| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
HERBAL MEDICINE |
From the Centre for Evaluation of Medicines, St Joseph's Healthcare Hamilton, Ontario, Canada (Mr Singh, Dr Levine) and the Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada (Dr Levine).
Address for reprints: Address for correspondence: Mitchell A. H. Levine, Centre for Evaluation of Medicines, 105 Main St. East, Level One, Hamilton, ON, Canada L8N 1G6; e-mail: levinem{at}mcmaster.ca.
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
Key Words: Natural health products • herbals • drug interaction • pharmacoepidemiology • NPHS
Burgeoning public interest in natural products has brought increased attention from the medical research community, leading to the recognition that many NHPs have quantifiable pharmacological effects. As such, there exists the potential for interference with conventional drugs, whereby NHPs may either antagonize therapeutic efficacy or conversely produce additive or synergistic effects that increase the likelihood of drug toxicity.5-7 The potential for drug-NHP interactions is suggested by pharmacological investigations, case reports of adverse effects, and a small number of controlled trials.7-9 Several common natural products can interact with medications.6,10 For example, St John's wort has been shown to induce cytochrome P450 3A4 and P-glycoprotein-mediated metabolism, resulting in increased excretion and a potential reduction in the therapeutic efficacy of a number of important drugs, including digoxin, certain anti-HIV agents, and cyclosporin.6,11,12 However, these studies notwithstanding, there is generally a lack of high-quality scientific information on the potential for drug interactions for most NHPs.5,13 Uncertainty about the potential for a given drug-NHP combination to interact is further compounded by the complex chemical composition of most NHPs, the lack of standardization in manufacturing and quality control, and variability in dosing and administration.
Although there is evidence that a substantial proportion of the population engages in the concurrent use of NHPs and drugs, there is little epidemiological information regarding the incidence of interactions between NHPs and drugs. In Canada, reports of adverse effects associated with NHPs (including drug interactions) are collected by Health Canada through the Canadian Adverse Drug Reaction Monitoring Program, the same voluntary reporting system used for pharmaceuticals.14,15 Although case reports are valuable in generating hypotheses regarding drug-NHP combinations that may interact, voluntary reporting cannot be relied on to estimate the incidence of interactions.16 The number of drug-NHP interaction case reports is relatively small given the popularity of NHPs.7 However, because there may be significant underreporting, it is difficult to assess whether this truly reflects the rarity of drug-NHP interactions.7,14
Another potential source of information on the epidemiology of drug-NHP interactions are surveys assessing potential interactions based on patterns of combined use. Four small surveys have attempted to assess the prevalence of potential drug-NHP interactions. In an oncology clinic at a US Veterans Administration hospital, Lee et al13 found that of the 61% of subjects who reported use of a dietary supplement (including vitamins), 12% were at risk for a potential interaction with a drug. Rogers et al17 found that 5.6% of drug-NHP combination users in a US emergency room were at risk for an interaction. In a survey of elderly patients at a memory clinic, 27% of those using drugs and herbal remedies at the same time were at risk for an interaction.18 Finally, 1 interaction among 16 NHP users was observed in a survey of elderly at a day hospital.19 Because of the small numbers and specialized populations in these studies, they are insufficient to predict the degree to which NHPs are combined with potentially interacting drugs in the population at large.
Given the paucity of information in this area, we undertook an analysis of potential drug-NHP interactions in the National Population Health Survey. Our intent was to assess the degree to which potentially adverse combinations of drugs and NHPs are used in the Canadian population, as well as to identify the groups most at risk so that preventative interventions may be considered.
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
18 years of age). Most respondents were interviewed by phone. Proxy responses were allowed for children younger than 12 years of age and adults unable to respond to the survey. Further details regarding the design of the NPHS have been published elsewhere.20,21 All NPHS respondents were asked a series of questions regarding the use of medications and "other health products" in the prior 2 days. Up to 12 agents in each category were listed for each respondent. Dose and frequency were not recorded. Of the multitude of "other health products" reported, NHPs were defined in this study as botanical and naturally derived nonbotanical products such as glucosamine. Meal replacement and weight gain formulas, vitamins and minerals with recommended daily intakes (RDIs), and protein, amino acid, and creatine supplements were excluded from the analysis.
Analysis
The prevalence of use for each NHP reported by adult respondents in the NPHS was tabulated. Potential drug-NHP interactions were assessed for each adult respondent who reported the concurrent use of at least 1 NHP and 1 conventional medication with systemic exposure (ie, topical, inhaled, and other medicines with primarily local effects were excluded). The first step in this process was the identification and compilation of the drug interactions that have been associated with the NHPs reported by NPHS respondents. Literature searches in Medline and the Allied and Complementary Medicine (AMED) databases garnered clinical studies, case reports, in vitro and animal studies, and reviews documenting the evidence for interactions involving commonly used NHPs. Compendia of natural products and herbal remedies such as the Natural Medicines Comprehensive Database22 were another important source of interaction information, especially for less common NHPs.
To further characterize the importance of each of these interactions, a system was needed to classify both their clinical significance and the underlying quality of evidence. In the absence of a standardized drug-NHP interaction resource, clinical significance of potential interactions was rated according to an ordinal scale used by Brazier and Levine10 in their review of herb-drug interactions. In this classification scheme, "major" interactions are interactions that require urgent medical attention or hospitalization, or caused death or permanent damage. "Moderate" interactions are characterized by symptoms that cause interruption in the normal activities of the sufferer or require nonurgent medical attention. "Minor" interactions produce symptoms not requiring medical attention. A fourth category was reserved for interactions that have the potential to cause adverse effects due to alterations in pharmacokinetic or pharmacodynamic parameters, although the clinical effects of these changes are currently unknown. Brazier and Levine10 also assessed the quality of the evidence used to support the interactions and identified 4 categories: randomized controlled trial data, observational data from cohort or case-controlled studies, data from case reports or case series, and "theoretical" data. The latter was reserved for interactions that were supported by evidence obtained from either in vitro or animal experiments, or reasoning that arose from an understanding of pharmacological mechanisms (ie, where clinical data in humans were lacking). In the study presented here, the clinical significance and the evidence quality for potential interactions were both assigned by a physician clinical pharmacologist (ML) and a pharmacist (SS) before the epidemiological analysis was conducted. Each survey respondent's NHP-drug combinations were screened through a computer-assisted algorithm, and all potential interactions were tagged with both a clinical significance and evidence quality indicator.
Statistical analyses were conducted to ascertain both the overall prevalence of potential interactions and the prevalence within subgroups defined by various demographic, socioeconomic, lifestyle, and health characteristics. All analytical guidelines provided by Statistics Canada for analysis of the NPHS were followed. The analytical sample weights and bootstrapping methods provided by Statistics Canada were employed to obtain accurate point estimates and confidence intervals. Also in accordance with the agency's recommendations, all population prevalence estimates with a coefficient of variation (CV) between 16.6% and 33.3% were considered to be of "marginal" precision and are annotated as such in this report. Estimates with a CV greater than 33.3% or those based on less than 5 subjects are not reported. All statistical analyses were conducted with SPSS v.11.0 at the Statistics Canada Research Data Centre, housed at McMaster University, Hamilton, Ontario. Because the study was composed of an analysis of preexisting survey results, the study required and received approval from Statistics Canada through a peer review process that assessed ethical and scientific issues. No research ethics board evaluation was required.
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
|
A minimum of 1 potential drug-NHP interaction was identified in 28.4% (95% CI, 24.0%-32.8%) of combination users, representing 14.5% (95% CI, 12.0%-17.0%) of all NHP users and 1.4% (95% CI, 1.1%-1.6%) of the total adult population in Canada. The majority (71%) exhibited only 1 interaction. Ninety percent of all potential interactions were of unknown clinical significance, and most were cited in the literature based only on theoretical evidence. A further breakdown by clinical significance level (ie, major, moderate, or minor) for the remaining 10% cannot be presented because of the small number of respondents in each category. These interacting drug-NHP pairs, their associated clinical significance levels, and evidence base are presented in Table II. Ginkgo biloba was implicated in all 3 interactions of major significance, 2 of which were associated with the potential for major bleeding due to combined use with acetylsalicylic acid (ASA) or warfarin. However, combinations with potentially major outcomes were not highly prevalent. For example, ginkgo-ASA was the most frequently observed major interaction, yet it represented less than 1% of all potential interactions among drug-NHP combination users. Case reports or case series formed the evidence base for all clinically classifiable interactions.
|
|
The 10 most commonly observed potential drug-NHP interactions, together accounting for 50% of all interactions, are listed in Table III. All 10 interactions were of unknown clinical significance and supported by theoretical evidence. Garlic, fish oils, ginkgo, gamma-linolenic acid, and glucosamine were the NHPs implicated in these interactions. As some of the most commonly used NHPs, these agents together accounted for 75% of all potential interactions in the NPHS. Among pharmaceuticals, interactions were most common with ASA and nonsteroidal antiinflammatory drugs (NSAIDs), all of which involved potentiation of antiplatelet effects and a consequent increase in the risk of bleeding.
|
Characteristics of Individuals With Potential Drug-NHP Interactions
Prevalence estimates for potential interactions by selected respondent characteristics are presented in Table IV. Female drug-NHP combination users had a higher prevalence of potential interactions than male users (63% vs 48%, P < .0005), but there was no difference between white and nonwhite respondents. Older combination users were more likely to have a potential interaction (eg, 73% and 69% prevalence in respondents aged >65 years and between 56 and 65 years, respectively, vs 38% among combination users between 18 and 25 years of age).
|
In terms of socioeconomic status, higher education was associated with a lower probability of interaction. Respondents who had less than a high school education were 70% more likely to exhibit at least 1 potential interaction as compared to those who were postsecondary graduates. A similar pattern, although not statistically significant, was seen with increasing annual personal income (data not shown). Among disease states, high blood pressure and diabetes were strongly associated with potential interaction. Deteriorating health status, as measured by the total number of chronic conditions, also increased interaction prevalence. For example, respondents with 3 conditions were more than 3 times as likely as those with no conditions to have a potential interaction. The medication classes most associated with potential interactions were antihypertensives, antidiabetic medications, and diuretics. The risk of an interaction also increased with the number of prescription medicines (ie, over-the-counter drugs [OTCs] excluded) that were used by each respondent. Individuals reporting the use of 4 or more prescribed drugs were more than twice as likely to have a potential interaction as those not using a prescription medicine (ie, OTCs only).
Although nonsignificant, respondents who reported using a regular physician were nearly one third less likely to have a drug-NHP interaction. These estimates are not shown because of unacceptably large variability. Interaction potential was distributed more or less uniformly across other health care use variables, including consultation in the past year with a naturopath, herbalist, or other alternative providers.
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
Within the subset of drug-NHP combination users in the NPHS, more than one quarter exhibited at least 1 potential drug-NHP interaction; that is, they were using a combination that had been cited in the literature as potentially causing harm. Fourteen percent of all NHP users, or 1.4% of the adult population in Canada, was therefore at risk of an interaction between a drug and NHP. Although studies on the prevalence of drug-NHP interactions are few in number, Dergal et al18 found that a similar proportion (27%) of combination users exhibited a potential interaction among seniors at a memory disorders clinic. In contrast, Rogers et al17 reported that only 6% of combination users in their convenience sample of emergency room patients had a potential interaction. However, the relevance of comparing our results with these studies is uncertain given their small samples and specialized populations.
Most interactions (90%) were of unknown clinical significance and were conjectured based on the pharmacological activities of the implicated drug and NHP. Many of these interactions consisted of the potential for bleeding due to combinations of NHPs and drugs with additive or synergistic anticoagulant or antiplatelet effects. Not surprisingly, given the common use of ASA for its antiplatelet properties in heart disease and the popularity of garlic as a cardiovascular tonic, the potential interaction between these 2 agents was seen in 21% of all garlic users and more than 3% of all NHP users. However, whether the effects of such theoretical interactions are clinically consequential is unknown because data on clinical outcomes are lacking.
Ten percent of all potential interactions were classified as having some identifiable clinical significance. All interactions of major clinical significance involved ginkgo biloba. Of particular note was the interaction between ginkgo and ASA, which was observed in about 9% of all users of ginkgo biloba. Cases of major bleeding events (eg, hyphema) in subjects using this combination have been reported in the literature.23 The combination of ginkgo with ASA (or NSAIDs) or warfarin requires caution. In fact, some sources advocate that such combinations should be avoided altogether.6,9,23,24 The use of ginkgo therefore requires special vigilance from both users and health care providers, especially among patients with cardiovascular disease.
The evidence underlying the interactions that were designated as clinically significant consisted of case reports or case series. Given the difficulty in establishing causality from case reports, it is clear that higher quality (cohort and case control) studies are needed to better evaluate the clinical consequences associated with the most commonly observed potential drug-NHP interactions.
Many of the most common interactions identified (regardless of whether their clinical significance was classifiable or was unknown) involved cardiovascular medications and NHPs purported to have cardiovascular benefits. NHP use by heart patients therefore deserves special scrutiny from health care providers so that interactions with drugs can either be prevented or managed appropriately.
Perhaps as important as the interactions discovered in the National Population Health Survey were some that were not found to any significant degree. The prevalence of interactions with major clinical consequences was low. Also, many drug-NHP interactions that have been widely cited in the literature as being of potential clinical importance were either absent or infrequent in our analysis. For example, potential interactions with warfarin were quite rare (accounting for 1.8% of all interactions), as were potentially problematic combinations of drugs and St John's wort. In fact, St John's wort combinations with digoxin, selective serotonin reuptake inhibitors (SSRIs), immunosuppressants, and antiretroviral drugs, all of which may have serious clinical consequences, were not found at all in the data.
A cross-sectional survey such as the National Population Health Survey is not suited to detect interactions with serious consequences because they would cause prompt discontinuation or death and would result in a low prevalence. Nevertheless, the paucity of these and other combinations may indicate that most NHP users successfully avoid many well-documented drug-NHP interactions of major clinical significance.
The clinical characteristics of the survey respondents who demonstrated the highest correlations with the presence of at least 1 interaction were diabetes and high blood pressure. This is not surprising given the large number of NHP interactions with antidiabetic and cardiovascular medicines. The probability of a potential interaction also increased with the number of chronic medical conditions and the number of prescription medicines used by each respondent. The latter association simply reflects the increased chance of interaction as the total number of drug-NHP combinations used by any 1 respondent rises. Other findings include modest associations between interactions and either lower education or smoking. Given the well-established correlations between lower socioeconomic status and poor health status,25 the higher prevalence of potential interactions among these respondents may be due to the use of more medications secondary to poorer health.
This study is the first to evaluate the risk factors for experiencing a potential drug-NHP interaction. In the drug-drug interaction literature, Linnarsson26 found a strong correlation between the probability of a potential drug-drug interaction and increasing age among users of 2 or more medicines in Sweden. Perhaps of even greater relevance to the present discussion is a Finnish study regarding potential interactions due to OTC medicines because, like NHPs, they are consumed through self-selection. In the Finnish study, older age, poor self-reported health status, the presence of a long-term illness, the use of more than 3 prescription drugs, and lower education were all associated with a higher probability of potential interaction in unadjusted analyses.27 Only the latter 3 remained significant in a multivariate analysis. The associations between the risk of a potential interaction and lower education, chronic disease, and the total number of medications that we observed are in accord with these studies and suggest that self-medication practices in these groups require the greatest vigilance.
Study Limitations
The main advantage to using NPHS data for the study of drug-NHP interactions in Canada was the internal and external validity of the results given the representative sample, low nonresponse rates, and meticulous administration. However, a number of limitations must also be addressed. A relatively small sample size of drug-NHP combination users was available for an analysis of interactions. Although this aspect did not impair our ability to produce precise estimates of the total prevalence of potential interactions, it did prevent the presentation of a breakdown by clinical significance level among the 10% of interactions with known clinical significance. The sample of combination users also prevented us from analyzing interactions in potentially important subpopulations, such as within specific ethnic groups or in patients with rarer disease states. Similarly, although it would have been of interest to assess drug interactions with agents used in specific traditions of natural medicine, such as Traditional Chinese Medicine or Ayurveda, the number of combination users was either nil or exceedingly small. Specific studies in populations that employ these traditional systems would therefore be of value.
The possibility of underreporting because of the methodology employed in the NPHS should not be overlooked. Herbs and other NHPs are widely used in a variety of foods, beverages, and multivitamin supplements. However, because these were not specifically queried in the survey, it is possible that their use was not reported. Furthermore, the possibility of response bias due to missing data (ie, the 11% of drug-NHP combination users classified as unevaluable) cannot be dismissed. The true prevalence of potential drug-NHP interaction in the population may therefore be higher than that measured in this study. The crosssectional nature of the data and the relatively short recall period of 2 days employed in the NPHS may also miss a number of respondents who only occasionally use drugs and NHPs in combination. This, in turn, would result in underestimating the true proportion of the population at risk for drug-NHP interactions.
Implications
Awareness of the nature and prevalence of common potential drug-NHP interactions, as well as predisposing factors, is important for encouraging users and health providers to apprise themselves of potential risks associated with combination use. Many interacting combinations can probably be used safely with appropriate education and monitoring. However, there is evidence that NHP use is often not reported to health professionals. Estimates of disclosure rates to physicians range from 20% to 50%.3,28,29 There are also reports that most users obtain advice and information on NHPs from nonprofessional personal contacts, health food stores, and the media.30,31 Furthermore, 1 study demonstrated that adverse effects from herbal remedies are less likely to be reported to physicians than those due to conventional OTC drugs.32
In light of those observations, as well as the present results that nearly 1 in 8 NHP users is at risk for an interaction, a number of initiatives are required on the part of health professionals. Physicians, nurses, and pharmacists must be more vigilant in (1) inquiring about and documenting NHP use with the same alacrity applied to conventional medicines, (2) maintaining an up-to-date working knowledge of common NHPs and potential interactions with drugs, (3) encouraging patients to engage in dialogue prior to NHP use, and (4) reporting suspected NHP-related adverse events and interactions to appropriate regulatory agencies. These measures are especially important for the elderly, cardiac patients, patients with diabetes, and individuals with multiple conditions and medications. Users of antiplatelet and anticoagulant medicines are of special concern because of the large number of potentially serious interactions associated with this class of medicines.
Regulatory agencies should also adapt existing reporting systems or perhaps create new ones, so that adverse effects and drug interactions associated with NHPs are captured more effectively. This may involve measures such as promotional or educational activities directed at health care providers and consumers to inform them of the importance of reporting NHP-related events, as well as the existence of reporting mechanisms. In addition, the move toward greater regulation of NHPs by regulatory agencies, such as Canada's Natural Health Products Directorate, will both improve manufacturing and quality control standards and facilitate a more consistent and comprehensive appraisal of NHP-associated risks, including the potential for interactions with drugs.
|
ACKNOWLEDGEMENTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
1. Singh SR, Levine MAH. Natural health product use in Canada: analysis of the National Population Health Survey. Can J Clin Pharmacol. 2006;13: e240-e250.[Medline] [Order article via Infotrieve]
2. Troppmann L, Johns T, Gray-Donald K: Natural health product use in Canada. Can J Public Health. 2002;93: 426-430.[Web of Science][Medline] [Order article via Infotrieve]
3. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990-1997. JAMA. 1998; 280: 1569-1575.
4. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population. JAMA. 2002;287: 337-344.
5. Ernst E. Herb-drug interactions: potentially important but woefully under-researched. Eur J Clin Pharmacol. 2000;56: 523-524.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
6. Miller LG. Herbal medicinals: selected considerations focusing on known or potential drug-herb interactions. Arch Intern Med. 1998;158: 2200-2211.
7. Fugh-Berman A. Herb-drug interactions. Lancet. 2000;355: 134-138.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
8. Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs. Drugs. 2001;61: 2163-2175.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
9. Braun, L. Herb-drug interaction guide. Aust Fam Phys. 2001; 30: 581-582.[Medline] [Order article via Infotrieve]
10. Brazier N, Levine MAH. Drug-herb interaction among commonly used conventional medicines: a compendium for health care professionals. Am J Ther. 2003;10: 163-169.[CrossRef][Medline] [Order article via Infotrieve]
11. Wang Z, Gorski C, Hamman MA, Huang S, Lesko LJ, Hall SD. The effects of St. John's wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther. 2001;70: 317-326.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
12. Sugimoto K, Ohmori M, Tsuruoka S, et al. Different effects of St. John's wort on the pharmacokinetics of simvastatin and pravastatin. Clin Pharmacol Ther. 2001;70: 518-524.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
13. Lee AH, Ingraham SE, Kopp M, Foraida MI, Jazieh A-R. The incidence of potential interactions between dietary supplements and prescription medications in cancer patients at a Veterans Administration hospital. Am J Clin Oncol. 2006;29: 178-182.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
14. Walji R, Boon H. Reporting adverse events and drug interactions associated with natural health products: development of a theoretical framework. In: Pharmacovigilance of Herbal Medicines: Current State and Future Directions, London, UK, 26-28 April, 2006. Drug Saf. 2006;29: 341-370.[CrossRef]
15. Marles RJ. Regulatory approach to herbal medicine safety in Canada. In: Pharmacovigilance of Herbal Medicines: Current State and Future Directions, London, UK, 26-28 April, 2006. Drug Saf. 2006;29: 341-370.
16. Carson JL, Strom BL, Maislin G. Screening for unknown effects of newly marketed drugs. In: Strom BL, ed. Pharmacoepidemiology. 2nd ed. Chichester, UK: John Wiley; 1994: 431-447.
17. Rogers EA, Gough JE, Brewer KL. Are emergency department patients at risk for herb-drug interactions? Acad Emerg Med. 2001;8: 932-934.[Web of Science][Medline] [Order article via Infotrieve]
18. 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: 879-886.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
19. Frank C. Natural health product use in a day hospital population. Geriatr Today. 2001;4: 64-67.
20. Catlin G, Will P. The National Population Health Survey: highlights of initial developments. Health Rep. 1992;4: 313-319.[Medline] [Order article via Infotrieve]
21. Tambay JL, Catlin G. Sample design of the National Population Health Survey. Health Rep. 1995;7: 1-11.[Medline] [Order article via Infotrieve]
22. Therapeutic Research Faculty. Natural Medicines Comprehensive Database. Available at: www.naturaldatabase.com. Accessed February 15, 2003 to April 30, 2003.
23. Scott GN, Elmer GW. Update on natural product-drug interaction. Am J Health-System Pharm. 2002;59: 339-347.
24. Abebe W. Herbal medication: potential for adverse interactions with analgesic drugs. J Clin Pharm Ther. 2002;27: 391-401.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
25. Goldman N. Social inequalities in health: disentangling the underlying mechanisms. Ann N Y Acad Sci. 2001;954: 118-139.[Web of Science][Medline] [Order article via Infotrieve]
26. Linnarsson R. Drug interactions in primary health care. Scand J Primary Health Care. 1993;11: 181-186.[Medline] [Order article via Infotrieve]
27. Sihvo S, Klaukka T, Martikainen J, Hemminki E. Frequency of daily over-the-counter drug use and potential clinically significant over-the-counter-prescription drug interactions in the Finnish adult population. Eur J Clin Pharmacol. 2000;56: 495-499.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
28. Brazier N, Bedard M, Brazil K, et al. The use of natural health products (NHP) by Ontario seniors. Clin Pharm Ther. 2001; 69: P14.
29. Hensrud DD, Engle DD, Scheitel SM. Underreporting of the use of dietary supplements and nonprescription medications among patients undergoing a periodic health examination. Mayo Clin Proc. 1999;74: 443-447.[Abstract]
30. Perkin JE, Wilson WJ, Schuster K, Rodriguez J, Allen-Chabot A. Prevalence of nonvitamin, nonmineral supplement usage among university students. J Am Dietetic Assoc. 2002;102: 412-414.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
31. Harnack LJ, Rydell SA, Stang J. Prevalence of use of herbal products by adults in the Minneapolis/St. Paul, Minn. Metropolitan Area. Mayo Clin Proc. 2001;76: 688-694.[Abstract]
32. Barnes J, Mills SY, Abbot NC, Willoughby M, Ernst E. Different standards for reporting ADRs to herbal remedies and conventional OTC medicines: face-to-face interviews with 515 users of herbal remedies. Br J Clin Pharmacol. 1998;45: 496-500.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Engdal, O. Klepp, and O. G. Nilsen Identification and Exploration of Herb-Drug Combinations Used By Cancer Patients Integr Cancer Ther, March 1, 2009; 8(1): 29 - 36. [Abstract] [PDF]
|
|
|
|
 |
|
 J. Pesreira, J. Arkinson, and K. Li Use of nonvitamin dietary supplements with prescription medications: Examining the patterns Can Fam Physician, August 1, 2008; 54(8): 1142 - 1144. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
