The antiretroviral activity of Pseudohypericin is associated with interference with the proper assembly and maturation of retrovirus cores, likely affecting processing of gag-encoded precursor polyproteins or disrupting gag and gag-pol polyprotein interactions within the plasma membrane. Pseudohypericin also directly inactivates mature retroviruses, leading to loss of reverse transcriptase activity, but this is not due to direct inhibition of the purified reverse transcriptase enzyme. In sonodynamic therapy, Pseudohypericin acts via generation of singlet oxygen and other reactive oxygen species, leading to mitochondrial dysfunction, including loss of mitochondrial membrane potential (ΔΨm) and opening of the mitochondrial permeability transition pore (mPTP), which triggers the mitochondria-caspase apoptotic pathway. [1][2]

Antiretroviral activity is present in pseudohyperin [1].

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Pseudohypericin directly inactivates murine and human retroviruses as measured by reverse transcriptase assays. For radiation leukemia virus (RadLV) and human immunodeficiency virus (HIV), exposure to Pseudohypericin resulted in a concentration-dependent reduction in reverse transcriptase activity, although exact IC50 values are not provided. The inhibitory capacity of hypericin exceeds that of Pseudohypericin. This inhibition is not a direct effect on the active enzyme itself, as Pseudohypericin does not affect commercially purified reverse transcriptase. The loss of reverse transcriptase activity is not due to viral particle lysis, as activity could not be found in either pellet or supernatant fractions after ultracentrifugation. [1]

In sonodynamic therapy, Pseudohypericin (0.4 μg/mL) combined with ultrasound (1.0 MHz, 0.5 W/cm², 15 min) induced significant THP-1 macrophage apoptosis. The mode of cell death was predominantly apoptosis rather than necrosis, as determined by Annexin V-FITC flow cytometry. Apoptosis was caspase-dependent, as the broad-spectrum caspase inhibitor z-VAD-FMK (20 μM) prevented the decrease in cell viability. Pseudohypericin-SDT increased intracellular reactive oxygen species levels, with singlet oxygen identified as a major contributor (scavenged by sodium azide, 10 mM). The reactive oxygen species scavenger N-acetyl cysteine (1 mM) reversed the loss of cell viability and reduced the expression of cleaved caspase 9 and cleaved PARP. Pseudohypericin-SDT caused loss of mitochondrial membrane potential as shown by JC-1 staining; this was prevented by N-acetyl cysteine and sodium azide. Pseudohypericin-SDT induced opening of the mitochondrial permeability transition pore, detected by calcein-AM quenching, which was inhibited by cyclosporin A (0.5 μM), bongkrekic acid (100 μM), and DIDS (1 μM). Pseudohypericin-SDT induced translocation of BAX from cytosol to mitochondria and release of Cytochrome C from mitochondria to cytosol, as shown by Western blot. These effects were prevented by N-acetyl cysteine. Pseudohypericin-SDT upregulated cleaved caspase 9, cleaved caspase 3, and cleaved PARP expression. [2]

In the Friend virus model, a single intravenous administration of Pseudohypericin at a dose of 150 μg per mouse co-administered with Friend virus on the day of inoculation led to 100% survival of BALB/c mice for 240 days. Lower doses (50 and 10 μg per mouse) were protective but did not achieve 100% survival. Pseudohypericin is less potent than hypericin at lower doses. [1]

In the LP-BM5 murine immunodeficiency virus (MAIDS) model, intraperitoneal injections of Pseudohypericin (150 μg per mouse) once every 2 weeks beginning on day 14 after virus inoculation prevented detectable viremia for at least 90 days. The same biweekly treatment significantly ameliorated lymphoproliferative disease, reducing spleen weight from 1.886 ± 0.44 g (LP-BM5 alone) to 0.999 ± 0.34 g (50% inhibition of splenomegaly). Injections of Pseudohypericin beginning on days 21, 28, or 33 post-virus inoculation (when viremia was already present) led to prompt reduction of viremia. [1]

For reverse transcriptase assays, virus (RadLV or HIV) was collected from producing cells and exposed to Pseudohypericin for 1 hour at 4°C (RadLV) or 37°C (HIV). After exposure, virus was pelleted at 50,000 × g, lysed with 0.5% Triton X-100, and analyzed for reverse transcriptase activity. Pseudohypericin did not affect the activity of commercially purified reverse transcriptase enzyme. [1]

In sonodynamic therapy studies, for reactive oxygen species measurement, THP-1 macrophages were loaded with DCFH-DA (20 μM) for 30 min at 37°C, then fluorescence was measured at 488 nm excitation and 525 nm emission. For mitochondrial membrane potential assessment, cells were incubated with JC-1 (10 mg/mL) for 20 min at 37°C, and fluorescence was measured at 488 nm excitation and 530 nm and 590 nm emission. For mitochondrial permeability transition pore opening, cells were loaded with calcein-AM (5 μM) in the presence of cobalt chloride (5 mM) for 15 min at 37°C, and fluorescence was measured at 488 nm excitation and 525 nm emission. For Western blot, proteins (50 μg) were resolved by SDS-PAGE, transferred to PVDF membranes, and probed with antibodies against BAX, Cytochrome C, caspase 9, cleaved caspase 9, caspase 3, cleaved caspase 3, PARP, cleaved PARP, HSP60, and β-actin. [2]

THP-1 monocytic leukemia cells were differentiated into macrophages with phorbol-12-myristate-13-acetate (100 ng/mL) for 72 hours. Cells were then incubated with Pseudohypericin (0.4 μg/mL) for 4 hours in RPMI 1640 medium with 10% fetal bovine serum. Ultrasound exposure was performed at 1.0 MHz, 0.5 W/cm², 15 min. Cell viability was measured by CCK-8 assay after various treatments. For apoptosis analysis, cells were stained with Annexin V-FITC and propidium iodide and analyzed by flow cytometry. For reactive oxygen species detection, cells were incubated with DCFH-DA (20 μM) for 30 min at 37°C and fluorescence was imaged by confocal microscopy. For mitochondrial membrane potential, cells were stained with JC-1 (10 mg/mL) for 20 min at 37°C and fluorescence was measured by fluorospectrophotometer and fluorescence microscopy. For mitochondrial permeability transition pore opening, cells were loaded with calcein-AM (5 μM) and cobalt chloride (5 mM) for 15 min at 37°C. For Western blot, cells were lysed and mitochondrial and cytosolic fractions were separated. Proteins were detected with specific antibodies. Inhibitors used included: N-acetyl cysteine (1 mM, ROS scavenger), sodium azide (10 mM, singlet oxygen scavenger), mannitol (hydroxyl radical scavenger), superoxide dismutase (100 μg/mL), catalase (100 μg/mL), z-VAD-FMK (20 μM, caspase inhibitor), cyclosporin A (0.5 μM, mPTP inhibitor), bongkrekic acid (100 μM, mPTP inhibitor), DIDS (1 μM, mPTP inhibitor). [2]

In the Friend virus model, BALB/c mice (10 per group) were inoculated intravenously with 10⁶ focus-forming units of Friend virus. Pseudohypericin was given as a single intravenous dose of 10, 50, or 150 μg per mouse at the time of virus inoculation. Survival was followed for 240 days. [1]

In the LP-BM5 murine immunodeficiency virus model, C57BL/6 mice were inoculated intraperitoneally with LP-BM5 virus. Pseudohypericin (150 μg per mouse) was given intraperitoneally once every 2 weeks beginning on day 14 after infection. Mice were bled from the periorbital plexus at weekly intervals, and sera were assayed for reverse transcriptase activity. In a separate experiment, spleen weights were measured. Injections starting on days 21, 28, or 33 post-infection (when viremia was already present) led to prompt reduction of viremia. [1]

Absorption, Distribution and Excretion
The antidepressant effect of Hypericum perforatum is primarily composed of hypericin, hyperoside, and flavonoids. Therefore, two open-label Phase I clinical trials aimed to obtain pharmacokinetic data for Hypericum perforatum extract tablets containing the following components: hypericin, pseudohypericin, hyperoside, the flavonoid aglycone quercetin, and its methylated form isorhamnetin. Each trial enrolled 18 healthy male volunteers who received either a single oral dose or multiple daily doses (once every 14 days) of the test formulation containing 900 mg of dried Hypericum perforatum extract (STW 3-VI, Laif 900). Concentration-time curves were determined for the five components at 48 hours after a single dose and at 24 hours on day 14 after two weeks of continuous daily administration. Following a single dose, key pharmacokinetic parameters were determined as follows: ... Hypericin: AUC(0-∞) = 97.28 hr × ng/mL, Cmax = 10.2 ng/mL, tmax = 2.7 hr, elimination half-life 17.19 hr... Similar results were obtained after multiple doses to reach steady state. Other pharmacokinetic characteristics calculated from the obtained data included mean residence time (MRT), lag time, peak-to-trough fluctuation (PTF), lowest plasma concentration (Cmin), and mean plasma concentration (Cav). The data for the five components were largely consistent with previously published data. The investigational formulation was well tolerated. These two open-label Phase I clinical trials aimed to investigate the bioavailability of five components in a tablet containing Hypericum extract, which are considered key components for antidepressant effects. Each trial enrolled 18 healthy male volunteers who received the investigational formulation (containing 612 mg of St. John's wort dry extract, trade name STW-3, Laif 600) either as a single oral dose or once-daily or multiple-dose administration for 14 days. Concentration-time profiles of hypericin, pseudohypericin, hyperoside, quercetin (a flavonoid aglycone), and its methylated form isorhamnetin were measured within 48 hours of the single dose and on day 14 after two weeks of continuous daily administration. Key pharmacokinetic parameters determined after a single dose were as follows: ...pseudohypericin: AUC(0-∞) = 93.03 hr × ng/mL, Cmax = 8.50 ng/mL, tmax = 3.0 hr, elimination half-life 25.39 hr...similar results were obtained after multiple doses to reach steady state. Other pharmacokinetic characteristics calculated from the obtained data included mean residence time (MRT), lag time, peak-to-trough fluctuation (PTF), lowest plasma concentration (Cmin), and mean plasma concentration (Cav). Data for hypericin, pseudohypericin, and hyperoside were largely consistent with previously published data, but some discrepancies were observed in the absorption rate of hypericin and the absorption and elimination timeline of hyperoside. The investigational formulation was well tolerated.
Hypericum perforatum extracts are used to treat depression. They contain various substances, among which the naphthalene-anthrone compounds hypericin and pseudohypericin are characteristic components. These compounds have been shown to be phototoxic in cell culture and animal studies. A placebo-controlled randomized clinical trial assessed the increase in skin photosensitivity after high-dose administration of Hypericum perforatum extracts in humans by monitoring plasma concentrations of hypericin and pseudohypericin. The study was divided into single-dose and multiple-dose groups. In the single-dose trial phase, 13 volunteers were enrolled in a double-blind, four-way crossover study and received either placebo or 900, 1800, or 3600 mg of standardized Hypericum extract (LI 160), containing 0, 2.81, 5.62, and 11.25 mg of total hypericin (total hypericin being the sum of hypericin and pseudohypericin), respectively. Peak plasma total hypericin concentrations were observed approximately 4 hours after administration, at 0, 0.028, 0.061, and 0.159 mg/L, respectively…
This study evaluated the effects of cimetidine and carbamazepine on the pharmacokinetics of hypericin and pseudohypericin, components of St. John's wort (SJW). In a placebo-controlled, double-blind study, 33 healthy volunteers were randomized to three groups and received St. John's wort extract (LI160) in combination with different drugs (placebo, cimetidine, and carbamazepine) for 7 days. Previously, volunteers received only St. John's wort during the 11-day induction period. Pharmacokinetic parameters of hypericin and pseudohypericin were measured on days 10 and 17. Intergroup comparisons showed no statistically significant differences in AUC(0-24), Cmax, and tmax between hypericin and pseudohypericin. However, intragroup comparisons showed that, compared with baseline pharmacokinetics, cimetidine combination therapy significantly increased the median AUC (0-24) of hypericin from 119 (range 82-163 ug hr/L) to 149 ug hr/L (61-202 ug hr/L), while carbamazepine combination therapy decreased the median AUC (0-24) of pseudohypericin from 51.0 (16.4-102.9 ug hr/L) to 36.4 ug hr/L (14.0-102.0 ug hr/L). The pharmacokinetics of hypericin and pseudohypericin were minimally affected by the co-administration of the enzyme inhibitors and inducers cimetidine and carbamazepine. To investigate the single-dose and steady-state pharmacokinetics of hypericin and pseudohypericin, we studied 13 healthy male volunteers aged 25–30 years who orally received St. John's wort LI 160 extract. Following oral administration of 250, 750, and 1500 μg of hypericin and 526, 1578, and 3156 μg of pseudohypericin, the median peak plasma concentrations (Cmax) of hypericin were 1.3, 7.2, and 16.6 μg/L, respectively, while the median peak plasma concentrations of pseudohypericin were 3.4, 12.1, and 29.7 μg/L, respectively. The Cmax and AUC values of the lowest dose groups were significantly lower than those of the higher dose groups. The lag time of hypericin was 1.9 hours, significantly longer than that of pseudohypericin (0.4 hours). Following administration of 750 μg hypericin, the median half-lives for absorption, distribution, and elimination were 0.6, 6, and 43.1 hours, respectively; following administration of 1578 μg pseudohypericin, the corresponding median half-lives were 1.3, 1.4, and 24.8 hours, respectively; and the corresponding Cmax values were 8.8 and 8.5 μg/L, respectively. Hypericin and pseudohypericin were initially distributed in central blood volumes of 4.2 L and 5 L, respectively. The systemic bioavailability of hypericin and pseudohypericin in the extracts was 14% and 21%, respectively.

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Biological Half-Life
After administration of 750 μg hypericin, the median half-lives for absorption, distribution, and elimination were 0.6, 6, and 43.1 hours, respectively; after administration of 1578 μg pseudohypericin, the median half-lives for absorption, distribution, and elimination were 1.3, 1.4, and 24.8 hours, respectively…
Each trial enrolled 18 healthy male volunteers who received the test formulation containing 900 mg of St. John's wort dry extract (STW 3-VI, Laif 900), either as a single oral dose or multiple daily doses over 14 days. Concentration-time curves were determined for the five components within 48 hours after a single dose and within 24 hours on day 14 after two weeks of continuous daily administration. Key pharmacokinetic parameters were determined after a single dose as follows: …pseudohypericin: …elimination half-life of 17.19 hours…similar results were obtained after multiple doses to reach steady state. Each trial enrolled 18 healthy male volunteers who received the investigational formulation containing 612 mg of St. John's wort dry extract (STW-3, Laif 600), administered either as a single oral dose or multiple daily doses over 14 days. Key pharmacokinetic parameters were determined after a single dose as follows: ...hypericin: elimination half-life of 25.39 hours... Similar results were obtained after multiple doses to reach steady state...

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Interactions
In healthy volunteers, St. John's wort reduced the area under the curve (AUC) of the HIV-1 protease inhibitor indinavir by an average of 57% (standard deviation 19) and by an extrapolated 8-hour indinavir trough concentration of 81% (16). Such a significant reduction in indinavir exposure could lead to drug resistance and treatment failure. Hypericum perforatum (Hp) has been used to treat a variety of conditions, including mild to moderate depression. Recently, Hp has been reported to possess multiple anti-inflammatory activities. Following an anti-inflammatory bioassay (lipopolysaccharide (LPS)-induced prostaglandin E2 (PGE2) production), the ethanol extract of Hp was fractionated and four components were identified. When the concentrations detected in the H. pylori fraction were combined into a four-component system, these components (0.1 μM chlorogenic acid (compound 1), 0.08 μM ferulic acid flavonoids (compound 2), 0.07 μM quercetin (compound 3), and 0.03 μM hypericin (compound 4)) explained most of the fraction's activity under light activation, but only partially explained its activity under dark conditions. One component, photoactivated hypericin, was necessary, but not sufficient, to explain the four-component system's inhibition of LPS-induced PGE2. Both the H. pylori fraction and the four-component system inhibited lipoxygenase and cytophospholipase A2, both active enzymes in the PGE2-mediated inflammatory response. The four-component system inhibited the production of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α), while the hypericin (H. pylori) fraction inhibited the production of the anti-inflammatory cytokine interleukin-10 (IL-10). Therefore, Hp components and specific components exhibited blocking effects on pro-inflammatory mediators but did not enhance the effects of anti-inflammatory mediators. The authors evaluated the pharmacokinetic interactions between St. John's wort (SJW) extract with low hypericin content and alprazolam, caffeine, tolbutamide, and digoxin. Previous studies on other SJW products have shown significantly reduced plasma concentrations of certain co-administered drugs, attributed to the induction of cytochrome P-450 (CYP) and P-glycoprotein (P-gp) activity by SJW. Two randomized, placebo-controlled studies enrolled 28 healthy volunteers (aged 18–55 years). In Study A, subjects received a single dose of alprazolam (1 mg; CYP3A4 substrate) and caffeine (100 mg; CYP1A2) on days 1 and 11, respectively. In Study B, subjects received a single dose of tolbutamide (500 mg; CYP2C9) on days 1 and 11, and multiple doses of digoxin (0.75 mg on days -2 and -1, and 0.25 mg daily from day 1 to day 11; P-gp substrate). Subjects also received either St. John's wort (Esbericum capsules; 240 mg extract daily, 3.5 mg hypericin) or placebo from days 2 to 11. Blood samples were drawn on days 1 and 11 for pharmacokinetic analysis. At study end, there were no statistically significant differences in the primary pharmacokinetic parameters AUC_0-24, caffeine (AUC_0-12), paraxanthine, tolbutamide, 4-hydroxytolbutamide, and digoxin between the placebo and St. John's wort groups. The change in AUC induced by St. John's wort was less than 12% of the median initial AUC in subjects in Studies A and B, and therefore not clinically significant. On day 11, the trough concentrations of hypericin and pseudohypericin were 2.0 (range 0.6–4.1) μg/L and 1.0 (0.2–3.9) μg/L, respectively, while the concentration of hyperoside was below the limit of quantitation (< 1 μg/L). The pharmacokinetics of the probe drug under investigation were only slightly affected by co-treatment with Esbericum capsules. This is likely primarily due to the lower plasma concentration of hyperoside, as this St. John's wort component has been shown to activate PXR receptors, which regulate the expression of CYP3A4 and P-gp…
The current interest in and widespread use of herbal medicines makes interactions between herbs and drugs possible when used concurrently. Kava (Piper methysticum Forst. F.) was once one of the top ten best-selling herbs in Europe and North America before recent reports of significant hepatotoxicity from its use. This adverse reaction was not previously observed in traditional kava drinks prepared by water infusion, unlike commercial products extracted using organic solvents. Calovalin, the active ingredient of calva, is a potent inhibitor of multiple CYP450 enzymes, meaning it is highly likely to interact pharmacokinetically with drugs metabolized by the same CYP450 enzymes and other herbs. Furthermore, some calovalins have been shown to have pharmacological effects, such as blocking GABA receptors and sodium and calcium ion channels, which may lead to pharmacodynamic interactions with other substances with similar pharmacological properties. St. John's wort (Hypericum perforatum L.) is widely used to treat mild to moderate clinical depression and has long been considered safer than conventional medications. However, its active ingredients, hypericin, pseudohypericin, and hyperoside, can induce the expression of intestinal P-glycoprotein/MRD1 and the intestinal and hepatic CYP3A4 enzymes, thereby significantly reducing the distribution and metabolism of its cofactors. In addition, St. John's wort is a potent inhibitor of the uptake of neurotransmitters such as serotonin, norepinephrine, and dopamine, all of which are involved in mood regulation. Therefore, the possibility of pharmacodynamic interactions between St. John's wort and drugs with similar mechanisms of action, such as kava and St. John's wort, is very high. However, sufficient evidence is currently lacking to confirm actual pharmacokinetic and/or pharmacodynamic interactions between these drugs and kava or St. John's wort. This review briefly summarizes the existing data on drug interactions between kava and St. John's wort and these drugs, highlighting the urgent need for detailed studies to identify clinically significant interactions that may cause adverse effects in these herbal remedies. More complete data on interactions with pseudohypericin (a total of 8 types) can be found on the HSDB record page.

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[1]. Studies of the mechanisms of action of the antiretroviral agents hypericin and pseudohypericin. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5963-7.

[2]. Apoptosis of THP-1 Macrophages Induced by Pseudohypericin-Mediated Sonodynamic Therapy Through the Mitochondria-Caspase Pathway. Cell Physiol Biochem. 2016;38(2):545-57.

Hypericin is a polycyclic aromatic hydrocarbon fused at both the ortho and pericyclic positions. It has been reported to exist in Hypericum tomentosum, Hypericum montanum, and other organisms with relevant data. Mechanism of Action Cytoplasmic thioredoxin reductase (TrxR1) and mitochondrial thioredoxin reductase (TrxR2) exhibit significant concentration- and time-dependent inhibition when incubated with both naphthalenedianthrone compounds, hypericin and hypericin. Hypericin is a potent inhibitor of TrxR1 (IC50 = 4.40 μM), significantly stronger than hypericin (IC50 = 157.08 μM). Conversely, the IC50 value of hypericin for TrxR2 is 7.45 μM, while that of hypericin is 43.12 μM. Compared to hypericin, hypericin typically requires a longer time to inhibit TrxR1, especially at hypericin. We analyzed these significant differences in inhibitory potency and inhibitory spectra using molecular modeling. Notably, both compounds bind to the NADPH-binding pocket of the enzyme. The binding of the two naphthalenedianthrones to thioredoxin reductase appears to be particularly strong, as the inhibitory effect is fully preserved after gel filtration. Furthermore, we found that the inhibition of TrxR by hypericin and hypericin does not involve the selenool/thiol motif at the active site, which has been confirmed by biochemical and modeling studies. The resulting inhibitory pattern is very similar to that of the two naphthalenedianthrones on glutathione reductase. Since the thioredoxin system is highly overexpressed in cancer cells, the inhibitory effects of hypericin and hypericin (two natural compounds with significant anticancer properties) on it may provide new clues to elucidating their mechanism of action and open new prospects for future cancer treatment.

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Therapeutic Use
Antiviral Drugs; Enzyme Inhibitors
/Experimental Treatment/ Two aromatic polycyclic diketone compounds, hypericin and pseudohypericin, possess potent antiretroviral activity; these substances are found in plants of the genus Hypericum. Both compounds are effective in preventing viral infection symptoms following various retroviral infections, both in vivo and in vitro. Pseudohypericin and hypericin may interfere with viral infection and/or transmission by directly inactivating the virus or preventing viral shedding, budding, or assembly on the cell membrane. These compounds have no significant activity against viral protein transcription, translation, or translocation to the cell membrane, nor do they have a direct effect on polymerases. This characteristic distinguishes their mechanism of action from major antiretroviral nucleoside analogues. Hypericin and pseudohypericin exhibit low in vitro cytotoxicity, but their concentrations are sufficient to produce significant antiviral effects in mouse tissue culture models using radioactive leukemia virus and Friend virus. Administration of these compounds to mice at low doses sufficient to prevent retroviral infection appears to have no adverse side effects. The lack of toxicity at this therapeutic dose also applies to humans, as these compounds have been tested in patients as antidepressants and have shown significant benefits. These observations to date suggest that pseudohypericin and hypericin may be effective tools for treating retroviral infections such as acquired immunodeficiency syndrome (AIDS). St. John's wort (Hypericum perforatum L.) is widely used to treat mild to moderate clinical depression and has long been considered safer than conventional medications.

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Drug Warning
In the United States, St. John's wort (Hypericum perforatum), like other herbs, is listed as a dietary supplement by the U.S. Food and Drug Administration (FDA). Therefore, it does not require the rigorous safety and efficacy reviews of standard medications…
…Concomitant use of St. John's wort and indinavir significantly reduces indinavir plasma concentrations, likely due to induction of the cytochrome P450 metabolic pathway. …Currently, only pharmacokinetic data for concomitant use of indinavir and St. John's wort are available.
However, based on these results, St. John's wort is expected to significantly reduce the blood concentrations of all currently marketed HIV protease inhibitors (PIs) and may also reduce the concentrations of other drugs with similar metabolic pathways (to varying degrees), including non-nucleoside reverse transcriptase inhibitors (NNRTIs). Therefore, concurrent use of St. John's wort with PIs or NNRTIs is not recommended, as this may lead to insufficient antiretroviral drug concentrations, resulting in loss of virological response and the development of drug resistance or cross-resistance. St. John's wort (Hypericum perforatum L.) is widely used to treat mild to moderate clinical depression and has long been considered safer than conventional medications. However, its active ingredients, hypericin, pseudohypericin, and hyperoside, can induce the expression of intestinal P-glycoprotein/MRD1 and the intestinal and hepatic CYP3A4 enzymes, thereby significantly reducing the distribution and metabolism of its cofactors. Furthermore, St. John's wort is a potent inhibitor of the uptake of neurotransmitters such as serotonin, norepinephrine, and dopamine, all of which are involved in mood regulation. Therefore, there is a high probability of pharmacodynamic interactions between St. John's wort and other drugs with similar mechanisms of action that are also used to improve mood.

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Pseudohypericin is a naturally occurring polycyclic aromatic dione (C₃₀H₁₆O₉, M_r 520.43) isolated from Hypericum triquetrifolium Turra. Its chemical structure consists of a flat core of eight fused aromatic rings with six phenolic hydroxyls and a seventh hydroxyl group side-chain substitution (hydroxymethyl). The substitution of the seventh hydroxyl group in Pseudohypericin diminishes antiretroviral activity compared to hypericin. Pseudohypericin possesses antiretroviral activity against Friend virus, LP-BM5 murine leukemia virus, and human immunodeficiency virus (HIV). It also has potential as a sonosensitizer for sonodynamic therapy of atherosclerosis by inducing macrophage apoptosis via the mitochondria-caspase pathway. The median elimination half-life of Pseudohypericin is reported elsewhere (in a reference cited by [2]) to be 24.8 h, but this is not an original finding of the provided literature. [1][2]

C30H16O9

520.4426

520.079

55954-61-5

4978

Brown to black Solid

2.0±0.1 g/cm3

994.7±65.0 °C at 760 mmHg

569.2±30.8 °C

0.0±0.3 mmHg at 25°C

2.169

6.75

7

9

1

39

1190

0

O([H])C1C2=C(C([H])=C(C3C4C(=C([H])C(=C5C(=C6C(C([H])=C(C([H])([H])[H])C7=C8C(C([H])([H])O[H])=C([H])C(C=1C8=C(C=32)C(C=45)=C76)=O)=O)O[H])O[H])O[H])O[H])O[H]

NODGUBIGZKATOM-UHFFFAOYSA-N

InChI=1S/C30H16O9/c1-7-2-9(32)19-23-15(7)16-8(6-31)3-10(33)20-24(16)28-26-18(12(35)5-14(37)22(26)30(20)39)17-11(34)4-13(36)21(29(19)38)25(17)27(23)28/h2-5,31,34-39H,6H2,1H3

9,11,13,16,18,20-hexahydroxy-5-(hydroxymethyl)-24-methyloctacyclo[13.11.1.12,10.03,8.04,25.019,27.021,26.014,28]octacosa-1(26),2,4(25),5,8,10,12,14(28),15(27),16,18,20,23-tridecaene-7,22-dione

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)