This thesis applied a novel interdisciplinary approach for pharmacovigilance to examine the use of complementary and integrative medicine (CIM), focusing on herbal remedies, to manage pediatric attention-deficit hyperactivity disorder (ADHD). The safety and potential risk of herb-drug interactions in ADHD management were first evaluated through an assessment of available information on the safety and efficacy of natural health products (NHPs) commonly used by ADHD patients as a means of identifying knowledge gaps. A clinical questionnaire was administered to caregivers of pediatric patients with ADHD to determine the factors and related outcomes of CIM use, including adverse events. A systematic search was conducted to further identify clinical adverse events involving herbal remedies and ADHD drugs to determine causal links to herb-drug interactions. In vitro analysis of identified herbal remedies was conducted to determine their potential for pharmacokinetic interactions, specifically on carboxylesterase-1 (CES1) mediated metabolism. The presented research builds on otherwise scarce evidence of the safety of herbal remedies for ADHD, particularly with respect to herb-drug interactions and adverse events (AEs) associated with concurrent use of NHPs and ADHD prescription drugs. Beyond studies conducted on the pharmacokinetic safety of herbal remedies through the cytochrome P450 pathways that metabolize some ADHD drugs, including amphetamine, atomoxetine and guanfacine, few data were available for CES1, which metabolizes methylphenidate, the first line of drug used to manage ADHD. The clinical questionnaire revealed that 40% of patients had used CIM and confirmed the use of a variety of CIM. Moreover, the majority of CIM users were also concurrently taking ADHD medication, and eight mild adverse events were self-reported. The systematic search on the adverse event reporting system highlighted a potential NHP-drug interaction between methylphenidate and St. John’s wort, and the overall poor quality of NHP-related adverse event reports. As a follow-up from the adverse event results, various commercial St. John’s wort products showed variable inhibition of recombinant human CES1 in vitro. Although the concentration of marker phytochemicals was not correlated to inhibition, hyperforin showed stronger activity than hypericin and quercetin. The preliminary in vitro investigation revealed that the herbal remedies used by ADHD patients have the potential to interact with CES1 mediated metabolism, with Rhodiola rosea identified as the most potent inhibitor. Further investigation on various commercial products of Rhodiola rosea revealed both reversible and irreversible inhibition of recombinant CES1. However, the inhibition was not dependent on the concentration of marker phytochemicals, and rosarin, rosavin, rosin, and salidroside were not potent inhibitors of recombinant CES1. Moreover, a commercial Rhodiola rosea extract showed concentration-dependent inhibition of human liver microsome meditated metabolism of methylphenidate. Overall, results from this thesis suggest potential risk from use of NHPs concurrently with conventional medicine used to manage ADHD. Improved evidence and pharmacovigilance for the use of NHPs in a pediatric population is warranted.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/40653 |
| Date | 16 June 2020 |
| Creators | Mazhar, Hajra |
| Contributors | Harris, Cory Steven, Robaey, Philippe |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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