pharmacodynamic

Experimental approaches for studying uptake and action of herbal medicines.: Phytother Res. 2007 Mar;21(3):210-4 Authors: Sumantran VN

In order to gain wider credibility, herbal medicines must go through the rigorous scientific scrutiny to which synthetic drugs are subjected, and this includes investigating their absorption, bioavailability and metabolism. This review describes approaches for determining how active compounds in herbal formulations enter the systemic circulation. To assess how bioactive molecules enter the target organs and cells, specific cell lines and organ culture models can be used, followed by in vitro models to show how they may regulate digestion, energy balance and metabolism. This could lead to a better understanding of how herbal medicines affect digestion and absorption; fundamental questions which should be answered in addition to their mechanism of action.

Herbal diterpenoids induce growth arrest and apoptosis in colon cancer cells with increased expression of the nonsteroidal anti-inflammatory drug-activated gene.: Eur J Pharmacol. 2006 Dec 23; Authors: Ko JK, Leung WC, Ho WK, Chiu P

Novel chemotherapeutic agents derived from active phytochemicals could be used as adjuvants and improve the anti-carcinogenicity of standard drug treatments. However, their precise mechanisms of action are sometimes unclear. In this study, the anti-carcinogenic effect of the herbal diterpenoid pseudolaric acid B (PAB) on the growth and apoptosis of colon cancer cells was investigated, and to compare that with the more toxic compound triptolide. PAB induced growth inhibition and apoptosis in HT-29 cells, which were associated with cell cycle arrest at the G(2)/M phase, modulation of cyclin expression and downregulation of the protooncogene c-myc. In addition, PAB also inhibited bcl-x(L) expression, induced cleavage of procaspase-3 and its substrate poly(ADP-ribose) polymerase (PARP), which together caused DNA fragmentation and nuclear chromatin condensation. Concomitantly, the modulation of the growth-related and apoptotic factors by PAB was accompanied by the increased protein and gene expression of the nonsteroidal anti-inflammatory drug-activated gene (NAG-1), which occurred along with cyclooxygenase-2 inhibition. The effects of PAB on PARP cleavage and NAG-1 overexpression were not reversible upon removal of the drug from the culture medium. Similar cytotoxic and pro-apoptotic effects were also attained by treating the HT-29 cells with another diterpenoid triptolide, but its actions on cell cycle progression and on the upstream transcriptional regulation of NAG-1 both took place in a less coherent manner. These findings exemplify the potential of herbal terpenoids, particularly PAB, in modulating colon cancer carcinogenesis through known molecular targets and precise mechanism of action.

Interactions between natural health products and antiretroviral drugs: pharmacokinetic and pharmacodynamic effects.: Clin Infect Dis. 2006 Oct 15;43(8):1052-9 Authors: Lee LS, Andrade AS, Flexner C

Concurrent use of natural health products (NHPs) with antiretroviral drugs (ARVs) is widespread among human immunodeficiency virus-infected patients. This article reviews the clinical pharmacokinetic and pharmacodynamic interactions between NHPs and ARVs. Many NHPs are complex mixtures and are likely to contain organic compounds that may induce and/or inhibit drug metabolizing enzymes and drug transporters. Although the weight of evidence for the effects of certain NHPs varies and many studies of these products lack scientific rigor, it has been observed that St. John's wort clearly induces cytochrome P450 3A4 and P-glycoprotein and reduces protease inhibitor and nonnucleoside reverse-transcriptase inhibitor concentrations, thereby increasing the likelihood of therapeutic failure. Limited clinical research suggests that intake of garlic and vitamin C results in reductions in ARV concentrations. The intake of milk thistle, Echinacea species, and goldenseal inhibits cytochrome P450 enzymes in vitro and may increase ARV concentrations, but by clinically unimportant amounts. Intake of fish oil reduces ARV-induced hypertriglyceridemia without significantly affecting lopinavir concentrations. Before recommending the use of NHPs as adjuncts to ARV use, studies should first exclude significant pharmacokinetic interactions and ensure that ARV efficacy is maintained.

Black Cohosh (Actaea racemosa, Cimicifuga racemosa) Behaves as a Mixed Competitive Ligand and Partial Agonist at the Human mu Opiate Receptor.: J Agric Food Chem. 2006 Dec 27;54(26):9852-9857 Authors: Rhyu MR, Lu J, Webster DE, Fabricant DS, Farnsworth NR, Wang ZJ

Black cohosh is a commonly used botanical dietary supplement for the treatment of climacteric complaints. Because the opiate system in the brain is intimately associated with mood, temperature, and sex hormonal levels, the activity of black cohosh extracts at the human &mgr; opiate receptor (hMOR) expressed in Chinese hamster ovary cells was investigated. The 100% methanol, 75% ethanol, and 40% 2-propanol extracts of black cohosh effectively displaced the specific binding of [3H]DAMGO to hMOR. Further studies of the clinically used ethanol extract indicated that black cohosh acted as a mixed competitive ligand, displacing 77 +/- 4% [3H]DAMGO to hMOR (Ki = 62.9 &mgr;g/mL). Using the [35S]GTP&ggr;S assay, the action of black cohosh was found to be consistent with an agonist, with an EC50 of 68.8 +/- 7.7 &mgr;g/mL. These results demonstrate for the first time that black cohosh contains active principle(s) that activate hMOR, supporting its beneficial role in alleviating menopausal symptoms. Keywords: Black cohosh; menopause; hot flashes; opiate; botanical dietary supplement.

Bidens pilosa suppresses interleukin-1beta-induced cyclooxygenase-2 expression through the inhibition of mitogen activated protein kinases phosphorylation in normal human dermal fibroblasts.: J Dermatol. 2006 Oct;33(10):676-83 Authors: Yoshida N, Kanekura T, Higashi Y, Kanzaki T

Bidens pilosa (BP) Linn. var. radiata is a plant used in traditional folk medicine. It is clinically effective in various diseases; the pathogenesis of most of these involves cyclooxygenase (COX)-2. To investigate the mechanism on which the clinical effectiveness of BP is based, we examined its effects on COX-2 expression and its major product, prostaglandin (PG)E(2), under conditions of inflammation. We induced inflammation in normal human dermal fibroblasts with interleukin (IL)-1beta and examined the effects of BP on COX-2 expression and PGE(2) production using Western blotting and competitive enzyme immunoassay, respectively. The functional involvements of mitogen activated protein kinases (MAPK) ERK1/2, p38, and JNK in COX-2 expression were also examined by Western blotting. IL-1beta-induced COX-2 expression was regulated by MAPK pathways, especially by p38. BP inhibited the phosphorylation of MAPKs, COX-2 expression, and subsequent PGE(2) production. The physiological activities and clinical effectiveness of BP observed under diverse conditions may be partly attributable to its ability to inhibit MAPK, mainly p38, activity, COX-2 expression, and subsequent PGE(2) production.

PMID: 17040496 [PubMed - indexed for MEDLINE]

Bisandrographolide from Andrographis Paniculata activates TRPV4 channels.: J Biol Chem. 2006 Aug 9; Smith PL, Maloney KN, Pothen RG, Clardy J, Clapham DE

Many transient receptor potential channels (TRP) are activated or blocked by various compounds found in plants; two prominent examples include the activation of TRPV1 channels by capsaicin and the activation of TRPM8 channels by menthol. We sought to identify additional plant compounds that are active on other types of TRP channels. We screened a library of extracts from fifty Chinese herbal plants using a calcium-imaging assay to find compounds active on TRPV3 and TRPV4 channels. An extract from the plant Andrographis paniculata potently activated TRPV4 channels. The extract was fractionated further, and the active compound was identified as bisandrographolide A (BAA). We used purified compound to characterize the activity of BAA on certain TRPV channel subtypes. Although BAA activated TRPV4 channels with an EC50 of 790-950 nM, it did not activate or block activation of TRPV1, TRPV2 or TRPV3 channels. BAA activated a large TRPV4-like current in immortalized mouse keratinocytes (308 cells) that have been shown to express TRPV4 protein endogenously. This compound also activated TRPV4 currents in cell-free outside-out patches from HEK293T cells overexpressing TRPV4 cDNA suggesting that BAA can activate the channel in a membrane delimited manner. Another related compound, andrographolide, found in abundance in the plant Andrographis was unable to activate or block activation of TRPV4 channels. These experiments show that BAA activates TRPV4 channels, and we discuss the possibility that activation of TRPV4 by BAA could play a role in some of the effects of Andrographis extract described in traditional medicine.

[Compensatory reactions of immune system and action of Purple Coneflower (Echinacea purpurea (L.) Moench) preparations]: Medicina (Kaunas). 2004;40(7):657-62 Authors: Jurkstiene V, Kondrotas AJ, Kevelaitis E

The objective of the study was to investigate the mechanisms of action of Purple Coneflower (Echinacea purpurea (L.) Moench) preparations on the immune system and to define which part of the plant is the most effective as an immunostimulator. MATERIAL AND METHODS: The extracts from overground parts and roots of Purple Coneflower were injected into rabbits at the dose of 1 ml/kg. The stimulation of T lymphocytes in vitro was tested by incubation of rabbit blood with the different concentrations of the Purple Coneflower preparation (10, 50, 100 microg/ml) and assessed by the method of spontaneous rosettes. The number of lymphocytes, which bind to heterogenic erythrocytes, was counted. In order to determine the local effect, 30 ml of Purple Coneflower preparation (95 mg of dry material/1 ml) was used for the rinsing of mouth cavity in humans. The reaction of phagocytosis was assessed by using latex particles and calculating phagocytosis activity and phagocytosis index. RESULTS: Purple Coneflower extracts from roots were more effective phytoimmunostimulators than those from overground parts. They significantly increased in vivo the number of leucocytes and lymphocytes, especially T lymphocytes, in peripheral blood of rabbits as compared with the control group (p<0.001). The stimulation of T lymphocytes by Purple Coneflower preparation in vitro was the most pronounced at the concentration of 50 microg/ml (20.8+/-1.01% of spontaneous rosettes, p<0.001 with control). An increase in concentration till 100 microg/ml was followed by non-specific inhibition (9.16+/-1.6% of spontaneous rosettes, p>0.05 with control). Purple Coneflower preparations activated phagocytosis of neutrophils in vitro and in vivo. After rinsing mouth cavity with 30 ml of Purple Coneflower root preparation for 15 minutes, phagocytosis activity was significantly increased till 36% (p<0.05 as compared with the control (27%), where physiological solution was used for the rinsing). This local application of Purple Coneflower root preparation has significantly increased phagocytosis index up to 1.03 (p<0.02 as compared with the control index (0.65) after rinsing of the mouth cavity with physiological solution). CONCLUSIONS: Purple Coneflower preparations from roots activate the cellular immunity and stimulate phagocytosis of neutrophils in vitro, in vivo and after rinsing of mouth cavity.

An anthraquinone with potent quinone reductase-inducing activity and other constituents of the fruits of Morinda citrifolia (noni).: J Nat Prod. 2005 Dec;68(12):1720-2 Authors: Pawlus AD, Su BN, Keller WJ, Kinghorn AD

Morinda citrifolia, commonly known as noni, has a long history of utilization throughout much of tropical Polynesia and is considered to be the second most important medicinal plant in the Hawaiian Islands. Recently, the use of noni as a dietary supplement in the United States has greatly increased. Bioassay-guided fractionation of a dichloromethane-soluble partition of a MeOH extract of noni fruits has led to the isolation of an extremely potent quinone reductase inducer, 2-methoxy-1,3,6-trihydroxyanthraquinone (1). This new anthraquinone (1) was nearly 40 times more potent than a positive control, l-sulforaphane. Furthermore, compound 1 demonstrated no discernible cytotoxicity at the highest dose tested. In addition to compound 1, 11 known compounds were also isolated and identified in the present investigation. This is the first report of the isolation of anthraquinones from noni fruits.

The red wine phenolics piceatannol and myricetin act as agonists for estrogen receptor alpha in human breast cancer cells.: J Mol Endocrinol. 2005 Oct;35(2):269-81 Authors: Maggiolini M, Recchia AG, Bonofiglio D, Catalano S, Vivacqua A, Carpino A, Rago V, Rossi R, Andò S

Previous epidemiological reports have suggested that red wine intake is associated with beneficial health effects due to the ability of certain phytochemical components to exert estrogen-like activity. It has been also documented that estrogens induce the proliferation of hormone-dependent breast cancer cells by binding to and transactivating estrogen receptor (ER) alpha, which in turn interacts with responsive DNA sequences located within the promoter region of target genes. In order to provide further insight into the positive association between wine consumption and the incidence of breast carcinoma in postmenopausal women, we have evaluated the estrogenic properties of two abundant wine-derived compounds, named piceatannol (PIC) and myricetin (MYR), using as model systems the hormone-sensitive MCF7 and the endocrine-independent SKBR3 breast cancer cells. On the basis of our experimental evidence PIC and MYR may contribute to the estrogenicity of red wine since: (1) they transactivate endogenous ER alpha; (2) they activate the agonist-dependent activation function (AF) 2 of ER alpha and ER beta in the context of the Gal4 chimeric proteins; (3) they rapidly induce the nuclear immunodetection of ER alpha; (4) they regulate the expression of diverse estrogen target genes; (5) they compete with 17beta-estradiol for binding to ER alpha and ER beta; and--as a biological counterpart of the aforementioned abilities--(6) they exert stimulatory effects on the proliferation of MCF7 cells. Hence, the estrogenic activity of PIC and MYR might be considered at least as a potential factor in the association of red wine intake and breast tumors, particularly in postmenopausal women.

Mechanisms involved in the anti-inflammatory effect of a standardized willow bark extract.: Arzneimittelforschung. 2005;55(11):677-87 Authors: Khayyal MT, El-Ghazaly MA, Abdallah DM, Okpanyi SN, Kelber O, Weiser D

A standardized willow bark extract (STW 33-I) has been examined to clarify its possible mechanism of action as an anti-inflammatory agent. Various facets have been investigated in two inflammation models: the 6-day air pouch model in rats, representing the acute state and the adjuvant induced arthritis representing the chronic one. Parameters included leukocytic infiltration, levels of cytokines and prostanoids in blood, and effects on cyclo-oxygenase (COX)-1 and/or COX-2 enzymes as well as effects involving free radical production. The effect of the extract was compared at two dose levels with comparable anti-inflammatory doses of acetylsalicylic acid (CAS 50-78-2, ASA) as a non-selective COX inhibitor, and celecoxib (CAS 169590-42-5) as a selective COX-2 inhibitor. On a mg/kg basis, the extract was at least as effective as ASA in reducing inflammatory exudates and in inhibiting leukocytic infiltration as well as in preventing the rise in cytokines, and was more effective than ASA in suppressing leukotrienes, but equally effective in suppressing prostaglandins. On COX-2, STW 33-I was more effective than ASA. The present findings show that STW 33-I significantly raises GSH (reduced glutathione) levels, an effect which helps to limit lipid peroxidation. The extract was more potent than either ASA or celecoxib. Higher doses of the extract also reduced malondialdehyde levels and raised shows definite superiority to either ASA or celecoxib in protecting the body against oxidative stress. It is therefore evident that STW 33-I is at least as active as ASA on all the parameters of inflammatory mediators measured, when both are given on a similar mg/kg dose. Considering, however, that the extract contains only 24% salicin (molecular weight 286.2), while ASA has a molecular weight of 180.3, it follows that on a molar basis of salicin vs salicylate, the extract contains less than a sixth of the amount of salicin as the amount of salicylate in ASA. Thus it appears that STW 33-I with its lower "salicin" content than an equivalent dose of ASA, is at least as active as ASA on the measured parameters, a fact that leads one to speculate that other constituents of the extract contribute to its overall activity. The presence of polyphenols in STW 33-I probably plays a significant role in enhancing its free radical scavenging properties. The fact that STW 33-I was superior to ASA in this respect would suggest that the extract may have a better anti-inflammatory effect than ASA on a weight to weight basis, with possibly less side effects.