What makes phytomedicines unique?

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Chapter 11 What makes phytomedicines unique?

Phytomedicines have particular attributes, which are not encountered when using synthetic drugs or single compounds. Although many natural products have been isolated and are used therapeutically as single ingredients, for example most alkaloids (morphine, hyoscine), cardiac glycosides (digoxin), anticancer agents (paclitaxel, vincristine) and other highly potent drugs. Many more are used in the form of herbal remedies or phytomedicines. Either the whole herb or an extract of the plant is prepared, and may be combined with other herbs or extracts.

Also, there is a continuum between products which are a (health) food and those which are a potent herbal medicine (called the food–medicine interface). In the area of food research, considerable efforts have been put into understanding the benefits of a ‘balanced diet’ and thus a diet which is composed of a complex combination of mixtures. However, in medicines research in general and specifically in research on herbal medicines systematic research has only been developed since the start of this century (Williamson 2001).

Generally, highly toxic drugs are used as single entities since the dose needs to be very precise, but the natural mixture found in a plant extract may have benefits conferred by some form of interaction between the components. Conversely, there may be toxic ingredients present that do not contribute to the therapeutic efficacy and which are, therefore, undesirable. If the toxic component is also one of the active principles, then the usual assessment of risk:benefit profile applies, but quite often the toxic compound serves no useful purpose and must either be removed or some form of limit test applied. Some examples are discussed in Chapter 10.

Phytomedicines often take a while to produce a measurable improvement and appear to have a cumulative effect; for this reason, long-term therapy is routine. This is not a unique property of natural products but is also found in conventional medicines (e.g. the antidepressants, where several weeks of treatment may be necessary before a clinical improvement is seen). The use of drug combinations is also not confined to herbal products; for example, cancer chemotherapy and the treatment of HIV and hypertension routinely use drug combinations. In addition, although many phytomedicines may have been characterized phytochemically, their mechanism of action is still unknown, which makes isolation of one constituent impossible.

Properties of mixtures

Herbal practitioners have always argued that the effects of combinations of ingredients, such as those found in herbal medicines, contribute to the efficacy of phytomedicines, but until recently there has been little evidence to demonstrate that this is the case. In the absence of direct (i.e. clinical) evidence to demonstrate that combination effects are taking place, indirect evidence may be useful, for example, instances where it appears that the dose of supposed active constituents, calculated on the basis of the amount of a known constituent, is too low to have an effect, but clinical and pharmacological evidence has shown that the preparation is in fact effective. This is the case with willow bark, which will be discussed later. In general, synergistic and other interactions within herbal mixtures are considered to be positive, enabling lower doses of potent compounds to be used and reducing the incidence and severity of side effects. The properties of mixtures described below apply to all types of combinations between two or more drugs, whether of herbal or synthetic origin. They also apply to drug interactions, which are also a form of synergistic, antagonistic or additive effect, and the mechanisms of interaction are the same. The body does not know or care where a therapeutic agent originated; it deals with them all in the same way, and with the same mechanisms and the same enzymes!

Synergistic, multi-factorial and polyvalent effects

Synergy and other forms of interaction between the constituents of herbal extracts is expected, and widely cited as a fundamental tenet of phytotherapy, but it is still poorly documented, despite a great deal of interest. Interactions may result in enhancement of a therapeutic effect, reduction of toxicity or preservation of stability. Synergy is a specific type of interaction, and needs to be proven experimentally; however, although it may take place, it actually may not be the most important type of interaction occurring in herbal mixtures. Not only may two or more components of a mixture interact with each other, but also single constituents may interact with different pharmacological targets. Thus, the various interaction mechanisms involved in the action of phytomedicines are now mainly referred to as multi-factorial effects (also known as polyvalent action) and may include the following:

• Several compounds affecting a single target, either directly or indirectly: this may include synergy, the metabolism of one active altered by the presence of others in the extract, or the bioavailability of a component changed by the presence of another. These are true interactions and may include pharmacokinetic and pharmacodynamic interactions

• A single compound affecting multiple targets: this is not an interaction between components of a mixture of course, but it helps to explain why a particular herbal medicine (or any drug, for that matter) can be used for different purposes

• Multiple compounds affecting multiple related targets: these are not necessarily interactions, but the result of a number of constituents acting in different ways; however, interactions could certainly also be taking place. There may be cases where the effect of one compound cancels out the effect of another by antagonism and this would not be known unless fractionation of an extract before testing had been carried out.

Several or all of these mechanisms may be taking place at the same time, and the overall effect is, therefore, the result of a complex interaction between different components of a mixture and different targets which may all be relevant in the treatment of a particular condition. There may be unwanted interactions in or between phytomedicines, such as the presence of high levels of tannins in a herbal drug, which may complex with and inhibit the absorption of proteins and alkaloids. As with conventional medicines, interactions may be mediated via the induction or inhibition of cytochrome P450 enzymes or P-glycoprotein, and these are discussed below. It must also be remembered that herbalists use preparations and mixtures not necessarily intended to target a particular enzyme or biochemical system. The use of phytomedicines has been described as the ‘herbal shotgun’ approach, as opposed to the ‘silver bullet’ method of conventional medicine. This approach would not only encompass synergy in a herb, but would even include routine practices such as adding a laxative to a formula for haemorrhoids.

While here we focus on the unique characteristics of complex mixtures, novel concepts and approaches in pharmacology show ‘the other side of the coin’. Network pharmacology and systems biology are used to represent the different types of relationships between biological entities such as genes, proteins, chemical compounds, and transcription factors. In essence, the single drug single target view is giving way to a more complex understanding of networks within an organism affected by a medicine and the complexity of the intervention (Pujol et al 2010).

Mechanisms of interaction

Interactions can also be classified as:

• pharmacodynamic: where the effects of one drug are altered or added to by the presence of another at the site of action (so-called ‘pharmacological’ interactions)

• pharmacokinetic: processes involving absorption, distribution, metabolism and excretion.

An example of both is provided by Ayurveda, where an ancient combination formula known as ‘Trikatu’ contains black pepper (Piper longum). Pepper contains the alkaloid piperine, which has many useful pharmacological activities (anti-inflammatory, anti-allergic, digestive), which add to the desired effects of the other ingredients in the formula. These could be considered to be pharmacodynamic interactions. However, piperine is also known to increase the bioavailability of a number of drugs by enhancing absorption. Piperine modulates the multidrug transporter P-glycoprotein and influences the efflux of other compounds, both herbal and synthetic drugs, from cells (Najar et al 2010). P-gp (the ‘permeability protein’) is a trans-membrane ATP-binding cassette transporter or pump, which transports various molecules across intra- and extra-cellular membranes, especially in the gut, kidney, liver and blood–brain barrier. It regulates the distribution and bioavailability of many drugs by blocking or facilitating entry into cells. Thus, increased intestinal expression of P-gp will reduce absorption of drugs that are substrates, reducing bioavailability, lowering drug plasma concentrations, and, therefore, reducing efficacy. Inhibition of P-gp will conversely increase plasma concentrations, which may lead to enhanced efficacy, but also, possibly, drug toxicity. Many other natural products are also known to modulate P-gp, and these include curcumin, quercetin, hesperidin and epigallocatechin gallate. They affect the bioavailability of not only other herbal components, but also ‘conventional’ drugs, and this is an untapped therapeutic area which remains to be explored. Inhibition of P-gp by non-toxic, common elements of the diet may even help to delay or inhibit resistance to, for example, antibiotics and anti-cancer drugs.

Piperine, along with many other natural compounds, also inhibits both constitutive and inducible cytochrome P450 (CYP-450) drug metabolizing enzymes. Inhibition reduces the metabolism (and, therefore, rate of clearance from the body) of any other substance metabolized by the same enzymes, whether of herbal or other origin, and thus enhances its blood levels. The opposite can occur: CYP enzymes can be induced, enhancing the clearance of any drug metabolized by the same enzymes.

Measuring synergy

The general understanding of synergy is that it is an effect seen by a combination of substances that is greater than would have been expected from a consideration of individual contributions. It does, however, have a precise mathematical definition, which may depend on the method used to prove it. Such methods have been discussed extensively (Berenbaum 1989

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