Pharmacokinetics of Brexpiprazole, Quetiapine, Risperidone, and Its Active Metabolite Paliperidone in a Postpartum Woman and Her Baby.

BACKGROUND: Brexpiprazole is a second-generation antipsychotic approved in Japan in 2018; however, information on placental passage and breast milk transfer remains limited. In this report, the patient, a 30-year-old pregnant woman with schizophrenia, was medicated with brexpiprazole, risperidone, and quetiapine. METHODS: The study used high-performance liquid chromatography-tandem mass spectrometry to determine the concentrations of brexpiprazole, quetiapine, risperidone, and its active metabolite (paliperidone) in maternal and neonatal plasma, cord venous plasma, and breast milk. Maternal plasma samples were obtained approximately 2 and 8 hours after the last administration of antipsychotics on the day of delivery and at the estimated drugs' trough time on days 1, 3, and 5 after delivery. RESULTS: The maternal plasma concentrations of brexpiprazole, quetiapine, and paliperidone increased by approximately 3.5-fold on the fifth day compared with those on the day of delivery, whereas the risperidone concentration remained almost constant. Moreover, the neonatal plasma concentrations of the 4 drugs immediately after birth were indistinguishable from the umbilical cord concentrations and gradually decreased, except for risperidone. Relative infant doses of these compounds were below 1.1%. CONCLUSIONS: Pregnancy status notably alters the pharmacokinetic properties of antipsychotics. Therefore, close and careful monitoring of clinical symptoms should be considered during pregnancy and after delivery. Although brexpiprazole is transferred to neonates through the placenta, breastfeeding is still possible because the relative infant dose value of this drug was much less than 10%.

Population pharmacokinetics of everolimus in renal transplant recipients receiving long-term multiple immunosuppressive therapy.

Everolimus is used for immunosuppression after renal transplantation. This study aimed to develop a population pharmacokinetic (PopPK) model of everolimus using therapeutic drug monitoring (TDM) data of patients under long-term multiple immunosuppressive therapy, including tacrolimus. To develop the model, 185 renal transplant recipients with 3358 everolimus blood concentrations during a median postoperative period of 35.3 months were included. The PopPK model is described as a one-compartment model with first-order absorption. The population mean of apparent clearance is 8.92 L/h (relative standard error = 3.6%), and this negatively correlated with the dose-normalized concentration (C/D) of tacrolimus and hematocrit value, and positively correlated with a daily dose of everolimus (i.e. TDM effect). The usefulness of dose adjustment using the final popPK model was assessed by a simulation study. The ratio of the first trough measurement within the therapeutic range of 3-8 ng/mL increased from 69.8% in the original dose to 87.9% in the individual dose calculated by the final PopPK model. The tacrolimus C/D ratio before initiating everolimus therapy and the hematocrit value were useful to estimate the initial dose of everolimus and can improve the safety and effectiveness of immunosuppressive therapy involving everolimus.

The Efficacy of Bepotastine Besilate Compared With Hydroxyzine Pamoate for Preventing Infusion Reactions to the First Dose of Rituximab in Patients With Non-Hodgkin Lymphoma: Protocol for a Phase II, Double-Blind, Multicenter Randomized Trial.

BACKGROUND: Rituximab, an anti-CD20 monoclonal antibody, can cause infusion reactions (IRs), especially during the initial rituximab infusion therapy. Generally, patients are administered a histamine H1-receptor antagonist before the rituximab infusion, along with an antipyretic analgesic, to prevent or reduce IRs. Multiple retrospective case-control studies indicate that the second generation of histamine H1-receptor antagonists might be more effective than the first generation in suppressing IRs caused by the rituximab infusion. OBJECTIVE: This study aimed to assess the efficacy of first- and second-generation histamine H1-receptor antagonists for preventing IRs resulting from the initial infusion of rituximab in patients diagnosed with non-Hodgkin lymphoma. METHODS: This is a phase II, double-blind, active-controlled randomized trial. It will be a multicenter study conducted across 3 facilities that aims to enroll a total of 40 patients diagnosed with non-Hodgkin lymphoma who will receive their initial rituximab infusion. Participating patients will be administered hydroxyzine pamoate or bepotastine besilate, representing first- or second-generation histamine H1-receptor antagonists, respectively. This will be combined with 400-mg acetaminophen tablets taken approximately 30 minutes before the first infusion of rituximab. The primary end point of this trial is to assess severe IRs, equivalent to grade 2 or higher as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, that occur within a 4-hour period after the initiation of rituximab infusion. The secondary end points include assessing the severity of the initial IR, the maximum severity of the IR, and the duration between rituximab infusion initiation and the onset of the first IR within a 4-hour period. Additionally, the trial will evaluate histamine H1-receptor antagonist-induced drowsiness using the visual analogue scale, with each patient providing their individual response. RESULTS: This study began with patient recruitment in April 2023, with 17 participants enrolled as of November 12, 2023. The anticipated study completion is set for February 2026. CONCLUSIONS: This study is the first randomized controlled trial comparing the effects of oral first- and second-generation histamine H1-receptor antagonists in preventing IRs induced by the initial administration of rituximab. The findings from this study hold the potential to establish the rationale for a phase III study aimed at determining the standard premedication protocol for rituximab infusion. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs051220169; https://jrct.niph.go.jp/latest-detail/jRCTs051220169. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/54882.

Luteolin Protects Against 6-Hydoroxydopamine-Induced Cell Death via an Upregulation of HRD1 and SEL1L.

Parkinson's Disease (PD) is caused by many factors and endoplasmic reticulum (ER) stress is considered as one of the responsible factors for it. ER stress induces the activation of the ubiquitin-proteasome system to degrade unfolded proteins and suppress cell death. The ubiquitin ligase 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation 1 (HRD1) and its stabilizing molecule, the suppressor/enhancer lin-12-like (SEL1L), can suppress the ER stress via the ubiquitin-proteasome system, and that HRD1 can also suppress cell death in familial and nonfamilial PD models. These findings indicate that HRD1 and SEL1L might be key proteins for the treatment of PD. Our study aimed to identify the compounds with the effects of upregulating the HRD1 expression and suppressing neuronal cell death in a 6-hydroxydopamine (6-OHDA)-induced cellular PD model. Our screening by the Drug Gene Budger, a drug repositioning tool, identified luteolin as a candidate compound for the desired modulation of the HRD1 expression. Subsequently, we confirmed that low concentrations of luteolin did not show cytotoxicity in SH-SY5Y cells, and used these low concentrations in the subsequent experiments. Next, we demonsrated that luteolin increased HRD1 and SEL1L mRNA levels and protein expressions. Furthermore, luteolin inhibited 6-OHDA-induced cell death and suppressed ER stress response caused by exposure to 6-OHDA. Finally, luteolin did not reppress 6-OHDA-induced cell death when expression of HRD1 or SEL1L was suppressed by RNA interference. These findings suggest that luteolin might be a novel therapeutic agent for PD due to its ability to suppress ER stress through the activation of HRD1 and SEL1L.

A model-based pharmacokinetic assessment of drug-drug interaction between tacrolimus and nirmatrelvir/ritonavir in a kidney transplant patient with COVID-19.

We experienced a patient with a remarkable and prolonged increase in tacrolimus blood concentrations when nirmatrelvir/ritonavir was concomitantly used. The inhibitory intensity and duration of nirmatrelvir/ritonavir on tacrolimus pharmacokinetics were examined using a model-based analysis. A renal transplant patient taking oral tacrolimus continuously was treated with nirmatrelvir/ritonavir for 5 days. The baseline tacrolimus trough blood concentration was 4.2 ng/mL. Tacrolimus was discontinued on Day 6 after the concomitant administration of nirmatrelvir/ritonavir, and the trough concentration increased to 96.4 ng/mL on Day 7. The model-based analysis showed that tacrolimus clearance decreased to 35% and bioavailability increased by 18.7-fold after the coadministration of nirmatrelvir/ritonavir, compared with before the coadministration. Therefore, nirmatrelvir/ritonavir drastically decreased both the apparent clearance and apparent volume of distribution. Simulated tacrolimus concentrations could be best fitted to the observed concentrations when the inhibitory effects of nirmatrelvir/ritonavir were modeled to disappear over about 10 days by first-order elimination. In conclusion, nirmatrelvir/ritonavir greatly increases tacrolimus concentrations by not only reducing clearance, but also increasing bioavailability. Interactions between nirmatrelvir/ritonavir and low-bioavailability drugs which are substrates for CYP3A and P-glycoprotein, such as tacrolimus, are harmful, and concomitant use of these medicines should be avoided.

Significance of pharmacist intervention to oral antithrombotic therapy in the pharmaceutical outpatient clinic of cardiovascular internal medicine: a retrospective cohort study.

BACKGROUND: Optimised antithrombotic therapy requires clinical experience and an understanding of the current guidelines. This retrospective study aimed to evaluate whether pharmacist interviews and interventions with patients taking oral antithrombotic drugs in the pharmaceutical outpatient cardiology clinic had favourable clinical outcomes including decreased bleeding. METHODS: The participants included patients visiting the outpatient clinic of cardiovascular internal medicine at the Kobe University Hospital from January-December 2017, and were taking oral antithrombotic medication. The observation period was from the first visit to the outpatient clinic to October 2021 or death. Patients who received pharmacist intervention more than twice were defined as the pharmacist intervention group. Two control patients per one pharmacist intervention group individual were selected from the non-intervention pool matched for age, gender and antithrombotic medication type. RESULTS: Of the 895 eligible patients, 132 were in the pharmacist intervention group and 264 were selected for the matched non-intervention group. Bleeding events according to the Bleeding Academic Research Consortium criteria over type 2 were significantly lower in the pharmacist intervention group compared with the non-intervention group (17.4% versus 28.4%, P = 0.019). There were no significant differences in mortality and heart failure hospitalisation frequency, stroke, or cardiovascular events between the groups. Multivariate analysis identified age (≥ 65 years) and pharmacist intervention as factors associated with bleeding (odds ratio = 2.29 and 0.51, respectively). CONCLUSION: Pharmacist intervention in the outpatient clinic of cardiovascular internal medicine was effective in reducing the risk of bleeding in patients undergoing antithrombotic therapy.

Efficacy and Long-Term Safety of Ibuprofen Gargle for Oral Lichen Planus: A Study Protocol of Randomized Crossover and Long-Term Extension Trials.

Oral lichen planus (OLP) is a type of chronic and refractory stomatitis characterized by abnormal keratinization, which is often painful. There is no consensus regarding treatment options for OLP, particularly in the presence of pain. The current study protocol focuses on the short-term efficacy and long-term safety of an ibuprofen gargle for pain management in patients with OLP. Patients (n = 24) with painful OLP will be enrolled. During a crossover study period, patients in the ibuprofen-placebo (IP) group will receive an ibuprofen gargle (0.6%) on day 1, a placebo gargle on day 2, and an ibuprofen gargle on days 3-5 at least once daily. Patients in the placebo-ibuprofen (PI) group will receive a placebo gargle on day 1, an ibuprofen gargle on day 2, and an ibuprofen gargle on days 3-5 at least once daily. The primary endpoint of the crossover study period is the change in pain level as measured by a visual analogue scale score from before gargle administration to 5 min after gargle administration on days 1 and 2. The primary endpoint of the long-term extension study is assessment of long-term safety. The results of this study may support existing evidence regarding the effectiveness of ibuprofen rinses in treating OLP.

Phytochemical characterization of Rosa multiflora Thunb. (Rosaceae) in Japan and South Korea, with a focus on the bioactive flavonol glycoside 'multiflorin A'.

Dried achene or anthocarpous accessory fruits of Rosa multiflora Thunb., Rosae fructus ("Eijitsu" in Japanese), have been used in clinical practice to improve constipation within traditional Japanese medicine. Recently, it has been claimed that the efficacy of this crude drug is decreasing, and multiflorin A, the purgative component, was not detected within the tested samples. In order to clarify the causes of this issue, we investigated Rosa section Synstylae (Rosaceae), including R. multiflora, growing in Japan and South Korea with a focus on the secondary metabolite, multiflorin A. We recognize that there are two chemotypes based on the presence (Type I) or absence (Type II) of multiflorin A. Type I contains quercitrin, multinoside A, multiflorin B, and multinoside A acetate as major index compounds. Type II contains hyperin, isoquercitrin, quercetin 3-O-glucuronide, and 3'-methoxy-isoquercitrin as the major index compounds. The chemotype of Rosa section Synstylae (Rosaceae) plants collected in Japan (excluding Tsushima Island) were all classified as Type I with exception of two species, R. luciae and R. sambucina. On the other hand, both Type I and Type II were detected within Rosae fructus obtained from R. multiflora collected in South Korea and Tsushima Island, Japan. The results indicate that Rosae fructus from R. multiflora (Type I) from Japan, excluding Tsushima Island, should be employed clinically, which we describe as purgative.

Anti-inflammatory activities of Ophiopogonis Radix on hydrogen peroxide-induced cellular senescence of normal human dermal fibroblasts.

Ophiopogonis Radix (Ophiopogon root), which nourishes the yin, has been used in clinical practice to promote fluid secretion and to moisturize the lungs and skin in traditional Chinese and Japanese (Kampo) medicine. To evaluate this traditional medicinal effect, we investigated the anti-chronic inflammatory effect of Radix Ophiopogonis on senescent cells. Conversely, although several phenotypes of Ophiopogon japonicus Ker-Gawler (Liliaceae) are prevalent in Japan and China, we used these Ophiopogon roots by considering them as one crude drug, Ophiopogonis Radix. In this study, it was revealed that there are two chemotypes (Types A and B) in the root of the original plant, O. japonicus. Methylophiopogonanone A (compound 1) and methylophiopogonanone B (compound 2) were isolated as index compounds from Type A and compound 1 and ophiopogonanone A (compound 3) from Type B. In addition, ophiopogonin B (compound 4) was isolated as the main steroidal saponin from both Type A and B. The results indicated that two different methanol extracts (from Types A and B) and the main constituents of O. japonicus (compound 1-4), significantly downregulated the expression of interleukin (IL)-6 and IL-8, which were enhanced by senescent normal human dermal fibroblasts. Moreover, the two different methanol extracts and compounds 1-4 decreased IL-6 production in a strong and concentration-dependent manner by the ELISA method.