Plant adaptogens increase lifespan and stress resistance in C. elegans.

Extracts of plant adaptogens such as Eleutherococcus senticosus (or Acanthopanax senticosus) and Rhodiola rosea can increase stress resistance in several model systems. We now show that both extracts also increase the mean lifespan of the nematode C. elegans in a dose-dependent way. In at least four independent experiments, 250 microg/ml Eleutherococcus (SHE-3) and 10-25 microg/ml Rhodiola (SHR-5) significantly increased life span between 10 and 20% (P < 0.001), increased the maximum lifespan with 2-3 days and postponed the moment when the first individuals in a population die, suggesting a modulation of the ageing process. With higher concentrations, less effect was observed, whereas at the highest concentrations tested (2500 microg/ml Eleutherococcus and 250 microg/ml Rhodiola) a lifespan shortening effect was observed of 15-25% (P < 0.001). Both adaptogen extracts were also able to increase stress resistance in C. elegans: against a relatively short heat shock (35 degrees C during 3 h) as well as chronic heat treatment at 26 degrees C. An increase against chronic oxidative stress conditions was observed in mev-1 mutants, and during exposure of the wild type nematode to paraquat (10 mM) or UV stress, be it less efficiently. Concerning the mode of action: both adaptogens induce translocation of the DAF-16 transcription factor from the cytoplasm into the nucleus, suggesting a reprogramming of transcriptional activities favoring the synthesis of proteins involved in stress resistance (such as the chaperone HSP-16) and longevity. Based on these observations, it is suggested that adaptogens are experienced as mild stressors at the lifespan-enhancing concentrations and thereby induce increased stress resistance and a longer lifespan.

The influence of adaptogens on ultraweak biophoton emission: a pilot-experiment.

In the present study, the effect of plant adaptogens (Rhodiola rosea and ADAPT-232) on human photon emission has been determined. In a randomized double blind placebo-controlled study, 30 subjects were randomly assigned to three groups: one group (n = 10) taking placebo pills, one group (n = 10) taking Rhodiola rosea (SHR-5) pills and one group (n = 10) taking ADAPT-232 supplements (the latter being a fixed combination of the following three adaptogens: Eleutherococcus senticosus, Rhodiola rosea and Schisandra chinensis). All subjects underwent measurements to determine ultra-weak photon emission (UPE) of the dorsal side of their hands using a photon-counting device, both before and after a week of taking the supplements. In addition, the experienced levels of stress and fatigue (tiredness) were evaluated. After 1 week of supplementation, the Rhodiola group showed a significant decrease (p = 0.027) in photon emission in comparison with the placebo group. Furthermore, after supplementation, a significant decrease (p = 0.049) concerning the experienced level of fatigue in the Rhodiola group was observed compared with the placebo group. No significant changes were observed between the ADAPT-232 and the placebo group.

Adhatoda vasica: a critical review of ethnopharmacological and toxicological data.

Adhatoda vasica (L.) Nees is a well-known plant drug in Ayurvedic and Unani medicine. It has been used for the treatment of various diseases and disorders, particularly for the respiratory tract ailments. During the last 20 years, several scientific reports on oxytocic and abortifacient effects of vasicine and alkaloid derived from the plant have appeared. This leads to questions concerning the safety of A. vasica as a herbal medicine. In this article, the major data on traditional uses as well as ethnopharmacological and toxicological studies, both published and unpublished, are reviewed and commented upon. The data have been evaluated from the point of view of correctness, reliability, relevance and importance for the overall evaluation of the safety of A. vasica.

Testicular toxicity assessment of Andrographis paniculata dried extract in rats.

The possible testicular toxicity of Andrographis paniculata, Nees (Acanthaceae) standardized dried extract was evaluated in male Sprague Dawley rats for 60 days. No testicular toxicity was found with the treatment of 20, 200 and 1000 mg/kg during 60 days as evaluated by reproductive organ weight, testicular histology, ultrastructural analysis of Leydig cells and testosterone levels after 60 days of treatment. It is concluded that Andrographis paniculata dried extract did not produce subchronic testicular toxicity effect in male rats.

Rosenroot (Rhodiola rosea): traditional use, chemical composition, pharmacology and clinical efficacy.

The aim of this review article was to summarize accumulated information related to chemical composition, pharmacological activity, traditional and official use of Rhodiola rosea L. in medicine. In total approximately 140 compounds were isolated from roots and rhizome - monoterpene alcohols and their glycosides, cyanogenic glycosides, aryl glycosides, phenylethanoids, phenylpropanoids and their glycosides, flavonoids, flavonlignans, proanthocyanidins and gallic acid derivatives. Studies on isolated organs, tissues, cells and enzymes have revealed that Rhodiola preparations exhibit adaptogenic effect including, neuroprotective, cardioprotectiv e, anti-fatigue, antidepressive, anxiolytic, nootropic, life-span increasing effects and CNS stimulating activity. A number of clinical trials demonstrate that repeated administration of R. rosea extract SHR-5 exerts an anti-fatigue effect that increases mental performance (particularly the ability to concentrate in healthy subjects), and reduces burnout in patients with fatigue syndrome. Encouraging results exist for the use of Rhodiola in mild to moderate depression, and generalized anxiety. Several mechanisms of action possibly contributing to the clinical effect have been identified for Rhodiola extracts. They include interactions with HPA-system (cortisol-reducing), protein kinases p-JNK, nitric oxide, and defense mechanism proteins (e.g. heat shock proteins Hsp 70 and FoxO/DAF-16). Lack of interaction with other drugs and adverse effects in the course of clinical trials make it potentially attractive for use as a safe medication. In conclusion, Rhodiola rosea has robust traditional and pharmacological evidence of use in fatigue, and emerging evidence supporting cognition and mood.

Double-blind, placebo-controlled, randomised study of single dose effects of ADAPT-232 on cognitive functions.

The aim of this study was to assess the effect of a single dose of ADAPT-232 (a standardised fixed combination of Rhodiola rosea L., Schisandra chinensis (Turcz.) Baill., and Eleutherococcus senticosus Maxim) extracts on mental performance, such as attention, speed and accuracy, in tired individuals performing stressful cognitive tasks. The pilot study (phase IIa) clinical trial took the form of a double-blind, placebo-controlled, randomised, with two parallel groups. Forty healthy females aged between 20-68 years, who claimed to have felt stressed over a long period of time due to living under psychologically stressful conditions were selected to participate in the pilot study. In addition, a Stroop Colour-Word test (Stroop CW) was used to exhaust/prepare the volunteers prior to the d2 test used for assessment of cognitive function of patients. The participants were randomised into two groups, one (n=20) of which received a single tablet of ADAPT-232 (270mg), while a second (n=20) received a single tablet of placebo. The effects of the extract were measured prior to treatment and two hours after treatment using the d2 Test of Attention (d2). The results of the d2 test showed a significant difference (p<0.05) in attention, speed, and accuracy (TN-E scores) between the two treatment groups. The subjects in the ADAPT-232 group quickly (two hours after verum was taken) gained improved attention and increased speed and accuracy during stressful cognitive tasks, in comparison to placebo. There was also a tendency of ADAPT-232 to reduce percentage of errors, which means better accuracy, quality of the work, and degree of care in the volunteers under stressful conditions. No serious side effects were reported, although a few minor adverse events, such as sleepiness and cold extremities, were observed in both treatment groups.

Comparative study of Rhodiola preparations on behavioral despair of rats.

The antidepressant-like activity of an extract of the roots of Rhodiola rosea (RR), its combination with piperine containing extract (RPE), pure substances isolated from Rhodiola, such as rhodioloside, rosavin, rosin, rosarin, tyrosol, cinnamic alcohol, cinnamaldehyde and cinnamic acid has been assessed in laboratory animals through application of the Porsolt behavioural despair assay. RR increased the swimming time of rats in a dose dependent manner (ED50=7 mg/kg) and, when administered at 20mg/kg, exhibited a stronger anti-depressant type effect than either imipramine (at 30 mg/kg) or an extract of Hypericum perforatum (at 20mg/kg). Rhodioloside, and tyrosol were identified as active principles of the extract, whereas rosavin, rosarin, rosin, cinnamic alcohol, cinnamaldehyde, cinnamic acid were inactive. A fixed combination of rhodioloside, rosavin, rosarin and rosin was more active than any of the individual components alone, indicating a synergistic effect of the ingredients in RR extract. Piperine in combination with Rhodiola (RPE) distorts pharmacological effect of Rhodiola most probably due to changes of pharmacokinetic profile of rhodioloside and rosavin. RPE cannot provide predictable therapeutic effect due to herb-herb interaction. Moreover, concomitant treatment of RPE with other drugs should also be excluded due to drug-piperine interaction.

Impact of Chisan (ADAPT-232) on the quality-of-life and its efficacy as an adjuvant in the treatment of acute non-specific pneumonia.

A double-blind, placebo-controlled, randomized (simple randomisation), pilot (phase III) study of Chisan, (ADAPT-232; a standardised fixed combination of extracts of Rhodiola rosea L., Schisandra chinensis Turcz. Baill., and Eleutherococcus senticosus Maxim) was carried out on two parallel groups of patients suffering from acute nonspecific pneumonia. Sixty patients (males and females; 18-65 years old) received a standard treatment with cephazoline, bromhexine, and theophylline: in addition, one group of 30 patients was given Chisan mixture, whilst the second group of 30 patients received a placebo, each medication being taken twice daily from the beginning of the study for 10-15 days. The primary outcome measurements were the duration of antibiotic therapy associated with the clinical manifestations of the acute phase of the disease, together with an evaluation of mental performance in a psychometric test and the self-evaluation of quality-of-life (QOL) (WHOQOL-Bref questionnaires) before treatment and on the first and fifth days after clinical convalescence. The mean duration of treatment with antibiotics required to bring about recovery from the acute phase of the disease was 2 days shorter in patients treated with Chisan compared with those in the placebo group. With respect to all QOL domains (physical, psychological, social and ecological), patients in the Chisan group scored higher at the beginning of the rehabilitation period, and significantly higher on the fifth day after clinical convalescence, than patients in the control group. Clearly, adjuvant therapy with ADAPT-232 has a positive effect on the recovery of patients by decreasing the duration of the acute phase of the illness, by increasing mental performance of patients in the rehabilitation period, and by improving their QOL. Both the clinical and laboratory results of the present study suggest that Chisan (ADAPT-232) can be recommended in the standard treatment of patients with acute non-specific pneumonia as an adjuvant to increase the QOL and to expedite the recovery of patients.

Randomized trial of a fixed combination (KanJang) of herbal extracts containing Adhatoda vasica, Echinacea purpurea and Eleutherococcus senticosus in patients with upper respiratory tract infections.

The clinical efficacy of KanJang oral solution, a fixed combination of standardised extracts of Echinacea purpurea, Adhatoda vasica and Eleutherococcus senticosus, was compared with the combined extracts of Echinacea purpurea and Eleutherococcus senticosus alone (Echinacea mixture) in a controlled, double blind, randomized trial, and with Bromhexine (a standard treatment) in a controlled, open, randomized clinical trial on patients with non-complicated acute respiratory tract infections. Many of the parameters evaluated, such as severity of coughing, frequency of coughing, efficacy of mucus discharge in the respiratory tract, nasal congestion and a general feeling of sickness, showed significantly greater improvement in patients treated with KanJang compared with those receiving the standard treatment. However, no significant differences in the improvement of these symptoms (except in a reduced frequency of coughing) were observed between patients treated with the Echinacea mixture and those receiving the standard treatment. The only explanation is that the lack of extract of A. vasica in the Echinacea mixture reduces its efficacy compared with the complete KanJang oral solution even though direct double-blind comparison yielded no significant differences between these two groups of patients. The recovery time of patients being treated with KanJang or Echinacea mixture was 2 days shorter than that of patients receiving the standard treatment. None of the patients completing the study reported adverse reactions to the medication taken. The significance of the results obtained in this study is discussed with respect to the efficacy of KanJang in the treatment of acute respiratory infection and to the concept that multi-drug therapy offers higher efficacy compared with mono-drug treatment of such infections.

A phase I clinical study of Andrographis paniculata fixed combination Kan Jang versus ginseng and valerian on the semen quality of healthy male subjects.

The safety of different doses of Kan Jang--a fixed combination of Andrographis paniculata special extract (SHA-10) and Acanthopanax senticosus--compared to two extensively used medicinal plants, Valeriana officinalis and Panax ginseng in the form of standardized extracts, has been examined. A phase I clinical study was designed to evaluate the effect on semen quality of healthy males in terms of spermatogenesis and quality of semen. The results of the study revealed no significant negative effect of Kan Jang on male semen quality and fertility, but rather a positive trend with respect to the number of spermatozoids in the whole ejaculate, the percentage of active (normokinetic) forms of spermatozoids, and fertility indexes, together with a decrease in the percentage of inactive (diskinetic) forms of spermatozoids. In the group receiving ginseng, no significant negative effects on the fertility parameters were revealed and there was a clear decrease in the percentage of diskinetic forms of spermatozoids. Subjects receiving valerian showed a temporary increase in the percentage of normokinetic spermatozoids and a decrease in diskinetic forms, but these changes had no effect on fertility indices. The results indicate that Kan Jang, ginseng and valerian are safe with respect to effects on human male sterility when administered at dose levels corresponding to approximately 3 times the human daily dose.

Plant adaptogens. III. Earlier and more recent aspects and concepts on their mode of action.

Stimulus-response coupling systems responsible for defence and adaptation of organism to stressors are multi-target and very complicated pharmacological systems, including the neuroendocrine (stress) and immune system. The mode of action of adaptogens is basically associated with the stress-system (neuroendocrine-immune complex) and can be directed on the various targets of the system involved in regulation (activation and inhibition) of stimulus-response coupling. However, clinical studies performed according to the most modern standards are quite limited. On the other hand there is an extensive amount of clinical experience and also established use in self care etc. These aspects are planned to be dealt within a subsequent article which will be devoted to the application in three areas: self care, adjuvants in medicine and curative action in some diseases. At this stage, nevertheless, it seems possible to define some most important "stress-markers" for evaluation of efficiency of adaptogens in experimental and clinical pharmacological studies. They can be both activating (catecholamines, LT-s, cytokines, NO, etc.--"switch on" system--which activates energetic and other resources of the organism), and deactivating (corticosteroids and PGE2-endogenous mediators of cellular communications, which protect cells and whole organism from overreacting to the activating messengers--"switch off" system) stress-messengers. The balance between the activities of the "switch on" and "switch off" systems reflects the well being of the organism. It could be established on different levels of the homeostasis (heterostasis) with different levels of the sensitivity to stressors (Figure 8). The response of stress system--"reactivity" is different at the various levels of heterostasis and depends on adaptation--capacity of the organism (or a cell) to protect itself. In the process of adaptation to stressor's effects the basal levels mediators of switch on (e.g. NO) and switch of (e.g. cortisol) systems are increasing but their balance (the ratio) does not change. In other words, adaptogens increase the capacity of stress system to respond to external signals at the higher level of the equilibrium of activating and deactivating mediators of stress response. Consequently, plant adaptogens can be defined as "smooth" pro-stressors which reduce reactivity of host defense systems and decrease damaging effects of various stressors due to increased basal level of mediators involved in the stress-response. In further studies of adaptogens it seems important to find correlation between adaptogenic activity (a decrease in the "reactivity" of the organism--the basal level of activating and deactivating messengers: ILs, LTB4, NO, PGE2, cortisol, but not their ratio) and their therapeutic efficiency (symptomatic evaluation).

Controlled clinical study of standardized Andrographis paniculata extract in common cold - a pilot trial.

Kanjang(®) tablets (standardized Andrographis paniculata extract) have proven effective in the initial treatment of commond cold and sinusitis. Kanjang(®) tablets is a herbal formula, which has been developed by the Swedish Herbal Institute in Gothenburg. The tablets have shown a beneficial effect with regards to the subjective experience of initial symptoms of common cold and uncomplicated sinusitis, as well as to the duration of the symptoms. The preparation has been used in the Nordic countries for more than 12 years, mainly for reducing symptoms of common cold and sinusitis, and shortening the duration of the symptoms. In this controlled, double-blind study performed as a pilot trial at the Health Center, Hallehälsan, during the autumn of 1992, conducted in 50 patients, both subjective symptoms as well as duration of the symptoms were significantly reduced. From the results evaluated it is quite clear that Kanjang(®) tablets decrease the subjective symptoms of common cold as well as shortening of the period of sick leave significantly.

Methods of phytochemical standardisation of rhizoma Cimicifugae racemosae.

The methanolic extract of roots of Cimicifuga racemosa and its methanolysis products have been analysed by GC-MS. 2-Hexylcyclopropaneoctanoic acid (9,10-methylenehexadecanoic acid) was found to be the marker most specific for the identification for this herb. For the phytochemical standardisation of Rhizoma Cimicifugae racemosae, validated methods for the quantitative analysis of formononetin (by TLC-fluorometry), of isoferulic acid (by GC-MS of the methyl ester), and of total triterpene glycosides (transformed to coloured complexes and measured photometrically) in roots of C. racemosa have been developed. The contents of formononetin, isoferulic acid and total triterpene glycosides (measured as actein) in the herb ranged from 0.0031 to 0.0035, from 1.22 to 1.35 and from 20.09 to 22.06 mg/g dry weight, respectively.

Inhibitory effect of andrographolide from Andrographis paniculata on PAF-induced platelet aggregation.

Andrographolide, an active principle of the Chinese drug Andrographis paniculata, used for prevention and treatment of common cold in Scandinavia and known as an antiinflammatory, antiviral, antithrombotic, hypotensive and antiatherosclerotic drug, was investigated for its suggested influence on the biosynthesis of eicosanoids and the platelet-activating factor (PAF). Whereas in isolated human polymorph-nuclear leukocytes (PMNL) no influence on the biosynthesis was found, it could be shown that andrographolide inhibits PAF-induced human blood platelet aggregation in a dose dependent manner (IC50-5 microM). These results indicate that andrographolide has a mechanism of action different from that of non-steroidal antiinflammatory drugs (NSAID) and most likely associated with the cardiovascular and antithrombotic activity described of Andrographis paniculata.

Effect of andrographolide and Kan Jang--fixed combination of extract SHA-10 and extract SHE-3--on proliferation of human lymphocytes, production of cytokines and immune activation markers in the whole blood cells culture.

The immunomodulatory properties of a diterpene lactone andrographolide and Kan Jang--a standardized fixed combination of Andrographis paniculata extract SHA-10 and Eleutherococcus senticosus extract SHE-3 were investigated. Their role on spontaneous and phytohemagglutinin (PHA)-induced proliferation of human peripheral blood lymphocytes (PBL) and on production of interferon-gamma (INF-gamma) and tumor necrosis factor-alpha (TNF-alpha) were determined in vitro. Proliferation of PBL induced by PHA was enhanced by co stimulation with andrographolide and Kan Jang. At the same time andrographolide and Kan Jang inhibit spontaneous proliferation of PBL in vitro. These preparations also have effect on the formation of INF-gamma, TNF-alpha and some immune activation markers such as neopterin (Neo), beta-2-microglobulin (beta2MG), and soluble receptor for interleukin-2 (sIL-2R or sCD25) in blood cells culture. Andrographolide and Kan Jang stimulate the INF-gamma, Neopterin and beta2MG formation, but do not have any significant effect on the production of INF-gamma and Neopterin in PHA stimulated blood cells. An opposite effect on these immune makers was observed in the PHA-stimulated blood cells: both andrographolide and Kan Jang increase the formation of TNF-alpha and beta2MG in cultivated whole blood cells. Thus, andrographolide and Kan Jang can have an in vitro effect on the activation and proliferation of immunocompetent cells as well on the production of key cytokines and immune activation markers. The results show an overall higher effect of the fixed combination as compared with the equivalent amount of the pure substance andrographolide. The data are consistent with results from clinical studies of Kan Jang and contributed to a better understanding of these results.

Reduction of serum hepatic transaminases and CPK in sport horses with poor performance treated with a standardized Schizandra chinensis fruit extract.

Sport horses with long lasting high levels of gamma Glutamiltransferase (gGT) and Glutamic Oxalacetic Transaminase (GOT) and Creatinine Phosphokinase (CPK) and poor performance were administered during 14 days 3 g of Caval D'Or®, a standardized dried extract of Schizandra chinensis (fructus) orally. At day "0" the horses were divided into two groups: group 1 received a placebo and group 2 received Caval D'Or®. The results showed that Caval D'Or® is able to reduce significantly the levels of gGT and GOT in the serum at day 7 and 14 after administration. The CPK levels were also reduced by day 7 and 14 after administration of Caval D'Or®. It is concluded that Caval D'Or® facilates the recovery of sport horses in training with poor performance that show high levels of transaminases and CPK.

Comparative controlled study of Andrographis paniculata fixed combination, Kan Jang and an Echinacea preparation as adjuvant, in the treatment of uncomplicated respiratory disease in children.

A three-arm study comparing the efficacy of Kan Jang, a fixed herbal combination containing standardized Andrographis paniculata (N.) SHA-10 extract, with Immunal, a preparation containing Echinacea purpurea (L.) extract, in uncomplicated common colds was carried out in 130 children aged between 4 and 11 years over a period of 10 days. The study was designed as an adjuvant treatment of Kan Jang and Immunal with a standard treatment. The patients were assigned to one of the three groups. In control group C; 39 patients received only standard treatment. Kan Jang and Immunal were used as an adjuvant to this therapy in the other two groups. Adjuvant group A; 53 patients treated with Kan Jang tablets concomitant to standard treatment, and adjuvant control group B; 41 patients treated with concomitant Immunal. It was found that the adjuvant treatment with Kan Jang, was significantly more effective than Immunal, when started at an early stage of uncomplicated common colds. The symptoms of the disease were less severe in the Kan Jang group. The effect of Kan Jang was particularly pronounced in two objective parameters, amount of nasal secretion g/day and nasal congestion. Kan Jang also accelerated the recovery time, whereas Immunal did not show the same efficacy. The use of standard medication was significantly less in the Kan Jang adjuvant group than in either the Immunal or standard treatment group. Kan Jang treatment was well tolerated and no side effects or adverse reactions were reported.

A randomized, controlled study of Kan Jang versus amantadine in the treatment of influenza in Volgograd.

Two randomized, parallel-group clinical studies with a verum and a control group were performed to investigate the effect of a standardized extract (SHA-10) of Andrographis panaiculata (N.) fixed combination Kan Jang in the treatment of diagnosed influenza viral infection. The pilot study was performed on 540 patients with 71 Kan Jang-treated patients with the second phase conducted enrolling 66 patients. The differences in the duration of sick leave and frequency of post-influenza complications indicate that the Kan Jang phytopreparation not only contributes to quicker recovery, but also reduces the risk of post-influenza complications. Kan Jang was well tolerated by patients.