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Sulfation predominates the pharmacokinetics, metabolism, and excretion of forsythin in humans: major enzymes and transporters identified.
Pan, LL, Yang, Y, Hui, M, Wang, S, Li, CY, Zhang, H, Ding, YH, Fu, L, Diao, XX, Zhong, DF
Acta pharmacologica Sinica. 2021;(2):311-322
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Abstract
Forsythin extracted from Forsythiae Fructus is widely used to treat fever caused by the common cold or influenza in China, Japan and Korea. The present study aimed to analyze the pharmacokinetics, metabolism and excretion routes of forsythin in humans and determine the major enzymes and transporters involved in these processes. After a single oral administration, forsythin underwent extensive metabolism via hydrolysis and further sulfation. In total, 3 of the 13 metabolites were confirmed by comparison to reference substances, i.e., aglycone M1, M1 sulfate (M2), and M1 glucuronide (M7). Hydrolysis was the initial and main metabolic pathway of the parent compound, followed by extensive sulfation to form M2 and a reduced level of glucuronidation to form M7. In addition, the plasma exposure of M2 and M7 were 86- and 4.2-fold higher than that of forsythin. Within 48 h, ~75.1% of the administered dose was found in urine, with M2 accounting for 71.6%. Further phenotyping experiments revealed that sulfotransferase 1A1 and UDP-glucuronosyltransferase 1A8 were the most active hepatic enzymes involved in the formation of M2 and M7, respectively. The in vitro kinetic study provided direct evidence that M1 showed a preference for sulfation. Sulfated conjugate M2 was identified as a specific substrate of organic anion transporter 3, which could facilitate the renal excretion of M2. Altogether, our study demonstrated that sulfation dominated the metabolism and pharmacokinetics of forsythin, while the sulfate conjugate was excreted mainly in the urine.
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The clinical efficacy of external application of mirabilite and rhubarb combined with intrathoracic chemotherapy in treating malignant pleural effusion: A prospective, randomized, controlled clinical trial.
Zhang, H, Jiang, M, Gao, L, Lin, Z
Medicine. 2021;(7):e24758
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Abstract
BACKGROUND Malignant pleural effusion (MPE) is one of the commonest causes of an exudative pleural effusion. Breathlessness, dyspnea and other symptoms often seriously distress and affect the quality of life. The external application of mirabilite and rhubarb (EAMR) combined with intrathoracic infusion of cisplatin, as an alternative treatment for MPE, is popular in China. The study aims to assess its effectiveness and safety combined with intrathoracic chemotherapy. METHODS This study is a prospective, randomized controlled clinical trial. Patient visits were performed at baseline and days 14 and 28 after treatment. Clinical outcomes were measured after chest drain placement using the criterion of efficacy refer to WHO standard, and QLQ-C30 questionnaire. RESULTS Database records of patients treated in our institution for MPE between October, 2016 and March, 2019. The study included 84 eligible patients. They were categorized with a randomization schedule into treatment group (N = 42) and control group (N = 42). There is statistical significance in the comparison of the total effective rate between these 2 groups (66.67% vs 54.76%, P < .05). Furthermore, there is statistical significance in the comparison of items of Physical (1.95 ± 0.50 vs 2.19 ± 0.58%, P < .05), Pain (1.98 ± 0.42 vs 2.07 ± 0.32, P < .05), and Global Health (1.23 ± 0.64 vs 1.13 ± 0.23%, P < .05) between these 2 groups. None of the patients had adverse reactions such as skin allergy and chest tightness. CONCLUSIONS The total effective rate of treatment group using extra external application of mirabilite rhubarb powder is significantly higher than that of control group. The improvement of patients' clinical symptoms is greater in treatment group and no adverse reactions is found. Therefore, external application of mirabilite and rhubarb combined with intrathoracic infusion of cisplatin is an effective method for the treatment of MPE, which is worth popularizing.
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Novel sulfate tablet PBK-1701TC versus oral sulfate solution for colon cleansing: A randomized phase 3 trial.
Yang, HJ, Park, DI, Park, SK, Lee, CK, Kim, HJ, Oh, SJ, Moon, JR, Lee, BJ, Koh, JS, Kim, HS, et al
Journal of gastroenterology and hepatology. 2020;(1):29-36
Abstract
BACKGROUND AND AIM PBK-1701TC is a novel sulfate tablet-based that contains 320 mg of simethicone and delivers 90% of the salt and water delivered by oral sulfate solution (OSS) preparation. This study evaluated the efficacy, safety, and tolerability of PBK-1701TC compared with OSS in bowel preparation for colonoscopy. METHODS This randomized, multicenter, phase 3 non-inferiority trial included adults aged 19 years or older with a body mass index of 19-30 kg/m2 undergoing colonoscopy at five university hospitals in Korea. The primary efficacy endpoint was successful bowel-cleansing rate, defined as Harefield Cleansing Scale grade A or B as evaluated by blinded central readers. Secondary endpoints included the presence of residual air bubbles. Adverse events and laboratory evaluations were monitored to assess safety. Tolerability was assessed via participant interview. RESULTS Overall, 235 participants were randomized, and 224 were included in the per-protocol analysis (PBK, 112; OSS, 112). Successful bowel cleansing was achieved for 95.5% (107/112) in the PBK group, which was non-inferior to the OSS group (98.2%, 110/112) with a difference of -2.7% (one sided 97.5% confidence limit, -8.1%). The participants in the PBK group had fewer intraluminal bubbles (0.9% vs 81.3%, P < 0.001) and reported a lower incidence of nausea and vomiting, with better acceptance, taste, and willingness to repeat the regimen than those in the OSS group (all P < 0.05). CONCLUSION The novel sulfate tablet, PBK-1701TC, was non-inferior to OSS with respect to bowel-cleansing efficacy and exhibited better safety and tolerability in adults undergoing colonoscopy.
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Efficacy and safety of a natural mineral water rich in magnesium and sulphate for bowel function: a double-blind, randomized, placebo-controlled study.
Bothe, G, Coh, A, Auinger, A
European journal of nutrition. 2017;(2):491-499
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Abstract
PURPOSE The present placebo-controlled, double-blind, randomized trial aimed to investigate whether a natural mineral water rich in magnesium sulphate and sodium sulphate (Donat Mg) may help to improve bowel function. METHODS A total of 106 otherwise healthy subjects with functional constipation were randomly assigned to consume 300 or 500 mL of a natural mineral water as compared to placebo water, over a course of 6 weeks. The 300-mL arms were terminated due to the results of a planned interim analysis. Subjects documented the complete spontaneous bowel movements, spontaneous and overall bowel movements/week, stool consistency, gastrointestinal symptoms and general well-being in a diary. Change in the number of complete spontaneous bowel movements was defined as the primary outcome. RESULTS For the 75 subjects in the 500-mL arms, the change in the number of complete spontaneous bowel movements per week tended to be higher in the active group when compared to placebo after 6 weeks (T2 = 1.8; p value = 0.036; one-sided). The mean number of spontaneous bowel movements significantly increased over the course of the study, with significant differences between study arms considering the whole study time (F test = 4.743; p time × group = 0.010, 2-sided). Stool consistency of spontaneous bowel movements (p < 0.001) and the subjectively perceived symptoms concerning constipation (p = 0.005) improved significantly with the natural mineral water as compared to placebo. CONCLUSIONS The daily consumption of a natural mineral water rich in magnesium sulphate and sodium sulphate improved bowel movement frequency and stool consistency in subjects with functional constipation. Moreover, the subjects' health-related quality of life improved. CLINICAL TRIAL REGISTRATION EudraCT No 2012-005130-11.
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Consumption of a diet rich in Brassica vegetables is associated with a reduced abundance of sulphate-reducing bacteria: A randomised crossover study.
Kellingray, L, Tapp, HS, Saha, S, Doleman, JF, Narbad, A, Mithen, RF
Molecular nutrition & food research. 2017;(9)
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Abstract
SCOPE We examined whether a Brassica-rich diet was associated with an increase in the relative abundance of intestinal lactobacilli and sulphate-reducing bacteria (SRB), or alteration to the composition of the gut microbiota, in healthy adults. METHODS AND RESULTS A randomised crossover study was performed with ten healthy adults who were fed a high- and a low-Brassica diet for 2-wk periods, with a 2-wk washout phase separating the diets. The high-Brassica diet consisted of six 84 g portions of broccoli, six 84 g portions of cauliflower and six 300 g portions of a broccoli and sweet potato soup. The low-Brassica diet consisted of one 84 g portion of broccoli and one 84 g portion of cauliflower. Faecal microbiota composition was measured in samples collected following 2-wk Brassica-free periods (consumption of all Brassica prohibited), and after each diet, whereby the only Brassica consumed was that supplied by the study team. No significant changes to the relative abundance of lactobacilli were observed (p = 0.8019). The increased consumption of Brassica was associated with a reduction in the relative abundance of SRB (p = 0.0215), and members of the Rikenellaceae, Ruminococcaceae, Mogibacteriaceae, Clostridium and unclassified Clostridiales (p < 0.01). CONCLUSION The increased consumption of Brassica vegetables was linked to a reduced relative abundance of SRB, and therefore may be potentially beneficial to gastrointestinal health.
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Influence of lithium treatment on GDNF serum and CSF concentrations in patients with early Alzheimer's disease.
Straten, G, Saur, R, Laske, C, Gasser, T, Annas, P, Basun, H, Leyhe, T
Current Alzheimer research. 2011;(8):853-9
Abstract
Preclinical and clinical studies gave evidence that lithium could be useful in the treatment of Alzheimer's disease (AD). One possible mechanism of action might be the induction of neurotrophins. Recently, we found a significant increase of brain-derived neurotrophic factor (BDNF) serum levels in AD patients treated with lithium and a significant decrease of ADAS Cog sum scores in comparison to placebo-treated patients. In another previous study we have shown that glial cell line-derived neurotrophic factor (GDNF) levels in CSF of patients with early AD are increased most probably due to an upregulated expression in CNS as an adaptive process of the impaired brain to enhance neurotrophic support at least in early stages of disease. Here we assessed the influence of a lithium treatment on GDNF serum and cerebrospinal fluid (CSF) concentrations in a subset of a greater sample recruited for a randomized, single-blinded, placebo-controlled, parallel-group multicenter 10-week study, investigating the efficacy of lithium treatment in AD patients. We found a significant negative correlation of lithium concentration in serum with GDNF concentration in CSF at the end of treatment (r = -0.585, p = 0.036) and with the difference of GDNF concentration in CSF before and after treatment (r = - 0.755, p = 0.003). However, we could not show a difference in GDNF concentrations between the patients after the treatment with lithium or placebo (serum, mean ± standard deviation: 434.3 ± 117.9 pg/ml versus 543.8 ± 250.0 pg/ml, p = 0.178; CSF, 62.3 ± 37.4 pg/ml versus 72.8 ± 43.9 pg/ml, p = 0.511). The findings of the present investigation indicated that beneficial effects of the lithium treatment might reduce the necessity of enhanced GDNF expression in the CNS in early AD.
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Alteration of sulfate and hydrogen metabolism in the human colon by changing intestinal transit rate.
Lewis, S, Cochrane, S
The American journal of gastroenterology. 2007;(3):624-33
Abstract
OBJECTIVES Changes in intestinal transit rate are also implicated in the etiology of many colonic diseases and strongly influence many metabolic processes in the colon. We set out to investigate whether intestinal transit time could influence the activity of the hydrogen-consuming bacterial flora and sulfate metabolism. METHODS Normal volunteers underwent four interventions while taking a low-sulfate diet: placebo, sulfate supplements, or sulfate supplements with either senna or loperamide. Stools were cultured and analyzed for sulfate, sulfide, methionine, sulfate reduction rates, methionine reduction rates, acetic acid production rates, methane production rates, short-chain fatty acids, and bile acids. Urine was analyzed for sulfate. RESULTS The addition of sulfate alone increased fecal and urinary excretion of sulfate, fecal sulfide, sulfate reduction rates, and acetic acid production rates; it reduced fecal methanogenic bacterial concentrations. Faster intestinal transit increased fecal sulfate, sulfide, bile acids, the reduction rates of sulfate, and methionine and the production rates of acetic acid. Reduction in fecal methanogens and methane production was seen. The reverse effects were seen with loperamide. CONCLUSIONS Both sulfate supplements and changes in intestinal transit rate markedly alter the activity of the colonic bacterial flora with respect to sulfate metabolism and hydrogen disposal. Dietary influences on intestinal transit and sulfate consumption may influence disease processes. While a variety of processes govern sulfate metabolism and hydrogen disposal, our knowledge is far from complete. How far the observed changes in sulfate metabolism seen in certain diseases are relevant to the pathogenesis of the disease or secondary to the disease itself is unclear.