Chun-Su Yuan

GINSENG PHARMACOLOGY: MULTIPLE CONSTITUENTS AND MULTIPLE ACTIONS

Ginseng is a highly valued herb in the Far East and has gained popularity in the West during the last decade. There is extensive literature on the beneficial effects of ginseng and its constituents. The major active components of ginseng are ginsenosides, a diverse group of steroidal saponins, which demonstrate the ability to target a myriad of tissues, producing an array of pharmacological responses. However, many mechanisms of ginsenoside activity still remain unknown. Since ginsenosides and other constituents of ginseng produce effects that are different from one another, and a single ginsenoside initiates multiple actions in the same tissue, the overall pharmacology of ginseng is complex. The ability of ginsenosides to independently target multireceptor systems at the plasma membrane, as well as to activate intracellular steroid receptors, may explain some pharmacological effects. This commentary aims to review selected effects of ginseng and ginsenosides and describe their possible modes of action. Structural variability of ginsenosides, structural and functional relationship to steroids, and potential targets of action are discussed.

Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Third Edition).

The actual incidence of neurologic dysfunction resulting from hemorrhagic complications associated with neuraxial blockade is unknown. Although the incidence cited in the literature is estimated to be less than 1 in 150,000 epidural and less than 1 in 220,000 spinal anesthetics, recent epidemiologic surveys suggest that the frequency is increasing and may be as high as 1 in 3000 in some patient populations. Overall, the risk of clinically significant bleeding increase with age, associated abnormalities of the spinal cord or vertebral column, the presence of an underlying coagulopathy, difficulty during needle placement, and an indwelling neuraxial catheter during sustained anticoagulation (particularly with standard heparin or low-molecular weight heparin). The need for prompt diagnosis and intervention to optimize is also consistently reported. In response to these patient safety issues, the American Society of Regional Anesthesia and Pain Medicine (ASRA) convened its Third Consensus Conference on Regional Anesthesia and Anticoagulation. Practice guidelines or recommendations summarize evidence-based reviews. However, the rarity of spinal hematoma defies a prospective randomized study, and there is no current laboratory model. As a result, the ASRA consensus statements represent the collective experience of recognized experts in the field of neuraxial anesthesia and anticoagulation. These are based on case reports, clinical series, pharmacology, hematology, and risk factors for surgical bleeding. An understanding of the complexity of this issue is essential to patient management.

Regional anesthesia in the anticoagulated patient: Defining the risks (the second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation)

Neuraxial anesthesia and analgesia provide several advantages over systemic opioids, including superior analgesia, reduced blood loss and need for transfusion, decreased incidence of graft occlusion, and improved joint mobility following major knee surgery. 1-4 New challenges in the management of patients undergoing neuraxial block have arisen over the last 2 decades, as medical standards for the prevention of perioperative venous thromboembolism were established. 5,6 Concern for patient safety in the presence of potent antithrombotic drugs has resulted in avoidance of regional anesthesia. Indeed, perioperative anesthesia and analgesia are often determined by the antithrombotic agent. 7 Conversely, although the anesthesia community is well aware of the potential for spinal bleeding, other specialties have only recently become cognizant of the risk, as documented by case reports

Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial.

Methylnaltrexone is a quaternary opioid antagonist with limited ability to cross the blood‐brain barrier and the potential to antagonize the peripherally mediated effects of opioids. The effectiveness of methylnaltrexone in preventing morphine‐induced changes in gastrointestinal motility and transit without affecting analgesia was evaluated in humans. Twelve healthy volunteers were given intravenous placebo, placebo plus 0.05 mg/kg morphine, or 0.45 mg/kg methylnaltrexone plus 0.05 mg/kg morphine. Oral‐cecal transit time was assessed by the pulmonary hydrogen measurement technique, and analgesia was measured with use of the cold‐pressor test. Morphine significantly increased oral‐cecal transit time from 104.6 ± 31.1 minutes (mean ± SD) to 163.3 ± 39.8 minutes (p < 0.01). Methylnaltrexone prevented 97% of morphine‐induced increase in oral‐cecal transit time (106.3 ± 39.8 minutes; not significant compared with baseline; p < 0.01 compared with morphine alone). Methylnaltrexone did not affect the analgesic effect of morphine on both pain intensity and pain bothersomeness ratings. At a higher dose of morphine (0.1 mg/kg), our preliminary results indicated that 0.45 mg/kg methylnaltrexone also prevented the morphine‐induced delay in oral‐cecal transit time, with no effect on analgesia. Methylnaltrexone may be a useful adjunct to opioids for the relief of opioid‐induced constipation.

Ginsenosides from American ginseng: Chemical and pharmacological diversity

Ginseng occupies a prominent position in the list of best-selling natural products in the world. Compared to the long history of use and widespread research on Asian ginseng, the study of American ginseng is relatively limited. In the past decade, some promising advances have been achieved in understanding the chemistry, pharmacology and structure-function relationship of American ginseng. To date, there is no systematic review of American ginseng. In this review, the different structures of the ginsenosides in American ginseng are described, including naturally occurring compounds and those resulting from steaming or biotransformation. Preclinical and clinical studies published in the past decade are also discussed. Highlighted are the chemical and pharmacological diversity and potential structural-activity relationship of ginsenosides. The goal is that this article is a useful reference to chemists and biologists researching American ginseng, and will open the door to agents in drug discovery.

Isolation and analysis of ginseng: advances and challenges

Ginseng occupies a prominent position in the list of best-selling natural products in the world. Because of its complex constituents, multidisciplinary techniques are needed to validate the analytical methods that support ginsengs use worldwide. In the past decade, rapid development of technology has advanced many aspects of ginseng research. The aim of this review is to illustrate the recent advances in the isolation and analysis of ginseng, and to highlight new applications and challenges. Emphasis is placed on recent trends and emerging techniques.

Brief communication: American ginseng reduces warfarin's effect in healthy patients: a randomized, controlled Trial.

Context Consuming ginseng, a commonly used herbal dietary supplement, has been associated with a decrease in warfarins anticoagulant effect in at least 1 case report. Contribution Healthy volunteers took warfarin with and without concurrently taking ginseng. Ginseng consumption lowered the international normalized ratio and decreased plasma warfarin levels. Cautions Patients and physicians should be aware that ginseng is among many substances that can interfere with warfarins anticoagulant effect. The Editors The beneficial effects of several commonly used botanicals have been documented (1), but data on the safety of these herbs are limited. At least 16% of people using prescription medication concurrently take herbal supplements. An estimated 15 million Americans are at risk for herbdrug interactions (2). Advocated for almost every purpose, including maintaining general health, combating fatigue, and improving immune function (3), ginseng is one of the best-selling herbs in the United States (4). Herbs such as ginseng may interact with medications that have a narrow therapeutic index, such as warfarin, a commonly used oral anticoagulant (5, 6). A widely cited case report showed a substantial decrease in the anticoagulant effect of warfarin after ginseng consumption in a patient who was previously maintained with stable warfarin therapy (7). We conducted a randomized, double-blind, placebo-controlled trial to evaluate the potential interactions between American ginseng and warfarin. Methods Patients Nine men and 11 nonpregnant women (who were paid

The safety and efficacy of oral methylnaltrexone in preventing morphine‐induced delay in oral‐cecal transit time

250 after trial completion) were enrolled in this study. Patients were screened with a medical history, physical examination, 12-lead resting electrocardiography, complete blood and platelet counts, international normalized ratio (INR) (the prothrombin time testcontrol ratio) (8), blood chemistry tests, and urinalysis. Patients agreed to abstain from tobacco products for at least 2 weeks before and during the study, abstain from alcohol and other medications during the study, and limit caffeine-containing products for 48 hours before and during the study. Protocol The institutional review board approved this 4-week study conducted at the University of Chicago Medical Center, Chicago, Illinois. All patients provided written, informed consent. Patients received oral warfarin, 5 mg daily, for the first 3 consecutive days during week 1. Beginning in week 2, patients were randomly assigned to receive either oral American ginseng, 1.0 g, or placebo, twice daily, for 3 consecutive weeks. During week 4, all patients again received oral warfarin, 5 mg daily, for the first 3 consecutive days (Appendix Figure). Ginseng or placebo assignment was determined by a table of random numbers with blocks of 8 (4 ginseng and 4 placebo assignments per block), from which sealed, opaque envelopes were prepared and opened sequentially as patients were enrolled in the study. A biostatistician who did not acquire data prepared the assignments. Patients and investigators were blinded to the treatment groups. Patients were instructed to eat a balanced diet to maintain a consistent amount of vitamin K and to avoid drastic changes in dietary habits. The daily intake of vitamin Kcontaining foods was recorded 1 week before the study to obtain the baseline value and to adjust the diet if vitamin K intake was high. Patients recorded their daily diet throughout the study period, completed a written weekly questionnaire, and were asked to report any adverse events. Blood samples were obtained at the same time (0.5 hour) on days 1, 3, 4, 5, and 7 of weeks 1 and 4 to measure INR and plasma warfarin levels (detection limit, 0.1 g/mL). Study Drugs Warfarin (3-(-acetonylbenzyl)-4-hydroxycoumarin or Coumadin, DuPont Pharmaceuticals, Wilmington, Delaware) is a racemic mixture composed of equal amounts of 2 optical isomers. In our laboratory, we ground the root of American ginseng (Panax quinquefolius, Wisconsin Ginseng Board, Wausau, Wisconsin) from 1 lot into a fine powder and placed 0.5 g in nontransparent capsules. Using a high-performance liquid chromatography method, we found that the total ginsenoside content was 5.19%. The constituent split was as follows: ginsenoside Rb1, 1.93%; Rb2, 0.20%; Rc, 0.61%; Rd, 0.42%; Re, 1.68%; and Rg1, 0.35%. We prepared identical placebo capsules that contained cornstarch powder. Statistical Analysis The primary end point of this study was the change in peak INR (week 4 week 1). Additional analysis end points were change in INR area under the curve (AUC) (week 4 week 1), defined as the area under the INR versus time curve; change in peak plasma warfarin level; change in warfarin AUC (week 4 week 1), defined as the area under the plasma warfarin level versus time curve; and weekly vitamin K intake. The AUC was calculated on the basis of the trapezoidal rule by using measurements for days 1 through 7. We compared changes in peak INR, INR AUC, peak plasma warfarin level, and warfarin AUC between the ginseng and placebo groups by using the Wilcoxon rank-sum test. We calculated the difference in median changes between the 2 groups and corresponding 95% CIs according to the method described by Hollander and Wolfe (9), which is based on consideration of all pairwise differences between the 2 sets of observations. We calculated the Spearman rank correlation coefficients to examine the correlation between the change in peak INR and change in peak plasma warfarin levels. Repeated-measures analysis of variance (ANOVA) models were used to test differences in vitamin K intake between the groups and over time. A P value less than 0.05 was considered statistically significant. Stata, version 8 (Stata Corp., College Station, Texas), and Minitab, version 13 (Minitab, Inc., State College, Pennsylvania), were used for statistical analysis. Role of the Funding Sources The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results Data from all 20 patients (12 patients in the ginseng group and 8 patients in the placebo group) were used in the analysis. For the 6 men and 6 women in the ginseng group (7 patients were white, 3 patients were black, 1 patient was Hispanic, and 1 patient was Asian), the mean age and body weight (SD) were 30.2 7.2 years and 69.220.6 kg, respectively. For the 3 men and 5 women in the placebo group (3 patients were white, 2 patients were black, 2 patients were Hispanic, and 1 patient was Asian), the mean age and body weight (SD) were 24.3 4.0 years and 62.09.1 kg, respectively (Appendix Table). In both groups, INR generally reached peak levels on day 4 after 3 consecutive days of warfarin administration. The Figure shows changes in individual peak INR, INR AUC, peak plasma warfarin level, and warfarin AUC from weeks 1 to 4. The modest reduction in INR magnitude in the ginseng group was statistically significant compared with the change in the placebo group (P= 0.0012). Changes in INR AUC, peak plasma warfarin level, and warfarin AUC were also statistically significantly greater in the ginseng group. The Table summarizes results for the primary and secondary end points. Figure. Changes in individual peak international normalized ratio ( INR ), INR area under the curve ( AUC ), peak plasma warfarin level, and warfarin AUC in weeks 1 and 4 in American ginseng or placebo groups. A. P B. P C. P D. P Appendix Figure. Study flow chart showing American ginseng and placebo dosing and blood sample collection. Table. Changes in Peak International Normalized Ratio, International Normalized Ratio Area under the Curve, Peak Plasma Warfarin Level, and Warfarin Area under the Curve between Weeks 1 and 4 in American Ginseng and Placebo Groups Appendix Table. Patient Information For both peak warfarin level and AUC, the changes in the placebo group were not statistically significant and therefore probably reflected random variation in the small sample size. The Spearman rank correlation coefficient between changes in peak INR values and changes in peak warfarin levels was 0.72 (P< 0.001). One patient (patient 18) in the ginseng group had a high baseline INR (1.32) on day 1 compared with that in the other patients (mean INR [SD], 0.94 0.04). For this patient, peak INR after warfarin administration on day 4 was 5.16. After ginseng administration, the peak INR was 2.75 and the corresponding AUC decreased from 17.46 to 11.1. The patients peak plasma warfarin level also decreased from 1.6 g/mL during week 1 to 0.9 g/mL in week 4. If this patient is excluded from the analysis, the results remain statistically significant. No unusual medical or drug history or diet was noted for this patient. For weeks 1, 2, 3, and 4, average daily vitamin K intake (SD) for the ginseng group was 32.3 5.2 g/d, 42.6 7.6 g/d, 41.9 8.6 g/d, and 34.0 5.5 g/d, respectively. The average daily vitamin K intake (SD) for the placebo group for weeks 1, 2, 3, and 4 was 36.4 11.2 g/d, 32.0 8.4 g/d, 39.5 8.7 g/d, and 38.6 11.4 g/d, respectively. Vitamin K intake did not statistically significantly differ between the 2 groups (P> 0.2) or over time (P> 0.2). No adverse effects of clinical importance occurred in this study. Discussion Among the several different species of ginseng, the major active components are ginsenosides, which are a diverse group of steroidal saponins (3). Ginseng may promote bleeding in surgical patients (6). Ginsenosides prolonged both thrombin time and activated partial thromboplastin time in rats (10) and inhibited platelet aggregation in vitro in human platelets (11). In our healthy patients, however, ginseng reduced the anticoagulant effect of warfarin. We selected the commonly consumed American ginseng and a dose at the high end of the recommended range (12). Warfarin indirectly interferes with blood clotting by depressing the hepatic synthesis of vitamin Kdependent coagulation factors. The atte

Regional anesthesia in the anticoagulated patient: Defining the risks

Methylnaltrexone is a quaternary opioid antagonist with limited ability to cross the blood‐brain barrier that has the potential to antagonize the peripherally mediated gastrointestinal effects of opioids. In recent trials in human volunteers, we demonstrated that intravenous methylnaltrexone prevented morphine‐induced changes in gastroin‐testinal motility and transit, without affecting analgesia. In this study, 14 healthy volunteers were first given three ascending oral doses of methylnaltrexone to obtain safety and tolerance data (phase A study). In phase B, these subjects were then given single‐blind oral placebo and intravenous placebo, followed by randomized, double‐blind oral placebo and intravenous morphine (0.05 mg/kg) or oral methylnaltrexone (19.2 mg/kg, an established highest and safe dose based on previous administrations of two smaller doses of 0.64 mg/kg and 6.4 mg/kg in phase A) and intravenous morphine (0.05 mg/kg). Oral‐cecal transit time was assessed by the pulmonary hydrogen measurement technique after lactulose ingestion. Morphine significantly increased oral‐cecal transit time from 114.6 ± 37.0 minutes (mean ± SD) to 158.6 ± 50.2 minutes (p < 0.001). Oral methylnaltrexone (19.2 mg/kg) completely prevented morphine‐induced increase in oral‐cecal transit time (110.4 ± 45.0 minutes; not significant compared with baseline; p < 0.005 compared with morphine alone). These sessions were then followed by single‐blind evaluations of descending doses of methylnaltrexone. We observed that 6.4 mg/kg oral methylnaltrexone significantly attenuated the morphine‐induced delay in oral‐cecal transit time (p < 0.005 compared with morphine alone), and a dose‐dependent response was obtained. There was no correlation between oral methylnaltrexone effects on the transit time and the drug plasma concentration, suggesting direct preferential luminal effects of oral methylnaltrexone. Oral methylnaltrexone may have a clinical value in the prevention and treatment of constipation induced by long‐term opioid use.

American ginseng: potential structure-function relationship in cancer chemoprevention.

umerous studies have documented the safety of neuraxial anesthesia and analgesia in the anticoagulated patient. Patient management is based on ppropriate timing of needle placement and catheter removal relative to the iming of anticoagulant drug administration. Familiarity with the pharmacology f hemostasis-altering drugs, the clinical studies involving patients undergoing euraxial blockade while receiving these medications, as well as the case reports f spinal hematoma will guide the clinician in management decisions. New challenges in the management of the anticoagulated patient undergoing euraxial blockade have arisen as medical standards for the prevention of periperative venous thromboembolism were established. Likewise, as more efficaious anticoagulants and antiplatelet agents have been introduced, patient mangement has become more complex. In response to these patient safety issues, the merican Society of Regional Anesthesia and Pain Medicine (ASRA) convened its econd Consensus Conference on Neuraxial Anesthesia and Anticoagulation. It is mportant to note that although the consensus statements are based on a thorugh evaluation of the available information, in some cases, data are sparse. ariances from recommendations contained in this document may be acceptable ased on the judgment of the responsible anesthesiologist. The consensus stateents are designed to encourage safe and quality patient care, but cannot guarntee a specific outcome. They are also subject to timely revision as justified by volution of information and practice. Finally, the current information focuses on