Herbal Science Research - interaction

[Oral anticoagulants: a literature review of herb-drug interactions or food-drug interactions]

Site Editor — Fri, 02 Nov 2007 15:44:55 -0700

[Oral anticoagulants: a literature review of herb-drug interactions or food-drug interactions]: J Pharm Belg. 2007; 62(3): 69-75 Bourget S, Baudrant M, Allenet B, Calop J

OBJECTIVE: To identify herbal medicines and food products which can interact with anticoagulant therapy. MATERIAL AND METHOD: Literature review using key words: "anticoagulants", "herb-drug interaction", "food-drug interaction", "drug chinese herbal", "medicine herbal", "plant preparation", "dietary supplements". Data sources: Medline (january 1966 to june 2006) and Pascal (1987 to 2006). Case reports, systematic reviews, in vitro studies, clinical studies published in french or in english (or with an english extract) have been undertaken. RESULTS: Eighty articles were selected (two both including a case report and a study): 14 systemic review, 43 case reports, 25 studies (17 studies in humans: nine randomized and controlled, three controlled), six controlled studies in animals and two in vitro studies. DISCUSSION: A wide range of herbal medicines and food products can interact with anticoagulants. Clinical relevance of these effects is difficult to characterise (nature of existing reports, contradiction between studies, difficult extrapolation to human). CONCLUSION: It is difficult to predict the incidence or severity of such interactions. However, awareness of these potential interactions is necessary to achieve optimal anticoagulation therapy: pharmacist can play a crucial role identifying such interactions in case of disturbed INR; clinicians should be informed to monitor closely the therapy, particularly when such products are started or discontinued.

An examination of the bleeding complications associated with herbal supplements, antiplatelet and anticoagulant medications.

Site Editor — Thu, 04 Oct 2007 05:45:22 -0700

An examination of the bleeding complications associated with herbal supplements, antiplatelet and anticoagulant medications.: J Dent Hyg. 2007;81(3):67 Authors: Spolarich A, Andrews L

Dental professionals routinely treat patients taking prescription, nonprescription, and herbal medications that are known or have the potential to alter bleeding. Prescription anticoagulant and antiplatelet medications, as well as over-the-counter drugs such as aspirin, are typically taken to reduce the risk of thromboembolic events, including stroke. Herbal supplements are widely used for a variety of indications, and both patients and health care practitioners are often unaware of the anticoagulant and antiplatelet effects that occur as either predictable pharmacologic effects or adverse side effects of herbal medicines. In addition, patient use of these herbal supplements is usually undisclosed to health care providers. The purpose of this literature review is to examine the mechanisms of action of drugs and herbs that alter bleeding, and to educate dental professionals as to the proper care and management of patients using these medications. Decision-making strategies, including interpretation of laboratory tests, and when to discontinue the use of these medications are discussed. Patients undergoing routine dental and dental hygiene procedures do not need to discontinue the use of anticoagulant and antiplatelet medications. However, alterations in drug use may be required for those patients undergoing invasive surgical procedures. It is recommended that herbal supplements must be discontinued 2 weeks prior to receiving invasive surgical procedures. Dental practitioners must learn to weigh the risks of discontinuing drug therapy against the potential risks to patients, and implement risk reduction strategies to minimize adverse bleeding complications associated with dental treatment.

PMID: 17908423 [PubMed - in process]

Dietary supplements, herbs and oral anticoagulants: the nature of the evidence.

Site Editor — Thu, 04 Oct 2007 05:43:54 -0700

Dietary supplements, herbs and oral anticoagulants: the nature of the evidence.: J Thromb Thrombolysis. 2007 Sep 29; Authors: Wittkowsky AK

In the US, the use of dietary supplements, including vitamins, minerals, amino acids, and herbal products, is extensive. Nonetheless, the majority of patients report that they have little information about the risks, benefits, and adverse effects of medicines, or about their potential interactions with prescription drugs. Patients taking warfarin are at particular risk of interactions with dietary supplements, yet approximately 30% use herbal or natural product supplements on a regular basis. No current governmental regulations or voluntary programs address dietary supplement interactions with prescription drugs. Case reports represent the majority of the evidence surrounding drug interactions between warfarin and dietary supplements. Those of the highest quality include, as an assessment of causality, a modification of the recently published Drug Interaction Probability Scale. Despite positive case reports, formal drug interaction studies are often negative, suggesting that numerous patient-specific influences other than the suspected interaction alone may be responsible for a particular observation. The cranberry-juice/warfarin interaction is a recent example of such a discrepancy. Healthcare providers can play an active role in improving quantity and the quality of case reports of interactions involving warfarin and dietary supplements. A registry of anticoagulant interactions with dietary supplements has been proposed, and is currently being developed through Clotcare Online Resource ( http://www.clotcare.com ). The goal of this registry is to obtain high quality case-based evidence of drug interactions between anticoagulants and dietary supplements, to define these interactions based on clinical and monitoring outcomes, and to analyze likelihood of causation using a modification of the Drug Interaction Probability Scale.

PMID: 17906915 [PubMed - as supplied by publisher]

[Effect of chinese herbs in enhancing prednisone for treatment of refractory rheumatoid arthritis]

Site Editor — Sat, 22 Sep 2007 18:15:33 -0700

[Effect of chinese herbs in enhancing prednisone for treatment of refractory rheumatoid arthritis]: Zhongguo Zhong Xi Yi Jie He Za Zhi. 2007 Aug; 27(8): 742-4 Liu W, Liu XY, Wang Y

OBJECTIVE: To investigate the Chinese herbal medicine in enhancing effect of prednisone for treatment of refractory rheumatoid arthritis (RA). METHODS: One hundred and twenty patients with refraetory RA were assigned to two groups, the treated group was orally administered with Qingbi Tablet, a patent Chinese herbal preparation formulated based on the clearing heat and removing toxic substances principle, and the control group was treated with intramuscular injection of amethopterin (MTX), oral intake of voltaren 75 mg and hydroxychloroquine 0.2 g once a day. Besides prednisone was given to all patients orally, the initiating dosage used in the treated group was lesser than that in the control group. The clinical index, dosage and adverse reaction of prednisone were recorded every 2 weeks. RESULTS: The curative effect evaluated by American College of Rheumatology (ACR) standard showed no statistical difference between the two groups (P > 0.05). Either clinical or laboratory indexes were improved significantly in both groups (P < 0.05), but the improvement in resting pain, patient's self-evaluation and doctor's evaluation in the treated group were better than those in the control group, showing statistical difference (P < 0.05). The 20-week total amount of prednisone used in the treated group was less than that in the control group (32,935 mg vs. 51,170 mg), while the dosage of prednisone used in various observation time points between the two groups was also significantly different respectively (P < 0.05), the former was less than the latter. CONCLUSION: Chinese herbal medicine can enhance the effect of prednisone in patients of refractory RA and alleviate the adverse reactions of prednisone.

Research on biomodulatory effect of natural compounds.

Site Editor — Mon, 11 Jun 2007 06:20:26 -0700

Research on biomodulatory effect of natural compounds.: Neuro Endocrinol Lett. 2006 Dec;27 Suppl 2:53-6 Authors: Miadoková E, Nadová S, Trebatická M, Grolmus J, Kopásková M, Rauko P, Mucaji P, Grancai D

OBJECTIVES: The purpose of this study was to determine whether the extract isolated from the artichoke Cynara cardunculus L. (ECC) had antimutagenic effect and was able to enhance the therapeutic effect of cytostatic drug cis-platinum (cis-Pt). METHODS: The potential antimutagenic activity of ECC was assayed by a test on sex-linked recessive lethal mutations detection in Drosophila melanogaster males treated with ethylmethane sulfonate (EMS). The possible enhancement of cytostatic/cytotoxic effect of cis-Pt by ECC was evaluated in the cell revitalization assay by measuring cell viability via Trypan blue exclusive assay using mouse leukemia cells L1210. RESULTS: EMS was both toxic and genotoxic in D. melanogaster males. It statistically significantly increased the frequency of sex-linked recessive lethal mutations in comparison to the negative control. Furthermore, ECC statistically significantly reduced the genotoxic effect of EMS. It acted in a desmutagenic manner via EMS inactivation. In the cell revitalization assay, ECC enhanced the cytotoxic/cytostatic effect of cis-Pt. The therapeutic potential of ECC was established on the basis of statistically significantly lowered recovery of cis-Pt pre-treated mouse leukemia cells in the presence of ECC. CONCLUSIONS: The results imply that the extract isolated from artichoke C. cardunculus L. has marked beneficial activities antimutagenic and therapeutic effect enhancing) and its potential biomedical application in the combination therapy of cancer and some neurodegenerative diseases may be suggested.

Role of P-glycoprotein in the intestinal absorption of glabridin, an active flavonoid from the root of Glycyrrhiza glabra.

Site Editor — Mon, 11 Jun 2007 06:19:10 -0700

Role of P-glycoprotein in the intestinal absorption of glabridin, an active flavonoid from the root of Glycyrrhiza glabra.: Drug Metab Dispos. 2007 Apr;35(4):539-53 Authors: Cao J, Chen X, Liang J, Yu XQ, Xu AL, Chan E, Wei D, Huang M, Wen JY, Yu XY, Li XT, Sheu FS, Zhou SF

Glabridin is a major constituent of the root of Glycyrrhiza glabra, which is commonly used in the treatment of cardiovascular and central nervous system diseases. This study aimed to investigate the role of P-glycoprotein (PgP/MDR1) in the intestinal absorption of glabridin. The systemic bioavailability of glabridin was approximately 7.5% in rats, but increased when combined with verapamil. In single-pass perfused rat ileum with mesenteric vein cannulation, the permeability coefficient of glabridin based on drug disappearance in luminal perfusates (P(lumen)) was approximately 7-fold higher than that based on drug appearance in the blood (P(blood)). Glabridin was mainly metabolized by glucuronidation, and the metabolic capacity of intestine microsomes was 1/15 to 1/20 of that in liver microsomes. Polarized transport of glabridin was found in Caco-2 and MDCKII monolayers. Addition of verapamil in both apical (AP) and basolateral (BL) sides abolished the polarized transport of glabridin across Caco-2 cells. Incubation of verapamil significantly altered the intracellular accumulation and efflux of glabridin in Caco-2 cells. The transport of glabridin in the BL-AP direction was significantly higher in MDCKII cells overexpressing PgP/MDR1 than in the control cells. Glabridin inhibited PgP-mediated transport of digoxin with an IC(50) value of 2.56 microM, but stimulated PgP/MDR1 ATPase activity with a K(m) of 25.1 microM. The plasma AUC(0-24h) of glabridin in mdr1a(-/-) mice was 3.8-fold higher than that in wild-type mice. These findings indicate that glabridin is a substrate for PgP and that both PgP/MDR1-mediated efflux and first-pass metabolism contribute to the low oral bioavailability of glabridin.

Differences in perceived risks and benefits of herbal, over-the-counter conventional, and prescribed conventional, medicines [..

Site Editor — Wed, 06 Jun 2007 00:18:00 -0700

Differences in perceived risks and benefits of herbal, over-the-counter conventional, and prescribed conventional, medicines, and the implications of this for the safe and effective use of herbal products.: Complement Ther Med. 2007 Jun; 15(2): 84-91. Authors: Lynch N, Berry D

OBJECTIVES: To investigate people's views about the efficacy and specific risks of herbal, over-the-counter (OTC) conventional, and prescribed conventional medicines, and their likelihood of taking a second (herbal or OTC conventional) product in addition to a prescribed medicine. METHODS: Experiment 1 (1 factor within-participant design); Experiment 2 (1 factor between-participant design). Convenience samples of general population were given a hypothetical scenario and required to make a number of judgements. RESULTS: People believed herbal remedies to be less effective, but less risky than OTC and prescribed conventional medicines. Herbal medicines were not seen as being safer simply because of their easier availability. Participants indicated that they would be more likely to take a herbal medicine than a conventional OTC medicine in addition to a prescribed medicine, and less likely to consult their doctor in advance. CONCLUSION: People believe that herbal medicines are natural and relatively safe and can be used with less caution. People need to be given clear information about the risks and benefits of herbal medicines if they are to use such products safely and effectively.

Effect of valerian, valerian/hops extracts, and valerenic acid on glucuronidation in vitro.

Site Editor — Wed, 06 Jun 2007 00:10:24 -0700

Effect of valerian, valerian/hops extracts, and valerenic acid on glucuronidation in vitro.: Xenobiotica. 2007 Feb;37(2):113-23 Authors: Alkharfy KM, Frye RF

Valerian preparations alone or in combination with hops are popular over-the-counter products used for sleep disturbances or anxiety. Therefore, it is important to characterize the effect of these products on the activity of human drug-metabolizing enzymes. The inhibitory effects of valerian and valerian/hops extracts as well as valerenic acid (a major constituent of valerian) on glucuronidation were evaluated in human liver microsomes and with expressed uridine 5'-diphosphate (UDP)-glucuronosyltransferases (UGT). Methanolic extracts of two herbal preparations caused significant reductions in the rate of formation of acetaminophen, oestradiol, morphine, and testosterone glucuronides. Oestradiol glucuronidation at the 3-hydroxy position was inhibited by nearly 87% in microsomal incubations. In addition, marked reductions in UGT1A1 and UGT2B7 activities were observed in the presence of the herbal extracts using oestradiol and morphine as probe substrates, respectively. Valerenic acid also demonstrated significant inhibitory effects on the glucuronidation of acetaminophen, oestradiol, and morphine with both microsomes and expressed UGTs. The relatively low IC50 values obtained for valerenic acid in microsomal incubations may indicate that this essential oil contributes to the effects observed with herbal extracts in inhibiting glucuronidation in vitro. Overall, these findings suggest that valerian-containing products may interfere with the glucuronidation of endo- and xenobiotics.

[Effects of the flavonoids on cytochrome P-450 CYP1, 2E1, 3A4 and 19]

Site Editor — Wed, 30 May 2007 01:01:34 -0700

[Effects of the flavonoids on cytochrome P-450 CYP1, 2E1, 3A4 and 19]: Yao Xue Xue Bao. 2007 Jan;42(1):8-12 Authors: Zheng J, Zhou HH

Flavonoids are present in fruits, vegetables and beverages derived from plants, and in many dietary supplements or herbal remedies. A number of naturally occurring flavonoids have been shown to modulate the CYP450 system, including the induction or inhibition of these enzymes. This review focuses on the flavonoid effects on cytochrome P450 (CYP) enzyme CYP1, 2E1, 3A4 and 19. Flavonoids alter CYPs by various mechanisms, including the stimulation of gene expression via specific receptors and/or CYP protein, or mRNA stabilization and so on. But in vivo and in vitro, the effects of flavonoids are not always coincident as a result of concentrations of flavonoids, genetic and environmental factors. As well, flavonoids may interact with drugs through the induction or inhibition of their metabolism. Much attention should be paid to the metabolism interaction of the flavonoids when coadministered with other drugs.

Adverse interactions between herbal and dietary substances and prescription medications: a clinical survey.

Site Editor — Fri, 25 May 2007 02:19:14 -0700

Adverse interactions between herbal and dietary substances and prescription medications: a clinical survey.: Altern Ther Health Med. 2007 Mar-Apr;13(2):30-5 Authors: Bush TM, Rayburn KS, Holloway SW, Sanchez-Yamamoto DS, Allen BL, Lam T, So BK, Tran de H, Greyber ER, Kantor S, Roth LW

CONTEXT: Patients often combine prescription medications with herbal and dietary substances (herein referred to as herbal medicines). A variety of potential adverse herb-drug interactions exist based on the pharmacological properties of herbal and prescription medications. OBJECTIVE: To determine the incidence of potential and observed adverse herb-drug interactions in patients using herbal medicines with prescription medications. DESIGN: Consecutive patients were questioned about their use of herbal medicines in 6 outpatient clinics. Patients reporting use of these products provided a list of their prescription medications, which were reviewed for any potential adverse herb-drug interactions using a comprehensive natural medicine database. Any potential adverse herb-drug interactions prompted a review of the patient's chart for evidence of an observed adverse herb-drug interaction. MAIN OUTCOME MEASURE: The rate of potential and observed adverse herb-drug interactions. RESULTS: Eight hundred four patients were surveyed, and 122 (15%) used herbal medicines. Eighty-five potential adverse herb-drug interactions were found in 49 patients (40% of herbal medicine users). Twelve possible adverse herb-drug interactions in 8 patients (7% of herbal medicine users) were observed. In all 12 cases, the severity scores were rated as mild, including 8 cases of hypoglycemia in diabetics taking nopal (prickly pear cactus). CONCLUSIONS: A substantial number of potential adverse herb-drug interactions were detected and a small number of adverse herb-drug interactions observed, particularly in diabetics taking nopal. Screening for herbal medicine usage in 804 patients did not uncover any serious adverse interactions with prescription medications.

A mechanistic study on altered pharmacokinetics of irinotecan by St. John's wort.

Site Editor — Fri, 11 May 2007 15:35:53 -0700

A mechanistic study on altered pharmacokinetics of irinotecan by St. John's wort.: Curr Drug Metab. 2007 Feb;8(2):157-71 Authors: Hu ZP, Yang XX, Chen X, Cao J, Chan E, Duan W, Huang M, Yu XQ, Wen JY, Zhou SF

Irinotecan (CPT-11) is an important anticancer drug in management of advanced colon cancer. A marked protective effect on CPT-11-induced blood and gastrointestinal toxicity is obtained by combination of St. John's wort (SJW) in recent clinical and rat studies. However, the mechanism is unclear. This study aimed to explore the effects of SJW on the pharmacokinetics of CPT-11 and its major metabolites (SN-38 and SN-38 glucuronide) in rats and the underlying mechanisms using several in vitro models. Short-term (3 days) and long-term (14 days) pretreatment with SJW were conducted in rats to examine the effects of co-administered SJW on the plasma pharmacokinetics of CPT-11, SN-38 and SN-38 glucuronide. Rat liver microsomes and a rat hepatoma cell line, H4-II-E cells, were utilized to study the effects of aqueous and ethanolic extracts (AE and EE) and major active components (hyperforin, hypericin and quercetin) of SJW on CPT-11 and SN-38 metabolism and intracellular accumulation. Co-administered SJW for consecutive 14 days significantly decreased the initial plasma concentration (C0) of CPT-11, the area under the concentration-time curve (AUC(0-10hr)) and maximum plasma concentration (Cmax) of SN-38. The ethanolic extracts (EE) of SJW at 5 microg/ml significantly decreased SN-38 glucuronidation by 45% (P < 0.05) in rat hepatic microsomes. Pre-incubation of aqueous SJW extracts (AE) at 10 microg/ml, SJW EE at 5 microg/ml, and quercetin at 10 microM significantly increased the glucuronidation of SN-38 in H4-II-E cells. A 2-hr pre-incubation of quercetin (100 microM) significantly increased the intracellular accumulation of CPT-11 (P < 0.05). However, pre-incubation of hypericin (20 nM and 200 nM) and hyperforin (1 microM) significantly decreased the intracellular accumulation of CPT-11. In addition, pre-incubation of hypericin, SJW EE and quercetin significantly increased the intracellular accumulation of SN-38. Aqueous and ethanolic SJW extracts and its major active components did not alter the plasma protein binding of CPT-11 and SN-38. These results indicated that the aqueous and ethanolic extracts of SJW and its major active components could markedly alter glucuronidation of SN-38 and intracellular accumulation of CPT-11 and SN-38, which probably provides partial explanation for the altered plasma pharmacokinetics of CPT-11 and SN-38 and the antagonizing effects on the toxicities of CPT-11. Further studies are needed to explore the role of both pharmacokinetic and pharmacodynamic components in the protective effect of SJW against the toxicities of CPT-11.

The extent of induction of CYP3A by St. John's wort varies among products and is linked to hyperforin dose.

Site Editor — Sat, 20 Jan 2007 00:23:18 -0800

The extent of induction of CYP3A by St. John's wort varies among products and is linked to hyperforin dose.: Eur J Clin Pharmacol. 2006 Jan;62(1):29-36 Authors: Mueller SC, Majcher-Peszynska J, Uehleke B, Klammt S, Mundkowski RG, Miekisch W, Sievers H, Bauer S, Frank B, Kundt G, Drewelow B

OBJECTIVE: Induction of CYP3A by St. John's wort (SJW) extracts with high hyperforin (HYF) content is well described. Since SJW products vary in the amount of HYF and other main constituents, the aim of the study was to evaluate the effect on CYP3A function of SJW preparations with a range from very low to high HYF content. METHODS: Forty-two male, healthy volunteers were randomized into six parallel SJW medication groups with varying composition especially with regard to HYF content. Midazolam plasma concentration profiles were characterized after a single oral dose of 7.5 mg midazolam on the day before and on the 14th day of SJW medication. RESULTS: All SJW preparations tested resulted in a decrease in midazolam AUC, although the extent of the effect differed. The extract LI 160 (HYF 41 mg/day) decreased midazolam AUC0-12h by 79.4% (95% CI -88.6; -70.1), which was significantly greater than the effect by any other medication (p<0.05). SJW powder tablets 2.7 g/day (HYF 12 mg/day) resulted in a midazolam AUC0-12h decrease of 47.9% (95% CI -59.7;-36.2), while 2.7 g/day SJW powder tablets that were almost devoid of HYF (0.13 mg/day) reduced midazolam AUC0-12h by only 21.1% (95% CI -33.9; -8.3). Considering all six SJW medications tested, the extent of midazolam AUC decrease correlated significantly with increasing HYF dose (r=-0.765, p<0.001), but not with hypericin dose (r=-0.067; p=0.673). CONCLUSION: The extent of induction of CYP3A varies among St. John's wort products and depends on hyperforin dose.

Evidence-based systematic review of saw palmetto by the Natural Standard Research Collaboration.

Site Editor — Fri, 19 Jan 2007 18:42:13 -0800

Evidence-based systematic review of saw palmetto by the Natural Standard Research Collaboration.: J Soc Integr Oncol. 2006;4(4):170-86 Authors: Ulbricht C, Basch E, Bent S, Boon H, Corrado M, Foppa I, Hashmi S, Hammerness P, Kingsbury E, Smith M, Szapary P, Vora M, Weissner W

Here presented is an evidence-based systematic review including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.

Interactions between natural health products and antiretroviral drugs: pharmacokinetic and pharmacodynamic effects.

Site Editor — Fri, 19 Jan 2007 18:40:12 -0800

Interactions between natural health products and antiretroviral drugs: pharmacokinetic and pharmacodynamic effects.: Clin Infect Dis. 2006 Oct 15;43(8):1052-9 Authors: Lee LS, Andrade AS, Flexner C

Concurrent use of natural health products (NHPs) with antiretroviral drugs (ARVs) is widespread among human immunodeficiency virus-infected patients. This article reviews the clinical pharmacokinetic and pharmacodynamic interactions between NHPs and ARVs. Many NHPs are complex mixtures and are likely to contain organic compounds that may induce and/or inhibit drug metabolizing enzymes and drug transporters. Although the weight of evidence for the effects of certain NHPs varies and many studies of these products lack scientific rigor, it has been observed that St. John's wort clearly induces cytochrome P450 3A4 and P-glycoprotein and reduces protease inhibitor and nonnucleoside reverse-transcriptase inhibitor concentrations, thereby increasing the likelihood of therapeutic failure. Limited clinical research suggests that intake of garlic and vitamin C results in reductions in ARV concentrations. The intake of milk thistle, Echinacea species, and goldenseal inhibits cytochrome P450 enzymes in vitro and may increase ARV concentrations, but by clinically unimportant amounts. Intake of fish oil reduces ARV-induced hypertriglyceridemia without significantly affecting lopinavir concentrations. Before recommending the use of NHPs as adjuncts to ARV use, studies should first exclude significant pharmacokinetic interactions and ensure that ARV efficacy is maintained.

Analysis of the interaction of phytoestrogens and synthetic chemicals: An in vitro/in vivo comparison.

Site Editor — Wed, 17 Jan 2007 06:32:55 -0800

Analysis of the interaction of phytoestrogens and synthetic chemicals: An in vitro/in vivo comparison.: Toxicol Appl Pharmacol. 2006 Dec 5; Authors: Charles GD, Gennings C, Tornesi B, Kan HL, Zacharewski TR, Bhaskar Gollapudi B, Carney EW

In the evaluation of chemical mixture toxicity, it is desirable to develop an evaluation paradigm which incorporates some critical attributes of real world exposures, particularly low dose levels, larger numbers of chemicals, and chemicals from synthetic and natural sources. This study evaluated the impact of low level exposure to a mixture of six synthetic chemicals (SC) under conditions of co-exposure to various levels of plant-derived phytoestrogen (PE) compounds. Estrogenic activity was evaluated using an in vitro human estrogen receptor (ER) transcriptional activation assay and an in vivo immature rat uterotrophic assay. Initially, dose-response curves were characterized for each of the six SCs (methoxyclor, o,p-DDT, octylphenol, bisphenol A, beta-hexachlorocyclohexane, 2,3-bis(4-hydroxyphenyl)-propionitrile) in each of the assays. The six SCs were then combined at equipotent ratios and tested at 5-6 dose levels spanning from very low, sub-threshold levels, to a dose in which every chemical in the mixture was at its individual estrogenic response threshold. The SC mixtures also were tested in the absence or presence of 5-6 different levels of PEs, for a total of 36 (in vitro) or 25 (in vivo) treatment groups. Both in vitro and in vivo, low concentrations of the SC mixture failed to increase estrogenic responses relative to those induced by PEs alone. However, significant increases in response occurred when each chemical in the SC mixture was near or above its individual response threshold. In vitro, interactions between high-doses of SCs and PEs were greater than additive, whereas mixtures of SCs in the absence of PEs interacted in a less than additive fashion. In vivo, the SC and PE mixture responses were consistent with additivity. These data illustrate a novel approach for incorporating key attributes of real world exposures in chemical mixture toxicity assessments, and suggest that chemical mixture toxicity is likely to be of concern only when the mixture components are near or above their individual response thresholds. However, these data suggest that extrapolation from in vitro assays to in vivo mixture effects should be approached with caution.

Conjugating berberine to a multidrug efflux pump inhibitor creates an effective antimicrobial.

Site Editor — Sat, 13 Jan 2007 22:12:55 -0800

The subject of multidrug resistance pumps (MDR) is interesting, particularly when it comes to the comparative MDR activity of the berberine HCL isolate and the apparent synergy inherent in a biochemically-complex extract of Berberis vulgaris. The surprise value of this abstract, however, is the statement "The plant antimicrobial berberine, the active component of the medicinal plants echinacea and golden seal". Holy phytochemistry Batman! Berberine is the active constituent of Echinacea????

Conjugating berberine to a multidrug efflux pump inhibitor creates an effective antimicrobial.: ACS Chem Biol. 2006 Oct 24;1(9):594-600 Authors: Ball AR, Casadei G, Samosorn S, Bremner JB, Ausubel FM, Moy TI, Lewis K

In bacteria, multidrug-resistance pumps (MDRs) confer resistance to chemically unrelated amphipathic toxins. A major challenge in developing efficacious antibiotics is identifying antimicrobial compounds that are not rapidly pumped out of bacterial cells. The plant antimicrobial berberine, the active component of the medicinal plants echinacea and golden seal, is a cation that is readily extruded by bacterial MDRs, thereby rendering it relatively ineffective as a therapeutic agent. However, inhibition of MDR efflux causes a substantial increase in berberine antimicrobial activity, suggesting that berberine and potentially many other compounds could be more efficacious if an effective MDR pump inhibitor could be identified. Here we show that covalently linking berberine to INF 55 , an inhibitor of Major Facilitator MDRs, results in a highly effective antimicrobial that readily accumulates in bacteria. The hybrid molecule showed good efficacy in a Caenorhabditis elegans model of enterococcal infection, curing worms of the pathogen.

The Induction of CYP1A2, CYP2D6 and CYP3A4 by Six Trade Herbal Products in Cultured Primary Human Hepatocytes.

Site Editor — Sat, 13 Jan 2007 21:34:04 -0800

The Induction of CYP1A2, CYP2D6 and CYP3A4 by Six Trade Herbal Products in Cultured Primary Human Hepatocytes.: Basic Clin Pharmacol Toxicol. 2007 Jan; 100(1): 23-30 Authors: Hellum BH, Hu Z, Nilsen OG

The aim of this study was to evaluate the in vitro inductive potential of six commonly used trade herbal products on CYP1A2, CYP2D6 and CYP3A4 metabolic activities. Herbal components were extracted from the trade products in a way that ensured a composition equal to that present in the original product. Primary human hepatocytes and specific CYP substrates were used. Classic inducers were used as positive controls and herbal extracts were added in in vivo-relevant concentrations. Metabolites were determined by high performance liquid chromatography (HPLC). St. John's wort and common valerian were the strongest inducing herbs. In addition to induction of CYP3A4 by St. John's wort, common valerian and Ginkgo biloba increased the activity of CYP3A4 and 2D6 and CYP1A2 and 2D6, respectively. A general inhibitory potential was observed for horse chestnut, Echinacea purpurea and common sage. St. John's wort inhibited CYP3A4 metabolism at the highest applied concentration. Horse chestnut might be a herb with high inhibition potentials in vivo and should be explored further at lower concentrations. We show for the first time that G. biloba may exert opposite and biphasic effects on CYP1A2 and CYP2D6 metabolism. Induction of CYP1A2 and inhibition of CYP2D6 were found at low concentrations; the opposite was observed at high concentrations. CYP2D6 activity, regarded generally as non-inducible, was increased by exposure to common valerian (linear to dose) and G. biloba (highest concentration). An allosteric activation is suggested. From the data obtained, G. biloba, common valerian and St. John's wort are suggested as candidates for clinically significant CYP interactions in vivo.

Does a kampo medicine containing schisandra fruit affect pharmacokinetics of nifedipine like grapefruit juice?

Site Editor — Wed, 04 Oct 2006 19:05:57 -0700

Does a kampo medicine containing schisandra fruit affect pharmacokinetics of nifedipine like grapefruit juice?: Biol Pharm Bull. 2006 Oct;29(10):2065-9 Authors: Makino T, Mizuno F, Mizukami H

Herb-drug interaction has attracted attention as medicinal topics recently. However, the drug information is sometimes confusing. Previous in vitro studies revealed that schisandra fruit had strong inhibitory effect on CYP3A4 and claimed the possibilities of its herb-drug interaction. In the present study, we evaluated the inhibitory effects of schisandra fruit and shoseiryuto, an herbal formula in Japanese traditional kampo medicine containing eight herbal medicines including schisandra fruit, on rat CYP3A activity in vitro, and the effect of shoseiryuto on pharmacokinetics of nifedipine in rats, in comparison with those of grapefruit juice, a well-characterized natural CYP3A inhibitor. Shoseiryuto and its herbal constituents, schisandra fruit, ephedra herb and cinnamon bark exhibited in vitro inhibitory effect of CYP3A. Although shoseiryuto inhibited rat CYP3A activity in vitro with a degree comparable to grapefruit juice, shoseiryuto did not significantly affect a plasma concentration profile of nifedipine in rats as grapefruit juice did. These results indicate that in vivo experiments using the extract of herbal medicine prepared with the same dosage form as patients take are necessary to provide proper information about herb-drug interaction.

Influence of Garlic (Allium sativum) on the Pharmacokinetics of Docetaxel.

Site Editor — Wed, 04 Oct 2006 18:20:56 -0700

Influence of Garlic (Allium sativum) on the Pharmacokinetics of Docetaxel.: Clin Cancer Res. 2006 Aug 1; 12(15): 4636-40
Cox MC, Low J, Lee J, Walshe J, Denduluri N, Berman A, Permenter MG, Petros WP, Price DK, Figg WD, Sparreboom A, Swain SM

PURPOSE: The herbal supplement garlic (Allium sativum) is commonly used by cancer patients. Preclinical studies have shown that allicin, a major component of garlic, may affect cytochrome P450 3A4 (CYP3A4) activity. This study examines the influence of garlic supplementation on the pharmacokinetics of docetaxel, a CYP3A4 substrate. EXPERIMENTAL DESIGN: Women with metastatic breast cancer were treated with docetaxel (30 mg/m(2)) given weekly for 3 of 4 weeks. Three days after the initial dose of docetaxel, patients received 600 mg of garlic twice daily for 12 consecutive days. Docetaxel pharmacokinetics were assessed during the first three administrations. RESULTS: In 10 evaluable patients, the mean baseline clearance of docetaxel was 30.8 L/h/m(2) [95% confidence intervals (95% CI), 16.7-44.9]. Coadministration of garlic reduced mean clearance of docetaxel to 23.7 L/h/m(2) (95% CI, 15.5-31.8) and 20.0 L/h/m(2) (95% CI, 13.3-26.7) on days 8 and 15, respectively (P = 0.17). Additional pharmacokinetic variables of docetaxel, including peak concentration (P = 0.79), area under the curve (P = 0.36), volume of distribution (P = 0.84), and half-life (P = 0.36), were also not statistically significantly different. The mean area under the curve ratio between day 15 and day 1 was 3.74 in three individuals with the CYP3A5*1A/*1A genotype (all African American) compared with 1.02 in six individuals with the CYP3A5*3C/*3C genotype (all Caucasian). CONCLUSIONS: This study indicates that garlic does not significantly affect the disposition of docetaxel. However, it cannot be excluded that garlic decreases the clearance of docetaxel in patients carrying a CYP3A5*1A allele.

Hyperforin in St. John's wort drug interactions.

Site Editor — Fri, 09 Jun 2006 07:23:48 -0700

Hyperforin in St. John's wort drug interactions.: Eur J Clin Pharmacol. 2006 Feb 14;:1-9 Authors: Madabushi R, Frank B, Drewelow B, Derendorf H, Butterweck V

Recently, interactions of herbal medicines with synthetic drugs came into focus of particular interest. In the past 3 years, more than 50 papers were published regarding interactions between St. John's wort (Hypericum perforatum L.; SJW) and prescription drugs. Co-medication with SJW resulted in decreased plasma concentrations of a number of drugs including amitriptyline, cyclosporine, digoxin, indinavir, irinotecan, warfarin, phenprocoumon, alprazolam, dextrometorphane, simvastatin, and oral contraceptives. Sufficient evidence from interaction studies and case reports indicate that SJW is a potent inducer of cytochrome P450 enzymes (particularly CYP3A4) and/or P-glycoprotein. Recent studies could show that the degree of enzyme induction by SJW correlates strongly with the amount of hyperforin found in the product. Products that do not contain substantial amounts of hyperforin (<1%) have not been shown to produce clinically relevant enzyme induction. On the other hand, some evidence suggests that hyperforin may also contribute to the antidepressant activity of SJW. However, clinical studies using SJW preparations with a low hyperforin amount (<1%) clearly demonstrated the superiority of this plant extract over placebo and its equivalence to imipramine and fluoxetine in the treatment of mild to moderate forms of depression. In the present paper clinical significant SJW interactions are critically evaluated against the background of hyperforin.

Differences Between Herbal and Nonherbal Users in Dental Practice.

Site Editor — Fri, 09 Jun 2006 07:13:32 -0700

Differences Between Herbal and Nonherbal Users in Dental Practice.: J Dent Hyg. 2006;80(1):10 Authors: Tam KK, Gadbury-Amyot CC, Cobb CM, Williams KB

PURPOSE: The purposes of this study were to describe basic demographics and health belief differences between herb users and nonherb users, any potential herb-drug interactions, and examine the association between dental chart noted and questionnaire self-reported use of herbal remedies. METHODS: A 3-part survey instrument was administered to a convenience sample of 149 individuals at a dental clinic and two dental practices. The first part ascertained demographic information and prescription drug use using open-ended and closed-ended questions. The second part listed 51 individual/combination herbs and the third part assessed healthcare behavior using a 5-point Likert scale. A chart audit compared written responses between a patient's medical/dental history chart and his/her survey on herbal use. Descriptive analyses and MANOVA were used to examine the relationship between herbal users and nonusers. RESULTS: Eighty participants (54%) reported using some form of herbs. They were characterized as mostly female (71%), who were less likely to disclose herbal usage to practitioners (p< .05), believed in herbal effectiveness (p< .05), and reported a more positive perceived level of health status compared to nonusers (p= .02). Although herb users reported a willingness to disclose use of herbs to health practitioners, only three patients had any written documentation of their herb use in their medical/dental health chart (p= .0001). Fifty-five herb users were also taking prescription drugs (69%) that could potentially lead to herb-drug interactions. CONCLUSION: The findings provide supportive evidence that dental hygiene practitioners need to be aware of their patients' use of herbs. Knowing potential risks, side effects, and possible drug interactions is necessary for patient management and each patient's oral health.

MDR- and CYP3A4-mediated drug-herbal interactions.

Site Editor — Fri, 09 Jun 2006 04:35:48 -0700

MDR- and CYP3A4-mediated drug-herbal interactions.: Life Sci. 2006 Jan 24; Authors: Pal D, Mitra AK

According to recent epidemiological reports, almost 40% of American population use complimentary and alternative medicine (CAM) during their lifetime. Patients detected with HIV or cancer often consume herbal products especially St. John's wort (SJW) for antidepressants in combination with prescription medicines. Such self-administered herbal products along with prescribed medicines raise concerns of therapeutic activity due to possible drug-herbal interactions. P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) together constitute a highly efficient barrier for many orally absorbed drugs. Available literature, clinical reports and in vitro studies from our laboratory indicate that many drugs and herbal active constituents are substrates for both P-gp and CYP3A4. Results from clinical studies and case reports indicate that self-administered SJW reduce steady state plasma concentrations of amitriptyline, cyclosporine, digoxin, fexofenadine, amprenavir, indonavir, lopinavir, ritonavir, saquinavir, benzodiazepines, theophyline, irinotecan, midazolan and warfarin. This herbal agent has been also reported to cause bleeding and unwanted pregnancies when concomitantly administered with oral contraceptives. Most of these medicinal agents and SJW are substrates for P-gp and/or CYP3A4. In vitro studies from our laboratory suggest that short-term exposure with pure herbal agents such as hypericin, kaempferol and quercetin or extract of SJW resulted in higher uptake or influx of ritonavir and erythromycin. Hypericin, kaempferol and quercetin also caused a remarkable inhibition of cortisol metabolism with the percent intact cortisol values of 64.58%, 89.6% and 90.1%, respectively, during short-term in vitro experiments. Conversely, long-term exposure of herbal agents (hyperforin, kaempferol and quercetin) showed enhanced expression of CYP3A4 mRNA in Caco-2 cells. In another study, we observed that long-term exposure of hypericin, kaempferol, quercetin and silibinin resulted in higher MDR-1 mRNA expression in Caco-2 cells. Therefore, herbs can pharmacokinetically act as inhibitors or inducers. Medicinal agents that are substrates P-gp-mediated efflux and/or CYP-mediated metabolism are likely to be potential candidates for drug-herbal interactions. The duration of exposure of cells/healthy volunteers/animals to herbals appears to be critical for drug-herbal interaction. An increase in plasma drug concentration is possible during concomitant administration of SJW and prescribed drugs. In contrast, prolonged intake of herbal supplement followed by drug administration may result in subtherapeutic concentrations. Therefore, clinical implications of such drug herbal interactions depend on a variety of factors such as dose, frequency and timing of herbal intake, dosing regimen, route of drug administration and therapeutic range. In vitro screening techniques will play a major role in identifying possible herb-drug interactions and thus create a platform for clinical studies to emerge. Mechanisms of drug-herbal interaction have been discussed in this review article.

Kavalactones fail to inhibit alcohol dehydrogenase in vitro.

Site Editor — Fri, 09 Jun 2006 04:25:14 -0700

Kavalactones fail to inhibit alcohol dehydrogenase in vitro.: Phytomedicine. 2006 Feb;13(3):192-5 Authors: Anke J, Fu S, Ramzan I

In recent years, Kava kava (Piper methysticum, Forst. f., Piperaceae), a folkloric beverage and popular herbal remedy, has been implicated in a number of liver failure cases. Many hypotheses as to the mechanism of its hepatotoxicity, for example interactions with other co-ingested medication, have been postulated. This present study investigated whether pharmacokinetic interactions between kava constituents and alcohol via alcohol dehydrogenase (ADH) inhibition by individual kavalactones might explain its claimed hepatotoxic effects. Four kavalactones, (+/-)-kavain, methysticin, yangonin and desmethoxyyangonin, fail to inhibit ADH in vitro at 1, 10 or 100muM concentrations.

Ginkgo biloba: Evaluation of CYP2C9 Drug Interactions In Vitro and In Vivo.

Site Editor — Fri, 09 Jun 2006 04:24:59 -0700

Ginkgo biloba: Evaluation of CYP2C9 Drug Interactions In Vitro and In Vivo.: Am J Ther. 2006 Jan-Feb;13(1):24-31 Authors: Mohutsky MA, Anderson GD, Miller JW, Elmer GW

Ginkgo biloba extract is one of the most widely used herbal products in the United States. However, bleeding episodes in patients taking Ginkgo biloba and warfarin have been documented. Therefore, in vitro and in vivo inhibition studies were done to ascertain the influence of ginkgo on CYP2C9, the P-450 isozyme responsible for the metabolism of the most potent warfarin enantiomer, (S)-warfarin. Ginkgo extract inhibited human liver microsomal CYP2C9 with an apparent Ki =14.8 mug/mL, and the inhibition was increased by acid hydrolysis (apparent Ki = 9.1 mug/mL). Two open-label, crossover pharmacokinetic studies in healthy subjects were performed using tolbutamide and diclofenac as probe CYP2C9 substrates. In contrast to the in vitro inhibition of CYP2C9, no interactions between Ginkgo biloba extract and CYP2C9 probe substrates were observed in vivo as evidenced by the lack of effect on the steady-state pharmacokinetics of diclofenac or on the urinary metabolic ratio of tolbutamide.

Evidence-based drug-herbal interactions.

Site Editor — Fri, 09 Jun 2006 04:23:57 -0700

Evidence-based drug-herbal interactions.: Life Sci. 2006 Jan 17; Authors: Chavez ML, Jordan MA, Chavez PI

Due to the growing use of herbals and other dietary supplements healthcare providers and consumers need to know whether problems might arise from using these preparations in combination with conventional drugs. However, the evidence of interactions between natural products and drugs is based on known or suspected pharmacologic activity, data derived from in vitro or animal studies, or isolated case reports that frequently lack pertinent information. The usefulness of such information is questionable. More recently an increasing number of documented case reports, in vivo studies, and clinical trials have evaluated herbal-drug interactions. Results have sometimes been contradictory and more research is needed. Since there is a lack of rigorous studies that can establish the clinical significance of herb-drug interactions, an evidence-based evaluation of the current literature concerning commonly used herbal-drug interactions, as well as other dietary supplements, was conducted.

In vitro and in vivo assessment of herb drug interactions.

Site Editor — Fri, 09 Jun 2006 04:23:18 -0700

In vitro and in vivo assessment of herb drug interactions.: Life Sci. 2006 Jan 18; Authors: Venkataramanan R, Komoroski B, Strom S

Herbal products contain several chemicals that are metabolized by phase 1 and phase 2 pathways and also serve as substrates for certain transporters. Due to their interaction with these enzymes and transporters there is a potential for alteration in the activity of drug metabolizing enzymes and transporters in presence of herbal components. Induction and inhibition of drug metabolizing enzymes and transporters by herbal component has been documented in several in vitro studies. While these studies offer a system to determine the potential for a herbal component to alter the pharmacokinetics of a drug, they cannot always be used to predict the magnitude of any potential effect in vivo. In vivo studies are the ultimate way to determine the clinical importance of herb drug interactions. However, lack of content uniformity and lack of documentation of the bioavailability of herbal components makes even in vivo human studies difficult to interpret as the effect may be product specific. It appears that St. John's wort extract is probably one of the most important herbal product that increases the metabolism and decreases the efficacy of several drugs. Milk thistle on the other hand appears to have minimal effect on phase 1 pathways and limited data exists for phase 2 pathways and transporter activity in vivo. Further systematic studies are necessary to assess the significance of herb drug interactions.

Fatal seizures due to potential herb-drug interactions with Ginkgo biloba.

Site Editor — Fri, 09 Jun 2006 04:21:25 -0700

Fatal seizures due to potential herb-drug interactions with Ginkgo biloba.: J Anal Toxicol. 2005 Oct;29(7):755-8 Authors: Kupiec T, Raj V

Alternative therapy including herbal drugs and complementary medicine is becoming increasingly popular. However, the rise in the incidence of herb-drug interactions is causing concern, especially in the absence of warning labels addressing potential adverse effects. We present the case of a 55-year-old male who suffered a fatal breakthrough seizure, with no evidence of non-compliance with his anticonvulsant medications. The autopsy report revealed subtherapeutic serum levels for both anticonvulsants Depakote and Dilantin. Concomitant with his prescribed medications, the decedent was also self-medicating with a cornucopia of herbal supplements and nutraceuticals, prominent among which was Ginkgo biloba. Ginkgo, an herbal extract from the leaves of the Ginkgo biloba tree, has been used medicinally for centuries and has been touted as a cure for a variety of medical conditions. The induction of Cytochrome P450 enzymes by components of herbal drugs has been known to affect the metabolism of various drugs. Dilantin is primarily metabolized by CYP2C9, and secondarily metabolized by CYP2C19. Valproate metabolism is also modulated in part by CYP2C9 and CYP2C19. A recent study revealed significant inductive effect of ginkgo on CYP2C19 activity. CYP2C19 induction by ginkgo could be a plausible explanation for the subtherapeutic levels of Dilantin and Depakote. Additionally, ginkgo nuts contain a potent neurotoxin, which is known to induce seizure activity. Evidence of other herbal drugs diminishing the efficacy of anticonvulsant medication does exist; however, there has been only one other documented instance of ginkgo potentiating seizure activity in the presence of anticonvulsant therapy. Highlighting the potential adverse effects and drug interactions of ginkgo on the packaging of the drug may help prevent inadvertent use in vulnerable individuals.

Ginkgo biloba-an appraisal.

Site Editor — Fri, 09 Jun 2006 04:07:46 -0700

Ginkgo biloba-an appraisal.: Kathmandu Univ Med J (KUMJ). 2004 Jul-Sep;2(3):225-9 Authors: Dubey AK, Shankar PR, Upadhyaya D, Deshpande VY

Ginkgo biloba has been used in traditional Chinese medicine for about 5000 years. A standardized preparation, EGb 761 has been recently prepared. The pharmacologically active constituents, flavonol glycosides and the terpene lactones are standardized. The terpene lactones comprise of ginkgolides A, B, C and bilobalides. The extract scavenges excess free radicals and pretreatment with EGb 761 reduces damage by free radicals in patients undergoing coronary bypass surgery. The action of platelet activating factor is antagonized and platelet aggregation is reduced. Blood flow is increased. Release of prostacyclines and nitric oxide was shown to be stimulated. Ginkgo biloba has been found to be useful in the treatment of Alzheimers disease and cognitive impairment. EGB 761 has shown beneficial effect in aging and mild cognitive impairment. Bilobalide has been shown to be protective against glutamate-induced excitotoxic neuronal death. Early studies indicate a potential role in age-related macular degeneration and some types of glaucoma. Anticancer action is related to antioxidant, anti-angiogenic and gene regulatory actions. Ginkgo biloba has shown overall improvement in about 65% of patients with cerebral impairment and a similar percentage suffering from peripheral vascular diseases. A recent study suggested that phytoestrogens in Ginkgo biloba may have a role as alternative hormone replacement therapy. Recent trials have not shown a beneficial effect of Ginkgo biloba in tinnitus and acute mountain sickness. Ginkgo biloba increased the bioavailability of diltiazem. The extract has been shown to protect against doxorubicin-induced cardiotoxicity and gentamicin-induced nephrotoxicity in animals. Ginkgo biloba inhibits microsomal enzymes and has a potential for drug interactions. Further studies to establish the efficacy of Ginkgo biloba are required.

Inhibitory effect of thai plant extracts on P-glycoprotein mediated efflux.

Site Editor — Fri, 09 Jun 2006 04:05:08 -0700

Inhibitory effect of thai plant extracts on P-glycoprotein mediated efflux.: Phytother Res. 2006 Jan 5;20(1):79-81 Authors: Junyaprasert VB, Soonthornchareonnon N, Thongpraditchote S, Murakami T, Takano M

Curcuminoids from Curcuma longa L. and extracts of Psidium guajava L., Andrographis paniculata (Burm. f.) Nees, Phyllanthus emblica L. and Solanum trilobatum L. were investigated for their inhibitory effect on P-glycoprotein (P-gp) on the efflux transport of rhodamine 123 (Rho-123 ) in Caco-2 cells and rat ileum. Of the five tested samples, curcuminoids and an extract of P. guajava showed the highest inhibitory effect on P-gp mediated efflux of Rho-123 in Caco-2 cells. Additionally, they were found to have equal potential in inhibiting Rho-123 efflux transport from serosal to mucosal surfaces of the rat ileum. Copyright (c) 2006 John Wiley & Sons, Ltd.

Inhibitory effect of thai plant extracts on P-glycoprotein mediated efflux.

Site Editor — Fri, 09 Jun 2006 04:04:56 -0700