Wednesday, November 21, 2012

Evaluation of Documented Drug Interactions and Contraindications Associated With Herbs and Dietary Supplements


International Journal of Clinical Practice

A Systematic Literature Review

H.-H. Tsai, H.-W. Lin, A. Simon Pickard, H.-Y. Tsai, G. B. Mahady
  Nov 16, 2012 Authors & Disclosures
Int J Clin Pract. 2012;66(11):1056-1078. © 2012  Blackwell Publishing

Abstract and Introduction

Abstract

Background and Aims: The use of herbs and dietary supplements (HDS) alone or concomitantly with medications can potentially increase the risk of adverse events experienced by the patients. This review aims to evaluate the documented HDS-drug interactions and contraindications.

Methods: A structured literature review was conducted on PubMed, EMBASE, Cochrane Library, tertiary literature and Internet.

Results: While 85 primary literatures, six books and two web sites were reviewed for a total of 1,491 unique pairs of HDS-drug interactions, 213 HDS entities and 509 medications were involved. HDS products containing St. John's Wort, magnesium, calcium, iron, ginkgo had the greatest number of documented interactions with medications. Warfarin, insulin, aspirin, digoxin, and ticlopidine had the greatest number of reported interactions with HDS. Medications affecting the central nervous system or cardiovascular system had more documented interactions with HDS. Of the 882 HDS-drug interactions being described its mechanism and severity, 42.3% were due to altered pharmacokinetics and 240 were described as major interactions. Of the 152 identified HDS contraindications, the most frequent involved gastrointestinal (16.4%), neurological (14.5%), and renal/genitourinary diseases (12.5%). Flaxseedechinacea, andyohimbe had the largest number of documented contraindications.

Conclusions: Although HDS-drug interactions and contraindications primarily concerned a relatively small subset of commonly used medications and HDS entities, this review provides the summary to identify patients, HDS products, and medications that are more susceptible to HDS-drug interactions and contraindications. The findings would facilitate the health-care professionals to communicate these documented interactions and contraindications to their patients and/or caregivers thereby preventing serious adverse events and improving desired therapeutic outcomes.

Introduction

The marketing and consumer use of herbs and dietary supplements (HDS) has risen dramatically in the USA over the past two decades. [1,2] It is estimated that > 50% of patients with chronic diseases or cancers ever use HDS, [3] and nearly one-fifth of patients take HDS products concomitantly with prescription medications. [4,5] Despite their widespread use, the potential risks associated with combining HDS with other medications are poorly understood by these consumers. Although many HDS users believe that HDS are safe, [6] HDS products have been reported to be associated with mild-to-severe adverse effects such as heart problems, chest pain, abdominal pain and headache. [2,7,8]Because a majority of patients often fail to disclose that they have taken HDS products to their healthcare providers, e.g. one study estimated only 30% disclosure, [9] patient-provider communication concerning the risks and benefits of HDS is critically important.
A major challenge for healthcare providers in counselling patients about HDS is that the available clinical evidence may be ambiguous and sometimes conflicting for HDS adverse events and drug interactions. [10,11] Also, there are often practice-based barriers to identifying the evidence on HDS–drug interactions, [12] including lack of familiarity or access to HDS-related textbooks and databases.[13,14] In general, fewer and less rigorous studies are available for HDS than that of prescription drugs, particularly with respect to randomised controlled clinical trials. [15] Many available references for HDS list numerous 'potential HDS–drug interactions' with little clinical significance or risk. Many reference books are replete with errors that serve only to confuse healthcare practitioners or consumers. The aim of this review was to provide healthcare professionals with a resource that concisely summarises the scientific evidence for HDS–drug interactions and contraindications from 2000 to 2010.

Methods

Evidence Resources and Literature Search

This review of HDS–drug interactions and contraindications focused on the evidence in the primary literature and tertiary literature (i.e. textbooks) related to HDS or drug interactions.[16–21] Important online resources about HDS, including the website of National Center for Complementary and Alternative Medicine (NCCAM), [22] and Office of Dietary Supplements [23]were also included. The definition of HDS used for this study was the official definition of dietary supplements as stated in the Dietary Supplement Health and Education Act of 1994 (DSHEA). [24] HDS refers to any herbal product or dietary supplement product containing one of the following ingredients: vitamin, mineral, other botanical, amino acid, or other dietary substance. Thus, traditional foods or fruit products, not listed in the definition (e.g. avocado, grapefruit, and onion, etc.), were not included in this review.
The primary literature was obtained by searching databases, i.e. MEDLINE (via PubMed), EMBASE and Cochrane Library. Search terms included, but were not limited to the medical subject headings (MeSH terms) or key words that encompassed 'herb drug interactions', 'dietary supplements' OR 'vitamins' OR 'minerals' OR 'amino acids' OR 'botanical' OR 'herbal medicine' OR 'phytotherapy' combined with 'contraindications' OR 'drug interactions'. The searches were performed in English only for the period of January 2000 to December 2010. The articles were selected based on the titles and abstracts and reviewed independently by two authors (HHT, HWL). Literature without related information, including studies regarding efficacy of HDS, regulation of HDS or methods of assay, was excluded. All relevant articles were selected without restriction for animal studies, clinical trials, observational studies (including case reports) or review articles.

Data Extraction and Synthesis

Two standardised data abstraction checklists were developed and used to perform the review (one for the HDS–medication interactions and the other for HDS contraindications). All pairs of HDS–drug interactions documented in the retrieved literature sources (except for those interaction pairs with consequences that may benefit to users) were extracted. Because most HDS products or ingredients are not recommended for use during pregnancy or lactation, [25] documented contraindications for these conditions were not further reviewed. All relevant data were extracted, compiled and classified all by one qualified reviewer, and then validated by another. Any disagreements related to the abstraction of data were resolved by consensus.
We grouped HDS products/ingredients into three categories: herb/botanical, vitamin/mineral/amino acid (VMA) and others. The most common drugs were grouped according to the Anatomical Therapeutic Chemical (ATC) classification system. [26] Possible mechanisms and the severity ratings of each pair of interactions were retrieved using the Interactions database in MicroMedex® [27] and 'Natural Product/Drug Interaction Checker' in Natural Medicines Comprehensive Database® (NMCD®). [28] We categorised the mechanisms for pairs of interactions into four types: pharmacokinetics, pharmacodynamics, both (pharmacokinetics plus pharmacodynamics) and unknown. The severity of each documented interaction was categorised as contraindicated, major, moderate and minor based upon MicroMedex®, and major, moderate and minor based upon NMCD®, respectively. The definitions of 'major', 'moderate' and 'minor' were similar in these two databases. For instance, a major interaction may cause life-threatening damage and/or serious adverse effect(s), and a minor interaction would result in a negligible effect(s). However, contraindicated interactions were rated as 'major' severity in NMCD®. The types of contraindications were categorised based on Goldman: Cecil Medicine®. [29] All data were compiled and managed using an Excel spreadsheet. Descriptive analyses to define the frequency or proportion of the evidence associated with the interaction pairs, the corresponding mechanisms and severity ratings of interactions and the types of contraindications for certain populations or patients was performed.

Results

Literature Search

Finally, 461 articles of primary literature were initially identified. Eighty-five articles with full text, including 54 review articles, other than the 6 books and 2 web sites were selected for further review (Figure 1). The summaries of the animal studies, observational studies and clinical trials to retrieve information about HDS–drug interactions and contraindications for the original studies are listed in Table 1 , Table 2 and Table 3 , respectively. The summaries of the retrieved books and reviewed articles to retrieve information about HDS–drug interactions and contraindications were listed in Appendix 1 ,Appendix 2 and Appendix 3 , respectively. Among the original studies ( n = 31), more than half ( n = 16) were clinical trials. All of these articles contained information about HDS–drug interactions, [12,30–113] but only five articles provided descriptive information about HDS contraindications. [55–57,59,102]
Figure 1.
Flow chart of primary literature search

Quantity of Retrieved Evidence

After excluding the evidence regarding HDS not recommended for human use (i.e. anvirzel, belladonna, chaparral, comfrey, ephedra and pennyroyal) [16,19,21–23] and the duplicates, a total of 1491 unique pairs of documented interactions between HDS and individual drugs were identified. Among these pairs, 814 pairs (54.6%) were retrieved from the primary literature, 1018 pairs (68.3%) from books and only 23 pairs of interactions were identified in the two reviewed web sites. Among these interactions, the corresponding mechanism and severity was determined for 507 pairs (34.0%) using MicroMedex® and 763 pairs (51.2%) in the NMCD® online database. In total, 882 pairs (59.2%) of documented HDS–drug interactions were identified for their potential mechanism and severity. In terms of contraindications, there were 128, 15 and 9 documented HDS contraindications retrieved from books, primary articles and web sites, respectively, for a total of 152.

HDS–drug Interactions

Among all included interactions between HDS and individual drugs, 166 different herbs/botanical products, 28 VMA and 19 other supplements accounted for 890 pairs (59.7%), 529 pairs (35.5%) and 72 pairs (4.8%) of documented interactions, respectively (Figure 2). The top five herbs/botanical products, which were documented to have the most interactions with individual medications, were St John's Wort ( Hypericum perforatum), ginkgo ( Ginkgo biloba), kava ( Piper methysticum), digitalis (Digitalis purpurea) and willow ( Salix alba). For example, St John's Wort, magnesium, calcium, iron and ginkgo have been documented to interact with 147, 102, 75, 71 and 51 individual medications, respectively. Furthermore, a total of 509 unique drugs contributed to the 1491 documented pairs of interactions with HDS. The majority of these medications ( n = 100) were categorised as treatment for central nervous system (CNS), second were those medications affecting the cardiovascular system and then systemic anti-infective drugs ( n = 90 and 75, respectively) (Figure 3). The medications that most contributed to documented interactions with HDS were warfarin, insulin, aspirin, digoxin and ticlopidine. Not surprisingly, warfarin was documented to have interactions with over 100 HDS entities (Figure 4).
Figure 2.
Herbs and dietary supplements tended to have documented interactions with medications in each caterory. VMA, vitamin/mineral/amino acid; DS, dietary supplements; DHEA, dehydroepiandrosterone
Figure 3.
Distribution of medications that might have interactions with herbs and dietary supplements. ATC, anatomical therapeutic chemical. The number of total medications was 509
Figure 4.
Medications with the largest number of interactions with herbs and dietary supplements. HDS, herbs and dietary supplements
Among 882 pairs of interactions with identified mechanisms, a total of 373 pairs (42.3%) were attributable to pharmacokinetic-related mechanisms, i.e. affected the absorption, distribution, metabolism or excretion of the HDS/drug. Approximately 40.1% of all interaction pairs accounted for pharmacodynamic-related mechanisms, and 8.5% were attributed to a combination of both mechanisms. No mechanism was identifiable for the remaining 9.1% of pairs. Among the 373 documented HDS interaction pairs that were pharmacokinetic-related, 87 pairs were associated with St John's Wort (23.3%), whereas calcium supplements were involved in 47 pairs of documented interactions (12.6%), and iron was involved in 42 pairs of interactions (11.3%). St John's Wort was documented to reduce the effectiveness of alprazolam, amitriptyline, imatinib, midazolam, nifedipine and verapamil via the CYP (Cytochrome P450) 3A4 pathway, and the plasma levels of fexofenadine and digoxin via PgP (p-glycoprotein) pathway. Some drugs (i.e. atorvastatin, cyclosporin, indinavir, nevirapine and simvastatin) were documented to interact with St John's Wort through both pathways. [37,99] Among the 354 documented interactions that were pharmacodynamic-related, kava accounted for 4.8% pairs of interactions (17 pairs). St John's Wort and ginkgo were both involved in 15 pairs of interactions (4.2%). Risk of additive serotonergic effects were increased when St John's Wort was used concurrently with monoamine oxidase inhibitors (MAOI), selective serotonin reuptake inhibitors (SSRI), or tryptamine-based drugs causing symptoms of anxiety, dizziness, restlessness, nausea and vomiting. [16–18,20] As a result of their pharmacological actions on the GABA receptor, synergism in CNS adverse events may result from taking barbiturates or benzodiazepines in combination with kava. [16,20,98] Furthermore, kava may worsen the extrapyramidal effects associated with the use of droperidol, haloperidol, metoclopramide or risperidone because of a dopamine. [21,98]
Among the 507 documented interaction pairs identified with a severity rating in MicroMedex®, 69.4% were categorised as the moderate interactions, 17.2% as major interactions, 10.3% as minor interactions and 3.1% were attributable to the contraindications. As for the 763 pairs of documented interactions being identified with the severity rating based on the NMCD®, the majority documented interaction pairs were categorised as moderate (69.2%), major (26.5%) and minor (4.3%). Approximately, 240 documented HDS–drug interactions were categorised as major severity in either database ( Table 4 and Table 5). For example, the following pairs of interactions were considered as being contraindicated for concurrent use in MicroMedex®: l-Tryptophan vs. MAOI (i.e. isocarboxazid, phenelzine and tranylcypromine) or venlafaxine and St John's wort vs. protease inhibitors (i.e. amprenavir, fosamprenavir and indinavir), irinotecan, rasagiline or voriconazole, respectively. Among the 390 documented interaction pairs having severity ratings in both databases, 41.3% were inconsistent. For example, the combination of alfalfa ( Medicago sativa) and warfarin were considered as the minor interaction in MicroMedex®; however, it was rated as the major interaction in NMCD®. The combination of St John's Wort with quetiapine, quinidine, risperidone or sildenafil gave severity ratings major according to NMCD®, and no interaction was reported in MicroMedex®.

HDS Contraindications

Fifty-nine HDS from 152 reports were contraindicated for use among patients with specific disease states. The reports were classified into 19 disease states, including gastrointestinal diseases, neurologic disorders, renal/genitourinary diseases, neoplastic disorders, diseases of the liver/gallbladder/bile ducts and cardiovascular diseases (Figure 5). Flaxseed ( Linum usitatissimum), echinacea ( Echinacea purpurea) and yohimbe ( Pausinystalia yohimbe) had the highest number of documented contraindications. For example, flaxseed was documented to have contraindications associated with gastrointestinal disorders such as acute or chronic diarrhoea, oesophageal stricture, inflammatory bowel disease, hypertriglyceridemia and prostate cancer. [21] Echinacea was contraindicated for use among patients with rheumatoid arthritis, systemic lupus erythematosus, leukosis, multiple sclerosis, tuberculosis and HIV infection. [16,18] Yohimbe was contraindicated in patients with anxiety, bipolar disorder, depression, mania and schizophrenia, as well as benign prostate hypertrophy and kidney disease. [21,22]
Figure 5.
Common contraindications for HDS use. *Other contraindications of gastrointestinal diseases included fecal impaction for aloe vera and oesophageal stricture for flaxseed. †Other contraindications of neurologic disorders included multiple sclerosis for echinacea and posttraumatic stress disorder for yohimbe. HDS, herbs and dietary supplements

Discussion

In this study, we summarised the evidence of HDS–drug interactions and contraindications that have been reported in the primary and tertiary literature. The existing evidence suggests that some HDS products/ingredients have potentially harmful drug interactions that are predominately moderate in their severity. HDS products containing St John's Wort, magnesium, calcium, iron, and ginkgo had the greatest number of documented interactions with drugs. Medications affecting the CNS and cardiovascular system tended to have more documented interactions with these HDS. Of all listed medications, warfarin was documented to have the greatest number of HDS interactions. HDS products containing herbal remedies were more likely to have documented interactions with medications and the contraindications than vitamins, minerals and other types of dietary supplements.
Some of the commonly used herbal remedies such as echinacea, flaxseed, ginkgo and St John's Wort have featured more prominently in industry or government sponsored clinical trials, academic studies and official monographs. [114,115] Some of these HDS entities have undergone more rigorous scientific evaluations. The clinical evidences for HDS are often mixed in terms of their support for efficacy and/or effectiveness. The benefits of HDS treatment must be balanced against the potential harmful effects including adverse events, and the potential for drug interactions or disease state contraindications. Furthermore, there often may be just a self-medicating 'indication creep', where patients who have a certain disease or condition unrelated to the supportive therapy with these HDS. For example, WHO monographs listed that echinacea products could be used in supportive therapy of colds and infections but were contraindicated for patients with autoimmune diseases. [116] Even though the evidence to support the immunological effects of echinacea was still controversial, [117] 6.4% of patients with arthritis/lupus reportedly used echinacea in the 2002 NHIS. [4] Thus, patients need to understand that advantages of using echinacea products are outweighed by the potential harm if they have a specific disease state.
Patients using medications that have a narrow therapeutic range (i.e. warfarin, digoxin) were at greater risk for adverse outcomes because of HDS–drug interactions. [20] This was particularly important for patients on anticoagulants (i.e. warfarin) who concomitantly took HDS products that had antiplatelet or anticoagulant effects (e.g. danshen, dong quai, garlic, ginger and ginkgo). [70,75] In particular, HDS products that contained vitamin K or metabolites related to vitamin K (e.g. coenzyme Q10) had the potential to reduce the effects of warfarin. [75] However, some conflicting information regarding warfarin–HDS interactions was observed when the evidence was retrieved from different literature sources. For instance, in a case study, the international normalised ratio (INR) decreased in patients when ginseng was administered with warfarin in some case reports, [12,66,118] but other in vitro studies demonstrated that several components of Panax ginseng had anticoagulant effects. [12] Furthermore, a controlled clinical trial of healthy subjects revealed that there was no significant interaction when ginseng was administered with warfarin. [12,17,20,31,64] This discrepancy may be attributed to the fact that there are several different species of ginseng on the market [i.e. Asian ginseng ( Panax ginseng), American ginseng ( Panax quinquefolius), Siberian ginseng ( Eleutherococcus senticosus)], different extract types and different doses used. Another interesting example is the concomitant use of warfarin with green tea. Some studies suggested that green tea may enhance the anticoagulant effects of warfarin. [19,75]However, much of the literature suggested that the content of vitamin K in green tea might antagonise the effect of warfarin. [16,17,68,70,75] Regardless, it is important to regularly monitor the INR levels of warfarin users who also use HDS products that might influence the anticoagulation effect.
In addition, patients on a digoxin regime who have been taking an HDS should check to ensure that their plasma concentration of digoxin is indeed within the therapeutic ranges. If this is not the case, then the pharmacist usually should recommend to their patients to stop taking these HDS or have their digoxin dose adjusted by their healthcare providers; for example, as digoxin serum concentrations are usually measured by fluorescence polarisation immunoassay or microparticle enzyme immunoassay, which may be influenced by ginseng and danshen ( Salvia miltiorrhiza). [20,58] False digoxin levels may confuse laboratory results and result in inappropriate patient management. Furthermore, aloe vera ( Aloe barbadensis), buckthorn ( Rhamnus catartica), cascara ( Rhamnus purshiani), licorice ( Glycyrrhiza glabra) and senna ( Cassia senna) may cause hypokalaemia and result in digoxin toxicity. [16,17,33,47]As a result, digoxin users should be told to avoid taking the aforementioned herbal remedies.
In this study, the documented evidence of HDS–drug interactions and contraindications were systematically reviewed from the published literature. This was done because healthcare professionals, in general, use only textbooks, journal and review articles, as well as Internet as their major information source for HDS. [119] Although the NCCAM and Office of Dietary Supplements are the two most commonly used, free online resources about HDS, [120] only limited information is available related to HDS interactions and contraindications on these sites. Furthermore, only 59% of documented HDS–drug interactions could be identified with either their mechanisms and/or severity in either of the two common drug interaction resources (i.e. MicroMedex® and NMCD®). Among them, over 40% of the interactions differed in their severity rating, which is likely to create confusion among healthcare providers about the potential harmful effects associated with a given HDS–drug interactions. Concerns about disagreements across literature resources and databases for drug interactions have been raised before, [121] and these increase the difficulty in implementing an evidence-based clinical practice for HDS products in clinical care. The intention of this review was to evaluate the evidence of HDS interactions and contraindications and to assist clinical practitioners in identifying patients with specific disease states and drug regimens that are more susceptible to these HDS–drug interactions and contraindications.
One of the limitations of this review was that it included all relevant information identified in the literature, regardless of the evidence types or quality of the studies. Although some HDS–drug interactions with little or no clinical significance were included in this study, their severity grading was based upon the available version of MicroMedex® and NMCD®. In order to reduce any personal bias, only those pairs of interactions with evidence retrieved from the aforementioned two databases were included to categorise the corresponding mechanisms and the severity rating. Consequently, we were unable to evaluate 41% of the interaction pairs for the corresponding mechanisms and severity in this study. Another limitation was the concern of publication bias, which might arise as only HDS products and medications that have been published in the literature on the basis of evidence-based medicine. Therefore, there are many potential HDS–drug or disease interactions that may exist but are simply without documented outcomes. Lastly, only reports, books or articles published in English were included in this review. Those evidence regarding traditional herbal medicine or folk therapies, which were published in other languages (e.g. Chinese, Japanese), might be missing. Thus, it is very likely that the amount of documented HDS–drug interactions and/or contraindications in this review might be under-reported.

Conclusions

This review provides a structured summary of the evidence of the most widely documented HDS interactions and contraindications with medications. Although our findings primarily concern with a relatively small subset of commonly used medications and HDS entities, it is recommended that healthcare professionals should be paid more attention towards those pairs of interactions between any HDS products that contain St John's Wort, magnesium, calcium, iron and ginkgo, and medications that affect the CNS or the cardiovascular system. These findings should be helpful for healthcare professionals to identify the priority areas where communication regarding HDS usages has the greatest potential to prevent adverse events and to improve patient's therapeutic outcomes.

References

  1. Radimer K, Bindewald B, Hughes J, Ervin B, Swanson C, Picciano MF. Dietary supplement use by US adults: data from the National Health and Nutrition Examination Survey, 1999–2000. Am J Epidemiol 2004; 160: 339–49.
  2. Timbo BB, Ross MP, McCarthy PV, Lin CT. Dietary supplements in a national survey: prevalence of use and reports of adverse events. J Am Diet Assoc 2006; 106: 1966–74.
  3. Miller MF, Bellizzi KM, Sufian M, Ambs AH, Goldstein MS, Ballard-Barbash R. Dietary supplement use in individuals living with cancer and other chronic conditions: a population-based study. J Am Diet Assoc 2008; 108: 483–94.
  4. Gardiner P, Graham RE, Legedza AT, Eisenberg DM, Phillips RS. Factors associated with dietary supplement use among prescription medication users. Arch Intern Med 2006; 166: 1968–74.
  5. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 2002; 287: 337–44.
  6. Blendon RJ, DesRoches CM, Benson JM, Brodie M, Altman DE. Americans' views on the use and regulation of dietary supplements. Arch Intern Med 2001; 161: 805–10.
  7. Palmer ME, Haller C, McKinney PE et al. Adverse events associated with dietary supplements: an observational study. Lancet 2003; 361: 101–6.
  8. Shalansky S, Lynd L, Richardson K, Ingaszewski A, Kerr C. Risk of warfarin-related bleeding events and supratherapeutic international normalized ratios associated with complementary and alternative medicine: a longitudinal analysis. Pharmacotherapy 2007; 27: 1237–47.
  9. Mehta DH, Gardiner PM, Phillips RS, McCarthy EP. Herbal and dietary supplement disclosure to health care providers by individuals with chronic conditions. J Altern Complement Med 2008; 14: 1263–9.
  10. Kemper KJ, Amata-Kynvi A, Dvorkin L et al. Herbs and other dietary supplements: healthcare professionals' knowledge, attitudes, and practices. Altern Ther Health Med 2003; 9: 42–9.
  11. Suchard JR, Suchard MA, Steinfeldt JL. Physician knowledge of herbal toxicities and adverse herbdrug interactions. Eur J Emerg Med 2004; 11: 193– 7.
  12. Coxeter PD, McLachlan AJ, Duke CC, Roufogalis BD. Herb-drug interactions: an evidence based approach. Curr Med Chem 2004; 11: 1513–25.
  13. Silverstein DD, Spiegel AD. Are physicians aware of the risks of alternative medicine? J Community Health 2001; 26: 159–74.
  14. Zeolla MM, Cerulli J. Use of and familiarity with dietary supplement information references by practicing pharmacists. J Am Pharm Assoc 2008; 48: 401–4.
  15. Miller LG, Hume A, Harris IM et al. White paper on herbal products. American College of Clinical Pharmacy.Pharmacotherapy 2000; 20: 877–91.
  16. Cassileth BR. Herb-Drug Interactions in Oncology. Lewiston, NY: BC Decker, Inc., 2003.
  17. Gaby AR. A-Z Guide to Drug-Herb-Vitamin Interactions. New York: Three Rivers Press, 2006.
  18. Mahady GB. Botanical Dietary Supplements: Quality, Safety and Efficacy. Lisse, The Netherlands: Swets & Zeitlinger Publishers, 2001.
  19. Mason P. Dietary Supplements. London: Pharmaceutical Press, 2001.
  20. Tatro DS. Drug Interaction Facts. Saint Louis: Wolters Kluwer Health/Facts & Comparisons, 2010.
  21. Ulbricht CE. Natural Standard Herbs & Supplement Reference: Evidence-Based Clinical Review. St Louis, MO: Mosby/Elsevier, 2005.
  22. National Center for Complementary and Alternative Medicine. Herbs at a Glance. http://nccam.nih.gov/health/herbsataglance.htm (accessed October 2011).
  23. Office of Dietary Supplements. Dietary Supplement Fact Sheets. http://ods.od.nih.gov/factsheets/list-all (accessed October 2011).
  24. Dietary Supplement Health and Education Act of 1994. Public Law 103–417 1994. http://ods.od.nih.gov/about/dshea_wording.aspx (accessed February 2011).
  25. Ernst E. Herbal medicinal products during pregnancy: are they safe? Br J Obstet Gynaecol 2002; 109: 227–35.
  26. WHO Collaborating Centre for Drug Statistics Methodology. ATCDDD Index 2011. http://www.whocc.no/atc_ddd_index (accessed December 2011).
  27. MICROMEDEX_ 1.0 (Healthcare Series). Interaction Database. http://www.thomsonhc.com/hcs/librarian/ND_T/HCS/ND_PR/Main/CS/A304ED/DUPLICATIONSHIELDSYNC/

    95C0EB/ND_ PG/PRIH/ND_B/HCS/ND_P/Main/PFActionId/hcs.Interactions.FindDrugInteractions (accessed November 2011).
  28. Natural Medicines Comprehensive Database. Natural ProductDrug Interaction Checker. http://naturaldatabase.therapeuticresearch.com/nd/Search.-aspx?s=ND&cs=&pt=7&rli=1&sh= (accessed December 2011).
  29. Goldman L, Ausiello DA, Arend W, Armitage JO. Cecil Medicine: Expert Consult. Philadelphia, PA: Saunders Elsevier, Inc., 2007.
  30. Ernst E. Herb-drug interactions: potentially important but woefully under-researched. Eur J Clin Pharmacol 2000; 56: 523–4.
  31. Fugh-Berman A. Herb-drug interactions. Lancet 2000; 355: 134–8.
  32. McIntyre M. A review of the benefits, adverse events, drug interactions, and safety of St. John's Wort ( Hypericum perforatum): the implications with regard to the regulation of herbal medicines. J Altern Complement Med 2000; 6: 115–24.
  33. Semaan N. Integration of complementary disciplines into the oncology clinic. Part III. Herbal medicine–drug interactions: the role of the pharmacist. Curr Probl Cancer 2000; 24: 213–22.
  34. Barone GW, Gurley BJ, Ketel BL, Abul-Ezz SR. Herbal supplements: a potential for drug interactions in transplant recipients. Transplantation 2001; 71: 239–41.
  35. Fugh-Berman A, Ernst E. Herb-drug interactions: review and assessment of report reliability. Br J Clin Pharmacol2001; 52: 587–95.
  36. Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: a systematic review. Drugs 2001; 61: 2163–75.
  37. Markowitz JS, DeVane CL. The emerging recognition of herb-drug interactions with a focus on St. John's wort (Hypericum perforatum). Psychopharmacol Bull 2001; 35: 53–64.
  38. Rogers EA, Gough JE, Brewer KL. Are emergency department patients at risk for herb-drug interactions? Acad Emerg Med 2001; 8: 932–4.
  39. Block KI, Gyllenhaal C. Clinical corner: herb-drug interactions in cancer chemotherapy: theoretical concerns regarding drug metabolizing enzymes. Integr Cancer Ther 2002; 1: 83–9.
  40. Dergal JM, Gold JL, Laxer DA et al. Potential interactions between herbal medicines and conventional drug therapies used by older adults attending a memory clinic. Drugs Aging 2002; 19: 879– 86.
  41. Ly J, Percy L, Dhanani S. Use of dietary supplements and their interactions with prescription drugs in the elderly.Am J Health Syst Pharm 2002; 59: 1759–62.
  42. Lyons TR. Herbal medicines and possible anesthesia interactions. AANA J 2002; 70: 47–51.
  43. Myers SP. Interactions between complementary medicines and warfarin. Aust Prescr 2002; 25: 54– 6.
  44. Wang Z, Hamman MA, Huang SM, Lesko LJ, Hall SD. Effect of St John's wort on the pharmacokinetics of fexofenadine. Clin Pharmacol Ther 2002; 6: 414–20.
  45. Buehler BA. Interactions of herbal products with conventional medicines and potential impact on pregnancy. Birth Defects Res B Dev Reprod Toxicol 2003; 68: 494–5.
  46. Chavez ML, Jordan MA, Chavez PI. Evidence-based drug-herbal interactions. Life Sci 2006; 78: 2146–57.
  47. Williamson EM. Drug interactions between herbal and prescription medicines. Drug Saf 2003; 26: 1075–92.
  48. Zhou S, Gao Y, Jiang W, Huang M, Xu A, Paxton JW. Interactions of herbs with cytochrome P450. Drug Metab Rev 2003; 35: 35–98.
  49. Gurley BJ, Gardner SF, Hubbard MA et al. In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantiumEchinacea purpurea, milk thistle, and saw palmetto. Clin Pharmacol Ther 2004; 5: 428–40.
  50. Huang SM, Lesko LJ. Drug-drug, drug-dietary supplement, and drug-citrus fruit and other food interactions: what have we learned? J Clin Pharmacol 2004; 44: 559–69.
  51. Ohnishi N, Yokoyama T. Interactions between medicines and functional foods or dietary supplements. Keio J Med2004; 53: 137–50.
  52. Peng CC, Glassman PA, Trilli LE, Hayes-Hunter J, Good CB. Incidence and severity of potential drug-dietary supplement interactions in primary care patients: an exploratory study of 2 outpatient practices. Arch Intern Med2004; 164: 630–6.
  53. Yin QP, Tomlinson B, Waye MM, Chow Albert HL, Chow Moses SS. Pharmacogenetics and herb-drug interactions: experience with Ginkgo biloba and omeprazole. Pharmacogenetics 2004; 14: 841– 50.
  54. Yoshioka M, Ohnishi N, Koishi T et al. Studies on interactions between functional foods or dietary supplements and medicines. IV. Effects of Ginkgo biloba leaf extract on the pharmacokinetics and pharmacodynamics of nifedipine in healthy volunteers. Biol Pharm Bull 2004; 27: 2006–9.
  55. Bartlett H, Eperjesi F. Possible contraindications and adverse reactions associated with the use of ocular nutritional supplements. Ophthalmic Physiol Opt 2005; 25: 179–94.
  56. Bressler R. Herb-drug interactions: interactions between saw palmetto and prescription medications. Geriatrics2005; 60: 32–4.
  57. Bressler R. Herb-drug interactions: interactions between kava and prescription medications. Geriatrics 2005; 60: 24–5.
  58. Bressler R. Herb-drug interactions: interactions between ginseng and prescription medications. Geriatrics 2005; 60: 16–7.
  59. Bressler R. Herb-drug interactions: St. John's wort and prescription medications. Geriatrics 2005; 60: 21–3.
  60. Bressler R. Herb-drug interactions: interactions between Ginkgo biloba and prescription medications. Geriatrics2005; 60: 30–3.
  61. Chiang HM, Fang SH, Wen KC et al. Life-threatening interaction between the root extract of Pueraria lobata and methotrexate in rats. Toxicol Appl Pharmacol 2005; 209: 263–8.
  62. Gurley BJ, Gardner SF, Hubbard MA et al. Clinical assessment of effects of botanical supplementation on cytochrome P450 phenotypes in the elderly: St John's wort, garlic oil, Panax ginseng and Ginkgo bilobaDrugs Aging 2005; 22: 525–39.
  63. Gurley BJ, Gardner SF, Hubbard MA et al. In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes. Clin Pharmacol Ther 2005; 77: 415–26.
  64. Hu Z, Yang X, Ho PCL et al. Herb-drug interactions: a literature review. Drugs 2005; 65: 1239–82.
  65. Izzo AA. Herb-drug interactions: an overview of the clinical evidence. Fundam Clin Pharmacol 2005; 19: 1–16.
  66. Izzo AA, Di Carlo G, Borrelli F, Ernst E. Cardiovascular pharmacotherapy and herbal medicines: the risk of drug interaction. Int J Cardiol 2005; 98: 1–14.
  67. Jan WC, Lin LC, Chen CF, Tsai TH. Herb-drug interaction of Evodia rutaecarpa extract on the pharmacokinetics of theophylline in rats. J Ethnopharmacol 2005; 102: 440–5.
  68. Marder VJ. The interaction of dietary supplements with antithrombotic agents: scope of the problem. Thromb Res2005; 117: 7–13.
  69. Singh YN. Potential for interaction of kava and St. John's wort with drugs. J Ethnopharmacol 2005; 100: 108–13.
  70. Daugherty NE, Smith KM. Dietary supplement and selected food interactions with warfarin. Orthopedics 2006; 29: 309–14.
  71. Gurley BJ, Barone GW, Williams DK et al. Effect of milk thistle ( Silybum marianum) and black cohosh (Cimicifuga racemosa) supplementation on digoxin pharmacokinetics in humans. Drug Metab Dispos 2006; 34: 69–74.
  72. Haller CA. Clinical approach to adverse events and interactions related to herbal and dietary supplements. Clin Toxicol (Phila) 2006; 44: 605–10.
  73. Jiang X, Blair EY, McLachlan AJ. Investigation of the effects of herbal medicines on warfarin response in healthy subjects: a population pharmacokinetic-pharmacodynamic modeling approach. J Clin Pharmacol 2006; 46: 1370–8.
  74. Meijerman I, Beijnen JH, Schellens JH. Herb-drug interactions in oncology: focus on mechanisms of induction.Oncologist 2006; 11: 742–52.
  75. Nutescu EA, Shapiro NL, Ibrahim S, West P. Warfarin and its interactions with foods, herbs and other dietary supplements. Expert Opin Drug Saf 2006; 5: 433–51.
  76. Venkataramanan R, Komoroski B, Strom S. In vitro and in vivo assessment of herb drug interactions. Life Sci2006; 78: 2105–15.
  77. Yang XX, Hu ZP, Duan W, Zhu YZ, Zhou SF. Drug-herb interactions: eliminating toxicity with hard drug design.Curr Pharm Des 2006; 12: 4649– 64.
  78. Gurley BJ, Swain A, Barone GW et al. Effect of goldenseal ( Hydrastis canadensis) and kava kava ( Piper methysticum) supplementation on digoxin pharmacokinetics in humans. Drug Metab Dispos 2007; 35: 240–5.
  79. Marchetti S, Mazzanti R, Beijnen JH, Schellens JH. Concise review: clinical relevance of drug drug and herb drug interactions mediated by the ABC transporter ABCB1 (MDR1, P-glycoprotein). Oncologist 2007; 12: 927–41.
  80. Nekvindova J, Anzenbacher P. Interactions of food and dietary supplements with drug metabolising cytochrome P450 enzymes. Ceska Slov Farm 2007; 56: 165–73.
  81. Skalli S, Zaid A, Soulaymani R. Drug interactions with herbal medicines. Ther Drug Monit 2007; 29: 679–86.
  82. Sulli MM, Ezzo DC. Drug interactions with vitamins and minerals. US Pharm 2007; 1: 42–55.
  83. Tang J, Sun J, Zhang Y, Li L, Cui F, He Z. Herbdrug interactions: effect of Ginkgo biloba extract on the pharmacokinetics of theophylline in rats. Food Chem Toxicol 2007; 45: 2441–5.
  84. Yetley EA. Multivitamin and multimineral dietary supplements: definitions, characterization, bioavailability, and drug interactions. Am J Clin Nutr 2007; 85: 269S–76S.
  85. Cranwell-Bruce L. Herb-drug interactions. Medsurg Nurs 2008; 17: 52–4.
  86. Fan L, Zhang W, Guo D et al. The effect of herbal medicine baicalin on pharmacokinetics of rosuvastatin, substrate of organic anion-transporting polypeptide 1B1. Clin Pharmacol Ther 2008; 83: 471–6.
  87. Gardiner P, Phillips R, Shaughnessy AF. Herbal and dietary supplement–drug interactions in patients with chronic illnesses. Am Fam Physician 2008; 77: 73–8.
  88. Gurley BJ, Swain A, Hubbard MA et al. Supplementation with goldenseal ( Hydrastis canadensis), but not kava kava ( Piper methysticum), inhibits human CYP3A activity in vivo. Clin Pharmacol Ther 2008; 83: 61–9.
  89. Gurley BJ, Swain A, Hubbard MA et al. Clinical assessment of CYP2D6-mediated herb-drug interactions in humans: effects of milk thistle, black cohosh, goldenseal, kava kava, St. John's wort, and Echinacea. Mol Nutr Food Res 2008; 52: 755–63.
  90. Gurley BJ, Swain A, Williams DK, Barone G, Battu SK. Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: comparative effects of St. John's wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics. Mol Nutr Food Res 2008; 52: 772–9.
  91. Mohammed Abdul MI, Jiang X, Williams KM et al. Pharmacodynamic interaction of warfarin with cranberry but not with garlic in healthy subjects. Br J Pharmacol 2008; 154: 1691–700.
  92. Nowack R. Herb-drug interactions in nephrology: documented and theoretical. Clin Nephrol 2008; 69: 319–25.
  93. Nowack R. Review article: cytochrome P450 enzyme, and transport protein mediated herb-drug interactions in renal transplant patients: grapefruit juice, St John's Wort - and beyond! Nephrology (Carlton) 2008; 13: 337–47.
  94. Okonta JM, Uboh M, Obonga WO. Herb-drug interaction: a case study of effect of ginger on the pharmacokinetic of metronidazole in rabbit. Indian J Pharm Sci 2008; 70: 230–2.
  95. Samuels N, Finkelstein Y, Singer SR, Oberbaum M. Herbal medicine and epilepsy: proconvulsive effects and interactions with antiepileptic drugs. Epilepsia 2008; 49: 373–80.
  96. Sood A, Sood R, Brinker FJ, Mann R, Loehrer LL, Wahner-Roedler DL. Potential for interactions between dietary supplements and prescription medications. Am J Med 2008; 121: 207–11.
  97. Tomlinson B, Hu M, Lee VW. In vivo assessment of herb-drug interactions: possible utility of a pharmacogenetic approach? Mol Nutr Food Res 2008; 52: 799–809.
  98. Ulbricht C, Chao W, Costa D, Rusie-Seamon E, Weissner W, Woods J. Clinical evidence of herbdrug interactions: a systematic review by the natural standard research collaboration. Curr Drug Metab 2008; 9: 1063–120.
  99. Borrelli F, Izzo AA. Herb-drug interactions with St John's wort ( Hypericum perforatum): an update on clinical observations. AAPS J 2009; 11: 710–27.
  100. Chang JC, Wu YT, Lee WC, Lin LC, Tsai TH. Herb-drug interaction of silymarin or silibinin on the pharmacokinetics of trazodone in rats. Chem Biol Interact 2009; 182: 227–32.
  101. Goldman RD, Vohra S, Rogovik AL. Potential vitamin-drug interactions in children: at a pediatric emergency department. Paediatr Drugs 2009; 11: 251–7.
  102. Holcomb SS. Common herb-drug interactions: what you should know. Nurse Pract 2009; 34: 21– 9.
  103. Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: an updated systematic review.Drugs 2009; 69: 1777–98.
  104. Lapi F, Vietri M, Moschlni M et al. Definition of potential interactions between synthetic drugs, herbal drugs and dietary supplements during preoperative anaesthesiological assessment: a cross-sectional study in Tuscan County, Italy. Drug Saf 2009; 32: 982.
  105. Shord SS, Shah K, Lukose A. Drug-botanical interactions: a review of the laboratory, animal, and human data for 8 common botanicals. Integr Cancer Ther 2009; 8: 208–27.
  106. Toselli F, Matthias A, Gillam EM. Echinacea metabolism and drug interactions: the case for standardization of a complementary medicine. Life Sci 2009; 85: 97–106.
  107. Abad MJ, Bedoya LM, Bermejo P. An update on drug interactions with the herbal medicine Ginkgo bilobaCurr Drug Metab 2010; 11: 171–81.
  108. Cheng CW, Fan W, Ko SG, Song L, Bian ZX. Evidence-based management of herb-drug interaction in cancer chemotherapy. Explore (NY) 2010; 6: 324–9.
  109. Chien CF, Wu YT, Lee WC, Lin LC, Tsai TH. Herb-drug interaction of Andrographis paniculata extract and andrographolide on the pharmacokinetics of theophylline in rats. Chem Biol Interact 2010; 184: 458–65.
  110. Kim BH, Kim KP, Lim KS et al. Influence of Ginkgo biloba extract on the pharmacodynamic effects and pharmacokinetic properties of ticlopidine: an open-label, randomized, two-period, two-treatment, two-sequence, single-dose crossover study in healthy Korean male volunteers. Clin Ther 2010; 32: 380–90.
  111. Nieminen TH, Hagelberg NM, Saari TI et al. St John's wort greatly reduces the concentrations of oral oxycodone.Eur J Pain 2010; 14: 854–9.
  112. Rogovik AL, Vohra S, Goldman RD. Safety considerations and potential interactions of vitamins: should vitamins be considered drugs? Ann Pharmacother 2010; 44: 311–24.
  113. Simmons T, Schneir AB. Hypertensive crisis from a MAOI/Supplement interaction leading to myocardial infarction and acute heart failure. Clin Toxicol 2010; 48: 631.
  114. Barnes PM, Powell-Griner E, McFann K, Nahin RL. Complementary and alternative medicine use among adults: United States, 2002. Adv Data 2004; 343: 1–19.
  115. Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. Natl Health Stat Report 2008; 12: 1–23.
  116. World Health Organization. WHO Monographs on Selected Medicinal Plants, Vol. 1. Geneva http://whqlibdoc.who.int/publications/1999/9241545178.pdf (accessed January 2012)
  117. Barnes J, Anderson LA, Gibbons S, Phillipson JD. Echinacea species ( Echinacea angustifolia (DC.) Hell.,Echinacea pallida (Nutt.) Nutt., Echinacea purpurea (L.) Moench): a review of their chemistry, pharmacology and clinical properties. J Pharm Pharmacol 2005; 57: 929–54.
  118. Sparreboom A, Cox MC, Acharya MR, Figg WD. Herbal remedies in the United States: potential adverse interactions with anticancer agents. J Clin Oncol 2004; 22: 2489–503.
  119. Howard N, Tsourounis C, Kapusnik-Uner J. Dietary supplement survey of pharmacists: personal and professional practices. J Altern Complement Med 2001; 7: 667–80.
  120. McHughes M, Timmermann BN. A review of the use of CAM therapy and the sources of accurate and reliable information. J Manag Care Pharm 2005; 11: 695–703.
  121. Vitry AI. Comparative assessment of four drug interaction compendia. Br J Clin Pharmacol 2007; 63: 709–14.




3 comments:

Anonymous said...

Υοur current post рrovidеs cοnfiгmed
helpful to mе peгsonally. It’s very useful and you're obviously very educated of this type. You have opened up my personal face to varying opinion of this specific subject with intriquing, notable and reliable articles.
My website - ambien

Anonymous said...

Yοuг current report has proѵеn beneficial to
myself. Ӏt’s ехtгemely еduсatiоnal anԁ you're obviously very experienced in this area. You have popped my personal sight to different thoughts about this topic along with intriguing, notable and strong articles.

Here is my website: Buy Valium Online
Take a look at my web blog :: Buy Valium Online

Anonymous said...

It's not my first time to visit this web page, i am browsing this web page dailly and take good data from here every day.

Feel free to visit my blog post; natural cellulite treatment