Changes in psychopharmacotherapy for patients with schizophrenia in a psychiatric institution in Japan: A 12-year prescription survey pre- and post-introduction of clozapine.

Psychopharmacotherapy for patients with schizophrenia in Japan has a long history of polypharmacy, which is rare worldwide but remains a critical problem. One reason for this is that clozapine was not available in Japan until 2009. We aimed to investigate the changes in psychopharmacotherapy in patients with schizophrenia over 12 years pre- and post-introduction of clozapine to clarify how psychopharmacotherapy for patients with schizophrenia has changed with the introduction of clozapine. We retrospectively collected data from the medical records of inpatients diagnosed with schizophrenia at the Okayama Psychiatric Medical Center. Chlorpromazine equivalent (CP-eq) decreased from 1276.6 mg/day in 2009 to 613.9 mg/day in 2020. The prescribed daily dose/defined daily dose (PDD/DDD) decreased from 3.0 in 2009 to 1.2 in 2020. The monotherapy rate increased from 24.4 % in 2009 to 74.6 % in 2020. Our institution began using clozapine in 2010, and the prescription rate for clozapine increased to 37.3 % in 2020. The prescription rate for more than three antipsychotics decreased from 27.8 % in 2009 to 0.8 % in 2020. The increase in clozapine prescription has contributed to an increased rate of antipsychotic monotherapy and a decreased rate of polypharmacy, promoting the optimization of schizophrenia medication. Clozapine therapy should be further promoted in Japan to reduce treatment-resistant schizophrenia due to polypharmacy as much as possible.

Vancomycin Hydrochloride as a Risk Factor for Acute Kidney Injury: A Retrospective Study.

INTRODUCTION: The incidence of acute kidney injury (AKI) caused by vancomycin hydrochloride (VCM) was reported to be 5-43%. VCM-induced AKI was reported to be more likely to occur 4-17 days after initiating VCM treatment; however, it may occur earlier. The aim of this study was therefore to investigate risk factors for the development of AKI within two (AKI2days) and seven (AKI7days) days of VCM administration. METHODS: This was a single-center, retrospective study including patients who underwent VCM therapy between April 1, 2013, and December 31, 2019. AKI was evaluated based on the Kidney Disease: Improving Global Outcomes criteria. RESULTS: In total, 287 patients were enrolled. The incidence of VCM-induced AKI within 7 days was 10.8% (31/286 cases), and the incidence of AKI within 2 days was 5.9% (15/252 cases). Serum VCM trough concentrations and tazobactam-piperacillin (TZP) were shown to be a risk factor for VCM-induced AKI. The serum VCM trough concentration was 12.67 µg/mL within the 48 h threshold (AKI2days) and 19.03 µg/mL within the 7-day threshold (AKI7days). CONCLUSION: Our study demonstrated that high serum VCM trough concentrations and the combination of VCM and TZP were independent risk factors for VCM-induced AKI. Avoiding the concomitant use of TZP, or thorough monitoring of renal function with the concomitant use of TZP, may be helpful in reducing the occurrence of AKI. Furthermore, monitoring serum VCM trough concentrations within 2 days may effectively reduce the incidence of AKI.

Risk Factors for Lenvatinib-Induced High-Grade Hypothyroidism in Patients with Hepatocellular Carcinoma: A Retrospective Study.

INTRODUCTION: Lenvatinib mesylate (LEN) is an orally administered tyrosine kinase inhibitor used for the treatment of various cancers, including hepatocellular carcinoma (HCC). HCC treatment with LEN is associated with a very high incidence of adverse events, especially hypothyroidism. This study investigated the incidence of hypothyroidism due to LEN and the relationships between hypothyroidism incidence and patient demographics by analyzing clinical laboratory data from HCC patients treated with LEN. METHODS: This was a single-center, retrospective study of HCC patients who received LEN between April 19, 2018, and September 30, 2020. The observation period was from 1 week before the start of LEN administration to 1 month after the end of administration. RESULTS: In total, 61 patients with HCC were enrolled. High-grade hypothyroidism (CTCAE Grade 2-3) was found in 36.1% (22/61 patients). In high-grade hypothyroidism, eosinophil (EOSINO) count was significantly low (p = 0.029). The cutoff value of EOSINO count was estimated to be approximately 150/µL. The adjusted odds ratios of high-grade hypothyroidism for current smoking and EOSINO count <150/µL were 0.237 (95% confidence interval: 0.063-0.893) and 4.219 (95% confidence interval: 1.119-15.92), respectively. CONCLUSION: The results showed that noncurrent smoking and EOSINO count <150/µL are risk factors for LEN-induced high-grade hypothyroidism.

Optimal timing for therapeutic drug monitoring of voriconazole to prevent adverse effects in Japanese patients.

BACKGROUND: The optimal timing for therapeutic drug monitoring (TDM) of voriconazole in Asians, who have higher rates of poor metabolisers than non-Asians, is unclear. This can cause unexpectedly high concentrations and delays in reaching steady-state levels. OBJECTIVES: To determine the appropriate timing of TDM in Japanese patients receiving voriconazole. PATIENTS/METHODS: Trough levels (Cmin ) were measured on days 3-5 (recommended timing, RT) and days 6-14 (delayed timing, DT) after starting voriconazole in patients receiving an appropriate dosage. Considering bioavailability, Cmin was only compared in patients receiving oral voriconazole. RESULTS: A total of 289 and 186 patients were included in the safety and pharmacokinetic analyses, respectively. There was a significant difference in Cmin measured no later than and after day 5 (3.59 ± 2.12 [RT] vs. 4.77 ± 3.88 µg/mL [DT], p = .023), whereas no significant difference was observed on cutoff day 6 (3.91 ± 2.60 vs. 4.40 ± 3.94 µg/mL, p = .465), suggesting that Cmin close to the steady-state was achieved after day 5. DT causes a delay in achieving the therapeutic range. The hepatotoxicity rates were 21.5% and 36.8% in the RT and DT groups, respectively (p = .004); DT was an independent risk factor for hepatotoxicity. CONCLUSION: Although steady-state concentrations may not be achieved by day 5, early dose optimisation using RT can prevent hepatotoxicity in Japanese patients. TDM should be performed on days 3-5 to ensure safety. However, subsequent TDM may be necessary due to a possible further increase in Cmin .

Evaluation of risk factors for uric acid elevation in COVID-19 patients treated with favipiravir.

The objective of this retrospective study was to identify the clinical risk factor associated with uric acid elevation in coronavirus disease (COVID-19) patients treated with favipiravir. Uric acid elevation was defined as an unexplained increase of ≥1.5 times in the patient's uric acid level from baseline. Twenty-nine COVID-19 patients were included in the study. Uric acid elevation developed during favipiravir therapy in 12 (41.4%) patients and the median onset time was 4.5 days after starting favipiravir. In multiple logistic regression analysis, the favipiravir dosage (adjusted OR = 1.69 [1.02-2.81], P = 0.044) and younger patient age (adjusted OR = 0.91 [0.83-0.99], P = 0.040) were significant clinical risk factors for uric acid elevation. No significant between-group difference was noted in the uric acid elevation and non-elevation groups in the clinical recovery after favipiravir therapy. The uric acid levels of patients administered with favipiravir should be monitored closely.

Increased inosine levels in drug-free individuals with at-risk mental state: A serum metabolomics study.

AIM: At-risk mental state (ARMS) has been recently attracting attention with respect to the improvement of the management and outcome of psychiatric diseases, such as schizophrenia. Since only a few studies have reported on biological alterations in ARMS, serum metabolomics was carried out in ARMS subjects and healthy controls using liquid chromatography with high-resolution mass spectrometry. METHODS: Serum samples were collected from ARMS subjects (n = 24; male: 12; female 12) and age- and sex-matched healthy controls (n = 23 male: 11, female: 12). After serum pre-treatment, liquid chromatography with high-resolution mass spectrometry was performed. Multivariate analyses, such as orthogonal partial least-squares discriminant and volcano plot analyses, were performed. RESULTS: Serum inosine, lactate, taurine, 2,3-dihydroxypropanoate and glutamate levels differed between the two groups. A significant increase in inosine levels was detected in the positive- and negative-ion modes; however, significant differences were not observed in the levels of other purine-related metabolites (hypoxanthine, xanthine and urate) between the two groups. CONCLUSION: Increased inosine levels may serve as biological markers for ARMS, in addition to alterations in the levels of lactate and certain amino acids.

Occurrence of Infusion-Related Reactions due to Obinutuzumab Therapy for Follicular Lymphoma.

BACKGROUND: Obinutuzumab is used to treat follicular lymphoma in Japan. Its characteristic adverse event is infusion- related reactions(IRRs). Although interruption of administration improves many IRRs, serious symptoms can occur; thus, timing the interruption to correspond with the onset of these symptoms is necessary. However, the specific symptoms and timing of IRRs caused by obinutuzumab remain unclear. Therefore, the purpose of this study was to clarify the specific symptoms and timing of the onset of IRRs with obinutuzumab treatment. METHODS: Thirty patients were administered obinutuzumab for one year from October 2018 to September 2019. The frequency of IRRs, expression time, severity, symptoms, and correspondence were investigated. RESULTS: IRRs occurred in 13 patients(43.3%), and all occurred after the first dosing. In 9 of 13 cases(69.2%), IRRs occurred within 90 min of the first dosage. Grade 3 symptoms were expressed in 1 of 13 cases (7.7%). The symptoms of IRRs were throat discomfort, breathing difficulty, skin rash, chills, and fever. CONCLUSIONS: Most IRRs due to obinutuzumab occurred within 90 min of the first dosage. They were mostly Grade 2 or lower, and the frequency of serious IRRs was low. Thus, careful observation of symptoms during treatment with obinutuzumab is necessary.

Separation of vigabatrin enantiomers using mixed-mode chromatography and its application to determine the vigabatrin enantiomer levels in rat plasma.

Mixed-mode chromatography-comprising a mixed phase with reversed and ionic phases, enabling hydrophobic and ion-exchange interactions simultaneously-was applied to identify vigabatrin enantiomers by HPLC with pre-column fluorescence derivatization with 2,5-dioxopyrrolidin-1-yl (4-(((2-nitrophenyl)sulfonyl)oxy)-6-(3-oxomorpholino)quinoline-2-carbonyl)prolinate (Ns-MOK-(S)-Pro-OSu). The MOK-(S)-Pro-vigabatrin enantiomers were efficiently separated within 12 min (total analysis time per sample: 28 min, including washing and equilibrium time for the column). The mobile phase was H2O/CH3OH/10 mM ammonium formate (pH 2.0) (20/20/60, v/v/v). Column temperature was maintained at 60℃. The proposed HPLC method could successfully monitor plasma vigabatrin enantiomer levels in rats administered (±)-vigabatrin (50 mg/kg, p.o.).

Development of a Derivatization Reagent with a 2-Nitrophenylsulfonyl Moiety for UHPLC-HRMS/MS and Its Application to Detect Amino Acids Including Taurine.

Taurine (Tau) has some important ameliorating effects on human health and is present in bivalve. For the selective analysis of Tau with other amino acids, we designed a derivatization reagent, 2,5-dioxopyrrolidin-1-yl(4-(((2-nitrophenyl)sulfonyl)oxy)-6-(3-oxomorpholino)quinoline-2-carbonyl)pyrrolidine-3-carboxylate (Ns-MOK-ß-Pro-OSu). After derivatization with Ns-MOK-ß-Pro-OSu, amino acids with Tau in Japanese littleneck clams were determined through ultra-high-performance-liquid chromatography with high-resolution tandem mass spectrometry (UHPLC-HRMS/MS) using an octadecyl silica column. We could detect 18 amino acids within 10 min. Tau, valine, glutamine, glutamic acid, and arginine in the clams were determined in the negative ion mode using the characteristic fragment ion, C6H4N1O5S, which corresponded to the 2-nitrobenzenesulfonylate moiety. The fragment ion, C6H4N1O5S, was recognized as a common feature regardless of the amino acid to be derivatized, and it was convenient for detecting amino acid derivatives with high selectivity and sensitivity. Therefore, highly selective quantification using UHPLC-HRMS/MS was possible using Ns-MOK-ß-Pro-OSu.

Development of derivatization reagents bearing chiral 4-imidazolidinone for distinguishing primary amines from other amino acids and application to the liquid chromatography-tandem mass spectrometric analysis of miso.

We designed and synthesized three novel derivatization reagents bearing chiral 4-imidazolidinone, namely succinimidyl 2-(3-((benzyloxy)carbonyl)-1-methyl, ethyl, and -phenyl-5-oxoimidazolidin-4-yl)acetates (CIMs), for use in liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The CIMs were able to discriminate primary amines from other compounds such as secondary amines and phenols, based on their unique m/z reduction of precursor ion to form product ion in MS/MS. As amino acid derivatization reagents, the CIMs were compared in terms of enantioseparation of amino acid and detection sensitivity. CIMa-OSu with 1-methyl-5-oxoimidazolidinone moiety gave the best optical resolution and detection sensitivity among the CIM reagents. Next, we applied (R)-CIMa-OSu to determine amino acids in miso by LC-triple-quadrupole MS. The proposed method achieved simultaneous determination of 20 l-amino acids and two d-amino acids (d-alanine and d-serine) in the sample with a high sensitivity (limits of detection 5-238 fmol, signal-to-noise ratio 3.3). After derivatization with CIMa-OSu, it was possible to determine whether each peak in the chromatogram was a component of primary amine or not, by using a high-resolution orbitrap MS instrument.

Risk factors for clozapine-induced central nervous system abnormalities in Japanese patients with treatment-resistant schizophrenia.

The purpose of this study was to assess the risk factors for clozapine-induced central nervous system (CNS) abnormalities (i.e., electroencephalogram [EEG] abnormalities, myoclonus, and seizures). We retrospectively analyzed data from 106 patients with schizophrenia who received clozapine treatment through our hospital. A review of the EEG recordings showed that 71 of these patients (67.0 %) developed CNS abnormalities after initiating clozapine treatment. EEG abnormalities, myoclonus, and seizures occurred in 53.8 %, 38.7 %, and 8.5 % of the patients, respectively. Multivariate logistic regression analysis showed that the risk factors for clozapine-induced CNS abnormalities were concomitant lithium usage (odds ratio, 4.560; 95 % confidence interval, 1.750-11.900) and shorter illness durations before clozapine initiation (odds ratio, 0.796; 95 % confidence interval, 0.649-0.976). However, plasma clozapine levels and the usage of antiepileptics did not exhibit associations with the risks of CNS abnormalities. Clinicians should monitor their patients for incident CNS abnormalities when administering lithium in combination with clozapine regardless of plasma clozapine levels or the usage of antiepileptics. This is especially true for patients with short illness durations.

Fluorimetric determination of the enantiomers of vigabatrin, an antiepileptic drug, by reversed-phase HPLC with a novel diastereomer derivatization reagent.

Herein, determination of an antiepileptic drug, (±)-vigabatrin (VB), was performed by reversed-phase HPLC with fluorimetric detection using a newly designed and synthesized fluorescence derivatization reagent, 2,5-dioxopyrrolidin-1-yl (4-{[(2-nitrophenyl)sulfonyl]oxy}-6-(3-oxomorpholino)quinoline-2-carbonyl)prolinate [Ns-MOK-(R)- or (S)-Pro-OSu]. During the derivatization of VB with Ns-MOK-(R)-Pro-OSu at 60°C, the nosyl (Ns) group, which was introduced to protect a phenolic hydroxy group, was released within 30 min to produce MOK-(R)-Pro-VB, which was detected fluorimetrically at 448 nm with an excitation wavelength of 333 nm. The VB enantiomers were separated on an octadecylsilica (ODS) column with a resolution value of 5.57, because Ns-MOK-(R)-Pro-OSu bears an optically active D-proline structure. A complete separation of MOK-(R)-Pro-(R)- and -(S)-VB enantiomers was achieved on the ODS column within 40 min using stepwise gradient elution, and the detection limits were ~0.80 and 0.37 pmol on the column, respectively. The proposed HPLC with fluorimetric detection method was successfully used for determining VB enantiomers in VB-spiked human serum following solid-phase extraction with an anion-exchange cartridge.

Retrospective cohort study of the efficacy and safety of dabigatran: real-life dabigatran use including very low-dose 75 mg twice daily administration.

BACKGROUND: Dabigatran is a direct thrombin inhibitor and an anticoagulant that is prescribed to prevent ischemic stroke and systemic embolism in non-valvular atrial fibrillation. Dabigatran (150 mg twice daily) is non-inferior to warfarin for the prevention of stroke and systemic embolism. A dose reduction to 110 mg twice daily should be considered for patients with decreased renal function, elderly patients, and those with a history of gastrointestinal bleeding. A small number of patients are prescribed 75 mg twice daily; however, excessive dose reduction below that indicated on the package insert may decrease the effectiveness of dabigatran. In this study, we investigated the incidence of thromboembolic events and hemorrhagic complications in patients receiving different doses of dabigatran, including patients receiving the very low-dose of 75 mg twice daily. METHODS: Five hospitals in Meguro and Setagaya areas of Tokyo were included in this study. The subjects were patients receiving dabigatran in the hospitals from March 2011 to February 2014. Thromboembolic events (stroke, systemic embolism, and transient cerebral ischemic attack) and hemorrhagic complications occurring before December 2014 were retrospectively evaluated. RESULTS: A total of 701 subjects received dabigatran during the study period: 187 patients (26.7%) received 150 mg twice daily (normal dose), 488 patients (69.6%) received 110 mg twice daily (low-dose), and 26 patients (3.7%) received 75 mg twice daily (very low-dose). Thromboembolism occurred in 4 (2.1%), 11 (2.3%), and 3 patients (11.5%), in the normal dose, low-dose, and very low-dose groups, respectively. The odds ratio of the 75 mg dose to the 150 and 110 mg doses was 5.73 (95% CI, 1.55-21.2; p = 0.009), and the incidence with the 75 mg dose was higher than that with the other doses. Although the number of events was limited, it should be noted that 3 patients in the very low-dose group had thromboembolic events. CONCLUSIONS: The results suggest that sufficient anticoagulation efficacy may not be maintained when the dabigatran dose is excessively reduced to 75 mg twice daily.

Succinimidyl (3-[(benzyloxy)carbonyl]-5-oxo-1,3-oxazolidin-4-yl)acetate on a triazole-bonded phase for the separation of dl-amino-acid enantiomers and the mass-spectrometric determination of chiral amino acids in rat plasma.

Changes in the levels of amino-acid enantiomers are associated with some serious diseases; consequently, amino acid monitoring in peripheral blood can be used to diagnose and predict the onset of disease. Herein, we report the design and synthesis of a new chiral derivatization reagent, namely succinimidyl (4S)-(3-[(benzyloxy)carbonyl]-5-oxo-1,3-oxazolidin-4-yl)acetate ((S)-COXA-OSu), for the separation of dl-amino-acid enantiomers. The usefulness of (S)-COXA-OSu was examined as a derivatization reagent for LC-MS/MS following certification of its total optical purity (>99%). The enantiomeric separations of amino-acid derivatives tagged with the reagent were examined using a triazole-bonded phase. (S)-COXA-OSu enabled the simultaneous enantiomeric separation of more than 40 α-amino acids. (S)-COXA-amino-acid derivatives were efficiently converted into their product ions, from which formaldehyde (CH2O) was eliminated [M-30] from the oxazolidinone moiety of COXA by collision-induced dissociation during LC-MS/MS. Limits of detection were in the 0.0138-0.518 pmol/injection range. For precise and accurate quantitation, we synthesized and used a stable-isotope-labeled (S)-COXA-OSu that was used as an internal standard in LC-MS/MS-determination experiments. Finally, changes in plasma amino-acid levels in rats, following administration of S-methyl-l-cysteine, an alanine-serine-cysteine transporter-1 (Asc-1) inhibitor, were successfully detected by LC-MS/MS using (S)-COXA-OSu.