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ARTICLE INFO Article history: Received 25 February 2013 Received in revised form 16 May 2013 Accepted 2 July 2013 Keywords: (--)-Epigallocatechin-3-gallate Food--drug interaction Green tea extract Nadolol Pharmacokinetics ABSTRACT Green [...]

Background: Benzbromarone is a widely used uricosuric drug which increases urinary excretion of uric acid and then lowers serum urate levels. Recently, it has been reported that benzbromarone is predominantly metabolized to 6-hydroxybenzbromarone by CYP2C9, which is a polymorphic enzyme. The aim of this study was to clarify the influences of CYP2C9 genotype on pharmacokinetics and pharmacodynamics of benzbromarone.Methods: In a controlled, open-label study, a single oral dose of 100 mg benzbromarone was administered to 20 healthy volunteers (Male/Female: 13/7) stratified for CYP2C9 genotypes (CYP2C9*1/*1:15; CYP2C9*1/*3:4; CYP2C9*3/*3:1). Plasma concentrations of benzbromarone and 6-hydroxybenzbromarone were measured until 24 hr after the administration. Uric acid levels in urine were determined before and after the administration.Results: AUCs of benzbromarone in CYP2C9*1/*1 and CYP2C9*1/*3 were 35.7±17.8 and 29.5±4.9 hr μg/mL, respectively, and there was no significant difference between CYP2C9*1/*1 and CYP2C9*1/*3. On the other hand, AUC in CYP2C9*3/*3 was 3.2 fold higher (113 hr μg/mL) than that in CYP2C9*1/*1. Compared to CYP2C9*1/*1, AUC ratio of 6-hydroxybenzbromarone to benzbromarone was reduced by 8% in CYP2C9*1/*3 and by 64% in CYP2C9*3/*3. There was no significant difference in urine uric acid levels among CYP2C9 genotypes.Conclusion: These results suggested that the pharmacokinetics of benzbromarone is altered in the subjects with CYP2C9*3/*3 genotype.Clinical Pharmacology & Therapeutics (2005) 79, P13–P13; doi: 10.1016/j.clpt.2005.12.044 [ABSTRACT FROM AUTHOR]

Intrarenal dopamine plays a protective role against the development of diabetic nephropathy during the early stages of the disease. In streptozotocin-induced diabetic mice with renal-specific catechol- O -methyl transferase knockout, intrarenal dopamine was found to suppress glomerular hyperfiltration, reduce oxidative stress and inflammation, and inhibit fibrosis. However, although dopamine activation in streptozotocin-induced diabetic models has been shown to provide renal protection, the role of dopamine in models of naturally induced diabetes mellitus is still unclear. In the present study, we orally administered 10 mg/kg benserazide, a peripheral decarboxylase inhibitor, to spontaneously diabetic Torii rats daily to investigate the activation of the renal dopaminergic system during the progression of diabetic nephropathy. Our findings show that peripheral dopamine decreased urinary 8-iso-prostaglandin F 2α and suppressed increases in plasma cystatin C levels. This study demonstrates that a reduction in peripheral dopamine can exacerbate renal dysfunction, even in the early stages of diabetic nephropathy characterized by glomerular hyperfiltration, thereby clarifying the pivotal role of endogenous peripheral dopamine in modulating oxidative stress and kidney performance. NEW & NOTEWORTHY By administering a peripheral decarboxylase inhibitor, we revealed that peripheral dopamine inhibits both the increase in urinary 8-iso-prostaglandin F 2α , an oxidative stress marker, and the increase in plasma cystatin C, an early renal dysfunction marker, even in the early stages of diabetic nephropathy characterized by glomerular hyperfiltration. By visualizing renal dopamine precursor distribution, we highlighted the role of endogenous renal dopamine in oxidative stress and renal function following the onset of glomerular hyperfiltration.

Secondary spontaneous pneumothorax (SSP) due to bevacizumab has been reported in other malignancies but not in cervical cancer. We present the case of a 57-year-old woman with stage IIIB cervical cancer who developed SSP during bevacizumab chemotherapy. Despite complete remission with cisplatin-based chemoradiotherapy, she experienced a recurrence 9 months later. A thoracoscopic surgery was performed to remove a lung nodule and bulla. Subsequently, local cervical lesion recurrence and lung metastases were noted, and paclitaxel and carboplatin combined with bevacizumab were administered. After two cycles, a grade-1 left pneumothorax occurred, attributed to bevacizumab-induced tissue fragility. The patient improved within 7 days with conservative management. Bevacizumab was discontinued, and pneumothorax did not recur. This case highlights the rare occurrence of SSP in patients with cervical cancer treated with bevacizumab and underscores the importance of appropriate management of such patients, especially those who have undergone early thoracic surgery., Competing Interests: Conflict of interestNo conflicts of interest., (© The Author(s) under exclusive licence to The Japan Society of Clinical Oncology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Objective: Aromatherapy is a holistic healing method to promote health and well-being by using natural plant extracts. However, its precise mechanism of action and influence on the endocrine system remains unclear. Since recent studies reported that a neuropeptide, oxytocin, can attenuate anxiety, we hypothesized that if oxytocin secretion is promoted through aromatherapy, it may improve mood and anxiety. The present study is aimed to investigate the relationship between oxytocin and the effects of aromatherapy with lavender oil on anxiety level, by measuring salivary oxytocin levels in healthy men and women., Methods: We conducted a randomized open crossover trial in 15 men and 10 women. Each participant received a placebo intervention (control group) and aromatherapy with lavender oil (aromatherapy group). For the aromatherapy group, each participant spent a 30-min session in a room with diffused lavender essential oil, followed by a 10-min hand massage using a carrier oil containing lavender oil. Anxiety was assessed using the State-Trait Anxiety Inventory (STAI) before the intervention, 30-min after the start of intervention, and after hand massage, in both groups. Saliva samples were collected at the same time points of the STAI., Results: In women, either aromatherapy or hand massage was associated with a reduction in anxiety levels, independently. Moreover, salivary oxytocin levels were increased after aromatherapy. On the other hand, in men, anxiety levels were decreased after aromatherapy, as well as after hand massage, regardless of the use of lavender oil. However, there were no significant differences in changes of salivary oxytocin levels between the control and aromatherapy groups during the intervention period. Interestingly, there was a positive correlation between anxiety levels and salivary oxytocin levels before the intervention, but a negative correlation was observed after hand massage with lavender oil., Conclusion: The results of the present study indicate that in women, aromatherapy with lavender oil attenuated anxiety with increase in oxytocin level in women, whereas in men, there was no clear relationship of aromatherapy with anxiety or oxytocin levels but, there was a change in correlation between anxiety and oxytocin. The results of the present study suggest that the effect of aromatherapy can vary depending on sex., Competing Interests: Author DN was employed by Nitto Boseki Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nakajima, Yamachi, Misaka, Shimomura and Maejima.)

Aim: Ovarian surveillance in women with hereditary breast and ovarian cancer who do not undergo risk-reducing salpingo-oophorectomy has been controversial. Therefore, this study aimed to demonstrate the clinical features of ovarian surveillance at our institution using a technique that combines serum cancer antigen 125 measurements, transvaginal ultrasonography, and uterine endometrial cytology., Methods: We retrospectively examined 65 women, who had not undergone risk-reducing salpingo-oophorectomy diagnosed with hereditary breast and ovarian cancer between 2000 and 2021 at our hospital. Clinical information was obtained and analyzed through a chart review. The details of the treatment course were reviewed for patients who had developed ovarian cancer., Results: Overall, 5 of the 65 women were diagnosed with ovarian cancer based on abnormal findings during periodic surveillance. All patients who developed ovarian cancer were asymptomatic, even if the cancer was at an advanced stage. Two of the 65 patients had endometrial cytology abnormalities, both of whom had ovarian cancer. All patients who developed ovarian cancer underwent primary debulking surgery, and complete gross resection was achieved. None of the patients experienced ovarian cancer recurrence., Conclusions: The ovarian surveillance strategy at our institution for women with hereditary breast and ovarian cancer who do not undergo risk-reducing salpingo-oophorectomy can identify asymptomatic ovarian cancer and contribute to achieving complete gross resection during primary surgery. Ovarian surveillance may contribute to a reduction in ovarian cancer mortality., (© 2024 Japan Society of Obstetrics and Gynecology.)

The high prevalence of obesity has become a pressing global public health problem and there exists a strong association between increased BMI and mortality at a BMI of 25 kg/m 2 or higher. The prevalence of obesity is higher among middle-aged adults than among younger groups and the combination of aging and obesity exacerbate systemic inflammation. Increased inflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha (TNFα) are hallmarks of obesity, and promote the secretion of hepatic C-reactive protein (CRP) which further induces systematic inflammation. The neuropeptide oxytocin has been shown to have anti-obesity and anti-inflammation effects, and also suppress sweet-tasting carbohydrate consumption in mammals. Previously, we have shown that the Japanese herbal medicine Kamikihito (KKT), which is used to treat neuropsychological stress disorders in Japan, functions as an oxytocin receptors agonist. In the present study, we further investigated the effect of KKT on body weight (BW), food intake, inflammation, and sweet preferences in middle-aged obese mice. KKT oral administration for 12 days decreased the expression of pro-inflammatory cytokines in the liver, and the plasma CRP and TNFα levels in obese mice. The effect of KKT administration was found to be different between male and female mice. In the absence of sucrose, KKT administration decreased food intake only in male mice. However, while having access to a 30% sucrose solution, both BW and food intake was decreased by KKT administration in male and female mice; but sucrose intake was decreased in female mice alone. In addition, KKT administration decreased sucrose intake in oxytocin deficient lean mice, but not in the WT lean mice. The present study demonstrates that KKT ameliorates chronic inflammation, which is strongly associated with aging and obesity, and decreases food intake in male mice as well as sucrose intake in female mice; in an oxytocin receptor dependent manner., Competing Interests: HO and KM were employed by Tsumura & Co. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Maejima, Yokota, Yamachi, Misaka, Ono, Oizumi, Mizuno, Hidema, Nishimori, Aoyama, de Wet and Shimomura.)

Asia is at a critical juncture of health development. The population is aging and shrinking. At the same time, the economy is developing rapidly. These two factors, which necessitate a new paradigm of health development: departing from dependence on Official Development Assistance (ODA) and transitioning towards a model with more involvement of industries (private sector), academia, and health care providers, the so-called public-private partnership (PPP) model. The Economic Research Institute for ASEAN and East Asia (ERIA) is studying the potential for broader application of the new concept for collaboration between Asian countries and Japan. In this article, the authors attempt to introduce the complete picture of a new health ecosystem advocated by Japan. We first look at the impacts of population aging and shrinking, followed by introducing two new approaches; regional and country-specific, with the involvement of ERIA. Then, the outcomes of the projects and Japanese technology, services and products relevant to the older population are introduced. Finally, based on the various projects and products, we focus more closely on the new health development model, the PPP model. We start from the theory and move to examine a tool for implementation, which is the formulation of a dialogue forum named the MEX (Medical Excellence X, where X can be substituted by the acronym of any participating country) project. The experience of these projects and case studies will benefit all ASEAN member countries and beyond. ERIA finds that the facilitation works of the Institute catalyze the progress. ERIA will remain committed to helping the endeavors initiated by Japan for the benefit of all., Competing Interests: The authors have no conflicts of interest to disclose., (2024, National Center for Global Health and Medicine.)

Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests.

Clozapine (CLZ) is extensively used for treatment-resistant schizophrenia (TRS) with caution to avoid serious adverse events such as agranulocytosis and drug-drug interactions (DDIs). In the current report, we present a case of a 35-year-old male non-smoking TRS patient whose steady-state plasma trough concentrations (C trough ) of CLZ and its active metabolite, N-desmethylclozapine (NDMC), were significantly increased after initiating oral administration of lemborexant (LEM), a dual orexin receptor antagonist, for the treatment of insomnia. The patient experienced oversedation with sleepiness and fatigue while maintaining high levels of C trough of CLZ. The increased concentrations of CLZ returned to normal ranges after the discontinuation of LEM dosing, implying a pharmacokinetic DDI between CLZ and LEM. To gain insight into possible mechanisms, we performed in vitro assays of CYP1A2- and CYP3A4-mediated CLZ metabolism by measuring the formations of NDMC and clozapine N-oxide (CNO). In accordance with previous studies, the incubation of CLZ with each enzyme resulted in the production of both metabolites. LEM had only a weak inhibitory effect on CYP1A2- and CYP3A4-mediated CLZ metabolism. However, the preincubation of LEM with CYP3A4 in the presence of NADPH showed a significant enhancement of inhibitory effects on CLZ metabolism with IC 50 values for the formations of CNO and NDMC of 2.8 μM and 4.1 μM, respectively, suggesting that LEM exerts as a potent time-dependent inhibitor for CYP3A4. Taken together, the results of the current study indicate that co-medication of CLZ with LEM may lead to increase in exposure to CLZ and risks of CLZ-related adverse events., (© 2023 British Pharmacological Society.)

In this study, we developed stabilized astaxanthin (AX) nanoparticles (sNP/AX) to improve the physicochemical properties, oral bioavailability, and hepatoprotection of AX. A flash nanoprecipitation technique was used with a multi-inlet vortex mixer to prepare the sNP/AX. Vitamins E (VE) and C (VC) were used as co-stabilizers with poloxamer 407 as a stabilizer to inhibit the oxidative degradation of AX during sNP/AX formation and storage. VC stabilized AX in the aqueous phase during the preparation, whereas VE markedly improved the storage stability of sNP/AX, as evidenced by the AX contents remaining at 94 and 81% after 12 weeks of storage at 4 °C and 25 °C, respectively. The mean sNP/AX diameter was 215 nm, which resulted in higher AX release properties than those of crystalline AX. Rats, orally administered sNP/AX (33.2 mg AX/kg), exhibited higher systemic exposure to AX, whereas oral absorption in the crystalline AX group was negligible. In the rat hepatic injury model, oral pretreatment with sNP/AX (33.2 mg AX/kg) markedly attenuated hepatic damage, as shown by the histopathological analysis and reduced levels of plasma biomarkers for hepatic injury. These findings suggest that strategically including antioxidative additives in the sNP/AX has the potential to improve the physicochemical and nutraceutical properties of AX.

To determine the impact of the coverage of risk-reducing salpingo-oophorectomy (RRSO) and mastectomy (RRM) as well as genetic testing for BRCA pathogenic variants by the national insurance system in Japan. We compared the clinical background of women who underwent RRSO at our institution before and after its coverage by the national insurance system. Those who underwent RRSO between January 2017 and December 2019 and between April 2020 and March 2022 were classified as Period. A and B, respectively. Overall, 134 women underwent RRSO during the study period. In Period A and B, 45 and 89 women underwent RRSO for the study period was 36 and 24 months, respectively. Compared with Period A, the number of women who underwent RRSO per month increased by threefold in Period B (p < 0.01). In addition, the number of women who underwent surgery for breast cancer along with RRSO increased in Period B (p < 0.01). Although the number of women who underwent concurrent RRM with RRSO in Period B increased, the difference was not statistically significant. Compared with Period A, the number of women diagnosed with BRCA pathogenic variant increased by 3.9-fold, and the proportion of women who underwent concurrent hysterectomy at the time of RRSO decreased from 66 to 7.9% in Period B (p < 0.01). Owing to the introduction of the national insurance system, the number of women who underwent RRSO and concurrent surgery for breast cancer at the time of RRSO increased in Japan., (© 2023. The Author(s).)

Burn injury is the leading cause of death and disability worldwide and places a tremendous economic burden on society. Systemic inflammatory responses induced by thermal burn injury can cause muscle wasting, a severe involuntary loss of skeletal muscle that adversely affects the survival and functional outcomes of these patients. Currently, no pharmacological interventions are available for the treatment of thermal burn-induced skeletal muscle wasting. Elevated levels of inflammatory cytokines, such as interleukin-6 (IL-6), are important hallmarks of severe burn injury. The levels of signal transducer and activator of transcription 3 (STAT3)-a downstream component of IL-6 inflammatory signaling-are elevated with muscle wasting in various pro-catabolic conditions, and STAT3 has been implicated in the regulation of skeletal muscle atrophy. Here, we tested the effects of the STAT3-specific signaling inhibitor C188-9 on thermal burn injury-induced skeletal muscle wasting in vivo and on C2C12 myotube atrophy in vitro after the administration of plasma from burn model mice. In mice, thermal burn injury severity dependently increased IL-6 in the plasma and tibialis anterior muscles and activated the STAT3 (increased ratio of phospho-STAT3/STAT3) and ubiquitin-proteasome proteolytic pathways (increased Atrogin-1/MAFbx and MuRF1). These effects resulted in skeletal muscle atrophy and reduced grip strength. In murine C2C12 myotubes, plasma from burn mice activated the same inflammatory and proteolytic pathways, leading to myotube atrophy. In mice with burn injury, the intraperitoneal injection of C188-9 (50 mg/kg) reduced activation of the STAT3 and ubiquitin-proteasome proteolytic pathways, reversed skeletal muscle atrophy, and increased grip strength. Similarly, pretreatment of murine C2C12 myotubes with C188-9 (10 µM) reduced activation of the same inflammatory and proteolytic pathways, and ameliorated myotube atrophy induced by plasma taken from burn model mice. Collectively, these results indicate that pharmacological inhibition of STAT3 signaling may be a novel therapeutic strategy for thermal burn-induced skeletal muscle wasting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ono, Saito, Sakamoto, Maejima, Misaka, Shimomura, Nakanishi, Inoue and Kotani.)

Green tea (GT) alters the disposition of a number of drugs, such as nadolol and lisinopril. However, it is unknown whether GT affects disposition of hydrophilic anti-allergic drugs. The purpose of this study was to investigate whether pharmacokinetics of fexofenadine and pseudoephedrine are affected by catechins, major GT components. A randomized, open, 2-phase crossover study was conducted in 10 healthy Japanese volunteers. After overnight fasting, subjects were simultaneously administered fexofenadine (60 mg) and pseudoephedrine (120 mg) with an aqueous solution of green tea extract (GTE) containing (-)-epigallocatechin gallate (EGCG) of ~ 300 mg or water (control). In vitro transport assays were performed using HEK293 cells stably expressing organic anion transporting polypeptide (OATP)1A2 to evaluate the inhibitory effect of EGCG on OATP1A2-mediated fexofenadine transport. In the GTE phase, the area under the plasma concentration-time curve and the amount excreted unchanged into urine for 24 hours of fexofenadine were significantly decreased by 70% (P < 0.001) and 67% (P < 0.001), respectively, compared with control. There were no differences in time to maximum plasma concentration and the elimination half-life of fexofenadine between phases. Fexofenadine was confirmed to be a substrate of OATP1A2, and EGCG (100 and 1,000 μM) and GTE (0.1 and 1 mg/mL) inhibited OATP1A2-mediated uptake of fexofenadine. On the contrary, the concomitant administration of GTE did not influence the pharmacokinetics of pseudoephedrine. These results suggest that intake of GT may result in a markedly reduced exposure of fexofenadine, but not of pseudoephedrine, putatively by inhibiting OATP1A2-mediated intestinal absorption., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Oxytocin (Oxt) is known to regulate social communication, stress and body weight. The activation of Oxt receptors (OTR) has clinical potential to abate stress disorders and metabolic syndrome. Kamikihito (KKT) is a traditional Japanese medicine used to treat psychological stress-related disorders. We investigated the effects of KKT, its ingredients and chemical components on Oxt neurons and OTR. C-Fos expression was examined after oral and peripheral administration of KKT in rats. Electrophysiological change of Oxt neurons and Oxt release upon application of KKT were measured in rat brain slice. The direct effect of KKT, its ingredients and its chemical components were examined by cytosolic Ca 2+ ([Ca 2+ ] i ) measurement in Oxt neurons and OTR-expressing HEK293 cells. Both intraperitoneal and oral administration of KKT in rats induced c-Fos expression in neurons of the paraventricular nucleus (PVN) including Oxt neurons. Application of KKT induced activation of Oxt neurons and Oxt release. KKT increased [Ca 2+ ] i in OTR-expressing HEK293 cells, and failed to activate with OTR antagonist. KKT-induced PVN Oxt neuron activation was also attenuated by OTR antagonist. Seven chemical components (rutin, ursolic acid, (Z )-butylidenephtalide, p-cymene, senkunolide, [6]-shogaol, [8]-shogaol) of three ingredients (Zizyphi Fructus, Angelicae Acutilobae Radix, Zingiberis Rhizoma) from KKT had potential to activate OTR. KKT can directly activate PVN Oxt neurons by interacting with OTR. The interaction of seven chemical components from KKT may contribute to activate OTR. Effect of KKT on Oxt neurons and OTR may contribute to the treatment of Oxt related disorders.

A 71-year-old woman was admitted to our hospital because of sudden onset of weakness on the left side of her body. Her medical history was unremarkable, and on physical examination, hemiparesis and hyperreflexia on the left side were found. MRI of the brain showed multiple areas of restricted diffusion in both parietal lobes and in the cerebellum, consistent with embolic shower. Magnetic resonance angiography showed no abnormal findings. A contrast-enhanced CT scan revealed multiple pulmonary emboli. Abdominal MRI showed a 135 mm left ovarian tumour composed of a solid and a cystic component with liquid level formation. After a total hysterectomy and bilateral adnexectomy, the histopathology confirmed a seromucinous borderline tumour. Therefore, the patient was diagnosed with Trousseau's syndrome associated with an ovarian seromucinous borderline tumour. To our knowledge, this is the first report mentioning a borderline ovarian tumour detected as Trousseau's syndrome., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Nadolol is a hydrophilic and nonselective β-adrenoceptor blocker with a bioavailability of 30%, relatively longer half-life, negligible metabolism, and predominant renal excretion. Previous studies have reported that nadolol is a substrate of P-glycoprotein, and the coadministration with itraconazole, a typical P-glycoprotein inhibitor, results in elevated plasma concentrations and cumulative urinary excretion of nadolol. In this study, we assessed whether measurements of urinary-excreted nadolol can be an alternative method of plasma pharmacokinetics for P-glycoprotein-mediated drug interactions in humans. We reanalyzed the pooled data set of plasma concentration and urinary excretion of nadolol from our previous clinical studies in a total of 32 healthy Japanese adults. The area under the plasma concentration-time curve from 0 to infinity (AUC 0-∞ ) of nadolol in individual subjects was significantly correlated with the maximum plasma concentration (r = 0.80, P < .01) and the cumulative amount excreted into urine (A e ) at 4 (r = 0.51, P = .01), 8 (r = 0.63, P < .01), 24 (r = 0.75, P < .01), and 48 (r = 0.77, P < .01) hours. Significant correlations were also observed between the AUC and A e during the same respective periods. In the drug interactions of nadolol with itraconazole, rifampicin, a well-known P-glycoprotein inducer, or grapefruit juice, there were significant correlations between the differences in AUC 0-48 and those in A e, 0-48 from the controls in individual subjects. These results suggest that the measurements of urinary excretion of nadolol can be employed as a sensitive and reliable alternative to plasma pharmacokinetics for the evaluation of P-glycoprotein-mediated drug interactions., (© 2021, The American College of Clinical Pharmacology.)

Lisinopril, a highly hydrophilic long-acting angiotensin-converting enzyme inhibitor, is frequently prescribed for the treatment of hypertension and congestive heart failure. Green tea consumption may reduce the risk of cardiovascular outcomes and total mortality, whereas green tea or its catechin components has been reported to decrease plasma concentrations of a hydrophilic β blocker, nadolol, in humans. The aim of this study was to evaluate possible effects of green tea extract (GTE) on the lisinopril pharmacokinetics. In an open-label, randomized, single-center, 2-phase crossover study, 10 healthy subjects ingested 200 mL of an aqueous solution of GTE containing ~ 300 mg of (-)-epigallocatechin gallate, a major catechin component in green tea, or water (control) when receiving 10 mg of lisinopril after overnight fasting. The geometric mean ratio (GTE/control) for maximum plasma concentration and the area under the plasma concentration-time curve of lisinopril were 0.289 (90% confidence interval (CI) 0.226-0.352) and 0.337 (90% CI 0.269-0.405), respectively. In contrast, there were no significant differences in time to reach maximum lisinopril concentration (6 hours in both phases) and renal clearance of lisinopril (57.7 mL/minute in control vs. 56.9 mL/minute in GTE). These results suggest that the extent of intestinal absorption of lisinopril was significantly impaired in the presence of GTE, whereas it had no major effect on the absorption rate and renal excretion of lisinopril. Concomitant use of lisinopril and green tea may decrease oral exposure to lisinopril, and therefore result in reduced therapeutic efficacy., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Aims: The aim of this study was to investigate the effects of a single green tea (GT), administered concomitantly or 1 hour before nadolol intake on nadolol pharmacokinetics., Methods: In a randomized 3-phase crossover study, 11 healthy volunteers received an oral administration of nadolol with, or 1 hour after preingestion of brewed GT, or with water in a volume of 150 mL., Results: Geometric mean ratio with 90% confidence interval for nadolol AUC 0-48 was 0.371 (0.303-0.439) with concomitant GT. In addition, ingestion of GT 1 hour before nadolol administration resulted in a significant reduction of nadolol AUC 0-48 with geometric mean ratio of 0.536 (0.406-0.665). There were no differences in time to maximal plasma concentration and renal clearance of nadolol among groups., Conclusion: These results suggest that single concomitant ingestion of GT substantially decreases plasma concentrations of nadolol. Moreover, the reduction in nadolol bioavailability could persist for at least 1 hour after drinking a cup of GT., (© 2020 The British Pharmacological Society.)

Objective: Memantine, a drug for Alzheimer's disease, is considered to suppress excessive stimulation of N-methyl-D-aspartic acid receptors and to prevent neuronal death. However, a recent report indicated that the neuronal K ATP channel also can become a target of memantine. The K ATP channel is a key regulator of insulin secretion in pancreatic β cells. Therefore, if memantine could inhibit the K ATP channel in pancreatic β cells, it would be an effective drug for both Alzheimer's disease and diabetes. However, there is no report on the effect of memantine on the K ATP channel in pancreatic β cells. Therefore, we investigated whether memantine affect the blood glucose level, insulin secretion and K ATP channel activity in pancreatic β cells., Results: An intraperitoneal glucose tolerance test was performed with or without memantine (1 mg/kg) injection in intact mice. Insulin secretion from isolated islets was measured under low (2 mM) and high (20 mM) glucose concentrations with or without memantine (1 μM). The effect of memantine (1 μM) on K ATP channel currents in isolated pancreatic β cells was recorded using the whole-cell patch-clamp technique. Memantine had no effect on the blood glucose level, insulin secretion from isolated islets or K ATP channel current in pancreatic β cells.

Purpose: The aim of the present study is to investigate a possible role of a single dose of (-)-epigallocatechin gallate (EGCG), the major catechin in green tea, for the pharmacokinetic interaction between green tea and nadolol in humans., Methods: In a randomized three-phase crossover study, 13 healthy volunteers received single doses of 30 mg nadolol orally with water (control), or an aqueous solution of EGCG-concentrated green tea extract (GTE) at low or high dose. Plasma concentrations and urinary excretion of nadolol were determined up to 48 h. In addition, blood pressure and pulse rate were monitored. In vitro transport kinetic experiments were performed using human embryonic kidney 293 cells stably expressing organic anion transporting polypeptide (OATP)1A2 to evaluate the inhibitory effect of EGCG on OATP1A2-mediated substrate transport., Results: Single coadministration of low and high dose GTE significantly reduced the plasma concentrations of nadolol. The geometric mean ratios with 90% CI for area under the plasma concentration-time curves from 0 to infinity of nadolol were 0.72 (0.56-0.87) for the low and 0.60 (0.51-0.69) for the high dose. There were no significant differences in T max , elimination half-life, and renal clearance between GTE and water phases. No significant changes were observed for blood pressure and pulse rate between phases. EGCG competitively inhibited OATP1A2-mediated uptake of sulphobromophthalein and nadolol with K i values of 21.6 and 19.4 μM, respectively., Conclusions: EGCG is suggested to be a key contributor to the interaction of green tea with nadolol. Moreover, even a single coadministration of green tea may significantly affect nadolol pharmacokinetics.

Purpose: The objective of this study is to assess the effects of green tea and its major catechin component, (-)-epigallocatechin gallate (EGCG), on CYP2C9-mediated substrate metabolism in vitro, and the pharmacokinetics of fluvastatin in healthy volunteers., Methods: The metabolism of diclofenac and fluvastatin in human recombinant CYP2C9 was investigated in the presence of EGCG. In a randomized three-phase crossover study, 11 healthy volunteers ingested a single 20-mg dose of fluvastatin with green tea extract (GTE), containing 150 mg of EGCG, along with water (300 mL), brewed green tea (300 mL), or water (300 mL) after overnight fasting. Plasma concentrations of fluvastatin and EGCG were measured by ultra-performance liquid chromatography with fluorescence detection and a single mass spectrometer., Results: EGCG inhibited diclofenac 4'-hydroxylation and fluvastatin degradation with IC 50 of 2.23 and 48.04 μM, respectively. Brewed green tea used in the clinical study also dose-dependently inhibited the metabolism of diclofenac and fluvastatin in vitro. However, no significant effects of GTE and brewed green tea were observed in plasma concentrations of fluvastatin. The geometric mean ratios with 90% CI for area under the plasma concentration-time curve (AUC 0-∞ ) of fluvastatin were 0.993 (0.963-1.024, vs. brewed green tea) and 0.977 (0.935-1.020, vs. GTE)., Conclusions: Although in vitro studies indicated that EGCG and brewed green tea produce significant inhibitory effects on CYP2C9 activity, the concomitant administration of green tea and fluvastatin in healthy volunteers did not influence the pharmacokinetics of fluvastatin.

Many patients treated with cardiovascular (CV) drugs drink green tea (GT), either as a cultural tradition or persuaded of its putative beneficial effects for health. Yet, GT may affect the pharmacokinetics and pharmacodynamics of CV compounds. Novel GT-CV drug interactions were reported for rosuvastatin, sildenafil and tacrolimus. Putative mechanisms involve inhibitory effects of GT catechins at the intestinal level on influx transporters OATP1A2 or OATP2B1 for rosuvastatin, on CYP3A for sildenafil and on both CYP3A and the efflux transporter p-glycoprotein for tacrolimus. These interactions, which add to those previously described with simvastatin, nadolol and warfarin, might lead, in some cases, to reduced drug efficacy or risk of drug toxicity. Oddly, available data on GT interaction with CV compounds with a narrow therapeutic index, such as warfarin and tacrolimus, derive from single case reports. Conversely, GT interactions with simvastatin, rosuvastatin, nadolol and sildenafil were documented through pharmacokinetic studies. In these, the effect of GT or GT derivatives on drug exposure was mild to moderate, but a high inter-individual variability was observed. Further investigations, including studies on the effect of the dose and the time of GT intake are necessary to understand more in depth the clinical relevance of GT-CV drug interactions., (Copyright © 2018. Published by Elsevier B.V.)

Nadolol is a nonmetabolized β-adrenoceptor antagonist and is a substrate of OATP1A2, but not of OATP2B1. However, other drug transporters involved in translocation of nadolol have not been characterized in detail. We therefore investigated nadolol as a potential substrate of the hepatic uptake transporters OATP1B1, OATP1B3, and OCT1 and of the renal transporters OCT2, MATE1, and MATE2-K expressed in HEK cells. Moreover, the importance of P-glycoprotein (P-gp) for nadolol transport was studied using double transfected MDCK-OCT1-P-gp cells. Nadolol was not transported by OATP1B1 and OATP1B3. In contrast, a significantly higher nadolol accumulation (at 1 and 10 μM) was found in OCT1, OCT2, MATE1, and MATE2-K cells compared to control cells (P < 0.01). Km values for OCT2-, MATE1-, and MATE2-K-mediated nadolol uptake were 122, 531, and 372 μM, respectively. Cimetidine (100 μM, P < 0.01) and trimethoprim (100 μM, P < 0.001) significantly inhibited OCT1-, OCT2-, MATE1-, and MATE2-K-mediated nadolol transport. The P-gp inhibitor zosuquidar significantly reduced basal to apical nadolol transport in monolayers of MDCK-OCT1-P-gp cells. In summary, nadolol is a substrate of the cation transporters OCT1, OCT2, MATE1, MATE2-K, and of P-gp. These data will aid future in vivo studies on potential transporter-mediated drug-drug or drug-food interactions with involvement of nadolol.

Background: Inflammation is one of major mechanisms contributing to the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. Pentraxin 3 (PTX3), produced in response to inflammatory signals, acts as a humoral arm of the innate immunity. Here we investigated the role of PTX3 produced from bone marrow-derived cells in myocardial I/R injury using PTX3-deficient (PTX3KO) mice., Methods and Results: PTX3KO mice and wild-type littermate (WT) mice were lethally irradiated and injected with bone marrow (BM) cells, generating four types of mice (WT(WT-BM), WT(PTX3KO-BM), PTX3KO(WT-BM) and PTX3KO(PTX3KO-BM)). Six weeks after BM transplantation, the myocardial I/R procedure (45 min of left descending coronary artery ligation followed by 48 h of reperfusion) was performed. Infarct size was greater in WT and PTX3KO mice with BM from PTX3KO donor (WT(PTX3KO-BM) and PTX3KO(PTX3KO-BM)) compared with WT and PTX3KO mice with BM from WT donor (WT(WT-BM) and PTX3KO(WT-BM)). Localization of PTX3 was observed in neutrophils and macrophages in WT and PTX3KO mice with BM from WT donor (WT(WT-BM) and PTX3KO(WT-BM)), while only in endothelial cells in WT mice with BM from PTX3KO donor (WT(PTX3KO-BM)). Infiltration of neutrophils and generation of reactive oxygen species (ROS) at ischemic border zones were greater in PTX3KO mice with BM from PTX3KO donor (PTX3KO(PTX3KO-BM)) than PTX3KO mice with BM from WT donor (PTX3KO(WT-BM)). Plasma levels and cardiac expressions of interleukin-6 were higher in PTX3KO mice with BM from PTX3KO donor (PTX3KO(PTX3KO-BM)) than PTX3KO mice with BM from WT donor (PTX3KO(WT-BM)). However, no significant differences in infarct size, infiltration of neutrophils, generation of ROS and plasma and cardiac levels of interleukin-6 were observed between WT and PTX3KO mice with BM from WT donor and between WT and PTX3KO mice with BM from PTX3KO donor. These results indicated that the lack of PTX3 produced from BM-derived cells, and not from cardiac resident cells, exacerbated myocardial injury after I/R., Conclusion: PTX3 produced from bone marrow-derived cells plays a crucial role in cardiac protection against myocardial I/R injury by attenuating infiltration of neutrophils, generation of ROS and inflammatory cytokine., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Green tea catechins inhibit the function of organic anion transporting polypeptides (OATPs) that mediate the uptake of a diverse group of drugs and endogenous compounds into cells. The present study was aimed at investigating the effect of green tea and its most abundant catechin epigallocatechin gallate (EGCG) on the transport activity of several drug transporters expressed in enterocytes, hepatocytes and renal proximal tubular cells such as OATPs, organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATEs), and P-glycoprotein (P-gp). Uptake of the typical substrates metformin for OCTs and MATEs and bromosulphophthalein (BSP) and atorvastatin for OATPs was measured in the absence and presence of a commercially available green tea and EGCG. Transcellular transport of digoxin, a typical substrate of P-gp, was measured over 4 hours in the absence and presence of green tea or EGCG in Caco-2 cell monolayers. OCT1-, OCT2-, MATE1- and MATE2-K-mediated metformin uptake was significantly reduced in the presence of green tea and EGCG (P < 0.05). BSP net uptake by OATP1B1 and OATP1B3 was inhibited by green tea [IC50 2.6% (v/v) and 0.39% (v/v), respectively]. Green tea also inhibited OATP1B1- and OATP1B3-mediated atorvastatin net uptake with IC50 values of 1.9% (v/v) and 1.0% (v/v), respectively. Basolateral to apical transport of digoxin was significantly decreased in the presence of green tea and EGCG. These findings indicate that green tea and EGCG inhibit multiple drug transporters in vitro. Further studies are necessary to investigate the effects of green tea on prototoypical substrates of these transporters in humans, in particular on substrates of hepatic uptake transporters (e.g. statins) as well as on P-glycoprotein substrates.

Sensitive to the massive diffusion of purported metabolic and cardiovascular positive effects of green tea and catechincontaining extracts, many consumers of cardiovascular drugs assume these products as a "natural" and presumably innocuous adjunctive way to increase their overall health. However, green tea may interfere with the oral bioavailability or activity of cardiovascular drugs by various mechanisms, potentially leading to reduced drug efficacy or increased drug toxicity. Available data about interactions between green tea and cardiovascular drugs in humans, updated in this review, are limited so far to warfarin, simvastatin and nadolol, and suggest that the average effects are mild to modest. Nevertheless, in cases of unexpected drug response or intolerance, it is warranted to consider a possible green tea-drug interaction, especially in people who assume large volumes of green tea and/or catechin-enriched products with the conviction that "more-is-better".

Important export pumps expressed in the apical membrane of enterocytes are P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance protein 2 (MRP2). They are believed to be a crucial part of the bodies' defense mechanisms against potentially toxic, orally administered xenobiotics. In particular P-gp and BCRP also limit the bioavailability of drugs. Inhibition of these intestinal export pumps by concomitantly administered drugs leads to increased plasma concentrations, whereas induction can reduce absorption of the substrate drugs and decrease plasma concentrations. The role of polymorphisms in genes encoding for these transporters will also be discussed. Taken together this review will focus on the role of intestinal export pumps using selected examples from clinical studies in humans., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

To evaluate effects of itraconazole, rifampicin and grapefruit juice on pharmacokinetics and pharmacodynamics of a hydrophilic non-selective β-adrenoceptor blocker nadolol, we conducted an open-label, four-way crossover study in 10 healthy male volunteers. A single oral dose of 30 mg nadolol was administered with water (control), itraconazole (100 mg), or grapefruit juice (300 mL), or after a 6-day pretreatment with rifampicin (450 mg/day). Plasma concentrations and urinary excretions of nadolol were measured over 48 hours after its dosing. Systolic and diastolic blood pressures and pulse rate were periodically recorded after nadolol administration as pharmacodynamic parameters. Itraconazole increased the peak plasma concentration and the area under the plasma concentration-time curve (AUC0-∞ ) of nadolol by 468% and 224% of control, respectively (P < .001). A slight, but not statistically significant, decrease in AUC0-∞ of nadolol was observed in rifampicin and grapefruit juice phases as compared to control. Elimination half-life for nadolol did not differ among the four phases. During itraconazole phase, nadolol reduced pharmacodynamic parameters to a greater extent than the other phases. These results suggest that itraconazole substantially increases the oral availability of nadolol possibly by the inhibition of intestinal P-glycoprotein, whereas grapefruit juice has little effect on nadolol pharmacokinetics., (© The Author(s) 2013.)

A rapid and quantitative analytical method for the simultaneous determination of green tea catechins using ultra-performance liquid chromatography/electrospray ionization-mass spectrometry was developed. Total analytical run time was 3.5 min for the detection of (-)-epicatechin (EC), (-)-epicatechin-3-O-gallate (ECG), (-)-epigallocatechin (EGC), (-)-epigallocatechin-3-O-gallate (EGCG) and myricetin as the internal standard (IS) in rat plasma. The calibration curves were linear over the range of 10-5000 ng/mL for all the catechins. The inter- and intra-day precision (relative standard deviation) and accuracy (percentage deviation) of the method were both lower than 10%. The average extraction recoveries in plasma ranged from 68.5 to 86.5%, and the lower limits of quantification of EC, EGC, ECG and EGCG were 10 ng/mL with a signal-to-noise ratio of >10. The assay developed was successfully applied to a pharmacokinetic study of catechins following intravenous and intragastric administrations of green tea extract in rats. Plasma concentrations of four catechins were detected up to 5-24 h after administration, and the pharmacokinetic parameters of catechins were in agreement with previous studies. From these findings, taken together with the high productivity and precision, the developed method could be a reliable and reproducible tool for the evaluation of pharmacokinetic properties of catechins., (Copyright © 2012 John Wiley & Sons, Ltd.)

The effects of green tea catechins on the main drug-metabolizing enzymatic system, cytochrome P450 (CYP), have not been fully elucidated. The objective of the present study was to evaluate the effects of green tea extract (GTE, total catechins 86.5%, w/w) and (-)-epigallocatechin-3-gallate (EGCG) on the activities of CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A in vitro, using pooled human liver and intestinal microsomes. Bupropion hydroxylation, amodiaquine N-deethylation, (S)-mephenytoin 4'-hydroxylation, dextromethorphan O-demethylation and midazolam 1'-hydroxylation were assessed in the presence or absence of various concentrations of GTE and EGCG to test their effects on CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A activities, respectively. Each metabolite was quantified using UPLC/ESI-MS, and the inhibition kinetics of GTE and EGCG on CYP enzymes was analyzed. In human liver microsomes, IC50 values of GTE were 5.9, 4.5, 48.7, 25.1 and 13.8 µg/mL, for CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A, respectively. ECGC also inhibited these CYP isoforms with properties similar to those of GTE, and produced competitive inhibitions against CYP2B6 and CYP2C8, and noncompetitive inhibition against CYP3A. In human intestinal microsomes, IC50 values of GTE and EGCG for CYP3A were 18.4 µg/mL and 31.1 µM, respectively. EGCG moderately inhibited CYP3A activity in a noncompetitive manner. These results suggest that green tea catechins cause clinically relevant interactions with substrates for CYP2B6 and CYP2C8 in addition to CYP3A.

The aim of the present study was to clarify the involvement of P-glycoprotein (P-gp) or organic anion transporting polypeptide (Oatp) 1a5 in the pharmacokinetics of nadolol (NDL), a non-metabolized hydrophilic β-adrenoceptor blocker, in rats. Pretreatment with itraconazole (ICZ, P-gp inhibitor, 50 mg/kg) for 30 min before oral administration of NDL (10 mg/kg) significantly increased the area under the plasma concentration-time curve (AUC₀₋∞)of NDL by 1.7-fold compared with control. Intragastric administration of dexamethasone (DEX, 8 mg/kg) for 4 consecutive days increased P-gp level in the intestine and the liver. In line with this, DEX pre-treatment decreased maximum plasma concentration (C(max)) of NDL by 28% of control. To inhibit the intestinal Oatp1a5, naringin (NRG, 0.145 mg/kg) was preadministered orally for 30 min before the oral administrations of NDL or celiprolol (CEL, 10 mg/kg, Oatp1a5 substrate). Although NRG markedly reduced C(max) and AUC₀₋∞ of CEL by 60% and 65% of control, respectively, little difference was observed in the plasma concentration of NDL between NRG and control. These results suggest that P-gp is greatly involved in the pharmacokinetics of NDL, while the involvement of Oatp1a5 in the pharmacokinetics of NDL may be less than that of celiprolol in rats.

We previously reported a case of pulmonary hypertension, where the symptoms were improved by oral L-arginine (arginine) administration. Arginine may increase nitric oxide (NO) production in the pulmonary artery. Exhaled NO may reflect pulmonary artery NO production. It has been demonstrated that exhaled NO concentration is higher in patients with allergic diseases, but whether oral arginine administration alters exhaled NO is unknown. Therefore, in this study, we investigated whether oral arginine administration increases exhaled NO among healthy volunteers with and without a history of allergy. Eleven subjects were given a single oral dose (200 mg/kg) of arginine, and their plasma arginine concentrations and exhaled NO were measured up to 150 minutes. Baseline values of exhaled NO concentration were significantly higher in those with a history of allergy (56.4±20.3 ppb, n=5, P< 0.05) than those without (16.8±4.0 ppb, n=6). Oral arginine increased exhaled NO, which peaked at 60 minutes after the administration in those with a history of allergy (85.2±44.8 ppb, n=5). However, the increase in exhaled NO was not significant compared to the baseline values. In contrast, plasma arginine concentration was increased significantly by arginine administration (P< 0.01), regardless of an allergy history. These results suggested that the difference in exhaled NO concentration was not due to a difference in arginine absorption. Serum IgE level was significantly higher in the group with a history of allergy. Eosinophils and white blood cells were within normal range in all subjects. We conclude that oral arginine administration does not significantly increase exhaled NO, regardless of allergy history. However, as arginine administration has been reported to be effective in patients with pulmonary hypertension, it will be necessary to test exhaled NO in subjects with pulmonary hypertension in the future.

Effects of green tea extract (GTE) on the activity of cytochrome P450 (CYP) enzymes and pharmacokinetics of simvastatin (SIM) were investigated in rats. Inhibitory effects of GTE on CYP3A activity were investigated in rat hepatic microsomes (RHM) using midazolam (MDZ) 1'-hydroxylation as a probe reaction. SD female rats received a single oral dose of GTE (400 mg/kg) or troleandomycin (TAO, a CYP3A selective inhibitor, 500 mg/kg), followed 30 min later by SIM (20 mg/kg). Plasma concentrations of SIM and its active metabolite, simvastatin acid, were determined up to 6 h after the SIM administration using LC/MS/MS. In RHM, GTE inhibited MDZ 1'-hydroxylation with IC₅₀ and K(i)(app) values of 12.5 and 18.8 µg/mL, respectively, in a noncompetitive manner. Area under plasma concentration-time curves for SIM in the GTE and TAO groups were increased by 3.4- and 10.2-fold, respectively, compared with the control. The maximum concentrations of SIM were higher in the GTE (3.3-fold) and TAO (9.5-fold) groups. GTE alters the pharmacokinetics of SIM, probably by inhibiting intestinal CYP3A.

Vasoactive intestinal peptide (VIP) has been considered as a promising drug candidate for asthma and COPD because of its potent immunomodulating and anti-inflammatory activities. Recently, our group developed a new VIP derivative, [R(15, 20, 21), L(17), A(24,25), des-N(28)]-VIP-GRR (IK312548), with improved chemical and metabolic stability. In the present study, a dry powder inhaler system of IK312548 was designed for inhalation therapy with minimal systemic side effects, the physicochemical properties of which were also evaluated with a focus on morphology, particle size distribution, inhalation performance, and peptide stability. Laser diffraction and cascade impactor analysis suggested high dispersion and deposition in the respiratory organs with a fine particle fraction of 31.2%. According to UPLC/ESI-MS and circular dichroic spectral analyses, no significant changes in the purity and structure of VIP derivative were observed during preparation of respirable formulation. Anti-inflammatory properties of IK312548 respirable powder (RP) were characterized in antigen-sensitized asthma/COPD-model rats. There were marked inflammatory cells infiltrated into the lung tissues of experimental asthma/COPD-model rats; however, intratracheal administration of IK312548-RP led to significant reductions of recruited inflammatory cells in lung tissues and BALF by 72 and 78%, respectively. Thus, respirable powder formulation of IK312548 might be a promising medication for asthma, COPD, and other airway inflammatory diseases., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Vasoactive intestinal peptide (VIP) has been thought to be a promising candidate for asthma/chronic obstructive pulmonary disease (COPD), and our group previously developed several long-lasting VIP derivatives. The objective of the present study was to clarify the therapeutic potential of new VIP derivatives with improved chemical and metabolic stability. Exposure of rat alveolar L2 cells to cigarette smoke extract (CSE) for 1h led to release of lactate dehydrogenase (LDH) and decreased viability in a CSE concentration-dependent manner. There appeared to be marked induction of apoptosis after CSE exposure, as demonstrated by 59% elevation of caspase-3 activity and TUNEL staining. In contrast, a stabilized VIP derivative, [R(15,20,21), L(17)]-VIP-GRR (IK312532), at a concentration of 10(-7)M, exhibited 71% attenuation of LDH release and 85% decrease of the number of apoptotic cells. In addition to IK312532, new VIP derivatives also showed anti-apoptotic effects against CSE toxicity and marked reduction of nitric oxide production. In terms of cytoprotective effects, [R(15,20,21), L(17), A(24,25), des-N(28)]-VIP-GRR was more effective than VIP and IK312532, possibly due to the improved stability. Thus, the present study is the first to demonstrate that novel stabilized VIP derivatives exert anti-apoptotic and cytoprotective effects on CSE-induced cytotoxicity., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: It has been reported that pomegranate juice significantly increased the AUC of orally administered carbamazepine in rats, which suggests that pomegranate may inhibit the cytochrome P450 3A (CYP3A)-mediated carbamazepine metabolism., Objective: The aim of the present study was to clarify the effect of repeated consumption of pomegranate juice on CYP3A activity by assessing the pharmacokinetics of midazolam, a typical CYP3A probe drug, and its metabolites in healthy volunteers., Methods: An open-label, randomized, single-center, 2-period crossover study was conducted on healthy Japanese volunteers. Each subject received 200 mL of pomegranate juice twice daily for 2 weeks. On day 14, they were administered 15 μg/kg midazolam orally with either pomegranate juice or water. Plasma concentrations and urinary excretions of midazolam, 1'-hydroxymidazolam, and 4-hydroxymidazolam were determined up to 24 hours using LC/MS/MS and analyzed by a noncompartmental method., Results: Sixteen subjects (11 men and 5 women) were enrolled and completed the study. The mean (SD) age was 24.1 (4.8) years (range 22-40), mean body weight was 62.9 (8.8) kg (range 45.6-79.9). Differences in the mean AUC(0-∞) were 12.7 (4.4) and 14.2 (6.6) ng/mL/h in pomegranate juice and control groups, respectively (geometric mean ratio: 1.02 [95% CI, 0.95-1.09]; P = 0.40). Differences in C(max) for midazolam did not reach the level of statistical significance (5.1 [1.7] vs 5.0 [2.0] ng/mL, geometric mean ratio: 0.95 [95% CI, 0.79-1.11]; P = 0.68). Excretions of 1'-hydroxymidazolam (P = 0.34) and 4-hydroxymidazolam (P = 0.32) were not significantly altered by ingestion of pomegranate juice., Conclusion: In this small Japanese adult volunteer population receiving single subtherapeutic doses of midazolam, 2 weeks' consumption of pomegranate juice did not significantly alter the pharmacokinetic profile of midazolam compared with that of the control. Protocol identifier: UMIN000004459., (Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.)