Substances & Homeopatic Remedies

Hypericum perforatum

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Extracts of Hypericum perforatum L. (St John's wort) are now successfully competing for status as a standard antidepressant therapy. Because of this, great effort has been devoted to identifying the active antidepressant compounds in the extract. From a phytochemical point of view, St John's wort is one of the best-investigated medicinal plants. A series of bioactive compounds has been detected in the crude material, namely flavonol derivatives, biflavones, proanthocyanidines, xanthones, phloroglucinols and naphthodianthrones. Although St John's wort has been subjected to extensive scientific studies in the last decade, there are still many open questions about its pharmacology and mechanism of action. Initial biochemical studies reported that St John's wort inhibits the synaptosomal uptake of serotonin, dopamine and noradrenaline (norepinephrine) with approximately equal affinity. However, other in vitro binding assays carried out using St John's wort extract demonstrated significant affinity for adenosine, GABA(A), GABA(B) and glutamate receptors. In vivo St John's wort extract leads to a downregulation of beta-adrenergic receptors and an upregulation of serotonin 5-HT(2) receptors in the rat frontal cortex and causes changes in neurotransmitter concentrations in brain areas that are implicated in depression. In studies using the rat forced swimming test, an animal model of depression, St John's wort extracts induced a significant reduction of immobility. In other experimental models of depression, including acute and chronic forms of escape deficit induced by stressors, St John's wort extract was shown to protect rats from the consequences of unavoidable stress. Recent neuroendocrine studies suggest that St John's wort is involved in the regulation of genes that control hypothalamic-pituitary-adrenal axis function. With regard to the antidepressant effects of St John's wort extract, many of the pharmacological activities appear to be attributable to the naphthodianthrone hypericin, the phloroglucinol derivative hyperforin and several flavonoids. This review integrates new findings of possible mechanisms that may underlie the antidepressant action of St John's wort and its active constituents with a large body of existing literature.  
  (Butterweck V. Institute of Pharmacology and Toxicology, Universitatsklinikum Munster, Munster, Germany.)


 


Dal punto di vista della tossicità, l'iperico è più sicuro dell'aspirina. Negli Stati Uniti, ogni anno da cinquecento a mille persone muoiono a causa dell'aspirina, in genere per emorragie inteme. L'iperico, al confronto, non ha registrato un solo decesso in almeno 2400 anni di impiego farmacologico.
Infatti l'unico effetto tossico di cui siamo a conoscenza si manifesta in alcuni animali a pelo corto, come la pecora, che muore non tanto per avere ingerito, brucando, grandi quantità di erba di san Giovanni, ma per essersi esposta al sole successivamente: questa è la ragione per cui in Australia l'iperico è considerato un'erba dannosa. L'iperico aumenta la sensibilità dell'animale alla luce, per cui questo si ammala e talvolta muore a causa delle ustioni (in termini medici si parla di fototossicità).
Questo fenomeno, per quanto teoricamente possibile negli uomini, non è mai stato documentato in rapporto alle dosi di iperico raccomandate per la cura della depressione. Anche nel caso della ricerca sull'AIDS, che implica la somministrazione di iperico per via endovenosa in quantità trentacinque volte superiori a quelle per la depressione, gli effetti fototossici sono stati scarsi e comunque mai letali. (E allo studio la possibilità di ricorrere a dosi più elevate di iperico sfruttandone le proprietà antivirali).
Tuttavia il rischio della fototossicità va considerato se il paziente ha già manifestato una sensibilità specifica alla luce solare o se è in cura con altri farmaci fotosensibilizzanti, come la Clorpromazina o le Tetracicline.
In uno studio condotto su 3250 pazienti sottoposti a iperico, solo il 2,4 per cento ha manifestato effetti collaterali.
Tali effetti collaterali tendono a essere lievi. Le affezioni gastrointestinali rappresentano lo 0,6 per cento, le reazioni allergiche lo 0,5 per cento, l'astenia lo 0,4 per cento, l'agitazione lo 0,3 per cento.
(E interessante tuttavia notare che, in quindici studi condotti su 1008 pazienti, gli effetti collaterali nel gruppo di controllo, cui era stato somministrato un innocuo placebo, sono stati leggermente superiori a quelli del gruppo sottoposto a iperico: 4,8 per cento nel gruppo del placebo contro 4,1 per cento nel gruppo dell'iperico. Anche il tasso delle interruzioni si è dimostrato superiore nel gruppo del placebo: 1,8 per cento rispetto allo 0,4 per cento nel gruppo dell'iperico.)
Un valore superiore viene riportato dal British Medical Journal in una rassegna di sei studi sull'iperico: il 10,8 per cento dei pazienti ha manifestato effetti collaterali con l'iperico (simili a quelli elencati sopra) contro il 35,9 per cento di effetti collaterali nei pazienti trattati con farmaci antidepressivi tradizionali. Anche in base a questo valore, il British Medicai Journal ha concluso che gli effetti collaterali dell'iperico sono "rari e di lieve entità".
Sempre il British Medical Journal ha proposto che vengano svolti ulteriori studi sui possibili effetti collaterali dell'iperico a lungo termine, una raccomandazione che sottoscriviamo di tutto cuore, forti anche di quei riscontri positivi nella storia della medicina popolare che abbiamo già ricordato, come pure dei ventidue milioni di persone che in Germania hanno assunto l'iperico per oltre un anno senza manifestare alcun nuovo effetto, o effetti negativi più diffusi, rispetto a quelli riscontrati da studi clinici effettuati sul breve periodo.
A questo proposito vale la pena segnalare che alcuni dei più preoccupanti effetti collaterali degli antidepressivi tradizionali - disfunzioni sessuali, interazioni negative con l'alcol o con altri farmaci, secchezza delle fauci, cefalea - non sono stati individuati nei pazienti trattati con l'iperico.
Inoltre, gli effetti negativi dell'iperico si sono dissolti quando i pazienti ne hanno sospeso l'uso. Non sono dunque stati rilevati effetti collaterali "irreversibili": in altre parole non si è verifìcato alcun danno permanente e tutti gli effetti nocivi sono scomparsi non appena i pazienti hanno smesso di assumere l'iperico.
A ogni buon conto, se paragonati ai sintomi della depressione, gli effetti negativi dell'iperico sono lievi. Ricordiamo che sono stimati in 21.000 i suicidi (il 70 per cento del totale) causati direttamente dalla depressione non curata. E vari studi hanno dimostrato che, per ogni suicidio, vi sono dieci tentati suicidi e un centinaio d'individui che meditano seriamente di togliersi la vita.
La depressione non curata è la causa principale dell'alcolismo e dell'abuso di droghe. Una percentuale significativa di divorzi, di violenza nei confronti dei familiari, di assenteismo, di perdita del lavoro e di fallimenti è attribuibile a una depressione trascurata.
Si stima che negli Stati Uniti le perdite associate alla depressione superino i quaranta miliardi di dollari l'anno. E chi può stabilire il prezzo della sofferenza quotidiana dei dodici milioni di americani e dei tre milioni circa di italiani che soffrono di depressione ma che non ricevono alcun trattamento?
Se li paragoniamo ai sintomi della depressione, gli effetti collaterali dell'iperico appaiono trascurabili. Per la maggior parte delle persone che soffrono di depressione, i potenziali benefici superano di gran lunga l'eventuale rischio nell'assunzione dell'iperico.
La bassa percentuale di effetti negativi dell'iperico - in particolare nelle dosi raccomandate per la cura della depressione - lo colloca nella categoria delle erbe, delle vitamine, dei minerali e dei farmaci "da banco". Dunque, a condizione di essere sempre attenti ai potenziali effetti collaterali, i consumatori bene informati possono assumere l'iperico con assoluta tranquillità.

Topical application of St John's wort (Hypericum perforatum L.) and of its metabolite hyperforin inhibits the allostimulatory capacity of epidermal cells.
Schempp CM - British Journal of Dermatology - 2000 May; 142(5): 979-84  
Author Affiliation: Department of Dermatology, Photodermatology Unit, University Medical Center, Haupstr 7, D-79104 Freiburg, Germany.  
Authors: Schempp CM; Winghofer B; Ludtke R; Simon-Haarhaus B; Schopf E; Simon JC  
St John's wort (Hypericum perforatum) is a traditional herbal medicine that is used for the topical treatment of superficial wounds, burns and dermatitis. The characteristic metabolites of St John's wort are the photodynamic active plant pigment hypericin and the phloroglucin- derivative hyperforin. To date, no studies on immunomodulatory properties of topical preparations of St John's wort have been performed. Here, we investigated the alloantigen presenting function of human epidermal cells (EC) exposed to Hypericum ointment in vivo in a mixed EC lymphocyte reaction (MECLR). The effect of Hypericum ointment was compared with the immunosuppressive effect of solar-simulated radiation (SSR). Subsequently, we tested purified hyperforin in vivo and in vitro in a MECLR to evaluate its possible contribution to the effect of the Hypericum ointment. Furthermore, we assessed the effect of hyperforin on the proliferation of peripheral blood mononuclear cells (PBMC) in vitro. Compared with untreated skin, treatment with Hypericum ointment resulted in a significant suppression of the MECLR (P </= 0.001) that was similar to the effect of SSR. The combination of Hypericum ointment plus SSR was not significantly different from either treatment alone. EC isolated from skin treated with the hyperforin containing ointment also showed a reduced capacity to stimulate the proliferation of allogeneic T cells (P </= 0.001). Similarly, in vitro incubation of EC with hyperforin suppressed the proliferation of alloreactive T cells (P </= 0.001). Furthermore, hyperforin inhibited the proliferation of PBMC in a dose-dependent manner, without displaying pronounced toxic effects as determined by Trypan blue staining. The results demonstrate an inhibitory effect of Hypericum extract and of its metabolite hyperforin on the MECLR and on the proliferation of T lymphocytes that may provide a rationale for the traditional treatment of inflammatory skin disorders with Hypericum extracts.  

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Equivalence of St John's wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depression.
Schrader E - International Clinical Psychopharmacology - 2000 Mar; 15(2): 61-8  
Author Affiliation: Praxis Klinische Arzneimittelforschung, Pohlheim, Germany.  
Treatment with St John's wort extract tablets (hypericum Ze 117) and the commonly used slow serotonin reuptake inhibitor (SSRI) fluoxetine was compared in patients with mild-moderate depression with entry Hamilton Depression Scale (HAM-D) (21-item) in the range 16-24, in a randomized, double-blind, parallel group comparison in 240 subjects; fluoxetine: 114 (48%), hypericum: 126 (52%). After 6 weeks' treatment, mean HAM-D at endpoint decreased to 11.54 on hypericum and to 12.20 on fluoxetine (P < 0.09), while mean Clinical Global Impression (CGI) item I (severity) was significantly (P < 0.03) superior on hypericum, as was the responder rate (P = 0.005). Hypericum safety was substantially superior to fluoxetine, with the incidence of adverse events being 23% on fluoxetine and 8% on hypericum. The commonest events on fluoxetine were agitation (8%), GI disturbances (6%), retching (4%), dizziness (4%), tiredness, anxiety/nervousness and erectile dysfunction (3% each), while on hypericum only GI disturbances (5%) had an incidence greater than 2%. We concluded that hypericum and fluoxetine are equipotent with respect to all main parameters used to investigate antidepressants in this population. Although hypericum may be superior in improving the responder rate, the main difference between the two treatments is safety. Hypericum was superior to fluoxetine in overall incidence of side-effects, number of patients with side-effects and the type of side-effect reported.  

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Effect of the Hypericum perforatum extract on serotonin turnover in the mouse brain.
Yu PH - Pharmacopsychiatry - 2000 Mar; 33(2): 60-5  
Author Affiliation: Department of Psychiatry, University of Saskatchewan, Saskatoon, Canada.  
St. John's Wort, a traditional herbal medicine obtained from the extract of Hypericum perforatum, has been used in the treatment of mild depression. Its mechanism of action remains to be established. The present study confirmed that Hypericum extract exhibited very weak inhibitory activities towards MAO. Mouse brain MAO activities was unchanged following either acute or chronic treatment with Hypericum extract. 5-HIAA levels were found to be significantly increased in the cerebral cortex, hypothalamus, hippocampus and caudate 3 h after treatment with the Hypericum extract at a dose as low as 10 mg/Kg. An increase of 5-HT levels was also observed in hypothalamus and hippocampus. The increase of brain 5-HIAA was not further enhanced following chronic administration of the herb. The Hypericum extract significantly reduced the plasma tryptophan levels, the precursor of 5- HT. The action of Hypericum extract is consistent with the notion that serotonergic system is involved. The effect of Hypericum extract on the brain 5-HIAA and 5-FIT levels appeared to be quite different from the effect of classical 5-HT re-uptake blockers.  

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Effect of acute administration of hypericum perforatum-CO2 extract on dopamine and serotonin release in the rat central nervous system.
Di Matteo V - Pharmacopsychiatry - 2000 Jan; 33(1): 14-8  
Author Affiliation: Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, Santa Maria Imbaro Chieti, Italy.  
Authors: Di Matteo V; Di Giovanni G; Di Mascio M; Esposito E  
The hydromethanolic extract of Hypericum perforatum has been shown to be an effective antidepressant, although its mechanism of action is still unclear. In this study, in vivo microdialysis was used to investigate the effects of Hypericum perforatum-CO2 extract on dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT), and 5- hydroxyindoleacetic acid (5-HIAA) release in various areas of brain. Administration of Hypericum perforatum extract (1 mg/kg, p.o.) caused a slight, but significant increase of DA outflow both in the nucleus accumbens and the striatum. The maximal increase of DA efflux (+19.22+/- 1.93%, relative to the control group) in the nucleus accumbens occurred 100 min after administration of Hypericum perforatum. In the striatum, the extract maximally enhanced DA outflow (+24.83+/-7.49 %, relative to the control group) 80 min after administration. Extraneuronal DOPAC levels were not significantly affected by Hypericum perforatum treatment. Moreover, Hypericum perforatum (1 mg/kg, p.o.) did not produce any significant effect on either 5-HT or 5-HIAA efflux in the ventral hippocampus. This study shows for the first time that Hypericum perforatum extract is capable of increasing in vivo DA release.  

BJOG. 2000 Jul;107(7):870-6. Related Articles, Links  
A pilot study of Hypericum perforatum for the treatment of premenstrual syndrome.
Stevinson C, Ernst E.
Department of Complementary Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, UK.

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.