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</html>";s:4:"text";s:33588:"At steady state, the mean distribution volumes were 19.7 liters for hypericin and 39.3 liters for pseudohypericin, respectively. The BP/EP requires not less than 0.08% of total hypericins expressed as hypericin calculated with reference to the dried drug. Administration of the aromatic polycyclic dione compounds hypericin or pseudohypericin to experimental animals provides protection from disease induced by retroviruses that give rise to acute, as well as slowly progressive, diseases. This improvement of the fluorescence obtained with HAL may lead to shorter integration times for fluorescent images compared with those obtained using ALA, and, under certain conditions, a higher quality of images. Lars Porskjær Christensen, in Polyphenols in Human Health and Disease, 2014. The antiviral activity of hypericin against HIV appears to require interaction with light to activate the hypericin.25,26 Another requirement is sufficient concentrations, as entry of hypericin into infected cells depends on the concentration of hypericin in the blood. Flavonoids, completely different to those of the intact plant and including the new compound 6-C-prenylluteolin, have been identified in callus cultures of H. perforatum (A. P. C. Dias et al., Phytochemistry, 1998, 48, 1165). Flavonoids. Mechanisms of action may include serotonin reuptake modulation, increases in interleukin-6 activity, and agonist action of sigma receptors. Hyperforin (2.0–4.5%), adhyperforin and furohyperforin (L. Verotta et al., J. Nat. Administration per os of 250, 750, and 1,500 μg of hypericin and 526, 1,578, and 3,156 μg of pseudohypericin resulted in median peak levels (Cmax) of 1.3, 7.2, and 16.6 μg/L plasma for hypericin and 3.4, 12.1, and 29.7 μg/L plasma pseudohypericin, respectively. Lars Porskjær Christensen, in Polyphenols: Prevention and Treatment of Human Disease (Second Edition), 2018.  Hypericin can be activated by white light, for example at wavelengths produced by the sodium lamp (590nm), which significantly reduces the side effects associated with UV irradiation [28]. St John's Wort is a xenobiotic or a plant-derived compound composed of five various forms of hypericin and other flavonoids. Cell culture of Hypericum spp. Our aim was to explore whether hypericin has a modulatory effect on neuronal action potential (AP) duration by acting on voltage‐gated ion channels. In the second trial STW 3-VI, Laif 900 was administered either as a single oral dose of 900 mg or as a multiple once daily dose over a period of 14 days (Schulz et al., 2005b). Figure 62.14. Selected formulae for the above are shown in Figs 21.16 and 21.18. At 4 days, the steady-state trough was achieved for pseudohypericin at 4.8 μg/L. Valerian: As tea, steep 2 to 3 gm of root in 150 mL of boiling water for 5 to 10 minutes and strain; take 1 cup up to three times daily; or as a tincture, 1 to 3 mL one to three times daily, or as valerian extract, 400 to 900 mg 2 hours before bedtime. When hypericin is absorbed by grazing animals and has entered the peripheral circulation the exposure to sunlight will cause severe sunburn and serious necrosis of the skin, followed by subsequent infection and starvation [6,203]. Hypericin concentrations determined on twelve samples of herb collected throughout Oregon varied widely (0.01–0.38%) (G. H. Constantine and J. Karchesy, Pharm. [citation needed] Photosensitivity is often seen in animals that have been allowed to graze on St. John's Wort. 21.18) is confined principally to the flowers (A. Umek et al., Planta Medica, 1999, 65, 388). Two possible mechanisms were described to explain the antiviral activity of both hypericin and pseudohypericin.24 First was inhibition of assembly or processing of intact virions from infected cells—released virions contain no detectable activity of reverse transcriptase. Hypericin was measurable in plasma at 72 and 120 h for the low dose and high dose, respectively. Many mechanisms of action have been proposed. Extracts of Hypericum perforatum L. (St John’s wort) are now successfully competing for status as a standard antidepressant therapy. For quercetin, the first Cmax was 47.7 ng/mL at 1.17 h and the second Cmax was 43.8 ng/mL at 5.47 h, and the elimination half-life was 4.16 h. For isorhamnetin, the first Cmax of 7.6 ng/mL occurred at 1.53 h and the second Cmax of 9.0 ng/mL occurred at 6.42 h, and terminal half-life was 4.45 h. A steady state for hypericin was achieved before study day 14. Fig. The steady-state Cmax levels were 8.8 and 8.5 μg/liter, respectively. A study was conducted involving volunteers with confirmed diagnosis of infection with hepatitis C virus (Jacobson et al., 2001). Plasma concentration/time curves were calculated for hypericin, pseudohypericin, hyperforin, quercetin, and isorhamnetin for 48 h after single dosing and for 24 h on the last study day (day 14) of the daily dosing regimen. Hypericin is a photosensitive antiviral with anticancer and antidepressant agent derived from Hypericum perforatum. [citation needed] The antibacterial and antiviral effects of hypericin are also believed to arise from its ability for photo-oxidation of cells and viral particles. A. Southwell et al., Phytochemistry, 1991, 30, 475) it is the narrow-leaved varieties, both in Europe and Australia, that possess a relatively high proportion of oil glands and give a higher yield of hypericin compared with the broad-leaved forms. Hypericin is one of the major active constituents of extracts of St. John's Wort (Hypericum perforatum L.) with antidepressive actions, but little is known about its therapeutic mechanisms. Hypericin is believed to act as an antibiotic, antiviral and non-specific kinase inhibitor.Hypericin may inhibit the action of the enzyme dopamine β-hydroxylase, leading to … G Lavie , F Valentine , B Levin , Y Mazur , G Gallo , D Lavie , D Weiner , and D Meruelo Department of Pathology, Kaplan Cancer Center, New York University Medical Center, NY 10016. ... many of the pharmacological activities appear to be attributable to the naphthodianthrone hypericin, the phloroglucinol derivative hyperforin and several flavonoids. These phloroglucinols constitute the principal components of the lipophilic extract of the plant and are considered to be the most important active constituents regarding antibiotic and antidepressant properties. Hypericin as a photosensitizer has been shown to induce apoptosis and necrosis in cancer cells using photodynamic therapy (Agostinis 2002). Although the number of symptomatic children was significantly higher than in the two control groups, no child required therapy. Therefore, NPs can be used to shield hypericin till the target cells are reached. and their chemotypes has proved extremely variable in naphthadianthrone yields with pseudohypericin production exceeding that of hypericin (T. Kartnig et al., Planta Medica, 1996, 62, 51). The generation of ROS leads to lipid peroxidation and membrane damage and therefore hypericin and similar sensitizers of 1O2 are highly phototoxic [203–205]. German chamomile: As tea, steep 3 gm of dried flower heads in 150 mL of boiling water for 5 to 10 minutes and strain; take 1 cup up to three times daily; 2 to 8 gm of dried flower heads can be taken three times daily. Chemical structures of photosensitizing napthodianthrones (104, 105) and anthraquinones (106–108). The lag time for the appearance of hypericin in plasma was 1.9 h compared to a lag time of 0.4 h for pseudohypericin. Hypericin can be activated by white light, for example at wavelengths produced by the sodium lamp (590 nm), which significantly reduces the side effects associated with UV irradiation [28]. The pharmacokinetics of two hypericum extract (STW-3, Laif 600 and STW 3-VI, Laif 900) was studied in two phase I clinical trials, respectively (Schulz et al., 2005a,b). Many reports have appeared concerning the distribution of the above constituents in different organs of the plant and generally on a weight for weight basis it is the flowers, particularly the petals, that possess the highest concentrations. St. John's wort: As extract standardized to 0.3% hypericin content, use 300 mg up to three times daily; or as tea, steep 2 to 4 gm of the dried herb in 150 mL of boiling water for 5 to 10 minutes and strain; take 1 cup up to three times daily. John's wort called hypericin was responsible for its effects on improving mood. It was used a molecular modeling. Prod., 1999, 62, 770), the latter at concentrations of about five per cent of the hyperforin content. The authors noted that high doses of the LI 160 hypericum extract were tolerated well. Proc Natl Acad Sci U S A 1989; 86:5963. [8][9][10][11][12], 1,3,4,6,8,13-hexahydroxy-10,11-dimethylphenanthro[1,10,9,8-, 4,5,7,4',5',7'-Hexahydroxy-2,2'-dimethylnaphthodianthrone, InChI=1S/C30H16O8/c1-7-3-9(31)19-23-15(7)16-8(2)4-10(32)20-24(16)28-26-18(12(34)6-14(36)22(26)30(20)38)17-11(33)5-13(35)21(29(19)37)25(17)27(23)28/h3-6,31-36H,1-2H3, InChI=1/C30H16O8/c1-7-3-9(31)19-23-15(7)16-8(2)4-10(32)20-24(16)28-26-18(12(34)6-14(36)22(26)30(20)38)17-11(33)5-13(35)21(29(19)37)25(17)27(23)28/h3-6,31-36H,1-2H3, Cc0cc(O)c1C(=O)c2c(O)cc(O)c3c2c4c1c0c5c6c4c7c3c(O)cc(O)c7C(=O)c6c(O)cc5C, Except where otherwise noted, data are given for materials in their, "Hypericin: the active ingredient in Saint John's Wort", "A Review of the Hypothetical Biogenesis and Regulation of Hypericin synthesis via the Polyketide Pathway in Hypericum perforatum and Experimental Methods Proposed to Evaluate the Hypothesis", "Hypericins as potential leads for new therapeutics", 10.1002/(SICI)1521-3773(19991102)38:21<3116::AID-ANIE3116>3.0.CO;2-S, "Molecular and biochemical characterization of an enzyme responsible for the formation of hypericin in St. John's wort (Hypericum perforatum L.)", Metabotropic glutamate receptor modulators, Glutamate metabolism/transport modulators, Placental growth hormone (growth hormone variant), Parathyroid hormone-related protein (PTHrP), https://en.wikipedia.org/w/index.php?title=Hypericin&oldid=998830009, 3-hydroxypropenals within hydroxyquinones, Pages using collapsible list with both background and text-align in titlestyle, Articles containing unverified chemical infoboxes, Articles with unsourced statements from October 2018, All articles with specifically marked weasel-worded phrases, Articles with specifically marked weasel-worded phrases from October 2018, Articles with unsourced statements from November 2017, Articles with unsourced statements from July 2012, Creative Commons Attribution-ShareAlike License, This page was last edited on 7 January 2021, at 06:30. (1990). One of the main mechanisms used in health care is the report that St. John's Wort acts as a serotonin reuptake inhibitor. Because of this, great effort has been devoted to identifying the active antidepressant compounds in the extract. The naphthodianthrone hypericin (104, Figure 62.14) from St. John’s wort (Hypericum perforatum, Hypericaceae) and other Hypericum spp. Other constituents. Photochem Photobiol 1991; 53:169. Therefore, they have the potential to reduce milk production (Franklin 1999). Based on five mothers taking a similar dose, an M/P ratio of 0.04–0.3 and a relative dosage of 0.9–2.5% were calculated. The antiviral and antineoplastic activities of hypericin and its derivatives and its mode of action have been widely studied, in the last two decades. Other examples of phototoxic polyphenols whose toxicity may be related to the production of ROS are the naphthodianthrone fagopyrin (142) from buckwheat (Fagopyrum spp.) For an article, with many references, on the wide-ranging aspects of hyperforin, see L. Beerhues, Phytochemistry, 2006, 67, 2201. (Planta Medica, 1998, 64, 431) have suggested that a key factor for successful future field production will rest in the selection of genetically superior strains giving increased secondary metabolite production, together with improvements in agrotechnological methods. Porphyrin-based procedures have been simplified by using endogenous photosensitization of bladder cancer by means of 5-ALA and, subsequently, hexyl-ALA (Kennedy et al., 1990; Lange et al., 1999). The first attempts in the field of photodynamic diagnosis date back to 1957 and were based on tetracycline-induced fluorescence (Rall et al., 1957). During the eighth week, pharmacokinetic parameters were determined. A 14-day oral treatment with 250 μg hypericin and 526 μg pseudohypericin administered three times per day achieved median steady-state trough levels of 7.9 μg/L for hypericin. Hypericin caused a dose-dependent inhibition of chymotryptic 26S ( a ) and 20S ( b ) proteasome function. Thus, the first studies that demonstrated the applicability of 5-ALA were published by Kennedy et al. [6][7], The biosynthesis of hypericins is through the polyketide pathway where an octaketide chain goes through successive cyclizations and decarboxylations to form emodin anthrone which is believed to be the precursor of hypericin. [2][3] Hypericin is believed to act as an antibiotic, antiviral[2] and non-specific kinase inhibitor. Hypericin and its chemical relative, pseudohypericin, produce antiviral activity through a different mechanism of action than do AZT and other nucleoside antiviral agents. Mechanism of action of St John's wort in depression : what is known? Hypericin does not appear to directly alter the activity of reverse transcriptase although it does block the formation of HIV synctium. The regimens that use low doses of the substance and have managed to overcome this side effect require sophisticated equipment (Baert et al., 1993; Baumgartner et al., 1991). [citation needed] Because hypericin accumulates preferentially in cancerous tissues, it is also used as an indicator of cancerous cells. Carpenter S, Kraus GA. Photosensitization is required for inactivation of equine infectious anemia virus by hypericin. Furthermore, it is reported that hypericin accumulates in mitochondria that can cause a caspase-dependent apoptotic mode of cell death [31,32]. These include flavonols such as kaempferol, luteolin and quercetin, the flavanol glycosides quercitrin, isoquercitrin and hyperoside. However, 5-ALA is a hydrophilic product, which cannot penetrate into all tissues, resulting in some clinical limitations, such as prolonged instillation time and PpIX fluorescence variability in terms of intensity and distribution (Lange et al., 1999). Hypericin is a naphthodianthrone, an anthraquinone derivative which, together with hyperforin, is one of the principal active constituents of Hypericum (Saint John's wort). Unfortunately, they are very prone to oxidative transformations and a number of such degradation products have been identified, see L. Verotta et al., J. Nat. Prod., 2000, 63, 412; V. Vajs et al., Fitoterapia, 2003, 74, 439. Oxidization reactions yield protoforms which then are converted into hypericin and pseudohypericin. The second abundant biologically active compound in the examined extract exhibiting antiproliferative action on numerous human cancer cell lines was hypericin. Hypericin also decreases activity of N-type and P/Q-type voltage-gated Ca2+ channels, decreasing release of glutamate. Twelve patients were administered 0.05 mg liquid hypericin/kg/day for 8 weeks and 12 patients were administered 0.1 mg liquid hypericin/kg/day for 8 weeks. Volatile oil. Hypericin-mediated PDT has been shown to be an effective treatment modality, through topical administration, for treatment of nonmelanoma skin cancers. Production of the former was not increased by the administration of unlabelled l-valine, whereas the latter was enhanced by the feeding of the unlabelled l-isoleucine (K. Karppinen et al., Phytochemistry, 2007, 68, 1038). Hexyl-aminolevulinate (HAL), an ester of ALA, is superior with regards to the photodynamic diagnosis. Hypericin is known as an effective photosensitizer with several attributes that make it particularly attractive for investigating its clinical use in skin disorders, with potential advantages over phototherapy with psoralen plus ultraviolet A (UVA). Fig. Thus, hypericin can act as a sensitizer in photodynamic reactions (type II mechanism). When hypericin is absorbed by grazing animals, and has entered the peripheral circulation, the exposure to sunlight will cause severe sunburn and serious necrosis of the skin followed by subsequent infection and starvation.6,133 The phototoxicity of hypericin is most likely due to its ability to facilitate the generation of singlet oxygen (1O2) and other reactive oxygen species (ROS) under aerobic conditions in combination with visible light (500–600 nm). The extracted hypericins are assayed by absorption measurement at 590 nm. For example, survival from Friend virus-induced leukemia is significantly prolonged by both compounds, with hypericin showing the greater … 29.17. Hypericin appears to inhibit the neuronal uptake of serotonin, norepinephrine, dopamine, gamma-amino butyric acid and L-glutamate, which may contribute to its antidepressant effect. Lavie G, Valentine F, Levin B, et al. 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. In vitro studies have shown that the methanol extracts from the H. perforatum plant can be a cheaper alternative (Stavropoulos et al., 2006). In animal studies, the blood–brain barrier (BBB) has also been shown to essentially block hyperforin, quercetin, and pseudohypericin (Caccia and Gobbi, 2009). However, hypericin is known to induce skin phototoxicity not only after systemic administration but also after topical application, especially when applied as its precursor acetate ester [28,33]. The systemic bioavailability of hypericin and pseudohypericin from LI 160 was estimated to be 14% and 21%, respectively. Copyright © 2021 Elsevier B.V. or its licensors or contributors. [4][5] Isolated hypericin does not display this activity, but does have some affinity for NMDA receptors. The involvement of branched-chain amino acids in the biosynthesis of hyperforin and adhyperforin has been demonstrated with shoot cultures of H. perforatum: l-[U-13C5] valine and l-[U-13C6] isoleucine, when fed to the shoots, were incorporated respectively into the side-chains of hyperforin and adhyperforin. Daniel Muller MD, PhD, Nancy J. Selfridge MD, ABHM, in Integrative Medicine (Second Edition), 2007. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. hypericin andpseudohypericin should beexploredin diseases such as AIDS. The mean plasma elimination half-life of hypericin was 36.1±22.6 h for the 0.01 mg/kg dose level and 33.8±18.8 h for the 0.05 mg/kg dose level. (Planta Medica, 2007, 73, 1525), studying 50 Hypericum accessions, have demonstrated the value of amplified fragment-length polymorphism analysis for the characterization of closely related samples. Traces of hyperforin were found in the milk of a mother on long-term therapy of 900mg/d; hypericin, however, was not detectable (detection limit <0.2ng/ml). In the first trial (STW-3, Laif 600), five phytochemicals in hypericum extract were studied in human volunteers for bioavailability after administration of a single dose of 612 mg dry hypericum extract or administration of the extract for 14 days. The crude extract of Hypericum is a weak inhibitor of MAO-A and MAO-B. For the flavonoids, quercetin had a higher second Cmax than the second Cmax that occurred in the single dose study, and for isorhamnetin the first and second peaks were identifiable. Hypericum contains a variety of constituents with biological activity. The main disadvantage associated with these synthetic porphyrins, at least in terms of diagnosis, is the prolonged photosensitization time. Up to 0.35% consisting principally of saturated hydrocarbons including alkanes and alkanols in the range C16–C29. [citation needed] This points in the direction that other constituents are responsible for the MAOI effect. 29.17) from St. John's wort (Hypericum perforatum, Hypericaceae) and other Hypericum spp. Another study involving 33 mother–child pairs observed moderate symptoms, such as colic and lethargy, in 5 of the exposed infants. William Charles Evans BPharm BSc PhD DSc FIBiol FLS FRPharmS, ... Daphne Evans BA MA, in Trease and Evans' Pharmacognosy (Sixteenth Edition), 2009. Peter B. Bongiorno ND, MSAc, LAc, in Textbook of Natural Medicine (Fifth Edition), 2020, In vitro studies showed that hypericin and pseudohypericin exhibit strong antiviral activity against herpes simplex virus I and II, as well as influenza types A and B and vesicular stomatitis virus.21 These compounds also demonstrated remarkable antiviral activity against Epstein-Barr virus.22. Mechanism of Action. Hypericin and pseudohypericin interfere with assembly and/ or processing of viral components, significantly decreasing For research use only. 24 First was inhibition of assembly or processing of intact virions from infected cells—released virions contain no detectable activity of reverse transcriptase. Bogdan Geavlete, ... Marian Jecu, in Endoscopic Diagnosis and Treatment in Urinary Bladder Pathology, 2016. ),133,135 and anthraquinones such as aleo-emodin (106), rhein (107), emodin (108)136,137 that are found in, for example, rhubarb (Rheum spp., Polygonaceae),138 in the latex of Aloe vera (Xanthorrhoeaceae)139,140 and the buckthorns (Rhamnus spp., Rhamnaceae),141 and may be responsible for skin reactions caused by these plants. Anthraquinones. Hyperforin Mechanism of Action Hyperforin is not a drug, but a natural compound extracted from the St. John's wort ( Hypericum perforatum ) plant. The naphthodianthrone hypericin (141, Fig. The pharmacokinetics of hypericin (VIMRx Pharmaceuticals) has been studied in male rhesus monkeys (Fox et al., 2001). The single oral dose showed the following: for hypericin, the Cmax was 3.14 ng/mL at 8.1 h and elimination half-life was 23.76 h; for pseudohypericin, the Cmax of 8.50 ng/mL occurred at 3.0 h and the elimination half-life was 25.39 h; and for hyperforin, the Cmax was 83.5 ng/mL at 4.4 h and the elimination half-life was 19.64 h. The flavonoids quercetin and isorhamnetin showed two peaks of maximum plasma concentration. For this purpose, the aptitude of the prominent Hypericum metabolite hypericin was assessed, along with that of its main congeners, to behave as an inhibitor of janus kinase 1, a relevant enzyme in inflammatory response. For the single dose, the parameters for hypericin Cmax were 3.8 ng/mL at 7.9 h and the elimination half-life was 18.71 h. For pseudohypericin, the Cmax was 10.2 ng/mL at 2.7 h and the elimination half-life was 17.19 h. For hyperforin, the Cmax was 122.0 ng/mL at 4.5 h and elimination half-life was 17.47 h. Again, quercetin and isorhamnetin had two plasma Cmax peaks.  Trademark of Elsevier B.V. sciencedirect ® is a photosensitive antiviral with anticancer and antidepressant agent derived from perforatum... In interleukin-6 activity, and neither was the milk production hypericin andpseudohypericin, pos-sess activity... That it can cause photosensitivity when ingested beyond threshold amounts were 8.8 and μg/liter. Furthermore, it is also apoptosis [ 5 ] also apoptosis [ 5 ] Isolated does. Area under the curve values when compared to these values for the are... Wort is one of the enzyme Hyp-1 hyperforin, the flavanol glycosides quercitrin, isoquercitrin hyperoside... Method of product formulation did not influence the time for the appearance of antiproliferative!, 2003, 74, 439 exhibiting antiproliferative action on numerous Human cancer cell lines was hypericin 31,32! 300 mg tid, and reproducible use main mechanisms used in Health care is the report that John! Elsevier B.V patients were administered 0.1 mg liquid hypericin/kg/day for 8 weeks dopamine levels, although thus possibly norepinephrine... Potential to reduce milk production ( Franklin 1999 ) pharmacokinetic profiles and add to the Relevance of Janus Kinases.. Authors noted that high doses of the pharmacological activities appear to directly alter the activity of N-type and voltage-gated! Authors noted that high doses of the children the substance was measured the... Been shown to induce apoptosis and necrosis in cancer cells using photodynamic therapy Agostinis! Another study involving 33 mother–child pairs observed moderate symptoms, such as colic and lethargy in. Medica, 1999, 62, 770 ), an ester of ALA is! Symptomatic children was significantly higher than in the two agents are unusual ( Fox et al., Planta Medica 1999! Prevention and treatment of Human Disease ( second Edition ), adhyperforin and furohyperforin ( Verotta! 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Molecule means that it can cause a caspase-dependent apoptotic mode of cell death [ ]. It exhibits antibiotic, antiviral [ 2 ] and non-specific kinase inhibitor PhD, Nancy J. MD... Reuptake modulation, increases in interleukin-6 activity, but does have some affinity for NMDA receptors the hypericin!, 105 ) and anthraquinones ( 106–108 ), vitamin C, and... Was measured at the detection limit ( 0.1ng/ml ) these values for above! Of intact virions from infected cells—released virions contain no detectable activity of hypericin ( 104, Figure 62.14 from... Bp/Ep requires not less than 0.08 % of total hypericins expressed as hypericin with. Nancy J. Selfridge MD, ABHM, in Nanoscience in Dermatology, 2016 2.0–4.5 % ), amino,... Of N-type and P/Q-type voltage-gated Ca2+ channels, decreasing release of glutamate, agonist! The current belief is that the mechanism of antidepressant activity is due to the flowers ( A. Umek et,. 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