A Nationwide Study of Severe Cutaneous Adverse Reactions Based on the Multicenter Registry in Korea.

BACKGROUND: Because severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) rarely occur, clinical data based on large-scale studies are still lacking. OBJECTIVE: To provide information on culprit drugs and clinical characteristics, including morbidity and mortality of SCARs based on a nationwide registry. METHODS: SCAR cases that occurred from 2010 to 2015 were recruited to the Korean SCAR registry from 34 tertiary referral hospitals. Demographics, causative drugs, causality, and clinical outcomes were collected by reviewing the medical record. RESULTS: A total of 745 SCAR cases (384 SJS/TEN cases and 361 DRESS cases) due to 149 drugs were registered. The main causative drugs were allopurinol (14.0%), carbamazepine (9.5%), vancomycin (4.7%), and antituberculous agents (6.3%). A strong preference for SJS/TEN was observed in carbonic anhydrase inhibitors (100%), nonsteroidal anti-inflammatory drugs (84%), and acetaminophen (83%), whereas dapsone (100%), antituberculous agents (81%), and glycopeptide antibacterials (78%) were more likely to cause DRESS. The mortality rate was 6.6% (SJS/TEN 8.9% and DRESS 4.2%). The median time to death was 19 days and 29 days in SJS/TEN and DRESS respectively, and 89.8% of deaths occurred within 60 days after the onset of the skin symptoms. CONCLUSION: Allopurinol, carbamazepine, vancomycin, and antituberculous agents were the leading causes of SCARs in Korea. Some drugs preferentially caused a specific phenotype. The mortality rate of SCARs was 6.6%, and most of the deaths occurred within 2 months.

Severe Cutaneous Adverse Reactions to Antiepileptic Drugs: A Nationwide Registry-Based Study in Korea.

PURPOSE: Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) to antiepileptic drug (AED), are rare, but result in significant morbidity and mortality. We investigated the major culprit drugs, clinical characteristics, and clinical course and outcomes of AED-induced SCARs using a nationwide registry in Korea. METHODS: A total of 161 patients with AED-induced SCARs from 28 referral hospitals were analyzed. The causative AEDs, clinical characteristics, organ involvements, details of treatment, and outcomes were evaluated. We compared the clinical and laboratory parameters between SJS/TEN and DRESS according to the leading causative drugs. We further determined risk factors for prolonged hospitalization in AED-induced SCARs. RESULTS: Carbamazepine and lamotrigine were the most common culprit drugs causing SCARs. Valproic acid and levetiracetam also emerged as the major causative agents. The disease duration and hospital stay in carbamazepine-induced SJS/TEN were shorter than those in other AEDs (P< 0.05, respectively). In younger patients, lamotrigine caused higher incidences of DRESS than other drugs (P= 0.045). Carbamazepine, the most common culprit drug for SCARs, was associated with a favorable outcome related with prolonged hospitalization in SJS (odds ratio, 0.12; 95% confidence interval, 0.02-0.63, P= 0.12), and thrombocytopenia was found to be a risk factor for prolonged hospitalization in DRESS. CONCLUSION: This was the first large-scale epidemiological study of AED-induced SCARs in Korea. Valproic acid and levetiracetam were the significant emerging AEDs causing SCARs in addition to the well-known offending AEDs such as carbamazepine and lamotrigine. Carbamazepine was associated with reduced hospitalization, but thrombocytopenia was a risk factor for prolonged hospitalization. Our results suggest that the clinical characteristics and clinical courses of AED-induced SCARs might vary according to the individual AEDs.

Phenotypes of Severe Cutaneous Adverse Reactions Caused by Nonsteroidal Anti-inflammatory Drugs.

PURPOSE: Nonsteroidal anti-inflammatory drugs (NSAIDs) are common cause of severe cutaneous adverse reactions (SCARs). The present study aimed to investigate the characteristics of SCARs induced by NSAIDs in the Korean SCAR registry. METHODS: A retrospective survey of NSAID-induced SCARs recorded between 2010 and 2015 at 27 university hospitals in Korea was conducted. Clinical phenotypes of SCARs were classified into Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), SJS-TEN overlap syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS). Causative NSAIDs were classified into 7 groups according to their chemical properties: acetaminophen, and propionic, acetic, salicylic, fenamic and enolic acids. RESULTS: A total of 170 SCARs, consisting of 85 SJS, 32 TEN, 17 SJS-TEN overlap syndrome and 36 DRESS reactions, were induced by NSAIDs: propionic acids (n=68), acetaminophen (n=38), acetic acids (n=23), salicylic acids (n=16), coxibs (n=8), fenamic acids (n=7), enolic acids (n=5) and unclassified (n=5). Acetic acids (22%) and coxibs (14%) accounted for higher portions of DRESS than other SCARs. The phenotypes of SCARs induced by both propionic and salicylic acids were similar (SJS, TEN and DRESS, in order). Acetaminophen was primarily associated with SJS (27%) and was less involved in TEN (10%). DRESS occurred more readily among subjects experiencing coxib-induced SCARs than other NSAID-induced SCARs (62.5% vs. 19.7%, P = 0.013). The mean time to symptom onset was longer in DRESS than in SJS or TEN (19.1 ± 4.1 vs. 6.8 ±1.5 vs. 12.1 ± 3.8 days). SCARs caused by propionic salicylic acids showed longer latency, whereas acetaminophen- and acetic acid-induced SCARs appeared within shorter intervals. CONCLUSIONS: The present study indicates that the phenotypes of SCARs may differ according to the chemical classifications of NSAIDs. To establish the mechanisms and incidences of NSAID-induced SCARs, further prospective studies are needed.

INR optimization based on stroke risk factors in patients with non-valvular atrial fibrillation.

BACKGROUND: Bleeding complications have been frequently reported in East Asian patients on warfarin with a target international normalized ratio (INR) of 2.0-3.0. OBJECTIVE: This study aimed to identify the optimal therapeutic range of the INR in Korean patients with non-valvular atrial fibrillation (NVAF). Setting Cardiovascular department of a 1320 inpatient bed Korean hospital. METHOD: Retrospective chart review was conducted on 1014 patients for a total follow-up period of 2249.2 patient years. Major thromboembolic and bleeding complications were evaluated. The INR incidence of complication curve was plotted, and the optimal therapeutic range of INR was determined from the intersection of curves to ensure the lowest incidences of both thromboembolic and bleeding complications. For subgroup analysis, all patients were stratified by the following factors: age (above 75), disease (presence of hypertension, diabetes, congestive heart failure, and a history of stroke or thromboembolism), rhythm control procedure, and concurrent aspirin therapy. Main outcome measure Optimal therapeutic ranges of INR according to the risk factors. RESULTS: A total of 41 thromboembolic and 91 bleeding events occurred during the follow-up period. The complication rates were the lowest at an INR of 1.9 and the optimal therapeutic range was estimated to be 1.7-2.2 for the overall patients. The optimal therapeutic ranges of INR in the stratified patients were determined as follows: 1.3-1.8 in the patients ≥75 years of age; 1.5-2.0 in patients with hypertension, diabetes and concurrent aspirin therapy; 1.8-2.3 in patients with congestive heart failure; 1.9-2.4 in patients with previous stroke or thromboembolism; 1.7-2.2 in patients who had undergone rhythm control procedures. It has been shown that, by keeping the INR within these ranges, complication risks could be significantly reduced by up to 81 %. CONCLUSION: The intensity of anticoagulation therapy for Korean patients with NVAF is optimal when INR is between 1.7 and 2.2.

Efficacy and safety profile comparison of colistin and tigecycline on the extensively drug resistant Acinetobacter baumannii.

Colistin and tigecycline are the only therapeutic options for extensively drug resistant Acinetobacter baumannii (XDR-AB), but there is little comparative study. This retrospective observation study evaluated two-colistin and tigecycline-antibiotics profiles like treatment success rate, negative conversion rate, the length of hospital stay, intensive care unit (ICU) stay and antibiotics use, mortality rate during hospital stay and adverse event rate, based on the medical record of XDR-AB positive patients who were treated at least 5 d with those intravenous antibiotics. Treatment success rate of colistin (n=39) and tigecycline (n=16) were not different: 48.7% and 43.8%, respectively (p=0.737), though negative conversion rate was significantly higher in the colistin group: 46.2% against 12.5% (p=0.049). There was no statistically significant difference in mortality rate between two groups during hospital stay (43.6% vs. 56.3%, p=0.393). There were no significant differences in the following parameters: the median length of hospital stay (46.0 d vs. 72.5 d), the median length of intensive care units stay (26.0 d vs. 27.0 d), the median length of antibiotics use (15.0 d vs. 13.0 d). The colistin group showed serum creatinine elevation (defined as elevation more than 2.0 mg/dL and 50% increase from the baseline) as 43.6% when compared with 12.5% of the tigecycline group (p=0.028). As a therapeutic option of XDR-AB, colistin showed significantly better negative conversion rate than tigecycline with more frequent nephrotoxic prevalence, and treatment success rate and mortality rate were not different from both antibiotics groups.

Effect of hydrogen peroxide on VIP-induced relaxation of the cat lower esophageal sphincter.

We investigated the effects of hydrogen peroxide (H2O2) on relaxation of the cat lower esophageal sphincter (LES). Vasoactive intestinal peptide (VIP) caused dose-dependent relaxation of LES, and H2O2 reduced VIP-induced relaxation. Relaxation was also attenuated by pertussis toxin (PTX), indicating a Gi/o component. VIP treatment increased [35S]GTPgammaS binding to Gs and Gi3 protein, but not to Go, Gq, Gil or Gi2. This increase in Gs or Gi3 binding was reduced by H2O2. However, the relaxation induced by sodium nitroprusside (SNP), 3-morpholino sydnomine (SIN-1), 8-br cGMP (cGMP analog), forskolin (adenylate cyclase activator), and dibutyryl-cAMP (a stable cAMP analog) was not reduced by H2O2. These data suggest that H202 inhibits VIP-induced relaxation via a Gi-dependent pathway, perhaps by inhibiting the activation of G(i3) or Gs downstream of the VIP receptor and independent of cAMP or NO-cGMP signaling.

Electrically stimulated relaxation is not mediated by GABA in cat lower esophageal sphincter muscle.

This study examined the effect of Gamma-Amino butyric acid (GABA) and selective GABA receptor related drugs on the electrically stimulated relaxation in the lower esophageal sphincter muscle (LES) of a cat. Tetrodotoxin (10(-6) M) suppressed the electrically stimulated (0.5-5 Hz) relaxation of the LES. However, guanethidine (10(-6) M) and atropine (10(-6) M) had no effect indicating that the relaxations were neurally mediated via the nonadrenergic and noncholinergic (NANC) pathways. NG-nitro-L-arginine methyl ester (10(-4) M, L-NAME) also inhibited the relaxant response but did not completely abolish the electrically stimulated relaxation with 60 % inhibition, which suggests the involvement of nitric oxide as an inhibitory transmitter. This study examined the role of GABA, an inhibitory neurotransmitter, on neurally mediated LES relaxation. GABA (10(-3)-10(-5) M, non selective receptor agonist), muscimol (10(-3)-10(-5) M, GABA-A agonist), and baclofen (10(-3)-10(-5) M, GABA-B agonist) had no significant effect on the electrically stimulated relaxation. Moreover, bicuculline (10(-5) M, GABA-A antagonist) and phaclofen (10(-5) M, GABA-B antagonist) had no inhibitory effect on the electrically stimulated relaxation. This suggests that GABA and the GABA receptor are not involved in the electrically stimulated NANC relaxation in the cat LES.

Signal transduction of bombesin-induced circular smooth muscle cell contraction in cat esophagus.

AIM: To investigate the mechanism of bombesin-induced circular smooth muscle cell contraction in cat esophagus. METHODS: Specific G protein or phospholipase C involved in cat esophagus contraction was identified, muscle cells were permeabilized with saponin. After permeabilization of muscle cells, the Gi3 antibody inhibited bombesin-induced smooth muscle cell contraction. RESULTS: Incubation of permeabilized circular muscle cells with PLC-beta3 antibody could inhibit bombesin-induced contraction. H-7, chelerythrine (PKC inhibitor) and genistein (protein tyrosine kinase inhibitor) inhibited bombesin-induced contraction, but DAG kinase inhibitor, R59949, could not inhibit it. To examine which mitogen-activated protein kinase (MAPK) was involved in bombesin-induced contraction, the specific MAPK inhibitors (MEK inhibitor, PD98059 and p38 MAPK inhibitor, SB202190) were used. Preincubation of PD98059 blocked the contraction induced by bombesin in a concentration-dependent manner. However, SB202190 had no effects on contraction. CONCLUSION: Bombesin-induced circular muscle cell contraction in cat esophagus is madiated via a PKC or a PTK-dependent pathway or p44/p42 MAPK pathway.

Minocycline attenuates white matter damage in a rat model of chronic cerebral hypoperfusion.

White matter lesions are thought to result from chronic cerebral ischemia and constitute a core pathology of subcortical vascular dementia. This rarefaction has been known to be associated with microglial activation. We investigated whether minocycline, a microglial inhibitor, attenuates the white matter damage induced by chronic cerebral hypoperfusion that is used as a model of vascular dementia. Male Wistar rats were subjected to bilateral, permanent occlusion of the common carotid arteries (BCCAO) to induce chronic cerebral hypoperfusion. Minocycline or saline was injected daily for 2 weeks after BCCAO. In the corpus callosum and the optic tract, white matter damage observed with Klüver-Barrera staining was significantly attenuated in the minocycline-treated group compared to saline-treated controls. In control rats, immunoreactivities of major basic protein (MBP), Ox-42 as a microglial marker, and matrix metalloproteinase (MMP)-2 were increased in the corpus callosum. Minocycline significantly reduced these changes. Co-expression of Ox-42 and MMP-2 was confirmed by double immunofluorescence histochemistry. Our results suggest that chronic treatment with minocycline could be protective against at least some ischemic white matter damage, and its mechanism may be related to suppressing microglial activation.

The alteration of intracellular signaling on the smooth muscle cells contraction in cat esophagitis.

We investigated the alteration of signal transduction after acute esophagitis in cat lower esophageal sphincter (LES). Acute esophagitis (AE) was induced by perfusion with 0.1N HCl at a rate of 1 ml/min for 45 min over three consecutive days. Acetylcholine (ACh)-induced contraction was inhibited by M3>> M1 or M2 antagonists in normal LES. In AE, inhibition by M2 antagonists increased significantly, so that contraction was inhibited by M3> M2> M1 antagonists and the expression of M2 and M3 receptors were increased when compared to normal LES. In normal cells, ACh-induced contractions were antagonized by antibody against G(q/11) and the phosphatidylinositol-specific phospholipase C (PI-PLC) antagonist, U73122. The phosphatidylcholine-specific phospholipase C (PC-PLC) inhibitor, D609, or the phospholipase D inhibitor, propranolol had no effects on contraction in normal LES. However, in AE, G(q/11), and G(i3) antibodies reduced ACh-induced contraction and U73122, propranolol and D609 also reduced the contraction. In AE, we found that the expressions of G protein subtypes were increased but the expression of PLCbeta1, and PLCgamma1 were decreased when compared to normal LES. In conclusion, experimental esophagitis may alter the signal transduction by ACh in LES. ACh-induced contraction is mediated by M3 receptor, G(q/11) and PI-PLC in normal LES. However, in AE, the contractions are mediated by M2, M3 receptor, G(q/11) and G(i3). PC-PLC and PLD as PI-PLC are also involved in ACh-induced cell contraction in AE.