Hyperforin is a structurally novel anti-depressant isolated from Hypericum perforatum commonly known as St.John’s Wort.Hyperforin belong to group of compound known as acylphloroglucinols. The peculiarity of Hyperforin is that it is chemically unrelated to synthetic antidepressants. Hyperforin is photo and oxygen labile compound that is highly unstable and difficult to isolate in pure form. Initially, Hypericin, a napthodianthrone compound was considered to be the anti depressant principle of the herb, but now it is better known as marker compound in Hypericum perforatum extract and is used as identification standard in Hypericum samples. The standardization of Hypericum perforatum is based on presence of both Hyperforin and Hypericin.
MECHANISM OF ACTION
From a number of in vivo, in vitro and clinical studies it has been shown that that hyperforin not only inhibits the neuronal uptake of serotonin, norepinephrine and dopamine, but it also inhibits ? amino butyric acid (GABA) and L-glutamate uptake. Recently it has been proposed that there occur a physiochemical interaction of Hyperforin with specific membrane structures, which contribute to anti depressant activity.
Methanolic extract CO2-extract Hyperforin
(1.5% Hyperforin) (38.8% Hyperforin) 100%
MAO-A activity 120µg/mL 520µg/mL -
MAO-B activity 370µg/mL >500µg/mL -
Inhibition of serotonin uptake 2.4±0.4µg/mL 0.26±0.06µg/mL 0.11±0.02µg/mL
Inhibition of noradrenaline uptake 4.5±2.1µg/mL 0.25±0.08µg/mL 0.04±0.01µg/mL
Inhibition of dopamine uptake 0.9±0.1µg/mL 0.06±0.03µg/mL 0.06±0.01µg/mL
Inhibition of GABA uptake 1.1±0.06µg/mL 0.12±0.04µg/mL 0.10±0.02µg/mL
Inhibition of L- glutamate uptake 21.25±10.47µg/mL 2.83±1.8µg/mL 0.45±0.37µg/mL
Table showing inhibitory effects of Hypericum perforatum extracts and pure Hyperforin on monoamine oxidase activity and synaptosomal uptake of neurotransmitters. Table shows IC50 values, i.e. the concentration required for 50% inhibition. (Adapted from Pharmacopsychitary 1998:31:16-21).
CLINICAL STUDIES
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 (300 mg, with a content of 0.5% Hyperforin), or Hypericum extract (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 (5% Hyperforin) exhibited the largest HAMD reduction versus day 0 (10.3 +/- 4.6 points; mean +/- SD), followed by the 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 hyperforindose, a significant monotonic trend was demonstrated in the Jonckheere-Terpstra test (p = 0.017). In pairwise comparisons, (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 (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.
PHARMACOKINETICS
After administration of a 400mg tablet of St. John's wort extract containing 14.8mg Hyperforin, a maximum plasma level of approximately 150ng/mL (280nM) hyperforin was reached after 3.5 hours. The oral bioavailability of Hyperforin in doses up to 30mg (i.e. 600mg St. John's wort extract) was high. The half-life of Hyperforin was 9 hours and the mean residence time 12 hours. No accumulation of Hyperforin occurred with repeated dosing. Estimated steady state plasma concentrations with 3x300mg extract per day were approximately 100ng/mL or 180nM. These data show that the oral bioavail-ability of Hyperforin is high and that steady-state plasma concentrations can easily be achieved and maintained with a three times daily dosing schedule. Nothing appears to be known about the metabolism of Hyperforin as yet.
DRUG INTERACTIONS
Amprenavir, synthetic antidepressants, cyclosporin and digoxin.
ADVERSE DRUG REACTIONS
Gastrointestinal upset, hypersensitivity, and mild to moderate photosensitivity in light-skinned persons.
PREGNANACY/LACTATION
Unknown.
CONTRAINDICATIONS
Allergy, hypersensitivity to Hyperforin and severe depression.
ACKNOWLEDGMENT
We are highly thankful to Dr A.S.Sandhu, Scientist, Department of Natural Products, National Institute of Pharmaceutical Education &Research (NIPER) and Dr.Satish Narula, Professor, Punjab Agriculture University, Ludhiana for their expertise in Botanical consultation.
REFERENCES
1.Chatterjee SS, Bhattacharya SK, Wonnemann M, Singer A, Muller WE. Hyperforin as a possible antidepressant component of hypericum extracts. Life Sciences 1998; 63: 499-510.
2. Muller WE, Singer A, Wonnemann M.Hyperforin--antidepressant activity by a novel mechanism of action. Department of Pharmacology, University of Frankfurt, Frankfurt/M., Germany. Pharmacopsychiatry 2001 Jul; 34 Suppl 1:S98-102
3.Eckert GP, Muller WE.Effects of hyperforin on the fluidity of brain membranes.Department of Pharmacology, Biocenter Niederursel, University of Frankfurt, Frankfurt/Main, Germany. Pharmacopsychiatry 2001 Jul;34 Suppl 1:S22-5.
4. 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.Department of Psychiatry, University of Munich, Germany. Pharmacopsychiatry 1998 Jun; 31 Suppl 1:54-9.
5. Chatterjee, S.S., Noldner, M., Koch, E., and Erdelmeier, C. 1998 Antidepressant Activity of Hypericum perforatum and Hyperforin: the Neglected Possibility. Pharmacopsychiat., 31 (Suppl): 7-15.
6. Chatterjee, S.S., Bhattacharya, S.K., Singer, A., Wonnemann, M., and Mueller, W.E. 1998 Hyperforin Inhibits Synaptosomal Uptake of Neurotransmitters In Vitro and Shows Antidepressant Activity In Vivo. Pharmazie, 53: 9.
7. Laakmann, G., Dienel, A., and Kieser, M. 1998 Clinical Significance of Hyperforin for the Efficacy of Hypericum Extracts on Depressive Disorders of Different Severities. Phytomed, 5: 435-442.
8. Erdelmeier CAJ.Hyperforin,possibly the major non-nitrogenous secondary metabolite of Hypericum perforatum L.Pharmacopsychiatry 1998; 31:2-6.
9. Muller WE, Singer A, Wonnemann M, Hafner U, Rolli M, Schafer C. Hyperforin represents the neurotransmitter reuptake inhibiting constituent of Hypericum extract. Pharmacopsychiatry 1998; 31: 16-21.
10. Dimpfel W, Schober F, Mannel M. Effects of a methanolic extract and a Hyperforin-enriched CO2 extract of St. Johns wort (Hypericum perforatum) on intracerebral field potentials in the freely moving rat (tele-stereo-EEG). Pharmacopsychiatry 1998; 31: 30-35.
11. Biber A, Fischer H, Romer A, Chatterjee SS. Oral bioavailability of Hyperforin from Hypericum extracts in rats and human volunteers. Pharmacopsychiatry 1998; 31: 36-43.
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