Veronika Butterweck

Hyperforin in St. John’s wort drug interactions

Recently, interactions of herbal medicines with synthetic drugs came into focus of particular interest. In the past 3 years, more than 50 papers were published regarding interactions between St. John’s wort (Hypericum perforatum L.; SJW) and prescription drugs. Co-medication with SJW resulted in decreased plasma concentrations of a number of drugs including amitriptyline, cyclosporine, digoxin, indinavir, irinotecan, warfarin, phenprocoumon, alprazolam, dextrometorphane, simvastatin, and oral contraceptives. Sufficient evidence from interaction studies and case reports indicate that SJW is a potent inducer of cytochrome P450 enzymes (particularly CYP3A4) and/or P-glycoprotein. Recent studies could show that the degree of enzyme induction by SJW correlates strongly with the amount of hyperforin found in the product. Products that do not contain substantial amounts of hyperforin (<1%) have not been shown to produce clinically relevant enzyme induction. On the other hand, some evidence suggests that hyperforin may also contribute to the antidepressant activity of SJW. However, clinical studies using SJW preparations with a low hyperforin amount (<1%) clearly demonstrated the superiority of this plant extract over placebo and its equivalence to imipramine and fluoxetine in the treatment of mild to moderate forms of depression. In the present paper clinical significant SJW interactions are critically evaluated against the background of hyperforin.

St. John's wort: Role of active compounds for its mechanism of action and efficacy

ZusammenfassungJohanniskraut (Hypericum perforatum L., SJW) enthält viele Verbindungen mit dokumentierter biologischer Aktivität. Zu den Inhaltstoffen, die das größte Interesse ausgelöst haben, zählen die Naphthodianthrone Hypericin und Pseudohypericin, eine große Zahl von Flavonoiden sowie die Phloroglucinole Hyperforin und Adhyperforin. Nach dem aktuellen Stand der wissenschaftlichen Erkenntnisse muss der Gesamtextrakt als der eigentliche Wirkstoff betrachtet werden. Trotz einiger offener Fragen ergibt sich aus der Gesamtdatenlage, dass mehrere Inhaltstoffgruppen zur antidepressiven Wirksamkeit des Pflanzenextraktes beitragen.SummarySt. Johns wort (Hypericum perforatum L., SJW) contains numerous compounds with documented biological activity. Constituents that have stimulated the most interest include the naphthodianthrones hypericin and pseudohypericin, a broad range of flavonoids, and the phloroglucinols hyperforin and adhyperforin. According to the actual state of scientific knowledge the total extract has to be considered as the active substance. Although there are some open questions, the bulk of data suggests that several groups of active compounds are contributing to the antidepressant efficacy of the plant extract.

Grapefruit‐Drug Interactions: Can Interactions With Drugs Be Avoided?

Grapefruit is rich in flavonoids, which have been demonstrated to have a preventive influence on many chronic diseases, such as cancer and cardiovascular disease. However, since the early 1990s, the potential health benefits of grapefruit have been overshadowed by the possible risk of interactions between drugs and grapefruit and grapefruit juice. Several drugs interacting with grapefruit are known in different drug classes, such as HMG‐CoA reductase inhibitors, calcium antagonists, and immunosu‐pressives. Currently known mechanisms of interaction include the inhibition of cytochrome P450 as a major mechanism, but potential interactions with P‐glycoprotein and organic anion transporters have also been reported. This review is designed to provide a comprehensive summary of underlying mechanisms of interaction and human clinical trials performed in the area of grapefruit drug interactions and to point out possible replacements for drugs with a high potential for interactions.

Lessons Learned from Herbal Medicinal Products: The Example of St. John’s Wort⊥

The example of St. Johns wort offers convincing evidence for the concept that modern methods of pharmacological and phytochemical research are effective in advancing the development of traditional herbal remedies. As a consequence of these efforts, it is known today that several compounds from different structural groups and with different mechanisms of action seem to be responsible for the observed antidepressant efficacy of St. Johns Wort. Co-effectors in the extract improve the bioavailability of active constituents such as hypericin (1) (pharmacokinetic synergy). Unwanted side effects are preventable without remarkable loss of activity when the responsible constituent(s) are carefully removed during the extraction process, as demonstrated for hyperforin (3), which is responsible for the induction of cytochrome P450 (CYP)-metabolizing enzymes (CYP3A4, in particular). On the basis of our findings, it is likely that positive interactions between single compounds occur more frequently in traditionally used herbal preparations than is known presently.

Long-term effects of St. John's wort and hypericin on monoamine levels in rat hypothalamus and hippocampus.

Hypericum perforatum L. (St. Johns wort) is one of the leading psychotherapeutic phytomedicines and, because of this, great effort has been devoted to clarifying its mechanism of action. Chronic effects of St. Johns wort and hypericin, one of its major active compounds, on regional brain amine metabolism have not been reported yet. We used a high-performance liquid chromatography system to examine the effects of short-term (2 weeks) and long-term (8 weeks) administration of imipramine, Hypericum extract or hypericin on regional levels of serotonin (5-HT), norepinephrine, dopamine and their metabolites in the rat brain. We focused our interest on the hypothalamus and hippocampus, as these brain regions are thought to be involved in antidepressant drug action. Imipramine (15 mg/kg, p.o.), Hypericum extract (500 mg/kg, p.o.), and hypericin (0.2 mg/kg, p.o.) given daily for 8 weeks significantly increased 5-HT levels in the hypothalamus (P<0.05). The 5-HT turnover was significantly lowered in both brain regions after 8 weeks of daily treatment with the Hypericum extract (both P<0.05). Consistent changes in catecholamine levels were only detected in hypothalamic tissues after long-term treatment. Comparable to imipramine, Hypericum extract as well as hypericin significantly decreased 3,4-dihydroxyphenylacetic acid and homovanillic acid levels in the hypothalamus (P<0.01). Our data clearly show that long-term, but not short-term administration of St. Johns wort and its active constituent hypericin modify levels of neurotransmitters in brain regions involved in the pathophysiology of depression.

Step by step removal of hyperforin and hypericin: activity profile of different Hypericum preparations in behavioral models

Herbal extracts of Hypericum perforatum L. (St. Johns wort, SJW) are now successfully competing for status as a standard antidepressant therapy. Because of this, great effort has been devoted to identifying the antidepressive active compounds. In the present study we used the following strategy to evaluate the relative pharmacological importance of various extract components: 1. preparation of an hydroalcoholic SJW extract containing both hyperforin (3.2%) and hypericin (0.15%) (extract A); 2. step by step removal of hyperforin and hypericin led to the following extracts: Extract B, devoid of hyperforin but still containing hypericin (0.14%) and Extract C, free of hypericin and hyperforin but enriched in flavonoids ( approximately 12%). We characterized the in vivo activity profile of all three preparations using the tail suspension test (TST) in mice and the forced swimming test (FST) in rats as screening models. We further investigated the activity of pure hyperforin. Extract B and C (500 mg/kg each) as well as pure hyperforin (8 mg/kg) significantly shortened immobility time in the TST after acute pre-treatment whereas extract A was inactive. In the FST all three extracts decreased immobility time in a dosage of 500 mg/kg after acute as well as after repeated treatment. The present results clearly show that an SJW extract free of hyperforin and hypericin exerts antidepressant activity in behavioral models, supporting our working hypothesis that flavonoids are part of the constituents responsible for the therapeutic efficacy of SJW extracts. We also could show that hyperforin contributes to the beneficial properties of SJW extract, confirming the hypothesis that the crude SJW extract contains several constituents with antidepressant activity.

Herbal Medicines in the Management of Urolithiasis: Alternative or Complementary?

Kidney stone formation or urolithiasis is a complex process that results from a succession of several physicochemical events including supersaturation, nucleation, growth, aggregation, and retention within the kidneys. Epidemiological data have shown that calcium oxalate is the predominant mineral in a majority of kidney stones. Among the treatments used are extracorporeal shock wave lithotripsy (ESWL) and drug treatment. Even improved and besides the high cost that imposes, compelling data now suggest that exposure to shock waves in therapeutic doses may cause acute renal injury, decrease in renal function and an increase in stone recurrence. In addition, persistent residual stone fragments and the possibility of infection after ESWL represent a serious problem in the treatment of stones. Furthermore, in spite of substantial progress in the study of the biological and physical manifestations of kidney stones, there is no satisfactory drug to use in clinical therapy. Data from IN VITRO, IN VIVO and clinical trials reveal that phytotherapeutic agents could be useful as either an alternative or an adjunctive therapy in the management of urolithiasis. The present review therefore critically evaluates the potential usefulness of herbal medicines in the management of urolithiasis.

Route of administration determines the anxiolytic activity of the flavonols kaempferol, quercetin and myricetin — are they prodrugs?

Several in vivo and in vitro studies have confirmed that flavonols are metabolized by the intestinal microflora to their corresponding hydroxyphenylacetic acids. In this article, a comparison of the anxiolytic activity of the flavonols kaempferol, quercetin and myricetin in the elevated plus maze after oral (po) and intraperitoneal (ip) administration to mice in a dose range of 0.1 to 2.0 mg/kg is presented. In addition, their corresponding metabolites p-hydroxyphenylacetic acid (p-HPAA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were tested after intraperitoneal administration. Anxiolytic activity was detected for kaempferol and quercetin only after oral administration. No anxiolytic effects were observed when kaempferol and quercetin were given via the intraperitoneal administration route. The corresponding hydroxyphenylacetic metabolites p-HPAA and DOPAC showed anxiolytic effects after intraperitoneal application. In order to further test the hypothesis that flavonoids are possible prodrugs which require activation by intestinal bacteria, gut sterilization was performed using pretreatment with the antibiotic enrofloxacin (7.5 mg/day, po, for 4 days). After antibiotic treatment, the anxiolytic effect of kaempferol and quercetin disappeared, whereas it was still present for the positive control diazepam. Our results support the hypothesis that flavonoids act as prodrugs which are transformed into their active hydroxyphenylacetic acid metabolites by intestinal microflora.

Anxiolytic activity of a phytochemically characterized Passiflora incarnata extract is mediated via the GABAergic system.

The purpose of this research was to assess the anxiolytic properties of a phytochemically characterized commercial extract from Passiflora incarnata (PI; Passifloraceae) in the elevated plus maze test in mice. Using an HPLC method, the flavonoids homoorientin, orientin, vitexin, and isovitexin were identified as major compounds. Following oral administration, the extract exerted an anxiolytic effect that was comparable to diazepam (1.5 mg/kg) at a dose of 375 mg/kg and exhibited a U-shaped dose-response curve. In addition, antagonism studies using the GABA (A)/benzodiazepine receptor antagonist flumazenil and the 5-HT (1A)-receptor antagonist WAY-100 635 were conducted. The active dose was effectively antagonized by flumazenil, but not by WAY-100 635. This study is the first demonstration of the IN VIVO, GABA-mediated anxiolytic activity of an HPLC- characterized extract of Passiflora incarnata.

Kaempferol from the leaves of Apocynum venetum possesses anxiolytic activities in the elevated plus maze test in mice

The present work evaluated the anxiolytic activity of an aqueous extract of Apocynum venetum L. (Apocynaceae) and bioguided its fractionation using the elevated plus maze (EPM) in mice as a model of anxiety. A single treatment of AV extract markedly increased the percentage time spent on the open arms of the EPM in two distinct concentration ranges of 22.5-30 and 100-125 mg/kg p.o., respectively, indicating a putative anxiolytic-like activity. Fractions showing anxiolytic effects in concentrations equal to 30 or 125 mg/kg of whole extract were antagonized using the benzodiazepine antagonist flumazenil (3 mg/kg i.p.) or the 5-HT(1A) receptor antagonist WAY-100635 (0.5 mg/kg i.p.). All active fractions in a concentration equal to 125 mg/kg were effectively blocked by the benzodiazepine antagonist flumazenil, while the anxiolytic activities of fractions in the lower dose equivalent to 30 mg/kg of whole extract were inhibited by the 5-HT(1A) receptor antagonist WAY-100635. Through further separation of AV fractions it was possible to isolate and characterize the flavonol kaempferol which showed an anxiolytic-like activity in concentrations from 0.02 to 1.0 mg/kg p.o. The anxiolytic activity of kaempferol was partially antagonized by concomitant administration of flumazenil, but not by WAY-100635. In conclusion, our study clearly demonstrates that AV extract possesses anxiolytic-like activity and that at least one of its flavonoids, kaempferol, can elicit the same kind of neuropharmacological activity.