Effect of RG (Coptis root and ginseng) formula in patients with type 2 diabetes mellitus: a study protocol for a randomized controlled and double-blinding trial.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a common metabolic disease with significant health, social, and economic consequences. Traditional Chinese medicine (TCM) could effectively regulate blood sugar and influence gut microbiota in T2DM patients. Preliminary studies showed that the Coptis root and ginseng (RG) formula could relieve insulin resistance and prevent the progression of diabetes in mice. OBJECTIVES: The purpose of this study is to explore the efficacy and safety of RG formula in the treatment of adult patients with T2DM, as well as observing its effects on gut microbiota. METHODS AND ANALYSIS: This trial is a randomized, double-blind, placebo-controlled study. A total of 60 participants will be randomized in a 1:1 ratio into an experiment group (RG formula) and a control group (placebo). Patients in both groups will be given diabetes education and basic blood glucose control. Glucose-lowering drugs with significant influence on gut microbiota will be avoided. This trial will last 25 weeks including 1-week run-in, 12-week intervention, and 12-week follow-up visit. The primary outcome is the change in the HbA1c. The secondary outcomes comprise the change in the fasting blood glucose (FBG), postprandial blood glucose (PBG), fasting insulin (FIL), fasting C-peptide(C-P), insulin resistance index (IRI), inflammatory factors, and species abundance of gut microbiota between the two groups. Safety of medication will also be evaluated. The correlation analysis will be explored between the glycemic indicators, inflammatory factors, and abundance of gut microbiota. DISCUSSION: This study will provide the clinical evidence for the efficacy of RG formula in regulating blood sugar and influencing gut microbiota, which will be beneficial to form the integrated therapeutic regimen in T2DM with TCM. TRIAL REGISTRATION: "Clinical Study on the Intervention of Coptis Root and Ginseng," Chinese Clinical Trials Registry ChiCTR 2100042126 . Registered on 14 January 2021.

Suppressive activity of RGX-365 on HMGB1-mediated septic responses

Abstract RGX-365 is the main fraction of black ginseng conmprising protopanaxatriol (PPT)-type rare ginsenosides (ginsenosides Rg4, Rg6, Rh4, Rh1, and Rg2). No studies on the antiseptic activity of RGX-365 have been reported. High mobility group box 1 (HMGB1) is recognized as a late mediator of sepsis, and the inhibition of HMGB1 release and recovery of vascular barrier integrity have emerged as attractive therapeutic strategies for the management of sepsis. In this study, we examined the effects of RGX-365 on HMGB1-mediated septic responses and survival rate in a mouse sepsis model. RGX-365 was administered to the mice after HMGB1 challenge. The antiseptic activity of RGX-365 was assessed based on the production of HMGB1, measurement of permeability, and septic mouse mortality using a cecal ligation and puncture (CLP)-induced sepsis mouse model and HMGB1-activated human umbilical vein endothelial cells (HUVECs). We found that RGX-365 significantly reduced HMGB1 release from LPS- activated HUVECs and CLP-induced release of HMGB1 in mice. RGX-365 also restored HMGB1-mediated vascular disruption and inhibited hyperpermeability in the mice. In addition, treatment with RGX-365 reduced sepsis-related mortality in vivo. Our results suggest that RGX- 365 reduces HMGB1 release and septic mortality in vivo, indicating that it is useful in the treatment of sepsis.

Herbal Supplements: Precautions and Safe Use.

The Food and Drug Administration (FDA) classifies herbal preparations as food supplements. New herbal supplements and products are not governed by the strict FDA drug approval process and there is no premarket approval required. The FDA prohibits manufacturers and distributors from marketing adulterated or misbranded products but does not rigorously define safe practices. Scientific evidence related to herbal supplements is limited. Herbal supplements have been associated with adverse reactions and herbal-drug interactions. Information and precautions for 20 common herbal supplements, including St. John's wort, ginseng, echinacea, and ginkgo, are reviewed. Resources for consumers and health care professionals are highlighted.

Standardised ginseng extract G115® potentiates the antidepressant-like properties of fluoxetine in the forced swim test.

OBJECTIVE: Ginsenosides, biologically active components of the root of Panax ginseng, have been reported to have therapeutic benefits in a number of disease states including psychiatric conditions such as major depressive disorder. Our objective was to determine if a standardised commercial ginseng extract, G115®, could reduce the signs of behavioural despair commonly observed in animal models of depression either alone or in combination with the selective serotonin reuptake inhibitor (SSRI) fluoxetine. METHODS: Male Sprague-Dawley (SD) rats (N = 51) were divided into four groups: vehicle control, G115® ginseng root extract, fluoxetine and fluoxetine plus G115®. Rats were trained to voluntarily consume treatments twice daily for 14 days and were then tested in an open field (OF), elevated plus maze (EPM) and forced swim test (FST). Post-mortem hippocampal and prefrontal cortex tissue was analysed for expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) by western blot. RESULTS: One-way Analysis of Variance revealed no significant group differences in the OF or plus-maze performance on any variable examined. In the FST, fluoxetine significantly reduced immobility time and increased latency to immobility. The effects of fluoxetine were further significantly potentiated by co-administration of G115®. Post-mortem tissue analysis revealed significant group differences in BDNF expression in the left hippocampus and left prefrontal cortex without any accompanying changes in TrkB expression. CONCLUSIONS: We conclude that oral G115® significantly potentiates the antidepressant-like effect of fluoxetine in the FST in the absence of potentially confounding effects on locomotion and anxiety.

The Effect of Korean Red Ginseng on Symptoms and Inflammation in Patients With Allergic Rhinitis.

Korean red ginseng (KRG) has been traditionally used in Korea for health improvement. However, the clinical effect of KRG intake on the symptoms in patients with allergic rhinitis remains unknown. Our study was performed to identify the clinical effects of KRG on patients with allergic rhinitis and to examine the effect of KRG on allergic inflammatory reaction. We evaluated 60 patients with allergic rhinitis. All the patients were treated for 4 weeks. The patients were divided into 3 groups, according to the medication. Twenty patients were treated with KRG, 20 patients with the placebo, and 20 patients with the antihistamine. The patients recorded their symptoms in a daily symptom diary card. The patients checked the peak nasal inspiratory flow rate 2 times a day. Total serum immunoglobulin E (IgE) and serum-specific IgE were measured by ImmunoCap method before and after 4-week medication. The Th2 cytokines interleukin-4 (IL-4), IL-5, and IL-10 were checked in the serum before and after the 4-week treatment. The eosinophil counts in the nasal smears were checked. Korean red ginseng group has shown the significant improvement in rhinorrhea, nasal itching, and eye itching. Both the antihistamine and KRG groups showed a significant decrease in total IgE level at the end of treatment. The serum IL-4 level and eosinophil counts in the nasal smears were significantly decreased both in the antihistamine and in the KRG groups. In conclusion, KRG might be a useful treatment modality for patients with allergic rhinitis.

A Review of Ginseng Clinical Trials Registered in the WHO International Clinical Trials Registry Platform.

Although ginseng has long been broadly used in clinical settings around the world, few clinical trials on ginseng have been conducted. The objective of this study was to provide a comprehensive evaluation of the characteristics of ginseng clinical trials registered in the WHO International Clinical Trials Registry Platform (ICTRP) as of December 2017 regarding their frequency, design, type of ginseng, dosage, duration, condition, funding sources, and publication status. A total of 134 ginseng clinical studies were registered from 2002 to 2017, of which 60.4% were completed and 23.1% are actively recruiting participants. A large number of trials were associated with aspects of high-quality trial design. Overall, 94% of the trials employed randomized allocation to study arms, 78.4% were double-blind studies using placebo as one of the control groups, and 71% were published as completed trials. Trials whose sample size was restricted to fewer than 100 participants accounted for 74.7% of the total. Of the primary funding sources for ginseng studies, 67.2% were nonindustry organizations. The ginseng clinical trials were heterogeneous with respect to ginseng species and variety, indications, dose, duration, and participant characteristics. Clearly, stricter and methodologically suitable studies are needed to demonstrate the efficacy and safety of ginseng.

The ginseng pimple: an inflammatory papule following ginseng consumption.

Ginseng is a popular herbal remedy derived from the plant roots of the Panax genus and has been used in traditional Asian medicine for thousands of years. In the United States, it has become increasingly popular and is taken for many conditions, including as an immune enhancer. Cutaneous adverse effects have been reported to occur following ginseng consumption, although detailed clinical descriptions are limited. A 60-year-old woman who repeatedly developed inflammatory papules following ginseng consumption is described and the characteristics of ginseng use in healthcare are reviewed.

Subchronic oral toxicity study of Korean red ginseng extract in Sprague-Dawley rats with a 4-week recovery period.

Ginseng is a major herbal remedy used in Asian countries for thousands of years and known to restore and enhance vital energy. Korean red ginseng, which is processed by steaming and drying fresh Panax ginseng, is most popular and contains unique ginsenosides, which have anticancer and anti-inflammatory properties. The present study was carried out to evaluate the repeated oral dose toxicity of Korean red ginseng extract. The test article was administered orally once a day to male and female Sprague-Dawley rats at dose levels of 0, 500, 1000, or 2000 mg/kg/day for 13 consecutive weeks (15 animals/sex/group in the vehicle control and 2000 mg/kg/day groups, and 10 animals/sex/group in the 500 and 1000 mg/kg/day groups). Ten animals per group were sacrificed at the end of the 13-week treatment period, and the remaining rats were sacrificed after a 4-week recovery period. Administration of Korean red ginseng extract did not result in any toxicologically significant changes in mortality, body weight, food consumption, ophthalmoscopy, hematology, serum biochemistry, gross pathological findings, absolute/relative organ weights, or histopathology. It was established that the no observed adverse effect level (NOAEL) of the test article was 2000 mg/kg/day for both sexes in this study.

Clinical judgement perplexed by initially undisclosed use of herbal medicine and unexpected cross-reactivity of immunoassay.

We report a case of symptomatic bradycardia caused by consumption of a Chinese herbal medicine which was initially undisclosed to the attending emergency physician. The scientific name of the herb is Panax japonicus. Electrocardiogram revealed sinus bradycardia. Laboratory tests were normal except for the detection of a high serum digoxin level. Further interrogation of the patient eventually disclosed ingestion of the herb which, however, did not contain any digoxin. Other active ingredients in the herb include various types of ginsenoside. These are digoxin-like substances that had caused the observed false-positive detection of digoxin by fluorescence polarization immunoassay due to cross-reactivity. Our case-report provides an important insight about a blind-spot in the field of laboratory medicine (clinical pathology), namely, the false positive detection of digoxin due to crossreactivity in the immunoassay when we come across digoxin-like substances in clinical scenarios, which has barely received attention in the medical literature. It also conveys a clear educational message that with full understanding of the laboratory methodology and its mechanistic rationale there are actually some tricks-of-the-trade that allow us to optimize the specificity of the biochemical tests and the treatment of digoxin-like substances overdose.

Over-the-counter natural products in cardiac surgery: a case of ginseng-related massive perioperative bleeding.

We present a case of massive perioperative bleeding due to severe coagulopathy following urgent aortic and mitral valve replacement. Bleeding was persistent despite prolonged and meticulous surgical haemostasis and required high-volume blood products transfusions. No obvious cause was found to justify the severity of the coagulopathy, which was later attributed to high preoperative intake of ginseng.This case highlights the powerful activity of certain over-the-counter remedies on haemostasis, in this particular case on coagulation status. This also reminds us the paramount importance of a sound and comprehensive drug history for surgical patients.

TCM-Mesh: The database and analytical system for network pharmacology analysis for TCM preparations.

With the advancement of systems biology research, we have already seen great progress in pharmacology studies, especially in network pharmacology. Network pharmacology has been proven to be effective for establishing the "compounds-proteins/genes-diseases" network, and revealing the regulation principles of small molecules in a high-throughput manner, thus would be very effective for the analysis of drug combinations, especially for TCM preparations. In this work, we have proposed the TCM-Mesh system, which records TCM-related information collected from various resources and could serve for network pharmacology analysis for TCM preparations in a high-throughput manner (http://mesh.tcm.microbioinformatics.org/). Currently, the database contains 6,235 herbs, 383,840 compounds, 14,298 genes, 6,204 diseases, 144,723 gene-disease associations, 3,440,231 pairs of gene interactions, 163,221 side effect records and 71 toxic records, and web-based software construct a network between herbs and treated diseases, which will help to understand the underlying mechanisms for TCM preparations at molecular levels. We have used 1,293 FDA-approved drugs, as well as compounds from an herbal material Panax ginseng and a patented drug Liuwei Dihuang Wan (LDW) for evaluating our database. By comparison of different databases, as well as checking against literature, we have demonstrated the completeness, effectiveness, and accuracy of our database.

Impact of Acute Energy Drink Consumption on Blood Pressure Parameters: A Meta-analysis.

OBJECTIVE: Hospitalizations associated with energy drinks have increased in the past decade. Whereas energy drinks are suspected to cause hemodynamic effects, the magnitude of risk remains controversial. We evaluated the effects of acute energy drink consumption on systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR). DATA SOURCES: A search in PubMed, Cumulative Index of Nursing and Allied Health Literature, and Cochrane database through December 31, 2015, was performed. STUDY SELECTION AND DATA EXTRACTION: Prospective clinical studies assessing the effects of commercially available energy drinks on BP and HR were included. A weighted mean change from baseline was calculated using the DerSimonian and Laird random-effects model for all end points. DATA SYNTHESIS: In all, 15 studies were included, encompassing a total of 340, 322, and 340 individuals for SBP, DBP, and HR, respectively. SBP and DBP increased significantly by 4.44 mm Hg (95% CI = 2.71 to 6.17; Cochrane Q P = 0.001) and 2.73 mm Hg (95% CI = 1.52 to 3.95; Cochrane Q P = 0.050), respectively. HR changed nonsignificantly by 0.80 beats per minute (95% CI = -1.26 to 2.87; Cochrane Q P < 0.001). The largest change in SBP was seen with drinks administering ≥200 mg of caffeine (6.44 mm Hg, 95% CI = 4.62 to 8.27). CONCLUSIONS: Our results indicate that acute consumption of caffeinated energy drinks significantly raises SBP and DBP. Further investigation of the ingredients in energy drinks and the impact of chronic energy drink consumption is warranted.

Electrocardiographic and blood pressure effects of energy drinks and Panax ginseng in healthy volunteers: A randomized clinical trial.

BACKGROUND: Energy drink usage has been linked to emergency room visits and deaths. The objective of the study is to assess the electrocardiographic and blood pressure effects of energy drinks, Panax ginseng and placebo in healthy individuals. METHODS: This was a randomized, double blinded, placebo controlled, crossover study. Young healthy volunteers with no comorbid conditions consumed 32oz of an energy drink, control drink with 800mg of Panax ginseng or matching placebo-control drink over 45min. Primary endpoints were QTc interval and systolic blood pressure. Secondary endpoints included QT interval, PR interval, QRS duration, heart rate, and diastolic blood pressure. All endpoints were assessed at baseline, 1, 2, 3.5, and 5.5h. RESULTS: A significant increase in QTc interval 2h post energy drink consumption was evident when compared to placebo (3.37±10.7ms and -3.19±11.8ms respectively; p=0.030). Similarly, systolic blood pressure 2h post energy drink consumption increased when compared to placebo (2.00±6.37mmHg and -2.67±5.83mmHg respectively; p=0.014). The PR interval significantly reduced over a 2h period post energy drink use in a clinically non-meaningful manner. Heart rate at 2h was not significantly higher in the energy drink group when compared to others. The QT interval, QRS interval and diastolic blood pressure were not impacted at any time point. CONCLUSIONS: Certain energy drinks consumed at a high volume significantly increase the QTc interval and systolic blood pressure by over 6ms and 4mmHg respectively. Panax ginseng does not have a significant impact on ECG or blood pressure parameters.

Traditional uses, botany, phytochemistry, pharmacology and toxicology of Panax notoginseng (Burk.) F.H. Chen: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax notoginseng (Burk.) F.H. Chen is a widely used traditional Chinese medicine known as Sanqi or Tianqi in China. This plant, which is distributed primarily in the southwest of China, has wide-ranging pharmacological effects and can be used to treat cardiovascular diseases, pain, inflammation and trauma as well as internal and external bleeding due to injury. AIMS OF THE REVIEW: This paper provides up-to-date information on investigations of this plant, including its botany, ethnopharmacology, phytochemistry, pharmacology and toxicology. The possible uses and perspectives for future investigation of this plant are also discussed. MATERIALS AND METHODS: The relevant information on Panax notoginseng (Burk.) F.H. Chen was collected from numerous resources, including classic books about Chinese herbal medicine, and scientific databases, including Pubmed, SciFinder, ACS, Ebsco, Elsevier, Taylor, Wiley and CNKI. RESULTS: More than 200 chemical compounds have been isolated from Panax notoginseng (Burk.) F.H. Chen, including saponins, flavonoids and cyclopeptides. The plant has pharmacological effects on the cardiovascular system, immune system as well as anti-inflammatory, anti-atherosclerotic, haemostatic and anti-tumour activities, etc. CONCLUSIONS: Panax notoginseng is a valuable traditional Chinese medical herb with multiple pharmacological effects. This review summarizes the botany, ethnopharmacology, phytochemistry, pharmacology and toxicology of P. notoginseng, and presents the constituents and their corresponding chemical structures found in P. notoginseng comprehensively for the first time. Future research into its phytochemistry of bio-active components should be performed by using bioactivity-guided isolation strategies. Further work on elucidation of the structure-function relationship among saponins, understanding of multi-target network pharmacology of P. notoginseng, as well as developing its new clinical usage and comprehensive utilize will enhance the therapeutic potentials of P. notoginseng.

Unexplained alveolar hemorrhage associated with Ginkgo and ginseng use.

The author presents a case of diffuse alveolar hemorrhage in a woman consuming Ginkgo biloba extract and ginseng. The patient had no illnesses or exposures that would predispose to diffuse alveolar hemorrhage, and an extensive evaluation revealed no etiology. The patient has had no further bleeding since discontinuing Ginkgo biloba extract and ginseng 1 year ago.

Drug reaction with eosinophilia and systemic symptoms syndrome probably induced by a lamotrigine-ginseng drug interaction.

The likelihood of a drug reaction with lamotrigine is increased by dose escalation that is too rapid or drug interactions that increase the concentration of lamotrigine. There is a well-documented interaction between valproic acid and lamotrigine in which lamotrigine levels are increased, subsequently increasing the risk of a drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. This syndrome is characterized by fever, lymphadenopathy, diffuse maculopapular rash, multivisceral involvement, eosinophilia, and atypical lymphocytes and has a mortality rate of 10-40%. We describe the first case, to our knowledge, of DRESS syndrome that was probably induced by a drug interaction between lamotrigine and ginseng. A 44-year-old white man presented to the emergency department after experiencing a possible seizure. His medical history included two other lifetime events concerning for seizures at ages 14 and 29 years old. After referral to the neurology clinic, he was diagnosed with generalized tonic-clonic seizure disorder, and lamotrigine was started with up-titration according to the drug's package insert to a goal dosage of 150 mg twice/day. The patient had also been taking deer antler velvet and ginseng that he continued during his lamotrigine therapy. On day 43 of therapy, the patient presented to the emergency department with a pruritic rash that had started on his extremities and spread to his torso. He was thought to have experienced a drug reaction to lamotrigine, and the drug was discontinued. Thirteen days later, the patient was admitted from the acute care clinic for inpatient observation due to laboratory abnormalities in the setting of continued rash, headache, and myalgias. His admission laboratory results on that day were remarkable for leukocytosis, with a white blood cell count up to 17.6 × 10(3) /mm(3) , with a prominent eosinophilia of 3.04 × 10(3) /mm(3) ; his liver enzyme levels were also elevated, with an aspartate aminotransferase level of 191 U/L, alanine aminotransferase level 473 U/L, alkaline phosphatase level 465 U/L, and total bilirubin level 1.4 mg/dl. Use of the Drug Interaction Probability Scale indicated that a drug interaction between lamotrigine and ginseng was the probable cause (score of 5). The proposed mechanism of the interaction is ginseng inhibition of the uridine diphosphate glucuronosyltransferase 2B7 enzyme, similar to the mechanism of the interaction with valproic acid. Clinicians should be aware of this probable drug interaction and avoid coadministration of ginseng and lamotrigine or use a more conservative dose titration of lamotrigine for patients who are also taking ginseng.

A rare cause of pulmonary embolism: panax.

INTRODUCTION: The aim of this case report is to present a patient with pulmonary embolism during a high-dose course of panax. CASE: A 41-year-old woman was admitted to the emergency department with sudden complaints of shortness of breath, sweating,weakness, and loss of conscious after panax pills intake. At pulmonary computed tomography angiography, hypodense filling defect compatible with pulmonary emboli was seen at the bifurcation level of right and left distal pulmonary arteries and at each of pulmonary lobary arteries. The patient was treated with pulmonary artery selective thrombolysis. Conclusion: Herbal products, which are used all over the world to support health, should not be taken indiscriminately because their ingredients' amounts and what kind of adverse effects may come up whether used alone or in combination cannot be known.

Manic psychosis associated with ginseng: a report of two cases and discussion of the literature.

BACKGROUND: Herbal medicine use, highly prevalent in the general population, is often a neglected component of the medical history. Herbs are presumed safe because they are "natural" self-care products. We call attention to the following issues: Panax ginseng, one of the most frequently used herbal medicines, has complex pharmacological activity, and can be associated with severe psychiatric symptoms. Physicians may be unfamiliar with herbal therapy risks, and the need for further education and systematic research is highlighted. OBJECTIVE: To describe two cases of new onset manic psychoses associated with high dose, chronic ginseng use, and review the relevant literature. CASE REPORTS: A 23-year-old man developed acute mania after one month of daily ginseng use and intermittent cannabis use. A 79-year-old man developed hypomania while using ginseng and yohimbine for erectile dysfunction, and had a recurrence of mania after stopping yohimbine but increasing his daily intake of ginseng. CONCLUSIONS/SUMMARY: Symptoms of mania fully remitted within days upon discontinuation of ginseng and supportive treatment. Available data prevent a clear determination of causation; however, ginseng-induced mania in the these and previous case reports is suggested by the following: patients had no prior psychiatric history, daily use of ginseng was temporally associated with mania onset, patients ingested much higher doses for a longer duration than recommended in Traditional Chinese Medicine (TCM), and withdrawal of ginseng led to rapid remission. Generally well tolerated, many physicians are unaware that ginseng may be associated with acute and significant psychiatric disturbances for certain at-risk individuals.