Exposure of Fexofenadine, but Not Pseudoephedrine, Is Markedly Decreased by Green Tea Extract in Healthy Volunteers.

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.

Impact of Green Tea Catechin Ingestion on the Pharmacokinetics of Lisinopril in Healthy Volunteers.

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 ß 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.

Goshajinkigan, a Traditional Japanese Medicine, Suppresses Voltage-Gated Sodium Channel Nav1.4 Currents in C2C12 Cells.

Goshajinkigan (GJG) is a traditional Japanese Kampo medicine used clinically to treat muscle pain in Japan. However, its underlying mechanism remains unclear. Since voltage-gated sodium channel (Nav) 1.4 is involved in skeletal muscle contraction, we investigated the possibility that GJG may affect Nav1.4 currents. By using an electrophysiological technique on skeletal muscle cell line C2C12, we found that GJG suppresses Nav1.4 currents in C2C12 cells. It is suggested that GJG may improve skeletal muscle stiffness or cramps by inhibiting abnormal Nav1.4 excitation. GJG may act as a Nav1.4 blocker and may be useful to treat muscle stiffness and clamps as well as easing the pain.

Effects of single green tea ingestion on pharmacokinetics of nadolol in healthy volunteers.

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 AUC0-48 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 AUC0-48 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.

Therapeutic effects of oxaliplatin-based neoadjuvant chemotherapy and chemoradiotherapy in patients with locally advanced rectal cancer: a single-center, retrospective cohort study.

BACKGROUND: Neoadjuvant chemoradiotherapy (NACRT) has now become the standard treatment for locally advanced rectal cancer (LARC). NACRT has decreased local relapse (LR) rate in patients with LARC; however, distant relapse has recently attracted much attention. This study aimed to assess the feasibility and efficiency of neoadjuvant chemotherapy (NAC) for LARC. METHODS: Data on patients with cT3/4 and N+ rectal cancer who were treated in our institution from April 2010 to February 2016 were reviewed retrospectively. Twenty-seven patients who received 2-9 cycles of oxaliplatin-based NAC and 28 patients who received NACRT (45 Gy delivered in 25 fractions and 5-fluorouracil-based oral chemotherapy) were analyzed. The primary and secondary endpoints of the present study were the 3-year relapse-free survival (RFS) and the local and distant relapse rates, respectively. RESULTS: Regardless of the kind of neoadjuvant therapy, no patient experienced any grade 3-4 therapy-related adverse events. The frequent toxic events were grade 1 diarrhea in patients with NACRT and neutropenia in patients with NAC. A significantly higher proportion of patients with NAC underwent laparoscopic surgery and anterior resection (p = 0.037 and p = 0.003, respectively). The percentages of patients with lymph node yield less than 12 in the NAC group, and those in the NACRT group were 26 and 68%, respectively (p = 0.002). Comparing the NAC with the NACRT groups, the local relapse and distant relapse rates were 7.4 and 7.1% and 7.4 and 18%, respectively. There were no significant differences in 3-year RFS and 4-year overall survival (OS) between NAC and NACRT (3-year RFS 85.2 vs. 70.4%, p = 0.279; 4-year OS 96.3 vs. 89.1%, p = 0.145, respectively). With an analysis excluding patients who received postoperative adjuvant chemotherapy, no patients who received NAC had a distant relapse, and there was a significant difference in 3-year RFS compared with the NACRT groups (94.4 vs. 63.2%, p = 0.043). CONCLUSION: These outcomes suggest that the therapeutic effect of oxaliplatin-based NAC is at least equal to that of NACRT and that NAC is a feasible and promising option for LARC.

High-Frequency Continuous Pulsed Magnetic Stimulation Does Not Adversely Affect Development on Whole Body Organs in Female Sprague-Dawley Rats.

OBJECTIVES: To conduct histopathological studies on various organs in three different groups of female rats for adverse effects of pulsed magnetic stimulation (MS). Blood tests and body and organ weights were also studied. METHODS: A high-frequency continuous magnetic stimulator was used (SMN-X, Nihon Kohden, Tokyo). Thirty-four female Sprague-Dawley rats (SPF) were randomly divided into three groups: treatment (MS) groups with 12 and 36 stimulations (seven rats in each); sham groups exposed only to sounds of stimulation for 12 and 36 times; (seven rats in each); and control groups with no stimulation or sound during the same periods of 12 and 36 stimulations (five rats in each). The MS group received magnetic stimulation at the maximum output level (560 mT peak) at 10 Hz for 25 min once daily for 5 days a week. After treatment various organs including genital organs were removed for histological and endocrinological examinations. RESULTS: No changes were seen in body and organ weights and daily behaviors among the three groups. No adverse influence of magnetic stimulation was noted on histopathological examinations of liver, spleen, kidney, lung, heart, thymus, urinary bladder, skeletal muscle and bone marrow. No intragroup changes were seen among the three groups with regard to endocrinological findings including blood cell counts, adrenocorticotropic hormone (ACTH), estrogen and progesterone levels. CONCLUSIONS: Pulsed magnetic stimulation exerted no apparent adverse effect on the various organs, hormone levels, body weight, and daily behaviors in female rats.

Investigation into the dosage of dietary sphingomyelin concentrate in relation to the improvement of epidermal function in hairless mice.

We previously found that dietary sphingomyelin (SPM) concentrate from bovine milk improved epidermal function. In this study, we investigated the dosage of dietary SPM concentrate from bovine milk in relation to the improvement of epidermal function. Thirteen-week-old hairless male mice were separated into four experimental groups, each fed one of four types of experimental diet: the control group, the low SPM group, the medium SPM group and the high SPM group. The mice were each fed the experimental diet for 6 weeks. The stratum corneum hydration and the transepidermal water loss (TEWL) were measured using a Corneometer and a Tewameter at 3 weeks and 6 weeks. After the feeding period, ceramides in the stratum corneum were analyzed. We found that the stratum corneum hydration in all the SPM groups was significantly higher than that in the control group, whereas TEWL in all the SPM groups was significantly lower than that in the control group. Ceramides increased significantly in mice fed the medium SPM diet and statistically tended to increase in mice fed the high SPM diet. Our results indicate that a daily intake of 17 mg SPM concentrate is enough to improve epidermal function in hairless mice.

Valsartan improves L-NAME-exacerbated cardiac fibrosis with TGF-ß inhibition and apoptosis induction in spontaneously hypertensive rats.

This study was designed to investigate whether chronic angiotensin II type 1 receptor blockade inhibits ventricular interstitial fibrosis with the induction of programmed cell death (apoptosis) in prolonged nitric oxide synthase (NOS) inhibition using N(G)-nitro-l-arginine methyl ester (L-NAME) in spontaneously hypertensive rats (SHR). Four groups of 20-week-old male SHR were studied for 3 weeks: the control group; the L-NAME group given 80 mg/L L-NAME in drinking water; and the groups given 1 or 30 mg/(kg day) of valsartan, respectively, with L-NAME. The L-NAME group showed marked cardiac tissue injuries with elevated blood pressure such as interstitial fibrosis, intimal thickening of small arteries, and myocardial necrosis. Caspase-3, an apoptosis inducer, immunoreactivity was increased in interstitial cells, and the tissue RNA expression of transforming growth factor-ß(1) (TGF-ß(1)) was also increased in the L-NAME group. Low-dose valsartan treatment did not affect blood pressure or cardiac weight but alleviated the L-NAME-induced interstitial fibrosis with increased mRNA level of caspase-3 in interstitial fibroblasts. High-dose valsartan significantly lowered blood pressure and decreased the mRNA levels of caspase-3 and TGF-ß(1). These data suggest that low-dose valsartan inhibits interstitial fibrosis by promoting apoptosis of the fibroblasts without blood pressure changes, which may provide the TGF-ß(1) inhibition in the development of interstitial fibrosis in severe hypertension rat model.

Serial (1)H-MRS of thalamus during deep brain stimulation of bilateral globus pallidus internus for primary generalized dystonia.

INTRODUCTION: The physiological mechanisms of deep brain stimulation (DBS) are not completely clear. Our understanding of them may be facilitated with the use of proton magnetic resonance spectroscopy ((1)H-MRS). METHODS: Serial (1)H-MRS of both thalami was performed during the course of DBS of bilateral globus pallidus internus in a patient with primary generalized dystonia. RESULTS: Two days after microelectrode implantation, a pulse frequency of 185 Hz was applied for stimulation. It resulted in relief of symptoms and a decrease of Burke-Fahn-Marsden dystonia rating scale (BFMDRS) scores, and was accompanied by a prominent increase of N-acetylaspartate (NAA)/choline-containing compounds (Cho) ratio, a mild increase of NAA/creatine (Cr) ratio, and a moderate decrease of Cho/Cr ratio. Two weeks later, for a search of the optimal stimulation mode, the pulse frequency was switched to 60 Hz, which resulted in clinical deterioration and significant increase of BFMDRS scores. At that time, all investigated (1)H-MRS-detected metabolic parameters had nearly returned to the pretreatment levels. CONCLUSION: Use of serial (1)H-MRS investigations of various brain structures during DBS in cases of movement disorders permits detailed evaluation of the treatment response, has a potential for its possible prediction, and may facilitate understanding of the physiological mechanisms of stimulation.