Sorting and Elaborating on the Combination Theory of Herb Pairs / 中医杂志

@#As the smallest combination unit of Chinese medicinals， herbal pairs serve as the bridge between medicinals and formulas， whose combination theory reflects the basic characteristics of Chinese medicinals combination and the core essence of prescription composition. Simultaneously， as a key combination of medicinals in clinical treatment of diseases， syndromes， and symptoms， herbal pairs are the main form of clinical medication in traditional Chinese medicine （TCM） as well as the characteristic advantage of treating diseases. This article summarized that “mutual complement of medicinals of same or antagonism flavor and nature” theory is the theoretical origin， and efficacy-enhancement and toxicity-attenuation is the core purpose of the combination of herbal pairs. The property theory of Chinese medicinals and the thought of differentiation and treatment are the main basis of the combination of herbal pairs， and pertinence and flexibility are the key points in clinical application. All mentioned above are expected to provide theoretical guidance for the clinical use and modern research of herbal pairs.

The dietary supplement of Ginkgo biloba: a comprehensive review of its potential interactions based on pre-clinical and clinical evidences / El suplemento dietético de Ginkgo biloba: una revisión exhaustiva de sus posibles interacciones basada en evidencias clínicas y preclínicas

This review present Gingko biloba (GB) interactions, based on clinical and pre-clinical presentations. Literature was retrieved using databases; ScienceDirect, PubMed, Google scholar, Web of Science, Scopus etc. 14/45 interactions were found with clinical presentations. More interactions (80%) were reported with drugs followed by herbs (11.1%), and nutraceuticals (6.7%) with major mechanisms of interaction observed as; inhibition of Cytochrome metabolizing enzymes (44.4%) and platelet-activating factor (PAF) i.e. 15.6%. Major clinical features were; increased bleeding (eye, parietal), hematomas (subdural), and seizures as well as increased blood pressure, priapism, loss of infection/antiviral failure, and coma. Drugs with major interactions belonged to anti-platelet/anti-coagulant and NSAIDs. Synergistic effects were observed for GB vs herbs (except cannabis which showed rhabdomyolysis), foods, and nutraceuticals (except pyridoxine where neurotoxicity was seen). GB use should be monitored and the patient may seek proper advice from a healthcare professional.

Esta revisión presenta las interacciones de Gingko biloba (GB), basadas en presentaciones clínicas y preclínicas. La literatura se recuperó utilizando bases de datos; ScienceDirect, PubMed, Google Scholar, Web of Science, Scopus, etc. Se encontraron 14/45 interacciones con presentaciones clínicas. Se informaron más interacciones (80%) con fármacos seguidos de hierbas (11,1%) y nutracéuticos (6,7%) con los principales mecanismos de interacción observados como; inhibición de las enzimas metabolizadoras del citocromo (44,4%) y factor activador de plaquetas (PAF), es decir, 15,6%. Las principales características clínicas fueron; aumento de sangrado (ojo, parietal), hematomas (subdural) y convulsiones, así como aumento de la presión arterial, priapismo, pérdida de infección / insuficiencia antiviral y coma. Los fármacos con interacciones importantes pertenecían a los antiplaquetarios/anticoagulantes y los AINE. Se observaron efectos sinérgicos para GB frente a hierbas (excepto cannabis que mostró rabdomiólisis), alimentos y nutracéuticos (excepto piridoxina donde se observó neurotoxicidad). Se debe controlar el uso de GB y el paciente puede buscar el asesoramiento adecuado de un profesional de la salud.

Jugos de fruta y productos herbáceos como perpetradores de interacciones farmacocinéticas mediadas por enzimas metabolizadoras y transportadores de membrana. Relevancia en clínica / Pharmacokinetic interactions of fruit juices and herbal preparations

Drug disposition in the human body is strongly influenced by transporters and metabolizing enzymes expressed in key organs including intestine, liver and kidney. Since drugs and chemicals present in foods such as fruit juices and herb-based products are substrates of the above-mentioned proteins, there is a high probability of pharmacokinetic interactions. Findings from preclinical and clinical studies helped to characterize the mechanisms by which the components of fruit juices and herbs act as perpetrators of pharmacokinetic interactions. The aim of this review is to provide an overview of pharmacokinetic fruit juice- and herb-drug interactions that could be relevant in the clinical setting.

Intravenous lipid emulsion therapy for cardiac arrest and refractory ventricular tachycardia due to multiple herb intoxication

Herbal products have been used for therapeutic purposes for a long time. However, many herbs can be toxic and even life-threatening. If refractory ventricular tachycardia (VT) is caused by herbal products and shows no response to conventional therapy, intravenous lipid emulsion (ILE) therapy can be considered. We report a case of herbal intoxication leading to refractory VT, which was successfully treated with ILE therapy. A 36-year-old woman with aplastic anemia presented with mental changes. She had taken an unknown herbal decoction three days before visiting the hospital. Soon after coming to the hospital, she went into cardiac arrest. Cardiopulmonary resuscitation was performed, and return of spontaneous circulation with VT was achieved. Synchronized cardioversion was then performed and amiodarone was administered. However, VT with pulse continued, so ILE therapy was attempted, which led to the resolution of VT.

Traditional Chinese medicine: herb-drug interactions with aspirin

Traditional Chinese medicine (TCM)-based herbal therapies have gained increasing popularity worldwide, raising concerns of its efficacy, safety profile and potential interactions with Western medications. Antithrombotic agents are among the most common prescription drugs involved in herb-drug interactions, and this article focused on aspirin, one of the most widely used antiplatelet agents worldwide. We discussed herbs that have potential interactions by exploring Western and TCM approaches to thrombotic events. Common TCM indications for these herbs were also highlighted, including possible scenarios of their concurrent usage with aspirin. With greater awareness and understanding of potential herb-drug interactions, TCM and Western physicians may collaborate more closely to identify, treat and, most importantly, prevent adverse drug events.

Effect of Puerarin on the Pharmacokinetics of Baicalin in Gegen Qinlian Decoction () in Mice / 中国结合医学杂志

<p><b>OBJECTIVE</b>To study the pharmacokinetics of puerarin (PUE) in Gegen Qinlian Decoction (, GQD), and the effects of PUE dosage variations on the pharmacokinetics of baicalin (BAL) in mice.</p><p><b>METHODS</b>GQD is composed of the concentrated granules of four Chinese herbs. Three dosages with different levels of PUE, including GQD, GQD co-administered with PUE, and GQD co-administration with two times the amount of PUE, were used to research the pharmacokinetics of PUE and BAL in mice. The indirect competitive enzyme-linked immunosorbent assay (icELISA) methods based on an anti PUE-monoclonal antibody (MAb)and BAL-MAb were employed to determine the concentration of PUE and BAL in mice blood.</p><p><b>RESULTS</b>After the co-administration of GQD with PUE, the area under the curves (AUC) of PUE increased 2.8 times compared with GQD. At the dose of GQD co-administration at two times that of PUE, the (AUC) of PUE was almost equal to that of GQD co-administration of PUE, showing non-linear pharmacokinetics. The (AUC) of BAL showed a good dose-related increase of PUE (r=0.993) in the range from 100 to 300 mg/kg, indicating that PUE dramatically affects the absorption of BAL in mice. There was no significant difference in the other pharmacokinetic parameters, such as the first time of maximum concentration (T), the second T, or the mean residence time.</p><p><b>CONCLUSIONS</b>The icELISA methods were successfully applied to pharmacokinetic studies of PUE and BAL in GQD in mice. The dosage variability of PUE of the main ingredient in GQD affects its own pharmacokinetic characteristics and the absorption characteristics of BAL.</p>

Atractylodes lancea rhizome water extract reduces triptolide-induced toxicity and enhances anti-inflammatory effects / 中国天然药物

The present study was designed to explore the influence of water extracts of Atractylodes lancea rhizomes on the toxicity and anti-inflammatory effects of triptolide (TP). A water extract was prepared from A. lancea rhizomes and co-administered with TP in C57BL/6 mice. The toxicity was assayed by determining serum biochemical parameters and visceral indexes and by liver histopathological analysis. The hepatic CYP3A expression levels were detected using Western blotting and RT-PCR methods. The data showed that the water extract of A. lancea rhizomes reduced triptolide-induced toxicity, probably by inducing the hepatic expression of CYP3A. The anti-inflammatory effects of TP were evaluated in mice using a xylene-induced ear edema test. By comparing ear edema inhibition rates, we found that the water extract could also increase the anti-inflammatory effects of TP. In conclusion, our results suggested that the water extract of A. lancea rhizomes, used in combination with TP, has a potential in reducing TP-induced toxicity and enhancing its anti-inflammatory effects.

The effect of Korean traditional alternative medicine products on thyroid function level in post-total thyroidectomy patients: A pilot study

PURPOSE: Although many Koreans consume traditional alternative remedial products to alleviate symptoms of fatigue, there have been no studies on their effect on thyroid function levels in thyroidectomized patients on levothyroxine replacement. The aim of this study was to assess the effect of Korean traditional alternative remedies on thyroid function levels in post total thyroidectomy patients.METHODS: A retrospective review of medical records from a single tertiary referral center was performed on patients who received total thyroidectomy from 2010 to 2015 and became euthyroid postoperatively. Gender, age, body mass index, preoperative thyroid function test results, interval to first hypothyroidism occurrence, recurrence of hypothyroidism, number and types of alternative remedy were evaluated.RESULTS: Postoperative hypothyroidism occurred among 174 out of 917 patients (18.9%) and 100 (57.5%) of them had a history of alternative medication usage. The first episode of hypothyroidism occurred at median of 38.5 months after operation in the 100 patients. Six of the 100 patients received an increased dosage of levothyroxine due to severe hypothyroidism but the rest received the same dose and were requested not to consume alternative products. All patients recovered to euthyroid status afterwards. Thirty-three patients subsequently experienced recurrence even after being restricted from consuming alternative remedial products. Apart from thyroiditis on pathology reports (P=0.001), there were no variables significantly related to the recurrent hypothyroidism.CONCLUSION: This pilot study demonstrated the possible role of consumption patterns of traditional alternative remedial products in thyroidectomized patients under hormone supplement in restoring euthyroid status without levothyroxine increase.

Effect of chongmyungtang, a traditional Korean polyherbal formula, on the Pharmacokinetic profiles of donepezil in rats

Chongmyungtang [CMT] is a famous Korean herbal medicine for improving learning and memory, which has been reported to have anti-cholinergic and neuroprotective effects. Therefore, drug-drug interactions were examined between CMT and donepezil as a first screening of combination therapy for cognitive deficits. Rats received oral coadministration of donepezil with distilled water as a control or donepezil with CMT as a combination. The distilled water or CMT was co-administered at intervals within 5min after donepezil or 1.5h intervals. The plasma samples were analyzed for donepezil concentration and its pharmacokinetic parameters of T[max], C[max], AUC, t[1/2] and MRT[inf]. In the single co-administration at intervals within 5min, donepezil was detected lower in the combination than control at 0.5h and 2h post-treatment [P<0.05]. In addition, the combination showed significant increases in MRT[inf] compared to the control [P<0.05]. This suggests drug-drug interactions between donepezil and CMT in the co-administration within 5 min. However, no meaningful differences were found in the pharmacokinetic profiles of donepezil by single dosing with CMT at 1.5h intervals and even by the repeated dosing for a week at 1.5h intervals potential combination therapy of donepezil with CMT

Effect of traditional Chinese medicine for treating human immunodeficiency virus infections and acquired immune deficiency syndrome: Boosting immune and alleviating symptoms / 中国结合医学杂志

To respond to the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) epidemic in China, the integration of antiretroviral therapy (ART) and traditional Chinese medicine (TCM) has important implications in health outcomes, especially in China where the use of TCM is widespread. The National Free TCM Pilot Program for HIV Infected People began in 5 provinces (Henan, Hebei, Anhui, Hubei, and Guangdong) in 2004, and quickly scaled up to 19 provinces, autonomous regions, and municipalities in China including some places with high prevalence, 26,276 adults have been treated thus far. Usually, people with HIV infection seek TCM for four main reasons: to enhance immune function, to treat symptoms, to improve quality of life, and to reduce side effects related to medications. Evidences from randomized controlled clinical trials suggested some beneficial effects of use of traditional Chinese herbal medicine for HIV infections and AIDS. More proofs from large, well-designed, rigorous trials is needed to give firm support. Challenges include interaction between herbs and antiretroviral drugs, stigma and discrimination. The Free TCM Program has made considerable progress in providing the necessary alternative care and treatment for HIV-infected people in China, and has strong government support for continued improvement and expansion, establishing and improving a work mechanism integrating Chinese and Western medicines.

Decreased absorption of midazolam in the stomach due to low pH induced by co-administration of Banha-sasim-tang

OBJECTIVES: Banha-sasim-tang (BST), which consists of seven different herbs, is one of the most popular herbal formulae for treating gastrointestinal disorders in Eastern Asia. The commonly used herbal medicine is often co-administered with other therapeutic drugs, which raises the possibility of herb–drug interactions and may modify the clinical safety profile of therapeutic drugs. METHODS: We investigated the potential herb–drug interactions between BST extract and midazolam (MDZ) in mice. The area under the plasma concentration-time curve (AUC) of MDZ and 1ʹ-hydroxymidazolam (1ʹ-OH-MDZ) was evaluated for both oral and intraperitoneal administration of MDZ, following oral administration of BST (0.5 and 1 g/kg). RESULTS: It was found that the AUC of MDZ and 1ʹ-OH-MDZ was lower in case of oral administration of MDZ. Administration of BST extract was not associated with hepatic cytochrome P450 activity. BST extract induced a strong reduction in pH and it has been reported that oral mucosal absorption of MDZ is lower at low pH. The decreased absorption rate of MDZ might be caused by the ingredients of BST and may not be related to other factors such as increased excretion of MDZ by P-glycoprotein. CONCLUSIONS: The altered pharmacokinetics of midazolam caused by co-administration with BST in vivo could be attributed to a decrease in pH and subsequent reduction of MDZ absorption rate.

Effects of diammonium glycyrrhizinate on hepatic and intestinal UDP-Glucuronosyltransferases in rats: Implication in herb-drug interactions / 中国天然药物

Glycyrrhizin is a major bioactive component of liquorice, which exerts multiple biochemical and pharmacological activities and is frequently used in combination with other drugs in the clinic. Mycophenolate mofetil (MMF), an immunosuppressant widely used in transplant patients, is metabolized by UDP-glucuronyltransferases (UGTs). Although significant evidence supports that glycyrrhizin could interact with the cytochrome P450s (CYPs), few studies have addressed its effects on UGTs. The present study aimed at investigating the regulatory effects of diammonium glycyrrhizinate (GLN) on UGTs in vitro and in vivo. We found that long-term administration of GLN in rats induced overall metabolism of MMF, which might be due to the induction of UGT1A protein expression. Hepatic UGT1A activity and UGT1A mRNA and protein expression were significantly increased in GLN-treated rats. UGT1A expression levels were also increased in the intestine, contradicting with the observed decrease in intestinal UGT1A activities. This phenomenon may be attributed to different concentrations of glycyrrhetinic acid (GA) in liver and intestine and the inhibitory effects of GA on UGT1A activity. In conclusion, our study revealed that GLN had multiple effects on the expression and activities of UGT1A isoforms, providing a basis for a better understanding of interactions between GLN and other drugs.

Potential herb-drug interaction in the prevention of cardiovascular diseases during integrated traditional and Western medicine treatment / 中国结合医学杂志

The combination of herbs and drugs is one of the most important approaches in the prevention and treatment of diseases in the integrated traditional and Western medicine (ITWM). While most medical practices have proved that the combination of herbs and drugs led to a clinical efficacy that was often superior to merely using only one of them; results from some studies have triggered adverse reactions to such an approach. Since few herb-drug interaction studies were carried out during treatments combining herbs and drugs, it really restricts the development of treatment and treatment theory of the combination of herbs and drugs. Given that herb-drug interactions may occur through the main pathway of cytochrome P450 enzymes and transporters; then to exhaustively study the role and impact of herbs in drug metabolism, as well as to establish a corresponding database, is of great significance for guiding the rational combination of herbs and drugs. When the herb-drug interaction information platform is implemented, we would get at ease a reasonable herb-drug prescription to achieve a better outcome, reduce dosage of some expensive drugs preserving the same efficacy, or even reduce some side effects of particular drugs; which might also promote the dynamic combination of Chinese and Western medicine, and accelerate the theory development of ITWM.

Interaction between warfarin and Chinese herbal medicines

In traditional Chinese medicine (TCM), the human body is divided into Yin and Yang. Diseases occur when the Yin and Yang balance is disrupted. Different herbs are used to restore this balance, achieving the goal of treatment. However, inherent difficulties in designing experimental trials have left much of TCM yet to be substantiated by science. Despite that, TCM not only remains a popular form of medical treatment among the Chinese, but is also gaining popularity in the West. This phenomenon has brought along with it increasing reports on herb-drug interactions, beckoning the attention of Western physicians, who will find it increasingly difficult to ignore the impact of TCM on Western therapies. This paper aims to facilitate the education of Western physicians on common Chinese herbs and raise awareness about potential interactions between these herbs and warfarin, a drug that is especially susceptible to herb-drug interactions due to its narrow therapeutic range.

Effects of Ayurvedic Rasayana botanicals on CYP3A4 isoenzyme system / 中西医结合学报

<p><b>OBJECTIVE</b>Consuming botanical dietary supplements or herbal drugs along with prescription drugs may lead to potential pharmacokinetic-pharmacodynamic (PK-PD) herb-drug interactions (HDI). The present study focuses on the importance of and novel approach for assessing HDI in integrative medicine with case examples of two frequently-used Ayurvedic Rasayana botanicals.</p><p><b>METHODS</b>The aqueous extracts of Asparagus racemosus (ARE) and Gymnema sylvester (GSE) were prepared as per Ayurvedic Pharmacopoeia of India. Chemoprofiling of these extracts was done using high-performance liquid chromatography (HPLC). Additionally, ARE was characterized for the presence of shatavarins IV and I using HPLC & mass spectroscopy respectively. Effects of ARE and GSE were investigated on rat liver microsome using testosterone probe drug assay. The changes in formation of metabolite (6-β hydroxy testosterone) were monitored on incubation of testosterone alone, testosterone with ketoconazole, ARE and GSE using HPLC. Half inhibitory concentration (IC50) was used to predict plausible HDI.</p><p><b>RESULTS</b>ARE and GSE showed no inhibition with IC50 values >1 000 μg/mL while the standard inhibitor ketoconazole completely abolished CYP3A4-dependent activity at 0.531 μg/mL and IC50 was found to be 0.036 μg/mL.</p><p><b>CONCLUSION</b>ARE and GSE prepared as per Ayurvedic Pharmacopoeia of India were found to be safe for CYP3A4-mediated inhibitory HDI in rats. Our in vitro study suggests the need of further in vivo investigation for HDI in order to provide clinical relevance.</p>

Advances in the study of enzymes and transporters-mediated pharmacokinetic mechanism for herb-drug interaction / 药学学报

With the wide application of Chinese herbal medicine, herb-drug interaction (HDI) has become increasingly prominent. Metabolic enzymes and transporters are the main targets of HDI, because the changes in expression and function of enzymes and transporters can influence the disposition of drugs. Metabolic enzymes are responsible for the metabolic clearance of drugs, including cytochrome P450 (CYP), UDP-glucuronyl transferase (UGT) and sulfotransferases (SULT); transporters widely expressed in the intestine, kidney, liver and brain are involved in the oral absorption, distribution and excretion of drugs. Pueraria, ginkgo, ginseng, St. John's wort and other Chinese herbal medicine often induce a HDI because those herbal medicines combined with chemical medicine are widely used in clinic. The components of herb medicines mentioned above are prone to interact with enzymes and transporters, which often induce a HDI. This paper reviews the advances in the study of enzymes and transporters-mediated pharmacokinetic mechanism of HDI.

Pre-treatment with puerarin affects pharmacokinetics of warfarin, but not clopidogrel, in experimental rats / 中国天然药物

The present study was designed to determine the effects of puerarin pre-treatment on the pharmacokinetics of the oral anticoagulant agent warfarin and the antiplatelet agent clopidogrel in rats. In the treatment group, rats was gavaged with warfarin or clopidogrel after repeated treatment with puerarin at intraperitoneal doses of 20, 60, or 200 mg·kg(-1) for 7 days, while rats in the control group were administrated only with the same dose warfarin or clopidogrel. Plasma samples were obtained at the prescribed times and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). The results showed that rats treated with puerarin at all the test doses of 20, 60 and 200 mg·kg(-1) were found to affect the pharmacokinetics of warfarin, but not clopidogrel, suggesting a potential herb-drug interaction between puerarin and warfarin.

Effects of Baicalin on Oral Pharmacokinetics of Caffeine in Rats

Scutellaria baicalensis is one of the most widely used herbal medicines in East Asia. Because baicalein and baicalin are major components of this herb, it is important to understand the effects of these compounds on drug metabolizing enzymes, such as cytochrome P450 (CYP), for evaluating herb-drug interaction. The effects of baicalin and baicalein on activities of ethoxyresorufin O-deethylase (EROD), methoxyresorufin O-demethylase (MROD), benzyloxyresorufin O-debenzylase (BROD), p-nitrophenol hydroxylase and erythromycin N-demethylase were assessed in rat liver microsomes in the present study. In addition, the pharmacokinetics of caffeine and its three metabolites (i.e., paraxanthine, theobromine and theophylline) in baicalin-treated rats were compared with untreated control. As results, EROD, MROD and BROD activities were inhibited by both baicalin and baicalein. However, there were no significant differences in the pharmacokinetic parameters of oral caffeine and its three metabolites between control and baicalin-treated rats. When the plasma concentration of baicalin was determined, the maximum concentration of baicalin was below the estimated IC50 values observed in vitro. In conclusion, baicalin had no effects on the pharmacokinetics of caffeine and its metabolites in vivo, following single oral administration in rats.

Effects of Ziziphus jujuba fruit extracts on cytochrome P450 (CYP1A2) activity in rats / 中国天然药物

Drug-drug interactions have become a serious problem in the clinic, since plant-based medicines are extensively used. The present study investigated the effects of Ziziphus jujuba fruit (ZJ) extract on the pharmacokinetics of phenacetin, a typical substrate of a cytochrome P450 enzyme CYP 1A2, in rats. The rats were pretreated with the water extract (1.0 g · kg(-1)) or the ethanolic extract (3.6 g · kg(-1)) of ZJ for 10 days, and the pharmacokinetics of phenacetin was investigated after intravenous administration. In an in vitro assay, acetaminophen formation in the hepatic microsomes of ZJ-treated rats was investigated to assess CYP1A2 activity. Our results demonstrated that the treatment with the water and ethanolic extracts of ZJ decreased the plasma concentration of phenacetin and increased the plasma concentration of acetaminophen, resulting in a 43.2% and 15.5% reduction in the AUC0-120 of phenacetin, respectively, and a 53.2% and 64.9% increase in the AUC0-120 of acetaminophen, respectively after intravenous administration. The water or ethanolic extract of ZJ significantly increased the clearance of phenacetin and acetaminophen formation in hepatic microsomes. In conclusion, ZJ extracts displayed effects on the pharmacokinetics of phenacetin and increased the CYP1A2 activity in rats. Therefore, precaution on drug-drug interactions should be taken when ZJ is co-administered with drugs metabolized by CYP1A2, which may result in decreased concentrations of these drugs.

Review of the regulations for clinical research in herbal medicines in USA / 中国结合医学杂志

In 2012, USA Food and Drug Administration (FDA) approved 39 new drugs, however, there are only two botanical drugs (one topical and one oral) approved by FDA since the publication of the FDA's industry guidelines for the botanical drug product in June 2004. The approval shows the Western guideline can be used for herbal medicines, authors investigate current regulation on herbal medicine clinical research, identify challenges conducting clinical trials, and seek to produce some guidance for potential investigators and sponsors considering a clinical trial in this area. Key words were formulated for searching on Medline and FDA website to locate relevant regulations for clinical research in herbal medicines to understand current environment for herbal medicine usage and examine the barriers affecting herbal medicine in clinical trials. Authors critically explore case study of the 1st FDA approved botanical drugs, Veregen (sinecatechins), green tea leaves extract, a topical cream for perianal and genital condyloma. In consideration of current regulation environment in USA, based on the findings and analysis through the literature review and Veregen case study, authors produce and propose a Checklist for New Drug Application of Herbal Medicines for potential investigators and sponsors considering in a herbal medicine clinical trial.