Oleanolic acid alleviates the extrapyramidal symptoms and cognitive impairment induced by haloperidol through the striatal PKA signaling pathway in mice.

Haloperidol, one of the representative typical antipsychotics, is on the market for schizophrenia but shows severe adverse effects such as extrapyramidal symptoms (EPS) or cognitive impairments. Oleanolic acid (OA) is known to be effective for tardive dyskinesia which is induced by long-term treatment with L-DOPA. This study aimed to investigate whether OA could ameliorate EPS or cognitive impairment induced by haloperidol. The balance beam, catalepsy response, rotarod and vacuous chewing movement (VCM) tests were performed to measure EPS and the novel object recognition test was used to estimate haloperidol-induced cognitive impairment. Levels of dopamine and acetylcholine, the phosphorylation levels of c-AMP-dependent protein kinase A (PKA) and its downstream signaling molecules were measured in the striatum. OA significantly attenuated EPS and cognitive impairment induced by haloperidol without affecting its antipsychotic properties. Valbenazine only ameliorated VCM. Also, OA normalised the levels of dopamine and acetylcholine in the striatum which were increased by haloperidol. Furthermore, the increased phosphorylated PKA, extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) levels and c-FOS expression level induced by haloperidol were significantly decreased by OA in the striatum. In addition, cataleptic behaviour of haloperidol was reversed by sub-effective dose of H-89 with OA. These results suggest that OA can alleviate EPS and cognitive impairment induced by antipsychotics without interfering with antipsychotic properties via regulating neurotransmitter levels and the PKA signaling pathway in the striatum. Therefore, OA is a potential candidate for treating EPS and cognitive impairment induced by antipsychotics.

Effect of D-pinitol on MK-801-induced schizophrenia-like behaviors in mice.

Schizophrenia is a chronic brain disorder characterized by positive symptoms (delusions or hallucinations), negative symptoms (impaired motivation or social withdrawal), and cognitive impairment. In the present study, we explored whether D-pinitol could ameliorate schizophrenia-like behaviors induced by MK-801, an N-methyl-D-aspartate receptor antagonist. Acoustic startle response test was conducted to evaluate the effects of D-pinitol on sensorimotor gating function. Social interaction and novel object recognition tests were employed to measure the impact of D-pinitol on social behavior and cognitive function, respectively. Additionally, we examined whether D-pinitol affects motor coordination. Western blotting was conducted to investigate the mechanism of action of D-pinitol. Single administration of D-pinitol at 30, 100, or 300 mg/kg improved the sensorimotor gating deficit induced by MK801 in the acoustic startle response test. D-Pinitol also reversed social behavior deficits and cognitive impairments induced by MK-801 without causing any motor coordination deficits. Furthermore, D-pinitol reversed increased expression levels of pNF-kB induced by MK-801 treatment and consequently increased expression levels of TNF-α and IL-6 in the prefrontal cortex. These results suggest that D-pinitol could be a potential candidate for treating sensorimotor gating deficits and cognitive impairment observed in schizophrenia by down-regulating transcription factor NF-κB and pro-inflammatory cytokines in the prefrontal cortex.

Effects of oleanolic acid and ursolic acid on depression-like behaviors induced by maternal separation in mice.

Oleanolic acid (OA) and ursolic acid (UA) are structural isomeric triterpenoids. Both triterpenoids have been reported to be able to improve depression. However, no studies have compared their effects in the same system. Whether OA or UA could ameliorate depression-like behaviors in maternal separation (MS)-induced depression-like model was investigated. MS model is a well-accepted mouse model that can reflect the phenotype and pathogenesis of depression. Depression is a mental illness caused by neuroinflammation or changes in neuroplasticity in certain brain regions, such as the prefrontal cortex and hippocampus. Depression-like behaviors were measured using splash test or forced swimming test. In addition, anxiety-like behaviors were also measured using the open field test or elevated plus-maze test. MS-treated female mice showed greater depression-like behaviors than male mice, and that OA improved several depression-like behaviors, whereas UA only relieved anxiety-like behavior of MS-treated mice. Microglial activation, expression levels of TNF-α, and mRNA levels of IDO1 were increased in the hippocampi of MS-treated female mice. However, OA and UA treatments attenuated such increases. In addition, expression levels of synaptophysin and PSD-95 were decreased in the hippocampi of MS-treated female mice. These decreased expression levels of synaptophysin were reversed by both OA and UA treatments, although decreased PSD-95 expression levels were only reversed by OA treatment. Our findings suggest that MS cause depression-like behaviors through female-specific neuroinflammation, changes of tryptophan metabolism, and alterations of synaptic plasticity. Our findings also suggest that OA could reverse MS-induced depression-like behaviors more effectively than UA.

Effects of Artemisia annua L. on postmenopausal syndrome in ovariectomized mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia annua L. (Asteraceae) has been used as an antipyretic and anti-parasitic drug in traditional medicine for more than 2000 years. It has also been prescribed to treat symptoms caused by deficiency of Yin, which might be observed in menopausal state from the point of view of traditional medicine. AIM OF THE STUDY: We hypothesized that A. annua might be useful for treating menopausal disorders with less adverse effects than hormone replacement therapy. Thus, the aim of the present study was to investigate effects of A. annua on postmenopausal symptoms of ovariectomized (OVX) mice. MATERIALS AND METHODS: OVX mice were employed as a model for postmenopausal disorders. Mice were treated with a water extract of A. annua (EAA; 30, 100 or 300 mg/kg, p.o.) or 17ß-estradiol (E2; 0.5 mg/kg, s.c.) for 8 weeks. Open field test (OFT), novel object recognition task (NOR), Y-maze test, elevated plus maze test (EPM), splash test and tail suspension test (TST) were conducted to determine whether EAA could ameliorate postmenopausal symptoms. Phosphorylated levels of extracellular signal-regulated kinase (ERK), protein kinase B (Akt), and glycogen synthase kinase-3ß (GSK-3ß), ß-catenin and expression level of synaptophysin in the cortex and hippocampus were evaluated by Western blot analysis. RESULTS: EAA treatment significantly increased the discrimination index in NOR, decreased the time in closed arm than in open arm in EPM, increased grooming time in splash test, and decreased immobility time in TST, as did E2 treatment. In addition, decreased phosphorylation levels of ERK, Akt, GSK-3ß, and ß-catenin and expression levels of synaptophysin in the cortex and hippocampus after OVX were reversed by administration of EAA and E2. CONCLUSION: These results suggest that A. annua can ameliorate postmenopausal symptoms such as cognitive dysfunction, anxiety, anhedonia, and depression by activating ERK, Akt, and GSK-3ß/ß-catenin signaling pathway and hippocampal synaptic plasticity, and that A. annua would be a novel treatment for postmenopausal symptoms.

Paeonol, the active component of Cynanchum paniculatum, ameliorated schizophrenia-like behaviors by regulating the PI3K-Akt-GSK3ß-NF-κB signalling pathway in MK-801-treated mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Cynanchum paniculatum (Bunge) Kitag. ex H. Hara (Asclepiadaceae) have been traditionally used in East Asia as analgesic or antiviral agents. Interestingly, some Chinese and Korean traditional medicinal books reported that the use of C. paniculatum in the treatment of psychotic symptoms, such as hallucinations and delusions. AIM OF THE STUDY: In this study, we aimed to investigate whether C. paniculatum could improve sensorimotor gating disruption in mice with MK-801-induced schizophrenia-like behaviors. We also aimed to identify the active component of C. paniculatum that could potentially serve as a treatment for schizophrenia and found that paeonol, the major constituent compound of C. paniculatum, showed potential as a treatment for schizophrenia. MATERIALS AND METHODS: To assess the effect of paeonol on mice with MK-801-induced schizophrenia-like behaviors, we carried out a series of behavioral tests related with symptoms of schizophrenia. In addition, we utilized Western blotting and ELISA techniques to investigate the antipsychotic actions of paeonol. RESULT: C. paniculatum extract (100 or 300 mg/kg) and paenol (10 or 30 mg/kg) significantly reversed MK-801-induced prepulse deficits in acoustic startle response test. In addition, paeonol (10 or 30 mg/kg) attenuated social novelty preference and novel object recognition memory on MK-801-induced schizophrenia-like behaviour in mice. Furthermore, the phosphorylation levels of PI3K, Akt, GSK3ß and NF-κB, as well as related pro-inflammatory cytokine, such as IL-1ß and TNF-α, were significantly reversed by the administration of paeonol (10 or 30 mg/kg) in the prefrontal cortex of MK-801-treated mice. CONCLUSIONS: Collectively, these data show that paeonol can potentially be used as an agent for treating sensorimotor gating deficits, negative symptoms, and cognitive deficits, such as those observed in schizophrenia with few adverse effects.

The effect of lansoprazole on MK-801-induced schizophrenia-like behaviors in mice.

As a heterogeneous disorder, schizophrenia is known to be associated with neuroinflammation. A recent study showed that several cytokines are higher in the plasma and cerebrospinal fluid of schizophrenia patients. Lansoprazole, a proton pump inhibitor used for treating erosive esophagitis, has been reported to reduce INF-γ-induced neurotoxicity and decrease inflammatory cytokines including IL-1ß, IL-6, and TNF-α. These findings persuaded us to examine whether lansoprazole ameliorates schizophrenia-like symptoms. The schizophrenia mouse model was induced by the acute administration of MK-801, an NMDA receptor antagonist. Sensorimotor gating, Barnes maze, and social novelty preference tests were conducted to evaluate schizophrenia-like behaviors. We found that lansoprazole (0.3, 1, or 3 mg/kg) ameliorated sensorimotor gating deficits, spatial learning, and social deficits caused by MK-801 treatment (0.2 mg/kg). The catalepsy test, balance beam test, and rotarod test were performed to reveal the adverse effects of lansoprazole on motor coordination. The behavioral results indicated that lansoprazole did not result in any motor function deficits. Moreover, lansoprazole decreased inflammatory cytokines including IL-6 and TNF-α only in the cortex, but not in the hippocampus. Collectively, these results suggest that lansoprazole could be a potential candidate for treating schizophrenia patients who suffer from sensorimotor gating deficits or social disability without any motor-related adverse effects.

Vessel Wall Changes on Serial High-Resolution MRI and the Use of Cilostazol in Patients With Adult-Onset Moyamoya Disease.

BACKGROUND AND PURPOSE: The natural course of adult-onset moyamoya disease (MMD) is unknown, and there is no medical treatment that halts its progression. We hypothesized that progressive shrinkage of large intracranial arteries occurs in adult-onset MMD, and that cilostazol inhibits this process. METHODS: Serial high-resolution magnetic resonance imaging (HR-MRI) was performed on 66 patients with MMD: 30 patients received cilostazol, 21 received other antiplatelets, and 15 received no antiplatelets or had poor compliance to them. Serial HR-MRI was performed (interval between MRI scans: 29.67±18.02 months, mean±SD), and changes in outer diameter, luminal stenosis, and vascular enhancement were measured. Factors affecting HR-MRI changes were evaluated, including vascular risk factors and the ring finger protein 213 gene variant. RESULTS: The progression of stenosis to occlusion, recurrent ischemic stroke, and the development of new stenotic segments were observed in seven, seven, and three patients, respectively. Serial HR-MRI indicated that the degree of stenosis increased with negative remodeling (outer diameter shrinkage). Patients who received cilostazol presented significantly larger outer diameters and lower degrees of stenosis compared with other groups (p=0.005 and p=0.031, respectively). After adjusting for clinical and genetic factors, only cilostazol use was independently associated with negative remodeling (odds ratio=0.29, 95% confidence interval=0.10-0.84, p=0.023). While vascular enhancement was observed in most patients (61 patients), the progression of enhancement or the occurrence of new vascular enhancement was rarely observed on follow-up HR-MRI (6 and 1 patients, respectively). CONCLUSIONS: Adult-onset MMD induces progressive shrinkage of large intracranial arteries, which cilostazol treatment may prevent. Further randomized clinical trials are warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02074111.

CLAIRE-Parallelized Diffeomorphic Image Registration for Large-Scale Biomedical Imaging Applications.

We study the performance of CLAIRE-a diffeomorphic multi-node, multi-GPU image-registration algorithm and software-in large-scale biomedical imaging applications with billions of voxels. At such resolutions, most existing software packages for diffeomorphic image registration are prohibitively expensive. As a result, practitioners first significantly downsample the original images and then register them using existing tools. Our main contribution is an extensive analysis of the impact of downsampling on registration performance. We study this impact by comparing full-resolution registrations obtained with CLAIRE to lower resolution registrations for synthetic and real-world imaging datasets. Our results suggest that registration at full resolution can yield a superior registration quality-but not always. For example, downsampling a synthetic image from 10243 to 2563 decreases the Dice coefficient from 92% to 79%. However, the differences are less pronounced for noisy or low contrast high resolution images. CLAIRE allows us not only to register images of clinically relevant size in a few seconds but also to register images at unprecedented resolution in reasonable time. The highest resolution considered are CLARITY images of size 2816×3016×1162. To the best of our knowledge, this is the first study on image registration quality at such resolutions.

Factors Associated With Voriconazole Concentration in Pediatric Patients.

BACKGROUND: Serum concentrations of voriconazole are difficult to predict, especially in pediatric patients, because of its complex pharmacokinetic characteristics. This study aimed to identify the factors associated with the concentration of voriconazole in pediatric patients. METHODS: This cohort study was based on retrospective data collection and involved the administration of voriconazole to pediatric patients younger than 18 years, between January 2010 and August 2017. Electronic medical records of the patients were reviewed to collect demographic characteristics, voriconazole treatment regimen, and factors that could potentially influence voriconazole trough concentrations. A voriconazole trough serum concentration of less than 1.0 mcg/mL or greater than 5.5 mcg/mL was defined as outside the therapeutic range and was set as the outcome of this study. RESULTS: Among the 114 patients enrolled, 61 patients were included in the analysis. Oral administration of a maintenance dose of voriconazole and C-reactive protein (CRP) level were significantly and independently associated with a low initial trough concentration of voriconazole (<1.0 mcg/mL). Alanine aminotransferase levels were a significant factor associated with a high initial trough concentration of voriconazole (>5.5 mcg/mL) after adjusting for sex, age, weight, and serum creatinine (odds ratio 5.42; 95% confidence interval 1.34-21.97). CONCLUSIONS: Considering the variability of voriconazole concentrations in pediatric patients, monitoring certain parameters and considering the route of administration could help determine the therapeutic range of voriconazole and subsequently avoid unwanted effects.

Factors affecting high-grade hepatotoxicity of tyrosine kinase inhibitors in cancer patients: a multi-center observational study.

PURPOSE: Although several studies have examined tyrosine kinase inhibitor (TKI)-induced hepatotoxicity, the majority of patients in those studies displayed low-grade (grade I-II) hepatotoxicity. The purpose of this study was to investigate factors affecting high-grade (grade III-IV) hepatotoxicity of TKIs. METHODS: This multi-center, retrospective study used individual patient data from five studies that examined factors affecting hepatotoxicity by TKIs (crizotinib, erlotinib, gefitinib, imatinib, and lapatinib). Odds ratio (OR) and adjusted OR (AOR) were estimated from univariate and multivariate analyses, respectively. RESULTS: Data from 1279 patients treated with TKIs were analyzed. The rate of patients who experienced high-grade hepatotoxicity after TKI administration was 5.5%. In multivariable analysis, H2 blockers and CYP3A4 inducers increased high-grade hepatotoxicity 2.2- (95% CI 1.255-3.944) and 3.3-fold (95% CI 1.260-8.698), respectively. Patients with liver metastasis revealed a 3.4-fold (95% CI 1.561-7.466) higher risk of high-grade hepatotoxicity. Among underlying malignancies, pancreatic cancer and other cancers including acute lymphoblastic leukemia increased the risk of high-grade hepatotoxicity by 2.6- and 24.3-fold, respectively, whereas breast cancer decreased the risk (AOR 0.3, 95% CI 0.106-0.852), compared to non-small cell lung cancer. In patients who administrated TKIs which form reactive metabolites, use of CYP3A4 inducers and liver metastasis increased incidence of high-grade hepatotoxicity by 3.0- and 2.3-fold, respectively. In patients with EGFR mutation, exon 19 deletion and use of proton pump inhibitors were risk factors for high-grade hepatotoxicity in addition to liver metastasis and use of H2 blockers. CONCLUSION: The use of H2 blockers, presence of liver metastasis, and CYP3A4 inducers were associated with high-grade hepatotoxicity of TKIs. In subgroup analyses, presence of exon 19 deletion, and/or proton pump inhibitors, was additional risk factors for high-grade hepatotoxicity in special patients and use of specific TKIs. Close liver function monitoring is recommended, especially in patients with liver metastasis or using H2 blockers or CYP3A4 inducers.

Low cyclosporine concentrations in children and time to acute graft versus host disease.

BACKGROUND: Achievement of target blood concentrations of cyclosporine (CsA) early after transplantation is known to be highly effective for reducing the incidence of acute graft versus host disease (aGVHD). However, no research has been conducted for predicting aGVHD occurrence with low CsA concentrations at different time periods. The objective of this study was to investigate the risk of aGVHD according to low CsA concentrations at lag days in children with allogenic hematopoietic stem cell transplantation (HSCT). METHODS: The records of 61 consecutive children who underwent allogeneic HSCT and received CsA as prophylaxis against aGVHD between May 2012 and March 2015 were retrospectively evaluated. The main outcome was any association between low CsA concentrations at lag days and aGVHD occurrence, which was examined for the first month after transplantation. Mean CsA concentrations at three lag periods were calculated: lag days 0-6, 7-13, and 14-20 before aGVHD occurrence. RESULTS: Patients whose mean CsA concentrations at lag days 0-6 did not reach the initial target concentration had 11.0-fold (95% confidence interval [CI]: 2.3-51.9) greater incidence of aGVHD. In addition, the AORs of low CsA concentrations at lag days 7-13 and 14-20 for developing aGVHD were 108.2 (95% CI: 7.7-1515.5) and 12.1 (95% CI: 1.1-138.1), respectively. CONCLUSIONS: After low CsA concentrations are detected, careful attention needs to be paid to prevent aGVHD.

Effects of Citrulline Supplementation on Body Weight in Patients With Hepatobiliary Pancreatic Surgery.

BACKGROUND: Many health benefits have been proposed for citrulline, but they lack evidence based on human research. This study was to evaluate whether an oral citrulline supplement affects body weight changes and laboratory values in patients with hepatobiliary and pancreatic surgery. METHODS: Patients who underwent hepatobiliary and pancreatic surgery during January to June 2015 were screened for analysis. Patients using citrulline during hospital stay and at discharge were classified as the citrulline group, whereas those without any records of citrulline were designated as the control group. The primary efficacy outcome was the change in body weight at discharge and at first outpatient visit. Other outcomes included change in laboratory values. RESULTS: A total of 138 patients were included in analysis. Citrulline group and control group did not differ with respect to baseline characteristics except for white blood cell count. Percent in change of body weight and body mass index from discharge to first outpatient visit was significantly different between the 2 groups, showing less weight loss in citrulline group than in controls (-0.8 ± 2.7% vs -2.5 ± 3.8%, P < 0.05). Especially in men, citrulline use significantly affected weight loss from the multivariate analysis (P < 0.05); percent change in weight in citrulline group was predicted to increase by 2.1 units. During hospital stay, significant differences between the 2 groups were found in changes of cholesterol and protein levels. CONCLUSION: Citrulline supplement reduced weight loss in surgical patients during recovery.

Effects of proton pump inhibitor use on risk of Clostridium difficile infection: a hospital cohort study.

BACKGROUND: Although there are several studies on the association between use of proton pump inhibitors (PPIs) and increased Clostridium difficile infection (CDI) risk, detailed studies analyzing the effects of PPI use on CDI risk are lacking. The present study investigated the association of the dose, duration, and types of PPIs with CDI risk. METHODS: A single-center, cohort study was conducted on patients admitted to a hospital. The exposed cohort comprised patients who were prescribed PPIs at least once during the study period, and a control cohort was prepared by randomly assigning an index date to patients who did not use PPIs ensuring the same distribution of index dates as in the exposed cohort and matching sex, age, hospitalization period, and date of admission. RESULTS: PPI use increased the risk of CDI by 1.8-fold [95% confidence interval (CI) 1.5-2.2]. CDI risk increased by 1.8-fold with esomeprazole (95% CI 1.4-2.2) and 2.0-fold with pantoprazole (95% CI 1.5-2.8). Patients who used a high dose had a higher risk than those who used a medium dose [adjusted hazard ratio (HR) 2.0 vs 1.3]. The risk of CDI increased 4.2-fold when the PPI exposure period was 6 days or shorter than 6 days. CONCLUSIONS: Our study showed that PPI use was associated with an increased risk of developing CDI and the risk of CDI was dose dependent. Therefore, PPIs should only be used at proper doses and only for the necessary indications to avoid CDI risk.

Risk factors for neutropenia and febrile neutropenia following prophylactic pegfilgrastim.

AIM: Neutropenia is a common side effect of myelosuppressive chemotherapy. Administration of granulocyte colony-stimulating factor is being used for neutropenia prophylaxis, but there are patients who develop neutropenia or febrile neutropenia despite prophylaxis. We attempted to identify potential risk factors for chemotherapy-induced neutropenia in patients with pegfilgrastim prophylaxis. METHODS: This was a single-center, retrospective, observational study of patients with breast cancer or diffuse large B-cell lymphoma. We obtained patients' data from electronic medical records, including baseline demographics and clinical characteristics regarding diseases, treatments and laboratory values. The outcome measures assessed were the incidence of neutropenia and febrile neutropenia. RESULTS: There were a total of 127 patients, including 77 patients with diffuse large B-cell lymphoma (DLBCL) and 50 patients with breast cancer, and we analyzed 722 chemotherapy cycles. We found 88 cases (12.2%) of grade 3 or 4 neutropenia and 39 cases of febrile neutropenia (5.4%). In the univariate analysis, variables associated with both grade 3 or 4 neutropenia and febrile neutropenia were age, cancer type, cancer stage, radiotherapy and platelet count. A multivariate logistic regression model revealed that age, radiotherapy and platelet count were significant factors in severe neutropenia, whereas platelet count was the only statistically significant factor in febrile neutropenia. Platelet counts of less than 150 000/mm3 increased the risk of neutropenia and febrile neutropenia approximately fourfold. In the subgroup analysis of patients with DLBCL, it was found that platelet count was a significant factor for both neutropenia and febrile neutropenia. CONCLUSION: Among cancer patients with pegfilgrastim prophylaxis, advanced age, absence of radiation therapy and low platelet count were independent predictors of neutropenia, and low platelet count was the predictor of febrile neutropenia.

Factors affecting crizotinib-induced hepatotoxicity in non-small cell lung cancer patients.

Crizotinib is an orally available tyrosine kinase inhibitor for patients with anaplastic lymphoma kinase-positive non-small cell lung cancer (NSCLC). Despite that crizotinib-induced hepatotoxicity may cause a dose reduction or interruption that can affect the patient's treatment, there is no study to investigate factors for crizotinib-induced hepatotoxicity. The purpose of this study was to evaluate factors affecting crizotinib-induced hepatotoxicity. From February 2012 to April 2018, a retrospective study was performed on NSCLC patients treated with crizotinib. Various factors were reviewed including sex, age, body weight, height, body surface area, underlying disease, smoking history, genetic mutation, and concomitant drugs. Among 153 patients, incidence of crizotinib-induced hepatotoxicity of grade I or higher was 83% (n = 127). The presence of liver disease or HBV revealed significant effect on hepatotoxicity within 28 days after crizotinib administration in univariate analysis. Patients with liver disease or HBV carriers revealed 2.3 times the hazard of time to hepatotoxicity compared to those without liver disease or HBV. Use of H2-antagonist or H2-antagonist/proton pump inhibitor revealed 1.7 times the hazard of time to hepatotoxicity compared to those that did not use those medications. Thus, close monitoring of liver function is recommended, especially in patients with liver impairment or using anti-acid secreting agents.

Factors affecting time to reach and recover from gefitinib-induced hepatotoxicity.

Gefitinib is an oral tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) for non-small-cell lung cancer with EGFR mutations. Although a few studies have analyzed the causes of gefitinib-induced hepatotoxicity, research focusing on the time intervals before and after hepatotoxicity has yet to be reported. Therefore, this study investigated two types of factors: the time to reach gefitinib-induced hepatotoxicity and the time for recovery. From January 2013 to December 2014, a retrospective study was carried out on 473 non-small-cell lung cancer patients who were treated with gefitinib. The following data were collected: sex, age, body weight, height, body surface area, underlying disease, Eastern Cooperative Oncology Group Performance Status, smoking history, gefitinib dose, EGFR mutation, and concomitant drugs. Multivariate models showed that patients with mutations in exon 19 had around two-fold higher hepatotoxicity (≥grade 2). Use of CYP3A4 inhibitors and smoking shortened time to hepatotoxicity ∼5-2-fold, respectively, whereas mutations in exon 21 prolonged time to hepatotoxicity by about 2.4-fold. Termination of gefitinib therapy showed 3.8-fold faster recovery. Our study showed that the concomitant use of CYP3A4 inhibitors, smoking, and exon 21 affected the time to reach gefitinib-induced hepatotoxicity. Among the factors examined in this study including hepatotonic use and gefitinib termination, only cessation of gefitinib therapy significantly accelerated recovery.

Effects of Concomitant Medication Use on Gefitinib-Induced Hepatotoxicity.

Gefitinib is a drug used for the treatment of non-small cell lung cancer (NSCLC) patients. Severe hepatotoxicity was observed, but only a few cases have been reported on the hepatotoxicity of gefitinib. This study aimed to investigate the association between gefitinib-induced hepatotoxicity and various factors including concomitant medications in lung cancer patients. From January 2013 to December 2014, a retrospective study was performed with NSCLC patients who were treated with gefitinib. Associations between hepatotoxicity and various factors including concomitant drugs were analyzed. Based on multivariate models, it was found that H2 antagonists, proton pump inhibitors (PPIs), and H2 antagonists or PPIs increased hepatotoxicity by about 1.5- to 1.7-fold. Patients younger than 65 years showed 1.6 times higher hepatotoxicity than those older than 65 years. Patients with EGFR mutations had around 2-fold higher hepatotoxicity, and the percentage of incidence of hepatotoxicity because of exon 19 deletion was 32.7%. Our study showed that anti-acid-secreting agents in addition to age younger than 65 years and EGFR mutation were associated with gefitinib-induced hepatotoxicity. Thus, close monitoring of liver function is recommended, especially for patients using anti-acid-secreting agents.

Association of symptom control with changes in lung function, bronchial hyperresponsiveness, and exhaled nitric oxide after inhaled corticosteroid treatment in children with asthma.

BACKGROUND: A key therapeutic approach to asthma, which is characterized by chronic airway inflammation, is inhaled corticosteroid (ICS). This study evaluated the association of symptom control with changes in lung function, bronchial hyperresponsiveness (BHR), and exhaled nitric oxide (eNO) after ICS treatment in asthmatic children. METHODS: A total of 33 children aged between 5 and 12 years with mild to moderate persistent asthma were treated with 160 µg ciclesonide per day for 3 months. At days 0 and 90, the following parameters were assessed: asthma symptom scores; lung function, including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and forced expiratory flow at 25-75% of forced vital capacity (FEF25-75%); BHR to methacholine and adenosine 5-monophosphate (AMP); and eNO. RESULTS: Asthma symptom scores, lung function parameters, BHR to methacholine and AMP, and eNO levels at day 90 were significantly improved versus day 0 (all p < 0.001). Symptom scores at day 90 were not correlated with changes in lung function and BHR to methacholine during the follow-up period, whereas those at day 90 were more closely correlated with changes in BHR to AMP (r = 0.511, p = 0.003) than with eNO (r = -0.373, p = 0.035). Additionally, changes in PC20 AMP were correlated with changes in PC20 methacholine (r = 0.451, p = 0.011) and eNO (r = -0.474, p = 0.006). CONCLUSIONS: Changes in the BHR to AMP, and to a lesser extent eNO, correlate with asthma symptom control after ICS treatment. BHR to AMP may better reflect the relationship between improved airway inflammation due to ICS treatment and asthma symptoms.

Erratum to: The relationship between quality of sleep and night shift rotation interval.

[This corrects the article DOI: 10.1186/s40557-015-0084-x.].