Modern Drug Discovery

In modern drug discovery, the sequence of events usually occurs as follows. Desirable pharmacologic properties for treatment of patients with a particular disease are speculated. The search begins for chemical agents that have these properties in the right potency. They must lack other properties that cause undesirable adverse effects. Compounds may be natural, nature derived, or synthetic. Test tube and animal research precede any testing in humans, and most compounds do not make it! (Only one herbal product has been developed in this way: Ginkgo biloba.) Resultant drug medicines are often prepared around a one-dimensional, receptor-based, reductionist, mechanistic approach to disease, for example, suppress a particular aspect of the immune or inflammatory response, raise levels of a neurotransmitter, and so forth. In other words, it is often anticipated how the drug will work with consideration of the active mechanism.

Phytopharmacologic Discovery

The term phytopharmacology as used here applies to research on herbs as medicines. This is distinct from the copious research aimed at discovering new chemical entities (drugs) in plants, which are often exotic or toxic and unknown to the main herbal traditions.

Essential differences between modern drug discovery and the way research is conducted on medicinal plants relate more to cultural, socioeconomic, and regulatory issues than to inherent differences between the subject materials. In phytopharmacologic discovery, we usually start with human use. Only then might scientists become interested in understanding how the herb works. It is therefore possible that an herb might act through a pharmacologic mechanism that has not yet been discovered.

So, with phytopharmacology, generally, some evidence of clinical efficacy is found before a mechanism of action is proposed. However, some differences relate to the subject material, particularly the chemical complexity and the fact that the plant is a living thing. Mechanisms may be complex and numerous because of chemical complexity. True mechanisms may be unknown and multidimensional. Activity may be based on the relationship between patient and plant physiology (the medicine was once alive).

Why should phytochemicals have biological activity in humans? Baker suggests an evolutionary kinship (Baker, 1995). Enzymes in animals can share a common ancestry with enzymes or proteins in plants. Phytochemicals that are substrates of a plant enzyme may also be capable of being substrates of the corresponding human enzyme. In Baker’s examples, phytochemicals interact with enzymes that metabolize animal hormones, leading to hormone-like effects. One of the best examples of this is glycyrrhetinic acid from licorice, which exerts a potent mineralocorticoid effect without ever interacting with mineralocorticoid receptors.

Herbs are complex. It was difficult enough to understand exactly how a drug like aspirin, a single chemical in use for more than 100 years, worked in the human body. The scientist who did so shared the Nobel Prize. In the case of a chemically complex herbal extract, the task is that much more difficult, perhaps even impossible with today’s technology and today’s one-dimensional approach to researching pharmacology and therapeutics.

Research techniques in phytopharmacology

It is worthwhile to examine the relative appropriateness of the research techniques used in phytopharmacology. On the face of it, these research techniques are the same as those used in conventional research:

• Molecular level: analyzing effects on enzymes, nucleic acids, proteins, etc.

• Subcellular level: analyzing effects on membranes and organelles

• Cells: analyzing effects on whole cells such as hepatocytes, lymphocytes, etc.

• Organs: analyzing effects on whole isolated organs such as heart, liver, etc.

• Animals: analyzing the whole animal response to an intervention in laboratory animals such as rats and mice

• Clinical: analyzing clinical effects on human or animal patients in a controlled setting such as the randomized controlled trial

These first four categories are studied as in vitro models. Given the chemical complexity of herbs, the uncertain pharmacokinetics of many phytochemicals, and the fact that most herbs are already used in humans, it is suggested that the best model for phytopharmacologic research is the 6-foot rat (i.e., the human volunteer) or other clinical patients such as dogs, cats, cows, and horses, using the appropriate species as a model.

Limitations of the In Vitro Test in the Context of Phytopharmacology:

During an in vitro test, an herbal extract comes into direct contact with test cells, as shown in the diagram (Figure 7-1). Often, levels of exposure are unrealistic. But the reality, after an herb is orally administered, is very different, as is represented in the next diagram (Figure 7-2).

Figure 7-1 A diagrammatic representation of the in vitro test for an herbal extract.

Figure 7-2 A diagrammatic representation of cellular exposure after oral ingestion of an herbal extract.

In other words, the cells of the body experience a modified version of the herbal extract and are often exposed to metabolites of the original compounds. Bowel flora play a special role here. In particular, some phytochemicals that are active in in vitro tests are not even absorbed. For this reason, extrapolation of in vitro research to whole body systems must be done with great caution. For more information on herbal pharmacokinetics and bowel flora metabolism of phytochemicals, the reader is referred elsewhere (Mills and Bone, 2000).

Examples of Phytopharmacologic Research on Humans and Domestic Animals:

So, in the face of this uncertainty, the best research model for herbs is the one that most closely resembles the clinical patient. Listed here are some examples of pharmacologic research that has been done on humans, but the same types of research could be conducted in a veterinary context.

A number of opportunities exist in which one can creatively devise herbal research using human volunteers. Many uncertainties are dealt with using this type of research, including extrapolation to the patient, bioavailability, and dosage.

Examples include the following:

• Pharmacokinetics and bioavailability studies

• Ex vivo research on isolated cells. In this example, the volunteer is administered the herb; then, cells such as blood cells are removed from the person and are studied to ascertain whether any of their features differ from those before treatment; blood cells from someone who did not take the herb (i.e., a control) are also analyzed

• Use of noninvasive techniques (e.g., electroencephalography [EEG], electrocardiography [ECG], ultra-sound, positron emission tomography [PET] scans, polysomnography)

• Change in physiologic function: hormone levels, urine output and quality, hepatic biotransformation, immune function, gastric acid output, etc.

• Performance: memory, cognitive function, intelligence quotient (IQ), endurance, recovery

Research Linking Quality and Efficacy

The issue of being able to relate the phytochemical content of an herb or herbal extract to its clinical efficacy is one of the potentially most fruitful areas of phytopharmacologic research but also one of the most complex, controversial, and difficult. Efficacy cannot occur without quality, but which phytochemicals in a plant define its quality from a therapeutic perspective?

The patient is a black box when it comes to many herbs; we do not know what is happening in terms of relating the clinical outcomes to the phytochemical input (Figure 7-3). But as represented in Figure 7-4, we can break the “black box” up into two components, whereby the digestive tract acts as a filtering process and often an agent of change (as discussed previously). If a plant compound is not absorbed (or its metabolites are not absorbed), we can probably discount its relevance from the quality perspective.

Figure 7-3 A representation of the patient as a black box in terms of clinical effects from an herbal extract. Which phytochemicals are important?

Figure 7-4 A two-component representation of the patient as a black box.

So, first, we need to determine the bioavailable constituents and then decide which bioavailable constituents are active. If a phytochemical is bioavailable (or its metabolites are bioavailable), this does not necessarily imply that it is important for activity.

How to preserve or enhance quality in studies of therapeutic efficacy

What can we conclude about quality in the face of this complexity and uncertainty? In the absence of conclusive evidence linking phytochemical components to human therapeutic activity, several pragmatic research approaches can be used to preserve or enhance quality and establish credible evidence for particular phytochemicals as markers of quality:

1. Preserve as much as possible—qualitatively and quantitatively—the phytochemicals found in the fresh plant. For example, with the globe artichoke, losses of phytochemicals occur very quickly on poor drying owing to plant enzymatic activity.

2. Using pharmacologic models, determine which bioavailable phytochemicals contribute to activity, and ensure that levels of these components are optimized. There might be many compounds—not just one or one class of compounds. In the case of Hypericum, in vivo or human research has demonstrated that the following phytochemicals (or groups) have antidepressant activity following oral doses: hypericin and pseudohypericin solubilized by the oligomeric proanthocyanidins (OPCs); hyperforin; and flavonoids, in particular, hyperoside and isoquercitrin (Butterweck, 2003a).

3. Prove a particular product works clinically, and then ensure that all future products reflect the same phytochemical profile. The best example of this is Ginkgo biloba.

Referring to the first approach of preserving what is in the fresh plant as much as possible, does that mean there should be a preference for fresh plant tinctures? At the risk of being controversial, the postulated advantages of fresh plant tinctures are not supported by phytochemical fact. There is too much water in a fresh plant for the direct manufacture of a sufficiently concentrated preparation. However, there is another important concern. The high water content and the unquenched enzymatic activity mean that phytochemicals are being decomposed as the tincture is being made. Cichoric acid in Echinacea purpurea is now a well-known example of this (Bauer, 1989).

Enzymatic activity can still degrade important phytochemicals when the dried herb comes into contact with gastric juices. So, placing dried herbs in capsules can mean that enzymatic degradation starts again when the herb enters the stomach.

The experiment represented in Figure 7-5 was carried out in a simulated stomach and mimics what happens when equivalent quantities of Echinacea tops are ingested either as just the dried herb in a capsule or as an extract in a capsule (Lehmann, 2002). Cichoric acid levels degrade to almost zero for the dried herb, indicating that enzymatic activity is still present.

Figure 7-5 Cichoric acid degradation: dried herb versus extract.

If an extract of the dried herb is often the best form to use because it avoids the problem of enzymatic activity, some important considerations should be observed:

• If compounds are known or suspected to be important for activity, it must be ensured that they are optimized by extraction, but not at the undue expense of others.

• Water is a poor solvent—yet it has been used traditionally. What do we make of this? For example, that the astragalosides in Astragalus are not water soluble?

• The extraction should be optimized to the known phytochemistry of the plant. For example, if it is resinous or contains essential oil, use a high ethanol content.

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