Chemical constituents and in vivo preliminary evaluation of the toxicological activity of Ouratea spectabilis (OCHNACEAE) and Clitoria guianensis (Fabaceae) leaves

Clitoria guianensis and Ouratea spectabilis, found in the Brazilian Cerrado, are used in folk medicine, despite the few chemical and biological studies reported in the literature. The present study aims to investigate the toxicity and effect of extracts from both species on the microcrustacean Artemia salina, and to determine the chemical composition of the hexane extract of O. spectabilis leaves and the EtOAc fraction of C. guianensis leaves. Kaempferitrin, a flavonoid isolated from of the EtOAc fraction of C. guianensis leaves, was identified by chemical analysis. Analysis of the hexane extract of O. spectabilis leaves using gas chromatography-mass spectrometry (GC-MS) suggested the presence of twenty-five known substances. The Hex, EtOAc, and EtOH crude extracts of C. guianensis leaves exhibited high and moderate toxicity against Artemia salina, with median lethal dose values (LD50) of 43.7, 25.4, and 233.4 mg.L−1, respectively. The acetone extract of O. spectabilis leaves showed moderate toxicity against Artemia salina with an LD50 value of 115.13 mg.L−1.

Antiviral activity of plant juices and green tea against SARS-CoV-2 and influenza virus.

Respiratory viruses pose a significant threat to global health. They initially infect the naso- and oropharyngeal regions, where they amplify, cause symptoms, and may also be transmitted to new hosts. Preventing initial infection or reducing viral loads upon infection might soothe symptoms, prevent dissemination into the lower airways, or transmission to the next individual. Several natural products have well-described direct antiviral activity or may ameliorate symptoms of respiratory infections. We thus analyzed the potential of plant-derived products to inactivate respiratory viral pathogens and determined the antiviral activity of black chokeberry (Aronia melanocarpae [Michx.] Elliott), elderberry (Sambucus nigra L.), and pomegranate (Punica granatum L.) juice, as well as green tea (Camellia sinensis [L.] Kuntze) on the infectivity of the surrogate-modified vaccinia virus Ankara, and the respiratory viruses severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A virus (IAV), and adenovirus Type 5. Black chokeberry and pomegranate juice, and green tea reduced SARS-CoV-2 and IAV titers by ≥80% or ≥99%. This suggests that oral rinsing with these products may reduce viral loads in the oral cavity which might prevent viral transmission.

Preparation of herbal tea as infusion or by maceration at room temperature using mistletoe tea as an example.

Herbal tea can be prepared by infusion or maceration at room temperature resulting in different compositions of extractable constituents, which possibly influences the mode of action or safety profile. Knowledge on this topic is limited. The aim of this study was to investigate the substantial differences between infusion and maceration as recommended preparation methods for the preparation of herbal mistletoe tea, a traditional remedy against cardiovascular diseases. No active substances are known but analytical marker substances such as proteins, triterpenoids, phenylpropane derivatives and flavonoids can be quantified within the herb and the different herbal tea preparations. Whereas phenylpropane derivatives were completely extracted by infusion and maceration, neither method dissolved viscotoxins. 43% of mistletoe lectins were extracted by maceration, whereas by infusion they are inactivated by thermal degradation. By contrast, oleanolic acid and betulinic acid are present in higher concentrations in infusates compared with macerates, but even infusion extracted less than 2%. Infusion extracted 43% of flavonoid-like substances and maceration only 31%. In conclusion this study determines some differences between both extraction methods on the profile of solved substances. The relevance of it should be determined in studies dealing with the efficacy of herbal mistletoe tea.

No clinically relevant CYP3A induction after St. John's wort with low hyperforin content in healthy volunteers.

OBJECTIVE: Induction of CYP3A by St. John's wort (SJW) products with high hyperforin content is well described. Since CYP3A induction is mediated by hyperforin in a concentration-dependent manner, and SJW preparations differ significantly in hyperforin content, the aim of the study was to evaluate the effect of an SJW powder with low hyperforin content on CYP3A function. METHODS: Twenty healthy male volunteers received an SJW powder with low hyperforin content for 2 weeks. Midazolam plasma concentration time profiles were characterized after a single oral dose of 7.5 mg midazolam on the day before and on the 14th day of SJW medication. RESULTS: Midazolam AUC(0-infinity) slightly decreased from 124.0 +/- 62.5 ng/ml.h at baseline to 105.6 +/- 53.2 ng/ml.h after SJW (P < 0.05), representing a mean 11.3% decrease (95% CI: -22.8 to 0.21). No significant change in midazolam C(max), t(1/2) and t(max) was observed. For all pharmacokinetic parameters, the 90% CI for the geometric mean ratio of treatment over baseline were within the no-effect boundaries of 0.70-1.43. CONCLUSION: Administration of an SJW product with low hyperforin content resulted in a mild induction of CYP3A not considered clinically relevant.

Hyperforin in St. John's wort drug interactions.

Recently, interactions of herbal medicines with synthetic drugs came into focus of particular interest. In the past 3 years, more than 50 papers were published regarding interactions between St. John's wort (Hypericum perforatum L.; SJW) and prescription drugs. Co-medication with SJW resulted in decreased plasma concentrations of a number of drugs including amitriptyline, cyclosporine, digoxin, indinavir, irinotecan, warfarin, phenprocoumon, alprazolam, dextrometorphane, simvastatin, and oral contraceptives. Sufficient evidence from interaction studies and case reports indicate that SJW is a potent inducer of cytochrome P450 enzymes (particularly CYP3A4) and/or P-glycoprotein. Recent studies could show that the degree of enzyme induction by SJW correlates strongly with the amount of hyperforin found in the product. Products that do not contain substantial amounts of hyperforin (<1%) have not been shown to produce clinically relevant enzyme induction. On the other hand, some evidence suggests that hyperforin may also contribute to the antidepressant activity of SJW. However, clinical studies using SJW preparations with a low hyperforin amount (<1%) clearly demonstrated the superiority of this plant extract over placebo and its equivalence to imipramine and fluoxetine in the treatment of mild to moderate forms of depression. In the present paper clinical significant SJW interactions are critically evaluated against the background of hyperforin.

The extent of induction of CYP3A by St. John's wort varies among products and is linked to hyperforin dose.

OBJECTIVE: Induction of CYP3A by St. John's wort (SJW) extracts with high hyperforin (HYF) content is well described. Since SJW products vary in the amount of HYF and other main constituents, the aim of the study was to evaluate the effect on CYP3A function of SJW preparations with a range from very low to high HYF content. METHODS: Forty-two male, healthy volunteers were randomized into six parallel SJW medication groups with varying composition especially with regard to HYF content. Midazolam plasma concentration profiles were characterized after a single oral dose of 7.5 mg midazolam on the day before and on the 14th day of SJW medication. RESULTS: All SJW preparations tested resulted in a decrease in midazolam AUC, although the extent of the effect differed. The extract LI 160 (HYF 41 mg/day) decreased midazolam AUC0-12h by 79.4% (95% CI -88.6; -70.1), which was significantly greater than the effect by any other medication (p<0.05). SJW powder tablets 2.7 g/day (HYF 12 mg/day) resulted in a midazolam AUC0-12h decrease of 47.9% (95% CI -59.7;-36.2), while 2.7 g/day SJW powder tablets that were almost devoid of HYF (0.13 mg/day) reduced midazolam AUC0-12h by only 21.1% (95% CI -33.9; -8.3). Considering all six SJW medications tested, the extent of midazolam AUC decrease correlated significantly with increasing HYF dose (r=-0.765, p<0.001), but not with hypericin dose (r=-0.067; p=0.673). CONCLUSION: The extent of induction of CYP3A varies among St. John's wort products and depends on hyperforin dose.

Hyperforin content determines the magnitude of the St John's wort-cyclosporine drug interaction.

OBJECTIVE: Hyperforin (HYF) has been discussed as a potential cause of the reduction in the bioavailability of numerous drugs seen with St John's wort (SJW) comedication. This study compared the effects of 2 SJW preparations with high and low HYF content on the pharmacokinetics of cyclosporine (INN, ciclosporin) (CSA). METHODS: In a crossover study, 10 renal transplant patients were randomized into 2 groups and received SJW extract (900 mg/d) containing low or high concentrations of HYF for 14 days in addition to their regular regimen of CSA. After a 27-day washout phase, patients were crossed over to the other SJW treatment for 14 days. Blood concentrations of CSA were measured by immunoassay. RESULTS: The study showed a significant difference between the effects of the 2 SJW preparations on CSA pharmacokinetics (area under the plasma concentration-time curve within one dosing interval [AUC 0-12 ], P < .0001, ANOVA). AUC 0-12 values (monoclonal) with high-HYF SJW comedication were 45% lower (95% confidence interval [CI], -37% to -54%; P < .05, Student-Newman-Keuls test) than for low-HYF SJW. The dose-corrected AUC 0-12 for CSA (monoclonal) decreased significantly compared with baseline by 52% (95% CI, -46% to -56%; P < .05) after 2 weeks of comedication with high-HYF SJW. Values of peak concentration in plasma and drug concentration at the end of one dosing interval were affected to a similar extent, with reductions by 43% (95% CI, -36% to -48%) and 55% (95% CI, -48% to -60%), respectively. In addition, a 65% (95% CI, 53% to 85%; P < .05) increase in daily CSA doses was required during high-HYF SJW treatment. In contrast, coadministration of low-HYF SJW did not significantly affect CSA pharmacokinetics and did not require CSA dose adjustments compared with baseline. CONCLUSION: HYF content of SJW extracts significantly affects the extent of the pharmacokinetic interaction between CSA and SJW.

Effect of St John's wort dose and preparations on the pharmacokinetics of digoxin.

BACKGROUND AND OBJECTIVE: St John's wort preparations vary in composition, main constituents, formulation, and daily dose administered. The aim of the study was to evaluate the possible pharmacokinetic interaction of marketed St John's wort formulations and doses with digoxin. METHODS: A randomized, placebo-controlled, parallel-group study was performed in 96 healthy volunteers in 3 study parts. A 7-day loading phase with digoxin was followed by 14 days of comedication with placebo or one of 10 St John's wort products varying in dose and formulation. The pharmacokinetics of digoxin was determined before comedication and on day 14 of comedication. RESULTS: Comedication comprised traditionally used Hypericum products; 2 g powder without hyperforin, tea, juice, oil extract, and placebo had no significant interaction with digoxin nor did hyperforin-free extract (Ze 117) or low daily doses of hyperforin-containing Hypericum powder (1 g, 0.5 g). However, comedication with the high-dose hyperforin-rich extract LI 160 resulted in a reduction of digoxin area under the curve from time 0 to 24 hours (AUC(0-24)) of -24.8% (95% confidence interval [CI], -28.3 to -21.3), a reduction in digoxin maximal plasma concentration (C(max)) of -37% (95% CI, -42 to -32), and a reduction in digoxin plasma concentration at 24 hours after previous dosing (C(trough)) of -19% (95% CI, -27 to -11). Comedication with 4 g Hypericum powder with comparable hyperforin content resulted in a reduction in digoxin AUC(0-24) of -26.6% (95% CI, -37.3 to -15.9), a reduction in digoxin C(max) of -38% (95% CI, -48 to -18), and a reduction in digoxin C(trough) of -19% (95% CI, -27 to -10). Two grams of Hypericum powder with half the hyperforin content resulted in a less prominent reduction in AUC(0-24) of -17.7% (95% CI, -21.6 to -13.7), C(max) (-21%; 95% CI, -40 to -2), and C(trough) (-13%; 95% CI, -21 to -5). CONCLUSIONS: The interaction of St John's wort and digoxin varies within St John's wort preparations and doses and seems to be correlated with the dose, particularly of hyperforin.