Pseudohypericine

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. [ ].

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 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. 

Brockmoller J, Reum T, Bauer S, Kerb R, Htibner WD, Roots I. (1997). Flypericin and pseudohypericin pharmacokinetics and effects on photosensitivity in humans. Pharmacopsychiatry. 30(suppl 2) 94-101. 

Kerb R, Brockmoiier J, Staffeldt B, Ploch M, Roots I. (1996). Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericin. Antimicrob Agents Chemother. 40(9) 2087-93. Kim HL, Streltzer J, Goebert D. (1999). St. John s wort for depression a meta-analysis of well-defined clinical trials. J Nerv Ment Dis. 187(9) 532-38. 

Staffeldt B, Kerb R, Brockmoller J, Ploch M, Roots I. (1994). Pharmacokinetics of hypericin and pseudohypericin after oral intake of the hypericum perforatum extract LI 160 in healthy volunteers. J Geriatr Psychiatry Neurol. 7(suppl 1) S47-53. 

Takahashi I, Nakanishi S, Kobayashi E, Nakano H, Suzuki K, Tamaoki T. (1989). Hypericin and pseudohypericin specifically inhibit protein kinase C possible relation to their antiretroviral activity. Biochem Biophys Res Common. 165(3) 1207-12. 

This herbal product has the most data available to support its usefulness as an antidepressant. Nevertheless, only minimal information is available about its pharmacology and its relative risk-benefit ratio. At least seven different biologically active chemicals have been isolated from crude extracts of hypericum. Several are ubiquitous in the plant kingdom. The exceptions are hypericin and pseudohypericin, which have been assumed to be responsible for any antidepressant activity of this product. Nevertheless, there is the potential for one or more of these seven compounds and their metabolites to mediate desired or undesired effects, particularly when used in combination with other medications (i.e., herb-drug interactions). 

St. John s wort and some individual constituents of the preparations have been administered orally, topically, and intravenously in various pharmaceutical formulations, including tinctures, teas, capsules, purified components, and tablets. These botanical preparations of St. John s wort are prepared from plant components (i.e., flowers, buds, and stalk) whose content of the wide array of structurally diverse bioactive constituents may differ (Table 1 and Fig. 2). Many commercial tablet and capsule formulations of St. John s wort are standardized using the ultraviolet absorbance of the naphtho-dianthrones, hypericin, and pseudohypericin, to contain 0.3% hypericin content. Thus, a 300 mg dose of St. John s wort contains approximately 900 pg hypericin per dose. Despite the standardization of dosage forms... 

Draves AH, Walker SE. Analysis of the hypericin and pseudohypericin content of commercially available St John s Wort preparations. Can J Clin Pharmacol 2003 10(3) 114-118. 

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. 

Figure 3 Structures of (A) hypericin (B) pseudohypericin (C) hyperforin (D) flavo-noids (R=H quercetin R=a-L-rhamnosyl quercitrine R=P-D-glucosyl isoquerci-trine R=P-D-galactosyl hyperoside R=P-D-rutinosyl rutin R=P-o-glucuronide miquelianin) and (E) procyandin B2.

Single- and multiple-dose pharmacokinetic studies with extracts of SJW were performed in rats and humans, which focused on the determination of plasma levels of the naphthodianthrones hypericin and pseudohypericin and the phloroglucinol derivative hyperforin. Results from pharmacokinetic... 

A placebo-controlled, randomized clinical trial with monitoring of hypericin and pseudohypericin plasma concentrations was performed to evaluate the increase in dermal photosensitivity in humans after application of high doses of SJW extract (Table 2) (73). The study was divided into a single-dose and a multiple-dose part. In the single dose crossover study, each of the 13 volunteers received either placebo or 900, 1800, or 3600 mg of the SJW extract LI 160. Maximum total hypericin plasma concentrations were observed about four hours after dosage and were 0, 28, 61, and 159ng/mL, respectively. Pharmacokinetic parameters had a dose relationship that appeared to follow linear kinetics (73). 

In another study, the concentrations of hypericin and pseudohypericin in serum and skin blister fluid after oral intake (single and steady state) of... 

LI 360 tablets containing 0.25mg hypericin and 0.52mg pseudohypericin. Abbreviations SJW, St. John s wort i.v., intravenous N, number of subjects tion half-life CL, clearance with regard to bioavailability. 

LI 160 tablets containing 300mg extract (0.25mg hypericin and 0.52mg pseudohypericin per tablet). 

Animal studies Early pharmacokinetic studies in mice report that maximum plasma concentrations of hypericin and pseudohypericin were reached at six hours and were maintained for at least eight hours. The aqueous-ethanolic SJW extract used in this study contained 1.0 mg of hypericin (77). 

Butterweck V, Petereit F, Winterhoff H, Nahrstedt A. Solubilized hypericin and pseudohypericin from Hypericum perforatum exert antidepressant activity in the forced swimming test. Planta Med 1998 64 291-294. 

Kerb R, Brockmoeller J, Staffeldt B, Ploch M, Roots I. Single-dose and steady state pharmacokinetics of hypericin and pseudohypericin. Antimicrob Agents Chemother 1996 40 2087-2093. 

Stock S, Hoelzl J. Pharmacokinetic tests of (14C)-labeled hypericin and pseudohypericin from Hypericum perforatum and serum kinetics of hypericin in man. Planta Med 1991 57 A61. 

Dianthrone derivatives Hypericin, pseudohypericin, anthranol, photohypericin, hypericodehydrodianthrone Flavanols Catechin polymers (condensed tannins), leucocyanidin, epicatechin Photodynamic, antidepressant [monoamine oxidase inhibitor (MAOI)], antiviral Astringent, anti-inflammatory, styptic, antiviral... 

Hypericum triquetrifolium Turra. H. chinensis L. Jin Ci Tau (St. John s wort) (whole plant) Hypericin, pseudohypericin, hyperin.33 Antidepressant, anti-HIV, antitumor. 

N.A. Hypericin, hyperoside, rutin, quercitin, chlorogenic acid, pseudohypericin, flavonoids.99 100 102 Antidepressant, anti-inflammatory, diuretic, antiseptic and astringent properties. 

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