Hyperforin

Potassium Competitive Acid Blockers The pregnane X receptor (PXR) is a promiscuous nuclear receptor, that has evolved to protect the body from toxic chemicals. It is activated by a wide variety of xenobiotics including several diugs like rifampicin, hyperforin ( the active ingredient of St. John s wort), clotrimazole and others. PXR heterodimerizes with the... 

Hyperforin, the major constituent in Hypericum perforatum (St. John s Wort), inhibits the enzymatic activity of 5-lipoxygenase and COX-1 in platelets, acts as a dual inhibitor of 5-lipoxygenase and COX-1, and might have some potential in inflammatory and allergic diseases connected to eicosanoids (32), Several Hypericum species are of medicinal value in Asia and the Pacific. One of these is Hypericum erectum Thunb., the potential of which as a source of 5-lipoxygenase is given here. 

Dana A, Ilse Z, Dingermann T, Muller WE, Steinhilber D, Werz O. Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase. Biochem Pharmacol 2002 64 1767-1775. 

Of all N Rs involved in xenobiotics metabolism induction, PX R is the most prominent one. PXR functions as a xenobiotic sensor and is activated by a large variety of chemically diverse compounds, for example lovastatin, nifedipine, rifampicin, SR12813, troglitazone or hyperforin (Chart 14.3), many of them standard therapeutic agents for common diseases [20-25]. 

Fig. 2.49. Profile of Hypericum perforatum extract with the H LC-MS attributions of the components detected. 1 = chlorogenic acid isomer 2 = 3-0- -coumaroylquinic acid 3 = chlorogenic acid 4 = rutin 5 = hyperoside 6 = isoquercitrin 7 = 3,3, , , 7-pentahydroxyflavanone 7-0-rhamnopyranoside 8 = quercitrin 9 = quercetin 10 = 13,118 tapigenin 11 = pSeudohypericin 12 = hypericin 13 = hyperforin analogue 14 = hyperform dialogue 15 = hyperforin 16 = adhyperforin. Reprinted with permission from M. Brolis eta. [ ].

Hyperforin Adhyperforin Caffeic acid Chlorogenic acid Gentisic acid Ferulic acid Monoterpenes Sesquiterpenes 1,5-dihydroxyxanthone... 

Extracts of hypericum may vary considerably in terms of the quantity and ratio of their constituents based on the extraction process used. Maximum extraction of hypericin and pseudohypericin is obtained with an 80% methanol solvent at 80°C (Wagner and Bladt 1994). Hyperforin is a lipophilic constituent of hypericum that is present in the oil extract (Chatterjee et al. 1998a). It is not very stable, but its presence is sustained by hot maceration of the flowers and storage in the absence of air (Maisenbacher and Kovar 1992). 

The pharmacokinetics of hyperforin have been studied in rats and humans (Biber et ai. 1998). In rats, after a 300 mg/kg orai dose of hypericum extract (WS 5572, containing 5% hyperforin), maximum piasma ieveis of 370 ng/mi (690 nM) are achieved at 3 hours. The haif-iife of hyperforin is 6 hours. Humans given a 300 mg tabiet of hypericum (containing 14.8 mg hyperforin) showed maximum piasma ieveis of 150 ng/mi (280 nM) at 3.5 hours. The haif-iife is 9 hours, and mean residence time is 12 hours. Pharmacokinetics of hyperforin are iinear up to 600 mg, and no accumuiation occurs after repeated doses. By comparison, effective and safe piasma ieveis of paroxetine and fluoxetine vary between 40 and 200 ng/mi (Preskorn 1997). The effective piasma concentration of hyperforin predicted from computer-fit data is approximateiy 97 ng/mi (180 nM), which couid be easiiy monitored (Biber et ai. 1998). There is a iinear correiation between orai dose of hyperforin and piasma ieveis, and steady-state concentrations of 100 ng/mi (180 nM) couid be achieved with three-times-daiiy dosing. 

Another action of hypericum constituents that is particularly relevant to antidepressant effects is the ability to inhibit neuronal reuptake of monoamines. The half-maximal inhibition for monoamine uptake is 100 times lower than for the inhibition of MAOA or MAOB (Chatterjee et al. 1998a). Hyperforin is the major contributor to this action, blocking reuptake of 5-HT, norepinephrine, and dopamine (Muller et al. 1998). Half-maximal inhibition occurs at nanomolar concentrations (80 to... 

In addition to reuptake effects, subchronic treatment with hyperforin down-regulates (S adrenergic receptors and up-regulates 5-HT2 receptors in frontal cortex of the rat (Muller and Rossol 1994,... 

Amino acid neurotransmitter Constituents of hypericum also appear to have effects on amino acid neurotransmission, particularly GABA. Hypericin and a crude extract bind to GABAA and GABAB receptors (Cott 1997). Hyperforin also inhibits synaptosomal GABA reuptake in the low micromolar range (IC50 values of 0.05-0.10 ug/ml). Activity at GABAA benzodiazepine receptors was noted in extracts of four hy-... 

Electrophysiological effects Extracts of hypericum were examined for their electrophysiological effects in animals. The onset of effects occurred 3-4 hours after administration. Frequencies affected first were in the alpha range and were maximal in the frontal cortex (Dimpfel and Hofmann 1995). Another study examined the EEG effects for two hypericum extracts in rats one extract high in hyperforin and lacking naphthodi-anthrones (C02), and another extract (LI 160) low in hyperforin. Both extracts showed similar early alpha effects, but only LI 160 had a late effect of increased delta frequencies. The alpha effects are comparable to... 

A review of case reports, clinical trials, post-marketing surveillance, and drug monitoring studies concurrently showed that the most common side effects were gastrointestinal, dizziness/confusion, and sedation (Ernst et al. 1998). Importantly, the side effects of hypericum in this study were comparable to placebo levels. A pharmacokinetic study showed that plasma levels of up to 300 ng/ml were well tolerated. Headache occured in one subject who was taking 1200 mg extract (59 mg hyperforin, plasma cone. >400 ng/ml) (Biber et al. 1998). 

Thus, the long tradition of hypericum as a treatment for depression has been well supported by modern scientific research. Several active constituents have been identified, including naphthodianthrones (e.g., hypericin), phloroglucinols (e.g., hyperforin) and flavonoids (amentoflavone). Research has delineated its pharmacokinetic properties, and many of its neurochemical mechanisms have been identified enhancing monoamine... 

Bhattacharya SK, Chakrabarti A, Chatterjee SS. (1998). Activity profiles of two hyperforin-containing hypericum extracts in behavioral models. Pharmacopsychiatry. 31(suppl 1) 22-29. 

Chatterjee SS, Bhattacharya SK, Wonnemann M, Singer A, Muller WE. (1998a). Hyperforin as a possible antidepressant component of hypericum extracts. Life Sci. 63(6) 499-510. 

Chatterjee SS, Noldner M, Koch E, Erdelmeier C. (1998b). Antidepressant activity of hypericum perforatum and hyperforin the neglected possibility. Pharmacopsychiatry. 31(suppl 1) 7-15. 

Dimpfel W, Schober F, Mannel M. (1998). Effects of a methanolic extract and a hyperforin-enriched C02 extract of St. John s Wort (Hypericum perforatum) on intracerebral field potentials in the freely moving rat (Tele-Stereo-EEG). Pharmacopsychiatry. 31(suppl 1) 30-5. 

Enns MW, Cox BJ, Parker JD, Guertin JE. (1998). Confirmatory factor analysis of the Beck anxiety and depression inventories in patients with major depression. J Affective Disord. 47(1-3) 195-200. Erdelmeier CA. (1998). Hyperforin, possibly the major non-nitrogenous secondary metabolite of Hypericum perforatum L. Pharmacopsychiatry. 31(suppl 1) 2-6. 

Laakmann G, Schule C, Baghai T, Kieser M. (1998). St. John s wort in mild to moderate depression the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry. 31(suppl 1) 54-59. 

Muller WE, Singer A, Wonnemann M, Hafner U, Rolli M, Schafer C. (1998). Hyperforin represents the neurotransmitter reuptake inhibiting constituent of hypericum extract. Pharmacopsychia y. 31(suppl 1) 16-21. 

Gey, C Kyrylenko, S Hennig, L., Nguyen, L.H., Biittner, A., Pham, H.D. et al. (2007) Phloroglucinol derivatives guttiferone G, aristoforin, and hyperforin inhibitors of human sirtuins SIRTl and SIRT2. Angewandte Chemie, 119, 5311-5314. 

Many constituents with potential biological activity have been extracted from the flowers and leaves, the parts of the plant used for medicinal purposes. These include naphthodianthrones, flavonoids, phlorogluci-nols, and xanthones. Hypericin, one of the naphthodianthrones, has traditionally been considered the main active ingredient, but it is not known whether this is the compound with antidepressant activity. Recent data suggest that a component called hyperforin may be more important than hypericin for the antidepressant activity. 

It is not possible to discuss pharmacokinetics when the active compound or compounds of St. John s wort are not known. The half-life of hypericin and hyperforin have been estimated at between 6 and 9 hours, with peak plasma concentrations at about 2-3 hours after administration. Some of the ingredients of Hypericum extracts are metabolized in the liver. 

Of particular concern is that this inconsistency in product and active constituent occurs even within the same batch. As part of a clinical study with St. John s wort. Hall et al. analyzed 10 capsules of St. John s wort from the same lot (lot 13207) and found the mean total weight to be 444 mg (4.6% CV) versus 300 mg as stated on the label. In addition, the dosage form was supposed to be standardized to contain 900 pg of hypericin, but the mean content was found to be 840 pg (6.6% CV). There was also variability of the hyperforin content (mean 11 mg and 5.7 /o CV), which was not stated on the label (21). Our experience (Lam YWF, unpublished data) with two random capsules from one batch of kava-kava also showed the same extent of undesirable variance the total content of the pharmacologically active kavalactone was 47.3 mg in one capsule and 39.4 mg in the second one. 

Many SJW products are standardized to either 0.3 /o hypericin or 4%i hyperforin. Some product labels stated standardization to hypericins. 

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