DIFFERENT MECHANISMS OF ACTION OF BIOACTIVE CONSTITUENTS

II. DIFFERENT MECHANISMS OF ACTION OF BIOACTIVE CONSTITUENTS

Observed effects may be the sum total of different classes of compounds having diverse mechanisms of action. The most widely used herbal medicine in Germany and Western countries is Gingko biloba (see Chapter 7). It is prescribed for ‘‘brain dysfunction’’ and to improve memory and cognition. In randomized placebo-controlled trials, the herb has been shown to improve memory impairment, cognitive performance, dementia, tinnitus, and inter- mittent claudication (9–11). The bioactive components of gingko are believed to include flavonoids and unique diterpenes called ginkolides. Gingkolides are potent inhibitors of the actions of platelet-activating factors, which are important for platelet activation and clotting (12). In addition, gingko Observed effects may be the sum total of different classes of compounds having diverse mechanisms of action. The most widely used herbal medicine in Germany and Western countries is Gingko biloba (see Chapter 7). It is prescribed for ‘‘brain dysfunction’’ and to improve memory and cognition. In randomized placebo-controlled trials, the herb has been shown to improve memory impairment, cognitive performance, dementia, tinnitus, and inter- mittent claudication (9–11). The bioactive components of gingko are believed to include flavonoids and unique diterpenes called ginkolides. Gingkolides are potent inhibitors of the actions of platelet-activating factors, which are important for platelet activation and clotting (12). In addition, gingko

Flavonoids are common compounds in plants with a role in the inhibition of interactions between plants and microbes. Soya products that contain flavonoids are thought to have potential health benefits in terms of cardiovascular health and postmenopausal symptoms and to prevent breast and prostate cancer. Genistein, one of the principal isoflavones in soy, has activity against the estrogen receptor and inhibits the tyrosine kinase receptor and DNA topoisomerase. It is also an antioxidant and affects the pathways of apoptosis (17). Ipriflavone, a synthetic isoflavone, was also shown to prevent bone loss through mechanisms that were different from the physiological estrogen (estradiol) in that it stimulated bone formation rather than sup- pressed bone resorption. Thus, whereas estradiol suppressed bone rate formation in ovariectomized rats, ipriflavone did not (18). Phytoestrogens also selectively activate the ER-beta more than the ER-alpha whereas the reverse is true for estradiol. Flavonoids are common in many herbal medi- cines including gingko and their myriad actions make analysis of outcome variables complicated.

III. SYNERGISMS AND OTHER COMBINATORIAL EFFECTS Synergistic interactions are thought to be of importance in phytomedicines, to

understand the efficacy of apparently low doses of active constituents in a herbal product. This concept, that a whole or partially purified extract of a plant offers advantages over a single isolated ingredient, also underpins the philosophy of herbal medicine. Clinical evidence to support the occurrence of synergy in phytomedicines is, however, scanty. Typically herbal medicines

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76 Yong and Loh

consist of hundreds of compounds that may vary slightly in their chemical groups but are still based on a common backbone. Thus dozens of flavanoids and flavanol glycosides have been described in epimedium including epime- dokoreanoside I, icariside I, icaritin, epimedoside A, epimedins A, B, and C, anydroicaritin, tricin, korepimedoside A and B, sagittatosides A, B, and C, sagittatins A and B, diphylloside A and B, baohuosides I–VII, and baohuosu (see Chapter 10). The major components of another common herb, ligusti- cum, were identified to be phthalides and their hydroxylated, oxygenated derivatives, including ligustilide, butylidenephthalide, cnidilide, neocnidilide, butylphthalide, cindium lactone, sedamonic acid and sedanolide, and the dihydroxylated derivatives (senkyunolide B–L) (see Chapter on 11). The activity of the leading psychotherapeutic herb Hypericum perfortum, or St. John’s wort, for the treatment of depression is now believed to be attributable to at least three classes of compounds: hypericins, hyperflorin, and flavonoids. Analysis of the pharmacological actions of these compounds using 42 biogenic amine receptors and transporters indicates that several pure sub- stances in St. John’s wort are potential central nervous system psychoactive agents and may contribute to the antidepressant efficacy of the plant in a complex manner (19). The biflavonoid amentoflavone significantly inhibited binding at serotonin [5-HT(1D), 5-HT(2C)], D(3)-dopamine, delta-opiate, and benzodiazepine receptors. The naphthodianthrone hypericin had signif- icant activity at D(3)- and D(4)-dopamine receptors and beta-adrenergic receptors. Hyperflorin acted mainly on the D(1)-dopamine receptor. These data revealed unexpected interactions of pure compounds with a number of neuronal receptors, transporters, and ion channels. Similar interactions and synergistic effects have been suggested for the common psychotrophic drugs kava-kava (Piper methysticum) and valerian (Valeriana officinalis). Synergis- tic mechanisms have also been suggested for Ginkgo biloba, Piper methysticum (kava-kava), Glycyrrhiza glabra, Cannabis sativa, and Salix alba (20,21).

IV. DOSE-RESPONSE RELATIONSHIPS Sometimes dose-dependent reversal of effects is encountered in efficacy

studies, wherein higher or lower dosages can produce different effects. There are suggestions that these findings should not be interpreted to mean that phytomedicines are not efficacious. For example, extracts of goldenrod (Solidago virgaurea) in low doses have no diuretic effect, whereas in thera- peutic doses (6–12 g dried herb per dose) diuretic effects can be demonstrated (22). Still higher doses in animals again result in antidiuretic effects. The soy phytoestrogen genistein can activate estrogen receptors (ER) at low doses but at higher doses it exhibits ER antagonistic effects. Genistein dosages that

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produce uterine hypertrophy in rats were 10-fold higher than that exhibiting bone protective activity (23).