ArticleLiterature Review

Drug-Induced Photosensitivity Culprit Drugs, Management and Prevention

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Abstract

Photo-induced drug eruptions are cutaneous adverse events due to exposure to a drug and either ultraviolet or visible radiation. Based on their pathogenesis, they can be classified as phototoxic or photoallergic drug eruptions, although in many cases it is not possible to determine whether a particular eruption is due to a phototoxic or photoallergic mechanism. In this review, the diagnosis, prevention and management of drug-induced photosensitivity are discussed. diagnosis is based primarily on the history of drug intake and the clinical appearance of the eruption, primarily affecting sun-exposed areas of the skin. Phototesting and photopatch testing can be useful adjuncts in making a diagnosis. The mainstay of management is prevention, including informing patients of the possibility of increased sun sensitivity and the use of sun protective measures. However, once the eruption has occurred, it may be necessary to discontinue the culprit medication and treat the eruption with a potent topical corticosteroid. Drugs that have been implicated in causing photosensitive eruptions are reviewed. Tetracycline, doxycycline, nalidixic acid, voriconazole, amiodarone, hydrochlorothiazide, naproxen, piroxicam, chlorpromazine and thioridazine are among the most commonly implicated medications. We review the medical literature regarding evidence for the culpability of each drug, including the results of phototesting, photopatch testing and rechallenge testing.

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... 99 Drucker and Rosen, suggested ten drugs to be considered potent photosensitisers, of which hydrochlorthiazide was the only antihypertensive. 100 Other drugs include diuretics (triamterene, furosemide), ACE inhibitors (ramipril, enalapril, quinapril), calcium channel blockers (nifedepine), beta-blockers (tilisolol), angiotensin receptor blockers (valsartan), centrally acting agents (clonidine, methyldopa), valsartan and methyl-dopa have been described to cause photosensitivity in the past, but these are mostly individual case reports. Amlodipine and nifedepine can cause photodistributed facial telangiectasia. ...
... Amlodipine and nifedepine can cause photodistributed facial telangiectasia. 99,100 In a study of 62 cases of thiazide induced photosensitivity, eczematous presentation was found to be the most common. 101 In most cases, phototesting revealed an abnormal response to UVA rays alone, or to both UVA and UVB. ...
... Histologically, the changes are consistent with a lichenoid dermatitis that show basal vacuolar alteration and prominent pigment incontinence. 100,108,115 Kubo et al. propose that diltiazem associated photodistributed hyperpigmentation must be a specific type of drug-induced photosensitive lichenoid eruption, probably in the UVB range. 116 Photoprotection, hydroquinone and tacrolimus cream have been tried. ...
Article
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Antihypertensive drugs are prescribed frequently and can cause cutaneous adverse reactions. The exact incidence and frequency of these reactions are unknown. Multiple antihypertensive drug consumption has contributed to a substantial increase in the number of cutaneous adverse reactions to them. Thus, there is a need for dermatologists and physicians to be aware of the wide range of available antihypertensives and the type of reactions that can be expected. This review article focuses on the various clinical presentations that have been implicated or associated with them. The diagnosis and management have been discussed in brief.
... Phototoxic reaction arises due to skin cell damage including sunburn eruption with erythema, edema and persistent hyperpigmentation; while photoallergic reaction is immunemediated response including eczematous itchy type reaction. However, it is difficult to distinguish between these two patterns of photosensitivity reactions, as they have dermatitic appearance (Drucker and Rosen, 2011;Monteiro et al., 2016). Photosensitive drug molecules are chromophores that absorb ultraviolet (UV) and/or visible radiation resulting in chemical reaction (Monteiro et al., 2016). ...
... Photosensitive drugs include some antimicrobials, antifungals, non-steroidal anti-inflammatory drugs (NSAIDs), diuretics, retinoids, …..etc. (Drucker and Rosen, 2011;Monteiro et al., 2016). ...
... A previous study revealed that photodegradation of ATRA is mainly attributed to UVA radiation (Tashtoush et al., 2008). Taking into account that UVA is characterized by deep penetration into the skin (Drucker and Rosen, 2011), thus the photosensitivity associated with ATRA therapy can be considered as a result of its photodegradation At each time interval, same letter means non-significant difference, while different letter means significant difference at (p < 0.05). (Tashtoush et al., 2008). ...
Article
All-trans retinoic acid is a natural retinoid and the physiologically active metabolite of vitamin A. The aim of the present study is to develop and optimize a nanostructured lipid carrier formulation to enhance the photostability of all-trans retinoic acid and alleviate its skin photosensitivity. Box–Behnken design was used for optimizing dependent variables such as particle size, zeta potential and viscosity. The total lipid (%), liquid lipid (%) and total surfactant (%) were selected as independent variables. The optimized formulation was characterized by particle size of 151 nm, zeta potential of −31 mV and viscosity of 2064 cps. In vitro photoprotection effect of the optimized formulation containing different types and concentrations of inorganic sunscreens was evaluated employing Transpore® tape assay. Sun protection factor and other spectroscopic indices revealed that 6% titanium dioxide was the best choice to be combined with the optimized formulation. After 6 h of ultraviolet A exposure, the optimized formulation and the optimized formulation combined with 6% titanium dioxide enhanced the photostability of all-trans retinoic acid by about 1.5 and 2 times, respectively, compared to its methanolic solution. In vivo photoprotection effect of the developed formulations was conducted on mice exposed to direct sun light for 4 days. Photographs of the mice's skin, biochemical analysis of the pro-inflammatory cytokines in the skin as well as histopathological examination, depicted that the optimized formulation promoted an obvious alleviation of the all-trans retinoic acid-induced photosensitivity, which was further potentiated by the addition of 6% titanium dioxide, compared to the marketed product.
... The lead compound, CMT-3, has shown efficacy in a pig-model of acute respiratory distress syndrome (ARDS), diabetes, arthritis and cancer [15,16,[25][26][27][28][29] and in phase II clinical trials in humans with Kaposi's sarcoma, as an anti-angiogenesis drug. However, this compound did result in adverse events, specifically increased photosensitivity in these subjects [30][31][32][33][34][35] and to date, has not been developed further. However, a pilot study by Ryan et al. [16] using a much lower oral/systemic dose of CMT-3 (i.e., 10mg/day), rather than the 50-150mg/day in the phase I and II studies on cancer patients [33][34][35] did appear to reduce IL-1β and MMP-8 in human periodontal pockets [36]. ...
... However, this compound did result in adverse events, specifically increased photosensitivity in these subjects [30][31][32][33][34][35] and to date, has not been developed further. However, a pilot study by Ryan et al. [16] using a much lower oral/systemic dose of CMT-3 (i.e., 10mg/day), rather than the 50-150mg/day in the phase I and II studies on cancer patients [33][34][35] did appear to reduce IL-1β and MMP-8 in human periodontal pockets [36]. ...
... First, the cohorts did not assess use of other tetracycline class members. Therefore, we cannot assess use of other tetracycline family antibiotics, particularly doxycycline that has recognised photosensitising properties (Layton and Cunliffe, 1993;Drucker and Rosen, 2011). The above-mentioned Danish study reported significantly increased risk of melanoma, SCC, and BCC associated with doxycycline use (Kaae et al, 2010). ...
... However, a case-control study did not find significant associations with skin cancer (ORo1) (de Vries et al, 2012). Another tetracycline class drug, minocycline, is not considered photosensitising (Drucker and Rosen, 2011). Second, tetracycline use was only asked once and not updated during follow-up. ...
Article
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Background: Tetracycline is a photosensitising medication that increases skin vulnerability to UV-related damage. Methods: We prospectively examined tetracycline use and risk of incident melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) based on 213 536 participants from the Nurses' Health Study (NHS), NHS2, and Health Professionals Follow-up Study. Information on ever use of tetracycline was asked via questionnaire. Diagnoses of melanoma and SCC were pathologically confirmed. Results: Tetracycline use was associated with a modestly increased risk of BCC (ncase=36 377), with a pooled hazard ratio (HR) of 1.11 (95% confidence interval (CI)=1.02-1.21, P-trend=0.05 by duration of use). Tetracycline use was not significantly associated with melanoma (ncase=1831, HR=1.09, 95% CI=0.94-1.27) or SCC (ncase=3332, HR=1.04, 95% CI=0.91-1.18) risk overall. However, we observed positive interactions between tetracycline use and adulthood UV exposure on SCC risk (P-interaction=0.05). Conclusion: Tetracycline use was associated with a modestly increased risk of BCC, but was not associated with melanoma or SCC.British Journal of Cancer advance online publication, 26 October 2017; doi:10.1038/bjc.2017.378 www.bjcancer.com.
... Phototoxicity is an acute reaction caused by damage initiated by the light-induced degradation of photoreactive or photoactive molecules. Because of the presence of chromophores in a drug's structure, their molecules absorb high-energy UV radiation which results in molecular changes or generates reactive oxygen species [122,123]. The active pharmaceutical substance or its metabolite must be present in the skin tissue during UV irradiation. ...
... Photoallergic reactions are rare, independent of dose, and appear after a few days of exposure to radiation. They are associated with the immune cell response, the drug or its degradation products act as haptens, via antigen presenting cells or T lymphocytes, which triggers an allergic reaction on repeated exposure [122][123][124][125]. Currently, the most appropriate test for the phototoxicity testing of soluble compounds is OECD TG 432 (in vitro 3T3 NRU phototoxicity test) [126]. ...
Article
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Topical treatment modalities have multiple advantages starting with the convenient application and non-invasive treatment and ending with the reduction of the risk of the systemic side effects. Active pharmaceutical substances must reach the desired concentration at the target site in order to produce a particular therapeutic effect. In contrast to other dosage forms topical agents applied to the skin may also be susceptible to photodegradation after application. That is why the knowledge of the susceptibility of these topical drugs to UV irradiation, which may contribute to their degradation or changes in chemical structure, is very important. Active pharmaceutical substances used in dermatology may differ both in chemical structure and photostability. Furthermore, various factors-such as light intensity and wavelength, pH, temperature, concentration-can influence the photodegradation process, which is reflected in particular in kinetics of photodegradation of active pharmaceutical substances as well as both the quantitative and qualitative composition of by-products. The aim of this study was to conduct a systematic review of the photostability of dermatological drugs, as well as of other substances commonly applied topically. The photostability of glucocorticosteroids, retinoids, and antifungal drugs as well as non-steroidal anti-inflammatory drugs applied topically and selected UV-filters have been discussed. Furthermore, the impact of photoinstability on the effectiveness of pharmacotherapy and some photostabilization strategies have been also included.
... We based potential confounder selection on data available in nationwide prescription, patient and education registries: (i) use of selected drugs with suggested photosensitizing properties, including oral retinoids, topical retinoids, tetracycline, macrolides, aminoquinolines and amiodarone [9,[25][26][27]; (ii) use of drugs with suggested cancer chemopreventive effects, including aspirin, nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) and statins [11]; (iii) history of diabetes, chronic obstructive pulmonary disease (COPD) and conditions associated with heavy alcohol consumption, derived from composite measures of hospital diagnoses and prescription use of disease-specific drugs (see Appendix S2); (iv) history of nonmelanoma skin cancer; (v) average Charlson Comorbidity Index (CCI) scores [28,29] (0 low; 1-2: medium; or ≥3: high), derived from diagnoses of 19 chronic conditions; and (vi) highest achieved education (short; medium; higher; unknown) as a measure of socio-economic status. Exposure to each potential confounder drug was defined as two or more prescriptions on separate dates, and hospital histories of each of the selected conditions were defined as a primary or secondary discharge or ambulatory diagnosis. ...
... Secondly, we performed subgroup analyses according to age and sex or with restriction to specific subsets of the study population: never-user of other photosensitizing drugs (as defined above); low comorbidity (CCI score = 0); no history of diabetes; or no history of nonmelanoma skin cancer. Thirdly, we repeated the main analyses for bendroflumethiazide, besides HCTZ the most frequently prescribed thiazide in Denmark, and for the loop diuretic furosemide that has been suggested to possess photosensitizing properties [9,[25][26][27]. In dose-response analyses of bendroflumethiazide, we used dose categories that were 10 times lower than for HCTZ because bendroflumethiazide is considered to be about 10 times as potent [30,31]. ...
Article
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Background: The diuretic hydrochlorothiazide is among the most frequently prescribed drugs in the United States and Western Europe, but there is suggestive evidence that hydrochlorothiazide use increases the risk of lip cancer. Objectives: To study the association between use of hydrochlorothiazide and squamous cell carcinoma of the lip. Methods: We conducted a case-control study using Danish nationwide registry data. From the Cancer Registry (2004-2012), we identified 633 case patients with squamous cell carcinoma (SCC) of the lip and matched them to 63,067 population controls using a risk-set sampling strategy. Hydrochlorothiazide use (1995-2012) was obtained from the Prescription Registry and defined according to cumulative use. Applying conditional logistic regression, we calculated odds ratios (ORs) for SCC lip cancer associated with hydrochlorothiazide use, adjusting for pre-defined potential confounders obtained from demographic, prescription, and patient registries. Results: Ever-use of hydrochlorothiazide was associated with an adjusted OR for SCC lip cancer of 2.1 (95% confidence interval (CI): 1.7-2.6), increasing to 3.9 (95%CI, 3.0-4.9) for high use (≥25,000 mg). There was a clear dose-response effect (p<0.001), with the highest cumulative dose category of hydrochlorothiazide (≥100,000 mg) presenting an OR of 7.7 (95%CI: 5.7-10.5). No association with lip cancer was seen with use of other diuretics or non-diuretic antihypertensives. Assuming causality, we estimated that 11% of the SCC lip cancer cases could be attributed to hydrochlorothiazide use. Conclusions: Hydrochlorothiazide use is strongly associated with an increased risk of lip cancer. This article is protected by copyright. All rights reserved.
... Също са докладвани разлики в чувствителността към доксициклин, ципрофлоксацин и рифампин при различните "хронични" изолати на Coxiella burnetii (65). Направена е in vitro селекция на щамове Coxiella burnetii, резистентни на тетрациклини (14). Въпреки това не са добре установени механизмите на антибиотична резистентност на Coxiella burnetii. ...
... Дългосрочното лечение с доксициклин и хидроксихлорохин не е без потенциални усложнения. И двете от тези лекарства могат да причинят фоточувствителност (14), а дългосрочната употреба на хидроксихлорохин може да доведе до ретинопатия (59). Съобщени са алергични реакции към двете лекарства (36). ...
... The mechanism through which fluoroquinolones causes phototoxicity has been studied extensively [32e36]; it is believed that fluoroquinolones mostly absorb UVA radiation more commonly than UVB radiation [37] leading to the formation of a reactive oxygen species which in turn causes cell damage and skin cell death [3,33,36e38]. This usually occurs within minutes to hours after exposure to sunlight and is clinically presented as an exaggerated sunburn with itching and burnings sensations localized on the sun-exposed areas, with severity ranging from mild to severe bullous reactions [39,40]. Generally, drug-induced phototoxicity is dose-dependent, meaning that if a patient receives a sufficiently high dose of the offending drug and is exposed to a high enough amount of solar radiations at the appropriate wavelength, phototoxicity will occur without requiring previous sensitization [1,39,41,42]. ...
... This usually occurs within minutes to hours after exposure to sunlight and is clinically presented as an exaggerated sunburn with itching and burnings sensations localized on the sun-exposed areas, with severity ranging from mild to severe bullous reactions [39,40]. Generally, drug-induced phototoxicity is dose-dependent, meaning that if a patient receives a sufficiently high dose of the offending drug and is exposed to a high enough amount of solar radiations at the appropriate wavelength, phototoxicity will occur without requiring previous sensitization [1,39,41,42]. Susceptibilities to these reactions are not well known, though it has been noted that the idiosyncratic nature of phototoxicity could be due to a reduced reactive oxygen species detoxification response in some individuals leading to variations in severity [6] and individual differences in drug metabolism and bioavailability [1]. Trakatelli et al. found that elderly patients are more susceptible to this type of reaction due to their use of many medications to treat chronic illnesses despite having lower sun exposure [43]. ...
Article
Lomefloxacin may be more likely than other fluoroquinolones to cause photosensitivity. However, the rate of photosensitivity is variable and a meta-analysis has yet to be performed. The aim of this meta-analysis is to compare the rate of photosensitivity between outpatients who received lomefloxacin and those who received other fluoroquinolones. PubMed, EMBASE, Cochrane Library databases and trial registries were searched for randomized controlled trials (RCTs) of outpatients through June 12, 2019. The study outcome was the rate of photosensitivity based on the intention-to-treat principle, estimated by risk difference (RD) as the primary analysis and Peto odds ratio (Peto OR) as the secondary analysis, with 95% confidence intervals (CIs) using random-effects models. Four RCTs (total of 2295 patients) were included in this meta-analysis. A statistically higher risk of photosensitivity was found with lomefloxacin than with other fluoroquinolones (RD, 3.4%; 95% CI, 0.7%-6.2%; P-value = 0.013; I2 = 10.9%). The odds of photosensitivity was also significantly higher with lomefloxacin (Peto OR, 5.81; 95% CI, 3.34 to 10.11; P-value <0.001; I2 = 0%). This meta-analysis of RCTs found significantly higher photosensitivity with lomefloxacin compared to other fluoroquinolones. Considering this finding and given its lack of additional efficacy compared to other fluoroquinolones, lomefloxacin as a fluoroquinolone option should potentially be reconsidered.
... A photosensitivity reaction is an adverse cutaneous reaction that occurs when a certain chemical or drug is applied topically or taken systematically at the same time that a person is exposed to ultraviolet radiation or visible light. That reaction is associated with distinct chemical structures of the drug that allow the absorption of UVR [6,7]. In phototoxic reactions the drugs may become activated by exposure to sunlight and cause direct tissue and cellular injury. ...
... Based on a review of the literature, cardiovascular drugs can be divided into photosensitizing (alpha-2 receptor agonists and thiazide diuretics), non-photosensitizing (alpha-blockers, beta-blockers, angiotensin receptor blockers [ARBs]) or undetermined (angiotensin-converting enzyme [ACE] inhibitors, calcium channel blockers) [5,6]. ...
Article
IntroductionActinic keratosis (AK) is a precancerous skin lesion. Currently, many experts treat actinic keratosis as squamous cell carcinoma in situ. It is well established that exposure of the skin to ultraviolet radiation is a major risk factor for the development of actinic keratosis. Some studies suggest an association between keratinocyte cancers and photosensitizing cardiovascular drugs. The aim of this study was to establish an association between cardiovascular drug use and the presence of AK.MethodsA total of 400 patients were enrolled into the study (200 with AK; 200 healthy persons in the control group). The group of patients with AK consisted of 106 women and 94 men (mean age 71 years). The control group included 102 women and 98 men (mean age 69 years). An analysis of the risk factors for developing actinic keratosis was performed in all patients with AK on the basis of a detailed, standardized interview.ResultsThe statistical analysis showed that features independently associated with increased risk of AK included: age > 80 years (OR 4.14; 95% CI 2.4–7.3), positive cancer history (OR 1.94; 95% CI 1.0–3.6), positive history of sunburns when < 18 years old (OR 2.18; 95% CI 1.3–3.7) and taking angiotensin-converting enzyme inhibitors (OR 2.28; 95% CI 1.2–4.3), angiotensin receptor AT1 blockers (OR 2.90; 95% CI 1.1–7.9) and calcium channel blockers (OR 2.4; 95% CI 1.0–5.3).Conclusion In conclusion, our study presented an association between cardiovascular drug use and the risk of developing AK.
... Numerous classes of drugs commonly used for the treatment of patients with HF have been associated with photo-induced, cutaneous drug eruptions, which are adverse effects that occur as a result of the exposure to a drug (and its presence in the skin) and ultraviolet or visible radiation 84 . Box 7 provides an overview of drugs that have been linked with drug-induced photosensitivity. ...
... Box 7 provides an overview of drugs that have been linked with drug-induced photosensitivity. Amiodarone can cause drug-induced photosensitivity in >50% of treated patients 84 . The typical presentation of this adverse effect is a burning and tingling sensation in sun-exposed skin, with associated erythema. ...
Article
Patients with heart failure are at a higher risk of cardiovascular events compared with the general population, particularly during domestic or international travel. Patients with heart failure should adhere to specific recommendations during travel to lower their risk of developing heart failure symptoms. In this Review, we aim to provide clinicians with a set of guidelines for patients with heart failure embarking on national or international travel. Considerations when choosing a travel destination include travel distance and time, the season upon arrival, air pollution levels, jet lag and altitude level because all these factors can increase the risk of symptom development in patients with heart failure. In particular, volume depletion is of major concern while travelling given that it can contribute to worsening heart failure symptoms. Pre-travel risk assessment should be performed by a clinician 4-6 weeks before departure, and patients should receive advice on potential travel-related illness and on strategies to prevent volume depletion. Oxygen supplementation might be useful for patients who are very symptomatic. Upon arrival at the destination, potential drug-induced photosensitivity (particularly in tropical destinations) and risks associated with the local cuisine require consideration. Special recommendations are needed for patients with cardiac implantable electronic devices or left ventricular assist devices as well as for those who have undergone major cardiac surgery.
... Drugs often associated with photosensitivity (eg tetracyclines, thiazides, chlorpromazine, amiodarone) were also elucidated by our study. 5,38,39 Although entecavir is not known to cause photosensitivity reactions, there were two such reports in our database, one of which was confirmed with skin biopsy showing deep perivascular dermatitis with eosinophils. The elderly patient was on entecavir for 5 months, and recovered 3 months after cessation of drug. ...
Article
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We analyzed the spontaneous adverse event database in Singapore to determine the types of cutaneous adverse drug reactions (CADRs) and causative drugs reported. We selected 10 CADRs‐of‐interest, and identified the suspected drugs and the characteristics of the at‐risk population. ADR reports received from 2006 to 2015 of the system organ class “Skin and Appendages Disorders” were analyzed based on patient demographics, the types of CADRs, suspected drugs, outcome, and latency period. Of the 104 372 reports analyzed, 56.2% involved females and 72.5% involved Chinese patients. The mean age was 41.1 years old. The top CADRs reported were rash (including nonspecified rash, follicular rash, maculopapular rash, and vesicular rash) (67.2%) and angioedema (13.9%). The drugs frequently associated with the CADRs‐of‐interest include nonsteroidal antiinflammatory drugs and antibiotics with angioedema, iohexol with urticaria, and antiepileptics and allopurinol with Stevens‐Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). A subgroup analysis based on age, sex, and race on the 10 CADRs‐of‐interest showed the following trends in reporting: Alopecia (reported more in females), drug hypersensitivity syndrome (more in males), angioedema (more in younger patients), and photosensitivity (more in older patients). In general, the racial distribution across each CADR‐of‐interest was consistent with that of Singapore's population, with slight deviations observed for SJS/TEN, photosensitivity and skin discoloration. We analyzed CADR reports from Singapore over 10 years, and identified the types of CADRs reported, and their associated drugs, latency periods and patient characteristics. Such information could add value to healthcare professionals as they assess CADR cases and evaluate suspected drugs.
... Cyclines, mainly doxycycline, were positively associated to DTCRs. While some case reports and case series demonstrate that cyclines could elicit DTCRs particularly FDE, DRESS and photosensitivity [28][29][30], our results should be cautiously considered as the reduced sample size, resulting in such wide confidence interval (1.4-84.9) and a lack of power to assess drugs accountability. ...
Article
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Purpose: To assess delayed-type cutaneous reactions (DTCRs) related to drugs, using a case-control approach to qualify drug risks. Methods: The study used the Tunisian pharmacovigilance database of Monastir. The association between drugs and DTCRs was assessed using a case/non-case method. Drugs were grouped according to the ATC Classification System. Patients were defined as "cases" if they have developed DTCRs regardless of the causality assessment. All other reports were "non-cases". Association between reactions and drugs was calculated using the reporting odds ratio (ROR) with 95% confidence intervals (CIs). A p value < 0.05 was considered significant. Results: The analysis was carried out on 1798 reports, of which 867 concerned DTCRs (cases) and 931 concerned non-cases. The calculated risk estimates were significant for cefotaxime (ROR 2.1; 95% CI 1.5 to 3), pristinamycin (ROR 4; 95% CI 2 to 7.9), sulfamethoxazole (ROR 4.4; 95% CI 1.6 to 11.7), oxacillin (ROR 2.2; 95% CI 1.2 to 3.8), doxycycline (ROR 10.8; 95% CI 1.4 to 84.9), carbamazepine (ROR 3.3; 95% CI 1.7 to 6.2), phenobarbital (ROR 2.3; 95% CI 1.03 to 5.1), allopurinol (ROR 3.6; 95% CI 1.8 to 7.2), furosemide (ROR 2.4; 95% CI 1.3 to 6.3), hydrochlorothiazide(ROR 2.9; 95% CI 1.3 to 6.3) and candesartan (ROR 4.7; 95% CI 1.3 to 16.6). Conclusion: Our findings corroborate risks for a number of drugs, such as antibacterials, antiepileptics and allopurinol in inducing DTCRs. Given the widespread use of these drug classes, awareness should be raised among patients and prescribers about these risks.
... Next, long-term treatment with doxycycline and hydroxychloroquine is not without potential complications. Drug-induced photosensitivity is a notorious adverse effect of doxycycline, and long-term use of hydroxychloroquine can lead to retinopathy [25,26]. Last, the cost-effectiveness of the screening has not been investigated. ...
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Background: Echocardiographic screening of acute Q-fever patients and antibiotic prophylaxis for patients with cardiac valvulopathy are considered an important approach to prevent chronic Q-fever-related endocarditis. During a large Q-fever epidemic in the Netherlands, routine screening echocardiography was discontinued, raising controversy in the international literature. We followed a cohort of acute Q-fever patients to estimate the risk for developing chronic Q-fever, and we evaluated the impact of screening in patients who were not yet known to have a valvulopathy. Methods: The study population consisted of patients diagnosed with acute Q-fever in 2007 and 2008. We retrospectively reviewed all screening echocardiographs and checked for development of chronic Q-fever eight years after the acute episode. Risks of developing chronic Q-fever in relation to the presence or absence of valvulopathy were analysed with logistic regression. Results: The cohort included 509 patients, of whom 306 received echocardiographic screening. There was no significant difference (p-value=0.22) in occurrence of chronic Q-fever between patients with a newly detected valvulopathy (2/84, 2.4%) and those with no valvulopathy (12/202, 5.9%). Two patients with a newly detected valvulopathy, who did not receive antibiotic prophylaxis, developed chronic Q-fever at a later stage. Conclusions: We found no difference in outcome between patients with and without a valvulopathy newly detected by echocardiographic screening. In retrospect, the two above-mentioned patients could have benefitted from antibiotic prophylaxis, but its omission must be weighed against the unnecessary large-scale and long-term use of antibiotics that would have resulted from universal echocardiographic screening.
... 9 However, in written literature severe skin reactions like erythema multiform, Stevens-Johnson syndrome (SJS); Lyell's Syndrome (Toxic Epidermal Necrolysis-TEN); Acute generalised exanthematous pustulosis (AGEP) caused by antidepressant including SSRIs, erythroderma, tanning, facial erythema, telangiectasia and photo distributed hyperpigmentation caused by only SSRI drugs have been reported. 5 In one case SJS/ TEN and in another case TEN was reported caused by fluoxetine. In another case hypersensitivity syndrome was reported. ...
... such as: hydrochlorothiazide and doxycycline. Based on their pathogenesis, they can be classified as phototoxic or photoallergic drug eruptions, although in many cases it is not possible to determine whether a particular eruption is due to a phototoxic or photoallergic mechanism (60). ...
Article
Adverse reactions to drugs are not frequent in childhood. Cutaneous reactions are the most frequent in this age group. Mild cutaneous reactions are immediate or delayed adverse reactions that do not seriously compromise the clinical condition of children. The patients usually early improve and recover the state of health. Although it is difficult to define the prevalence accurately, we could affirm that the rate adverse reaction to drugs are often over estimated by both the families and the physicians. Therefore, children may be prone to loss of school days and inappropriate or sub-optimal treatments. However, the identification of a true adverse reaction to drugs allows adequate treatment and alert to further exposure to harmful drugs.
... Doxycycline may be associated with photosensitivity, rash and erythrodermia. 32 Photosensitivity is the main dermatological side Review effect of doxycycline. A systematic review was recently available concerning phototoxicity related to doxycycline. ...
Article
Doxycycline is a second-generation tetracycline, available worldwide for half a century. It is an inexpensive broad-spectrum antimicrobial agent largely used in the management of several bacterial infections, particularly involving intracellular pathogens, as well as in the treatment of acne or for the prophylaxis of malaria. Physicochemical characteristics of doxycycline (liposolubility) allow a high diffusion in the tissues and organs. It has high bioavailability and a long elimination half-life allowing oral administration of one or two daily doses. Over the last decade, the prevalence of bacterial sexually transmitted infections (STIs) (syphilis, chlamydiosis, gonorrhoea and Mycoplasma genitalium infections) has increased in most countries, mainly in MSM, many of whom are infected with HIV. In light of increasing prevalence of resistance towards first-line regimens of some STI agents and recently updated recommendations for STI management, doxycycline appears to be an attractive option compared with other available antibiotics for the treatment of some STIs due to its efficacy, good tolerability and oral administration. More recently, indications for doxycycline in STI prophylaxis have been evaluated. Considering the renewed interest of doxycycline in STI management, this review aims to update the pharmacology of, efficacy of, safety of and resistance to doxycycline in this context of use.
... Photosensitive drug reactions occur when an exogenous chemical substance interacts with UV or visible radiation to produce cutaneous disease [1]. Over 300 drugs have been associated with photosensitivity [2]. ...
Article
Photosensitive drug reactions resulting in hyperpigmentation occur when there is an accumulation in the skin of melanin, heavy metals, or the drug itself. Herein we describe an immunocompromised orthotopic liver transplant patient with levofloxacin-induced hyperpigmentation with iron deposition. To identify the causal agent, consideration was given to medications the patient had taken long-term, as well as medications introduced more recently before the event. Levofloxacin and posaconzole emerged as the most likely culprit drugs, neither of which have a strong history in the literature of being associated with photosensitive hyperpigmentation. Levofloxacin was determined to be the culprit drug when the hyperpigmentation gradually resolved several weeks after discontinuation of levofloxacin, with continuation of posaconazole and all other long-term medications. This case highlights the challenges in identifying the causal agent in photosensitive drug reactions when patients are taking multiple medications. Key clinical data can be very helpful in making an assessment.
... All absorb UV and/or visible radiation, a characteristic that is essential for the chemical to be regarded as a photosensitizer. Some of the common ones include: 6. Psychiatric drugs: chlorpromazine (Thorazine), tricyclic antidepressants such as desipramine (Norpramin) and imipramine (Tofranil) 7. Acne medications: isotretinoin (Accutane) [20][21][22][23][24], [34]. (Figure 6) (Exhibit 5& 6) gene expression profile of skin at this time is characterized by increased expression of skin barrier genes, which help to repair the epidermal barrier and attenuate the inflammatory insult. ...
Preprint
The sunscreen industry is achieving remarkable worldwide prominence by responding to the growing need for skin protection with fast-paced innovation. Increased consumer awareness of the harmful effects of sunlight has fueled the demand for improved photo protection. The need for broad-spectrum protection from both UVA and UVB rays has inspired scientists worldwide to research new cosmetic formulations and delivery systems. More effective sunscreen actives, emollients and novel cosmetic and functional ingredients have been regularly added to the formulator’s repertoire. Creativity in innovation has been hindered only by regulatory agencies and patent restrictions worldwide. Familiarity with the current restrictive regulations and patent law infringements has become integral to any research effort attempting to provide improved protection to individuals affected by the sun’s damaging effects. The increasing incidence of skin cancers and photo damaging effects caused by ultraviolet radiation has increased the use of sun screening agents, which have shown beneficial effects in reducing the symptoms and reoccurrence of these problems. Unlike the situation in Europe where sunscreen ingredients are considered under cosmetics guidelines, the FDA is required to define sunscreens as drugs since they are advertised to prevent sunburn and, more recently, the risk of skin cancer. In the USA, the FDA has been regulating this industry since August 25, 1978, with the publication of the Advance Notice of Proposed Rulemaking. Sunscreens are considered drugs and cosmetics and therefore must be governed by the FDA-OTC monograph. With the variety of sunscreen agents used in cosmetic and UV protection products, Australia, Canada, and the European Union (EU) have also developed regulatory protocols on safe sunscreen product use. Unlike the USA though, Australia has approved 34 active sunscreen ingredients and the EU has approved 28 of these ingredients. Current FDA regulations allow labeling of sunscreen products to a maximum of 30þ, despite the many products currently available with numbers as high as 100. From a cosmetic formulation point of view, increasing the SPF number in a product is governed by simple chemical principles.
... It relies on assessing the viability of 3T3 fibroblasts exposed to test chemical in the presence and absence of light. Phototoxic compounds such as CPZ, amiodarone, protoporphyrin IX, norfloxacin, and anthracene described in NRU 3T3 PT test guideline are also known to act as photoallergens (Drucker and Rosen, 2011). Prior to 24 h incubation, Lys-and Cys-heptapeptides were exposed to 5 J/cm 2 UVA in the presence of test chemical. ...
Article
Full-text available
Chemical substances that induce an allergic response in skin upon contact are called skin allergens or sensitizers, while chemical substances that elicit an allergic response only in presence of light are called photoallergens or photo sensitizers. The Direct Peptide Reactivity Assay (DPRA, OECD N⁰ 442C, 2015) and the Amino Acid Derivative Reactivity Assay (ADRA) are in chemico assays used to discriminate between allergens and non-allergens. The DPRA and the ADRA, respectively, monitor the depletion of model peptides and modified amino acids induced by crosslinking with test chemicals. In the current study we compared these two assays and analyzed their suitability to predict skin sensitization potential of several chemical substances. In order to study the combined effect of a chemical compound and UV light, we modified DPRA (photo-DPRA) as well as ADRA (photo-ADRA) by introduction of a photo-irradiation parameter. Analysis using photo-DPRA and photo-ADRA correctly distinguished known photoallergens from non-photoallergens. Upon irradiation, photoallergens selectively showed higher depletion of model peptides or modified amino acids. Thus, photo-DPRA and/or photo-ADRA can serve as non-animal in vitro methods for the identification and assessment of photoallergens/ photosensitizers.
... Thus, the following AEDs were included: Carbamazepine, clonazepam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, topiramate, and valproic acid. Of these, AEDs with potential photosensitizing properties were identified from drug labels (19-22), a clinical database of druginduced skin eruptions (8), book chapters or reviews on photosensitizing drugs (23)(24)(25)(26), animal tests (27), clinical tests (28)(29)(30), and photochemical properties (31,32). On this basis, we classified carbamazepine, gabapentin, lamotrigine, oxcarbazepine, phenobarbital, phenytoin, pregabalin, topiramate, and valproic acid as photosensitizing. ...
Article
Background: Several antiepileptic drugs are photosensitizing; however, it is not known whether this confers an increased risk of skin cancer. Objective: To examine the association between common antiepileptic drugs and basal cell carcinoma, squamous cell carcinoma (SCC), and malignant melanoma. Methods: We conducted a nested case-control study identifying skin cancer patients in Denmark from 2004 through 2015 matched 1:10 with disease-free controls. We estimated odds ratios (ORs) for skin cancer associated with high cumulative use of antiepileptic drugs (≥500 defined daily doses) compared with nonuse. Results: Most antiepileptic drugs were not associated with skin cancer. SCC was associated with use of carbamazepine (OR, 1.88; 95% confidence interval, 1.42-2.49) and lamotrigine (OR, 1.57; 95% confidence interval, 1.12-2.22) with evidence of a dose-response relationship for carbamazepine. The estimated absolute risks were low; for example, 6335 person-years of high cumulative exposure to carbamazepine were required for 1 additional SCC to occur. Limitations: Data on important risk factors for skin cancer, such as sun exposure, were not available. Conclusions: Most antiepileptic drugs were not associated with skin cancer; however, carbamazepine and lamotrigine were associated with SCC. These findings need to be replicated and characterized further in other settings and have no direct clinical implications.
... This is considered a Th1 response with effector T-cell involvement and production of interferon gamma (IFN-γ), IL-12, and other cytokines and chemokines. 92,102,103 Type IVb: MPE is the classical entity with activated T cells, CD4, and CD8, which home to the skin and form a perivascular infiltrate that can be accompanied by eosinophils and neutrophils. Activated T cells are present with the expression of several activation markers and production of IL-4 and IL-5. ...
Article
Full-text available
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the leading cause of hypersensitivity drug reactions. The different chemical structures, cyclooxygenase 1 (COX-1) and/or COX-2 inhibitors, are taken at all ages and some can be easily obtained over the counter. Vasoactive inflammatory mediators like histamine and leukotriene metabolites can produce local/systemic effects. Responders can be selective (SR), IgE or T-cell mediated, or cross-intolerant (CI). Inhibition of the COX pathway is the common mechanism in CI, with the skin being the most frequent organ involved, followed by the lung and/or the nose. An important number of cases have skin and respiratory involvement, with systemic manifestations ranging from mild to severe anaphylaxis. Among SR, this is the most frequent entity, often being severe. Recent years have seen an increase in reactions involving the skin, with many cases having urticaria and/or angioedema in the absence of chronic urticaria. Aspirin, the classical drug involved, has now been replaced by other NSAIDs, with ibuprofen being the universal culprit. For CI, no in vivo/in vitro diagnostic methods exist and controlled administration is the only option unless the cases evaluated report repetitive and consistent episodes with different NSAIDs. In SR, skin testing (patch and intradermal) with 24-48 reading can be useful, mainly for delayed T-cell responses. Acetyl salicylic acid (ASA) is the test drug to establish the diagnosis and confirm/exclude CI by controlled administration. Desensitization to ASA has been extensively used in respiratory cases though it can also be applied in those cases where it is required.
... Długoterminowa i wysokodawkowa terapia tiorydazyną może prowadzić do wystąpienia przebarwień skórnych w zakresie barw od szarej do fioletowej [19]. Z kolei, w przeciwieństwie do chlorpromazyny, reakcje nadwrażliwości na światło są mniej powszechne, rzadziej dochodzi do zmian pigmentacyjnych w obrębie rogówki i soczewki, natomiast częściej dochodzi do uszkodzenia nabłonka barwnikowego siatkówki [20,35]. Istotną rolę odgrywa tu fakt, że zarówno chlorpromazyna jak i tiorydazyna ulegają hydroksylacji w pozycji 3 i 7 pierścienia fenotiazynowego. ...
Thesis
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Impact of phenothiazine derivatives on melanogenesis and antioxidant status of normal melanocytes Phenothiazine derivatives are used in the treatment of schizophrenia, but also have antihistamine, antitussive and antiemetic activities. There have been appeared numerous articles for last ten years on new biological properties of phenothiazines, among them anticancer, antibacterial, antiviral, antiprionic activity and modifying multidrug resistance. The mechanism of phenothiazines action includes the ability to interact with dopamine (D1 and D2) adrenergic (α1 and α2), histamine (H1), muscarinic (M1) and serotonergic (5HT1A and 5HT2A) receptors. Unfortunately, phenothiazine derivatives treatment entails a whole range of side effects, including changes in skin and ocular pigmentation, especially in case of long-term and/or high-dose therapy. Melanocytes are present in the skin, hair, eyes, inner ear, brain, heart, lung and adipose tissue, where as specialized, dendritic, pigmented cells play an important physiological role. They produce melanin pigment in multistage and complex process called melanogenesis. Melanin determines the colour of the skin, hair and eyes, protects against UV radiation and also has the ability to bind metal ions, drugs as well as to scavenge free radicals including reactive oxygen species. The melanogenesis process is regulated by many physical and biochemical factors like UV radiation, cyclic adenosine monophosphate and microphthalmia-associated transcription factor (MITF), which is involved in regulation of proliferation and differentiation of melanocytes. It has been established that free radicals can be both harmful and beneficial for cells depending on the environment. Beneficial effects of free radicals involve the important physiological role as regulatory mediators in cellular growth, proliferation, differentiation and apoptosis. In contrast, at high concentrations, free radicals can lead to oxidative stress damaging cell structures, including lipids and membranes, proteins and nucleic acids. The cellular response to oxidative stress includes non-enzymatic agents and antioxidant enzymes, among them the most important are superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). The aim of this study was to evaluate the effect of phenothiazine derivatives on biochemical processes in normal human melanocytes. Two key biochemical processes were evaluated in this study: melanogenesis as well as the process of oxidative stress induction and free radicals scavenging. In order to achieve this purpose cellular viability, melanin content, MITF protein content, tyrosinase activity as well as antioxidant enzymes: SOD, CAT, GPx activity and hydrogen peroxide content, were determined. On the basis of the obtained results it was found that viability of normal human epidermal melanocytes cultured in the presence of phenothiazine derivatives decreased with increasing drug concentration. Taking into account the determined EC50 values, cytotoxicity order of the analyzed drugs can be presented as follows: fluphenazine (1,24μM) > thioridazine (2,24μM) ≥ chlorpromazine (2,53μM) ≥ perphenazine (2,76μM) >> prochlorperazine (18,49μM). It has been stated that chlorpromazine, prochlorperazine and thioridazine in low concentrations (0,0001μM, 0,001μM) stimulate melanogenesis in normal melanocytes, while fluphenazine, perphenazine, prochlorperazine, and thioridazine in higher concentrations (≥1μM) decrease tyrosinase activity, melanin and MITF protein content. Furthermore, it has been demonstrated that all analyzed phenothiazine derivatives in concentrations ≥0,01μM are able to generate oxidative stress in normal human epidermal melanocytes. They cause an increase in SOD activity and H2O2 content, decrease in CAT activity and modulation of GPx activity. The changes in level of cell viability as well as in melanogenesis process and antioxidant status of normal human melanocytes in response to phenothiazine derivatives treatment may explain the role of melanin and oxidative stress in the mechanisms of phenothiazines side effects directed to pigmented tissues. Key words: phenothiazine derivatives, melanin, tyrosinase, MITF, SOD, CAT, GPx, H2O2
... These included medicines with known photosensitising properties including oral and topical retinoids, macrolides, tetracycline, aminoquinolines and amiodarone; as well as medicines with possible anticancer properties including prescription strength aspirin, non-steroidal anti-inflammatories (NSAIDs) and statins. 12,26 We defined use of these potential confounding medicines as at least two dispensings on different dates prior to the index date and excluded any dispensings occurring in the 12 months prior to the index date. 12 We further ascertained comorbidity burdens using the Charlson comorbidity index applied to hospitalisation records, 27 again excluding records occurring within 12 months of the index date. ...
Article
Recent European and US studies reported increased risks of skin cancers associated with hydrochlorothiazide (HCTZ) treatment. Our study aimed to determine the risk of lip cancer and malignant melanoma among Australians prescribed HCTZ. We conducted a case‐control study nested within a population of veterans residing in New South Wales in 2004‐2015, using Australian Department of Veterans’ Affairs data linked with cancer registrations, hospitalisation and prescription dispensings. Among DVA healthcare card holders 65 years and older, we identified incident cases of squamous cell carcinoma of the lip and of cutaneous melanoma, each matched with up to 20 controls through risk‐set sampling. We estimated odds ratios (ORs) associating HCTZ use with each cancer using conditional logistic regression, adjusting for predefined confounders. For lip cancer (45 cases), ever‐use of HCTZ yielded an OR of 2.6 (95%CI: 1.4 – 5.0) and high HCTZ use (≥25,000mg) an OR of 4.7 (95%CI: 1.6 – 13.7). For cutaneous melanoma (659 cases), ever‐use of HCTZ resulted in an OR of 1.2 (95%CI 1.0 – 1.5) and high HCTZ use in an OR of 1.2 (95%CI: 0.8 – 1.8). Our findings align with risk estimates from previous studies and provide further evidence that HCTZ’s photosensitising properties may promote carcinogenesis in sun‐exposed tissues.
... Photoallergic reactions can be confirmed by photopatch testing. Because most drugs causing photoallergy do so in collaboration with UVA wavelengths, the latter spectrum is (for practical purposes) the only one used for phototesting suspected photoallergic patients [28]. ...
Article
Full-text available
Purpose of review: The photodermatoses represent a group of disorders of sensitivity to light that continue to pose difficulties in diagnosis and management. Photodermatoses are of interest to allergists because many photosensitive skin disorders have immunologic underpinnings, and patients often present to clinic complaining of "allergy" to the sun. We provide a concise reference for allergists on the clinical recognition and management of photodermatitis. Recent findings: New developments in the understanding of immunomodulatory effects of light have demonstrated normally immunosuppressive responses in the skin to light exposure, and a blunted immunosuppressive response in the pathogenesis of many photodermatoses. Vitamin D plays an important role in immunomodulation and itself may be affected by photodermatoses due to the impact of photoprotective treatment strategies on circulating vitamin D levels. The elucidation of the immunological basis of many photodermatoses may provide guidance for developing new treatment modalities. Further research is necessary to determine the optimal management of vitamin D metabolism in patients with photodermatoses.
... Once the eruption has occurred, it may be necessary to discontinue that medication and treat the eruption with a potent topical corticosteroid. 11,12 ...
Article
Full-text available
p class="abstract"> Drugs are the central part of treatment of various disorders. The consequence of drug use may be either positive outcomes (clinical effect of the drug) or negative outcomes (adverse drug events). That is, it contains both risk and benefit. In recent years multiple disorders treated with many drugs by monotherapy or by fixed-dose therapy existing in the market which leads to increased drug-related problems one among that is drug-induced disorders. Morbidity and mortality have increased due to drug-induced disorders. This study was aimed to describe the various drugs induces skin disorders, its pathophysiology, diagnosis and treatment approach. We completed a review of the current evidence for various drug-induced skin disorders its causative drugs and therapeutic intervention of drug-induced skin disorders. A review through Medline, Embase, Pubmed, Wiley online library and selected studies related to drug-induced skin disorders. This is the comprehensive review of drug- induced skin disorders, designed to address prospectively its etiopathogenesis and clinical management. Penicillin, sulfa, phenyl-butazone, Tetracycline are the most common drug induces various skin disorders. There is not much significant differences in the clinical, histopathological or immuno-pathological features between various skin disorders and drug induced skin disorders. Hence knowing the etiopathology, and differential diagnosis is important to a proper treatment approach. </p
... The list of agents known to cause photosensitivity is extensive. Antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), diuretics, retinoids, hypoglycaemics and anticonvulsants are notable examples of drugs that can cause dermatoses in sun-exposed areas [4][5][6][7][8] . ...
Article
Full-text available
Drug-induced photosensitivity reactions are significant adverse effects. Ketoprofen is one of the most common drugs that can cause skin rash in sun-exposed areas. Non-steroidal anti-inflammatory drugs (NSAIDs), such as ketoprofen, are often used for a variety of symptoms, including pain and fever. An understanding of the presentation and clinical course of ketoprofen-induced photosensitivity is necessary to correctly diagnose and manage this condition. Ketoprofen-induced photosensitivity reactions usually present as photoallergic dermatitis, which is a cell-mediated immune process. The benzophenone moiety in ketoprofen plays a major role in ketoprofen′s ability to act as a photosensitizer. Several agents, such as fenofibrate and octocrylene have been found to be associated with aggravation of ketoprofen-induced photoallergic dermatitis or cross-photosensitization, and these reactions result from structural similarities with ketoprofen. Treatment of ketoprofen-induced photoallergic dermatitis includes discontinuation of ketoprofen, topical or systemic corticosteroids and avoidance of sun exposure and agents known to exacerbate dermatitis. In conclusion, photoallergic dermatitis is a significant adverse effect of ketoprofen. Some agents known to worsen dermatitis may be found in sun protection products (notably, octocrylene in sunscreen). Educating the patient to avoid these products is critical to treatment. Since NSAIDs, such as ketoprofen, are used commonly for a variety of illnesses, drug-induced photoallergic dermatitis should be high on the differential in individuals using these medications who present with acute onset of a rash in sun-exposed areas.
... 68 Tetracyclines Tetracyclines can induce photosensitive dermatitis and esophageal irritation. 73 They have not been convincingly shown to induce clinically significant IgE-mediated allergy or T-cellemediated hypersensitivity. Drug challenge is generally successful. ...
Article
Full-text available
Antibiotics are the most common class of medications that individuals report allergy or intolerance to. Adverse reactions are reported at a predictable rate with all antibiotic use that vary by antibiotic. Antibiotic allergy incidence rates are sex dependent, higher in females than in males. Most of these events are not reproducible or immunologically mediated. Antibiotic allergy prevalence increases with increasing age and is more common in hospitalized populations and in populations that use more antibiotics. Determining potential mechanisms for the observed symptoms of the adverse reactions is the starting point for effective management of antibiotic hypersensitivity. Skin testing and direct challenges are the primary tools used to determine acute tolerance in 2017. Commercially available in?vitro testing is not currently clinically useful in determining antibiotic hypersensitivity, with rare exceptions. Desensitization can be used when acute-onset immunologically mediated hypersensitivity is confirmed to safely administer a needed antibiotic. Desensitization is not possible when clinically significant T-cell-mediated delayed-type hypersensitivity is present. Effective management of antibiotic allergy is an important part of a comprehensive antibiotic stewardship program.
... Diabetes drugs: sulfonylureas such as chlorpropamide (Diabinese), glyburide (Micronase, DiaBeta, Glynase) Psychiatric drugs: chlorpromazine (Thorazine), tricyclic antidepressants such as desipramine (Norpramin) and imipramine (Tofranil) Acne medications: isotretinoin (Accutane) [53][54][55][56][57][58], (Figure 6) (Exhibit 5, 6). ...
Book
The sunscreen industry is achieving remarkable worldwide prominence by responding to the growing need for skin protection with fast-paced innovation. Increased consumer awareness of the harmful effects of sunlight has fueled the demand for improved photo protection. The need for broad-spectrum protection from both UVA and UVB rays has inspired scientists worldwide to research new cosmetic formulations and delivery systems. More effective sunscreen actives, emollients and novel cosmetic and functional ingredients have been regularly added to the formulator’s repertoire. Creativity in innovation has been hindered only by regulatory agencies and patent restrictions worldwide. Familiarity with the current restrictive regulations and patent law infringements has become integral to any research effort attempting to provide improved protection to individuals affected by the sun’s damaging effects. The increasing incidence of skin cancers and photo damaging effects caused by ultraviolet radiation has increased the use of sun screening agents, which have shown bene􀏐icial effects in reducing the symptoms and reoccurrence of these problems. Unlike the situation in Europe where sunscreen ingredients are considered under cosmetics guidelines, the FDA is required to de􀏐ine sunscreens as drugs since they are advertised to prevent sunburn and, more recently, the risk of skin cancer. In the USA, the FDA has been regulating this industry since August 25, 1978, with the publication of the Advance Notice of Proposed Rulemaking. Sunscreens are considered drugs and cosmetics and therefore must be governed by the FDA-OTC monograph. With the variety of sunscreen agents used in cosmetic and UV protection products, Australia, Canada, and the European Union (EU) have also developed regulatory protocols on safe sunscreen product use. Unlike the USA though, Australia has approved 34 active sunscreen ingredients and the EU has approved 28 of these ingredients. Current FDA regulations allow labeling of sunscreen products to a maximum of 30þ, despite the many products currently available with numbers as high as 100. From a cosmetic formulation point of view, increasing the SPF number in a product is governed by simple chemical principles
Article
Background: Many antihypertensive drugs (ADs) are photosensitizing, heightening reactivity of the skin to sunlight. Photosensitizing ADs have been associated with lip cancer, but whether they impact the risk of cutaneous squamous cell carcinoma (cSCC) is unknown. Objectives: To examine the association between AD use and cSCC risk among a cohort of non-Hispanic white individuals with hypertension enrolled in a comprehensive integrated healthcare delivery system in northern California (n = 28 357). Methods: Electronic pharmacy data were used to determine exposure to ADs, which were classified as photosensitizing, nonphotosensitizing or unknown, based on published literature. We identified patients who developed a cSCC during follow-up (n = 3010). We used Cox modelling to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). Covariates included age, sex, smoking, comorbidities, history of cSCC and actinic keratosis, survey year, healthcare utilization, length of health plan membership and history of photosensitizing AD use. Results: Compared with nonuse of ADs, risk of cSCC was increased with ever having used photosensitizing ADs (aHR = 1·17, 95% CI 1·07-1·28) and ever having used ADs of unknown photosensitizing potential (aHR = 1·11, 95% CI 1·02-1·20), whereas no association was seen with ever having used nonphotosensitizing ADs (aHR = 0·99; 95% CI 0·91-1·07). Additionally, there was a modest increased risk with an increased number of prescriptions for photosensitizing ADs (aHR = 1·12, 95% CI 1·02-1·24; aHR = 1·19, 95% CI 1·06-1·34; aHR = 1·41, 95% CI 1·20-1·67 for one to seven, eight to 15 and ≥ 16 fills, respectively). Conclusions: These findings provide moderate support for an increased cSCC risk among individuals treated with photosensitizing ADs.
Chapter
The ultraviolet radiation (UVR) spectrum is divided into three parts, each having different effects on the skin, although UVC does not penetrate the ozone layer of the atmosphere and is therefore currently irrelevant to skin disease. UVR is nonionizing, but changes the skin by reacting with endogenous light-absorbing chemicals (chromophores), which include DNA, RNA, urocanic acid and melanin. Clinically, UVR is helpful in the treatment of diseases such as psoriasis and eczema, but at the same time use of tanning lamps, particularly by young people, increases the risk of developing melanoma and non-melanoma skin cancers. UVB penetrates the epidermis and superficial dermis, stimulating the production and release of prostaglandins, leukotrienes, histamine, interleukin 1 (IL-1) and tumour necrosis factor a (TNF-a). Drugs, topical or systemic, and chemicals on the skin, can interact with UVR and cause immunological reactions.
Chapter
Class III antiarrhythmic drugs include amiodarone, bretylium, dofetilide, ibutilide, azimilide, and dronedarone. Among these, amiodarone is the most reported one to cause adverse cutaneous reactions. Amiodarone is a lipid soluble agent which accumulates in peripheral tissues including the adipose tissue, and the skin is one of the excretion ways of the drug. It has a very long half-life, up to 6 months, so it is stated that toxic side effects may also be seen after the withdrawal of the drug. It is associated with many cutaneous side effects such as photosensitivity and pigmentation being the well-known ones.
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Photodermatology
Article
Purpose of review: NSAIDs are the drugs most frequently involved in hypersensitivity reactions (HSR). These are frequently prescribed at all ages. HSR are of great concern and can affect people at any age. These drugs can induce reactions by stimulating the adaptive immune system (IgE or T cell), known as selective responders or more frequently by abnormalities in biochemical pathways related with prostaglandin metabolism. These are known as cross-intolerant. With some exceptions, skin testing and in-vitro studies are of little value in selective responders. Recent findings: In the last years, several classifications have been provided based on clinical symptoms, time interval between drug intake and appearance of symptoms, response to other nonchemically related NSAIDs and the diseases. Based on this classification, several well differentiated categories within each group of entities cross-intolerant and selective responders are now recognized. The most complex groups for evaluation are cross-intolerant in which three major groups exist: NSAIDs exacerbated respiratory disease, NSAIDs exacerbated cutaneous disease and NSAIDs-induced urticaria/angioedema in the absence of chronic spontaneous urticaria. Within the selective responders, there are two mechanisms involved: drug-specific IgE or T-cell effector responses. New entities have been added to this classification like mixed reactions within the cross-intolerant category, that must manifest as anaphylaxis and multiple immediate selective reactions. Summary: The precise evaluation of patients with NSAIDs hypersensitivity following established guidelines will improve not only our understanding but also the management of these entices. As the number of patients affected with NSAIDs is important, further studies are warranted.
Article
en Linked Article: Su et al. Br J Dermatol 2018; 179:1088–1094.
Article
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Antecedentes: Se desconoce el mecanismo inmunológico implicado en la reacción a la hidroclorotiazida, de amplio uso para el control de la hipertensión arterial. El corto periodo de latencia entre la toma del fármaco y la aparición de síntomas sugiere hipersensibilidad inmediata. Reporte de caso: Mujer de 63 años con hipertensión arterial quien en tres ocasiones presentó náuseas, vómitos, malestar general, tiritona, artralgias, sensación distérmica, dolor lumbar de características mecánicas y tos escasa no productiva, así como fiebre y opresión torácica con incremento de la disnea y desaturación hasta de 88 %, tras la toma de hidroclorotiazida. Conclusiones: La presentación clínica en la paciente fue similar a choque séptico, reacción alérgica rara cuyo diagnóstico es clínico Este tipo de reacción podría deberse a hipersensibilidad tipo III debido a la formación de inmunocomplejos. Evitar el fármaco implicado es clave para la buena evolución.
Article
Arterial hypertension is the most frequent cardiovascular risk factor in the cancer patients. Anti-cancer therapy very often induces arterial hypertension and the treatment with antihypertensive medications is inevitable. Additionally, anti-cancer therapy frequently induces cardiotoxicity that has been treated or even could be prevented by use of antihypertensive medications – primarily angiotensin converting enzyme inhibitors and beta-blockers. The association between antihypertensive drugs and cancer is matter of large debate in the last several years because of the conflicting results from available studies ranging from adverse to beneficial effect of various antihypertensive classes. The mechanisms of the relationship between antihypertensives and cancer are still in domain of hypothesis. Some studies described the association between different antihypertensive groups and malignancies. There are investigations that denied negative effects of antihypertensive medications on cancer occurrence, recurrence, cancer-related complications and mortality. On the other hand, there are researches that reported a beneficial effect of antihypertensive medication by decreasing mortality in the cancer patients. One should be aware of the discrepancy of investigated antihypertensives in these researches and heterogeneity of included patients - different age, cancer type, comorbidities, demographic characteristics, and anti-cancer therapy. This comprehensive review article aimed to summarize the current knowledge regarding the relationship between antihypertensive medications and cancer.
Article
Background Glutathione S‐transferases (GSTs) play a critical role in cellular protection against oxidative damage. Polymorphisms in three major GST loci have been described. A number of studies have looked for an association between GSTs and skin diseases. Purpose To ascertain the possibility that polymorphisms in the GSTM1, GSTT1 and GSTP1 genes may predict the development of photo‐induced and non‐photo‐induced drug eruptions. Methods A cohort of 40 patients with drug eruptions, 10 of whom had developed a photo‐induced drug reaction, and matched controls (116 for GSTM1 and GSTT1, 120 for GSTP1) were studied. Genotyping was conducted using direct sequencing and polymerase chain reaction. Results The GSTP1 Val/Val genotype was significantly associated with non‐photosensitive drug eruptions (OR=3.64, p value=0.038), whereas associations observed between GSTP1, GSTM1, GSTT1 polymorphisms and photosensitive drug eruptions did not reach statistical significance. Conclusions Variations in GSTP1 may affect the risk to develop non‐photo‐induced drug eruptions. These results warrant confirmatory studies in a larger patient sample.
Article
Photosensitive drug eruptions are cutaneous adverse events due to exposure to a medication and either ultraviolet or visible radiation. In this review, the diagnosis, prevention and management of drug-induced photosensitivity is discussed. Diagnosis is based largely on the history of drug intake and the appearance of the eruption primarily affecting sun-exposed areas of the skin. This diagnosis can also be aided by tools such as phototesting, photopatch testing and rechallenge testing. The mainstay of management is prevention, including informing patients of the possibility of increased photosensitivity as well as the use of appropriate sun protective measures. Once a photosensitivity reaction has occurred, it may be necessary to discontinue the culprit medication and treat the reaction with corticosteroids. For certain medications, long-term surveillance may be indicated because of a higher risk of developing melanoma or squamous cell carcinoma at sites of earlier photosensitivity reactions. A large number of medications have been implicated as causes of photosensitivity, many with convincing clinical and scientific supporting evidence. We review the medical literature regarding the evidence for the culpability of each drug, including the results of phototesting, photopatch testing and rechallenge testing. Amiodarone, chlorpromazine, doxycycline, hydrochlorothiazide, nalidixic acid, naproxen, piroxicam, tetracycline, thioridazine, vemurafenib and voriconazole are among the most consistently implicated and warrant the most precaution by both the physician and patient.
Article
Not uncommonly, pathologists encounter biopsies displaying inflammation at the dermoepidermal junction and confronted with its numerous diagnostic possibilities. As with other inflammatory dermatoses, the correct diagnosis relies on careful integration of clinical, laboratory, and histopathological features. Knowledge of clinical aspects of these disorders is crucial, and at times, lack of training in clinical dermatology can make clinicopathological correlation challenging for the pathologist. This review is organized following the classical classification of cell-poor (vacuolar) and cell-rich (lichenoid) interface processes. The various entities are described based on their clinical presentation along their clinical differential diagnosis followed by their histopathological features and pathological differential diagnosis. Our aim is to provide an updated, clinically relevant review that integrates nuanced clinical and pathological features, with an emphasis on clues that may help differentiate entities in the differential diagnosis.
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Background: Drug-induced photosensitivity refers to the development of cutaneous adverse events due to interaction between a pharmaceutical compound and sunlight. Although photosensitivity is a very commonly listed side effect of systemic drugs reliable data on its actual incidence are lacking so far. Objectives: A possible approach to evaluate the real-life extent of drug-induced photosensitivity would be an analysis of the frequency of exposure to a given photosensitizing drug combined with an indicator of its photosensitizing potential. This could serve as a basis for developing a pharmaceutical 'heatmap' of photosensitivity. Methods: The presented study investigated the number of reimbursed dispensed packages of potentially photosensitizing drugs in Germany (DE) and Austria (AT) between 2010 and 2017 based on nationwide health insurance-based databases. In addition, an indicator for the photosensitizing potential was established for each drug based on the number of reports on photosensitivity in literature. Results: This analysis includes means of 632.826.944 (+/-14.894.918) drug dispensings per year in DE and 113.270.754 (+/-1.964.690) in AT. Out of these, the mean percentage of drugs that enlist photosensitivity as a potential side effect was 49,5% (+/- 0,7)% in DE and 48,2% (+/- 1,2) in AT. When plotting the number of reimbursed dispensed packages versus the number of reports on photosensitivity two categories of drugs show high numbers for both parameters, that is diuretics and non-steroidal anti-inflammatory drugs (NSAIDs). Conclusions: Diuretics and NSAIDs appear to be responsible for the greatest part of exposure to photosensitizing drugs with potential implication on public health.
Article
The antihypertensive agent hydrochlorothiazide has been associated with increased risks of non-melanoma skin cancer (NMSC) and possibly some melanoma subtypes. Previous studies were, however, conducted in predominantly Caucasian populations. We therefore examined the association between hydrochlorothiazide and skin cancer risk in an Asian population. By using Taiwan’s National Health Insurance Research Database (NHIRD), we conducted three separate case–control studies of lip cancer, non-lip non-melanoma skin cancer and melanoma. Cases (n = 29,082) with a first-ever skin cancer diagnoses (2008–2015) were matched 1:10 to population controls. We estimated odds ratios (ORs) associating hydrochlorothiazide use with skin cancer risk by using conditional logistic regression. Hydrochlorothiazide use showed no overall association with any of the three outcomes: ORs for high cumulative use of HCTZ (≥50,000 mg) were 0.86 (95% CI 0.09–7.81) for lip cancer, 1.16 (95% CI 0.98–1.37) for non-lip NMSC and 1.07 (95% CI 0.65–1.76) for melanoma. There was some evidence of a dose–response pattern for non-lip NMSC, with an OR of 1.66 (95% CI 0.82–3.33) for 100,000–149,999 mg of HCTZ. The null findings were robust across subgroup and sensitivity analyses. Use of HCTZ appears safe in terms of skin cancer risk in an Asian population.
Article
An interaction between light's radiation and certain exogenous and endogenous substances can lead to the development of photoallergic and/or phototoxic dermatoses. Clinically, reactions may range from acute and self-limited to chronic and recurrent. Delays in diagnosis are not uncommon due to complex clinical presentations, broad differentials, and limited number of specialists who perform phototesting. Therefore, a critical understanding of these dermatoses is essential for accurate diagnosis and appropriate management. The epidemiology, light sources, mechanisms, clinical presentations, evaluation protocols, common culprits, treatments, key challenges, and future directions related to photoallergy and phototoxicity are reviewed herein.
Article
Purpose: To evaluate the long-term patient experience with tetracycline injections for treatment of festoons. Methods: Charts of all patients undergoing tetracycline injection for treatment of lower eyelid festoons at the Cole Eye Institute, Cleveland Clinic between 2008 and 2018 were identified using billing records. Patients were invited to participate in a questionnaire based on the FACE-Q checklist, a previously validated questionnaire for studying cosmetic procedure outcomes. Data from the questionnaire were summarized with size, mean and frequency. Results: One hundred two patients who received tetracycline injection during the study period were identified and sixty-one responses were obtained. The average follow-up time after injection was 3.6 years. Of 61 respondents, 36 (59%) noted improvement in their festoons after treatment and 27/33 (82%) noted improvement occurred within two months of treatment. Overall, 40/60 respondents (67%) would consider repeating tetracycline treatment. The most common adverse effects included discomfort (18%), swelling (15%) and bruising (13%). There was no statistically significant difference in questionnaire responses between males and females, except males were more likely to consider repeat injection (92% vs. 58%, p = 0.005). Conclusions: Tetracycline injection appears to improve festoons in a majority of patients with an acceptable side-effect profile, although more data are needed to determine the optimal dose and frequency and to identify possible rare and/or significant side-effects.
Article
Background: The risk of skin cancer associated with antihypertensive medication use is unclear, although thiazides have been implicated in regulatory safety warnings. We aimed to assess whether use of thiazides and other antihypertensives is associated with increased rates of keratinocyte carcinoma and melanoma. Methods: We conducted a population-based inception cohort study using linked administrative health data from Ontario, 1998-2017. We matched adults aged ≥ 66 years with a first prescription for an antihypertensive medication (thiazides, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, β-blockers) by age and sex to 2 unexposed adults who were prescribed a non-antihypertensive medication within 30 days of the index date. We evaluated each antihypertensive class in a separate cohort study. Our primary exposure was the cumulative dose within each class, standardized according to the World Health Organization's Defined Daily Dose. Outcomes were time to first keratinocyte carcinoma, advanced keratinocyte carcinoma and melanoma. Results: The inception cohorts included a total of 302 634 adults prescribed an antihypertensive medication and 605 268 unexposed adults. Increasing thiazide exposure was associated with an increased rate of incident keratinocyte carcinoma (adjusted hazard ratios [HRs] per 1 Defined Annual Dose unit 1.08, 95% confidence interval [CI] 1.03-1.14), advanced keratinocyte carcinoma (adjusted HR 1.07, 95% CI 0.93-1.23) and melanoma (adjusted HR 1.34, 95% CI 1.01-1.78). We found no consistent evidence of association between other antihypertensive classes and keratinocyte carcinoma or melanoma. Interpretation: Higher cumulative exposure to thiazides was associated with increased rates of incident skin cancer in people aged 66 years and older. Consideration of other antihypertensive treatments in patients at high risk of skin cancer may be warranted.
Article
Background: Hydrochlorothiazide (HCTZ), a common diuretic known to be photosensitizing and previously associated with non-melanoma skin cancer, was recently reported to be associated with two melanoma subtypes, nodular and lentigo, among residents of Denmark. Our goal was to examine whether Danish findings could be replicated in a US cohort, using a similar study design and analysis. Methods: Among non-Hispanic White enrollees of Kaiser Permanente Northern California, we conducted an analysis of 9,176 melanoma cases and 264,781 controls, matched on age, sex and time in health plan. We examined use of HCTZ prior to cancer diagnosis (cases) or comparable date for controls, categorized as never use, ever use and high use (>50,000 mg). Electronic health records provided data on prescriptions, cancer diagnoses, and covariates. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for education, income and number of dermatology, internal medicine and urgent care visits. Results: We observed a small increase in risk of melanoma, all types combined, associated with high use (>50,000 mg) of HCTZ (OR=1.11, 95% CI 1.00-1.23) and no evidence of a dose-response. Risk was more elevated for lentigo subtype (OR=1.57, 95% CI 1.01-2.42). The somewhat elevated risk for nodular subtype was not statistically significant (OR=1.22, 95% CI 0.78-1.90). There was very little association of high use with the superficial spreading subtype (OR=1.05, 95% CI 0.80-1.37). Conclusions: Our findings support a recent report of an association between high use of HCTZ and increased risk of the lentigo subtype of melanoma.
Article
Photosensitizing drug reactions are cutaneous eruptions that occur after exposure to ultraviolet radiation in patients using photosensitizing medications. The reactions can be broadly classified into phototoxic and photoallergic, with the former being much more common and well documented. There is an extensive list of photosensitizing medications, especially in the case of phototoxicity. The most common are amiodarone, chlorpromazine, doxycycline, hydrochlorothiazide, nalidixic acid, naproxen, piroxicam, tetracycline, thioridazine, vemurafenib, and voriconazole. Most of the medications implicated in photosensitivity share an action spectrum within the ultraviolet A range. Distinguishing between phototoxicity and photoallergy can be difficult, because some clinical overlap exists between the two disorders. It is often done based on pathogenesis, clinical presentation, and diagnosis. Management is similar for both types of reactions, with the gold standard being prevention. This review provides an overview of the photosensitizing drug reactions and highlights the similarities and differences between phototoxicity and photoallergy, as well as other photosensitizing drug reactions in the phototoxicity family including lichenoid reactions and pseudoporphyria.
Chapter
Patch testing is a method carried out by dermatologists to evaluate type IV hypersensitivity reactions. It is the gold standard in the diagnosis of allergic contact dermatitis. Based on the recent knowledge on the involvement of different subtypes of type IV hypersensitivity reactions in the immunopathogenesis of drug eruptions (Table 1. 1), patch testing is also of particular value in determining the responsible drug in certain drug eruptions such as eczematous eruption, maculopapular/morbilliform eruption, fixed drug eruption, photoallergic drug eruption, drug-induced Baboon syndrome (BS)/symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), and acute generalized exanthematous pustulosis (AGEP) as a first-step diagnostic method. It is also helpful in identifying the possible cross-reactive drugs and safe alternatives. Photopatch testing should be performed if there is suspicion of photoallergic drug eruptions.
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The interaction of sunlight with drug medication leads to photosensitivity responses in susceptible patients, and has the potential to increase the incidence of skin cancer. Adverse photosensitivity responses to drugs occur predominantly as a phototoxic reaction which is more immediate than photoallergy, and can be reversed by withdrawal or substitution of the drug. The bias and inaccuracy of the reporting procedure for these adverse reactions is a consequence of the difficulty in distinguishing between sunburn and a mild drug photosensitivity reaction, together with the patient being able to control the incidence by taking protective action. The drug classes that currently are eliciting a high level of adverse photosensitivity are the diuretic, antibacterial and nonsteroidal anti-inflammatory drugs (NSAIDs). Photosensitising chemicals usually have a low molecular weight (200 to 500 Daltons) and are planar, tricyclic, or polycyclic configurations, often with heteroatoms in their structures enabling resonance stabilisation. All absorb ultraviolet (UV) and/or visible radiation, a characteristic that is essential for the chemical to be regarded as a photosensitiser. The photochemical and photobiological mechanisms underlying the adverse reactions caused by the more photoactive drugs are mainly free radical in nature, but reactive oxygen species are also involved. Drugs that contain chlorine substituents in their chemical structure, such as hydrochlorthiazide, furosemide and chlorpromazine, exhibit photochemical activity that is traced to the UV-induced dissociation of the chlorine substituent leading to free radical reactions with lipids, proteins and DNA. The photochemical mechanisms for the NSAIDs that contain the 2-aryl propionic acid group involve decarboxylation as the primary step, with subsequent free radical activity. In aerated systems, the reactive excited singlet form of oxygen is produced with high efficiency. This form of oxygen is highly reactive towards lipids and proteins. NSAIDs without the 2-arylpropionic acid group are also photoactive, but with differing mechanisms leading to a less severe biological outcome. In the antibacterial drug class, the tetracyclines, fluoroquinolones and sulfonamides are the most photoactive. Photocontact dermatitis due to topically applied agents interacting with sunlight has been reported for some sunscreen and cosmetic ingredients, as well as local anaesthetic and antiacne agents. Prevention of photosensitivity involves adequate protection from the sun with clothing and sunscreens. In concert with the preponderance of free radical mechanisms involving the photosensitising drugs, some recent studies suggest that diet supplementation with antioxidants may be beneficial in increasing the minimum erythemal UV radiation dose.
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In a joint validation project eight laboratories from the European Cosmetic Industry Association (COLIPA) as well as FRAME (England) and ZEBET (Germany) are trying to develop validated in vitro methods to be incorporated into new international guidelines for acute phototoxicity testing. The first stage of the study involved selection of the most promising in vitro phototoxicity tests for further validation. 20 chemicals with known phototoxic properties (12 phototoxins, four UV-absorbing non-phototoxins and four non-UV absorbing non-phototoxins) were tested under identical conditions of UV exposure conditions (sun simulator, UVA 5 J/cm(2)) in a standardized cytotoxicity assay with Balb/c 3T3 fibroblasts (endpoint: neutral red uptake, NRU). 19 of the 20 chemicals were correctly classified by the 3T3 NRU phototoxicity test, and therefore, this simple assay for phototoxicity seems very promising and should be validated further.
Article
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Voriconazole is a triazole antifungal agent approved by the US Food and Drug Administration for serious fungal infections, including with Aspergillus, Fusarium, Pseudallescheria, and Scedosporium species. In initial clinical trials, approximately 2% of patients developed cutaneous reactions, including photosensitivity, cheilitis, and xerosis. Subsequent reports have implicated voriconazole as a cause of severe photosensitivity and accelerated photoaging, pseudoporphyria cutanea tarda, and aggressive squamous cell carcinoma. We report 5 melanoma in situ lesions in the setting of extreme photosensitivity associated with long-term voriconazole therapy. We recommend surveillance for skin cancer formation in all patients who require long-term voriconazole treatment, particularly those who manifest signs or symptoms of photosensitivity or chronic photodamage. Further study of the mechanism underlying voriconazole photosensitivity and oncogenesis is warranted.
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Systemic fungal infections pose a significant risk to patients following allogeneic hematopoietic cell transplantation (alloHCT). Voriconazole (Vfend, Pfizer) is an oral second-generation triazole antifungal agent that offers a broad spectrum of coverage against fungal species and is frequently utilized in the post-HCT setting. Herein, we describe 5 patients who were initially believed to be experiencing a flare of cutaneous chronic graft-versus-host disease (cGVHD), but who were actually exhibiting phototoxicity caused by voriconazole. A high index of suspicion for this adverse reaction in the post-alloHCT setting will prevent misdiagnosis and avoid inappropriate therapy for cGVHD.
Article
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Dapsone is an efficient anti-inflammatory and antimycobacterial agent. It is one of the main constituents of multidrug therapy (MDT). It acts by interference with folate metabolism. Dapsone-induced photosensitivity is a rare, non-dose-related adverse effect of the sulfone and can occur in patients with inflammatory skin disorders treated with dapsone. So far, only 12 cases seem to have been reported in the literature. We report a case of dapsone-induced photosensitivity in an Indian patient with leprosy.
Article
• Amiodarone (Cordarone) is an iodinated cardiac antiarrhythmic drug that causes a slate-gray discoloration of the sun-exposed skin and a yellow-brown stippling of the cornea. Histopathologically, biopsy specimens of aminodarone pigmentation sites disclose yellow-brown refractile granules in the reticular dermis. These granules were characterized by transmission electron microscopy as being concentrically arranged intralysosomal inclusions ("myelinlike" bodies) in dermal endothelial cells and perivascular smooth-muscle cells. Electron probe x-ray analysis of these same inclusions disclosed definite peaks for iodine, evidence for the presence of amiodarone or a metabolite of the drug at these sites. Amiodarone, then, concentrates in lysosomes and causes an accumulation of lipids similar to what has been seen with other cationic amphiphilic compounds, such as the glycosphingolipid stored in Fabry's disease. Amiodarone must be recognized as a cause of a drug-induced lipid storage disease with cutaneous and corneal manifestations. (Arch Dermatol 1983;119:914-918)
Article
Moxifloxacin, a broad-spectrum fluoroquinolone with the methoxy group at position 8 of the quinolone structure that is believed to confer reduced phototoxicity, was investigated in 32 healthy human male volunteers by a randomized double-blind placebo and positive control (lomefloxacin) phototest technique. A comparison of pre- and on-drug photosensitivity levels tested with an irradiation monochromator using relevant sunlight wavelengths, failed to demonstrate phototoxicity after administration of either placebo or moxifloxacin (200 mg or 400 mg/day) for 7 days. As expected, lomefloxacin (400 mg/day) phototoxicity was revealed at the UVA wavebands 335 ± 30 nm and 365 ± 30 nm (maximal at 24 h), with a phototoxic index of 3–4. The susceptibility to this effect rapidly normalized within 48 h of stopping the drug. No special protection from UVA wavelengths is necessary for those taking moxifloxacin.
Article
Editor,—The non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz is a recent addition to the armamentarium available to physicians in the treatment of HIV infection. However, at present the known side effect profile of this new agent is still in its infancy. We would like to report a case of photosensitivity associated with efavirenz. A 27 year old white homosexual man was commenced on combivir (zidovudine/lamivudine) and efavirenz in March of 1999. One month later he reported that he was well and had no major side effects associated with his new combination. However, 4 weeks further into treatment he represented with an itchy rash affecting …
Article
Moxifloxacin, a fluoroquinolone with potent activity against respiratory pathogens, is approved and considered as an alternative to β-lactams and macrolides for the treatment of acute bacterial sinusitis and lower respiratory tract infections. In this review, we critically examine its safety profile in comparison with other fluoroquinolones and other antibacterial classes sharing similar indications. Data were extracted from published clinical trials, meta-analyses, postmarketing studies, spontaneous report systems and case reports for rare effects. Global analysis did not reveal significantly higher incidences of drug-related adverse effects than for comparators. Tendon rupture was infrequent with moxifloxacin, including when used in elderly patients with chronic obstructive pulmonary disease. Severe toxic cutaneous reactions and allergies were very rare. Phototoxicity and CNS adverse effects were less common than with other fluoroquinolones. Although causing a 4–7 msec corrected QT interval prolongation, severe cardiac toxicity was neither seen in large cohorts or clinical trials nor reported to pharmacovigilance systems. Hepatotoxicity was not different from what was observed for other fluoroquinolones (excluding trovafloxacin) and less frequent than reported for amoxicillin-clavulanic acid or telithromycin. The data show that using moxifloxacin, in its accepted indications and following the corresponding guidelines, should not be associated with an excessive incidence of drug-related adverse reactions, provided the clinician takes care in identifying patients with known risk factors and pays due attention to the contraindications and warnings mentioned in the labelling.
Article
Seven of 160 patients receiving prolonged courses of doxycycline for moderate-severe acne developed uncommon side-effects. Five patients (3.1%) developed a photosensitive rash. In four of these this developed when the patients were abroad and they were subsequently able to continue the drug. Two patients (1.25%) developed symptoms of oesophagitis and had to discontinue therapy.
Article
Objective To assess the risk of squamous cell carcinoma (SCC) and the relation of dose to risk among groups of patients with psoriasis exposed to psoralen–UV-A (PUVA).Data Sources Four electronic databases were searched from 1984 to 1998.Study Selection In addition to the PUVA Follow-up Study, we included all English-language studies from the United States and Europe with at least 150 patients enrolled, who were followed up for at least 5 years as identified from our bibliographic search.Data Extraction A custom-designed questionnaire was used to extract data from each of the articles. For each study, if possible, we determined the incidence of basal cell carcinomas and SCCs and the incidence rate ratio of SCC among patients exposed to low-dose (we defined as <100 treatments or 1000 J/cm2) compared with high-dose PUVA (>200 treatments or 2000 J/cm2). Exact methods were used to calculate the incidence rate ratios.Data Synthesis In addition to our study, we identified and reviewed 8 other studies. Overall, the incidence among patients exposed to high-dose PUVA was 14-fold higher than among patients with low-dose exposure (95% confidence interval, 8.3-24.1); a greater dose-dependent increase in risk than that observed in the PUVA Follow-up Study.Conclusion Although the incidence of SCC reported among groups of PUVA-treated patients followed up for at least 5 years varies greatly, compared with the risk in low-dose patients, long-term high-dose exposure to PUVA was consistently observed to significantly increase the risk of SCC in all studies reviewed.
Article
Five months after starting nifedipine (Adalat®), two patients developed photodistributed facial telangiectasia, which became more noticeable with time. Neither patient complained of photosensitivity or flushing. Both patients reported a significant cosmetic improvement after discontinuing the drug. One commenced the closely related drug amlodipine 3 years later, with recurrence of telangiectasia. The photodistribution of the telangiectasia suggests a significant drug/light interaction.
Article
Solar urticaria is an uncommon disorder characterized by pruritus, erythema and whealing commencing within minutes of exposure to ultraviolet (UV) and visible light, and generally resolves in a few hours. We describe a 28-year-old woman who developed pruritus and erythema 5 min after sun exposure while on tetracycline for treatment of perioral dermatitis. Phototesting elicited urticarial reactions in the UVA, UVB and visible spectra. Repeat phototesting after cessation of tetracycline was negative. This report documents the first case of solar urticaria induced by tetracycline.
Article
BACKGROUND Onycholysis has been reported in association with the use of several noncytotoxic drugs and with chemotherapy in 135 patients. Onycholysis may be precipitated by exposure to ultraviolet radiation.METHODS The authors studied 91 patients who received paclitaxel and 187 patients who received doxorubicin.RESULTSOnycholysis occurred in 5 of 21 patients who received > 6 courses of weekly paclitaxel, developing in the summer months in all 5 patients. It did not occur in patients who received fewer weekly paclitaxel courses or those who were treated every 3 weeks. Onycholysis did not occur in 187 patients who received doxorubicin. Review of the literature revealed that onycholysis is nearly exclusively associated with anthracycline and taxane therapy.CONCLUSIONS Prolonged weekly paclitaxel, other taxanes, and anthracyclines cause onycholysis in some patients, which may be precipitated by exposure to sunlight. Patients receiving these drugs should protect their nails from sunlight. Cancer 2000;88:2367–71. © 2000 American Cancer Society.
Article
Background. The relative phototoxic risk of ofloxacin, one of the newer fluoroquinolones, was compared with that of an active control of known but low phototoxic risk, naproxen. Methods. A randomized, controlled, open-label trial was used with a standardized phototoxic assay completed at baseline, midway through, and at the termination of the 12-day trial. The trial was held at a dermatology research laboratory located at a large tertiary referral and teaching hospital. Thirty healthy volunteers who met the inclusion criteria and met none of the exclusion criteria were enrolled. Twenty-seven patients completed the trial. Three subjects failed to complete the trail. One subject developed an exaggerated response to the Initial photoexposure and was dropped from the study. The other two subjects failed to return for follow-up visits. Results. Both ofloxacin and the active control agent, naproxen, significantly increased the subjects’ response to the tested solar and ultraviolet irradiation. There was, however, no significant difference between the responses observed for ofloxacin versus naproxen at any time. Conclusions. Ofloxacin possesses a definite but low potential to cause phototoxic reactions in humans. These study data, in concert with surveillance data, suggest a hierarchy of phototoxic risk among the fluoroquinolones: fleroxacin ≫ lomefloxacin, pefloxacin ≫ ciprofloxacin > enoxacin, norfloxacin, ofloxacin. The impact that phototoxicity risk will have on selecting the optimum member of a large drug family appears to be substantial in outpatient and ambulatory settings and minimal in inpatient settings.
Article
We report two cases of systemic photosensitivity induced by simvastatin and pravastatin that presented as photodistributed erythema multiforme. One of them occurred in a 75-year-old woman who had been suffering recurrent eruptions following sun exposures over a period of 12 years. The other patient was a 54-year-old man who had a 1-week history of pruritic lesions on the face and the hands. They had no history of herpes simplex virus infection. In both cases, the close temporal relationship between drug ingestion and onset of the conditions suggested statin-induced photosensitivity. The diagnosis was confirmed by the marked reduction of UVB-MED or both UVA and UVB-MED while taking the drug and its normalization after discontinuing the statin intake.
Article
Hormonal contraceptives are a known but rarely reported cause of photosensitivity. A 35-year-old female developed several episodes of a prurigionous papulovesicular eruption located on sun-exposed areas that resolved without scarring in days. She had been using a transdermal contraceptive (EVRA: norelgestromin and ethinyloestradiol) for 3 years, and once it was stopped, the patient became asymptomatic. She had another episode after the use of oral contraceptives (YAZ: ethinyloestradiol and drospirenone). The biopsy of the lesions showed a spongiotic dermatitis. Minimal erythema dose was diminished when the patient was using EVRA and YAZ and became normal when they were withdrawn. Phototesting with UVA, photopatch testing and blood porphyrins were normal. Antinuclear antibodies were 1/80 initially and were 1/320 6 months later. Anti-deoxyribonucleic acid antibodies, extractable nuclear antigens, anti Ro and Anti La were negative and no systemic symptoms had developed. When all hormonal contraceptives were stopped, the patient became asymptomatic. We report a case of systemic photosensitivity induced by the contraceptive patch. To the best of our knowledge, no other cases induced by transdermal contraceptives have been reported previously.
Article
Drug-induced phototoxicity can be caused by topical or systemic agents and is diagnosed on the basis of clinical history, examination and appropriate investigations. Photopatch testing is the investigation of choice for topical photocontact allergic dermatitis, but its use in drug-induced phototoxicity has not been validated. We retrospectively analyzed the results of photopatch testing to the drug quinine sulfate in three patients in whom a diagnosis of drug-induced phototoxicity to this agent had been made. None of the three patients had positive photopatch test reactions at any time point. This demonstrates that in our patients, photopatch testing to quinine sulfate was not a useful additional investigation for diagnosing drug-induced phototoxicity.
Article
A 40-year-old male presented with a fresh case of pulmonary tuberculosis and itchy oozing rashes distributed characteristically over the sun exposed areas of the skin. These rashes had developed since six days following 10 days of start of antitubercular drugs (streptomycin, isoniazid, rifampicin, pyrazinamide and ethambutol at standard dosages). A possibility of drug-induced reaction was entertained and all the antitubercular drugs were discontinued; subsequently they were reintroduced in a sequential manner starting with small dosages, gradually increasing them to their normal dose. The rashes reappeared after introduction of pyrazinamide. We tried to desensitize this very important antitubercular drug but were not successful as the rashes reappeared. The patient was labeled as having pyrazinamide-induced phototoxicity and was started on a regimen containing streptomycin, isoniazid, rifampicin, ethambutol. Five months following treatment, the patient is now sputum negative for AFB. Pyrazinamide forms the integral part of most of the short course regimens, included in all the three categories of DOTS and with increasing coverage of DOTS therapy these rare cases may well be frequently encountered.
Article
Package inserts for the fluoroquinolones in Europe and the US contain warnings regarding these risks. US package inserts also carry 'black-box' warnings regarding the risk of tendon rupture and joint disorders with these agents; however, there is a substantial body of evidence to indicate that there are marked differences in the tolerability profiles of the individual agents within the fluoroquinolone class. These differences may be explained, at least in part, by structural differences: all fluoroquinolones share a basic quinolone core, with differences in specific side chains underlying the adverse event relationships. Furthermore, many of the fluoroquinolone-associated adverse effects and toxicities occur more frequently in patients with pre-existing risk factors, or in certain subpopulations. Notably, package inserts for the fluoroquinolones carry warnings regarding use in the elderly, paediatric patients and patients with preexisting, or factors predisposing to, seizure disorders. Because of this, many adverse reactions with these agents could be prevented by improving patient screening and education. The recent withdrawal of gatifloxacin due to dysglycaemia makes it timely to review the safety and tolerability of the individual agents in this class. Overall, it appears that levofloxacin is relatively well tolerated, with low rates of clinically important adverse events such as CNS toxicity, cardiovascular toxicity and dysglycaemia.
Article
Voriconazole is a broad-spectrum antifungal agent associated with photosensitivity and accelerated photoaging. A possible link with aggressive squamous cell carcinoma (SCC) has also been reported. We sought to determine the incidence and frequency of cutaneous SCC among patients undergoing long-term treatment with voriconazole who also manifest features of chronic phototoxicity. We conducted a retrospective review of patients who developed one or more squamous cell neoplasms during long-term treatment with voriconazole at 3 academic dermatology centers. A total of 51 cutaneous SCC were identified in 8 patients (median age 34.5 years, range 9-54) treated with chronic voriconazole (median duration 46.5 months, range 13-60). Underlying diagnoses included graft-versus-host disease, HIV, and Wegener granulomatosis. Signs of chronic phototoxicity and accelerated photoaging included erythema, actinic keratoses, and lentigo formation. The retrospective nature of the study cannot determine the true population risk of SCC associated with voriconazole therapy. A prospective cohort study is needed. A high index of suspicion for photosensitivity and SCC may be warranted with chronic voriconazole use when used in the setting of concurrent immunosuppression.
Article
Selective serotonin reuptake inhibitors (SSRIs) are a widely prescribed group of antidepressants. We report three cases of photosensitivity induced by fluvoxamine and paroxetine. These photoallergic reactions suggest cross-reactivity between different molecules. Methylation metabolism could explain common photosensitization. Although these drugs are widely prescribed, such photosensitization is rare. Nevertheless, we consider that clinicians and patients should be aware of the risk of photosensitization and these drugs should be stopped before phototherapy or prolonged sun exposure.
Article
We describe a patient who was treated with high-dose intravenous and intrathecal methotrexate for acute lymphoblastic leukemia, and who manifested a false photosensitivity reaction with no prior evidence of sun exposure. This patient later experienced delayed transient hemiparesis following methotrexate administration, although without long-term sequelae. The etiology of these events is obscure, but suggestive of a vasculitic or immune-mediated reaction to methotrexate. Pediatr Blood Cancer 2009;53:103-105. (C) 2009 Wiley-Liss, Inc.
Article
Five patients manifested cutaneous changes indistinguishable from those noted in some porphyric disorders, consisting of fragility, denudation, and blister formation of sun-exposed skin. Microscopical examination showed subepidermal bulla formation and the desposition of PAS-positive, diastase-resistant material and IgG in or around the upper dermal blood vessel walls. There was also electron microscopical evidence of vascular basal lamina reduplication and the deposition of a fine fibrillar material in and around these vessels. However, no abnormal porphyrin formation was noted. All five patients had been receiving 250 mg of tetracycline hydrochloride twice a day for at least six months and had had extensive sun exposure prior to the onset of the condition. For four patients, discontinuing the medication led to complete remission, despite subsequent sun exposure; the fifth patient was much improved, but her skin was still somewhat fragile seven months later. We concluded that these cutaneous changes resulted from a low-grade photosensitization by tetracycline hydrochloride.
Article
• A 52-year-old man developed contact and photoallergic dermatitis caused by diphenhydramine hydrochloride as well as contact dermatitis from paraphenylenediamine. The diphenhydramine photoallergy was elicited by long-wave ultraviolet light. The action spectrum differs from that noted in a recent report in which wavelengths shorter than 320 nm were responsible for eliciting diphenhydramine photoallergy. To the best of my knowledge, this is the third case of diphenhydramine photosensitivity reported in the English literature. The combination of both contact and photosensitivity to diphenhydramine has not previously been described. (Arch Dermatol 112:1124-1126, 1975)
Article
A photosensitivity reaction to vinblastine sulfate occurred in a patient receiving chemotherapy for Hodgkin disease. Ultraviolet light (UVL) testing revealed a decreased minimal erythema dose (MED), which returned to normal following discontinuation of the drug. Photoreactions to intradermal injections of vinblastine were produced in the patient and in five normal controls with a suberythema dose of UVL. Spectrophotometric studies confirmed absorption of vinblastine sulfate in the sunburn range. The clinical lesions and phototests could not be reproduced through window glass or aminobenzoic acid as sunscreens.
Article
Blistering of exposed areas has appeared in patients suffering from chronic renal failure treated with high doses of frusemide. The blistering, which resembles that occurring in nalidixic acid phototoxicity and in porphyria cutanea tarda, is considered phototoxic in nature.
Article
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.
Article
A 43-year-old farmer on tricyclic antidepressive drugs developed a severe photodermatitis with associated liver involvement. The lesions spread to covered areas of the skin, suggesting photoallergy clinically. Patch and photopatch testing revealed photoallergy and contact allergy to clomipramine and contact allergy also to carbamazepine. In addition, the patient had positive patch test reactions to chlorpromazine, balsam of Peru and fragrance-mix, as well as a positive photopatch test to fentichlor. UVA and UVB erythema thresholds were normal. In this patient, an initial episode of photosensitization, probably elicited by clomipramine, was accompanied by contact allergy to this drug and to carbamazepine. The contact sensitivity to clomipramine could also be elicited by oral provocation without UV light. Hypothetically, a photoproduct of clomipramine may have been the original sensitizer, this compound subsequently cross-reacting with clomipramine and, possibly with carbamazepine.
Article
Ciprofloxacin is one of the new series of broad-spectrum antibiotic quinolones, chemically related to nalidixic acid and which may, therefore, induce photosensitization of human skin. Three in vitro tests for phototoxicity: the destruction of histidine, killing of mouse peritoneal macrophages and inhibition of PHA-stimulated DNA synthesis in human lymphocytes have demonstrated this photosensitizing potential with UVA irradiation at an order of magnitude lower than that for nalidixic acid. The Candida albicans test and photohaemolysis were negative. Controlled irradiation monochromator phototesting of 12 subjects, before, during and after taking ciprofloxacin showed subclinical photosensitivity with significantly lowered minimal 24 h erythema doses at 335 +/- 30 nm, 365 +/- 30 nm and 400 +/- 30 nm but not at 305 +/- 5 nm or above 400 +/- 30 nm.
Article
A distinctive photodermatitis developed in 22 children who had been receiving naproxen for prolonged periods. The eruption was marked by erythema, vesiculation, or increased skin fragility characterized by easy scarring of sun-exposed skin. Results of biochemical studies for porphyria were normal, and other causes of photosensitivity were believed to be unlikely. Of the 22 patients, 21 had juvenile rheumatoid arthritis; one patient had systemic lupus erythematosus. Twenty of the patients had fair skin and blue eyes. In each case, all findings except scarring resolved when naproxen was discontinued. Attention must be paid to complaints suggesting photosensitivity in children receiving naproxen.
Article
Amiodarone (AD) induces photosensitivity in 75% of the patients treated with this drug. Phototoxic reactions can be experimentally elicited with UVA but not with UVB. The UVA-MED is significantly reduced after 12 months of treatment. The development of photosensitivity depends on the total dose of AD; 40 g is the minimal cumulative dose requirement. Under the regimens commonly used, photosensitivity can be expected after 4 months of continuous AD treatment and appears to be unrelated to the skin type. Photosensitivity gradually decreases and returns to normal between 4 and 12 months after the withdrawal of AD. AD-related hyperpigmentation develops after an average of 20 months of continuous AD treatment and a minimal total dose of 160 g AD in about 8% of the patients (mainly of skin type I). Electron microscopic examination of the sun-exposed skin of patients without AD discoloration shows pigment deposits similar to those already described in patients with AD hyperpigmentation in exposed and non-exposed skin. Light and electronmicroscopic examination of sun-exposed skin of both clinically photosensitive and non-photosensitive patients reveals perivascular inflammation even in the absence of a clinical rash. Reduplications of vascular basal laminae occur in sun-exposed skin of both patients with and without UVA photosensitivity but are absent from non-exposed skin. In one patient, followed for 33 months after drug withdrawal, massive AD-induced hyperpigmentation was found to be reversible.
Article
A 39-year-old white man who was taking quinidine developed a purpuric eruption in a photodistributed livedo reticularis-like pattern. This is the fourth reported case of a similar eruption in patients taking quinidine. Possible pathophysiologic mechanisms for nonthrombocytopenic drug-induced purpuras are discussed.