Unveiling the association between fluoroquinolones and aortic diseases using real-world database analysis and pharmacological experiments.

Fluoroquinolones, which are widely used antibiotics, have been linked to aortic disease, which prompted an FDA warning in 2018. Recent reports have challenged the perception that fluoroquinolones pose a significant risk for vascular diseases. This study aimed to investigate whether fluoroquinolones increase the risk of aortic diseases by focusing on the onset of aortic dissection. Levofloxacin (LVFX), a fluoroquinolone, was studied in vitro using cultured vascular cells and in vivo using a mouse model prone to aortic dissection. Risk of adverse drug events was analyzed using VigiBase, a global safety database, and a retrospective cohort analysis was conducted using the JMDC Claims database. LVFX resulted in endothelial cell injury and increased matrix metalloproteinases in vitro. However, in vivo studies showed no significant effect on elastin degradation or aortic dissection incidence. The effect of LVFX on endothelial injury was altered during the onset of dissection, exacerbating injury before onset but inhibiting it afterward. Safety database analysis showed no significant risk signals for aortic dissection associated with fluoroquinolones, which was supported by findings in the receipt database. Inconsistencies were observed in the in vitro and in vivo actions of fluoroquinolones and differences in their effects on aortic dissection and aneurysms. Despite cytotoxicity, the risk of aortic dissection was not significantly increased in clinical scenarios. Based on our findings, concerns regarding aortic diseases do not justify discontinuation of fluoroquinolone use. Further studies are needed to elucidate the conflicting actions of fluoroquinolones, taking into account background pathophysiology such as infection and inflammation.

Statins ameliorate oxaliplatin- and paclitaxel-induced peripheral neuropathy via glutathione-S-transferase.

Some therapeutic agents have been found to have effects beyond their primary indications. Peripheral neuropathy, a common side effect of chemotherapy, remains inadequately treated. Identifying additional properties of existing medications could thus uncover novel therapeutic avenues. Previous studies have identified an additional effect of simvastatin in reducing neuropathy; however, the mechanism underlying this effect remains unclear. We investigated the novel effects of statins on chemotherapy-induced peripheral neuropathy in mice. Mice treated with oxaliplatin or paclitaxel did not show exacerbation or improvement in cold sensations upon acetone testing with statin administration. However, concurrent oral statin treatment mitigated the nociceptive response to mechanical stimuli induced by each anti-tumor agent. Co-administration of a glutathione-S-transferase inhibitor, which modulates redox reactions, abolished the ameliorative effect of statins on mechanical nociceptive behavior. Additionally, the glutathione-S-transferase inhibitor did not affect normal sensory perception or impair the anti-tumor effect of chemotherapy agents. A search for GST-associated molecules and pathways using artificial intelligence revealed that GST regulates inflammatory cytokines as a regulatory or causative gene. Our findings suggest that statins have class effects that ameliorate cytotoxic anti-cancer drug-induced mechanical allodynia via GST pathway activation.

Outcome evaluation of pharmacist-physician collaborative protocol-based antimicrobial treatment for hospitalized stroke patients with aspiration pneumonia.

OBJECTIVES: To evaluate the efficacy and patient outcomes of pharmacist-physician collaborative protocol-based antimicrobial treatment regimens for antimicrobial stewardship. METHODS: Patients treated for aspiration pneumonia due to stroke within 48 h after admission to Kochi Medical School Hospital (January 2019 to December 2022) were included. Primary outcomes were the cumulative number of days of antimicrobial treatment and length of hospital stay. Secondary outcomes included the percentage of patients under-dosed with first-choice antimicrobial agents and inpatient mortality. RESULTS: Group A (66 patients) did not receive the antimicrobial treatment protocol, whereas group B (46 patients) did. There were no differences in the patient backgrounds. Group B had a significantly lower percentage of patients who were undertreated with the first-choice antimicrobial agent (9.1 % vs. 42.9 %). There was no significant difference in inpatient mortality between group A and group B (6.1 % vs. 4.3 %). The cumulative number of days of antimicrobial administration and the length of hospital stay were significantly lower in group B: 7.0 days (95 % CI, 6.0-8.0) vs. 9.0 days (95 % CI, 8.0-11.0) for antimicrobial administration, and 28.5 days (95 % CI, 22.0-35.0) vs. 43.0 days (95 % CI, 28.0-55.0) for hospital stay. CONCLUSIONS: Protocol-based antimicrobial treatment for aspiration pneumonia supports appropriate antimicrobial usage and improves patient quality of life. These findings will assist in the effective treatment of aspiration pneumonia in an aging society.

Asciminib, a novel allosteric inhibitor of BCR-ABL1, shows synergistic effects when used in combination with imatinib with or without drug resistance.

In the treatment of chronic myeloid leukemia (CML), resistance to BCR-ABL inhibitors makes it difficult to continue treatment and is directly related to life expectancy. Therefore, asciminib was introduced to the market as a useful drug for overcoming drug resistance. While combining molecular targeted drugs is useful to avoid drug resistance, the new BCR-ABL inhibitor asciminib and conventional BCR-ABL inhibitors should be used as monotherapy in principle. Therefore, we investigated the synergistic effect and mechanism of the combination of asciminib and imatinib. We generated imatinib-resistant cells using the human CML cell line K562, examined the effects of imatinib and asciminib exposure on cell survival using the WST-8 assay, and comprehensively analyzed genetic variation related to drug resistance using RNA-seq and real-time PCR. A synergistic effect was observed when imatinib and asciminib were combined with or without imatinib resistance. Three genes, GRRP1, ESPN, and NOXA1, were extracted as the sites of action of asciminib. Asciminib in combination with BCR-ABL inhibitors may improve the therapeutic efficacy of conventional BCR-ABL inhibitors and prevent the development of resistance. Its dosage may be effective even at minimal doses that do not cause side effects. Further verification of this mechanism of action is needed. Additionally, cross-resistance between BCR-ABL inhibitors and asciminib may occur, which needs to be clarified through further validation as soon as possible.

Effects of renin-angiotensin system inhibitor and beta-blocker use on mortality in older patients with heart failure with reduced ejection fraction in Japan.

Introduction: Guideline-directed medical therapy with renin-angiotensin system (RAS) inhibitors and beta-blockers has improved the survival of patients with heart failure (HF) and reduced left ventricular ejection fraction (HFrEF). However, it is unclear whether RAS inhibitors and beta-blockers can be administered to older patients with HF. Therefore, this study aimed to investigate the effects of beta-blockers and RAS inhibitors on the prognosis of older patients with HFrEF. Methods: Demographic, clinical, and pharmacological data from 1,061 patients with acute decompensated HF, enrolled in the Kochi Registry of Subjects with Acute Decompensated Heart Failure (Kochi YOSACOI study), were analyzed to assess their impact on mortality. Additionally, a machine learning approach was applied to complement the conventional statistical model for analysis. Patients with HFrEF (n = 314) were divided into the all-cause mortality within 2 years group (n = 80) and the survivor group (n = 234). Results: Overall, 41.1% (129/314) of the patients were aged ≥80, and 25.5% (80/314) experienced all-cause mortality within 2 years. Furthermore, 57.6% (181/314) and 79.0% (248/314) were prescribed RAS inhibitors and beta-blockers, respectively. Our analysis showed that RAS inhibitor use was associated with reduced all-cause mortality and cardiac death in patients with HFrEF of all ages (P < 0.001), and beta-blocker use had an interaction with age. Machine learning revealed that the use of beta-blockers altered the risk of mortality, with a threshold of approximately 80 years of age. Beta-blocker use was associated with lower all-cause mortality and cardiac death in patients with HFrEF aged <80 years (P < 0.001) but not in those aged ≥80 years (P = 0.319 and P = 0.246, respectively). These results suggest that beta blockers may differ in their all-cause mortality benefits according to age. Conclusions: RAS inhibitors prevented all-cause mortality and cardiac death at all ages, whereas beta-blockers had different effects depending on the patient's age. This study suggested that the choice of beta-blockers and RAS inhibitors is more important in older patients with HFrEF than in younger patients with the same condition.

The Association between PDE5 Inhibitors and Aneurysm/Arterial Dissection:A Pharmacovigilance Study Using WHO Safety Database.

Aneurysm and arterial dissection have been reported as adverse drug events, associated with angiogenesis inhibitors and fluoroquinolones. Specifically, several cases of severe arterial disease following cGMP-specific phosphodiesterase type 5 (PDE5) inhibitors usage have recently been reported. It is necessary to ascertain the risks of serious adverse events caused by PDE5 inhibitors. We aimed to evaluate the association of aneurysm and artery dissection with PDE5 inhibitors using VigiBase, which is a World Health Organization database of spontaneously reported adverse events, for explorative hypothesis-generating analysis. We performed disproportionality analysis using a dataset from inception in 1967 to December 2022 and calculated reporting odds ratios (ROR) between PDE5 inhibitors and arterial diseases. We extracted 195,839 reports on PDE5 inhibitors with 254 reports of arterial disease as adverse events from VigiBase. Disproportionality analysis showed disproportional signals for PDE5 inhibitors (ROR, 2.30;95% confidence intervals, 2.04-2.61);disproportional signals were detected in analyses restricting the lesion site to the aorta or cerebral arteries. From stratified analysis, disproportional signals were noted in females, as well as males, generally recognized as a risk factor for artery diseases. This real-world data analysis suggests that PDE5 inhibitors may play a role in the development of lethal arterial disease. J. Med. Invest. 71 : 134-140, February, 2024.

Atractylodes lancea (Thunb.) DC. [Asteraceae] rhizome-derived exosome-like nanoparticles suppress lipopolysaccharide-induced inflammation in murine microglial cells.

Background: Exosome-like nanoparticles (ELNs) mediate interspecies intercellular communications and modulate gene expression. Hypothesis/Purpose: In this study, we isolated and purified ELNs from the dried rhizome of Atractylodes lancea (Thunb.) DC. [Asteraceae] (ALR-ELNs), a traditional natural medicine, and investigated their potential as neuroinflammatory therapeutic agents. Methods: ALR-ELN samples were isolated and purified using differential centrifugation, and their physical features and microRNA contents were analyzed through transmission electron microscopy and RNA sequencing, respectively. BV-2 microglial murine cells and primary mouse microglial cells were cultured in vitro, and their ability to uptake ALR-ELNs was explored using fluorescence microscopy. The capacity of ALR-ELNs to modulate the anti-inflammatory responses of these cells to lipopolysaccharide (LPS) exposure was assessed through mRNA and protein expression analyses. Results: Overall, BV-2 cells were found to internalize ALR-ELNs, which comprised three microRNAs (ath-miR166f, ath-miR162a-5p, and ath-miR162b-5p) that could have anti-inflammatory activity. Pretreatment of BV-2 cells with ALR-ELN prevented the pro-inflammatory effects of LPS stimulation by significantly reducing the levels of nitric oxide, interleukin-1ß, interleukin-6, and tumor necrosis factor-α. Notably, the mRNA levels of Il1b, Il6, iNos, ccl2, and cxcl10 in BV-2 cells, which increased upon LPS exposure, were significantly reduced following ALR-ELN treatment. Moreover, the mRNA levels of heme oxygenase 1, Irf7, ccl12, and Irg1 also increased significantly following ALR-ELN treatment. In addition, pretreatment of primary mouse microglial cells with ALR-ELN prevented the pro-inflammatory effects of LPS stimulation by significantly reducing the levels of nitric oxide. Conclusion: Our findings indicate that ALR-ELNs exhibit anti-inflammatory effects on murine microglial cells. Further validation may prove ALR-ELNs as a promising neuroinflammatory therapeutic agent.

[Development and Assessment of a New Oral Selenium Fast-disintegrating Tablets].

Selenium is an essential trace element and its deficiency causes myositis, myocardial damage, and other symptoms. Patients receiving long-term intravenous nutrition or tube-feeding in particular are deficient in essential trace elements, including selenium, and require regular supplementation. In Japan, injectable selenium-containing products are listed on the National Health Insurance drug price list, and oral solutions are prepared and used in hospitals. However, these formulations have problems related to preservation and require complicated administration procedures. In this study, we developed a new fast-disintegrating tablet formulation of selenium, using SmartEx® (D-mannitol·low substituted hydroxypropylcellulose (L-HPC)·fully hydrolyzed polyvinyl alcohol (PVA) mixture) as a coprocessing additive, that can be administered orally or by feeding tube. The tablet formulation had excellent disintegrable capability, sufficient hardness, and did not cause tube blockage when administered in the simple suspension method. In addition, the tablet formulation showed no changes in properties in an accelerated test without packaging for 42 d, indicating that it could be stored for a long period. Fast-disintegrating tablets prepared with SmartEx® are expected to improve the adherence and quality of life of patients who require selenium supplementation.

Efficacy of 3-day versus 5-day aprepitant regimens for long-delayed chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based chemotherapy.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) is an ongoing problem. While effectiveness of triplet antiemetic regimens in the delayed CINV phase (24-120 hours after administration of chemotherapy) has been studied, their effectiveness in the long-delayed phase (120-168 hours post-administration) is unknown. We compared the efficacy of 3- and 5-day courses of a triplet antiemetic prophylaxis containing aprepitant (APR) in controlling long-delayed CINV after cisplatin (CDDP)-based chemotherapy. RESEARCH DESIGN AND METHODS: We obtained patient-level data from a nationwide, multicenter, prospective observational study in Japan. The incidence and timing of CINV after 3- and 5-day APR-containing regimens were compared using inverse probability treatment weighting. RESULTS: The analysis included 380 patients. The incidence rates of long-delayed nausea and vomiting were significantly reduced for the 5-day compared with the 3-day regimen (29.1% vs. 22.2%, p = 0.0042; 6.7% vs. 0%, p < 0.0001, respectively). Among those without CINV, vomiting was not reported after day 2 in the 5-day APR group but increased after day 4 in the 3-day APR group. CONCLUSION: A 5-day regimen triplet antiemetic prophylaxis with APR decreased long-delayed vomiting compared with a 3-day regimen in patients receiving CDDP-based chemotherapy. However, the 5-day regimen showed no advantage over the 3-day regimen against long-delayed nausea.

Atractylodes lancea rhizome derived exosome-like nanoparticles prevent alpha-melanocyte stimulating hormone-induced melanogenesis in B16-F10 melanoma cells.

Aberrant melanin overproduction can significantly impact an individual's appearance and cause mental and psychological distress. Current inhibitors of melanin production exert harmful side effects due to inadequate selectivity; thus a need to develop more selective melanin synthesis inhibitors is necessary. Extracellular vesicles are important agents of intercellular signalling in prokaryotes and eukaryotes. Recently, plant-derived nanoparticles, similar to mammalian exosomes, have attracted attention for their use in health research. In this study, to investigate the potential of plant-derived exosome-like nanoparticles (ELNs) as inhibitors of melanin production, we used hot water to extract ELNs from the rhizome of Atractylodes lancea (A-ELNs). The size of A-ENLs ranged from 34 to 401 nm and carried three microRNA: ath-miR166f, ath-miR162a-5p, and ath-miR162b-5p. These A-ENLs were applied to B16-F10 melanoma cells treated with α-melanocyte-stimulating hormone (α-MSH). After A-ELNs were taken up by B16-F10 cells, their melanin levels were significantly reduced. Furthermore, A-ELNs significantly reduced tyrosinase activity in B16-F10 cells and mRNA expression of microphthalmia-associated transcription factor (Mitf), tyrosinase, tyrosinase-related protein 1, and DOPA chrome tautomerase. These results suggest that A-ELN suppresses melanogenic enzymes expression by downregulating Mitf, thereby inhibiting melanin synthesis. Hence, A-ELN can be developed into a novel topical drug after additional studies and optimization.

Impact of areal socioeconomic status on prehospital delay of acute ischaemic stroke: retrospective cohort study from a prefecture-wide survey in Japan.

OBJECTIVES: To examine whether the Areal Deprivation Index (ADI), an indicator of the socioeconomic status of the community the patient resides in, is associated with delayed arrival at the hospital and poor outcomes in patients with acute ischaemic stroke from a prefecture-wide stroke database in Japan. DESIGN: Retrospective study. SETTING: Twenty-nine acute stroke hospitals in Kochi prefecture, Japan. PARTICIPANTS: Nine thousand and six hundred fifty-one patients with acute ischaemic stroke who were urgently hospitalised, identified using the Kochi Acute Stroke Survey of Onset registry. Capital and non-capital areas were analysed separately. PRIMARY AND SECONDARY OUTCOME MEASURES: Prehospital delay defined as hospital arrival ≥4-hour after stroke onset, poor hospital outcomes (in-hospital mortality and discharge to a nursing facility) and the opportunities of intravenous recombinant tissue plasminogen activator (rt-PA) and endovascular reperfusion therapy. RESULTS: In the overall cohort, prehospital delay was observed in 6373 (66%) patients. Among individuals residing in non-capital areas, those living in municipalities with higher ADI (more deprived) carried a significantly higher risk of prehospital delay (per one-point increase, OR (95% CI) 1.45 (1.26 to 1.66)) by multivariable logistic regression analysis. In-hospital mortality (1.45 (1.02 to 2.06)), discharge to a nursing facility (1.31 (1.03 to 1.66)), and delayed candidate arrival ≥2-hour of intravenous rt-PA (2.04 (1.30 to 3.26)) and endovascular reperfusion therapy (2.27 (1.06 to 5.00)), were more likely to be observed in the deprived areas with higher ADI. In the capital areas, postal-code-ADI was not associated with prehospital delay (0.97 (0.66 to 1.41)). CONCLUSIONS: Living in socioeconomically disadvantaged municipalities was associated with prehospital delays of acute ischaemic stroke in non-capital areas in Kochi prefecture, Japan. Poorer outcomes of those patients may be caused by delayed treatment of intravenous rt-PA and endovascular reperfusion therapy. Further studies are necessary to determine social risk factors in the capital areas. TRIAL REGISTRATION NUMBER: This article is linked to a clinical trial to UMIN000050189, No.: R000057166 and relates to its Result stage.

Exosome-like nanoparticles derived from Allium tuberosum prevent neuroinflammation in microglia-like cells.

OBJECTIVE: Exosome-like nanoparticles (ELNs), which are plant-derived extracellular membrane vesicles, can regulate mammalian gene expression. ELNs can cross the blood-brain barrier, making them potential therapeutic agents or drug-delivery carriers for neuroinflammation-related diseases. Here, we investigated the anti-neuroinflammatory potential of ELNs extracted from Allium tuberosum (A-ELNs). METHODS: A-ELNs were extracted, and their miRNA profile was characterized. A-ELNs were also applied to BV-2 microglial and MG-6 cells derived from C57/BL6 mice stimulated with lipopolysaccharide (LPS), followed by an examination of levels of inflammatory-related factors. To test their drug-carrying potential, A-ELNs were mixed with dexamethasone, an anti-inflammatory drug, to prepare dexamethasone-incorporated A-ELNs (Dex-A-ELNs). KEY FINDINGS: A-ELNs showed a particle size of 145 ± 2 nm and characteristic miRNAs. A-ELNs significantly decreased the LPS-induced nitric oxide (NO) and inflammatory cytokines levels in BV-2 and MG-6 cells. The mRNA expression of heme oxygenase-1 was significantly increased, and that of inducible NO synthase and inflammatory cytokines was significantly decreased by A-ELNs in BV-2 cells. Dex-A-ELNs inhibited NO production in BV-2 cells more potently than either A-ELNs or dexamethasone alone. CONCLUSION: A-ELNs can alleviate microglial inflammation. Their effects can be potentiated by incorporating anti-inflammatory drugs, such as dexamethasone, making them potential therapeutic agents or drug-delivery carriers for neuroinflammation.

Effectiveness of Palonosetron, 1-Day Dexamethasone, and Aprepitant in Patients Undergoing Carboplatin-Based Chemotherapy.

INTRODUCTION: Dexamethasone (DEX)-sparing strategy with 5-hydroxytryptamine-3 receptor antagonist (5HT3RA) and aprepitant (APR), as triplet antiemetic prophylaxis, is associated with poor control of delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving carboplatin (CBDCA)-based chemotherapy. This study aimed to evaluate whether using palonosetron (PALO) as a 5HT3RA provides superior control with CINV than first-generation (1st) 5HT3RA in triplet antiemetic prophylaxis with a DEX-sparing strategy. METHODS: Pooled patient-level data from a nationwide, multicenter, and prospective observational study were analyzed to compare the incidence of CINV between patients administered PALO and 1st 5HT3RA in combination with 1-day DEX and APR. RESULTS: No significant differences were observed in the incidence of CINV, pattern of CINV, or severity of nausea by type of 5HT3RA in triplet antiemetic prophylaxis with DEX-sparing strategy. In both groups, the incidence of nausea gradually increased from day 3, peaked on day 4 or 5, and then declined slowly. The visual analog scale scores in the delayed phase remained high throughout the 7-day observation period. CONCLUSION: Careful patient selection and symptom monitoring are needed when implementing the DEX-sparing strategy in triplet antiemetic prophylaxis for patients undergoing CBDCA-based chemotherapy. Furthermore, additional strategies may be needed to achieve better control of delayed CINV.

Glycyrrhizae Radix suppresses lipopolysaccharide- and diazepam-induced nerve inflammation in the hippocampus, and contracts the duration of pentobarbital- induced loss of righting reflex in a mouse model.

Nerve inflammation is linked to the development of various neurological disorders. This study aimed to examine whether Glycyrrhizae Radix effectively influences the duration of the pentobarbital-induced loss of righting reflex, which may increase in a mouse model of lipopolysaccharide (LPS)-induced nerve inflammation and diazepam-induced γ-aminobutyric acid receptor hypersensitivity. Furthermore, we examined the anti-inflammatory effects of Glycyrrhizae Radix extract on LPS-stimulated BV2 microglial cells, in vitro. Treatment with Glycyrrhizae Radix significantly decreased the duration of pentobarbital-induced loss of righting reflex in the mouse model. Furthermore, treatment with Glycyrrhizae Radix significantly attenuated the LPS-induced increases in interleukin-1ß, interleukin-6, and tumor necrosis factor-alpha at the mRNA level, and it significantly reduced the number of ionized calcium-binding adapter molecule-1-positive cells in the hippocampal dentate gyrus 24 h after LPS treatment. Treatment with Glycyrrhizae Radix also suppressed the release of nitric oxide, interleukin-1ß, interleukin-6, and tumor necrosis factor protein in culture supernatants of LPS-stimulated BV2 cells. In addition, glycyrrhizic acid and liquiritin, active ingredients of Glycyrrhizae Radix extract, reduced the duration of pentobarbital-induced loss of righting reflex. These findings suggest that Glycyrrhizae Radix, as well as its active ingredients, glycyrrhizic acid and liquiritin, may be effective therapeutic agents for the treatment of nerve inflammation-induced neurological disorders.

The Efficacy and Safety of Immune Checkpoint Inhibitor and Tyrosine Kinase Inhibitor Combination Therapy for Advanced or Metastatic Renal Cell Carcinoma: A Multicenter Retrospective Real-World Cohort Study.

We evaluated the efficacy and safety of combination therapy with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKI) as first-line therapy for patients diagnosed as having advanced or metastatic renal cell carcinoma (mRCC). We enrolled 51 patients to receive ICI+TKI therapy for mRCC at 9 Japanese institutions. The overall survival (OS) of the patients treated with ICI+TKI was the primary endpoint., and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Furthermore, we analyzed the clinical prognostic and predictive factors in patients with mRCC treated with ICI+TKI therapy. Seven months was the median follow-up period. The OS rates at 6, 12, and 18 months were 93.1, 82.5, and 68.8%, respectively. The median PFS for patients who received ICI+TKI was 19.0 months, ORR was 68.6%, and DCR was 88.2%. ICI+TKI-related adverse events occurred in 43 patients (84.3%) with any grade and in 22 patients (43.1%) with grade ≥3. Treatment selection with poor prognostic factors may be prudent, even though ICI+TKI is an efficacious and safe first-line treatment in patients with mRCC.

Risk Factors for Anticancer Drug-Induced Hyponatremia: An Analysis Using the Japanese Adverse Drug Report (JADER) Database.

Background and Objectives: Hyponatremia is among the most prevalent electrolyte abnormalities observed in patients with cancer during chemotherapy. Therefore, managing hyponatremia is crucial since it causes a severe electrolyte imbalance that can lead to significant mortality, and this study aimed to investigate the relationship between hyponatremia, anticancer drugs, and cancer types. Materials and Methods: Reported odds ratios were calculated and evaluated based on adverse event reports submitted to the Japanese Adverse Drug Event Report (JADER) database. Results: Overall, 2943 patients had hyponatremia. Notably, cisplatin, pemetrexed, and etoposide had marked hyponatremia signals. In addition, significant hyponatremia signals were detected for oesophageal, lung, and renal cancers. Conclusions: Hyponatremia has been reported in women and patients with lung cancer receiving cisplatin, with a growing trend in the number of elderly patients receiving cisplatin. Furthermore, since the onset of hyponatremia during cisplatin administration is frequently reported within 10 days, patient information should be thoroughly examined before and monitored throughout the administration, which can contribute to the early detection and prevention of hyponatremia.

Efficacy and Safety of Cabozantinib in Patients with Advanced or Metastatic Renal Cell Carcinoma: A Multicenter Retrospective Cohort Study.

A multicenter retrospective study was conducted to evaluate the efficacy and safety of cabozantinib in patients with advanced or metastatic renal cell carcinoma (mRCC). We enrolled 53 patients with mRCC who received cabozantinib at eight institutions in Japan. The primary endpoint was overall survival (OS). The secondary endpoints were objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). In addition, we analyzed prognostic factors in patients with mRCC treated with cabozantinib. The median follow-up period was 8 months, and the median OS was 20.0 months. The ORR and DCR were 39.6% and 83.0%, respectively. The median PFS was 11.0 months. PFS was significantly shorter in patients previously treated with at least two tyrosine kinase inhibitors and in those with C-reactive protein (CRP) ≥ 1.27 mg/dL (p = 0.021 and p = 0.029, respectively). Adverse events of any grade and grades ≥3 occurred in 42 (79.2%) and 10 (18.9%) patients, respectively. Cabozantinib is a useful treatment option for patients with mRCC and may benefit from earlier use. In this study, CRP ≥ 1.27 mg/dL is a poor prognostic factor in patients treated with cabozantinib, and careful follow-up may be required in treating patients with high CRP.

Central Nervous System Ischemia Associated with Bevacizumab: An Analysis of the Japanese Adverse Drug Event Report Database.

Bevacizumab is an inhibitor of vascular endothelial growth factor (VEGF) that prevents tumor growth. While bevacizumab is therapeutically effective, it induces several adverse events. Among these, central nervous system (CNS) ischemia can lead to death or permanent disability. In this study, we reviewed the Japanese Adverse Drug Event Report database to analyze the occurrence of CNS ischemia after bevacizumab administration. Significant associations between the occurrence of CNS ischemia and bevacizumab use were detected (adjusted reporting odds ratios (ROR): 2.68, 95% confidence interval (CI): 2.00-3.59, p < 0.001). Furthermore, an association between diagnosis of glioma and bevacizumab use was also detected (p < 0.001). These events occurred early after the start of treatment and then gradually decreased; however, more than half of CNS ischemia events were reported beyond 30 d after the first administration. In addition, a logistic regression suggested that CNS ischemia caused by bevacizumab was associated with glioma, underlying hypertension and aging. A poor prognosis was reported for several cases occurring in elderly patients (over 60 years of age). Although bevacizumab is a useful pharmacological treatment for cancer, caution should be taken to avoid severe adverse events. Accordingly, the patient's general and medical condition should be carefully examined before initiating treatment, and blood pressure should be continuously assessed throughout treatment with bevacizumab to prevent CNS ischemia.

Effectiveness and Safety of Molecular-Targeted Therapy after Nivolumab Plus Ipilimumab for Advanced or Metastatic Renal Cell Carcinoma: A Multicenter, Retrospective Cohort Study.

This study aimed to evaluate the effectiveness and safety of molecular-targeted therapies (MTTs) after the discontinuation of nivolumab and ipilimumab (NIVO+IPI) combination therapy in patients who had been diagnosed with advanced/metastatic renal cell carcinoma as real-world outcomes. We enrolled patients treated with MTTs following initial therapy with NIVO+IPI at nine institutions in Japan. We evaluated the objective response rate (ORR) as the primary endpoint and disease control rate (DCR), best overall response, and oncological outcomes (overall survival (OS) and progression-free survival (PFS)) as the secondary endpoints. We also evaluated factors predictive of disease progression after the administration of MTTs. Patients were followed up for a median of 8 months. The ORR was 44.8%, and the DCR was 72.4%. The median OS and PFS of MTTs after NIVO+IPI were 18 months and 8 months, respectively. A total of 31% of patients experienced grade 3/4 MTT-related adverse events. The median PFS in patients with bone metastases was significantly shorter than that in those without bone metastases (4 vs. 12 months, p = 0.012). MTTs may be a useful secondary treatment option after the discontinuation of NIVO+IPI.

Adverse Reaction Profiles Related to Gastrointestinal Bleeding Events Associated with BCR-ABL Tyrosine Kinase Inhibitors.

Background and Objectives: The aim of this study is to investigate the characteristics of gastrointestinal bleeding events associated with BCR-ABL tyrosine kinase inhibitor (TKI) treatment, using the reporting odds ratio (ROR) of the adverse event reports submitted to the Japanese Adverse Drug Event Report database between 2004 and 2020, and to examine the number of reported TKI-related gastrointestinal bleeding cases according to sex and age, as well as the actual number of TKI prescriptions issued in Japan. Materials and Methods: The RORs and 95% confidence intervals (CIs) of gastrointestinal bleeding events related to TKIs were calculated using the data of the 595,121 included cases. Results: Significant gastrointestinal bleeding events were detected for dasatinib (crude ROR: 4.47, 95% CI: 3.77-5.28) and imatinib (crude ROR: 1.22, 95% CI: 1.01-1.46). In multiple logistic regression analyses, significant gastrointestinal bleeding events were detected for dasatinib (adjusted ROR: 8.02, 95% CI: 5.75-10.2), imatinib (adjusted ROR: 1.81, 95% CI: 1.2-2.72), age (≥60 years, adjusted ROR: 2.22, 95% CI: 2.1-2.36), reporting year (adjusted ROR: 1.04, 95% CI: 1.04-1.05), and male sex (adjusted ROR: 1.47, 95% CI: 1.37-1.57). Interaction analysis revealed that the association of gastrointestinal bleeding with dasatinib was affected by age (≥60 years) and sex (female), with the number and proportion of dasatinib-related gastrointestinal bleeding cases increasing among those aged ≥60 years. Conclusions: Specific TKIs and patient characteristics were associated with gastrointestinal bleeding. Our results aid the prompt identification and treatment of TKI-related gastrointestinal bleeding.