HERBS, DRUGS AND PHYTOCHEMICALS

Most pharmaceutical medicines contain a single, highly purified, often artificially produced substance that has a well-known (and occasionally specifically designed) chemical structure that can be patented and owned by the company that developed it. The dosage of these chemicals can also be precisely calculated down to the microgram and can usually be characterised by a very clear pharmacokinetic profile. Additionally, pharmaceutical drugs tend to have a generally agreed upon mechanism of action and series of indications that guide their use within the Western medical model.

As most of these drugs do not exist in nature, they must go through extensive testing to ensure efficacy and safety. New drugs are assessed in test-tube and animal studies for their potential to cause cancer, fetal malformations and other toxic effects, and are ultimately tested on humans to further define the safety profile, pharmacokinetics and drug effectiveness in a targeted disease (Wierenga & Eaton 2003). This process is very costly and requires the application of highly specialised knowledge and infrastructure, as well as many years of concentrated effort. It is estimated that the development of a new drug requires the investment of approximately US$800 million, but it is also extremely lucrative (Di Masi & Grabowski 2003).

PHARMACOGNOSY

In 2001 and 2002, approximately one-quarter of the best-selling drugs worldwide were natural products or derived from natural products. Research on natural products further accounted for approximately 48% of the new chemical entities reported from 1981 to 2002.

Modern drug discovery from medicinal plants has evolved to become a sophisticated process that includes numerous fields of enquiry and various methods of analysis. Typically, the process begins with a botanist, ethnobotanist, ethnopharmacologist or plant ecologist collecting and identifying plants based on the biological activity suggested by their traditional use. Additionally, plants are randomly selected for inclusion in screening programs based on molecular targets identified through the human genome project (Balunas & Kinghorn 2005).

Pharmacognosy is the term used to refer to the study of botanical supplements and herbal remedies, as well as to the search for single-compound drugs from plants. Increasingly, pharmaceutical medicines and preclinical research into herbal medicines are focused on identifying suitable chemical entities that may form the basis for novel treatments (Balunas & Kinghorn 2005).

CHEMICAL COMPLEXITY

In contrast to pharmaceutical drugs, which are based on single molecules that may or may not be derived from natural substances, herbal medicines are chemically complex and may contain many hundreds or even thousands of different ‘phytochemicals’, including various macro- and micro-nutrients such as fats, carbohydrates and proteins, enzymes, vitamins and minerals. A group of important secondary metabolites are also present, which are generally chemicals used to defend against herbivores, pathogens, insect attack and microbial decomposition, or which are produced in response to injury or infection, or used for signalling and growth regulation. It is these compounds, such as tannins, isoflavones, saponins, flavonoids, glycosides, coumarins, bitters, phyto-oestrogens etc, that are often responsible for the therapeutic properties of herbal medicines (Mills & Bone 2001).

As the secondary metabolites largely dictate a herb’s pharmacological nature, a knowledge of herbal chemistry is essential to understand a herb’s use and provide valuable insight into its clinical effects. It is sometimes tempting to take the modern reductionist approach and predict the pharmacological activity of a herbal medicine from an understanding of the effects of one key constituent or chemical group; however, this is unlikely to be entirely accurate. In practice, the overall pharmacological activity and safety of each herb is the result of the interaction of numerous constituents, some of which have demonstrated pharmacological effects, rather than the effect of a single active ingredient.

An example of this is the herb Paullinia cupana, commonly known as guarana. As there are limited clinical studies on guarana, it is often reported that the herb owes its pharmacological activity to one key constituent, caffeine, which may be present in concentrations as high as 10%. Studies referring to the isolate caffeine provide some clues about the effects of guarana, but are not entirely accurate, as other important constituents are also present in the remaining 90%. This has been borne out recently in clinical studies of low-caffeine-containing guarana preparations, which still demonstrated significant effects on cognitive function.

Because of the range of phytochemicals present in plants, herbal medicines often include many different active substances with different pharmacokinetics that work at different sites with different mechanisms of action. Herbal medicines therefore potentially have multiple pharmacological actions and many different clinical indications. Furthermore, in addition to the active ingredients, herbs may also contain substances that act to inhibit or promote the active properties, and/or potential unwanted side effects of the active agents. Thus, although specific components may not be active themselves, they may influence the activity of other components by altering their solubility, absorption, distribution or half-life.

For instance, berberine is a constituent of herbs such as goldenseal and barberry and exhibits numerous activities in vitro; however, in vivo, it has poor bioavailability (Pan et al 2002). Berberine has been shown to upregulate the expression and function of the drug transporter P-glycoprotein (P-gp) (Lin et al 1999), thereby reducing the absorption of P-gp substrates. Studies with the P-gp inhibitor cyclosporine have shown that it increases berberine absorption six-fold, as it counteracts the inducing effect of berberine (Pan et al 2002). P-gp inhibitors are also found in nature, such as the virtually ubiquitous quercetin, and when they are present in the same herb competing effects on P-gp expression and function will occur.

The herb St John’s wort provides yet another example. The extraction method used in Germany in the product’s commercial manufacture was modified in the late 1990s, resulting in higher concentrations of hyperforin than previously obtained (Madabushi et al 2006). Since then, numerous reports and studies have identified pharmacokinetic drug interactions with St John’s wort, based on its ability to induce cytochromes and P-gp. It is now well established that hyperforin is the key constituent responsible for these unwanted effects, and St John’s wort preparations manufactured with this newer extraction method, such as LI 160, can put people at risk of interactions. Meanwhile, studies with low-hyperforin preparations, such as Ze117, have found that it fails to induce the same interactions (Madabushi et al 2006). Unfortunately, this distinction between St John’s wort preparations is not well known and many references and texts fail to mention this important point.

As these examples and many others in this book demonstrate, each herb is chemically complex and produces a pharmacological effect based on the total sum of actions produced by a myriad of constituents that may be acting in synergy. This complexity complicates the ability to test herbal medicines as they are most commonly used (that is, in their more natural states) and in combination with other herbal medicines.