Brian C. Foster

Impact of African herbal medicines on antiretroviral metabolism

We examined the effects of two African herbal medicines recommended for HIV/AIDS patients on antiretroviral metabolism. Extracts from Hypoxis and Sutherlandia showed significant effects on cytochrome P450 3A4 metabolism and activated the pregnane X receptor approximately twofold. P-glycoprotein expression was inhibited, with Hypoxis showing 42–51% and Sutherlandia showing 19–31% of activity compared with verapamil. Initiating policies to provide herbal medicines with antiretroviral agents may put patients at risk of treatment failure, viral resistance or drug toxicity.

Time‐Dependent Interaction Between Lopinavir/Ritonavir and Fexofenadine

This study investigated the effect of single‐dose and steady‐state lopinavir/ritonavir on the exposure to fexofenadine, as a measure of P‐glycoprotein activity. Sixteen volunteers (8 women) received single‐dose oral fexofenadine 120 mg alone, in combination with single‐dose ritonavir 100 mg or lopinavir/ritonavir 400/100 mg (randomized 1:1, stratified by sex), and in combination with steady‐state lopinavir/ritonavir 400/100 mg twice daily. Single‐dose ritonavir and lopinavir/ritonavir increased the area under the fexofenadine plasma concentration‐time curve from 0 to infinity (AUC∞) by 2.2‐ and 4.0‐fold, respectively (P < .02). Steady‐state lopinavir/ritonavir increased the fexofenadine AUC∞ by 2.9‐fold. No changes were observed in the fexofenadine elimination half‐life (P > .12). The fexofenadine AUC∞ was increased by lopinavir/ritonavir, likely due to increased bioavailability secondary to P‐glycoprotein inhibition. After repeated administration of lopinavir/ritonavir, the interaction was attenuated compared to the single‐dose effect, although a net inhibitory effect was maintained. Time‐dependent inhibition of P‐glycoprotein by lopinavir/ritonavir should be considered when P‐glycoprotein substrates are coadministered.

Study of Natural Health Product Adverse Reactions (SONAR): Active Surveillance of Adverse Events Following Concurrent Natural Health product and Prescription Drug Use in Community Pharmacies

Background Many consumers use natural health products (NHPs) concurrently with prescription medications. As NHP-related harms are under-reported through passive surveillance, the safety of concurrent NHP-drug use remains unknown. To conduct active surveillance in participating community pharmacies to identify adverse events related to concurrent NHP-prescription drug use. Methodology/Principal Findings Participating pharmacists asked individuals collecting prescription medications about (i) concurrent NHP/drug use in the previous three months and (ii) experiences of adverse events. If an adverse event was identified and if the patient provided written consent, a research pharmacist conducted a guided telephone interview to gather additional information after obtaining additional verbal consent and documenting so within the interview form. Over a total of 112 pharmacy weeks, 2615 patients were screened, of which 1037 (39.7%; 95% CI: 37.8% to 41.5%) reported concurrent NHP and prescription medication use. A total of 77 patients reported a possible AE (2.94%; 95% CI: 2.4% to 3.7%), which represents 7.4% of those using NHPs and prescription medications concurrently (95%CI: 6.0% to 9.2%). Of 15 patients available for an interview, 4 (26.7%: 95% CI: 4.3% to 49.0%) reported an AE that was determined to be “probably” due to NHP use. Conclusions/Significance Active surveillance markedly improves identification and reporting of adverse events associated with concurrent NHP-drug use. Although not without challenges, active surveillance is feasible and can generate adverse event data of sufficient quality to allow for meaningful adjudication to assess potential harms.

Community Identification of Natural Health Product– Drug Interactions

Background: The majority of Canadians use natural health products (NHPs), most of which are purchased in pharmacies. Community pharmacists regularly field inquiries regarding NHPs. As such, pharmacists are ideally placed to answer questions about NHP use and interactions with other medications. Objective: To identify community pharmacists’ familiarity with NHPs and NHP-related adverse events (AEs) and their knowledge and ability to counsel on potential and known NHP–drug interactions. Methods: Survey questions were derived from a literature review of previous surveys, data collected from Health Canada, and in consultation with clinicians, pharmacists, policy-makers, and researchers. A convenience sample of 321 community pharmacists in Alberta and British Columbia were asked to participate. Results: We received responses from 132 pharmacists, resulting in a response rate of 41% (132/321). A total of 19% of the sample had previously reported an adverse event to Health Canada. When asked specifically about NHP–drug interactions/AEs, 47% of pharmacists stated that they had identified a potential interaction; however, only 2 of these reported it to Health Canada. Pharmacists were most familiar (76% of respondents) with the interaction between sertraline and St. Johns wort and were least familiar with interactions between NHPs and antiretrovirals. Conclusions: This survey provides evidence to suggest that pharmacists encounter reportable NHP–drug interactions, yet rarely choose to report these events. The current lack of available data on NHP AEs makes it difficult to provide patients and healthcare providers with useful strategies for managing AEs and drug interactions. Changes to the current system of monitoring AEs due to NHPs and further education of healthcare professionals regarding NHP—drug interactions is required.

In vitro inhibitory effect of West African medicinal and food plants on human cytochrome P450 3A subfamily

AIM OF THE STUDY In Africa, medicinal plants are used intensively and concomitantly with allopathic medicines in the treatment of opportunity diseases by many patients or by healthy person to prevent diseases. However, there is little information about the interactions between medicines and botanical products used currently in West Africa area. Therefore, the aim of the present investigation is to study the effect of some plant products on CYP3A4, CYP3A5 and CYP3A7, three individual enzymes of CYP3A subfamily, in vitro. MATERIALS AND METHODS Teas and ethanolic extracts of medicinal, food and co-administered plants were evaluated on CYP3A4, CYP3A5 and CYP3A7 individual enzymes in vitro using fluorometric assays. RESULTS Extracts of adjuvant plants such as Aframomum cuspidatum, and Aframomum melegueta, as well as one medicinal plant (Harrisonia abyssinica) inhibited CYP3A4, CYP3A5 and CYP3A7 activity more than 90%. Phyllanthus amarus showed high inhibition of CYP3A5 and CYP3A7. Food plants (Solanum macrocarpon and Talinum triangulare) inhibited CYP3A4 and CYP3A5 less than 20%. CONCLUSION These results indicate that plants tested in this study affect in vitro the activity of the main three CYP3A subfamily enzymes. These active plants could interfere with the metabolism at phase I of conventional drugs in vivo as well act as pharmacoenhancers in herbal mixtures.

Modulation of human cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) in Caco-2 cell monolayers by selected commercial-source milk thistle and goldenseal products

In this study, we used an in vitro Caco-2 cell monolayer model to evaluate aqueous extracts of commercial-source goldenseal (Hydrastis canadensis) and milk thistle (Silybum marianum) capsule formulations, their marker phytochemicals (berberine and silibinin, respectively), as well as dillapiol, vinblastine, and the HIV protease inhibitor saquinavir for their ability to modulate CYP3A4 and ABCB1 expression after short-term exposure (48 h). Both upregulation and downregulation of CYP3A4 expression was observed with extracts of varying concentrations of the two natural health products (NHPs). CYP3A4 was highly responsive in our system, showing a strong dose-dependent modulation by the CYP3A4 inhibitor dillapiol (upregulation) and the milk thistle flavonolignan silibinin (downregulation). ABCB1 was largely unresponsive in this cellular model and appears to be of little value as a biomarker under our experimental conditions. Therefore, the modulation of CYP3A4 gene expression can serve as an important marker for the in vitro assessment of NHP-drug interactions.

Actions of ethnobotanically selected Cree anti-diabetic plants on human cytochrome P450 isoforms and flavin-containing monooxygenase 3

AIM OF THE STUDY Cree traditional medicine is commonly used concomitantly with prescribed drugs to treat health problems related to type II diabetes (T2D) that is endemic in the Cree population. However, the safety of traditional Cree medicines with respect to drug metabolism is unknown. MATERIALS AND METHODS Seventeen anti-diabetic plant extracts were screened for their potential inhibition of 11 isoforms of the drug-metabolizing cytochrome P450s (CYPs), and flavin-containing monooxygenase 3 (FMO3) in fluorometric plate reader assays. Comparative analyses were conducted to determine if particular extracts were more inhibitory, or if particular enzymes were more inhibited. RESULTS Many anti-diabetic plant extracts inhibited the CYPs, with CYP2C and 3A isoforms being most prone to inhibition. The order of inhibition for the enzymes by the Cree plant extracts was: 2C19>3A7>3A5>3A4>2C9>2C8>FMO3>1A2>2E1>19>2D6>2B6. Extracts from Rhododendron groenlandicum, Sorbus decora, and Kalmia angustifolia were identified as having strong inhibition towards many CYP isoforms. CONCLUSION These findings demonstrate that extracts from most plant species examined have the potential to affect CYP2C- and 3A4-mediated metabolism, and have the potential to affect the bioavailability and pharmacokinetics of conventional and traditional medicines during concomitant use.

The Inhibition of Human Cytochrome P450 by Ethanol Extracts of North American Botanicals

Abstract High-throughput enzyme inhibition screening assays were used to quantify the effect of ethanol extracts of 2 accessions of 10 North American (NA) botanicals against the activity of the human cytochrome P450s: CYP3A4, CYP19, and CYP2C19. In addition, phytochemical biomarkers within each extract were identified and quantified using HPLC-MS or GC. Extracts containing uncharacterized phytochemicals were identified taxonomically. The overall objective was to describe the relationship between types and quantities of phytochemicals in ethanol extracts and their ability to inhibit CYP activity. The top three inhibitors of CYP3A4 were Gaultheria procumbens. L. leaf > Rhodiola rosea. L. root > Arctostaphylos uva-ursi. L. Spreng leaf; of CYP19 were R. rosea. root > Rhododendron groenlandicum. (Oeder) Kron & Judd leaf > A. uva-ursi. leaf; and of CYP2C19 were Achillea millefolium. L. leaf and flower > Vaccinium. sp. L. leaf > Polygala senega. L. root. Equisetum arvense. L. leaf, Arctium lappa. L. root, and P. senega. root had the least effect on CYP3A4 and CYP19 activity. These results suggest that North American botanicals have the potential to inhibit the metabolism of drug-specific CYPs in vivo., causing a direct shift in the availability of drugs and their pharmacokinetics in the body. Furthermore, the concentration of certain phytochemical markers varied significantly between accessions (i.e., rosarin and essential oils), suggesting that the extent of metabolic inhibition is directly dependent upon the concentration of bioactive constituents in an extract.

Food and Therapeutic Product Interactions – A Therapeutic Perspective

Foods and therapeutic products are both used for well defined purposes. In simple terms food provides energy for sustenance, while therapeutic products are taken for managing ailments (1). However, over the years roles of foods have changed considerably. Now, food no longer is seen as simply the provider of energy, but it is expected to provide physiological benefits for good health and productive lifestyles. Well managed combination of foods and therapeutic products plays important role in the prevention and treatment of many diseases, including a number of chronic diseases such as cancer, diabetes, hypertension, obesity. Most often food is combined with medicine to enhance the benefits of medicine - an additive and/or synergistic effect: food-therapeutic product synergism. At the most basic level, food is a complex mixture of chemicals with many functional groups; hence, they not only confer positive effects, but may also make negative contributions. The later effect is of major concerns among the health practitioners and regulatory officials.

Pharmacy study of natural health product adverse reactions (SONAR): a cross-sectional study using active surveillance in community pharmacies to detect adverse events associated with natural health products and assess causality.

Objectives To investigate the rates and causality of adverse event(s) (AE) associated with natural health product (NHP) use, prescription drug use and concurrent NHP-drug use through active surveillance in community pharmacies. Design Cross-sectional study of screened patients. Setting 10 community pharmacies across Alberta and British Columbia, Canada from 14 January to 30 July 2011. Participants The participating pharmacy staff screened consecutive patients, or agents of patients, who were dropping or picking up prescription medications. Primary outcome measures Patients were screened to determine the proportions of them using prescription drugs and/or NHPs, as well as their respective AE rates. All AEs reported by the screened patients who took a NHP, consented to, and were available for, a detailed telephone interview (14%) were adjudicated fully to assess for causality. Results Over a total of 105 pharmacy weeks and 1118 patients screened, 410 patients reported taking prescription drugs only (36.7%; 95% CI 33.9% to 39.5%), 37 reported taking NHPs only (3.3%; 95% CI 2.4% to 4.5%) and 657 reported taking prescription drugs and NHPs concurrently (58.8%; 95% CI 55.9% to 61.6%). In total, 54 patients reported an AE, representing 1.2% (95% CI 0.51% to 2.9%), 2.7% (95% CI 0.4% to 16.9%) and 7.3% (95% CI 5.6% to 9.6%) of each population, respectively. Compared with patients who reported using prescription drugs, the patients who reported using prescription drugs and NHPs concurrently were 6.4 times more likely to experience an AE (OR; 95% CI 2.52 to 16.17; p<0.001). Combined with data from Ontario, Canada, a national proportion was calculated, which found that 45.4% (95% CI 43.8% to 47.0%) of Canadians who visit community pharmacies take NHPs and prescription drugs concurrently, and of those, 7.4% (95% CI 6.3% to 8.8%) report an AE. Conclusions A substantial proportion of community pharmacy patients use prescription drugs and NHPs concurrently; these patients are at a greater risk of experiencing an AE. Active surveillance provides a means of detecting such AEs and collecting high-quality data on which causality assessment can be based.