drug eruptions include drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). One class of medications that has been highly associated with such drug eruptions is antiepileptic drugs (AEDs). We attempt to investigate drug eruptions associated with AEDs as a class, as well as with individual AEDs, in Korea.METHODS: We used the Korea Institute of Drug Safety and Risk Management - Korea Adverse Event Reporting System (KIDS-KAERS) database, a nationwide database of adverse events reports, between January 2008 and December 2017 to investigate the reporting count of all drug eruptions and calculated the ratio of DRESS/SJS/TEN reports for each AED.RESULTS: Among a total of 2,942 reports, most were of rash/urticaria (2,702, 91.8%), followed by those of DRESS (109, 3.7%), SJS (106, 3.6%), and TEN (25, 0.85%). The common causative AEDs were lamotrigine (699, 23.8%), valproic acid (677, 23%), carbamazepine (512, 17.4%), oxcarbazepine (320, 10.9%), levetiracetam (181, 6.2%), and phenytoin (158, 5.4%). In limited to severe drug eruptions (DRESS, SJS, and TEN; total 241 reports), the causative AEDs were carbamazepine (117, 48.8%), lamotrigine (57, 23.8%), valproic acid (20, 8.3%), phenytoin (15, 6.3%), and oxcarbazepine (10, 4.2%). When comparing aromatic AED with non-aromatic AED, aromatic AEDs were more likely to be associated with severe drug eruption (aromatic AEDs: 204/1,793 versus non-aromatic AEDs: 37/1,149; OR, 3.86; 95% CI, 2.7–5.5). Death was reported in 7 cases; DRESS was the most commonly reported adverse event (n = 5), and lamotrigine was the most common causative AED (n = 5).CONCLUSION: Although most cutaneous drug eruptions in this study were rash or urticaria, approximately 8% of reports were of severe or life-threatening adverse drug reactions, such as SJS, TEN, or DRESS. When hypersensitivity skin reactions occurred, aromatic AEDs were associated with 4 fold the risk of SJS/TEN/DRESS compared with non-aromatic AEDs. Our findings further emphasize that high risk AEDs should be prescribed under careful monitoring, and early detection and prompt interventions are needed to prevent severe complications.]]>
Anticonvulsants ; Carbamazepine ; Drug Eruptions ; Drug Hypersensitivity Syndrome ; Drug-Related Side Effects and Adverse Reactions ; Exanthema ; Hypersensitivity ; Korea ; Pharmacovigilance ; Phenytoin ; Risk Management ; Skin ; Stevens-Johnson Syndrome ; Urticaria ; Valproic Acid

Terbinafine is now widely used for the treatment of dermatophytic infections of the skin and nails. Cutaneous side effects of terbinafine are rare and mild. They includes erythema, pruritus, urticaria, desqumation, and macular exanthem. In addition, fixed drug eruption, erythema multiforme, Stevens-Johnson syndrome, and erythema annulare centrifugum-like psoriatic drug eruption were recently described in the literatures. Herein, we reported a case of acute generalized exanthematous pustulosis induced by terbinafine.
Acute Generalized Exanthematous Pustulosis* ; Drug Eruptions ; Erythema ; Erythema Multiforme ; Exanthema ; Pruritus ; Skin ; Stevens-Johnson Syndrome ; Urticaria

Liver is the main place of drug metabolism. Mitochondria of hepatocytes are important targets of drug-induced liver injury. Mitochondrial autophagy could maintain the healthy operation of mitochondria in cells and the stable proliferation of cells. Therefore, the use of mitochondrial autophagy to remove damaged mitochondria is an important strategy of anti-drug-induced liver injury. Active ingredients that could enhance mitochondrial autophagy are contained in many traditional Chinese medicines, which could regulate the mitochondrial autophagy to alleviate relevant diseases. However, there are only a few reports on how to accurately and efficiently identify and evaluate such components targeting mitochondria from traditional Chinese medicine. Liquid chromatography-mass spectro-metry(LC-MS) combined with serum pharmacology in vivo can be used to accurately and efficiently find active ingredients of traditional Chinese medicine acting on mitochondrial targets. This paper reviewed the research ideas and methods of traditional Chinese medicine ingredients for increasing the hepatotoxicity of mitochondrial autophagy, in order to provide new ideas and methods for the study of active ingredients of traditional Chinese medicine targeting mitochondria.
Chemical and Drug Induced Liver Injury ; Drug-Related Side Effects and Adverse Reactions ; Drugs, Chinese Herbal/toxicity* ; Humans ; Medicine, Chinese Traditional ; Mitochondria

PURPOSE: Although severe cutaneous adverse drug reactions (SCARs) are rare, they are associated with high morbidity and mortality, and thus early diagnosis and treatment are critical for improving prognoses. However, few studies have reported the characteristics of SCARs in children. Thus, we aimed to evaluate the clinical characteristics, current management and prognosis of pediatric SCARs. METHODS: We analyzed pediatric data in the Korean SCARs registry, which was built retrospectively in 2016 with SCAR cases treated in 34 tertiary referral university hospitals during 2010–2015. Using these cases, we descriptively analyzed detailed data regarding etiology, clinical and laboratory features, treatment strategies, and prognosis. RESULTS: Forty-seven pediatric SCAR cases from 15 tertiary referral hospitals were included. The median patient age was 10 (interquartile range, 3-15.5) years and 68.1% (n = 32) were males. The culprit drug was identified in 95.7% (n = 45) of the patients; antibiotics (44.7%) and antiepileptic drugs (19.1%) were the most common and second most common culprits, respectively. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) cases presented with the largest area of skin involvement without permanent sequelae. Stevens-Johnson syndrome (SJS) cases involved relatively small areas of skin but serious sequelae in two children. Of 4 patients with toxic epidermal necrolysis (TEN), 1 died. Of all patients assessed, 36 (76.6%) received systemic steroids and 21 (44.7%) received intravenous immunoglobulin (IVIG). Thirteen (27.7%) received both systemic steroids and IVIG. Cyclosporine was administered to only 1 patient along with a systemic steroid. CONCLUSIONS: In patients with pediatric SCARs, including those with DRESS, SJS and TEN, clinical presentations were variable. Thus, there was no clear continuous disease spectrum. Although the mortality rate was low (2.1%), clinical suspicion may be the best tool for proactive SCAR management.
Anti-Bacterial Agents ; Anticonvulsants ; Child ; Cicatrix ; Cyclosporine ; Drug Eruptions ; Drug Hypersensitivity Syndrome ; Drug-Related Side Effects and Adverse Reactions ; Early Diagnosis ; Hospitals, University ; Humans ; Immunoglobulins ; Immunoglobulins, Intravenous ; Korea ; Male ; Mortality ; Prognosis ; Referral and Consultation ; Retrospective Studies ; Skin ; Steroids ; Stevens-Johnson Syndrome ; Tertiary Care Centers

Methotrexate(MTX) is a commonly used antimetabolite, which can be used in the treatment of a variety of diseases. However, hepatotoxicity in the use of MTX severely limits its clinical use. Therefore, how to prevent and treat hepatotoxicity of MTX has become an urgent clinical problem. This paper summarizes and analyzes relevant literatures on the prevention and treatment of hepa-totoxicity caused by MTX with traditional Chinese medicines and natural medicines in recent years. MTX-induced hepatotoxicity mechanisms include folate pathway, oxidative stress damage and adenosine pathway, of which oxidative stress theory is the main research direction. A total of 14 kinds of traditional Chinese medicine and natural medicine extracts including white peony root, and 21 kinds of natural monomer compounds, including berberine, play an anti-MTX-induced hepatotoxic effect by resisting oxidative stress, inhibiting inflammation and regulating signal pathways. According to current studies on the prevention and treatment of hepatotoxicity induced by MTX with traditional Chinese medicines and natural medicines, there are insufficiencies, such as partial and superficial mechanism studies, inadequate combination of experimental research and clinical practice, non-standard experimental design and lack of application of advanced technologies and methods. This paper systematically reviewed the effects and mechanisms of traditional Chinese medicines and natural medicines against hepatotoxicity induced by MTX and defined current studies and deficiencies, in the expectation of proposing new study strategies and directions and providing scientific basis for rational clinical use of MTX and development of new drugs against MTX hepatotoxicity.
Chemical and Drug Induced Liver Injury/prevention & control* ; Drug-Related Side Effects and Adverse Reactions ; Humans ; Liver/metabolism* ; Medicine, Chinese Traditional ; Methotrexate/toxicity* ; Oxidative Stress

OBJECTIVE: The purpose of this study was to investigate the incidence, cause, and influence of the adverse drug reactions (ADRs) associated with long-term intravenous antibiotics in patients with pyogenic spondylitis (PS). METHODS: We retrospectively reviewed the medical records of 84 patients with PS who underwent intravenous antibiotic therapy in our hospital from January 2001 to December 2012. ADRs were categorized to drug eruption, acute renal failure (ARF), hematologic toxicity, toxic hepatitis, pseudomembranous colitis (PMC), drug fever, and neuronal toxicity. Incidence and onset time of each ADR after antibiotic therapy were analyzed with the incidence of ADRs according to types of antibiotics. RESULTS: ADRs occurred in 38 of the 84 patients (incidence: 45.2%). The use of antibiotics was longer in the patients with ADRs (62.7 days) than in the patients without ADRs (44.3 day). The incidence of drug eruption, ARF, hematologic toxicity, toxic hepatitis, PMC, drug fever, and neuronal toxicity were 22.6, 11.9, 11.9, 10.7, 7.1, 3.6%, and 1.2%, respectively. The duration of antibiotics administration was related to the occurrence of PMC (p=0.001). ADRs were more common in patients treated by glycopeptides including vacomycin and teicoplanin. CONCLUSION: The incidence of ADRs due to long-term intravenous antibiotics was as high as 45.2% in patients with PS. Therefore, we speculate that the possibility of delayed ADRs should be considered after long-term use of the antibiotics. Furthermore, close observation is mandatory to identify and treat ADRs promptly, even though PS revealed the improvement after antibiotic therapy.
Acute Kidney Injury ; Anti-Bacterial Agents* ; Drug Eruptions ; Drug-Induced Liver Injury ; Drug-Related Side Effects and Adverse Reactions* ; Enterocolitis, Pseudomembranous ; Epidural Abscess ; Fever ; Glycopeptides ; Humans ; Incidence ; Medical Records ; Neurons ; Retrospective Studies ; Spondylitis* ; Teicoplanin

Acute generalized exanthematous pustulosis (AGEP) has symptoms of abrupt onset of a widespread pustular eruption on an erythematous. base. Most cases appear to be related to drug reactions, mainly antibiotics, but viral infections and hypersensitivity to mercury may cause AGEP. The essential features of AGEP include. (1) numerous (several dazen) small((5mm), mostly non follicular pustules arising on a widespread erythema:purpura and target-like lesions may be associated; (2) histology showing intraepidermal or subcorneal pustules associated with one or more of the following.clermal edema, vasculitis, perivascular eosinophils, or focal necrosis of keratinocytes; (3) fever (over 38C); (4) neutrophilia, and (5) acute evolution with spontaneous resulotion of pustules within 15 days. We report a case of AGEP which presented with widespread tiny pustules on the whole body except the face, palms and soles. There were petechia, purpura, and vesiculobullous lesions on the axilla, popliteal fossa and upper abdomen. A biopsy specimen from a pustule showed subcorneal pustules with perivascular polymorphous cellular infiltration, marked dermal edema and necrotic keratinocytes. There was complete resolution of the lesions within 10 days.
Abdomen ; Acute Generalized Exanthematous Pustulosis* ; Amoxicillin ; Anti-Bacterial Agents ; Axilla ; Biopsy ; Drug Eruptions ; Edema ; Eosinophils ; Fever ; Hypersensitivity ; Keratinocytes ; Necrosis ; Purpura ; Vasculitis

Adverse drug reactions are very common in clinical practice, and skin is one of the most frequent organs for adverse drug reactions. We report a case of a 71-year-old male patient who developed skin eruptions after switching formulation of quetiapine immediate release(IR) to quetiapine extended release(XR). He had been taking quetiapine IR(400mg/day) for treatment of manic episode which was developed one year ago. The patient showed great improvement of symptoms after taking quetiapine IR for about one year, thus dosage of medication was reduced to 50mg/day on the average. Unfortunately dose reduction has tended to worsen symptoms, so dose of quetiapine was increased again to 200mg/day with formulation changes to XR. Two days after he took new formulation, erythematous papules were occurred over his anterior neck and ventral side of left wrist. As he stopped quetiapine XR, the skin lesions gradually subsided. And he was successfully treated with readministration of quetiapine IR without any skin lesions.
Aged ; Dibenzothiazepines ; Drug Eruptions ; Drug Toxicity ; Humans ; Hypersensitivity ; Male ; Neck ; Skin ; Wrist ; Quetiapine Fumarate

BACKGROUND/AIMS: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) are severe cutaneous adverse reactions (SCARs) that also affect the internal organs with high mortality. However, there has been no previous nationwide study of SCARs in Korea. METHODS: Cases of SCARs were recruited from the nationwide Korean Pharmacovigilance Research Network database, collected from June 2009 to December 2010, by a spontaneous reporting system. We analyzed age, gender, route of administration and the causative agents. We also reviewed previously published cases of SCARs in Korea. RESULTS: In total, 100 cases of SJS (66 cases), TEN (7 cases), and DRESS (27 cases) were reported. The mean age of the patients was 54.1 +/- 19.8 years and the proportion of males to females was 1:0.88. In total, 81 drugs were reported as causative agents: SJS (61 drugs), TEN (15 drugs), and DRESS (29 drugs). The most commonly reported causative drug was allopurinol (12 cases). Allopurinol (8 cases) and levofloxacin (2 cases) were the most commonly reported causative drugs for SJS and TEN, respectively. In DRESS, allopurinol (4 cases) and vancomycin (4 cases) were the two most common causative drugs. Anti-infective drugs were the most common drug category (75 cases). Carbamazepine was the most commonly reported causative drug according to published cases in Korea. CONCLUSIONS: Allopurinol in the spontaneous reporting system and carbamazepine in the published cases were the most common single causative drugs in SCARs in Korea. Anti-infectives were the most common drug category in the spontaneous reporting system.
Allopurinol ; Carbamazepine ; Cicatrix ; Drug Hypersensitivity ; Drug Hypersensitivity Syndrome ; Drug-Related Side Effects and Adverse Reactions* ; Eosinophilia ; Female ; Humans ; Korea ; Levofloxacin ; Male ; Mortality ; Pharmacovigilance ; Stevens-Johnson Syndrome ; Vancomycin

Fixed drug eruption is an uncommon adverse drug reaction caused by delayed cell-mediated hypersensitivity. Levocetirizine is an active (R)-enatiomer of cetirizine and there have been a few reports of fixed drug eruption related to these antihistamines. We experienced a case of levocetirizine-induced fixed drug eruption and cross-reaction with other piperazine derivatives confirmed by patch test. A 73-year-old female patient presented with recurrent generalized itching, cutaneous bullae formation, rash and multiple pigmentation at fixed sites after taking drugs for common cold. She took bepotastine besilate (Talion®) and levocetirizine (Xyzal®) as antihistamine. She took acetaminophen, pseudoephedrine 60 mg / triprolidine 2.5 mg (Actifed®), dihydrocodeinebitartrate 5 mg / di-methylephedrine hydrochloride 17.5 mg / chlorpheniramine maleate 1.5 mg / guaifenesin 50 mg (Codening®) and aluminium hydroxide 200 mg / magnesium carbonate 120 mg (Antad®) at the same time. Patch test was done with suspected drugs and the result was positive with levocetirizine. We additionally performed patch test for other antihistamines such as cetirizine, hydroxyzine, fexofenadine and loratadine. Piperazine derivatives (cetirizine and hydroxyzine) were positive, but piperidine derivatives (fexofenadine and loratadine) were negative to patch test. There was no adverse drug reaction when she was challenged with fexofenadine. We report a case of levocetirizine-induced fixed drug eruption confirmed by patch test. Cross-reactions were only observed in the piperazine derivatives and piperidine antihistamine was tolerant to the patient.
Acetaminophen ; Aged ; Carbon ; Cetirizine ; Chlorpheniramine ; Common Cold ; Drug Eruptions ; Drug-Related Side Effects and Adverse Reactions ; Exanthema ; Female ; Guaifenesin ; Histamine Antagonists ; Humans ; Hydroxyzine ; Hypersensitivity ; Loratadine ; Magnesium ; Patch Tests ; Pigmentation ; Pruritus ; Pseudoephedrine ; Triprolidine