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%.

Alteration in facial skin blood flow during acute exposure to -10 and -30° head-down tilt in young human volunteers.

NEW FINDINGS: What is the central question of this study? Facial skin blood flow (SBF) might increase during head-down tilt (HDT). However, the effect of HDT on facial SBF remains controversial. In addition, the changes in facial SBF in the cheek (cheek SBF) during a steeper angle of HDT (>-12° HDT) have not been investigated. What is the main finding and its importance? This study showed that cheek SBF decreased during -30° HDT, alongside increased vascular resistance. Furthermore, vascular impedance was suggested to be elevated, accompanied by an increased hydrostatic pressure gradient caused by HDT. Constriction of the facial skin vascular bed and congestion of venous return owing to the steep angle of HDT can decrease facial SBF. ABSTRACT: Head-down tilt (HDT) has been used to simulate microgravity in ground-based studies and clinical procedures including the Trendelenburg position or in certain surgical operations. Facial skin blood flow (SBF) might be altered by HDT, but the effect of a steeper angle of HDT (>-12° HDT) on facial SBF remains unclear. We examined alterations in facial SBF in the cheek (cheek SBF) using two different angles (-10 and -30°) of HDT and lying horizontal (0°) in a supine position for 10 min, to test the hypothesis that cheek SBF would increase with a steeper angle of HDT. Cheek SBF was measured continuously by laser Doppler flowmetry. Cheek skin vascular resistance and the pulsatility index of cheek SBF were calculated to assess the circulatory effects on the facial skin vascular bed in the cheek. Cheek SBF decreased significantly during -30° HDT. In addition, the resistance in cheek SBF increased significantly during -30° HDT. The pulsatility index of cheek SBF increased during both -10 and -30° HDT. Contrary to our hypothesis, cheek SBF decreased during -30° HDT along with increased skin vascular resistance. Vascular impedance, estimated by the pulsatility index in the cheek SBF, was elevated during both -10 and -30° HDT, and elevated vascular impedance would be related to increased hydrostatic pressure induced by HDT. Skin vascular constriction and venous return congestion would be induced by -30° HDT, leading to deceased cheek SBF. The present study suggested that facial SBF in the cheek decreased during acute exposure to a steep angle of HDT (∼-30° HDT).

Long-duration spaceflight alters estimated intracranial pressure and cerebral blood velocity.

KEY POINTS: During long-duration spaceflights, some astronauts develop structural ocular changes including optic disc oedema that resemble signs of intracranial hypertension. In the present study, intracranial pressure was estimated non-invasively (nICP) using a model-based analysis of cerebral blood velocity and arterial blood pressure waveforms in 11 astronauts before and after long-duration spaceflights. Our results show that group-averaged estimates of nICP decreased significantly in nine astronauts without optic disc oedema, suggesting that the cephalad fluid shift during long-duration spaceflight rarely increased postflight intracranial pressure. The results of the two astronauts with optic disc oedema suggest that both increases and decreases in nICP are observed post-flight in astronauts with ocular alterations, arguing against a primary causal relationship between elevated ICP and spaceflight associated optical changes. Cerebral blood velocity increased independently of nICP and spaceflight-associated ocular alterations. This increase may be caused by the reduced haemoglobin concentration after long-duration spaceflight. ABSTRACT: Persistently elevated intracranial pressure (ICP) above upright values is a suspected cause of optic disc oedema in astronauts. However, no systematic studies have evaluated changes in ICP from preflight. Therefore, ICP was estimated non-invasively before and after spaceflight to test whether ICP would increase after long-duration spaceflight. Cerebral blood velocity in the middle cerebral artery (MCAv) was obtained by transcranial Doppler sonography and arterial pressure in the radial artery was obtained by tonometry, in the supine and sitting positions before and after 4-12 months of spaceflight in 11 astronauts (10 males and 1 female, 46 ± 7 years old at launch). Non-invasive ICP (nICP) was computed using a validated model-based estimation method. Mean MCAv increased significantly after spaceflight (ANOVA, P = 0.007). Haemoglobin decreased significantly after spaceflight (14.6 ± 0.8 to 13.3 ± 0.7 g/dL, P < 0.001). A repeated measures correlation analysis indicated a negative correlation between haemoglobin and mean MCAv (r = -0.589, regression coefficient = -4.68). The nICP did not change significantly after spaceflight in the 11 astronauts. However, nICP decreased significantly by 15% in nine astronauts without optic disc oedema (P < 0.005). Only one astronaut increased nICP to relatively high levels after spaceflight. Contrary to our hypothesis, nICP did not increase after long-duration spaceflight in the vast majority (>90%) of astronauts, suggesting that the cephalad fluid shift during spaceflight does not systematically or consistently elevate postflight ICP in astronauts. Independently of nICP and ocular alterations, the present results of mean MCAv suggest that long-duration spaceflight may increase cerebral blood flow, possibly due to reduced haemoglobin concentration.

Impact of the Lithium Cation on the Voltammetry and Spectroscopy of [XVM11O40]n- (X = P, As (n = 4), S (n = 3); M = Mo, W): Influence of Charge and Addenda and Hetero Atoms.

Polyoxometalates (POMs) have been proposed as electromaterials for lithium-based batteries because they provide access to multiple electron transfer reactions coupled to fast lithium ion transport processes and high stability over many redox cycles. Consequently, knowledge of reversible potentials and Li+ cation-POM anion interactions provides a strategic basis for their further development. In this study, detailed cyclic voltammetric studies of a series of [XVVM11O40]n- (XVM11n-) POMs (where X (heteroatom) = P (n = 4), As (n = 4), and S (n = 3) and M (addenda atom) = Mo, W) have been undertaken in CH3CN in the presence of LiClO4, with n-Bu4NPF6 also present when required to keep the ionic strength close to constant value of 0.1 M. An analysis of the data has allowed the impact of the POM charge, and addenda and hetero atoms on the reversible potentials and the interaction between Li+ and the oxidized XVVM11n- and reduced XVIVM11(n+1)- forms of the VV/IV redox couple to be determined. The SVV/IVM113-/4- process is independent of the Li+ concentration, implying the absence of the association of this cation with either SVVM113- or SVIVM114- redox levels. However, lithium-ion association constants for both VV and VIV redox levels were obtained from a comparison of simulated and experimental cyclic voltammograms for the reduction of the more negatively charged XVVM114- (X = P, As; M = Mo, W), since the Li+ interaction with these more negatively charged POMs is much stronger. The interaction between Li+ and the oxidized, XVVM11n-, and reduced, XVIVM11(n+1)-, forms was also investigated by 51V NMR and EPR spectroscopy, respectively, and it was confirmed that, due to their lower charge density, SVVM113- and SVIVM114- interact significantly less strongly with the lithium ion than XVVM114- and XVIVM115- (X = P, As). The lithium-POM association constants are substantially smaller than the corresponding proton association constants reported previously, which is attributed to a smaller surface charge density. The much stronger impact of Li+ on the WVI/V- and MoVI/V-based reductions that occur at more negative potentials than the VV/IV process also has been qualitatively evaluated.

Steady-state cerebral blood flow and dynamic cerebral autoregulation during neck flexion and extension in seated healthy young adults.

Neck flexion and extension show differences in various physiological factors, such as sympathetic nerve activity and intracranial pressure (ICP). We hypothesized that differences would exist in steady-state cerebral blood flow and dynamic cerebral autoregulation between neck flexion and extension in seated, healthy young adults. Fifteen healthy adults were studied in the sitting position. Data were collected during neck flexion and extension in random order for 6 min each on the same day. Arterial pressure at the heart level was measured using a cuff sphygmomanometer. Mean arterial pressure at the middle cerebral artery (MCA) level (MAPMCA ) was calculated by subtracting the hydrostatic pressure difference between heart and MCA levels from mean arterial pressure at the heart level. Non-invasive cerebral perfusion pressure (nCPP) was estimated as the MAPMCA minus the non-invasive ICP as determined from transcranial Doppler ultrasonography. Waveforms of arterial pressure in the finger and blood velocity in the MCA (MCAv) were obtained. Dynamic cerebral autoregulation was evaluated by transfer function analysis between these waveforms. The results showed that nCPP was significantly higher during neck flexion than during neck extension (p = 0.004). However, no significant differences were observed in mean MCAv (p = 0.752). Likewise, no significant differences were observed in any of the three indices of dynamic cerebral autoregulation in any frequency range. Although non-invasively estimated cerebral perfusion pressure was significantly higher during neck flexion than during neck extension, no differences in steady-state cerebral blood flow or dynamic cerebral autoregulation were evident between neck flexion and extension in seated healthy adults.

Association of STAT3, CYP3A5, and ABCG2 Polymorphisms With Osimertinib-induced Adverse Events in NSCLC Patients.

BACKGROUND/AIM: Osimertinib is a key drug for treating epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). Genetic differences may be associated to adverse events (AEs) induced by osimertinib. This retrospective observational multicenter study evaluated the association of genotypes, including STAT3 -1697C>G, CYP3A5 6986A>G, and ABCG2 421C>A, with the incidence of osimertinib-induced AEs in patients with EGFR mutation-positive NSCLC. PATIENTS AND METHODS: A total of 85 patients treated with osimertinib (Institution A: 33 patients, Institution B: 52 patients) were enrolled in the study. Single nucleotide polymorphisms were determined by real-time PCR, and the incidence of AEs was compared for each genotype. RESULTS: Paronychia incidence was 59% for the CC genotype, 19% for the CG genotype, and 19% for the GG genotype at STAT3 -1697C>G. A genotype-related trend was observed (Cochran-Armitage test, p=0.009). Multivariate analysis showed that the CC genotype at STAT3 -1697C>G and female sex were significant independent factors associated with paronychia [odds ratio (OR)=6.41, 95% confidence interval (CI)=1.94-21.20 and OR=3.40, 95%CI=1.03-11.22, respectively]. The incidence of diarrhea was 53% for the CC genotype, 30% for the AC genotype, and 29% for the AA genotype at ABCG2 421C>A, and a genotype-related trend was observed (p=0.048). However, the CC genotype at ABCG2 421C>A was not a significant independent factor associated with diarrhea in multivariate analysis. No significant associations were detected between other polymorphisms and the incidence of AEs. CONCLUSION: STAT3 -1697C>G may be a novel risk factor for osimertinib-induced paronychia in patients with NSCLC.

Shin'iseihaito (Xinyiqingfeitang) extract ameliorates ovalbumin-induced murine allergic rhinitis by regulating cytokines.

Shin'iseihaito (Xinyiqingfeitang) is a formula of traditional Japanese Kampo medicine and traditional Chinese medicine (TCM) and for chronic sinusitis. However, the precise action mechanism has been unknown. We examined the effect of shin'iseihaito extract (SSHT) on murine allergic rhinitis model using ovalbumin (OVA). We decocted the mixture of 9 crude drugs in water to prepare SSHT. SSHT (20 times amount of human dose) was orally administered to mice treated with OVA. After mice were sacrificed on day 28, immunoglobulin (Ig) E, interleukin (IL)-4, IL-13, interferon (IFN)-γ, and thymic stromal lymphopoietin (TSLP) levels in nasal lavage fluid samples were measured by enzyme-linked immunosorbent assay (ELISA). The pathological tissue sections from the nasal epithelial mucosa were histopathologically investigated by optical and scanning electron microscopies. We also investigated the effects of modified SSHTs prepared by removing one crude drug from shin'iseihaito to clarify the active ingredients. SSHT suppressed IgE, IL-4, IL-13, and TSLP levels, while increased the IFN-γ levels in OVA-induced allergic mice. Sensitization with OVA resulted in an increase in eosinophilia and goblet cells in murine nasal cavity tissue in comparison with those in untreated group, however, those were significantly reduced by the treatment with SSHT. The extracts of 8 crude drug's mixtures except for the removal of Gypsum fibrosum (GF) from shin'iseihaito counteracted on the suppressive effects of SSHT on IgE, IL-4, IL-13, and TSLP levels in nasal lavage fluid. Our result demonstrated that SSHT may contribute to inhibit the exacerbation of OVA-induced murine allergic rhinitis by regulating cytokines, and the components except for GF contributed anti-allergic effect of shin'iseihaito.

Short-Term Volume Loading Effects on Estimated Intracranial Pressure in Human Volunteers.

BACKGROUND: Short-term fluid loading is used as part of post-spaceflight medical procedures and clinical treatment in hospitals. Hypervolemia with hemodilution induced by rapid fluid infusion reportedly impaired dynamic cerebral autoregulation. However, the effects on intracranial pressure (ICP) remain unknown. Therefore, we estimated ICP noninvasively (nICP) to examine whether rapid fluid infusion would raise ICP.METHODS: Twelve healthy male volunteers underwent two discrete normal saline (NS) infusions (15 and 30 ml · kg-1 stages, NS-15 and NS-30, respectively) at a rate of 100 ml · min-1. The cerebral blood flow (CBF) velocity (CBFv) waveform from the middle cerebral artery obtained by transcranial Doppler ultrasonography was recorded, as was the arterial blood pressure (ABP) waveform at the radial artery obtained by tonometry. We then used these waveforms to calculate nICP, cerebral artery compliance, and the pulsatility index (PI) in an intracranial hydraulic model.RESULTS: nICP increased significantly in both infusion stages from preinfusion (preinfusion: 7.6 ± 3.4 mmHg; NS-15: 10.9 ± 3.3 mmHg; NS-30: 11.7 ± 4.2 mmHg). No significant changes were observed in cerebral artery compliance or PI. Although ABP did not change in any stage, CBFv increased significantly (preinfusion: 67 ± 10 cm · s-1; NS-15: 72 ± 12 cm · s-1; NS-30: 73 ± 12 cm · s-1).DISCUSSION: Hypervolemia with hemodilution induced by rapid fluid infusion caused increases in nICP and CBFv. No changes were observed in cerebral artery compliance or PI related to cerebrovascular impedance. These findings suggest that rapid fluid infusion may raise ICP with increased CBF.Kurazumi T, Ogawa Y, Takko C, Kato T, Konishi T, Iwasaki K. Short-term volume loading effects on estimated intracranial pressure in human volunteers. Aerosp Med Hum Perform. 2022; 93(4):347-353.

Effects of -10° and -30° head-down tilt on cerebral blood velocity, dynamic cerebral autoregulation, and noninvasively estimated intracranial pressure.

Steady-state cerebral blood flow (CBF) and dynamic cerebral autoregulation are reportedly maintained during -10° head-down tilt (HDT) despite slight increases in intracranial pressure (ICP). However, the higher ICP during -30° HDT may alter steady-state CBF and dynamic cerebral autoregulation. The present study hypothesized that steady-state CBF and dynamic cerebral autoregulation would be altered by higher ICP during -30° HDT than during 0° and -10° HDT. Seventeen healthy participants were positioned horizontal (0°) and in -10° HDT and -30° HDT for 10 min in random order on separate days. The arterial blood pressure waveform was obtained using a finger blood pressure device and the cerebral blood velocity waveform in the middle cerebral artery was obtained using transcranial Doppler sonography (TCD) for the last 6 min in each position. ICP was estimated using noninvasive ICP (nICP) based on TCD. Dynamic cerebral autoregulation was evaluated by spectral and transfer function analysis. Although nICP was significantly higher during -30° HDT (12.4 mmHg) than during -10° HDT (8.9 mmHg), no significant differences in steady-state mean cerebral blood velocity or transfer function gain in any frequency ranges were seen among all angles of HDT. Counter to our hypothesis, the present results suggest that steady-state CBF and dynamic cerebral autoregulation may be preserved during short-term -30° HDT despite the higher ICP compared with that during -10° HDT.NEW & NOTEWORTHY This appears to be the first study to evaluate steady-state cerebral blood flow (CBF), dynamic cerebral autoregulation, and intracranial pressure (ICP) during -30° head-down tilt (HDT) compared with those during -10° HDT using noninvasive measurements. The results suggest that steady-state CBF and dynamic cerebral autoregulation are preserved despite the higher ICP during short-term -30° HDT compared with -10° HDT.