmetic outcome after MAL-PDT was superior to that observed after cryotherapy or 5-FU. Adverse events were mainly transient, local, and of mild to moderate intensity. Conclusion: MAL-PDT is significantly more efficient than placebo-PDT and similar to standard treatment. Twelve months after treatment, the recurrence rates for both cryotherapy and 5-FU were slightly higher than for MAL-PDT. MAL-PDT gave better cosmetic results than both cryotherapy and 5-FU. Supported by Photocure ASA
Dr. Pinnell is a consultant to SkinCeuticals (Garland, Tex), and Dr Zielinski is president of Zielinski Research (San Diego, Calif).
P2502 A RANDOMIZED EUROPEAN COMPARISON OF MAL-PDT AND EXCISION SURGERY IN NODULAR BASAL CELL CARCINOMA: A 24-MONTH UPDATE Lesley Rhodes, MD, Photobiology Unit Dermatology Centre, Liverpool, England; Richard Groves, MD, Imperial College Faculty of Medicine, London, England; Peter Wolf, MD, University Hospital, Graz, Austria Objectives: To compare topical photodynamic therapy (PDT) with the use of the sensitizer methyl aminolevulinate (MAL) against standard excision surgery in nodular basal cell carcinoma (BCC). Methods: This was a prospective, randomized study. A total of 101 adults with previously untreated nodular BCC received MAL-PDT (n = 52) or surgery (n = 49). PDT was given twice, 7 days apart, with MAL cream (160 mg/g) and 75 J/cm2 red light (570-670 nm). Thirteen patients with a noncomplete response to PDT at 3 months (24% of lesions) were re-treated. The primary end point was clinically assessed lesion clearance at 3 months after treatment. Secondary end points were sustained response rate at 12 months and cosmetic outcome at 3 and 12 months. Cosmesis and lesion recurrence were further assessed at 24 months. Results: Data from 97 patients (105 lesions) were included in the 3-month perprotocol analysis. Complete response rates did not differ significantly between groups (51/52 [98%] lesions with surgery vs 48/53 [91%] lesions with MAL-PDT; difference [95% confidence interval], 4.8% [-3.4%-13.0%]; P =.25). At 12 months, tumor-free rates were 50 of 52 lesions (96%) with surgery compared with 44 of 53 lesions (83%) with MAL-PDT (P =.15). More patients treated with MAL-PDT than surgery had an excellent or good cosmetic outcome at all time points (significant at 12 and 24 months on patient assessment [P \.05], and at 3, 12, and 24 months on investigator evaluation [P \.001]). At 24 months, 5 lesions that had initially cleared with MAL-PDT had recurred, compared with 1 after surgery. Conclusions: MAL-PDT is an effective treatment for nodular BCC; although there is a trend for higher recurrence with this modality, it conveys the advantage over surgery of better cosmesis. Supported by Photocure SA
P158
J AM ACAD DERMATOL
P2504 CIPROFLOXACIN-INDUCED PHOTOTOXICITY IN PATIENTS WITH CYSTIC FIBROSIS Julia Tolland, MBBCh, Royal Hospitals Trust, Belfast, Northern Ireland; Stuart Elborn, MD, Kevin McKenna, MD, Belfast City Hospitals Trust, Belfast, Northern Ireland Phototoxic reactions with the quinolone group of antibiotics are well recognized. Ciprofloxacin has been reported to be a weak photosensitizer after exposure to ultraviolet A wavelengths of light. Rashes have been demonstrated clinically and subclinically by evidence of a decreased minimal erythema dose. The onset of the rash is most common 24 hours after taking the antibiotic; it typically lasts 48 hours and resolves with no pigmentary change. Incidence of the phototoxic potential of ciprofloxacin and other fluoroquinolones has been reported to be less than 2.4%. Ciprofloxacin is commonly used in the treatment of infections caused by Pseudomonas aeruginosa in patients with cystic fibrosis (CF). The incidence of phototoxic rashes with ciprofloxacin in this patient group appears to be increased (rates of 16%-52% have been reported). We carried out a questionnaire-based study. The study included 40 patients with CF with an age range of 19 to 49 years. The male-female ratio was 5:3. Thirty-one patients had taken ciprofloxacin in the previous 2 years. Eleven of these patients described getting a rash on photoexposed areas within 24 hours of taking ciprofloxacin. Liver and renal function in affected patients was within normal limits. Most patients were given suncare advice before taking the medication. Of the 11 patients, 6 used sunscreen, 5 did not. We therefore report an incidence of 35.5% of clinical phototoxic rashes secondary to ciprofloxacin in patients with CF. This is significantly higher than that reported for the general population. We postulate that patients with CF have an increased risk of photosensitivity, perhaps secondary to factors occurring at a cellular level. Nothing to disclose.
MARCH 2005
P2503
A PLACEBO-CONTROLLED EUROPEAN STUDY COMPARING MAL–PDT WITH CRYOTHERAPY AND 5-FLUOROURACIL IN PATIENTS WITH BOWEN’S DISEASE Colin Morton, MD, Department of Dermatology, Falkirk, Scotland; M. Horn, MD, University of Graz, Graz, Austria; J. Leman, MD, Department of Dermatology, Falkirk, Scotland; B. Tack, MD, Caen, France Background: Guidelines support topical photodynamic therapy (PDT) in treating certain nonmelanoma skin cancers, including Bowen’s disease. Methyl aminolevulinate (MAL) is a new topical agent, indicated in the treatment of actinic keratoses and basal cell carcinoma.
A TOPICAL ANTIOXIDANT SOLUTION CONTAINING VITAMIN C, VITAMIN E, AND FERULIC ACID PREVENTS ULTRAVIOLET RADIATION-INDUCED CASPASE-3 AND CASPASE-7 INDUCTION IN SKIN Sheldon Pinnell, MD, F.-Y. Lin, PhD, James M. Grichnik, MD, PhD, Duke University, Durham, NC, United States; J. E. Zielinski, PhD, Zielinski Research, San Diego, CA, United States New methods of photoprotection are necessary to prevent ultraviolet injury to skin resulting in skin cancer and photoaging changes. We have previously reported the photoprotective effect of topical application of 15% L-ascorbic acid and 1% atocopherol (J Am Acad Dermatol 2003;48:866). The solution provided 4-fold protection against ultraviolet irradiation and reduced cellular apoptosis measured as sunburn cells. The stability and photoprotection of 15% L-ascorbic acid and 1% atocopherol have been augmented by addition of 0.5% ferulic acid. This natural plant antioxidant increases the stability of L-ascorbic acid and doubles photoprotection of the solution against solar-simulated irradiation. In this study, we further explored the mechanism of antioxidant photoprotection by measuring caspase-3 and caspase-7 induction. Fifteen percent L-ascorbic acid, 1% a-tocopherol, or 15% L-ascorbic acid, 1% a-tocopherol, 0.5% ferulic acid antioxidant solutions were applied daily for 4 days to pig skin 0.5 mL to a 7.5- 3 10-cm patch. Antioxidant-treated and untreated skin was irradiated (4 minimal erythema doses) with a solar simulator fitted with a 295-nm band pass filter. Twenty-four hours later the irradiated skin was biopsied, frozen in liquid nitrogen, and shattered. Cell protein was extracted with detergents in the presence of protease inhibitors and electrophoresed in 12% sodium dodecyl sulfate--polyacrylamide gel, transferred to PVDF membranes and treated with rabbit anti-human cleaved caspase-3 or caspase-7 antibody. Densitometry of Western blots was performed using Kodak ID image analysis software. Levels of activated caspase-3 in control or vehicle-treated skin were 74% 6 32%; in skin treated with 15% Lascorbic acid and 1% a-tocopherol were 17% 6 16%; and in skin treated with 15% Lascorbic acid, 1% a-tocopherol, and 0.5% ferulic acid were 1.7% 6 2%. Corresponding levels of caspase-7 were 74 6 57, 20 6 0, and 1.2 6 1.4. All values are significant when compared with each other group (P \.01, two-tailed t test). Ferulic acid stabilizes an antioxidant solution of 15% L-ascorbic acid, 1% atocopherol and provides added photoprotection, resulting in reduced activation of caspase-3, its downstream product caspase-7, and subsequent apoptosis.
Objectives: To compare efficacy and safety of PDT using either MAL or placebo with cryotherapy and with 5-fluorouracil (5-FU). Methods: Two hundred twenty-five patients with 275 lesions were treated with either MAL-PDT (2 treatment sessions 1 week apart [n = 96]), placebo-PDT (n = 17), cryotherapy (n = 82), or 5-FU (n = 30). PDT was performed using 160 mg/g of MAL or placebo cream and a 3-hour application time with broadband red light (570-670 nm; total light dose, 75 J/cm2). Cryotherapy used liquid nitrogen spray, and the duration of the 5-FU treatment was 4 weeks. Lesion response and cosmetic outcome were assessed 3 and 12 months after the last treatment. Results: Three months after last treatment, 103 of 111 lesions (93%) treated with MAL-PDT, 4 of 19 lesions (21%) with placebo-PDT, 73 of 85 (86%) with cryotherapy, and 24 of 29 (83%) with 5-FU had responded completely. The 12-month recurrence rate was 15% for MAL-PDT, 24% for cryotherapy, and 21% for 5-FU. Overall cosmetic outcome after MAL-PDT was superior to that observed after cryotherapy or 5-FU. Adverse events were mainly transient, local, and of mild to moderate intensity. Conclusion: MAL-PDT is significantly more efficient than placebo-PDT and similar to standard treatment. Twelve months after treatment, the recurrence rates for both cryotherapy and 5-FU were slightly higher than for MAL-PDT. MAL-PDT gave better cosmetic results than both cryotherapy and 5-FU. Supported by Photocure ASA
Dr. Pinnell is a consultant to SkinCeuticals (Garland, Tex), and Dr Zielinski is president of Zielinski Research (San Diego, Calif).
P2502 A RANDOMIZED EUROPEAN COMPARISON OF MAL-PDT AND EXCISION SURGERY IN NODULAR BASAL CELL CARCINOMA: A 24-MONTH UPDATE Lesley Rhodes, MD, Photobiology Unit Dermatology Centre, Liverpool, England; Richard Groves, MD, Imperial College Faculty of Medicine, London, England; Peter Wolf, MD, University Hospital, Graz, Austria Objectives: To compare topical photodynamic therapy (PDT) with the use of the sensitizer methyl aminolevulinate (MAL) against standard excision surgery in nodular basal cell carcinoma (BCC). Methods: This was a prospective, randomized study. A total of 101 adults with previously untreated nodular BCC received MAL-PDT (n = 52) or surgery (n = 49). PDT was given twice, 7 days apart, with MAL cream (160 mg/g) and 75 J/cm2 red light (570-670 nm). Thirteen patients with a noncomplete response to PDT at 3 months (24% of lesions) were re-treated. The primary end point was clinically assessed lesion clearance at 3 months after treatment. Secondary end points were sustained response rate at 12 months and cosmetic outcome at 3 and 12 months. Cosmesis and lesion recurrence were further assessed at 24 months. Results: Data from 97 patients (105 lesions) were included in the 3-month perprotocol analysis. Complete response rates did not differ significantly between groups (51/52 [98%] lesions with surgery vs 48/53 [91%] lesions with MAL-PDT; difference [95% confidence interval], 4.8% [-3.4%-13.0%]; P =.25). At 12 months, tumor-free rates were 50 of 52 lesions (96%) with surgery compared with 44 of 53 lesions (83%) with MAL-PDT (P =.15). More patients treated with MAL-PDT than surgery had an excellent or good cosmetic outcome at all time points (significant at 12 and 24 months on patient assessment [P \.05], and at 3, 12, and 24 months on investigator evaluation [P \.001]). At 24 months, 5 lesions that had initially cleared with MAL-PDT had recurred, compared with 1 after surgery. Conclusions: MAL-PDT is an effective treatment for nodular BCC; although there is a trend for higher recurrence with this modality, it conveys the advantage over surgery of better cosmesis. Supported by Photocure SA
P158
J AM ACAD DERMATOL
P2504 CIPROFLOXACIN-INDUCED PHOTOTOXICITY IN PATIENTS WITH CYSTIC FIBROSIS Julia Tolland, MBBCh, Royal Hospitals Trust, Belfast, Northern Ireland; Stuart Elborn, MD, Kevin McKenna, MD, Belfast City Hospitals Trust, Belfast, Northern Ireland Phototoxic reactions with the quinolone group of antibiotics are well recognized. Ciprofloxacin has been reported to be a weak photosensitizer after exposure to ultraviolet A wavelengths of light. Rashes have been demonstrated clinically and subclinically by evidence of a decreased minimal erythema dose. The onset of the rash is most common 24 hours after taking the antibiotic; it typically lasts 48 hours and resolves with no pigmentary change. Incidence of the phototoxic potential of ciprofloxacin and other fluoroquinolones has been reported to be less than 2.4%. Ciprofloxacin is commonly used in the treatment of infections caused by Pseudomonas aeruginosa in patients with cystic fibrosis (CF). The incidence of phototoxic rashes with ciprofloxacin in this patient group appears to be increased (rates of 16%-52% have been reported). We carried out a questionnaire-based study. The study included 40 patients with CF with an age range of 19 to 49 years. The male-female ratio was 5:3. Thirty-one patients had taken ciprofloxacin in the previous 2 years. Eleven of these patients described getting a rash on photoexposed areas within 24 hours of taking ciprofloxacin. Liver and renal function in affected patients was within normal limits. Most patients were given suncare advice before taking the medication. Of the 11 patients, 6 used sunscreen, 5 did not. We therefore report an incidence of 35.5% of clinical phototoxic rashes secondary to ciprofloxacin in patients with CF. This is significantly higher than that reported for the general population. We postulate that patients with CF have an increased risk of photosensitivity, perhaps secondary to factors occurring at a cellular level. Nothing to disclose.
MARCH 2005