A pharmacovigilance approach for assessing the occurrence of suicide-related events induced by antiepileptic drugs using the Japanese adverse drug event report database.

Increased suicidality after antiepileptic drug (AED) treatment remains controversial. This study aimed to investigate the occurrence of suicide-related events (SREs) in Japan. SREs signals with AEDs used orally were evaluated by calculating reporting odds ratios (RORs) and information components (ICs) using the Japanese Adverse Drug Event Report (JADER) database from April 2004 to December 2021. Additionally, factors affecting the occurrence of SREs and time-to-onset from the initial AED treatment were analyzed. Of 22 AEDs, 12 (perampanel hydrate, nitrazepam, levetiracetam, clonazepam, clobazam, sodium valproate, phenobarbital, lamotrigine, lacosamide, gabapentin, zonisamide, and carbamazepine) showed signals of SREs. Patients in their 20 and 30 s, female sex, and concomitant use of multiple AEDs affected the occurrence of SREs. In six AEDs, the median time-to-onset of SREs in patients taking all AEDs was <100 days. The pharmacovigilance approach revealed that several AEDs displayed suicidality signals. Female patients, those in their 20 and 30 s, undergoing combination therapy with ≥2 AEDs, and patients early (<100 days from the initial treatment) in the course of AED therapy should be cautioned about SREs.

Neutrophil-Lymphocyte Ratio Is Associated With Occurrence of Febrile Neutropenia in Patients Treated With 5-Fluorouracil and Cisplatin.

BACKGROUND/AIM: This study aimed to determine whether a high neutrophil-lymphocyte ratio (NLR) was associated with the occurrence of febrile neutropenia (FN). PATIENTS AND METHODS: Japanese patients with esophageal cancer who had been treated with first-line 5-fluorouracil and cisplatin therapy at Fujita Health University from April 2016 to March 2021 were enrolled in this retrospective cohort study. The primary outcome was the identification of independent risk factors for FN. RESULTS: One hundred and fourteen patients were enrolled. Advanced cancer (hazard ratios (HR)=6.731) and an NLR ≥3 (HR=4.849) were identified as risk factors for FN. Furthermore, FN occurred earlier in patients with high NLR than in patients with low NLR. CONCLUSION: Advanced cancer and a high NLR might be predictors of the occurrence of severe neutropenia and FN in patients treated with 5-fluorouracil and cisplatin therapy.

Prognosis of Patients With Interstitial Lung Disease Induced by Different Pharmacological Types of Anticancer Drugs.

BACKGROUND/AIM: The aim of this study was to evaluate the effect of drug-induced interstitial lung disease (DILD) on treatment outcomes by comparing the mortality of patients with DILD induced by different pharmacological types of anticancer drugs. PATIENTS AND METHODS: Japanese patients with lung cancer who had received chemotherapy at Fujita Health University Hospital were enrolled. The primary outcome was the short-term mortality rate from the administration of chemotherapy that might have caused DILD. RESULTS: Eleven, 16, and 20 patients with DILD were assigned to the kinase inhibitor (KI), immune-checkpoint inhibitor (ICI), and cytotoxic anticancer drug groups, respectively. The 90-day mortality rate after the DILD event in the group treated with cytotoxic anticancer drugs was significantly higher than in the KI and ICI groups. CONCLUSION: Patients with DILD induced by cytotoxic anticancer drugs have poorer prognoses than those with DILD induced by KIs or ICIs.

Drug-induced Interstitial Lung Disease Has the Same Degree of Risk for Mortality as Old Age in Patients With Lung Cancer.

BACKGROUND/AIM: The aim of this study was to investigate the impact of drug-induced interstitial lung disease (DILD) on the mortality of patients with lung cancer. PATIENTS AND METHODS: Japanese patients with lung cancer who had received chemotherapy in Fujita Health University Hospital from January 2017 to December 2018 were enrolled in this study. The primary outcome was to identify independent factors associated with patient mortality. The secondary outcome was to identify the risk factor of DILD. RESULTS: Four hundred and fifty-seven patients were assigned to the current study. The multivariable analysis revealed that being aged 75 years or older, small cell lung carcinoma, cancer stage IV, and DILD event were risk factors of mortality. Male sex was identified as a risk factor of DILD. CONCLUSION: DILD event has the same degree of risk for mortality as age 75 years or older in lung cancer patients.

[Alteration in antibody-mediated immunity in patients with rituximab-combined chemotherapy and incidence of herpes zoster].

Rituximab, a chimeric monoclonal antibody against the CD20 protein, has an antineoplastic effect resulting from antibody dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In patients with rituximab-combined chemotherapy, a decline in immunoglobulin can be observed. This is more likely to cause virus reactivation, such as Herpes (H) zoster. However, this fact has not reported in a large-scale study. In order to research immunodeficiency conditions in patients with rituximab-combined therapy, we examined the alteration in immunoglobulin level throughout the treatment among 205 cases with B-cell lymphoma. We also studied the prevalence of H. zoster in those cases. The IgG level throughout the treatment was measured in 89 patients in the research. The median post-chemotherapy IgG level was 41.1% lower than its pre-chemotherapy IgG level. In 58 cases, the IgG level following chemotherapy was below the normal level. In 22 cases, the IgG level dropped to less than half of the pre-chemotherapy level. H. zoster developed in 17 cases (8.3%). There was no significant difference in IgG level between H. zoster-onset cases and non-H. zoster-onset cases. Antibody-mediated immunity can decrease greatly and prolong in cases with rituximab in combination with chemotherapy. Therefore, infection control is considered to be important.

Acceleration of matrix metalloproteinase-1 production and activation of platelet-derived growth factor receptor beta in human coronary smooth muscle cells by oxidized LDL and 4-hydroxynonenal.

Increases in matrix metalloproteinases (MMPs) at atherosclerotic lesions are involved in the migration of smooth muscle cells (SMCs) into the intima and to the rupture of plaques, being implicated in the progression of atherosclerosis. The present study examined the mechanisms underlying the production of MMP-1, interstitial collagenase-1, induced by oxidized low-density lipoprotein (oxLDL) and 4-hydroxynonenal (4-HNE), factors proposed to play a pivotal role in atherogenesis, in human coronary SMCs. oxLDL promoted the production of MMP-1 with the preceding phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Immunoprecipitation of platelet-derived growth factor receptor beta (PDGFR-beta) revealed that oxLDL induced tyrosine phosphorylation of the receptor. Inhibition of the activation of PDGFR-beta and ERK1/2 resulted in a suppression of the production of MMP-1. Consistently, 4-HNE also elicited the production of MMP-1 with the preceding phosphorylation of PDGFR-beta and ERK1/2. The 4-HNE-induced production of MMP-1 was prevented when the activation of PDGFR-beta and ERK1/2 was inhibited. The present results suggest that the activation of PDGFR-beta and ERK1/2 is involved in the production of MMP-1 in oxLDL- and 4-HNE-stimulated human coronary SMCs.

Suppression of oxidized LDL-induced PDGF receptor beta activation by ginkgo biloba extract reduces MMP-1 production in coronary smooth muscle cells.

AIM: An extract of Ginkgo Biloba L. was shown to have preventive effects on cardiovascular disorders, but the molecular mechanisms of its actions remain to be elucidated. Since matrix metalloproteinases (MMPs) are implicated in the rupture of atherosclerotic plaques and the subsequent occurrence of acute coronary syndrome, we examined the effects of a leaf extract (Ginkgolon-24) on the production of MMP-1 in human coronary smooth muscle cells stimulated with oxidized low-density lipoprotein (oxLDL) and 4-hydroxynonenal, which are factors proposed to play a pivotal role in atherogenesis. METHODS: The production of MMP-1 and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 were estimated by immunoblotting. The tyrosine-phosphorylated form of platelet-derived growth factor receptor beta (PDGFR-beta) was analyzed by immunoprecipitation of the receptor followed by immunoblotting. RESULTS: oxLDL and 4-hydroxynonenal accelerated the production of MMP-1 with the preceding phosphorylation of ERK1/2 and PDGFR-beta;. Pretreatment with Ginkgolon-24 inhibited the production of MMP-1 and phosphorylation of ERK1/2 induced by oxLDL and 4-hydroxynonenal, but did not affect the production and phosphorylation induced by phorbol ester. Furthermore, Ginkgolon-24 prevented tyrosine phosphorylation of the receptor induced by oxLDL and 4-hydroxynonenal. CONCLUSION: These results suggest that Ginkgo Biloba extract suppresses the oxLDL- and 4-hydroxynonenal-induced production of MMP-1, probably through the inhibition of PDGFR-beta activation in human coronary smooth muscle cells.

Comparison between hypersensitivity reactions to cycles of modified FOLFOX6 and XELOX therapies in patients with colorectal cancer.

PURPOSE: Although hypersensitivity reactions (HSRs) to oxaliplatin (L-OHP) therapy are well-documented, few reports have compared different therapies in terms of HSR occurrence. In this study, we compared the frequency and pattern of HSRs to modified FOLFOX6 (mFOLFOX6; 5-fluorouracil, levofolinate calcium and L-OHP infusions) and XELOX (capecitabine and L-OHP) therapies, and sought to identify risk factors associated with HSRs. METHODS: Patients who had received mFOLFOX6 or XELOX chemotherapeutic regimens for unresectable colon or rectal cancer or as adjuvant chemotherapy following colon cancer surgery between April 2012 and August 2015 were included. Potential correlation between treatment modalities (regimen, dosage and route of administration of L-OHP, and injection timing for dexamethasone administration) and HSRs was assessed. RESULTS: Among the 240 patients included in the study, 136 had received mFOLFOX6 therapy and 104 had received XELOX therapy. Although the frequency of HSRs did not differ between the two groups, incidence of HSRs in the first cycle was higher in the XELOX therapy group. Treatment method or cumulative dosage was not identified as a risk factor for HSR; however, the incidence of ≥grade-2 HSR was higher in cases where the cumulative L-OHP dosage was ≥600 mg/m2 and in patients in whom dexamethasone was not co-infused with L-OHP. CONCLUSION: Although HSR rates were comparable among patients treated with mFOLFOX6 and XELOX, HSRs tended to occur more frequently during the first cycle of XELOX therapy as compared to that with mFOLFOX6 therapy. Our findings warrant careful assessment of ≥grade-2 HSRs in patients who are prescribed cumulative L-OHP dosages of ≥600 mg/m2.