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Pharmacokinetics of active constituents of Rhodiola rosea SHR-5 extract
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The active constituents of Rhodola rosea extract SHR-S of the popular plant adaptogen Rhodiola. rosea are tyrosol, rhodioloside and rosavin. Validated capillary electrophoretic methods for the determination of these components in the blood was developed and used for a pharmacokinetic study in rats and human (n=16) volunteers. Rhodioloside was found to be quickly and completely absorbed into the blood of rats (bioauailability-75-90Eo), distributed within org&ns and tissues, and rapidly metabolised to tyrosol
following oral administration of SHR-5 at doses of 20 and 50 mg /hg. Many of the measured pharmacokinetic parameters of rhodioloside were significantly different when the pure compound was administered rather
than the extract. The basal leuel of tyrosol in blood plasma of rats increased following administration of SHR-S as a result both of absorption of free tyrosol present in the extract and of biotransformation of rhodioloside into
tyrosol, which occurred within the first 2 h. The pharmacohinetics and the rate of biotransformation of rhodioloside were essentially the same following single or multiple regimes of administration of SHR-S. Rosauin has low bioavailability (20-267oa) nd was quickly eliminated from the blood of rats that haue been administered SHR-5. The results of the study in humans showed that 16 healthy volunteers, after oral administration of two tablets of Rosenroot, reached a maximum concentration of rhodioloside and rosavin in blood plasma after 2 h, where the absorption rate constant was equal in both components. Although, in contrast to rhodioloside, rosavin was not detected in blood plasma at 0.5 h and t h after oral administration of two tablets of Rosenroot. The maximum concentration and elimination half-life of rhodioloside was 2-3 x higher than in rosavin. The AUC, -C *,and AUC-, values of rhodioloside were 3.5, 2.2 and 3.I-fold higher than in rosavin. Thus, the elimination of rhodioloside from the blood was 1.8 fold longer than the elimination time of rosavin.
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... 592 The pharmacokinetics of three active compounds (tyrosol, rhodioloside, and rosavin) of R. rosea extracts were studied in rodents 597-603 and healthy volunteers. 597 Salidroside was quickly absorbed into the blood of rats (t max = 1 h; bioavailability: 75%-90%) and metabolized to tyrosol within 2 h after oral administration of the R. rosea extract. The concentration of tyrosol attained its maximum value within 1.5-2.0 ...
... During this time period, the concentration of salidroside in human blood was about 587 ng/ml after 1 h and 483 ng/ml after 4 h. 597 It was found that after intravenous administration, salidroside was extensively metabolized to tyrosol and then distributed to various organs and cleared rapidly. The highest levels of p-tyrosol were detected in the heart, followed by the spleen, kidney, liver, and lungs. ...
... The highest levels of p-tyrosol were detected in the heart, followed by the spleen, kidney, liver, and lungs. 603 It should be noted that many of the measured pharmacokinetic parameters of purified salidroside were significantly different when the pure compound was administered (C max , Vdis, AUC, t-1/2, and higher t max and CI) rather than the total plant extract, 597 indicating an interaction with the other constituents of the plant extract. ...
Adaptogens comprise a category of herbal medicinal and nutritional products promoting adaptability, resilience, and survival of living organisms in stress. The aim of this review was to summarize the growing knowledge about common adaptogenic plants used in various traditional medical systems (TMS) and conventional medicine and to provide a modern rationale for their use in the treatment of stress-induced and aging-related disorders. Adapto-gens have pharmacologically pleiotropic effects on the neuroendocrine-immune system, which explain their traditional use for the treatment of a wide range of conditions. They exhibit a biphasic dose-effect response: at low doses they function as mild stress-mimetics, which activate the adaptive stress-response signaling pathways to cope with severe stress. That is in line with their traditional use for preventing premature aging and to maintain good health and vitality. However, the potential Med Res Rev. 2020;1-74. wileyonlinelibrary.com/journal/med | 1 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Background: The anti-influenza A virus activities and contents of previously isolated most active flavonoids (rhodiosin and tricin) from a standardized hydro-ethanolic R. rosea root and rhizome extract (SHR-5®), did not fully explain the efficacy of SHR-5®. Moreover, the mode of antiviral action of SHR-5® is unknown.
Purpose: To determine the anti-influenza viral principle of SHR-5® we evaluated i) the combined anti-influenza virus effect of rhodiosin and tricin, ii) the impact of its tannin-enriched fraction (TE), iii) its antiviral spectrum and mode of action, and iv) its propensity for resistance development in vitro.
Methods: The combined anti-influenza virus effect of rhodiosin and tricin and the impact of TE were investigated with cytopathic effect (CPE)-inhibition assays in MDCK cells. A tannin-depleted fraction (TD) and TE were prepared by polyamide column chromatography and dereplicated by LC-MS. Plaque-reduction assays provided insights into the anti-influenza virus profile, the mode of action, and the propensity for resistance development of SHR-5®.
Results: Our results i) did not reveal synergistic anti-influenza A virus effects of rhodiosin and tricin, but ii) proved a strong impact of TE mainly composed of prodelphinidin gallate oligomers. iii) TE inhibited the plaque-production of influenza virus A(H1N1)pdm09, A(H3N2), and B (Victoria and Yamagata) isolates (including isolates resistant to neuraminidase and/or M2 ion channel inhibitors) with 50% inhibitory concentration values between 0.12 - 0.53 µg/ml similar to SHR-5®. Mechanistic studies proved a virucidal activity, inhibition of viral adsorption, viral neuraminidase activity, and virus spread by SHR-5® and TE. iv) No resistance development was observed in vitro.
Conclusion: For the first time a comprehensive analysis of the anti-influenza virus profile of a hydro-ethanolic R. rosea extract (SHR-5®) was assessed in vitro. The results demonstrating broad-spectrum multiple direct anti-influenza virus activities, and a lack of resistance development to SHR-5® together with its known augmentation of host defense, support its potential role as an adaptogen against influenza virus infection.
The purpose of the present study was to examine the acute effects of an herbal supplement containing a 70:30 blend of Rhaponticum carthamoides extract and Rhodiola rosea extract, respectively, on performance fatigability and the affective responses prior to and following exercise. Thirty men (age = 22.3 ± 4.1 years) volunteered for this randomized, placebo-controlled, double-blind, cross-over study. Following familiarization, participants visited the laboratory on three separate occasions where they consumed one 350 mg dose, a 175 mg dose of the supplement plus 175 mg of maltodextrin, or a placebo. Participants completed feeling, arousal, and mood surveys at supplement ingestion and following testing. Ninety minutes following ingestion, participants performed five sets of 30 maximal, concentric, leg extension muscle actions at 180°/sec, with one minute of rest between sets. Peak torque, average torque, and total work were calculated for each set, and the rating of perceived exertion (RPE) was assessed after each set. Data were analyzed with a repeated measures analysis of variance and intent-to-treat approach. For the performance variables, there was no interaction (p ≥ 0.317) or treatment effect (p ≥ 0.660), however, all torque variables decreased across sets and plateaued at sets 4-5, whereas RPE increased across sets (p < 0.001). For the affective responses, there was no interaction (p ≥ 0.781) or treatment effect (p ≥ 0.314); however, participants felt better, had an improved mood, and felt more aroused following testing (p < 0.047). This combination of herbal extracts likely does not acutely influence performance fatigability during high-intensity, repeated muscle actions.
Golden root (Rhodiola rosea L., Crassulaceae) is a famous medical plant with a one-sided history of scientific interest in the roots and rhizomes as sources of bioactive compounds, unlike the herb, which has not been studied extensively. To address this deficiency, we used high-performance liquid chromatography with diode array and electrospray triple quadrupole mass detection for comparative qualitative and quantitative analysis of the metabolic profiles of Rhodiola rosea organs before and after gastrointestinal digestion in simulated conditions together with various biochemical assays to determine antioxidant properties of the extracts and selected compounds. R. rosea organs showed 146 compounds, including galloyl O-glucosides, catechins, procyanidins, simple phenolics, phenethyl alcohol derivatives, (hydroxy)cinnamates, hydroxynitrile glucosides, monoterpene O-glucosides, and flavonol O-glycosides, most of them for the first time in the species. The organ-specific distribution of compounds found for catechins, procyanidins, and cinnamyl alcohols and glucosides was typical for underground organs and flavonoids and galloylated glucoses concentrated in the herb. Extracts from rhizomes, leaves and flowers showed high phenolic content and were effective scavengers of free radicals (2,2-diphenyl-1-picrylhydrazyl (DPPH•), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS•+), O2•−, •OH) and protected β-carotene in a bleaching assay. Digestion in the gastric and intestine phase influenced the composition of R. rosea extracts negatively, affecting the content of catechins, procyanidins, and galloyl glucoses, and therefore, the antioxidativity level. After gut microbiota treatment, the antioxidant capacity of rhizome extract was lower than leaves and flowers due to the aglycone composition found in the colonic phase of digestion. Our study demonstrated that the herb of R. rosea is a rich source of metabolites with high antioxidant properties and could be a valuable plant for new bioactive products.
Adaptogens possess anti-fatigue and anti-stress activities that can increase mental and physical working performance against a background of fatigue or stress. The aim of the present study was to ascertain which mediators of stress response are significantly involved in the mechanisms of action of adaptogens, and to determine their relevance as biochemical markers for evaluating anti-stress effects in rabbits subjected to restraint stress. Blood levels of stress-activated protein kinase (SAPK/JNK), the phosphorylated kinase p-SAPK/p-JNK, nitric oxide (NO), cortisol, testosterone, prostaglandin E(2), leukotriene B(4) and thromboxane B(2) were determined in groups of animals prior to daily oral administration of placebo, rhodioloside or extracts of Eleutherococcus senticosus, Schizandra chinensis, Rhodiola rosea, Bryonia alba and Panax ginseng over a 7 day period. Ten minutes after the final treatment, animals were immobilized for 2 hours and blood levels of the markers re-determined. In the placebo group, only p-SAPK/p-JNK, NO and cortisol were increased significantly (by 200-300% cf basal levels) following restraint stress, whilst in animals that had received multiple doses of adaptogens/stress-protectors, the levels of NO and cortisol remained practically unchanged after acute stress. Rhodioloside and extracts of S. chinensis and R. rosea were the most active inhibitors of stress-induced p-SAPK/p-JNK. E. senticosus, B. alba and P. ginseng exerted little effect on p-SAPK/p-JNK levels. It is suggested that the inhibitory effects of R. rosea and S. chinensis on p-SAPK/p-JNK activation may be associated with their antidepressant activity as well as their positive effects on mental performance under stress.
The objective of this study was to assess the efficacy and safety of standardized extract SHR-5 of rhizomes of Rhodiola rosea L. in patients suffering from a current episode of mild/moderate depression. The phase III clinical trial was carried out as a randomized double-blind placebo-controlled study with parallel groups over 6 weeks. Participants, males and females aged 18-70 years, were selected according to DSM-IV diagnostic criteria for depression, the severity of which was determined by scores gained in Beck Depression Inventory and Hamilton Rating Scale for Depression (HAMD) questionnaires. Patients with initial HAMD scores between 21 and 31 were randomized into three groups, one of which (group A: 31 patients) received two tablets daily of SHR-5 (340 mg/day), a second (group B: 29 patients) received two tablets twice per day of SHR-5 (680 mg/day), and a third (group C: 29 patients) received two placebo tablets daily. The efficacy of SHR-5 extract with respect to depressive complaints was assessed on days 0 and 42 of the study period from total and specific subgroup HAMD scores. For individuals in groups A and B, overall depression, together with insomnia, emotional instability and somatization, but not self-esteem, improved significantly following medication, whilst the placebo group did not show such improvements. No serious side-effects were reported in any of the groups A-C. It is concluded that the standardized extract SHR-5 shows anti-depressive potency in patients with mild to moderate depression when administered in dosages of either 340 or 680 mg/day over a 6-week period.
A reversed-phase high performance liquid chromatographic method was developed to determine salidroside and tyrosol simultaneously in the Rhodiola rosea. The optimum condition was Nova-Pak C18 as stationary phase, 6.5% methanol in water as mobile phase and detection at UV 225 nm. The identification was carried out by comparing the retention time and IC/MS spectrum of the relevant peaks with those of isolated standards. The contents of salidroside and tyrosol in the samples gathered from various area in China were ranged over 1.3-11.1 mg/g and 0.3-2.2 mg/g, respectively.
The aim of this study was to investigate the effect of repeated low-dose treatment with a standardized extract SHR/5 of rhizome Rhodiola rosea L, (RRE) on fatigue during night duty among a group of 56 young, healthy physicians. The effect was measured as total mental performance calculated as Fatigue Index. The tests chosen reflect an overall level of mental fatigue, involving complex perceptive and cognitive cerebral functions, such as associative thinking, short-term memory, calculation and ability of concentration, and speed of audio-visual perception. These parameters were tested before and after night duty during three periods of two weeks each: a) a test period of one RRE/placebo tablet daily, b) a washout period and c) a third period of one placebo/RRE tablet daily, in a double-blind cross-over trial. The perceptive and cognitive cerebral functions mentioned above were investigated using 5 different tests. A statistically significant improvement in these tests was observed in the treatment group (RRE) during the first two weeks period. No side-effects were reported for either treatment noted. These results suggest that RRE can reduce general fatigue under certain stressful conditions.
Recent in vitro studies have demonstrated antioxidant properties of some virgin olive oil phenolic compounds. One of the prerequisites to extrapolate these data to an in vivo situation is the knowledge of their bioavailability in humans. In the present work we describe an analytical method which enables us to perform hydroxytyrosol and tyrosol quantitative determinations in human urine. This method was successfully used in bioavailability studies of both phenolic compounds after acute olive oil administration. Virgin olive oil was administered to healthy volunteers after a low phenolic diet. The dose administered of both phenolic compounds was estimated in reference to free forms of hydroxytyrosol and tyrosol present in virgin olive oil extracts before and after being submitted to hydrolytic conditions. These conditions mimic those occurring during digestion. Urine samples were collected before and after acute olive oil intake and analyzed by capillary gas chromatography-mass spectrometry. Hydroxytyrosol and tyrosol urinary recovery increased in response to olive oil administration, obtaining maximal values in the first 4 h. Our results further indicate that hydroxytyrosol and tyrosol are mainly excreted in conjugated form, since only 5.9 +/- 1.4% (hydroxytyrosol) and 13.8 +/- 5.4% (tyrosol) of the total amounts excreted in urine were in free form.
A randomized, double-blind, placebo-controlled, parallel-group clinical study with an extra non-treatment group was performed to measure the effect of a single dose of standardized SHR-5 Rhodiola rosea extract on capacity for mental work against a background of fatigue and stress. An additional objective was to investigate a possible difference between two doses, one dose being chosen as the standard mean dose in accordance with well-established medicinal use as a psychostimulant/adaptogen, the other dose being 50% higher. Some physiological parameters, e.g. pulse rate, systolic and diastolic blood pressure, were also measured. The study was carried out on a highly uniform population comprising 161 cadets aged from 19 to 21 years. All groups were found to have very similar initial data, with no significant difference with regard to any parameter. The study showed a pronounced antifatigue effect reflected in an antifatigue index defined as a ratio called AFI. The verum groups had AFI mean values of 1.0385 and 1.0195, 2 and 3 capsules respectively, whilst the figure for the placebo group was 0.9046. This was statistically highly significant (p < 0.001) for both doses (verum groups), whilst no significant difference between the two dosage groups was observed. There was a possible trend in favour of the lower dose in the psychometric tests. No such trend was found in the physiological tests.