检索问题
盐酸小檗碱目前在制剂开发方面进展如何？进入临床阶段有哪些药物？
基于所提供的证据，盐酸小檗碱（Berberine Hydrochloride）在制剂开发方面展现出广泛的潜力，并已有多项临床试验评估其在不同疾病治疗中的效果。小檗碱作为一种天然产物，存在于小檗属植物（如小檗、黄连、黄柏等）的根、根茎、茎和树皮中，在传统医学中具有悠久的药用历史，尤其在伊朗民间医学中应用广泛 。
制剂开发进展和临床应用方向：
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糖尿病和血脂异常：
- 改善胰岛素抵抗和降脂： 小檗碱最受关注的特性之一是其降低血脂和改善胰岛素抵抗的能力 。多项随机临床试验证实了其这些作用 。
- 降胆固醇机制： 小檗碱通过一种不同于他汀类药物的机制上调低密度脂蛋白受体（LDLR），即稳定LDLR mRNA，从而降低总胆固醇和低密度脂蛋白胆固醇 。在患有高胆固醇血症的受试者中，盐酸小檗碱（0.5克，每日两次，持续3个月）能够降低低密度脂蛋白胆固醇（从3.2 mmol/l降至2.4 mmol/l），同时降低甘油三酯水平（从2.3 mmol/l降至1.5 mmol/l），但对高密度脂蛋白胆固醇无影响 。
- 联合用药： 一种包含红曲米、小檗碱、多廿烷醇、虾青素、辅酶Q10和叶酸的营养补充剂（NComb，如Armolipid Plus）已被广泛研究，在轻中度血脂异常患者中，能够显著降低总胆固醇（11-21%）和低密度脂蛋白胆固醇（15-31%），其效果与低剂量他汀类药物相当 。对于他汀类药物不耐受的患者，这种组合可以作为一种有效的替代疗法 。
- 单药治疗： 一项随机、双盲、安慰剂对照试验（计划招募118名血脂异常患者）旨在评估小檗碱单药治疗血脂异常的疗效和安全性，主要观察指标是12周时低密度脂蛋白胆固醇的百分比降低 。
- 与益生菌联用： 一项针对新诊断的2型糖尿病患者的随机、双盲、安慰剂对照试验（PREMOTE研究）发现，小檗碱单独治疗或与益生菌联合治疗均能显著降低糖化血红蛋白水平，且效果优于安慰剂或单独益生菌治疗 。研究还指出，小檗碱的降糖作用与抑制Ruminococcus bromii对DCA的生物转化有关 。
- 对肥胖患者的影响： 在肥胖患者中，小檗碱能显著降低体重、血压以及Visfatin (Vis) 和Apelin (Ap) 基因表达，并增加Omentin (Ome) 表达，对身体成分、血压和代谢风险相关的脂肪因子基因表达有较好的影响 。
- 对非酒精性脂肪肝病 (NAFLD) 的作用： 小檗碱被认为是一种可能对非酒精性脂肪肝病及其相关参数产生积极影响的营养保健品，尤其在与生活方式改变相结合并长期适量使用时 。然而，一项网络荟萃分析显示，在治疗NAFLD方面，洋蓟叶提取物和柚皮素可能比小檗碱等其他天然产物表现出更好的治疗效果 。
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胃肠道疾病：
- 结直肠腺瘤的化学预防： 一项多中心、双盲、随机、安慰剂对照试验（在中国七个医院中心进行）研究了小檗碱（0.3克，每日两次）预防结直肠腺瘤复发的临床潜力与安全性。结果显示，小檗碱组的腺瘤复发率为36%，而安慰剂组为47%，表明小檗碱能安全有效地降低结直肠腺瘤复发的风险，可作为息肉切除术后的化学预防选择 。最常见的副作用是便秘，但发生率较低（小檗碱组1% vs 安慰剂组<0.5%），且未报告严重不良事件 。
- 溃疡性结肠炎 (UC)： 盐酸小檗碱已被报道对溃疡性结肠炎患者有效，但目前尚无关于其治疗UC的系统评价。一项正在进行的系统评价和荟萃分析协议旨在评估盐酸小檗碱治疗UC的有效性和安全性，以期为临床实践提供可靠结论 。
- 炎症性肠病 (IBD)： 黄连（Coptis chinensis）及其主要活性成分小檗碱已被广泛研究用于治疗炎症性肠病。小檗碱通过抑制氧化应激、抗伤害、保护肠黏膜上皮屏障、调节T辅助细胞和抗菌活性发挥治疗作用 。
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心血管疾病：
- 心血管、抗癌、胃肠道、中枢神经系统、内分泌等疾病： 临床试验表明，小檗碱具有广泛的治疗应用，包括心血管、抗癌、胃肠道、中枢神经系统和内分泌等方面的作用 。
- 室性早搏 (PVCs)： 一项对10项随机对照试验（涉及896名参与者）的荟萃分析发现，小檗碱是治疗室性早搏的一种有效且安全的辅助方法。与抗心律失常药物（AD）相比，小檗碱联合AD的有效率更高（RR = 1.26），且不良反应发生率无显著差异。小檗碱单独使用时，有效率与AD无显著差异，但不良反应发生率和复发率较低。研究建议，对于服用AD后出现严重不良反应的PVCs患者，小檗碱可作为替代疗法 。
- 降压和抗心律失常： 除了降脂作用，小檗碱还具有降压、正性肌力和III类抗心律失常的特性，这使其在心血管疾病治疗中可能成为一种有用的药物 。
- 高胆固醇血症的预防： 虽然红曲米产品和Armolipid在降低心血管事件风险方面有更确凿的证据，但小檗碱和佛手柑的益处证据尚不那么明确，专家对此的意见也存在分歧 。
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中枢神经系统疾病（卒中）：
- 一项关于植物提取物对卒中患者认知功能和生活质量影响的网络荟萃分析指出，小檗碱（SUCRA 84.1%）在降低改良Rankin量表（mRS）评分方面最有效，表明其可以改善卒中患者的认知功能和生活质量 。
安全性方面：
- 低毒性： 小檗碱在常用剂量下毒性非常低，临床益处显著且无重大副作用 。
- 胃肠道反应： 最常见的不良反应是轻微的胃肠道反应，如便秘 。这些胃肠道症状在治疗的第一个月内会减弱 。一项研究中，小檗碱组便秘发生率为1%，而安慰剂组小于0.5% 。
- 肝胆排泄和代谢： 小檗碱通过肝胆排泄，并经过I期脱甲基化和II期葡萄糖醛酸化代谢 。在糖尿病模型大鼠中，小檗碱的生物转化（向小檗红碱）被显著抑制，但小檗碱生物利用度显著增加 。
- 特殊人群的安全性：
- G6PD缺乏症新生儿： 过去，含有小檗碱的中药（如黄连和黄柏）在新加坡被禁用，因为小檗碱被认为会加重新生儿G6PD缺乏症引起的黄疸和核黄疸。然而，一项临床研究对慢性血细胞减少症的患者（其中一部分人服用含有黄连和黄柏的草药）进行分析，发现在传统剂量和适应症下，口服黄连和黄柏是安全的，未观察到器官毒性或电解质失衡，尽管少数地中海贫血中间型患者出现了短暂的血清胆红素升高，但这与贫血或肝功能恶化无关 。文献中关于小檗碱导致新生儿黄疸和核黄疸的证据存在争议 。
总结：
盐酸小檗碱的制剂开发已进入多个临床阶段，主要集中在糖尿病、血脂异常、胃肠道疾病（如结直肠腺瘤的预防和炎症性肠病）、心血管疾病（如室性早搏）以及卒中后的认知功能改善等领域。其低毒性、轻微副作用以及广泛的药理作用使其成为一种有前景的天然药物或营养补充剂。尽管在某些领域（如非酒精性脂肪肝病和高胆固醇血症的初级预防）可能存在更有效的替代品或专家意见分歧，但小檗碱在改善血糖血脂、预防结直肠腺瘤复发和辅助治疗室性早搏方面显示出明确的临床益处。未来的研究将进一步明确其在特定疾病中的最佳适应症、剂量和长期安全性。
References
1Berberine and barberry (Berberis vulgaris): A clinical review.PubMed
Mohsen Imenshahidi, Hossein Hosseinzadeh
Barberry (Berberis vulgaris L.) has different medicinal applications in folk medicine of Iran. Berberine, an alkaloid constituent of this plant, is present in the roots, rhizomes, stem, and bark of B. vulgaris and many other plants. There have been many clinical trials conducted that suggested a wide range of therapeutic applications. Here, we investigated the clinical uses of berberine and B. vulgaris in the treatment of different diseases in humans. An extensive search in electronic databases (PubMed, Scopus, Embase, Web of Sciences and Science Direct) was used to identify the clinical trials on B. vulgaris and berberine. Lipid-lowering and insulin-resistance improving actions are the most studied properties of berberine in numerous randomized clinical trials. There are also clinical trials regarding cardiovascular, anticancer, gastrointestinal, CNS, endocrine, and so on. Berberine has very low toxicity in usual doses and reveals clinical benefits without major side effects. Only mild gastrointestinal reactions may occur in some patients. The purpose of this review is to provide a summary concerning the clinical trials conducted on berberine to improve the clinical application of this nutraceutical in different diseases. In this review article, we used 77 clinical studies on human subjects.
2Gut microbiome-related effects of berberine and probiotics on type 2 diabetes (the PREMOTE study).PubMed
Yifei Zhang, Yanyun Gu, Huahui Ren, et al.
Human gut microbiome is a promising target for managing type 2 diabetes (T2D). Measures altering gut microbiota like oral intake of probiotics or berberine (BBR), a bacteriostatic agent, merit metabolic homoeostasis. We hence conducted a randomized, double-blind, placebo-controlled trial with newly diagnosed T2D patients from 20 centres in China. Four-hundred-nine eligible participants were enroled, randomly assigned (1:1:1:1) and completed a 12-week treatment of either BBR-alone, probiotics+BBR, probiotics-alone, or placebo, after a one-week run-in of gentamycin pretreatment. The changes in glycated haemoglobin, as the primary outcome, in the probiotics+BBR (least-squares mean [95% CI], -1.04[-1.19, -0.89]%) and BBR-alone group (-0.99[-1.16, -0.83]%) were significantly greater than that in the placebo and probiotics-alone groups (-0.59[-0.75, -0.44]%, -0.53[-0.68, -0.37]%, P < 0.001). BBR treatment induced more gastrointestinal side effects. Further metagenomics and metabolomic studies found that the hypoglycaemic effect of BBR is mediated by the inhibition of DCA biotransformation by Ruminococcus bromii. Therefore, our study reports a human microbial related mechanism underlying the antidiabetic effect of BBR on T2D. (Clinicaltrial.gov Identifier: NCT02861261).
3Berberine versus placebo for the prevention of recurrence of colorectal adenoma: a multicentre, double-blinded, randomised controlled study.PubMed
Ying-Xuan Chen, Qin-Yan Gao, Tian-Hui Zou, et al.
BACKGROUND: Chemoprevention of colorectal adenoma and colorectal cancer remains an important public health goal. The present study aimed to investigate the clinical potential and safety of berberine for prevention of colorectal adenoma recurrence. METHODS: This double-blind, randomised, placebo-controlled trial was done in seven hospital centres across six provinces in China. Individuals aged 18-75 years who had at least one but no more than six histologically confirmed colorectal adenomas that had undergone complete polypectomy within the 6 months before recruitment were recruited and randomly assigned (1:1) to receive berberine (0·3 g twice daily) or placebo tablets via block randomisation (block size of six). Participants were to undergo a first follow-up colonoscopy 1 year after enrolment, and if no colorectal adenomas were detected, a second follow-up colonoscopy at 2 years was planned. The study continued until the last enrolled participant reached the 2-year follow-up point. All participants, investigators, endoscopists, and pathologists were blinded to treatment assignment. The primary efficacy endpoint was the recurrence of adenomas at any follow-up colonoscopy. Analysis was based on modified intention-to-treat, with the full analysis set including all randomised participants who received at least one dose of study medication and who had available efficacy data. The study is registered with ClinicalTrials.gov, number NCT02226185; the trial has ended and this report represents the final analysis. FINDINGS: Between Nov 14, 2014, and Dec 30, 2016, 553 participants were randomly assigned to the berberine group and 555 to the placebo group. The full analysis set consisted of 429 participants in the berberine group and 462 in the placebo group. 155 (36%) participants in the berberine group and 216 (47%) in the placebo group were found to have recurrent adenoma during follow-up (unadjusted relative risk ratio for recurrence 0·77, 95% CI 0·66-0·91; p=0·001). No colorectal cancers were detected during follow-up. The most common adverse event was constipation (six [1%] of 446 patients in the berberine group vs one [<0·5%] of 478 in the placebo group). No serious adverse events were reported. INTERPRETATION: Berberine 0·3 g twice daily was safe and effective in reducing the risk of recurrence of colorectal adenoma and could be an option for chemoprevention after polypectomy. FUNDING: National Natural Science Foundation of China.
4Comparative Effects of and Berberine on Adipokines, Body Composition, and Metabolic Parameters in Obese Patients: A Randomized Study.PubMed
Cindy Bandala, Jazmín Carro-Rodríguez, Noemí Cárdenas-Rodríguez, et al.
UNLABELLED: (GS) and berberine (BBR) are natural products that have demonstrated therapeutic potential for the management of obesity and its comorbidities, as effective and safe alternatives to synthetic drugs. Although their anti-obesogenic and antidiabetic properties have been widely studied, comparative research on their impact on the gene expression of adipokines, such as resistin (Res), omentin (Ome), visfatin (Vis) and apelin (Ap), has not been reported. METHODOLOGY: We performed a comparative study in 50 adult Mexican patients with obesity treated with GS or BBR for 3 months. The baseline and final biochemical parameters, body composition, blood pressure, gene expression of Res, Ome, Vis, and Ap, and safety parameters were evaluated. RESULTS: BBR significantly decreased ( < 0.05) body weight, blood pressure and Vis and Ap gene expression and increased Ome, while GS decreased fasting glucose and Res gene expression ( < 0.05). A comparative analysis of the final measurements revealed a lower gene expression of Ap and Vis ( < 0.05) in patients treated with BBR than in those treated with GS. The most frequent adverse effects in both groups were gastrointestinal symptoms, which attenuated during the first month of treatment. CONCLUSION: In patients with obesity, BBR has a better effect on body composition, blood pressure, and the gene expression of adipokines related to metabolic risk, while GS has a better effect on fasting glucose and adipokines related to insulin resistance, with minimal side effects.
5Hypolipaemic nutraceutics: red yeast rice and Armolipid, berberine and bergamot.PubMed
Longina Kłosiewicz-Latoszek, Barbara Cybulska, Katarzyna Stoś, et al.
INTRODUCTION: Increased serum cholesterol levels constitute one of the main risk factors for cardiovascular diseases. Statins are a major method for reducing the levels which also lower the risk of cardiovascular events. However, these valuable drugs cannot be used in all patients who need them due to contraindications and intolerance. In such cases, help can be sought from nutraceutics that reduce the serum cholesterol concentration. Since there are numerous products of this type available at drugstores, registered as supplements, there seems to be a need to demonstrate their effectiveness in preventing cardiovascular diseases induced by atherosclerosis. In literature, increasingly more attention is drawn to red yeast rice, Armolipid, berberine and bergamot. BRIEF DESCRIPTION: This article presents knowledge about these nutraceutics based on clinical studies and expert statements relating to their use. The results of clinical studies and metaanalyses have shown that nutraceutics with cholesterol lowering properties, red yeast rice and Armolipid are the most favourable for reducing cardiovascular events. However, the evidence of benefits of berberine and bergamot is not so conclusive. CONCLUSIONS: Red yeast rice products and Armolipid may be used as an alternative treatment in statin intolerant patients, especially in combination with ezetimibe. These nutraceutics can be also considered, as an adjunct to diet therapy in primary prevention of cardiovascular diseases in patients with mild and moderate hypercholesterolaemia. The opinion of experts on berberine and bergamot is ambiguous.
6Effects of different natural products in patients with non-alcoholic fatty liver disease-A network meta-analysis of randomized controlled trials.PubMed
Hongshuai Liu, Yufei Li, Yan Jin, et al.
Due to a scarcity of appropriate therapeutic approaches capable of ameliorating or eliminating non-alcoholic fatty liver disease (NAFLD), many researchers have come to focus on natural products based on traditional medicine that can be utilized to successfully treat NAFLD. In this study, we aimed to evaluate the effects exerted by seven natural products (curcumin, silymarin, resveratrol, artichoke leaf extract, berberine, catechins, and naringenin) on patients with NAFLD. For this purpose, PubMed, Embase, Cochrane Library, and Web of Science, were searched for randomized controlled trials (RCTs) exclusively. The selected studies were evaluated for methodological quality via the Cochrane bias risk assessment tool, and data analysis software was used to analyze the data accordingly. The RCTs from the earliest available date until September 2022 were collected. This process resulted in 37 RCTs with a total sample size of 2509 patients being included. The results of the network meta-analysis showed that artichoke leaf extract confers a relative advantage in reducing the aspartate aminotransferase (AST) levels (SUCRA: 99.1%), alanine aminotransferase (ALT) levels (SUCRA: 88.2%) and low-density lipoprotein cholesterol (LDL-C) levels (SUCRA: 88.9%). Naringenin conferred an advantage in reducing triglyceride (TG) levels (SUCRA: 97.3%), total cholesterol (TC) levels (SUCRA: 73.9%), and improving high-density lipoprotein cholesterol (HDL-C) levels (SUCRA: 74.9%). High-density catechins significantly reduced body mass index (BMI) levels (SUCRA: 98.5%) compared with the placebo. The Ranking Plot of the Network indicated that artichoke leaf extract and naringenin performed better than the other natural products in facilitating patient recovery. Therefore, we propose that artichoke leaf extract and naringenin may exert a better therapeutic effect on NAFLD. This study may help guide clinicians and lead to further detailed studies.
7Efficacy and safety of berberine for premature ventricular contractions: a meta-analysis and systematic review of randomized controlled trials.PubMed
Meng Qiao, Chao Lei, Chaoren Tan, et al.
CONTEXT: Berberine is a potential drug that can effectively treat cardiovascular diseases, including premature ventricular contractions (PVCs). OBJECTIVE: This study was conducted to assess the efficacy and safety of berberine for PVCs. METHODS: The literature was searched using PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), Wanfang, and Chinese Biomedical Literature Database (CBM) for randomized controlled trials (RCTs) from inception to October 1, 2022. The risk of bias was assessed using the Revised Cochrane risk-of-bias tool for randomized trials, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was adopted to assess the quality of evidence. RESULTS: Ten RCTs with 896 participants were included in the meta-analysis. The results showed that compared to antiarrhythmic drugs (AD), berberine (BE) combined with AD had a higher effective rate (RR = 1.26; 95% CI:1.12, 1.42; = 0.0001) with no significant incidence of adverse reactions (RR = 0.93; 95% CI:0.33, 2.57; = 0.88), and BE alone had no significant difference in effective rate (RR = 0.91; 95% CI:0.77, 1.07; = 0.23), and a lower incidence of adverse reactions (RR = 0.38; 95% CI:0.15, 0.97; = 0.04) and recurrence rate (RR = 0.40; 95% CI:0.18, 0.88; = 0.02). CONCLUSIONS: The results suggest that BE is an effective and safe adjunctive method for PVCs. In addition, BE is recommended for patients with PVCs who had severe adverse reactions after administrating AD as an alternative therapy.
8Nutraceutical Approach to Non-Alcoholic Fatty Liver Disease (NAFLD): The Available Clinical Evidence.PubMed
Arrigo F G Cicero, Alessandro Colletti, Stefano Bellentani
Non-alcoholic fatty liver disease (NAFLD) is a clinical condition characterized by lipid infiltration of the liver, highly prevalent in the general population affecting 25% of adults, with a doubled prevalence in diabetic and obese patients. Almost 1/3 of NAFLD evolves in Non-Alcoholic SteatoHepatitis (NASH), and this can lead to fibrosis and cirrhosis of the liver. However, the main causes of mortality of patients with NAFLD are cardiovascular diseases. At present, there are no specific drugs approved on the market for the treatment of NAFLD, and the treatment is essentially based on optimization of lifestyle. However, some nutraceuticals could contribute to the improvement of lipid infiltration of the liver and of the related anthropometric, haemodynamic, and/or biochemical parameters. The aim of this paper is to review the available clinical data on the effect of nutraceuticals on NAFLD and NAFLD-related parameters. Relatively few nutraceutical molecules have been adequately studied for their effects on NAFLD. Among these, we have analysed in detail the effects of silymarin, vitamin E, vitamin D, polyunsaturated fatty acids of the omega-3 series, astaxanthin, coenzyme Q10, berberine, curcumin, resveratrol, extracts of , and probiotics. In conclusion, Silymarin, vitamin E and vitamin D, polyunsaturated fatty acids of the omega-3 series, coenzyme Q10, berberine and curcumin, if well dosed and administered for medium⁻long periods, and associated to lifestyle changes, could exert positive effects on NAFLD and NAFLD-related parameters.
9The effects of a nutraceutical combination on plasma lipids and glucose: A systematic review and meta-analysis of randomized controlled trials.PubMed
Matteo Pirro, Massimo Raffaele Mannarino, Vanessa Bianconi, et al.
Dyslipidemia and hyperglycemia are associated with an increased risk of ischemic cardiovascular disease. Positive effects of a nutraceutical combination comprising red yeast rice, berberine, policosanol, astaxanthin, coenzyme Q10 and folic acid (NComb) on plasma lipid and glucose levels have been reported in some but not all clinical trials. To address this inconsistency, we tried to estimate the size of lipid- and glucose-lowering effects of NComb through a systematic review and meta-analysis of randomized controlled trials. A systematic literature search in PubMed-Medline, SCOPUS and Google Scholar databases was conducted to identify randomized controlled trials investigating the effects of NComb on plasma lipids and glucose levels. Inverse variance-weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated for net changes in lipid and glucose levels using a random-effects model. Random-effects meta-regression was performed to assess the effect of putative confounders on plasma lipid and glucose levels. Fourteen trials (1670 subjects in the NComb arm and 1489 subjects in the control arm) met the eligibility criteria for lipid analysis and 10 trials (1014 subjects in the NComb arm and 962 subjects in the control arm) for glucose analysis. Overall, WMDs were significant for the impact of NComb supplementation on plasma levels of total cholesterol (-26.15mg/dL, p<0.001), LDL-cholesterol (-23.85mg/dL, p<0.001), HDL-cholesterol (2.53mg/dL, p<0.001), triglycerides (-13.83mg/dL, p<0.001) and glucose (-2.59mg/dL, p=0.010). NComb-induced amelioration of lipid profile was not affected by duration of supplementation nor by baseline lipid levels; conversely, a greater glucose-lowering effect of NComb was found with higher baseline glucose levels and longer durations of supplementation. In conclusion, the present results suggest that NComb supplementation is associated with improvement of lipid and glucose profile. Short-term beneficial effects of NComb supplementation appear to be maintained in the long term.
10Efficacy and safety of berberine for dyslipidemia: study protocol for a randomized double-blind placebo-controlled trial.PubMed
Ying Zhao, Yuan-Yuan Yang, Bao-Lin Yang, et al.
BACKGROUND: Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease and a leading cause of death worldwide. The clinical utility of commonly used lipid-lowering drugs such as statins and fibrates is sometimes limited by the occurrence of various adverse reactions. Recently, berberine (BBR) has received increasing attention as a safer and more cost-effective option to manage dyslipidemia. Thus, a high-quality randomized controlled trial to evaluate the efficacy and safety of BBR in the treatment of dyslipidemia is deemed necessary. METHODS/DESIGN: This is a randomized, double-blind, and placebo-controlled clinical trial. A total of 118 patients with dyslipidemia will be enrolled in this study and randomized into two groups at a ratio of 1:1. BBR or placebo will be taken orally for 12 weeks. The primary outcome is the percentage of low-density lipoprotein cholesterol reduction at week 12. Other outcome measures include changes in other lipid profiles, high sensitivity C-reactive protein, blood pressure, body weight, Bristol Stool Chart, traditional Chinese medicine symptom form, adipokine profiles, and metagenomics of intestinal microbiota. Safety assessment includes general physical examination, blood and urine routine test, liver and kidney function test, and adverse events. DISCUSSION: This trial may provide high-quality evidence on the efficacy and safety of BBR for dyslipidemia. Importantly, the findings of this trial will help to identify patient and disease characteristics that may predict favorable outcomes of treatment with BBR and optimize its indication for clinical use. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900021361 . Registered on 17 February 2019.
11Berberine--a novel approach to cholesterol lowering.PubMed
Sheila A Doggrell
Although low-density lipoprotein (LDL)-cholesterol lowering with the statins reduces the mortality and morbidity associated with coronary artery disease, considerable mortality and morbidity remains. Berberine upregulates the LDL receptor (LDLR) by a mechanism distinct from that of the statins, which involves stabilising the LDLR mRNA. In hamsters fed a high-fat and high-cholesterol diet for 2 weeks, the oral administration of berberine 100 mg/kg for 10 days reduced total serum cholesterol from approximately 4.8 to 2.7 mmol/l, and LDL-cholesterol from approximately 2.5 to 1.4 mmol/l. In subjects with hypercholesterolaemia, berberine hydrochloride (0.5 g b.i.d. for 3 months) reduced LDL-cholesterol (from 3.2 to 2.4 mmol/l) without any effect on high-density lipoprotein-cholesterol. Berberine also caused a reduction in triglyceride levels from 2.3 to 1.5 mmol/l. As berberine and statins both upregulate LDLR, their lipid-lowering profiles are similar. Thus, this mechanism is unlikely to make berberine an attractive alternative to statins for lipid lowering in most circumstances. However, the other effects of berberine (antihypertensive, inotropic and class III antiarrhythmic properties) may make it a useful agent in the treatment of cardiovascular disease.
12Hepatobiliary excretion of berberine.PubMed
Pi-Lo Tsai, Tung-Hu Tsai
Berberine is a bioactive herbal ingredient isolated from the roots and bark of Berberis aristata or Coptis chinensis. To investigate the detailed pharmacokinetics of berberine and its mechanisms of hepatobiliary excretion, an in vivo microdialysis coupled with high-performance liquid chromatography was performed. In the control group, rats received berberine alone; in the drug-treated group, 10 min before berberine administration, the rats were injected with cyclosporin A (CsA), a P-glycoprotein (P-gp) inhibitor; quinidine, both organic cation transport (OCT) and P-gp inhibitors; SKF-525A (proadifen), a cytochrome P450 inhibitor; and probenecid to inhibit the glucuronidation. The results indicate that berberine displays a linear pharmacokinetic phenomenon in the dosage range from 10 to 20 mg kg(-1), since a proportional increase in the area under the concentration-time curve (AUC) of berberine was observed in this dosage range. Moreover, berberine was processed through hepatobiliary excretion against a concentration gradient based on the bile-to-blood distribution ratio (AUC(bile)/AUC(blood)); the active berberine efflux might be affected by P-gp and OCT since coadministration of berberine and CsA or quinidine at the same dosage of 10 mg kg(-1) significantly decreased the berberine amount in bile. In addition, berberine was metabolized in the liver with phase I demethylation and phase II glucuronidation, as identified by liquid chromatography/tandem mass spectrometry. Also, the phase I metabolism of berberine was partially reduced by SKF-525A treatment, but the phase II glucuronidation of berberine was not obviously affected by probenecid under the present study design.
13To assess the effective and safety of berberine hydrochloride in ulcerative colitis: A protocol for systematic review and meta-analysis.PubMed
Yong Zhang, Jin Wang, Daorui Hou, et al.
BACKGROUND: Ulcerative colitis (UC) is an inflammatory bowel disease characterized by a relapsing and remitting course, and the curative medical therapy of UC is not yet available with its precise etiology unknown. Berberine hydrochloride, one of the main alkaloids in rhizomes of Coptis chinensis, has been reported the efficacy in patients with UC. However, there is no systematic review related to berberine hydrochloride for UC published. In this work, we will systematically evaluate the effectiveness and safety of berberine hydrochloride for UC by a meta-analysis method to provide a substantial conclusion for clinical practice. METHODS AND ANALYSIS: In this study, we will search the Chinese and English databases by electronic and manual search to find the related literature of berberine hydrochloride in the treatment of UC published from the inception date of each predefined database up to October 2020. Databases include PubMed, Embase, MEDLINE, Cochrane Library Central Register of Controlled Trials, China National Knowledge Infrastructure (CNKI) database, Wanfang Data Knowledge Service Platform, the VIP information resource integration service platform (cqvip), China Biology Medicine Disc (Sino Med), the Chinese Clinical Trial Registry (ChiCTR), and ClinicalTrials.gov. The 2 professional trained authors will independently select the qualified studies for data extraction and assess the risk of bias in included studies. Then the synthesis and analyses of data will be carried out in RevMan 5.4. The heterogeneity of statistics will be assessed by a heterogeneity X test and I tests. Sensitivity analysis is used to evaluate whether the outcomes of systematic review or meta-analysis are robust and reliable. The funnel plot is the main method to evaluate the bias of reporting. Finally, we will use The Grading of Recommendations Assessment, Development and Evaluation to evaluate the quality of evidence. RESULTS: The results of this study will be published in a peer-reviewed journal. CONCLUSION: Whether berberine hydrochloride is an effectiveness and safety for patients with UC will be judged in the conclusion of this systematic review. OSF REGISTRATION NUMBER: 10.17605/OSF.IO/X57U3.
14Tracking evidences of Coptis chinensis for the treatment of inflammatory bowel disease from pharmacological, pharmacokinetic to clinical studies.PubMed
Yuhan Yang, Chi Teng Vong, Shan Zeng, et al.
ETHNOPHARMACOLOGICAL RELEVANCE: Coptis chinensis (C. chinensis, Huanglian in Chinese), a famous traditional herbal medicine used for clearing heat and detoxification since thousands of years ago, is widely and traditionally used for clinical treatment of stomach inflammation, duodenum and digestive tract ulcers alone or through combing with other herbs in compound formulations. AIM OF THE REVIEW: Through literature reviews of C. chinensis and berberine (one of the most important bioactive compounds derived from this plant) for the treatment of inflammatory bowel disease (IBD), this review aims to provide beneficial information for further exploration of the potent bioactive constituents from C. chinensis, deep investigation on the molecular mechanisms for the treatment of IBD, as well as further research and development of brand new products from C. chinensis for clinical therapy of IBD. METHODS: "C. chinensis" and "IBD" were selected as the main keywords, and various online search engines, such as Google Scholar, PubMed, Web of Science, China National Knowledge Infrastructure database (CNKI) and other publication resources, were used for searching literatures. RESULTS: To present, C. chinensis together with other herbs are involved in plenty of Chinese herbal prescriptions for the treatment of IBD, but little research focused on the single therapeutic effects of C. chinensis or extracts from this herb for the treatment of this disease. Berberine, one of important and representative bioactive compound isolated from C. chinensis, was reported to treat IBD effectively at a big arising speed in recent years. However, systematically and comprehensively reviews on the research of C. chinensis and berberine for the treatment of IBD from the aspects of chemical constituents, pharmacological effects, pharmacokinetics as well as clinical studies are seldom accomplished by researchers. Bioactive components from C. chinensis exert therapeutic effects for the treatment of IBD mainly through the inhibition of oxidative stress, antinociception, protection of intestinal mucosal epithelial barrier, regulation of T helper cells, as well as antibacterial activity. Although numerous studies on bioactive compounds from C. chinense have been performed by clinical investigators in recent years, most of them should be performed in a more strict and standard way to ensure the safety and efficacy of these compounds. CONCLUSIONS: Berberine is considered as the representative and effective component from C. chinensis, but many other chemical components isolated from C. chinensis also have therapeutic effects for the treatment of IBD, which need deep research and further exploration. To accelerate research and development of C. chinensis and its bioactive components for the treatment of IBD, clinical trials are needed to clarify the effectiveness and safety of these chemical components from C. chinensis, as well as their molecular mechanisms for IBD treatment in vitro and in vivo. It is believed that continuous research and exploration on C. chinensis together with its bioactive compounds will bring great hope to the treatment of IBD.
15Systematic Review and Network Meta-Analysis of the Effects of Plant Extracts on Cognitive Function and Quality of Life in Stroke Patients.PubMed
Ji Li, Jingfen Jin, Yifeng Cheng, et al.
In recent years, numerous researchers have focused on plant extracts derived from traditional medicines to treat stroke, as these extracts may improve patients' cognitive function and quality of life. This study aims to evaluate the effects of nine distinct plant extracts ( Ginkgo biloba extract, Ginsenosides, Berberine, St. John's Wort extract, Resveratrol, Gastrodin, Crocus sativus L., Moringa oleifera Seed extract, and Panax Notoginseng Saponins) on cognitive function and quality of life in stroke patients. This study seeks to conduct a network meta-analysis to assess the impact of these plant extracts on cognitive function and quality of life in stroke patients. Researchers systematically searched the Embase, PubMed, Cochrane Library, and Web of Science databases from database inception through October 2024 searched for randomized controlled trials (RCTs) exclusively(no language restrictions). The selected studies were evaluated for methodological quality via the Cochrane bias risk assessment tool, and data analysis software was used to analyze the data accordingly. The primary outcome measures included the following assessment scales: National Institute of Health Stroke Scale (NIHSS), Modified Rankin Scale (mRS), Activities of Daily Living Scale (ADLs), Barthel Index (BI), Montreal Cognitive Assessment (MOCA), and Mini-Mental State Examination (MMSE). Treatment effects were ranked based on probability values derived from the surface under the cumulative ranking curve (SUCRA). Moreover, cluster analysis was applied to evaluate the effects of plant extracts on six scales that reflect cognitive function and quality of life in patients. After screening, 48 eligible randomized controlled trials were included, covering 6599 stroke patients and evaluating nine different plant extract treatments. Specifically, results from 33 trials were included in the NIHSS score, 10 in the mRS score, 11 in the ADL score, 11 in the BI score, nine in the MMSE score, and eight in the MOCA score. Findings indicate that St. John's Wort extract (SUCRA 71.2%) was the most effective in reducing NIHSS scores, Berberine (SUCRA 84.1%) was most effective in reducing mRS scores, and St. John's Wort extract (SUCRA 99.1%) showed the highest efficacy in enhancing ADL scores. Ginsenosides were the most effective in improving Barthel Index (SUCRA 74.7%), MMSE (SUCRA 93%), and MOCA (SUCRA 79.7%) scores. The NMA indicates that, compared to placebo, St. John's Wort extract, Berberine, and Ginsenosides can enhance cognitive function and improve quality of life in stroke patients. This study provides valuable insights into using plant extracts for stroke treatment, potentially guiding clinical practice, but there are some unavoidable limitations to our study, including heterogeneity, differences in extraction methods of plant extracts, and lack of consideration of social support systems and dose effects. Future longer follow-up, larger samples, and more methodologically rigorous randomized controlled trials are recommended to clearly establish the effects of different dosages on cognitive function and quality of life in stroke patients.
16Berberine-induced haemolysis revisited: safety of Rhizoma coptidis and Cortex phellodendri in chronic haematological diseases.PubMed
Yeh-ching Linn, Jiahui Lu, Lay-Cheng Lim, et al.
Two commonly used berberine-containing Chinese herbs, Rhizoma coptidis (RC) and Cortex phellodendri (CP), have been banned in Singapore for the past three decades due to implication of berberine in aggravating jaundice and kernicterus in neonates with glucose-6-phosphate dehydrogenase deficiency. Here we conducted a single arm, phase I/II clinical study on Chinese herbal medicine for patients with chronic cytopenic haematological conditions and we analysed a subset of 20 patients who also had RC, CP or both in their herbal concoction. We found no organ toxicity or electrolyte imbalance in these 20 patients where RC was administered for 1055 patient-days and CP for 1252 patient-days. In three patients with thalassemia intermedia, transient elevation in serum bilirubin level was observed but this was not associated with any aggravation of anaemia or liver dysfunction. A review of the literature found conflicting evidence of varying levels either supporting or refuting the allegation of neonatal jaundice and kernicterus caused by berberine. There were, however, very few clinical reports of adverse reaction attributable to RC or CP in oral TCM concoction. We conclude that based on traditional dosage and indication, the use of RC and CP in oral concoction is safe.
17The effects of Gegen Qinlian decoction and its main constituents on glucolipid metabolic disorders in diabetes: an overview of systematic reviews and meta-analysis.PubMed
Chongxiang Xue, Ying Chen, Cheng Tang, et al.
Currently, an increasing number of individuals diagnosed with diabetes mellitus (DM) are opting for combined functional substances in edible plant products, like herbal prescription or traditional Chinese medicine (TCM), to enhance the efficacy of blood glucose and lipid profile control. Among various TCM-included treatments available, Gegen Qinlian decoction (GQD) is frequently utilized. Nevertheless, the efficacy and safety of GQD and its main constituents (berberine, puerarin, etc.) in managing glucolipid metabolic disorders (GLMD) in DM remain under considerable debate. This overview aims to provide a concise summary of the key findings from systematic review and meta-analysis (SRMAs) on GQD and its main constituents for GLMD in DM, while also assessing the methodological quality of these reviews. A comprehensive search of online databases was conducted with no language restrictions, covering the period from inception to February 20th, 2025. The methodological quality, risk of bias, and strength of evidence of those included SRMAs were accessed. Overlapping randomized controlled trials (RCTs) were excluded, and the results of included meta-analysis were summarized. After screening, 35 studies matching the inclusion criteria were identified. The current evidence indicated that GQD, berberine, and puerarin appeared to be effective in improving the anti-diabetes role. As for blood lipid profile, it is indicated that GQD and berberine intervention could effectively reduce total cholesterol (TC), total triglycerides (TG), low-density lipoprotein (LDL-c) and increase high-density lipoprotein (HDL-c). Consequently, further high-quality primary studies are imperative to establish a more conclusive understanding of GQD and its main constituents for GLMD in DM.
18Pharmacokinetics of Five Alkaloids and their Metabolites in Normal and Diabetic Rats after Oral Administration of Rhizoma coptidis.PubMed
Xinchi Feng, Kun Wang, Shijie Cao, et al.
Rhizoma coptidis has been clinically used for a long time for the treatment of various diseases in China, such as hypertension, diabetes, and inflammation. Previous studies have shown that alkaloid components of Rhizoma coptidis extract could be extensively metabolized and the metabolites were also considered to be the therapeutic material basis. However, until now, pharmacokinetic studies of the metabolites have not been revealed yet. The aim of the present study was to characterize the pharmacokinetics and excretions of five main alkaloids (berberine, jatrorrhizine, palmatine, epiberberine, and coptisine) and their seven metabolites (berberrubine, demethyleneberberine, jatrorrhizine-3---D-glucuronide, thalifendine-10---D-glucuronide, berberrubine-9---D-glucuronide, demethyleneberberine-2--sulfate, and demethyleneberberine-2---D-glucuronide) in rats after oral administration of Rhizoma coptidis extract. Meanwhile, comparative pharmacokinetics and excretions of these analytes in diabetic model rats were also investigated, since Rhizoma coptidis is widely used for the treatment of diabetes. Our results showed that the existing forms of alkaloid components were phase II metabolites, highlighting the glucuronidation metabolic pathway. In diabetic model rats, the utilization of Rhizoma coptidis alkaloids was significantly increased and the biotransformation of berberine into berberrubine was significantly inhibited.
19Pharmacokinetics, excretion of 8-cetylberberine and its main metabolites in rat urine.PubMed
Yuli Hu, Shoujun Fan, Xiaobing Liao, et al.
Berberine (BBR) is a bioactive plant ingredient derived from the roots and bark of Berberis aristata and Coptis chinensis and has a wide variety of pharmacological effects. 8-cetylberberine (8-BBR-C16) is the berberine (BBR) derivative reconstructed from adding octadecyl at C-8 of BBR to enhance its activity. This study presents a reliable method for the determination of BBR and 8-BBR-C16 in rat plasma, urine and feces. BBR and 8-BBR-C16 were determined by HPLC-UV after liquid-liquid extraction for plasma samples, and solid-phase extraction for urinary and fecal samples. The method was linear over the concentration range of 10-300 ng·ml for the plasma samples, 25-2000 ng·ml for the urinary samples, and 100-2000 ng·g for the fecal samples. Furthermore, a metabolic investigation on urine was performed by LC/MS/MS analysis to identify the structures of 8-BBR-C16 metabolites by full scan and product ion scan. Adult Sprague-Dawley rats were divided into two groups. In the control group, rats received 80 mg·kg BBR, and in the drug-treated group, rats received 80 mg·kg 8-BBR-C16. The results indicate that there were significant differences in the pharmacokinetic parameters and in the accumulated excretion levels between the control group and the drug-treated group. The C and AUC of 8-BBR-C16 were 2.8 and 12.9 times higher than those of BBR, and the relative bioavailability of BBR to 8-BBR-C16 was 7.7%. The total excretion amount through the urine and feces of 8-BBR-C16 was 76.9%, but that of BBR was only 20.5%. Additionally, 8-BBR-C16 was metabolized in rat urine with phase I demethylation and phase II glucuronidation or sulfation.
20A nutraceutical approach (Armolipid Plus) to reduce total and LDL cholesterol in individuals with mild to moderate dyslipidemia: Review of the clinical evidence.PubMed
Vivencio Barrios, Carlos Escobar, Arrigo Francesco Giuseppe Cicero, et al.
Compelling evidence supports the effectiveness of the reduction of total and LDL cholesterol (TC and LDL-C) in primarily preventing cardiovascular events, within the framework of life-long prevention programs mainly consisting in lifestyle changes. Pharmacological treatment should be introduced when lifestyle changes, including use of nutraceuticals, have failed. ESC/EAS guidelines list a number of nutraceutical compounds and functional foods which have been individually studied in randomized, controlled clinical trials (RCTs). To date only a proprietary formulation of three naturally occurring substances with putative complementary lipid-lowering properties - red yeast rice, policosanol and berberine - combined with folic acid, astaxanthin, and coenzyme Q10 (Armolipid Plus) has been extensively investigated in several RCTs, 7 of which were placebo-controlled, 2 were ezetimibe comparators and 4 were "real life" studies comparing diet and Armolipid Plus to diet alone. The trials included mostly patients with mild to moderate dyslipidemia, treated for 6-48 weeks. The trials also included special populations and patients in whom statins were contraindicated or who could not tolerate them. Armolipid Plus has proved to be able to achieve significant reductions in TC (11-21%) and in LDL-C (15-31%) levels, which is equivalent to expectations from low dose statins. In patients intolerant to statins, who do not achieve their therapeutic target with ezetimibe, Armolipid Plus can achieve a further 10% improvement in TC and LDL-C. The safety and tolerability of Armolipid Plus were excellent, thought likely due to the intentional combination of low doses of its active ingredients: low enough not to be associated with untoward effects, but high enough to exert therapeutic effects in combination with other complementary substances. Consequently, in the event of intolerance to statins, Armolipid Plus offers an effective alternative, which is devoid of the safety risks associated with synthetic pharmacological therapy. In conclusion Armolipid Plus, in addition to dietary measures, could be a rational choice for individuals with mild to moderate hyperlipidemia and for all dyslipidemic patients in whom statins are not indicated or who cannot tolerate them.