Hypericum extracts

Philipp, Michael, Ralf Kohnen and Karl O. Hiller, Hypericum Extract Versus Imipramine or Placebo in Patients with Moderate Depression Randomised Multicentre Study ofTreatment for Eight Weeks , British Medical Journal 319 (1999) 1534-39... 

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. 

The pharmacokinetics of hypericin and pseudohypericin piasma have been studied as weii (Brockmoiier et ai. 1997). Human subjects receiving piacebo, or 900, 1800, or 3600 mg of a standardized hypericum extract (LI 160), which contained 0, 2.81, 5.62, and 11.25 mg of totai hypericin and pseudohypericin, achieved maximum total plasma concentrations at 4 hours (0.028, 0.061, and 0.159 mg/L, respectively). The half-lives of absorption, distribution, and elimination were 0.6, 6.0, and 43.1 hours, respectively, using 750 pg of hypericin, and are slightly different for 1578 pg of pseudohypericin (1.3, 1.4, and 24.8 hours, respectively) (Kerb et ai. 1996). The systemic availability of the hypericum extract LI 160 is between 14 and 21%. Comparable results are found in another study using LI 160 (Staffeldt et ai. 1994). Long-term dosing of 3 x 300 mg per day showed that steady-state levels of hypericin are reached after 4 days. 

The oral bioavailability of hypericum may be altered and improved by a combination of its constituents. A hypericum extract containing naphthodianthrones is inactive in a water suspension, but very effective when another constituent, procyanidin, is present. Procyanidin had the effect of increasing the water solubility of naphthodianthrones, and thus increasing their pharmacokinetic availability (Butterweck et ai. 1997). Further, the facilitative effect of procyanidin exhibited an inverted U curve. 

Reported clinical doses of hypericum extract range from 300 to 1200 mg per day. (Heiligenstein and Guenther 1998 Linde et al. 1996)... 

Opioid A recent study has shown activity of hypericum extracts at opioid receptors (Simmen et al. 1998). Extracts displace naloxone from p and x opioid receptors in the micromolar range (IC50 25 and 90 pg/ml, respectively). In contrast, extracts of the sedative herb Valeriana officinalis do not have this effect. This effect is due to unidentified constituents and not by the flavonoids quercetin or kaemferol. Opioids are known to have effects on emotion, so it is conceivable that activity of hypericum at p and k receptors contributes to its therapeutic effects (Gerra et al. 1998 Tejedor-Real et al. 1995 Walker and Zacny 1998). Although they are not conventional treatment for depression, opioids such as buprenorphine have been effective in treatment of refractory depression (Bodkin et a. 1995). However, for any further conclusions to be drawn, it would be necessary to further e uddate the opioid effects of hypericum to determine what functional effect, if any, hypericum has on the receptors. 

Other mechanisms A few other effects of hypericin, and a crude hypericum extract have been found, including affinity for NMDA, inositol triphosphate, and adenosine receptors. However, these are not likely to be significant to its therapeutic effects because concentrations required for these interactions are not likely to be achieved by oral administration (Cott 1997). Vasoactive effects are possible because hypericum extracts blocked the vasoconstricting effects of histamine and prostaglandin F2o in porcine coronary arteries, and some vasorelaxation occurs in one particular fraction. These effects are hypothesized to be mediated by inhibition of phosphodiesterase (Melzer et al. 1991). 

Hypericum also has effects on cytokine levels (Thiele et al. 1994). A hypericum extract (LI 160) given to people with depression and healthy... 

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... 

Studies in mice have shown a hypericum extract to increase exploration in an unfamiliar environment, prolong sedative sleep time, and antagonize the effects of reserpine. Other antidepressant-like effects are found on the water-wheel test, and chronic administration decreased aggression in socially isolated male mice (Okpanyi and Weischer 1987). 

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

Bladt S, Wagner FI. (1994). Inhibition of MAO by fractions and constituents of hypericum extract. J Geriatr Psychiatry Neurol. 7(suppl 1) S57-59. 

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. 

Kasper S. (1997). Treatment of seasonal affective disorder (SAD) with hypericum extract. Pharmacopsychiatry. 30(suppl 2) 89-93. 

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. 

Okpanyi SN, Weischer ML. (1987). [Animal experiments on the psychotropic action of a Hypericum extract]. Arzneimittelforschung. 37(1) 10-13. 

Schellenberg R, Sauer S, Dimpfel W. (1998). Pharmacodynamic effects of two different hypericum extracts in healthy volunteers measured by quantitative EEG. Pharmacopsychiatry. 31(suppl 1) 44-53. 

Schulz H, Jobert M. (1994). Effects of hypericum extract on the sleep EEG in older volunteers. J Geriatr Psychiatry Neuroi. 7(suppl 1) S39-43. 

Wagner H, Bladt S, MAO inhibition by fractions and constituents of Hypericum extract, Nervenheilkunde 12 349—352, 1993-... 

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. 

Hypericum extracts can have clinically significant interactions with prescribed medications (Rey and Walter, 1998 Ernst, 1999b Piscitelli et ah, 2000 Walter et ah, 2000). The more important interactions known are presented in Table 29.2. There is limited information about the mechanisms involved. The more common view is that St. John s wort extracts activate the... 

Thiele, B., Brink, I., and Ploch, M. (1994) Modulation of cytokine expression by Hypericum extract. / Geriatr Psychiatry Neurol 7 (Suppl 1) S60-S62. 

Woelk, H. (1994) Benefits and risks of the Hypericum extract LI 160 drug monitoring study with 3250 patients. J Geriatr Psychiatry Neurol 7 (Suppl 1) S34-S38. 

A number of studies have been performed on the efficacy of St. John s Wort as an antidepressant. Several meta-analyses of these studies have also been published. The first such metaanalysis involved 23 randomized trials (15 placebo-controlled and eight active-controlled) involving 1,757 outpatients. It concluded that there was preliminary evidence supporting hypericum extracts as being superior to placebo in patients with mild to moderate clinical depression ( 233). Two more recent reviews of subsequent, placebo-controlled studies also concluded that hypericum is more effective than placebo but possibly less effective than TCAs ( 234, 235). At least two large-scale, multicenter, double-blind, placebo- and active-controlled studies are ongoing in the United States, testing the efficacy of hypericum versus an SSRI in patients with major depression. The results of these studies should further clarify the role of hypericum in the treatment of depressive disorders. 

Muller WEG, Rolli M, Schafer C, et al. Effects of hypericum extract (LI 60) in biochemical models of antidepressant activity. Pharmacopsychiatry 1997 30 102-107. 

Teufel-Mayer R, Gleitz J. Effects of long-term administration of hypericum extracts on the affinity and density of central serotonergic 5-HT., 3 and 5-HT2a receptors. Pharmacopsychiatry 1997 30 113-116. 

Thiede HM, Walper A. Inhibition of MAO and COMT by hypericum extracts and hypericin. J Geriatr Psychiatr Neurol 1994 7(suppl 1) S54-S56. 

The pharmacological activity of SJW extracts has recently been reviewed (55-58). Recent reports have shown that the antidepressant activity of Hypericum extracts can be attributed to the phloroglucinol derivative hyperforin (59-62), to the naphthodianthrones hypericin and pseudohypericin (18,63-65), and to several flavonoids (66-69). The role and the mechanisms of action of these different compounds are still a matter of debate. But, taking these previous findings together, it is likely that several constituents are responsible for the clinically observed antidepressant efficacy of SJW. 

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