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PubMed2003

Hypericum perforatum extract demonstrates antioxidant properties against elevated rat brain oxidative status induced by amnestic dose of scopolamine.

This study was designed to investigate if the impairment of learning and memory induced by acute administration of scopolamine (1.4 mg/kg ip) in rats is associated with altered brain oxidative stress status. The passive avoidance paradigm was used to assess retrieval memory of rats after scopolamine treatment. Following retrieval testing, biochemical assessments of malondialdehyde (MDA), glutathione peroxidase (GSHPx), glutathione (GSH), and superoxide dismutase (SOD) levels/activities as oxidative stress indices were performed. This study also investigated the effect of acute administration of Hypericum perforatum extract (4.0, 8.0, 12.0, and 25.0 mg/kg ip), containing flavonoids with documented antioxidant activity, on brain oxidative status of nai;ve rats treated with amnestic dose of scopolamine. Results showed that administration of 1.4 mg/kg of scopolamine impaired retrieval memory of rats and that such amnesia was associated with elevated MDA and reduced GSH brain levels. In nai;ve rats, which have not been exposed to conditioned fear, scopolamine administration also increased MDA and reduced GSH levels, although with an increase in brain GSHPx activity. Pretreatment of the animals with Hypericum extract (4, 8, and 12 mg/kg) resulted in an antioxidant effect through altering brain MDA, GSHPx, and/or GSH level/activity. Since oxidative stress is implicated in the pathophysiology of dementia, the findings of this study may substantiate the value of scopolamine-induced amnesia in rats as a valid animal model to screen for drugs with potential therapeutic benefit in dementia. Exposure of animals to conditioned fear may be suggested to impair the balance between the rate of lipid peroxidation and the activation of GSHPx as a compensatory antioxidant protective mechanism. It is also concluded that low doses of Hypericum extract, demonstrating antioxidant activity, may be of value for demented patients exhibiting elevated brain oxidative status. Since depression commonly coexists with dementia, Hypericum extract as a drug with documented antidepressant action may also be a better alternative than several other antidepressant medications that have not been evaluated to test their effect on brain oxidative status during amnesia.

Amnesia↗
PubMed2005

Identification and quantification of hypericin and pseudohypericin in different Hypericum perforatum L. in vitro cultures.

Investigations have been made to develop an efficient protocol for micropropagation allowing to improve hypericin and pseudohypericin productions in Hypericum perforatum L. in vitro cultures. The role of growth regulator treatments has been particularly studied. Three in vitro culture lines with different morphological characteristics were obtained during H. perforatum micropropagation and referred to shoots, calli and plantlets according to their appearance. Multiplication and callogenesis from apical segments from sterile germinated seedlings were obtained on solid MS/B5 culture medium in the presence of N6-benzyladenine (BA) (0.1-5.0 mg/l BA). Regenerative potential of shoots was assessed on medium supplemented with auxins (0.05-1.0 mg/l), indole-3-acetic acid (IAA) or indole-3-butyric acid (IBA). The main goal of the research was to summarize the influence of plant growth regulators on hypericin and pseudohypericin productions in in vitro cultures of Hypericum. A rapid method for naphtodianthrone quantification was developed. The use of a reversed-phase high performance liquid chromatography (HPLC) method with fluorescence detection was used. Identification of the compounds was confirmed by electrospray ionization-mass spectrometry (ESI-MS) with electrospray in negative ion mode [M-H] . Calli, shoots and plantlets of H. perforatum produced hypericin and pseudohypericin. The concentration range of BA from 0.1 to 2.0 mg/l improved the production of hypericin (25-50 microg/g dry mass (DM)) and pseudohypericin (170-350 microg/g DM) in shoots. In callus cultures, BA (4.0-5.0 mg/l) did not changed hypericin contents (15-20 microg/g DM) but influenced pseudohypericin productions (120-180 microg/g DM). In the presence of auxins (IAA and IBA), Hypericum plantlets produced hypericin (30-100 microg/g DM) and pseudohypericin (120-400 microg/g DM). The presence of IAA did not influence naphtodianthrone productions in plantlets, but IBA decreased hypericin and pseudohypericin amounts in plantlets. The specific accumulation of the naphtodianthrones in in vitro cultures was influenced by phytohormonal supplementation of the medium. Results indicated that the production of hypericin and pseudohypericin could be increased by carefully adapted in vitro cultures. Hypericum in vitro cultures represent promising systems for hypericin and pseudohypericin productions.

Anthracenes↗
PubMed2004

Toxicity of Hypericum perforatum (St. John's wort) administered during pregnancy and lactation in rats.

The popularity of St. John's wort (Hypericum perforatum) for the treatment of depression is increasing and, in recent years, concerns about its use during pregnancy and breastfeeding have emerged. The purpose of this study was to investigate, in Wistar rats, the effects of a treatment with hypericum administered prenatally and during breastfeeding (from 2 weeks before mating to 21 days after delivery). Two doses of the extract were chosen, 100 mg/kg per day, which, based on surface area, is comparable to the dose administered to humans, and 1000 mg/kg per day. A microscopical analysis of livers, kidneys, hearts, lungs, brains, and small bowels was performed. A severe damage was observed in the livers and kidneys of animals euthanized postnatally on days 0 and 21. The lesions were more severe with the higher dose and in animals that were breastfed for 21 days; however, an important renal and hepatic damage was evident also with the dose of 100 mg/kg per day. In addition, similar serious hepatic and renal lesions were evident also in animals that were exposed to hypericum only during breastfeeding. In particular, a focal hepatic damage, with vacuolization, lobular fibrosis, and disorganization of hepatic arrays was evident; in the kidney, a reduction in glomerular size, disappearance of Bowman's space, and hyaline tubular degeneration were found. The results obtained in this study indicate that further, appropriate histological studies should be performed in other animal species to better evaluate the safety of hypericum extracts taken during pregnancy and breastfeeding.

Animals↗
PubMed2001

Investigation of some Hypericum species native to Southern of Brazil for antiviral activity.

Three plant species, Hypericum connatum, Hypericum caprifoliatum, Hypericum polyanthemum (Guttiferae), growing in Southern of Brazil were chemically investigated and tested for their antiviral activity against feline immunodeficiency virus (FIV). The chemical analysis revealed the presence of polyphenolic compounds such as tannins and flavonoids. Hypericin was not detected in these species. The aqueous extract (AE), the aqueous extract with low tannin concentration (LTCAE) and the methanolic extract (ME) were tested for their cytotoxic properties in concentrations of 50-150 microg/ml. AE was toxic to CRFK for the three species in all concentrations. LTCAE and ME varied between different concentrations being not toxic or allowing 80% of cell growth. LTCAE and ME (10-50 microg/ml) were analyzed for antiviral activity by inhibition of CPE and measuring FIV genome from cell culture supernatant. LTCAE of all species in this work did not cause any inhibition of FIV. Although no difference was seen in CPE, a lower number of viral particles in the supernatant was observed when FIV infected cells were treated with ME of H. connatum. These results suggest that some plants of the genus Hypericum from Southern Brazil contain compounds with potential antiviral activity against lentiviruses.

Animals↗
PubMed1999

Hypericum for depression. An update of the clinical evidence.

This review is aimed at providing an updated evaluation of the clinical evidence regarding Hypericum perforatum (St. John's wort) as an antidepressant, based on recently published randomised controlled trials. Computerised literature searches revealed six trials published since the metaanalysis by Linde et al. (1996) [Linde, K., Ramirez, G., Mulrow, C.D., Pauls, A., Weidenhammer, W., Melchart, D., 1996. St. John's wort for depression--an overview and meta-analysis of randomised clinical trials. Br. Med. J. 313, 253-258]. The results of these studies provide further evidence that hypericum is superior to placebo in treating mild or moderate depression. However, there is still insufficient evidence to assess the efficacy of hypericum in comparison with conventional, particularly modern, antidepressants. Furthermore, there remains a lack of trials assessing long-term effects, other types of depression and different preparations and doses. It is concluded that recent clinical trials strengthen the case for hypericum as an antidepressant, but more work needs to be done to answer the remaining questions.

Amitriptyline↗
PubMed2001

Efficacy and tolerability of hypericum extract WS 5572 versus placebo in mildly to moderately depressed patients. A randomized double-blind multicenter clinical trial.

We have investigated the antidepressant efficacy and safety of Hypericum perforatum (St. John's wort) extract WS5572 in a double-blind, placebo-controlled multicenter clinical trial. 72 patients (WS 5572: 37, placebo: 35) with a diagnosis of mild to moderate major depressive disorder (according to DSM-IV criteria) were randomized in 42 days of treatment with either 300 mg WS5572 t.i.d. or placebo. The primary efficacy variable was the change of the 17-item Hamilton Depression Scale (HAMD) total score between baseline and double-blind treatment. The study was conducted with an adaptive interim analysis, which led to early stopping because convincing treatment efficacy could already be demonstrated. Group differences in favor of WS 5572 were descriptively apparent as early as day 7 of randomized treatment and were statistically significant at days 28 (p = 0.011) and day 42 (p < 0.001). Between baseline and treatment end, the HAMD total score decreased from 19.7 +/- 3.4 to 8.9 +/- 4.3 points in the Hypericum group and from 20.1 +/- 2.6 to 14.4 +/- 6.8 points in the placebo group (mean +/- SD). Responder rates were consistently higher in the Hypericum group. Comparable group differences in favor of WS 5572 were also found for von Zerssen's Depression Scale (D-S; self-rating), Clinical Global Impressions (CGI) and a global patient's self-assessment (GPA). Tolerability was very good in both groups, with no adverse drug reactions and no clinically relevant changes in safety parameters. The results indicate that Hypericum extract WS 5572 is an effective and well-tolerated drug for the treatment of mild to moderate major depressive disorder.

Adult↗
PubMed2001

Hypericum extract and hyperforin: memory-enhancing properties in rodents.

Effects of a Hypericum extract in therapeutic use and hyperforin sodium salt were evaluated in rat and mouse avoidance tests. In a conditioned avoidance response (CAR) test on the rat, oral daily administration of hyperforin (1.25 mg/kg/day) or of the extract (50 mg/kg/day) before the training sessions considerably improved learning ability from the second day onwards until the day 7. In addition, the memory of the learned responses acquired during 7 consecutive days of administration and training was largely retained even after 9 days without further treatment or training. The observations made using different doses indicate that these learning-facilitating and/or memory-consolidating effects by the agents follow inverse U-shaped dose-response curves in dose ranges lower than (for hyperforin) or equal to (for Hypericum extract) their effective dose in the behavioral despair test for antidepressants. In a passive avoidance response test on the mouse, a single oral dose (1.25 mg/kg) of hyperforin not only improved memory acquisition and consolidation, but also almost completely reversed scopolamine-induced amnesia. The single Hypericum extract dose tested (25 mg/kg) did not reveal any significant effects in the passive avoidance response (PAR) test on the mouse. These observations suggest that the Hypericum extract could be a novel type of antidepressant with memory enhancing properties, and indicate that hyperforin is involved in its cognitive effects. Pure hyperforin seems to be a more potent antidementia agent than an antidepressant.

Amnesia↗
PubMed2001

Pharmacological and endocrine effects of Hypericum perforatum and hypericin after repeated treatment.

Clinical studies have demonstrated the antidepressant efficacy of Hypericum (St. John's wort) extracts comparable to tricyclic antidepressants such as imipramine. We examined the effects of Hypericum extract and hypericin, one active constituent, in the forced swimming test (FST) after treatment repeated for 14 days. It has recently been shown that hypericin was inactive in the FST after acute treatment, but remarkably active when solubilized by subfraction IIIc1 containing mainly procyanidin B2. Therefore, we investigated the cooperative effects of hypericin and procyanidin B2 after repeated treatment. Imipramine (15 mg/kg), Hypericum extract (500 mg/kg) and hypericin (0.1 mg/kg) given daily for 2 weeks significantly reduced immobility time in the FST. No differences were observed between animals receiving pure hypericin and those receiving hypericin in combination with procyanidin B2. As several antidepressants act on the neuroendocrine axis resulting in altered hormone concentrations, selected endocrine parameters were investigated after repeated treatment. Daily treatment with either imipramine, Hypericum extract or hypericin alone or in combination with procyanidin B2 for 14 days significantly decreased plasma ACTH and corticosterone levels. None of the substances had pronounced effects on plasma prolactin or LH levels. From our present data, we propose that cooperative effects of hypericin and procyanidin B2 are of important relevance for the acute, but not for the chronic effects of this polycylic quinone.

Adrenal Glands↗
PubMed2004

Genetic profiling of Hypericum (St. John's Wort) species by nuclear ribosomal ITS sequence analysis.

A PCR-based DNA amplification method was applied to genetically distinguish the popular dietary supplement Hypericum perforatum L. (common St. John's Wort) from other related Hypericum species. Nuclear ribosomal gene sequences of the internal transcribed spacer (ITS) region were analyzed for 50 Hypericum taxa native to the Old and New Worlds, representing 11 of the 36 currently accepted taxonomic sections. This study provides a genetic method for authentication of commercial H. perforatum preparations. In addition, these data allow a preliminary assessment of phylogenetic relationships within the genus, revealing three strongly supported monophyletic clades, plus several secondary monophyletic groupings. Using ITS gene sequences, we were able to distinguish H. perforatum from all other species of Hypericum included in this study.

DNA, Plant↗
PubMed1998

Oral bioavailability of hyperforin from hypericum extracts in rats and human volunteers.

Validated analytical methods suitable for determining hyperforin in plasma after administration of alcoholic Hypericum perforatum extracts containing hyperforin are described. After oral administration of 300 mg/kg Hypericum extract (WS 5572, containing 5% hyperforin) to rats maximum plasma levels of approximately 370 ng/ml (approx. 690 nM) were reached after 3 h, as quantified by a HPLC and UV detection method. Estimated half-life and clearance values were 6 h and 70 ml/min/kg respectively. Since therapeutic doses of Hypericum extracts are much lower than that used in rats, a more sensitive LC/MS/MS method was developed. The lower limit of quantification of this method was 1 ng/ml. Using this method, plasma levels of hyperforin could be followed for up to 24 h in healthy volunteers after administration of film coated tablets containing 300 mg hypericum extracts representing 14.8 mg hyperforin. The maximum plasma levels of approximately 150 ng/ml (approx. 280 nM) were reached 3.5 h after administration. Half-life and mean residence time were 9 and 12 h respectively. Hyperforin pharmacokinetics were linear up to 600 mg of the extract. Increasing the doses to 900 or 1200 mg of extract resulted in lower Cmax and AUC values than those expected from linear extrapolation of data from lower doses. Plasma concentration curves in volunteers fitted well in an open two-compartment model. In a repeated dose study, no accumulation of hyperforin in plasma was observed. Using the observed AUC values from the repeated dose study, the estimated steady state plasma concentrations of hyperforin after 3 x 300 mg/day of the extract, i.e., after normal therapeutic dose regimen, was approximately 100 ng/ml (approx. 180 nM).

Administration, Oral↗
PubMed1997

Controlled clinical trials of hypericum extracts in depressed patients--an overview.

In Germany, hypericum extracts are among the most widely prescribed antidepressants. Additionally, many preparations of St. John's wort are sold on the free market and one extract is even the best selling antidepressant in the country. In contrast to synthetic antidepressants, the approval procedures are not so strict, which implies that the pharmaceutical industry is not forced to conduct clinical trials suitable for licensing. Nevertheless, numerous studies on hypericum extracts including depressed patients have been published in the last 20 years. The purpose of this paper is to review these investigations in respect of methodological considerations and to draw conclusions pertaining to the proof of antidepressant efficacy. To this effect, a computer-assisted literature research was performed and manufacturers were asked to supply the author with study results. A total of 12 placebo-controlled trials with hypericum extracts were performed, mostly with positive results. Also in comparison with synthetic antidepressants (3 studies published), a similar reduction of depressive symptomatology was seen, although the comparators were not adequately dosed. No trials in severely depressed patients have been published yet. Since most studies on hypericum have methodological flaws, further studies are warranted.

Antidepressive Agents↗
PubMed1997

Effects of hypericum extract (LI 160) in biochemical models of antidepressant activity.

Since the mechanism of the antidepressant activity of hypericum extract is not yet understood, we tested possible effects of standardized hypericum extract (LI 160) in several biochemical models relevant for the mechanism of action of other antidepressant drugs. While LI 160 was only a weak inhibitor of MAO-A and MAO-B activity, it inhibited the synaptosomal uptake of serotonin, dopamine and norepinephrine with about equal affinity-2 micrograms/ml). Moreover, subchronic treatment of rats with hypericum extract led to a significant down-regulation of beta-receptors and to a significant up-regulation of 5-HT2-receptors in the frontal cortex. The data might suggest that hypericum extract acts via similar biochemical mechanisms to other antidepressants (e.g. tricyclics).

Adrenergic Uptake Inhibitors↗
PubMed2000

A pilot study of Hypericum perforatum for the treatment of premenstrual syndrome.

OBJECTIVE: To investigate whether Hypericum perforatum could relieve symptoms of premenstrual syndrome in a small group of women in order to establish a hypothesis and to test methods for conducting a future randomised controlled trial. DESIGN: Prospective, open, uncontrolled, observational study. SETTING: Department of Complementary Medicine, University of Exeter. POPULATION: Nineteen women with premenstrual syndrome who were in otherwise good physical and mental health and not taking other treatments for premenstrual syndrome. METHOD: Volunteers underwent a preliminary screening interview, completed Daily Symptom Ratings for one cycle, and attended a medical screening visit before being diagnosed with premenstrual syndrome. Participants took hypericum tablets for two complete menstrual cycles (1 x 300 mg hypericum extract per day standardised to 900 microg hypericin). MAIN OUTCOME MEASURES: Symptoms were rated daily throughout the trial using a validated measure. The Hospital Anxiety and Depression scale and modified Social Adjustment Scale were administered at baseline and after one and two cycles of treatment. RESULTS: There were significant reductions in all outcome measures. The degree of improvement in overall premenstrual syndrome scores between baseline and the end of the trial was 51%, with over two-thirds of the sample demonstrating at least a 50% decrease in symptom severity. Tolerance and compliance with the treatment were encouraging. CONCLUSION: The results of this pilot study suggest that there is scope for conducting a randomised, placebo-controlled, double-blind trial to investigate the value of hypericum as a treatment for premenstrual syndrome.

Adolescent↗
PubMed1994

Effects of hypericum extract on the expression of serotonin receptors.

The influence of hypericum extract LI 160 on the expression of serotonin receptors was investigated using a neuroblastoma cell line to establish a model for the regulation of neurotransmitters by immunologically active compounds such as cytokines. The cells were incubated with hypericum extract LI 160 in kinetic form for 2, 4, 6, 8, and 10 hours, then washed. The serotonin receptor expression analysis was compared to that of a placebo control solution. The neuroblastoma cells showed a clearly reduced expression of the serotonin receptors under treatment with hypericum extract. First stimulation experiments with interleukin-1 (IL-1) and hypericum extract suggest that a further reduction of the serotonin receptors is possible when IL-1 is added.

Animals↗
PubMed2003

Hypericum perforatum, a source of neuroactive lead structures.

Although St. John's wort has been known for thousands of years and has been used for a variety of medicinal purposes, understanding of its activity and mechanisms of action is relatively new and not well understood. While researchers originally thought the naphthodianthrone hypericin was responsible for Hypericum's antidepressant activity, it is now believed some other compound or a combination of constituents exerts their antidepressant activity on the body. Hypericum is unique in that it seems to impact all known neurotransmitters at some level, directly, or indirectly through receptor sensitivity and regulation. There has been a proliferation of clinical studies on Hypericum in the last ten years, and even though some of these studies might be methodologically flawed, the preponderance of the evidence proves Hypericum to be beneficial for the treatment of mild-to-moderate depression, with a very favorable side effect profile. One clinical trial carried out using two extracts with different hyperforin content indicate this constituent as (one of) the main active principle responsible for the antidepressant activity.

Bridged Bicyclo Compounds↗
PubMed2000

[Drug interactions of Hypericum perforatum (St. John's wort) are potentially hazardous].

Hypericum can lower the plasma levels of simultaneously administered drugs by induction of metabolism. Combinations of hypericum products with warfarin, cyclosporin, oral contraceptives, theophylline, fenprocoumon, digoxin and indinavir have led to reported interactions and reduced therapeutic activity. It is therefore not advisable to combine hypericum products with other drugs, especially CYP3A4 and p-glycoprotein substrates. Discontinuing hypericum after protracted use may lead to higher plasma levels of the drugs used simultaneously, with the risk of adverse effects. Registered homeopathic preparations with a dilution of 1 in 10,000 or weaker may be regarded as safe.

Anticoagulants↗
PubMed1998

Adverse effects profile of the herbal antidepressant St. John's wort (Hypericum perforatum L.).

UNLABELLED: This paper provides a systematic review of adverse drug reactions (ADRs) associated with the use of extracts of the herb St. John's wort (Hypericum perfbratum L.) for the treatment of mild to moderate depression. METHODS: Searches of four computerized literature databases were performed for records of (ADRs). Manufacturers of hypericum products, the international drug monitoring centre of the World Health Organization (WHO) and the national drug safety monitoring bodies of Germany and the United Kingdom were also contacted for information. RESULTS: Information on (ADRs) originates from case reports, clinical trials, post-marketing surveillance and drug monitoring studies. Collectively, the data suggest that hypericum is well tolerated, with an incidence of adverse reactions similar to that of placebo. The most common adverse effects are gastrointestinal symptoms, dizziness/confusion and tiredness/sedation. A potential serious adverse effect is photosensitivity, but this appears to occur extremely rarely. CONCLUSIONS: Hypericum has an encouraging safety profile. However, as most of the current data originate from short-term investigations, more long-term studies are desirable.

Antidepressive Agents↗
PubMed2001

Hypericin and pseudohypericin in some Hypericum species.

Hypericin and pseudohypericin were found in 27 of the 36 evaluated species from Hypericum L., belonging to 17 sections of the genus. Pseudohypericin is reported by us in 15 taxa for the first time. Most of the species contained both components and the amount of pseudohypericin usually exceeded that of hypericin. In H. hirsutum and H. empetrifolium only hypericin was found, whereas H. formosissimum yielded pseudohypericin only. The total content of hypericins varied widely from 0.009% in H. empetrifolium to 0.512% in H. boissieri and the largest amounts were established in taxa of sections Drosocarpium, Hypericum and Thasia. The distribution of hypericin and pseudohypericin in Hypericum species has an important taxonomic value for infrageneric classification of the genus. These components were not found in the primitive sections Ascyreia, Androsaemum, Inodora, Roscyna, Bupleuroides and Spachium but occur widely in Hypericum, Adenosepalum and the sections from Olympia group. Although the genera of subfamily Hypericoideae are characterized by the presence of anthrone derivatives, condensed anthrones such as hypericin and pseudohypericin have not been found in these genera and the remaining subfamilies of the Guttiferae.

Journal Article↗