Focus on Alternative and Complementary Therapies
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Focus Alternat Complement Ther©2005 Pharmaceutical Press
Focus Altern Complement Ther 2003; 8: 392–6
In the last 10 years two revolutionary paradigm shifts occurred in medicine, which have, surprisingly, received little attention from phytotherapists and Phytomedicine researchers.
Neither of these therapeutic strategies proposed at present by the new generation of clinicians and pharmacologists is absolutely new. Phytotherapy has long followed and developed these strategies by using mono-extracts or extract combinations containing mixtures of bioactive compounds and by activating primarily self-healing and protective processes of the human body, rather than attacking and directly destroying the damaging agents. These strategies are based on therapeutic experiences and the consideration that a complex pathophysiological process can be influenced more effectively and with fewer or less severe side-effects by a combination of several low-dosage compounds or the corresponding extracts than by a single high dosage isolated compound.
The rationalisation of both new concepts and strategies, however, requires scientific evidence. This is the greatest challenge phytotherapy is faced with at the beginning of the new century. At the same time, it can be a chance to gain full acceptance as a therapy that can be classified in its rationality equivalent to chemotherapy.
Therefore, I propose that phytomedicine research should focus on the following activities:
Owing to the enormous progress of specific high-tech analytical methods, we are able today to analyse even complex composed extracts and phytopreparations and to quantify the major active compounds, which are supposed to be responsible for the efficacy of an extract. The successful three-dimensional – high-performance liquid chromatography (HPLC) fingerprint analysis of a multiple extract combination of Kampo medicine prepared from eight herbal extracts and the quantification of their major constituents, illustrate the effectiveness of these modern tools.1 At the same time, these methods meet the quality standards of drug authorities and the reproducibility of pharmacological studies, along with the performance of good clinical practice (GCP), conforms to clinical trials requirements.
The following examples will explain the molecular biological screening approach in more detail. Most of the models operate on a receptor, signal transduction or genetic basis.
In an attempt to rationalise the cardiotonic activity of hawthorn (Crataegus oxyacantha) extract preparations, verified by numerous clinical studies, it was found that procyanidins and flavone C-glycosides appear to be the main constituents of the herb responsible for the therapeutically relevant cardiotonic activity.2 Recently, we have reported that a hawthorn extract containing procyanidins and flavonoids, exhibits in vitro an angiotensin-converting enzyme (ACE)-inhibiting effect,3 which, together with the endothelin-dependent, smooth-muscle-relaxing effect found recently in an aorta model,4 might account for the dilating effect on coronary vessels and a simultaneous reduction in blood pressure. Because the flavonoids also act as antioxidants, and cyclooxygenase- and 5-lipoxygenase-inhibitors and have a thrombocytes aggregation reducing effect, it is necessary to produce special hawthorn extracts which contain both active classes of compounds in enriched form and standardised in the content of these procyanidins and flavone C-glycosides. In conclusion, we can state that the pharmacological multivalence of hawthorn constituents justifies the therapeutic application of hawthorn for the treatment of heart insufficiency grades I and II.
Because the pharmacological role of garlic (Allium sativum) in the prevention and treatment of atherosclerosis has received increasing attention, we decided to investigate ajoene and allicin, two major constituents of fermented garlic juice, in a suitable molecular biological assay. It could be shown that both compounds inhibit the expression of inducible nitric oxide (iNO) synthase in activated macrophages. Because it is known that the inflammatory environment in human atherosclerotic lesions results in an expression of the inducible form of nitric oxide synthase5 and, subsequently, in the formation of peroxynitrite, thereby aggravating the atherogenic process, these results may provide an interesting basic contribution with regard to the beneficial effects claimed for garlic in atherosclerosis prophylaxis. If we consider all the other known pharmacological effects caused by garlic preparations, including thrombocyte aggregation-inhibiting, anti-inflammatory, antioxidant triglyceride-decreasing and cholesterol-decreasing effects, garlic can be designated as one of the most notable examples of a multivalent herbal drug, in which the major bioactive constituents reveal synergistic, cardiovascular-directed effects.
This example describes the attempt to evaluate and rationalise the pharmacological profile and therapeutic potential of a multi-extract preparation from traditional Chinese medicine (TCM). The research project, headed by Prof. Sucher of the University of Hong Kong, is the chemical and pharmacological investigation of a fixed herbal drug combination which has a great reputation in TCM for the prevention and therapy of stroke.6 The combination investigated consists of eight herbal drugs: root of Salvia miltiorhiza, rhizome of Ligusticum sinense, root of Paeonia rubra, root of Angelica pubescens, root of Stephania tetrandra, Ramulus c. Uncis of Uncaria rynchophylla, rhizome of Gastrodia elata and root of Panax ginseng. As a result of the detailed chemical and molecular-biological investigations the researchers were able to assign defined pharmacological effects and mechanisms of action to the individual herbal drugs and their major bioactive constituents. The individual TCM drugs were classified into four categories – channel-collateral-stroke affecting, anti-inflammatory, antithrombotic and neuroprotective – and described as improving blood circulation, increasing cerebral blood flow and protecting the brain from ischaemic and reperfusion injuries.6
Meanwhile, many other herbal drug extracts have been screened using new molecular biological in vitro assays. These include extract preparations of Hypericum, Ginkgo, Silybum, Harpagophytum or Vitex agnus-castus.
From all these results we can conclude:
It is a rule in classical pharmacology that if two bioactive substances of a mixture have the same pharmacological target, an additive effect can be expected. If, however, two or more substances of a mixture have different pharmacological targets, a pharmacologically synergistic effect may result that can be greater than expected for the individual substances taken together (provided that none of the substances in the mixture exerts an antagonising effect).7 Those dose–response investigations with two-component containing mixtures of bioactive pure compounds can be carried out using the isobol method as proposed by Berenbaum.8 We have carried out such an in vitro experiment using the thrombocyte aggregation assay with various mixtures of ginkgolide A and B, two major constituents of Ginkgo biloba. From the concave-up isobol curve we have obtained, a typical potentiated synergistic effect could be deduced.9 It is plausible that the isobol method cannot be applied to herbal extract mixtures. Here, detailed in vitro or in vivo comparative investigations with single constituents or mixtures and extract fractions or whole extracts must be performed. Evidence supporting the occurrence of synergy within phytomedicines is accumulating and has been reviewed recently by Williamson.10
The synergistic effects that have been measured exceed the effects of single compounds, or mixtures of them at equivalent concentrations, by a factor of two to four, or more. These synergistic additive or potentiated effects are of interest only if they can be verified by clinical studies.
The next two examples may be instructive.
The Cannabis sativa herb has received much attention recently because of the detection of an endogen cannabinoid system in some parts of the human brain and the immune system, represented by the two cannabinoid receptors CB1 and CB2. New molecular biological investigations resulted in the identification of arachidonyl-ethanol-amide (anandamide) and 2-arachidonyl-glyzerol (ether) as endogen CB-ligands.
According to current knowledge, this endogenic cannabinoid system plays an important role in the development of memory, in pain transduction and inhibition, in control of appetite, in lactation, in generation of emesis and as an immunomodulator. Among the most conspicuous pharmacological effects of (–) trans-Δ9-tetrahydro-cannabinol (THC), which came onto the drug market under the drug name Dronabinol,11 the muscle-relaxant, appetite stimulating and analgesic effects are the most interesting.
Meanwhile the idea of using THC as pure compound for the treatment of MS-patients has been given up after a comparative study with Cannabis illegaly has shown that the extract exhibited a much better antispastic activity than the THC substance alone, as measured in an immunogenic model of multiple sclerosis (MS).12 At present over 1% of MS patients take Cannabis for amelioration of spasticity and the pain associated with this condition.13 The reason for this better effect is probably due to the content of cannabidiol (CBD), in the extract, which amplifies the antispastic effect markedly and simultaneously reduces the undesirable psychotropic side-effects of THC. It is not yet clear how this amplifying antispastic effect can be explained on a molecular basis, but there are some indications that CBD increases the permeation of THC into the muscle cells.
The best clinical evidence for existing therapeutic synergism can be demonstrated by results obtained in a clinical trial performed with a standardised Hypericum extract in comparison with the synthetic psychopharmacon Imipramine in the treatment of patients with moderately severe depression.14 The Hypericum extract was administered over 6 weeks in a dose of 500 mg extract per day, which corresponds to about 8–10 mg bioactive compounds together (hypericins, hyperforin, xanthons, flavonoids, procyanidine). Imipramine was given in a concentration of 150 mg/day. The efficacy was measured by the procentual reduction of the HAMD-score values after 6 weeks’ treatment. The results of the comparative study show that 8–10 mg bioactive constituents of the Hypericum extract together are therapeutically equivalent to 150 mg imipramine. Interestingly, the Hypericum treatment has far fewer side-effects than the synthetic drug.7
The reason for this therapeutic equivalence of the medications has to be interpreted as a potentiated synergistic effect caused by the combination of Hypericum constituents, which are suggested to have different molecular targets in the brain. The possibility that the increased efficacy could be explained only due to an enhanced resorption rate of the constituents and thereby improved bioavailability, because of additional non-bioactive byproducts of the Hypericum extract, is not very likely and can be ruled out.
At present, more than 400 controlled, mono- and double-blind, placebo-controlled clinical trials have been performed, which meet all international requirements of performance and efficacy. About 80% of the existing studies have been made with standardised versions of long-used mono-extracts, including Ginkgo, Hypericum, Harpagophytum, Valeriana, Sabal, Urtica, Aesculus hippoc., Crataegus, Silybum or Echinacea. About 20% were tested against chemosynthetic drugs, showing therapeutic equivalence of both medications in the same indication. Clinical evidence is available for the therapeutic superiority of Salix root extract over an isolated single constituent thereof15 and for the herbal drug combinations Valeriana/Piper methysticum16 and Ginkgo/ginseng17 over only one of the two herbal drug combinations. It has to be emphasised that the concentrations of all bioactive constituents of a standardised extract applied together in these comparative studies, per day, were much lower than the applied amounts of the synthetic drug. This special dosage–effect relationship accounts for synergistic effects and at the same time for the absent or minimised side-effects described for these phytopreparations.
The new strategy of multitarget phytotherapy is explained in the following two examples of cancer and hepatitis B/C therapy.
The standard drug therapy for cancer in classical medicine uses cytostatic chemotherapeutics, which at ideal conditions arrest or destroy tumour cells. Most of the cytostatic drugs possess severe side-effects and reduce the quality of life. Apart from some exceptions, these drugs are not able to heal cancer patients or to extend their life span by more than 5 or 10 years.
The new strategy follows a quite different concept. It aims at the stimulation of defence and repair mechanisms of the healthy tissues (e.g., induction of apoptosis, inhibition of angiogenesis, stimulation of heat-shock proteins and oncogen-suppressor genes). This multitarget therapeutic concept requires a cocktail of several individual or multivalent drugs, which, in a concerted and synergistic way, might be able to arrest the tumour growth.
Many laboratories worldwide work on the development of such a multidrug and multitarget concept.
The standard therapy to treat hepatitis B + C uses interferon-β and/or some chemotherapeutic drugs such as ribaverine or lamivudine. The disadvantages are that the response rate for interferon is only 50–60% and the resistance rate for AZT and analogues is very high. The healing chances are limited. More success is expected with the new strategy of stimulating the immune system and repair mechanisms concertedly, to protect the healthy liver cell with antioxidants and inhibit apoptosis, as well as inflammatory and fibrotic processes.
The strategies explained in these two examples and the development of adequate and effective drug combinations without severe side-effects are still in their infancy. The key for the development of new drugs is the use of molecular biology, with its new assays on a molecular level, to find ways to interfere with the different pathophysiological processes for an effective causative therapy. With these tools in hand, phytomedicine research has a good chance of contributing to the achievement of this goal.
Two new paradigm shifts in medicine characterise the beginning of the twenty-first century: the gradual renunciation of the long-standing reliance on mono-substance therapy in favour of a multidrug therapy, and the transition to a new kind of multitarget therapy, through which the interference of drugs with protective-, repair- and immunostimulatory mechanisms of the human body, rather than with single disease-causing agents, gains more and more importance. Phytomedicine research has a good chance of contributing to these new strategies through the development of new and better drugs for an evidence-based and rational therapy. Great efforts in three research areas, however, are compulsory: (1) the increase in efforts to develop suitable standardisation methods for phytopreparations; (2) The integration of molecular biological assays into the screening of plant extracts, single isolated compounds thereof and phytopreparations; and (3) The performance of further placebo-controlled, mono- or double-blind, clinical trials, paralleled or followed by pharmacokinetic and bioavailability studies. One major concern will be to investigate the multivalent and multitarget actions of plant constituents and standardised extracts, with the aim of rationalizing the therapeutic superiority of many plant extracts over single isolated constituents.
Phytomedicine and chemosynthetic pharmaceutical research find themselves in a race to develop new medicines, with fewer or no side-effects, for therapeutic and preventive application in illnesses for which causality-based treatments are non-existent or imperfect.
