Abstract Amantadine intoxication occurred despite moderate renal dysfunction. This may have been affected by the use of donepezil, and we require careful attention to these combinations.
Resistance to lenvatinib mesylate (LEN), a systemic chemotherapy that can be administered orally, has been a major issue for treatment of hepatocellular carcinoma (HCC). Although HCC is the tumor that most exhibits intratumoral hypoxia, which has been shown to be involved in the development of treatment resistance, there are no reports of LEN resistance in HCC treatment under hypoxia. The purpose of our study was to elucidate the mechanism of treatment resistance to LEN under hypoxia using HCC cell lines. We confirmed LEN resistance under hypoxic conditions in HCC cell lines. There was a significant increase in the IC50 value of PLC/PRF/5 cells from 13.0±0.8 μM in normoxia to 21.3±1.1 μM in hypoxia, but in HepG2 cells, the increase was not significant. To elucidate the LEN resistance mechanism of PLC/PRF/5 cells under hypoxia, we performed microarray analysis and extracted genes that are thought to be related to this mechanism. Furthermore, in-silico analysis confirmed significant changes in the extracellular matrix, and among them, FN1 encoding fibronectin was determined as the hub of the gene cluster. The expression of fibronectin in PLC/PRF/5 cells examined with immunofluorescence staining was significantly elevated in and outside of cells under hypoxia, and tended to decrease when cells were exposed to LEN under normoxia. Furthermore, the fibronectin concentration in the culture solution of PLC/PRF/5 cells examined by ELISA was 2.3 times higher under hypoxia than under normoxia under LEN(-) conditions, and 1.6 times higher under hypoxia than under normoxia under LEN(+) conditions. It is assumed that in PLC/PRF/5 cells, fibronectin is probably suppressed as an indirect effect of LEN under normoxia, but transcription factors such as HIF-1α are induced under hypoxia, thus enhancing the production of fibronectin and attenuating the effect of LEN, resulting in drug resistance. This behavior of fibronectin with LEN exposure under hypoxia is probably specific to PLC/PRF/5 cells. Further studies should verify the combined effective inhibition of fibronectin and the MAPK pathway as a promising therapeutic strategy to enhance the value of LEN in HCC treatment.
Abstract Background Schizophrenia is a psychiatric disorder characterized by hallucinations, delusions, and other symptoms. Although treatment guidelines for schizophrenia have been established in Japan, drugs are not recommended for pediatric schizophrenia. Additionally, the temporal trends in prescribing antipsychotics for pediatric patients with schizophrenia are unclear. Therefore, we aimed to clarify the trends in antipsychotic prescriptions for Japanese pediatric outpatients from 2015 to 2022. Methods Administrative data (as of November 2023) of Japanese pediatric outpatients with schizophrenia aged 0–18 years who visited acute-care diagnosis procedure combination hospitals between January 1, 2015, and December 31, 2022, were included in this study. The target drugs for schizophrenia were all indicated for treating schizophrenia and marketed in Japan as of December 2022. Annual prescription trends for antipsychotics during this period were calculated based on their proportions. The Cochran–Armitage trend test was used to evaluate the proportion of prescriptions for each antipsychotic. Results The main drugs prescribed for these patients were aripiprazole and risperidone. Among male patients, the proportion of prescriptions for aripiprazole increased significantly from 21.2% in 2015 to 35.9% in 2022, whereas that for risperidone decreased significantly from 47.9% in 2015 to 36.7% in 2022 (both P < 0.001). Among female patients, the proportion of prescriptions for aripiprazole increased significantly from 21.6% in 2015 to 35.6% in 2022, whereas that for risperidone decreased significantly from 38.6% in 2015 to 24.8% in 2022 (both P < 0.001). Conclusions Aripiprazole and risperidone were primarily prescribed for pediatric schizophrenia in Japan during the study period. Additionally, the proportion of aripiprazole prescriptions increased over time.
Methadone is used to treat intractable cancer pain when other opioid analgesics are ineffective. Methadone tablets may be difficult to administer in cases of gastrointestinal passage obstruction. However, changing the route of methadone tablet administration is possible.
The multikinase inhibitor, regorafenib, is known to exert its antitumor effects by targeting several kinases, inhibiting interstitial intracellular signaling and suppressing tumor cell proliferation. Regorafenib causes gastrointestinal perforation and gastrointestinal fistula as adverse events, and discontinuation is recommended if these adverse events occur during administration. However, there are no prescribed standards for re-administration after discontinuation and for administration in patients with a history of gastrointestinal perforation. Herein, we report a case of gastrointestinal perforation in a patient, with a history of gastrointestinal microperforation, undergoing bevacizumab therapy, within a few days of starting regorafenib; this had a significant effect on the prognosis. The site of gastrointestinal perforation was consistent with previously reported sites around the tumor and at the anastomotic site. Based on a review of literature and our experience with the case presented here, we recommend that administration of regorafenib to patients with a history of gastrointestinal perforation should be avoided to the extent possible. Moreover, in case of prior administration of a drug reported to cause gastrointestinal perforation, such as an anti-VEGFR drug, the risk of gastrointestinal perforation should be considered during the administration of regorafenib. In the event of complaints, such as abdominal pain, gastrointestinal perforation should be considered as a differential diagnosis and appropriate tests and treatments should be initiated at an early stage.
Aims Several studies have shown that twice-daily injection of premixed insulin analog (MIX) therapy achieves glycemic control equivalent to that with basal-bolus (BB) therapy. However, glycemic fluctuations that lead to oxidative stress may be associated with the risk of diabetic complications. Therefore, in this study, we compared oxidative stress markers between MIX therapy and BB therapy. Methods In this cross-sectional study, we recruited a total of 37 patients (17 patients in the BB group and 20 patients in the MIX group) and compared urinary 8-isoprostane and urinary 8-hydroxydeoxyguanosine (8-OHdG) levels. Results There were no significant differences in urinary 8-isoprostane (BB vs MIX: 199±92 pg/mg Cr vs 266±107 pg/mg Cr) or urinary 8-OHdG (4.7±1.6 ng/mg Cr vs 5.4±1.9 ng/mg Cr, respectively). Conclusion These results suggest that MIX is equivalent to BB in terms of glycemic fluctuations and oxidative stress.
Lithium is considered the first-line option for the maintenance treatment of bipolar disorder.1, 2 Simultaneously, lithium requires attention (even at low doses) because increased concentration in the serum can cause toxicity and even death.3 Thirst, frequent urination, nausea, tremor, and kidney failure are generally known lithium adverse drug reactions (ADR); these ADR occur depending on the serum lithium concentrations.4 A survey by the Pharmaceuticals and Medical Devices Agency (PMDA) indicated that serum lithium concentration might not have been measured in 1200 of 2309 cases where lithium had been prescribed; the PMDA again recommended (in 2012) the regular measurement of serum lithium concentrations (https://www.pmda.go.jp/files/000145551.pdf). Therefore, the package insert clearly states that, while taking lithium, serum lithium concentrations must be monitored regularly once every 2–3 months. The Relief System for Sufferers from Adverse Drug Reactions was established by the PMDA in 1979; it provides quick relief for those who suffer from serious health problems (such as illness or disability) due to ADR, despite the proper use of drugs. In this system, benefit claims are reviewed at an expert meeting and eligible or ineligible cases are determined. In principle, all lithium-toxicity-related ADR are subject to this relief system; however, if serum lithium concentrations are not measured, the ADR are determined to be 'due to improper use' and may be 'ineligible cases.'5 In this study, we investigated the status of eligible and ineligible cases of lithium-related ADR benefit claims discussed in the PMDA's relief system, using all data from 2004 (the first year of disclosed data) to 2019. These data for the PMDA's relief system are open data to the public (http://www.pmda.go.jp/relief-services/index.html). Table 1 shows the overall results of this study. During the study period, 104 cases were eligible, and 33 cases were ineligible for benefits; the ratios did not vary significantly among years. The ratio of eligible and ineligible cases was almost the same according to the claimant's sex; regarding the claimant's age, the ratio was the highest in the 50s, followed by the 70s and 60s. The most common ADR included malignant syndromes, all of which were eligible. Conversely, lithium toxicity was observed in 15 eligible cases and in 21 ineligible cases, and then the ratio was significantly different between lithium toxicity and other ADR (P < 0.0001, χ2-test). This study reveals that the number of ineligible relief claims for lithium-related ADR in Japan has not decreased, even since the PMDA provided cautionary advice. Moreover, we consider that the number of claims has increased since 2012. The Japanese Society of Mood Disorders published treatment guidelines for bipolar disorder in March 2011, in which lithium is one of the most highly recommended therapeutic drugs.6 We speculate that the low ratio of lithium-toxicity-related eligible relief claims may be due to cases where proper measurement of serum lithium concentrations has not been performed. Lithium toxicity is roughly divided into acute (e.g., caused by overdosing), acute-on-chronic (e.g., when a patient with nephrogenic diabetes insipidus due to chronic lithium toxicity has difficulty drinking water), and chronic toxicity.7 Chronic toxicity occurs in patients who have already regularly used lithium, caused by increased serum lithium concentration because of an increase in the lithium dose or a decrease in lithium excretion due to renal dysfunction.7 Increased lithium concentrations in the serum associated with lower sodium intake have also been reported.8 From the above, regular measurement of serum lithium concentration in patients on lithium maintenance treatment in routine clinical practice is extremely important regarding its proper use. In conclusion, lithium toxicity may be prevented by properly measuring serum lithium concentrations; the necessity of performing appropriate therapeutic drug monitoring has become clear once again. Physicians prescribing lithium should not neglect serum lithium concentration monitoring. The authors declare that there are no conflicts of interest.
