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%.

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.

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.

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).

TGF-ß generates a population of cancer cells residing in G1 phase with high motility and metastatic potential via KRTAP2-3.

Transforming growth factor ß (TGF-ß) increases epithelial cancer cell migration and metastasis by inducing epithelial-mesenchymal transition (EMT). TGF-ß also inhibits cell proliferation by inducing G1 phase cell-cycle arrest. However, the correlation between these tumor-promoting and -suppressing effects remains unclear. Here, we show that TGF-ß confers higher motility and metastatic ability to oral cancer cells in G1 phase. Mechanistically, keratin-associated protein 2-3 (KRTAP2-3) is a regulator of these dual effects of TGF-ß, and its expression is correlated with tumor progression in patients with head and neck cancer and migratory and metastatic potentials of oral cancer cells. Furthermore, single-cell RNA sequencing reveals that TGF-ß generates two populations of mesenchymal cancer cells with differential cell-cycle status through two distinctive EMT pathways mediated by Slug/HMGA2 and KRTAP2-3. Thus, TGF-ß-induced KRTAP2-3 orchestrates cancer cell proliferation and migration by inducing EMT, suggesting motile cancer cells arrested in G1 phase as a target to suppress metastasis.

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.

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.

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.

Changes in cerebral oxygen saturation and cerebral blood flow velocity under mild +Gz hypergravity.

We previously reported that cerebral blood flow (CBF) was reduced by even mild +Gz hypergravity. Regional cerebral oxygen saturation as measured by near-infrared spectroscopy (C-rSO2) has been widely used to detect cerebral ischemia in clinical practice. For example, decreases in C-rSO2 reflect reduced CBF or arterial oxygen saturation. Thus it was hypothesized that C-rSO2 would decrease in association with reduced CBF during mild hypergravity. To test this hypothesis, we measured CBF velocity by transcranial Doppler ultrasonography and C-rSO2 during mild +Gz hypergravity while participants were in a sitting position. Among 17 male participants, 15 completed 21 min of exposure to +1.5 Gz generated by short-arm centrifuge. C-rSO2 and mean CBF velocity in the middle cerebral artery (MCBFVMCA) during centrifugation were averaged every 5 min and compared with pre-hypergravity (+1.0 Gz). C-rSO2 did not change significantly throughout centrifugation, although MCBFVMCA gradually decreased from the beginning (-1.2% at 0-5 min), and significantly decreased at 5-10 min (-4.8%), 10-15 min (-6.7%), and 15-20 min (-7.4%). Contrary to our hypothesis, decreases in C-rSO2 were not detected, despite reductions in CBF velocity during hypergravity. Since some assumptions, such as unaltered arteriovenous volume ratio, hemoglobin concentration, extracranial blood flow, and brain activity, need to be satisfied to monitor cerebral ischemia by C-rSO2, the present results suggest that these necessary assumptions for near-infrared spectroscopy are not always applicable, and that cerebral oxygenation may not precisely reflect decreases in CBF under mild +Gz hypergravity. NEW & NOTEWORTHY To our knowledge, this is the first study to evaluate simultaneously cerebral oxygenation monitored by near-infrared spectroscopy and cerebral blood flow (CBF) monitored by transcranial Doppler under +1.5 Gz hypergravity. Contrary to our hypothesis, there was no significant correlation between CBF velocity and regional cerebral oxygen saturation (C-rSO2). However, an incomplete case nearly involving syncope suggests the possibility that C-rSO2 can detect a remarkable decrease in CBF with development of presyncope during +Gz hypergravity.

Time-Dependent Changes in Cerebral Blood Flow and Arterial Pressure During Mild +Gz Hypergravity.

BACKGROUND: Artificial hypergravity has been proposed to prevent or treat various forms of physiological deconditioning experienced during spaceflight. We have previously reported that cerebral blood flow decreased at 15-21 min of +1.5-Gz centrifugation without decreases in arterial pressure at heart level. We reanalyzed our previous data to clarify time-dependent changes in cerebral blood flow and arterial pressure during mild +Gz hypergravity. METHOD: We reanalyzed data for 0-20 min during +1.5-Gz centrifugation on 13 male subjects for whom physiological data were steadily recorded. Mean cerebral blood flow velocity in the middle cerebral artery (MCBFVMCA), mean arterial pressure at heart level (MAPheart), and middle cerebral artery level (MAPMCA) during centrifugation were averaged every 5 min and compared with prehypergravity data (+1.0 Gz, 5 min). RESULTS: MAPheart did not change significantly, but MAPMCA decreased significantly throughout centrifugation compared to prehypergravity data (-16.7% to -24.7%). MCBFVMCA tended to be decreased at 0-5 min of +1.5-Gz centrifugation (-3.3%), but this was not statistically significant. MCBFVMCA was significantly decreased at 5-10 min (-5.5%). MCBFVMCA at 10-15 min and 15-20 min were also significantly decreased to almost the same level (-6.9% and -6.8%, respectively). DISCUSSION: No significant change in MAPheart was detected, whereas MAPMCA decreased significantly from the beginning of +1.5-Gz centrifugation. On the other hand, MCBFVMCA gradually decreased and became roughly flat in the latter half of 20-min centrifugation. Understanding the different time-dependent changes in cerebral blood flow and arterial pressure under mild +Gz hypergravity might be important for implementation of centrifuging as a countermeasure for spaceflight-induced deconditioning.Konishi T, Kurazumi T, Kato T, Takko C, Ogawa Y, Iwasaki K. Time-dependent changes in cerebral blood flow and arterial pressure during mild +Gz hypergravity. Aerosp Med Hum Perform. 2018; 89(9):787-791.

Effect of Hochuekkito (Buzhongyiqitang) on Nasal Cavity Colonization of Methicillin-Resistant Staphylococcus aureus in Murine Model.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) infections are largely preceded by colonization with MRSA. Hochuekkito is the formula composing 10 herbal medicines in traditional Kampo medicine to treat infirmity and to stimulate immune functions. We evaluated the efficacy of hochuekkito extract (HET) against MRSA colonization using a nasal infection murine model. Methods: We evaluated the effects of HET as follows: (1) the growth inhibition by measuring turbidity of bacterial culture in vitro, (2) the nasal colonization of MRSA by measuring bacterial counts, and (3) the splenocyte proliferation in mice orally treated with HET by the ³H-thymidine uptake assay. Results: HET significant inhibited the growth of MRSA. The colony forming unit (CFU) in the nasal fluid of HET-treated mice was significantly lower than that of HET-untreated mice. When each single crude drug-Astragali radix, Bupleuri radix, Zingiberis rhizoma, and Cimicifugae rhizome-was removed from hochuekkito formula, the effect of the formula significantly weakened. The uptake of ³H-thymidine into murine splenocytes treated with HET was significantly higher than that from untreated mice. The effects of the modified formula described above were also significantly weaker than those of the original formula. Conclusions: Hochuekkito is effective for the treatment of MRSA nasal colonization in the murine model. We suggest HET as the therapeutic candidate for effective therapy on nasal cavity colonization of MRSA in humans.

Comparison between the Effects of Oral and Intramuscular Administration of Shin'iseihaito (Xinyiqingfeitang) in a Streptococcus pyogenes-Induced Murine Sinusitis Model.

Streptococcus pyogenes (S. pyogenes) is a species of Gram-positive coccoid bacteria having many virulence factors. Its capsule and exotoxins can cause upper respiratory tract infections such as sinusitis. The general treatment for S. pyogenes-induced sinusitis is administration of antibiotics such as penicillin and macrolides; however, a serious problem associated with these antibiotics is their attenuated effect. Shin'iseihaito (Xinyiqingfeitang), a formula of Japanese traditional Kampo medicine and traditional Chinese medicine, has been used for the treatment of sinusitis. In general, formulas of Japanese traditional Kampo medicine are orally administered. This is in contrast to certain formulas of traditional Chinese medicine, which are being recently administered intramuscularly or intravenously. Regarding these traditional Chinese medicine formulas, the injection methodology is reported to be more effective than oral intake. In this study, we compared the efficacy between orally and intramuscularly administered Shin'iseihaito against S. pyogenes-induced sinusitis. We evaluated the antibacterial effect of Shin'iseihaito extract (SSHT) against S. pyogenes by K-B disk diffusion assay. Furthermore, we investigated the nasal colonization of S. pyogenes, determined cytokine (TNF-α, IL-1ß, and IL-6) levels, and conducted a splenocyte proliferative assay in a murine sinusitis model. SSHT displayed direct anti-S. pyogenes activity. Intramuscular administration of SSHT decreased the nasal colonization of S. pyogenes compared with oral administration. Thymidine uptake analysis revealed that the proliferation of splenocytes from S. pyogenes-infected mice under intramuscular SSHT treatment was upregulated compared to that of splenocytes from S. pyogenes-infected mice under oral SSHT treatment. We also found that TNF-α, IL-1ß, and IL-6 levels in the nasal discharge from intramuscularly treated S. pyogenes-infected mice were lower than those from orally treated mice. Our findings suggest that intramuscular administration of Shin'iseihaito may be useful for the treatment of murine S. pyogenes-induced sinusitis.

Effect of Shin'iseihaito (Xinyiqingfeitang) on Acute Streptococcus pneumoniae Murine Sinusitis via Macrophage Activation.

Streptococcus pneumoniae (S. pneumoniae) causes sinusitis. The general treatment of S. pneumonia sinusitis is by using antibiotics; however, one of their serious problems is the attenuation of their effect. Shin'iseihaito (Xinyiqingfeitang), a formula of Japanese traditional Kampo medicine, has been used for the treatment of sinusitis in Japan. In this study, we investigated the efficacy of Shin'iseihaito against S. pneumoniae-caused sinusitis in mice. Oral administration of Shin'iseihaito extract (SSHT) decreased the nasal colonization of S. pneumoniae in both prophylactic and therapeutic treatments, respectively, and the former was more effective than the latter. Histopathological analysis revealed that the epithelial tissue from S. pneumoniae-infected nose under SSHT treatment recovered the tissue destruction in comparison to infected nose. We also confirmed this result by scanning electron microscopic analysis. Murine peritoneal macrophages from SSHT-treated mice had significant phagocytic activity in comparison to those from untreated group. We also found that tumor necrosis factor-α, interleukin-1ß, interleukin-6, and monocyte chemotactic protein-1 levels and the migration of macrophages from S. pneumoniae-infected mice with the treatment with SSHT were increased compared to those from untreated group. Our data suggest that Shin'iseihaito may be useful for the treatment of S. pneumoniae-induced sinusitis.

Shin'iseihaito (Xinyiqingfeitang) Suppresses the Biofilm Formation of Streptococcus pneumoniae In Vitro.

Streptococcus pneumoniae (S. pneumoniae) is the important pathogen that causes otolaryngeal diseases such as sinusitis. S. pneumoniae frequently forms the biofilm to prevent severe circumstances such as antimicrobial agents. Shin'iseihaito (xinyiqingfeitang) is a formula of Japanese traditional Kampo medicine that has 9 crude drugs and provides the medicinal usage for sinusitis. The objective of the present study is to reveal the mechanism of antibiofilm activity by Shin'iseihaito extract (SSHT). SSHT significantly inhibited the formation of biofilm from S. pneumoniae ATCC 49619 in dose- and time-dependent manners. SSHT also significantly suppressed the biofilm formation by other five different cps types of S. pneumoniae clinical isolates. We found that the extracts of 8 out of 9 components in Shin'iseihaito had the inhibitory effects of biofilm formation, and the extract of the root of Scutellaria baicalensis had the strongest effect among the ingredients of Shin'iseihaito. We found that the capsule of SSHT-treated S. pneumoniae was significantly thinner than that of the untreated group and that SSHT reduced the hydrophobicity of bacterial cell surface. Our results suggest that Shin'iseihaito may be a useful agent for the treatment of S. pneumoniae-induced sinusitis because of the inhibition of biofilm formation of S. pneumoniae.

Effect of Shin'iseihaito on murine allergic reaction induced by nasal sensitization.

Shin'iseihaito (Magnolia Flower Lung-Clearing Decoction; xin yí qing fèi tang), a formula of traditional Japanese kampo medicine ( rì ben hàn yi) and traditional Chinese medicine (TCM; zhong yi), has been used for the treatment of chronic sinusitis. The objective of this study was to evaluate the anti-allergic effect of shin'iseihaito on murine allergic reaction induced by nasal sensitization using ovalbumin (OVA) as an antigen. Extract of shin'iseihaito (SSHT) could reduce the eosinophil, serum IgE and interleukin (IL)-4 levels, while increased the interferon (IFN)-γ levels in allergic mouse. Furthermore, allergic-murine serum treated with SSHT could not activate passive cutaneous anaphylaxis (PCA) reaction in murine model. Thus, our study showed that SSHT may possess anti-allergic activity. We suggested that SSHT may contribute to inhibit the exacerbation of allergic reaction induced by nasal sensitization.

Involvement of Monocarboxylate Transporter 4 Expression in Statin-Induced Cytotoxicity.

Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are the most widely used cholesterol-lowering agents for prevention of obstructive cardiovascular events. However, statins can cause a variety of skeletal muscle problems, and exercise leads to an increase in statin-induced muscle injury. Exercise induces the protein content of monocarboxylate transporter 4 (MCT4), which is expressed strongly in skeletal muscle and is thought to play a major role in the transport of metabolically important monocarboxylates such as l-lactate. We previously reported that α-cyano-4-hydroxycinnamate, an MCT4 inhibitor, increased the inhibition of growth of RD cells, a prototypic embryonal rhabdomyosarcoma cell line (an RD cell line), as a model of in vitro skeletal muscle, induced by a statin. However, it is unclear whether statin-induced RD cell cytotoxicity is associated with MCT4 expression. We, therefore, examined the relationship between statin-induced cytotoxicity and MCT4 expression in RD cells. Atorvastatin reduced the number of viable cells and upregulated MCT4, but not MCT1, mRNA level in a concentration-dependent manner. MCT4 knockdown suppressed atorvastatin-, simvastatin-, and fluvastatin-induced reduction of cell viability and apoptosis compared with negative control-treated cells. In this study, we demonstrated that MCT4 expression is associated with statin-induced cytotoxicity.