Abstract
Botanical products are frequently sold as dietary supplements and their use by the public is increasing in popularity. However, scientific evaluation of their medicinal benefits presents unique challenges due to their chemical complexity, inherent variability, and the involvement of multiple active components and biological targets. Translation away from preclinical models, and developing an optimized, reproducible botanical product for use in clinical trials, presents particular challenges for phytotherapeutic agents compared to single chemical entities. Common deficiencies noted in clinical trials of botanical products include limited characterization of the product tested, inadequate placebo control, and lack of rationale for the type of product tested, dose used, outcome measures or even the study population. Our group has focused on the botanical Centella asiatica due to its reputation for enhancing cognition in Eastern traditional medicine systems. Our preclinical studies on a Centella asiatica water extract (CAW) and its bioactive components strongly support its potential as a phytotherapeutic agent for cognitive decline in aging and Alzheimer's disease through influences on antioxidant response, mitochondrial activity, and synaptic density. Here we describe our robust, scientific approach toward developing a rational phytotherapeutic product based on Centella asiatica for human investigation, addressing multiple factors to optimize its valid clinical evaluation. Specific aspects covered include approaches to identifying an optimal dose range for clinical assessment, design and composition of a dosage form and matching placebo, sourcing appropriate botanical raw material for product manufacture (including the evaluation of active compounds and contaminants), and up-scaling of laboratory extraction methods to available current Good Manufacturing Practice (cGMP) certified industrial facilities. We also address the process of obtaining regulatory approvals to proceed with clinical trials. Our study highlights the complexity of translational research on botanicals and the importance of identifying active compounds and developing sound analytical and bioanalytical methods for their determination in botanical materials and biological samples. Recent Phase I pharmacokinetic studies of our Centella asiatica product in humans (NCT03929250, NCT03937908) have highlighted additional challenges associated with designing botanical bioavailability studies, including specific dietary considerations that need to be considered.
Highlights
Botanical products are widely used by the public for their reputed health care benefits
Our group has been studying the mechanisms and active compounds associated with the cognitive effects of a hot water extract of Centella asiatica (CA), “Centella asiatica water extract (CAW).” We have reported that CAW at doses of 200 to 1,000 mg/kg/day administered in the drinking water improves cognitive function in the Tg2576 [31] and 5xFAD [32, 33] mouse models of Alzheimer’s Disease (AD), and in aged wild-type (WT) mice [34,35,36]
This delivery format required the design of a new formulation with the addition of excipients to improve dispersion and palatability, and coloring agents to mask the placebo
Summary
Botanical products are widely used by the public for their reputed health care benefits. Consumers in the United States (US) spent over $10 billion on herbal supplements in 2020, a recordbreaking 17.3% increase from 2019 [1]. The popularity of these products arises from familiarity with their folk medicine uses, vigorous commercial advertising, and their ready availability for self-selection through retail outlets. Under DSHEA botanical products may be marketed without proof of efficacy, but must comply with labeling requirements limiting and qualifying the claims that are made. Consumers take these products with an expectation of a particular pharmacological effect or health benefit. The FDA does provide for the development and registration of herbal products as “botanical drugs” for which proof of efficacy is a requirement [2]
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