-IBIS-1.7.6-
rx
herb
Hypericum perforatum (St. John's wort)
Botanicals
definition
botanical name: Hypericum perforatum
synonyms: Saint John's Wort, Klamath Weed
parts used: fresh or dried flowering tops
qualities: bitter, sweet, cold, dry
affinities: nerves
actions:
internal: Anti-depressant, anti-inflammatory, anti-proliferative, anti-viral, astringent, nerve tonic, photodynamic, sedative, vulnerary.
external: Analgesic, anti-inflammatory, antimicrobial, vulnerary.
dosage:
» Tincture: (1:5 dried, 1:2 fresh) 2-4 ml. daily.
» Infusion: 2-4 g. dried herb daily.
» Standardized Extracts: Usually to 0.3% Hypericin. Suggested doses for depression are usually equivalent to 300mgthree times daily. (Manufacturer's preparations vary)
» Oil macerates: In topical application can be used liberally.
therapy:
» internal: Anxiety, depression (mild to moderate), concussion, enuresis, fibrositis, insomnia, irritability; menopausal changes, neuralgias including trigeminal neuralgia, sciatica, stress response, wounds including surgical trauma.
» external: Burns/sunburn, contusions and lacerations, dyspepsia, frostbite, hemorrhoids, herpetic lesions, neuralgias, rheumatic pains, sciatica, ulcers, varicose veins, wounds.
constituents:
» Flavonoids: Rutin, hyperin, isoquercitrin and dimers and polymers of catechin and epicatechin.
» Napthadianthrones: Hypericin, pseudohypericin, protohypericin,and others.
» Phloroglucinols: Hyperforin, adhyperforin.
» Essential oil: Monoterpenes, sesquiterpenes, triterpenes and sterols.
» Tannins.
pharmacology:
» Influence on neurotransmitters: In vitrothe phloroglucinol derivative hyperforin inhibits uptake of serotonin(5HT), dopamine(DA), Noradrenaline (NA), GABA, and Glutamate.(Chatterjee et al 1998) In vitrothe crude extract of Hypericum has weak receptor affinity for MAO-A and MAO B receptors. Isolated Hypericin does not display this activity, but does have affinity for NMDA receptors. In vitro the crude extract of Hypericum inhibits serotonin receptor expression.
(Cott J, Misra R, In Kanba S, Richelson E, NY 1997; Muller WE, Rossol R, J. Geriatric Psychiatry Neurology, 1994 7S63-64.)
» Anti-viral activity: The Hypericum dianthrones hypericin and pseudohypericin inhibit a variety of encapsulated viruses including Herpes simplex type 1 and 2 and Human HIV-1, murine CMV and parainfluenza-3 virus.
(Lopez-Bazocchi I, et al. Photochem. Photobiol. 1991,54:95-98; Weber N, et al. Antiviral Chemistry and Chemotherapy 1994 5:83-90.)
» Cytotoxic and antiproliferative effects: Recent studies have shown photodynamic antiproliferative activities for hypericin. Photoactivated hypericin inhibits proiferation and induces apoptosis of malignant T cells and neuroglioma cells in vitro.
(Fox F, et al. J Invest Dermatol, 1998; 111, 2:327-332; Miccoli L. Cancer Res. 1998 58, 24:5777-5786; Weller M.Neurol Res. 1997. 19,5:459-470.)
» Protein Kinase C inhibition: Hypericin inhibits glioma cell growth in vitro and induces glioma cell death due to inhibition of protein Kinase C.
(Couldwell W, et al. Neurosurgery 1994, 35:705-710.)
» Wound healing: Wound healing effects of Hypericum extracts are probably due to a combination of antibacterial action against Gram positive organisms including E coli, Staph aureus as well as increasing epithelisation and enhancing wound breaking strength.
(Shakirova KK, et al. Mikrobiol.Zh. 1970; 32:494-497; Rao S G, et al. Fitoterapia. 1991;6:508-510.)
» Cytochrome P450 induction: Recent pharmacological studies using caffeine and dextramethorphan probes show Hypericum to be an effective inducer of CytP450 enzymes. A preclinical study showed Hypericum extracts were able to significantly reduce serum levels of Digoxin when they were coadministered, compared to placebo.
(Ershefsky B, Gewerttz N, et al, cited in Ernst E. Lancet 1999;354(9195):2014-2016.)
clinical trials:
» Numerous clinical studies have shown that Hypericum is more effective than placebo in treating mild to moderate depressive disorders, and that it is at least as effective as standard anti-depressants, and has less side effects. Meta studies have been cautiously favourable, emphasising the need for long term studies and comparative trials.
» Mild to moderate depression: a meta-analysis of 23 randomized trials in a total of 1757 outpatients with mild or moderate depression found Hypericum extracts, after two to four weeks, superior to placebo and about as effective as standard antidepressants. However, in most of these studies the diagnosis of depression was not well established, the placebo response rate was lower than usually seen in such studies, the dosage of standard antidepressants was low, and the dosage of hypericin varied more than six-fold. One study lasted 12 weeks, three lasted eight weeks, one lasted only two weeks and the rest had a duration of four to six weeks. Even so, further positive studies continue to be published.
(Linde K, et al. BMJ, 1996;313:253.)
» SAD (Seasonal Affective Disorder): Recent research also suggests the effectiveness of Hypericum for treatment of SAD. Note that the flower classically blossoms on Summer solstice.
(Kasper, S. Pharmacopsychiatry 1997, 30 Suppl 2:89-93 Wheatley D, Curr Med Res Opin. 1999.151:33-37.)
AHPA Botanical Safety Rating: 2d
toxicity: 2
» No serious adverse effects have been reported with use of St. John's Wort at typical doses.
» Photosensitivity, although commonly publicized, is a rarely reported side effect. One clinical trial using high doses (double the normal theraputic dose) has confirmed increased photosensitivity to UVA/B irradiation in fair skinned people. Photosensitivity has been reported in only one patient taking an extract for depression. All other reports have been based upon grazing animals that have had phototoxic reactions after eating the plant.
(Golsch S, et al. Hautarzt 1997 Apr;48(4):249-252; Roots I, et al. 2nd Intnl Congress on Phytomedicine, Munich 1996.)
» In a study of 3250 patients, gastro-intestinal symptoms were the commonest reported side effects (0.6%) followed by allergic reactions (0.5%) and fatigue (0.4%). In a meta analysis of 23 studies, less than 20% of patients reported side effects compared to 35% taking standard anti-depressant medications.
(De Smet PAG, Nolen WA, BMJ, 1996 313:241-247; Wölk H, et al. J. Geriatric Psychiatry Neurology, 1994; 7 S34-38.)
contraindications:
» Suggested by Brinker as contraindicated during pregnancy due to its uterotonic action on rodent uteri. Reports of uterotnicity or adverse effects during pregnancy in humans are lacking.
(Brinker F. 1998, 124.)
» May cause changes in lactation, especially the nutritional quality and flavor; lactation may be reduced or cease altogether .
(Muenscher WC. 1951, 19; Westbrooks RG, Preacher JW.1986, 169.)
» Many authorities, including Commission E, state that Hypericum is contraindicated in ultraviolet light or solarium therapy due to potential photosensitizing effects if large doses of its hypericin component are used. Published case reports of UV or Solarium induced adverse reactions are lacking.
(Brinker F. 1998, 124; Bisset NG (ed.)1994, 274; De Smet PAG, et al. (eds.) 1993.)
» Potential for phototoxicity and hypersensitivity reactions; capable of causing a photosensitization characterized by erysipelas, dermatitis, and skin sores. Reports of phototoxicity are rare. However, cautions may be advisable. See toxicity section above.
(Duran N, Song PS. Phtyochemistry and Phytobiology. 1986.43: 677-680; Keeler RF, Tu AT. 1983.)
legal status: Hypericum is licensed in Germany for treatment of anxiety, depression and insomnia. In the USA, it is considered a dietary supplement and has not been evaluated by the FDA.
commentary:
» Hypericin standardized extracts and markercompounds: Recent studies suggest that hyperforin, a prenylated phloroglucinol component of Hypericum, is the most likely source of the antidepressant action. One theory is that Hypericum may inhibit pain because it inhibits the breakdown of serotonin and other pain-relieving substances. Despite some commercial claims, there is no evidence to suggest that extracts standardised to hypericin are more effective than other forms of Hypericum extracts. The recent elucidation of the role of hyperforin as a probable anti-depressive active principle seems to confirm this.
(Chatterjee SS, et al.1998a, 1998b)
drug interactions:
» herb possibly affecting drug class toxicity: Anesthetics, Major
» herb possibly affecting drug class toxicity: Benzodiazepines
» herb possibly affecting drug class toxicity: Monoamine Oxidase Inhibitors
» herb possibly affecting drug class toxicity: SSRI's
» herb affecting drug pharmacokinetics and toxicity: Cyclosporine (Sandimmune®)
» herb affecting drug pharmacokinetics and toxicity: Digoxin (Lanoxin®)
» herb affecting drug pharmacokinetics and toxicity: Indinavir (Crixivan®)
» herb possibly affecting drug toxicity: Ephedrine
» herb possibly affecting drug toxicity: Fluoxetine (Prozac®)
» herb possibly affecting drug toxicity: Levodopa, Carbidopa (Sinamet®)
» herb-nutrient potential interactions: Tyramine-containing Foods
» potential herbal synergy: Herb Groups: MAO Inhibitors
herb possibly affecting drug class performance: Anesthetics, Major
preoperative protocols: Murphy discussed cases of patients who had been taking herbs prior to surgery and how this had influenced the course of events, particularly the postponing of the procedure. She emphasized the importance of the perioperative team members asking patients about their use of herbal remedies during assessments of medication use. McLeskey et al found that 170 of 979 (17.4%) of presurgical patients were taking herbal products. Median age of herb users and non-users was 62 years. Of the patients taking these agents, 55% took only one product, 45% took multiple products. In decreasing order, the most commonly utilized herbs among this group were: gingko biloba (32.4%), garlic (26.5%), ginger (26.5%), ginseng and St. John's Wort (14%). Nutraceuticals most widely used were glucosamine (17%), chromium picolinate (17%) and chondroitin (12%). John B. Neeld, Jr, MD, President of the American Society of Anesthesiologists has suggested that patients should stop taking herbal medications at least 2 to 3 weeks before surgery. Neeld and others have specifically cautioned against feverfew (Tanacetum parthenium) potentially affecting PT time and increasing risk of bleeding, and St. John's Wort (Hypericum perforatum) and kava-kava (Piper methysticum) prolonging the sedative effect of anesthesia due to a presumed MAOI-like action. No clinical research, published case reports or substantive pharmacological analysis has confirmed these claims of adverse effects or interactions.
(Murphy JM. AORN J. 1999 Jan;69(1):173-5, 177-178, 180-183; McLeskey CH, et al. Annual Meeting of American Society of Anesthesiologists. October 1999; Voelker R. JAMA, 281(20).May 26, 1999.1882.)
herb possibly affecting drug class toxicity: Benzodiazepines
research: Amentoflavone, a constituent of various Hypericum species, efficiently inhibited binding of [3H]flumazenil to rat brain benzodiazepine binding sites of the GABAA-receptor in vitro.
(Baureithel KH, et al. Pharm Acta Helv 1997 Jun;72(3):153-157.)
herbal concerns: Any individual using a benzodiazepine and considering using St. John's Wort as a substitute or as a means of weaning themselves from the drug should do so only under supervision of a trained healthcare professional. Caution is especially indicated given the potential for the amentoflavone component of Hypericum to inhibit the action of the benzodiazepine.
herb possibly affecting drug class toxicity: Monoamine Oxidase Inhibitors
research: In vitro studies by Chatterjee et al found that the phloroglucinol derivative hyperforin inhibits uptake of serotonin (5HT), dopamine (DA), noradrenaline (NA), GABA, and glutamate. In vitro the crude extract of Hypericum has weak receptor affinity for MAO-A and MAO B receptors. Isolated hypericin does not display this activity, but does have affinity for NMDA receptors. Cott and Misra demonstrated that, in vitro, the crude extract of Hypericum inhibits serotonin receptor expression.
(Cott J , Misra R, 1997; Chatterjee SS, et al. Life Sci 1998a; 63(6):499-510; Chatterjee SS, et al. Pharmacopsychiatry 1998b Jun;31 Suppl 1:7-15;
herb possibly affecting drug class toxicity: SSRI's
reports: Since the emergence of Hypericum as a popular herbal supplement in recent years many have been concerned about the risk of serotonin syndrome due to excessive dosing and the combination of the herb with SSRI drugs. Demott has reported one case where a patient taking another SSRI drug, trazadone, may have experienced a serotonin syndrome reaction upon taking Hypericum with their drug. In that instance, the patient reported symptoms consistent with a serotonin syndrome such as confusion, flushing, perspiration, muscle twitching, and ataxia. Gordon reported on another case where a patient took one dose of paroxetine (Paxil) after using Hypericum for ten days and experienced nausea, lethargy, fatigue and weakness,
(Demott K. Clinical Psychiatry News 1998;26:28; Gordon JB. Am Fam Physician 1998;57:950; Perovic S, et al. Arzneimittelforschung. 1995 Nov;45(11):1145-1148.)
herbal concerns: Even though a potentially valuable synergy might conceivably develop from the careful combining of SSRI drugs and Hypericum, such experimentation would be premature until more thorough research has been conducted. However, this combined effect of Hypericum and an SSRI drug could potentially result in serotonin syndrome. Individuals taking SSRI drugs should avoid using Hypericum unless they have consulted with and are being monitored by their prescribing physician and/or a healthcare provided trained in medical herbalism. If transition from an SSRI medication to an herb such as Hypericum is desired, an initial phase of several weeks using low doses of both the medication and the herb is often advisable. At that the end of this period the withdrawal of the pharmaceutical can be carried out under close monitoring by the prescribing physician. In contrast, some practitioners advocate the phased withdrawal from use of the SSRI and a subsequent interval of one to two weeks before starting an herbal treatment such as Hypericum.
(Reichert RG. Quart Rev Nat Med Winter 1995; 275-278; Lieberman S. J Womens Health. 1998 Mar;7(2):177-182; Chatterjee SS, et al. Pharmacopsychiatry 1998 Jun;31 Suppl 1:7-15; Ramussen P. Aust J Med Herbalism . 1998; 10(1):8-13.)
herb affecting drug pharmacokinetics and toxicity: Cyclosporine (Sandimmune®)
reports: Ruschitzka et al. reported acute rejection in two cardiac transplant patients maintained on triple immunosuppressive therapy. Both individuals were using 900mg/d standardized Hypericum extracts, and cyclosporine levels were found to be below the therapeutic range; the levels returned on cessation of the herbal extract.
(Ruschitzka F, Meier PJ, Turina M, et al. Lancet 2000;355(9203):548-549.)
mechanism: Cyclosporine is metabolized by the 3A4 microsomal CYP450 isozyme. Hypericum extracts are known to induce CYP 450 isozymes, as well as affect membrane transporters in epithelial cells thus potentially causing a range of pharmacokinetic interactions.
(Ershefsky B, Gewerttz N, et al, cited in Ernst E. Lancet 1999;354(9195):2014-2016.)
herbal concern: Individuals with organ grafts who require stable levels of cyclosporine as part of immunosuppressive therapy should not take (nor stop taking if already regularly doing so) Hypericum extracts which could cause plasma levels of cyclosporine to fall below therapeutic range necessary to prevent graft rejection. The prescribing physician as well as a health care provider experienced with herbal medicines should be consulted before any adjuvant herbal therapy is used by organ graftees.
herb affecting drug pharmacokinetics and toxicity: Digoxin (Lanoxin)
research: Johne et al conducted a preclinical trial which showed that coadministration of standardized Hypericum extracts (900 mg daily) with digoxin (0.25 mg daily) in healthy subjects resulted in the previously stabilized plasma digoxin levels significantly decreasing compared to placebo after a single dose and after ten days.
(Johne A, et al. Clin Pharmacol Ther 1999 Oct;66(4):338-345)
mechanism: Since Digoxin is renally excreted Johne A, et al. suggest the mechanism of increased clearance may involve induction of P-glycoprotein drug transporters.
herbal concern: Patients stabilized on digoxin should advise their prescribing physician before consuming extracts of Hypericum. Physicians should always enquire about herb usage when prescribing Digoxin, along with accepted standard questions about concurrent medications. Ernst has suggested that interactions due to induction of Cytochrome P450 enzymes by Hypericum extracts may require a re-evaluation of the safety of Hypericum extracts.
(Ernst E. Lancet 1999;354(9195):2014-2016)
.
herb possibly affecting drug toxicity: Ephedrine
Pharmaceutical MAOI (monoamine oxidase inhibitor) substances, such as Eutonyl (pargyline), Furoxone (furazolidone), Laniazid, Marplan (isocarboxazid), Matulane (procarbazine), Nardil (phenelzine), Nydrazid, Parnate (tranylcypromine), Rifamate, Rimactane/INH, moclobemide, Selegiline (deprenyl), and tranycypromine, are known to interact with ephedrine and pseudoephedrine; there is also at least the theoretical possibility that herbs often considered as having actions similar to MAOI's such as Hypericum perforatum (St. John's Wort), might also.
herb possibly affecting drug toxicity: Fluoxetine (Prozac®)
reports: Since the emergence of Hypericum as a popular herbal supplement in recent years many have been concerned about the risk of serotonin syndrome due to excessive dosing and the combination of the herb with SSRI drugs. Demott has reported one case where a patient taking another SSRI drug, trazadone, may have experienced a serotonin syndrome reaction upon taking Hypericum with their drug. In that instance, the patient reported symptoms consistent with a serotonin syndrome such as confusion, flushing, perspiration, muscle twitching, and ataxia. Gordon reported on another case where a patient took one dose of paroxetine (Paxil) after using Hypericum for ten days and experienced nausea, lethargy, fatigue and weakness,
(Demott K. Clinical Psychiatry News 1998;26:28; Gordon JB. Am Fam Physician 1998;57:950.)
herbal concerns: Even though a potentially valuable synergy might conceivably develop from the careful combining of fluoxetine and Hypericum, such experimentation would be premature until more thorough research has been conducted. Individuals taking fluoxetine should avoid using Hypericum unless they have consulted with and are being monitored by their prescribing physician and/or a healthcare provided trained in medical herbalism. (See SSRI's above)
herb affecting drug pharmacokinetics and toxicity: Indinavir (Crixivan®)
research: A pre-clinical trial with healthy individuals found that Hypericum extracts reduced Indinavir plasma levels significantly.
(Piscitelli SC, Burstein AH, Chaitt D, et al. Lancet 2000;355(9203):547-548.)
mechanism: Hypericum extracts are known to induce CYP 450 isozymes, as well as affect membrane transporters in epithelial cells thus potentially causing a range of pharmacokinetic interactions.
(Ershefsky B, Gewerttz N, et al, cited in Ernst E. Lancet 1999;354(9195):2014-2016.)
herbal concerns: Individuals using the HIV-1 protease inhibitor Indinivar, who require stable drug levels levels should not take (nor stop taking if already regularly doing so) Hypericum extracts which could cause plasma levels of indinivar to fall below therapeutic range necessary to prevent graft rejection. The prescribing physician as well as a health care provider experienced with herbal medicines should be consulted before any adjuvant herbal therapy is used by organ graftees.Since other
antiretroviral agents are also metabolised by CYP3A4, same cautions should apply to related drugs.
herb possibly affecting drug toxicity: Levodopa, Carbidopa (Sinamet®)
mechanism: Use of Sinemet® (levodopa-carbidopa) with monoamine oxidase inhibitors (MAOI's), antidepressants, such as isocarboxazid, phenelzine (Nardil®), tranylcypromine (Parnate®), and procarbazine (Matulane®), can result in severe and dangerous elevations in blood pressure.
herbal concerns: MAOI's are usually discontinued 2-4 weeks before starting Sinemet® (levodopa-carbidopa) usage. Due to Hypericum having weak MAO-inhibitor activity, similar caution would be advised with regard to a potential interaction with Sinamet®.
herb - nutrient potential interactions: Tyramine-containing Foods
mechanism: Tyramine-containing foods, SSRI's and other drugs interacting with monoamine oxidase inhibitors are suggested as being contraindicated due to the inhibition of MAO by xanthones and a number of flavonoid components of St. John's Wort. In animal studies, sleeping time of narcotics is enhanced and the effects of reserpine are antagonised by Hypericum.
(Holzl J,et al.Planta Med. 1989.55:643; Okpanyi SN et al. Arzneim.-Forsch., 1987.37:10-13; Sparenberg B, et al.PZ Wiss., 1993.6:50-4, [Chem Abstr. 1 19:85914z].)
potential herbal synergy: Herb Groups: Neuroendocrine: MAO Inhibitors
herbal synergy: Whilst the MAOI activity of Hypericum extracts in vivo is not significant, there is a theoretical possibility that Hypericum extracts may synergize with herbs of known MAOI activity.
commentary:
Hypericum interactions with antidepressant drugs:
The in vitro MAOI activity of Hypericum constituents has not been demonstrated in vivo. Early experimental research led to unwarranted speculation that persists in the literature that Hypericum acts as a MAOI in humans. Therapeutic doses of Hypericum are orders of magnitude lower than those that would be required to achieve in vitro MAO inhibition. Thus although St. John's Wort has been regarded as a MAOI, the MAOI activity of Hypericum is not large enough to account for an antidepressant action based on this effect.
Current research indicates inhibition of reuptake of dopamine, serotonin, and norepinephrine to be among the actions that lead to receptor adaptive changes that produce the antidepressant effect. This presents the theoretical possibility of Hypericum interacting adversely with some antidepressants, albeit through a mechanism different than MAOI.
At this point any concern regarding an interaction between Hypericum and MAO-inhibitors is merely theoretical and no cases have been reported in the scientific literature. The reported pharmacological effects of many herbs are based on assays that may have little if any clinical relevance, and it is unlikely that negative interactions with substances that are known to negatively interact with MAOI pharmaceuticals would occur in a clinical context.
Footnotes
American Herbal Pharmacopoeia: St John's Wort Monograph. Santa Cruz, CA.1997.
Bhattacharya SK, Chakrabarti A, Chatterjee SS. Activity profiles of two hyperforin-containing hypericum extracts in behavioral models. Pharmacopsychiatry 1998 Jun;31 Suppl 1:22-29.
Abstract: The behavioral activity profile of a therapeutically used alcoholic hypericum extract containing hyperforin (4.5%) in rodent models was compared with that of an experimental CO2 extract devoid of hypericines but highly enriched in hyperforin (38.8%). The antidepressant activities of 50, 150 and 300 mg/ kg/day of the alcoholic extract were similar to those of 5, 15 and 30 mg/kg/day respectively of the CO2 extract. The ethanol extract in the same dose range potentiated dopaminergic behavioral responses, whereas these effects were either absent or less pronounced in the CO2 extract treated groups. By contrast, serotoninergic effects of the CO2 extract were more pronounced than those of the alcoholic extract. These and various other observations made during the study confirm that although the antidepressant action of hypericum extracts depends on their hyperforin contents, their spectrums of central activity are due to other component(s). Our working hypothesis that hyperforin and serotoninergic mechanisms are involved in the therapeutically observed antidepressant activities of hypericum extracts is in agreement with these observations.
Biber A, Fischer H, Romer A, Chatterjee SS. Oral bioavailability of hyperforin from hypericum extracts in rats and human volunteers. Pharmacopsychiatry 1998 Jun;31 Suppl 1:36-43.
Abstract: 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).
Bisset NG (ed.), Wichtl M. Herbal Drugs and Phytopharmaceuticals, Boca Raton, FL. CRC Press, 1994
Bradley PR, ed. British Herbal Compendium, vol 1. Bournemouth, Dorset, UK: British Herbal Medicine Association, 1992.
Brinker F. Herb Contraindications and Drug Interactions. Second edition. Sandy, OR: Eclectic Institute Inc ,1998.
Buter B, Orlacchio C, Soldati A, Berger K. Significance of genetic and environmental aspects in the field cultivation of Hypericum perforatum. Planta Med 1998 Jun;64(5):431-437.
Abstract: Agronomical and biochemical parameters of seven Hypericum perforatum (St. John's wort) accessions grown at three experimental sites in Switzerland were followed over a two year period (1995-1996). Significant effects of environmental (= site) and genetic factors (= accession) on flowering dates, plant length, and plant dry matter production (= plant yield) were observed in both years; rankings of sites and accessions with regard to plant yield were similar in both years despite the fact that the first year crop contributed only a minor part to the overall yield of both years together. Maximum dry matter production per year reached 159 dt/ha for the total plant and 54 dt/ha for the flowering segment (i.e. the pharmaceutically relevant, upper segment of the plants comprising the majority of flowers). HPLC analysis of the constituents covered eight secondary metabolites (amentoflavone, biapigenin, hyperforin, hypericin, hyperosid, pseudohypericin, quercetin, rutin). Generally, secondary metabolite contents were significantly lower in the first year of cultivation ranging from 12% (hyperosid) to 83% (hyperforin) of the contents measured in the 1996-crop. Significant genetic effects on the production of all tested secondary metabolites (except biapigenin) were observed in 1996 whereas environmental effects appeared to be less distinct (except for amentoflavone and pseudohypericin). In conclusion, genetic factors strongly affected plant yield as well as secondary metabolite content in H. perforatum cultivation; the availability of genetically superior plant material next to improved agrotechnological methods therefore is supposed to become a key factor for successful future field production.
Chatterjee SS, Bhattacharya SK, Wonnemann M, Singer A, Muller WE. Hyperforin as a possible antidepressant component of hypericum extracts. Life Sci 1998; 63(6):499-510.
Abstract: We demonstrate that the phloroglucinol derivative hyperforin is not only the major lipophilic chemical constituent of the medicinal plant Hypericum perforatum (St. John's wort) but also a potent uptake inhibitor of serotonin (5-HT), dopamine (DA), noradrenaline (NA), GABA and L-Glutamate with IC50 values of about 0.05-0.10 microg/ml (5-HT, NA, DA, GABA) and about 0.5 microg/ml (L-glutamate) in synaptosomal preparations. Furthermore, potencies of two different hypericum extracts in two conventional pharmacological paradigms useful for the detection of antidepressants (behavioral despair, learned helplessness), closely correlate with their hyperforin contents. In addition, most till now known neuropharmacological properties of the clinically used hypericum extracts can also be demonstrated with pure hyperforin. It appears, therefore, that this non-nitrogenous constituent is a possible major active principle responsible for the observed clinical efficacies of the extract as an antidepressant and that it could also be a starting point for drug discovery projects engaged in the search of psychoactive drugs with novel mode of action.
Chatterjee SS, Noldner M, Koch E, Erdelmeier C. Antidepressant activity of hypericum perforatum and hyperforin: the neglected possibility. Pharmacopsychiatry 1998 Jun;31 Suppl 1:7-15.
Abstract: Efforts leading to the identification of hyperforin as an antidepressive component of therapeutically used alcoholic hypericum extracts are described and discussed. Initially, the effects of this unique and major constituent of the herb were detected in peripheral organs using in vitro models and an extract was obtained by supercritical extraction of the herb by carbon dioxide. These extracts are highly enriched in hyperforin (38.8%) and are devoid of hypericines and numerous other components of alcoholic extracts. Studies with such an extract and with isolated hyperforin indicated that this acylphloroglucinol derivative can inhibit serotonin-induced responses and uptake of this neurotransmitter in peritoneal cells. Assuming that the effects of hyperforin were due to its actions on serotoninergic 5-HT3/5-HT4 receptors, further studies were conducted to investigate its effects on the CNS. These efforts revealed its antidepressant activity in the behavioral despair test and led to the working hypothesis that hyperforin and serotoninergic mechanisms are involved in the antidepressant activities of alcoholic hypericum extracts. The observations made during this study also indicate that hyperforin is the major, but not the only antidepressive component of alcoholic extracts.
Cott J , Misra R. Medicinal Plants: potential source for new psychotheraputic drugs In New Drug Developments, from Herbal Medicines in Neuropsychopharmacology, eds Kanba S, Richelson E, NY 1997.
Couldwell W, et al. Hypericin a potential antiglioma therapy. Neurosurgery 1994, 35:705-710.
D'Arcy PF. Adverse reactions and interactions with herbal medicines, part 1, adverse reactions. Adverse Drug Reactions and Toxicological Review 10 (Winter 1991) 189-208.
Demott K. St. Johns wort tied to serotonin syndrome. Clinical Psychiatry News 1998;26:28.
De Smet PAG, et al. (eds.) Adverse Effects of Herbal Drugs 2, Berlin: Springer-Verlag, 1993.
De Smet PAG, Nolen WA, St John's wort as an Antidepressant. BMJ, 1996 313:241-247.
Duran N, Song PS. Hypericin and its phytodynamic activity. Phtyochemistry and Phytobiology. 1986.43: 677-680.
Erdelmeier CA. Hyperforin, possibly the major non-nitrogenous secondary metabolite of Hypericum perforatum L. Pharmacopsychiatry 1998 Jun;31 Suppl 1:2-6.
Abstract: An overview of the constituents of Hypericum perforatum is given, with special emphasis on the acylphloroglucinol hyperforin. Previous work on the chemistry of hyperforin and on other components derived from hyperforin in H. perforatum is reviewed. A new optimized method of isolating hyperforin on a large scale is presented, including full spectroscopic characterization of the isolate.
Ernst E. Second thoughts about safety of St John's wort [published erratum appears in Lancet 2000 Feb 12;355(9203):580]. Lancet 1999;354(9195):2014-2016.
Fox F, et al. Photoactivated hypericin is an anti-proliferative agent that induces a high rate of apoptotic death of normal, transformed, and malignant T lymphocytes: implications for the treatment of cutaneous lymphoproliferative and inflammatory disorders.J Invest Dermatol, 1998;111, 2:327-332.
Abstract: Hypericin is a photodynamic compound activated by either visible (400- 700 nm) or UVA (320-400 nm) light, and has been shown to inhibit the growth of a variety of neoplastic cell types. In this study, hypericin was found to inhibit proliferative responses of malignant T cells derived from the blood of patients with cutaneous T cell lymphoma. Control cells included peripheral blood mononuclear cells (PBMC) from normal volunteers or Epstein-Barr virus-transformed lymphocytes. Cells from each of these populations were incubated with serial dilutions of hypericin or 8-methoxypsoralen and then stimulated with the mitogen ConA (10 microg per ml). Cultures were prepared in the dark to minimize photoactivation of the hypericin. Proliferation was measured by [3H]thymidine labeling after 72 h. Hypericin, photoactivated with 1.1- 3.3 J white light per cm2, inhibited cellular proliferation of malignant T cells with IC50 values from 0.34 to 0.53 microM, normal PBMC with IC50 values of 0.11-0.76 microM, and Epstein-Barr virus- transformed cells with IC50 values of 0.75-3.2 microM. UVA- photoactivated hypericin (0.5-2.0 J per cm2) could also inhibit proliferation with IC50 values of 0.57-1.8 microM, 0.7-4.6 microM, and 2.0-3.7 microM for malignant, normal, or Epstein-Barr virus-transformed cells, respectively. Hypericin, photoactivated with either UVA or white light, could induce near complete apoptosis (94%) in malignant cutaneous T cell lymphoma T cells, whereas lower levels of apoptosis (37-88%) were induced in normal PBMC. These data indicate that hypericin inhibits mitogen-induced proliferation of malignant T cells from patients with cutaneous T cell lymphoma, PBMC from normal individuals, as well as Epstein-Barr virus-transformed lymphocytes, and that inhibition of cell proliferation is dependent on the concentration of hypericin used and the dose of light required to photoactivate the compound. Induction of apoptosis is, in part, one mechanism by which photoactivated hypericin inhibits malignant T cell proliferation.
Golsch S, Vocks E, Rakoski J, Brockow K, Ring J [Reversible increase in photosensitivity to UV-B caused by St. John's wort extract].[Article in German] Hautarzt 1997 Apr;48(4):249-252.
Holzl J, Demisch L, Gollnik B. Investigations about Antidepressive and Mood Changing Effects of Hypericum perforatum. Planta Med. 1989.55:643.
Johne A, Brockmoller J, Bauer S, et al. Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort (Hypericum perforatum). Clin Pharmacol Ther 1999;66(4):338-345.
Abstract: Extracts of St John's wort (Hypericum perforatum) are widely used in the treatment of depression, often as an over-the-counter drug. In contrast to its frequent use, knowledge about the pharmacokinetics of ingredients and drug interactions of St John's wort is poor. We studied the interaction between hypericum extract LI160 and digoxin. METHODS: The pharmacokinetics of digoxin were investigated in a single- blind, placebo-controlled parallel study. After the achievement of steady state for digoxin on day 5, healthy volunteers received digoxin (0.25 mg/d) either with placebo (n = 12) or with 900 mg/d LI160 (n = 13) for another 10 days. Digoxin concentration profiles on day 5 were compared with day 6 (single-dose interaction) and day 15 (tenth day of co-medication). RESULTS: There was a highly significant combined-day- and-group effect for digoxin area under the plasma concentration-time curve [AUC(0-24); P = .0001], peak concentration in plasma (Cmax; P = .0001), and plasma drug concentration at the end of a dosing interval (P = .0003) by two-way ANOVA. No statistically significant change was observed after the first dose of hypericum extract [AUC(0-24) at day 6 of 18.1+/-2.9 microg x h/L and 17.7+/-3.0 microg x h/L, mean +/- SD for placebo and hypericum group, respectively]. However, 10 days of treatment with hypericum extract resulted in a decrease of digoxin AUC(0-24) by 25% (day 15, 17.2+/-4.0 microg x h/L and 12.9+/-2.3 microg x h/L; P = .0035). Furthermore, comparison with the parallel placebo group after multiple dosing showed a reduction in trough concentrations and Cmax of 33% (P = .0023) and 26% (P = .0095), respectively. The effect became increasingly pronounced until the tenth day of co- medication. CONCLUSION: As with grapefruit juice, a food product, physicians should also be aware of potential drug-herb interactions. The interaction of St John's wort extract with digoxin kinetics was time dependent. The mechanism involved may be induction of the P- glycoprotein drug transporter.
Keeler RF, Tu AT. Handbook of Natural Toxins. New York: Marcel Dekker, Inc. 1983.
Kasper S.Treatment of seasonal affective disorder (SAD) with hypericum extract. Pharmacopsychiatry 1997, 30 Suppl 2:89-93.
Abstract:Seasonal affective disorder (SAD) is a subgroup of major depression and characterized by a regular occurrence of symptoms in autumn/winter and full remission or hypomania in spring/summer. Light therapy (LT) and recently pharmacotherapy with specific antidepressants have been shown to be beneficial. Within the array of pharmacotherapy hypericum extract has also been found to be effective in a single-blind study (Martinez et al., 1994). In this 4 weeks treatment study 900 mg of hypericum was associated with a significant reduction in the total score of the Hamilton Depression Rating Scale. There was no significant difference when bright light therapy was combined with hypericum, compared to the situation without bright light therapy. Overall, hypericum was well tolerated and therefore the data suggest that pharmacological treatment with hypericum may be an efficient therapy in patients with SAD, which needs to be substantiated in further controlled studies.
Laakmann G, Schule C, Baghai T, Kieser M. St. John's wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry 1998 Jun;31 Suppl 1:54-59.
Abstract: In a randomized, double-blind, placebo-controlled, multicenter study, the clinical efficacy and safety of two different extracts of St. John's wort were investigated in 147 male and female outpatients suffering from mild or moderate depression according to DSM-IV criteria. Following a placebo run-in period of three to seven days, the patients were randomized to one of three treatment groups: During the 42-day treatment period, they received 3 x 1 tablets of either placebo, Hypericum extract WS 5573 (300 mg, with a content of 0.5% hyperforin), or Hypericum extract WS 5572 (300 mg, with a content of 5% hyperforin). The manufacturing process for the two Hypericum preparations was identical, so that they differed only in their hyperforin content. Efficacy regarding depressive symptoms was assessed on days 0, 7, 14, 28, and 42, using the Hamilton Rating Scale for Depression (HAMD, 17-item version) and the Depression Self-Rating Scale (D-S) according to von Zerssen. In addition, the severity of illness was also rated by the investigators on days 0 and 42 using the Clinical Global Impression (CGI) scale. The last observation of patients withdrawn from the trial prematurely was carried forward. At the end of the treatment period (day 42), the patients receiving WS 5572 (5% hyperforin) exhibited the largest HAMD reduction versus day 0 (10.3 +/- 4.6 points; mean +/- SD), followed by the WS 5573 group (0.5% hyperforin; HAMD reduction 8.5 +/- 6.1 points) and the placebo group (7.9 +/- 5.2 points). As regards the change in the HAMD total score between day 0 and treatment end and its relationship to the hyperforin dose, a significant monotonic trend was demonstrated in the Jonckheere-Terpstra test (p = 0.017). In pairwise comparisons, WS 5572 (5% hyperforin) was superior to placebo in alleviating depressive symptoms according to HAMD reduction (Mann-Whitney U-test: p = 0.004), whereas the clinical effects of WS 5573 (0.5% hyperforin) and placebo were descriptively comparable. These results show that the therapeutic effect of St. John's Wort in mild to moderate depression depends on its hyperforin content.
Lieberman S. Nutriceutical review of St. John's wort (Hypericum perforatum) for the treatment of depression. J Womens Health. 1998 Mar;7(2):177-182. (Review)
Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D. St John's wort for depression--an overview and meta-analysis of randomised clinical trials. BMJ, 313:253, 1996.
Lopez-Bazocchi I, et al. Antiviral activity of the photoactive plant pigment hypericin. Photochem. Photobiol. 1991,54:95-98.
McLeskey CH, Meyer TA, Baisden CE, Gloyna DF, Roberson CR. The incidence of herbal and selected nutraceutical use in surgical patients. Annual Meeting of American Society of Anesthesiologists (ASA) October 1999.
Abstract: An estimated 60 million American adults are reported to use herbal products. Consumers assume, because these products are natural, they are harmless. However, reports of allergic reactions, adverse effects and drug-herb interactions are surfacing. Following IRB approval, a questionnaire was given to 979 presurgical patients. Subjects were asked to indicate the amount and duration of products taken. Age and surgical procedure were noted. 170 surgical patients (17.4%) reported taking such products. Median age of herb users and non-users was 62 years. Of the patients taking these agents, 55% took only one product, 45% took multiple products. In decreasing order, the most commonly utilized herbs among this group were: gingko biloba (32.4%), garlic (26.5%), ginger (26.5%), ginseng and St. John's Wort (14%). Nutraceuticals most widely used were glucosamine (17%), chromium picolinate (17%) and chondroitin (12%). Over 40 herbs were listed as occasionally taken. Females represented 63% of herbal users and 54% of non-users (p=0.05). 19.3% of female patients took one or more of these products vs. 14.5% of male patients. Neurosurgical, gynecologic and orthopedic surgical patients' use of herbals was slightly higher than other surgical groups at 21%, 21% and 20%. Recently one-third of the American public has been identified as users of herbal products. Our lower incidence may result from reluctance of patients to admit taking such products or lack of understanding among patients regarding drug intake and contents of these products. Anesthesia providers, surgeons, and patients should be aware that these medications may not be harmless and are in increasing use. Adverse effects and drug-herbal interactions may suggest alterations in an anesthetic plan.
Miccoli L. Light-induced photoactivation of hypericin affects the energy metabolism of human glioma cells by inhibiting hexokinase bound to mitochondria. Cancer Res. 1998 58, 24:5777-5786.
Abstract: Glucose-dependent energy required for glioma metabolism depends on hexokinase, which is mainly bound to mitochondria. A decrease in intracellular pH leads to a release of hexokinase-binding, which in turn decreases glucose phosphorylation, ATP content, and cell proliferation. Thus, intracellular pH might be a target for therapy of gliomas, and a search for agents able to modulate intracellular pH was initiated. Hypericin, a natural photosensitizer, displays numerous biological activities when exposed to light. Its mechanism and site of action at the cellular level remain unclear, but it probably acts by a type II oxygen-dependent photosensitization mechanism producing singlet oxygen. Hypericin is also able to induce a photogenerated intracellular pH drop, which could constitute an alternative mechanism of hypericin action. In human glioma cells treated for 1 h with 2.5 microg/ml hypericin, light exposure induced a fall in intracellular pH. In these conditions, mitochondria-bound hexokinase was inhibited in a light- and dose-dependent manner, associated with a decreased ATP content, a decrease of mitochondrial transmembrane potential, and a depletion of intracellular glutathione. Hexokinase protein was effectively released from mitochondria, as measured by an ELISA using a specific anti- hexokinase antibody. In addition to decreased glutathione, a response to oxidative stress was confirmed by the concomitant increase in mRNA expression of gamma-glutamyl cysteine synthetase, which catalyzes the rate-limiting step in overall glutathione biosynthesis, and is subject to feedback regulation by glutathione. Hypericin also induced a dose- and light-dependent inhibition of [3H]thymidine uptake and induced apoptosis, as demonstrated by annexin V-FITC binding and cell morphology. This study confirmed the mitochondria as a primary target of photodynamic action. The multifaceted action of hypericin involves the alteration of mitochondria-bound hexokinase, initiating a cascade of events that converge to alter the energy metabolism of glioma cells and their survival. In view of the complex mechanism of action of hypericin, further exploration is warranted in a perspective of its clinical application as a potential phototoxic agent in the treatment of glioma tumors.
Muenscher WC. Poisonous Plants of the United States. New York: The MacMillan Company.1951.
Muller WE, Rossol R, Effects of Hypericum Extract on the supression of serotonin receptors. J. Geriatric Psychiatry Neurology, 1994 7S63-64.
Muller WE, Singer A, Wonnemann M, Hafner U, Rolli M, Schafer C. Hyperforin represents the neurotransmitter reuptake inhibiting constituent of hypericum extract. Pharmacopsychiatry 1998 Jun;31 Suppl 1:16-21.
Abstract: Hydroalcoholic hypericum extract inhibits the synaptosomal uptake of serotonin, norepinephrine, and dopamine with about similar affinities and leads to a significant down-regulation of cortical beta-adrenoceptors and 5-HT2-receptors after subchronic treatment of rats. While neither hypericine nor kaempferol did show any reuptake inhibiting properties, hyperforin was identified as the unspecific reuptake inhibitor of hypericum extracts with half-maximal inhibitory concentrations for the three synaptosomal uptake systems mentioned above between 80 and 200 nmol/l. Moreover, a hyperforin-enriched (38%) CO2 extract also leads to a significant beta-receptor down-regulation after subchronic treatment. The data suggest hyperforin as the active principle of hypericum extracts in biochemical models of antidepressant activity.
Murphy JM. Preoperative considerations with herbal medicines. AORN J.1999 Jan;69(1):173-5, 177-178, 180-183.
Okpanyi SN, Weischer ML. Experimental Animal Studies of the Psychotropic Activity of a Hypericum Extract. Arzneim.-Forsch., 1987.37:10-13.
Piscitelli SC, Burstein AH, Chaitt D, et al. Indinavir concentrations and St John's wort [letter]. Lancet 2000;355(9203):547-548.
St John's wort reduced the area under the curve of the HIV-1 protease inhibitor indinavir by a mean of 57% (SD 19) and decreased the extrapolated 8-h indinavir trough by 81% (16) in healthy volunteers. A reduction in indinavir exposure of this magnitude could lead to the development of drug resistance and treatment failure.
Rao S G, et al. Calendula and Hypericum: two homeopathic drugs promoting wound healing in rats. Fitoterapia. 1991;6:508-510.
Ramussen P. St. John's Wort: A review of its use in depression. Aust J Med Herbalism .1998; 10(1):8-13.
Reichert RG. St. John's Wort as a Ttricyclic Medication Substitute for Mild to Moderate Depression. Quart Rev Nat Med Winter 1995; 275-278.
Roots I, et al. Evaluation of the photosensitisation of the skin upon single and multiple dose intake of Hypericum extract: Second Intn'l Congress on Phytomedicine, Munich 1996
Ruschitzka F, Meier PJ, Turina M, et al. Acute heart transplant rejection due to Saint John's wort [letter]. Lancet 2000;355(9203):548-549.
We report here acute rejection in two transplant patients due to a metabolic interaction of St John's wort and cyclosporin.
Schellenberg R, Sauer S, Dimpfel W. Pharmacodynamic effects of two different hypericum extracts in healthy volunteers measured by quantitative EEG. Pharmacopsychiatry 1998 Jun;31 Suppl 1:44-53.
Abstract: A double-blind, randomized, placebo-controlled parallel-group trial (phase I) was performed to evaluate the central pharmacodynamic effects of two hypericum extracts with different contents of hyperforin (0.5% and 5.0%) but identical hypericin content. Three groups of 18 volunteers between 18 and 35 years of age participated in the trial. The volunteers receiving verum took 900 mg of the extract once a day for 8 consecutive days. The primary aim of this study was to observe the frequency bands, i.e., delta (1.25-4.5 Hz), theta (4.75-6.75 Hz), alpha-1 (7.0-9.5 Hz), alpha-2 (9.75-12.5 Hz), beta-1 (12.75-18.5 Hz), and beta-2 (18.75-35 Hz). This was the first study of its kind testing hypericum controlled on the basis of its hyperforin contents. A quantitative topographic EEG (qEEG) was performed on days 1 and 8 as an indicator of drug-induced pharmacological action. The volunteers' electrophysiological data were obtained prior to application and 2, 4, 6, 8, and 10 hours post administration. Plasma samples for evaluation of the pharmacokinetics of hyperforin were also obtained. The qEEG results of the placebo group on days 1 and 8 showed no significant changes with regard to their physiological daily rhythm. In both verum groups (0.5% and 5.0% hyperforin content), reproducible central pharmacodynamic effects were apparent in comparison to placebo, in particular with the extract containing 5.0% of hyperforin. A peak pharmacodynamic efficacy was observed between 4 and 8 hours post administration. These results were confirmed on day 8 of the trial. The extract containing 5.0% hyperforin showed a marked tendency to produce higher increases in qEEG baseline power performances than the one containing 0.5% hyperforin. These higher baseline outputs on day 8 were seen at the delta, theta, and alpha-1 frequency values. Compared to placebo there was a significant increase in qEEG power performance in the delta and beta-1 frequency values exclusively for the extract containing 5.0% hyperforin. The theta and alpha-1 frequency values showed a noticeable tendency more emphasized on day 8 than on day 1. Preclinical trials in rats have been observed with similar changes in the frequency bands mentioned above, especially in the cholinergic (delta), noradrenergic (theta) and serotonergic (alpha) neurotransmitter systems. These experimental findings suggest that hypericum extracts with a high hyperforin content have a shielding effect on the central nervous system.
Shakirova KK, et al. Antimicrobial properties of some species of St John's Wort cultivated in Uzbekistan. Mikrobiol.Zh. 1970; 32:494-497.
Sparenberg B, Demisch L, Hoelzl J. Antidepressive constituents of St. Johnswort.. PZ Wiss., 1993.6:50-4, (Chem Abstr. 1 19:85914z).
Staffeldt B, Kerb R, Brockmoller J, Ploch M, Roots I. Pharmacokinetics of hypericin and pseudohypericin after oral intake of the hypericum perforatum extract LI 160 in healthy volunteers. J Geriatr Psychiatry Neurol 1994 Oct;7 Suppl 1:S47-S53.
Voelker R. Herbs and Anesthesia. JAMA, May 26, 1999;281(20),1882.
Weber N, et al. The antiviral agent hypericin has in vitro activity against HSV-1 through non specific association with viral and cellular membranes. Antiviral Chemistry and Chemotherapy. 1994 5:83-90.
Weller M.. Hypericin-induced apoptosis of human malignant glioma cells is light- dependent, independent of bcl-2 expression, and does not require wild- type p53. Neurol Res. 1997. 19,5:459-470.
Abstract:Hypericin and tamoxifen are experimental agents for the adjuvant chemotherapy of malignant glioma. We report that hypericin and tamoxifen induce apoptosis of 7 human malignant glioma cell lines in a concentration- and time-dependent manner. Illumination is essential for the cytotoxicity of hypericin but not tamoxifen. Apoptosis is unaffected by inhibitors of RNA and protein synthesis or free radical scavengers, does not require wild-type p53 activity, and occurs in glioma cells expressing high levels of bcl-2. There is no correlation between hypericin and tamoxifen-induced cytotoxicity and inhibition of protein kinase C (PKC). Ectopic expression of a murine bcl-2 transgene provides modest protection from tamoxifen but does not affect hypericin toxicity. Hypericin and tamoxifen do not modulate glioma cell killing induced by tumor necrosis factor-alpha (TNF-alpha) or CD95 ligand. Both drugs augment the acute cytotoxicity of various cancer chemotherapy drugs but fail to shift their EC50 values in modified colony formation assays. These data do not provide further supportive evidence how to enhance the limited efficacy of tamoxifen treatment for human malignant glioma. However, hypericin is a promising agent for the treatment of malignant glioma if local photodynamic activation of hypericin in the glioma tissue can be achieved.
Westbrooks RG, Preacher J W. Poisonous Plants of North America. Los Angeles: University of Southern California Press.1986.
Wheatley D, Hypericum in seasonal affective disorder (SAD).Curr Med Res Opin. 1999.151:33-37.
Abstract: Volunteers from the membership of the SAD Association took part in a postal survey, before and after eight weeks' treatment with Hypericum (Kira), using an 11-item rating scale. The maximum score is 44 and the mean score in 168 patients using Kira alone was 21.3. This fell to 13 at endpoint (p 0.001). The corresponding figures for 133 patients using Kira + light therapy were 20.6 and 11.8, respectively (p 0.001). In both groups, there was significant improvement in anxiety, loss of libido and insomnia. There were no significant between-group differences on any measure except that improvement in sleep was greater in the Kira + light group (p 0.01). On the results of this survey, Hypericum would appear to be an effective treatment for SAD.
Wichtl M. (ed.) Herbal Drugs and Phytopharmaceuticals, Boca Raton: CRC Press, 1994.
Wölk H, Burkhard G, Grünwald J. et al. Benefits and Risks of the Hypericum extract IL60: drug monitoring study with 3250 patients. J. Geriatric Psychiatry Neurology, 1994; 7 S34-38.