Comparison of biomarker and chromatographic analytical approaches to pharmacokinetic study of sitagliptin.

The pharmacokinetic profiling of active compounds is necessary for drug development and application. Approaches to a pharmacokinetic study based on biological markers are alternatives to traditional approaches based on chromatographic methods. The aim of the study was to compare two analytical approaches to pharmacokinetics investigation for an example of sitagliptin in rabbits after one dose oral administration. The method for sitagliptin quantification in rabbit plasma samples based on a correlation between its concentration and dipeptidyl peptidase IV activity was proposed, validated, and applied. The high-performance liquid chromatography (HPLC)-ultraviolet (UV) method was also validated and applied for the same sample analysis. The plasma pharmacokinetics of sitagliptin after oral administration to the rabbits in one dose was characterized after two analytical assays. The close values of the main pharmacokinetic parameters were obtained after two approaches. The nontraditional approach based on correlation of special marker activity and active substance concentration appears to be more sensitive than HPLC-UV. Thus, the sitagliptin concentrations determined by biomarker assay were higher than the lower limit of quantification (LLOQ) for a longer period (more timepoints) than after the HPLC-UV assay. This feature may influence the values of some calculated concentration-dependent (area under the curve [AUC]0-t , etc.) and time-dependent parameters (mean residence time [MRT], T1/2 , etc.). The values of Tmax obtained by the two approaches were similar and adequate for oral drug administration that confirms the correctness of biomarker selection for pharmacokinetics assessment. The obtained results on the example of sitagliptin confirms that the biomarker approach is adequate and applicable for a pharmacokinetics study. Similar approaches may be effective for individual compounds and complex mixtures when it is difficult or impossible to analyze them traditionally by chromatographic methods.

Pharmacokinetic Study of Bioactive Glycopeptide from Strongylocentrotus droebachiensis After Intranasal Administration to Rats Using Biomarker Approach.

A glycopeptide fraction (GPF) from internal organs of green sea urchins (Strongylocentrotus droebachiensis Müller, Strongylocentrotidae) has been reported to be an effective bronchitis treatment. In this study, we evaluated the pharmacokinetic and tissue distribution of GPF, following single and repeated intranasal (i/n) administration over the course of seven days in rats. The method measuring lactate dehydrogenase as biomarker was used to analyse the plasma and tissue concentrations of GPF. GPF appears in the plasma 15 min after single i/n administration (100 µg/kg) and reaches its maximum at 45 min. The area under the curve (AUC)0-24 and Cmax were similar using both i/n and intravenous administration, while mean residence time (MRT) and T1/2 after i/n administration were significantly higher compared with intravenous (i/v) administration. The absolute bioavailability of GPF after i/n administration was 89%. The values of tissue availability (ft) provided evidence about the highest concentration of GPF in the nose mucosa (ft = 34.9), followed by spleen (ft = 4.1), adrenal glands (ft = 3.8), striated muscle (ft = 1.8), kidneys (ft = 0.5), and liver (ft = 0.3). After repeated dose administration, GPF exhibited significantly higher AUC0-24 and MRT, indicating its accumulation in the plasma.

Pharmacokinetic and Tissue Distribution of Fucoidan from Fucus vesiculosus after Oral Administration to Rats.

Fucus vesiculosus L., known as bladderwrack, belongs to the brown seaweeds, which are widely distributed throughout northern Russia, Atlantic shores of Europe, the Baltic Sea, Greenland, the Azores, the Canary Islands, and shores of the Pacific Ocean. Fucoidan is a major fucose-rich sulfated polysaccharide found in Fucus (F.) vesiculosus. The pharmacokinetic profiling of active compounds is essential for drug development and approval. The aim of the study was to evaluate the pharmacokinetics and tissue distribution of fucoidan in rats after a single-dose oral administration. Fucoidan was isolated from F. vesiculosus. The method of measuring anti-activated factor X (anti-Xa) activity by amidolytic assay was used to analyze the plasma and tissue concentrations of fucoidan. The tissue distribution of fucoidan after intragastric administration to the rats was characterized, and it exhibited considerable heterogeneity. Fucoidan preferentially accumulates in the kidneys (AUC0–t = 10.74 µg·h/g; Cmax = 1.23 µg/g after 5 h), spleen (AUC0–t = 6.89 µg·h/g; Cmax = 0.78 µg/g after 3 h), and liver (AUC0–t = 3.26 µg·h/g; Cmax = 0.53 µg/g after 2 h) and shows a relatively long absorption time and extended circulation in the blood, with a mean residence time (MRT) = 6.79 h. The outcome of this study provides additional scientific data for traditional use of fucoidan-containing plants and offers tangible support for the continued development of new effective pharmaceuticals using fucoidan.

Characterization of volatile and semi-volatile compounds in green and fermented leaves of Bergenia crassifolia L. by gas chromatography-mass spectrometry and ID-CUBE direct analysis in real time-high resolution mass spectrometry.

Chemical compositions of volatile and semi-volatile components in green and fermented leaves of Bergenia crassifolia L. were studied. Leaf components were identified using gas chromatography with low resolution mass spectrometry and direct analysis in real time (DART) high resolution mass spectrometry with an ID-CUBE ion source. Phytol, nerolidol, geraniol, linalool, alpha-bisabolol, alpha-bisabololoxide B, alpha-cadinol, delta-cadinene, alpha-terpineol and several other marker compounds of special interest were defined, for which the process of fermentation significantly changed their content in the leaves. Low resolution El GC-MS and ID-CUBE DART-HRMS were found to be complementary methods, as they provide different information, helpful to increase the confidence of identification.

Antiallergic effects of pigments isolated from green sea urchin (Strongylocentrotus droebachiensis) shells.

This study was undertaken to evaluate possible antiallergic effects of an extract of pigments from green sea urchin (Strongylocentrotus droebachiensis) shells. Effects were studied on animal models - guinea pig ileum contraction, rabbit eyes allergic conjunctivitis, and rabbit local skin irritation. The extract significantly reduced, in a dose-dependent manner, the histamine-induced contractions of the isolated guinea pig ileum with ID50 =1.2 µg/mL (in equivalents of spinochrome B), had an inhibitory effect on the model of ocular allergic inflammation surpassing the reference drug olopatadine, and did not show any irritating effect in rabbits. The extract predominantly contained polyhydroxy-1,4-naphthoquinone which would be responsible for the pharmacological activity. The active compounds of the extract were evaluated in silico with molecular docking. Molecular docking into H1R receptor structures obtained from molecular dynamic simulations showed that all spinochrome derivatives bind to the receptor active site, but spinochrome monomers fit better to it. The results of the present study suggest possibilities for the development of new agents for treating allergic diseases on the base of pigments from sea urchins shells.

ID-CUBE direct analysis in real time high-resolution mass spectrometry and its capabilities in the identification of phenolic components from the green leaves of Bergenia crassifolia L.

RATIONALE: Bergenia crassifolia is a plant widely used in herbal medicine. Its chemical composition has been little studied, and no studies using high-resolution mass spectrometry (HRMS) have been performed. Its phenolic components are of particular interest, due to the interest in such compounds in medicine and cosmetics. The ID-CUBE, a simplified Direct Analysis in Real Time (DART) ion source, suitable for the fast MS analysis of liquids without complex sample preparation, offers a new method of studying extracts of such plant. Coupling the ID-CUBE with a high-resolution mass spectrometer can provide identification of extract components. METHODS: Mass spectral conditions were optimized for model solutions of the flavonoid naringenin and used for the identification of phenolic compounds in green leaves extracts of Bergenia crassifolia. OpenSpot sample cards with a metal grid surface were used for sample introduction into the ID-CUBE ion source on an Obitrap mass spectrometer. The samples were applied as 5-µL aliquots of the extract onto the metal grid of the card. Sample ionization was stimulated in the ion source within 20 s by applying an electric current to the metal grid to thermally desorb the analytes into the gas flow of metastable helium atoms from the ID-CUBE. RESULTS: Elemental compositions were assigned to abundant ions in the mass spectra of the extracts. The major phenolic components were confirmed by their [M-H](-) ions. Thirty-six other marker ions were found, and elemental compositions were suggested for 30% of them, based on a search for compounds found in herbal extracts. CONCLUSIONS: The ID-CUBE-Orbitrap MS coupling allowed the rapid accurate mass determination of the phenolic components (and other compounds) in herbal extracts. Higher confidence in component identification could be provided by using additional structural elucidation methods, including tandem mass spectrometry (MS/MS), and this will be the focus of future studies.

Effect of Leonurus cardiaca oil extract in patients with arterial hypertension accompanied by anxiety and sleep disorders.

Leonurus cardiaca L. (Lamiaceae) is used traditionally for its sedative, hypotensive and cardiotonic effects. Due to the lack of clinical data regarding its effect in patients, a study was carried out to assess the clinical efficacy of Leonurus oil extract (LOE) in patients with arterial hypertension stages 1 and 2, accompanied by anxiety and sleep disorders. Fifty patients were treated for 28 days with 1200 mg LOE per day. Positive effects of LOE on psycho-emotional status and arterial blood pressure in patients with stage 1 hypertension were observed 1 week earlier than in patients with stage 2 hypertension. According to the Clinical Global Impression (CGI) scale, a significant improvement in the symptoms of anxiety and depression was observed in 32% of patients, a moderate improvement in 48% and a weak effect in 8%; 12% of patients did not respond to therapy. Side effects were minimal in all groups. Leonurus oil extract may therefore be a potentially effective therapeutic agent for patients with arterial hypertension and concurrent psycho-neurological disorders.

Pharmacological evaluation of Potentilla alba L. in mice: adaptogenic and central nervous system effects.

CONTEXT: Potentilla alba L. (Rosaceae) rhizomes have anti-inflammatory, antioxidant, and adaptogenic effects and are used for the treatment of diarrhea and intestinal colic. However, the data concerning the adaptogenic and central nervous system activities of P. alba are fragmentary. OBJECTIVES: To determine the effect of oral administration of dried P. alba extract on the swimming endurance, light/dark exploration, and open-field tests for mice. MATERIALS AND METHODS: The mice were orally administered Rhodiola rosea extract (RR group); dry extract of P. alba at doses of 12, 36, or 72 mg/kg (groups: PA12, PA36, and PA72); or distilled water (control group) for 7 consecutive days. RESULTS: The swimming times of the RR, PA36, and PA72 groups were significantly longer than those of the control group. The administration of P. alba significantly increased the light time, latency time, and the number of rearings in a dose-dependent manner. In the open-field test, the P. alba extract at a dose of 12 mg/kg produced a significant increase in the frequency of head dipping and the number of squares crossed and a significant decrease in grooming compared with the control treatment. CONCLUSION: The current findings demonstrate that P. alba extracts significantly increased swimming endurance time and have anxiolytic-like action with a predominant locomotor component.

Therapeutic efficacy of arginine-rich exenatide on diabetic neuropathy in rats.

Diabetes mellitus is characterized by metabolic dysregulation associated with a number of health complications. More than 50% of patients with diabetes mellitus suffer from diabetic polyneuropathy, which involves the presence of peripheral nerve dysfunction symptoms. The aim of this study was to evaluate the potential of a new synthetic arginine-rich exendin-4 (Peptide D) in the treatment of complications caused by diabetes, including peripheral neuropathy, in rats. Diabetes was induced by administering streptozotocin (STZ). Three groups of diabetic rats were treated with Peptide D (0.1, 1, and 10 µg/kg). One group of diabetic rats was treated with Byetta® (1 µg/kg) for 80 days. Neuropathic pain development was assessed by tactile allodynia. STZ-treated rats showed an increased level of tactile allodynia unlike naïve animals. A histological study revealed that the diameter of the sciatic nerve fibers in STZ-treated rats was smaller than that of the naïve animals. An IHC study demonstrated decreased expression of myelin basic protein (MBP) in the sciatic nerve of diabetic rats compared to that in the naïve animals. Peptide D reduced the severity of tactile allodynia. This effect was more pronounced in the Peptide D treated groups than in the group treated with Byetta®. Peptide D and Byetta® treatment resulted in increased MBP expression in the sciatic nerve and increased diameter of myelinated nerve fibers. These findings suggest that poly-arginine peptides are promising agents for the treatment of peripheral polyneuropathies.

Metabolite profiling and mechanisms of bioactivity of snake autolysate - A traditional Uzbek medicine.

ETHNOPHARMACOLOGICAL RELEVANCE: Aqueous autolysate from the snake Eryx miliaris (SNA) has been used in traditional medicine of Uzbekistan as anti-inflammatory, hepatoprotective and immunomodulatory agent. However, little is known about the chemical composition and its mechanisms of activity. AIM OF THE STUDY: This is our first attempt to analyse the composition of snake autolysate using gas chromatography with mass spectrometry (GC-MS) and to investigate the mechanisms of anti-inflammatory and hyaluronidase activity of fingerprinted E. miliaris autolysate to support their use in the traditional Uzbek medicine. MATERIALS AND METHODS: Aqueous autolysate was evaporated and derivatised for GC-MS analysis of metabolites. For quantification, lipids were extracted from autolysate by solvent extraction and derivatised by esterification and silylation. Biological activity was evaluated with lipid peroxidation, cyclooxygenase (COX) inhibition and antihyaluronidase activity tests. RESULTS: GC-MS analysis of SNA enabled the identification of 27 compounds. Short chain fatty acids (SCFA, 21%), amino acid/derivatives 39% (incl. 2-piperidinone 19%), phenyl (7%), and OH-Phenyl (10%) derivatives covered 77%. Other derivatives (9%) included succinic acid and 3-indole acetic acid). Long chain fatty acids (C16-C18) accounted for 3%. The lipid concentration of SNA was 1.2 mg/mL (0.12%). Three concentration levels (1.0-20.0 µg/mL) did not inhibit COX-1 and COX-2 in vitro and malondialdehyde level was not decreased by SNA in lipid peroxidation model. However, SNA was a potent inhibitor of the hyaluronidase enzyme activity in a dose dependent manner with IC50 = 0.086 mL/mL. CONCLUSION: The results from GC-MS analyses of SNA lead us to the identification of a wide range of major chemical structures of the metabolites and their derivatives with several categories. Pharmacological studies support the traditional use of SNA and show one of its possible mechanisms of activity via inhibition of hyaluronidase.

Chemical and antioxidant evaluation of Indian gooseberry (Emblica officinalis Gaertn., syn. Phyllanthus emblica L.) supplements.

Indian gooseberry (Emblica officinalis Gaertn.) (Euphorbiaceae) has a distinguished history in Ayurveda medicine and is ascribed a number of medicinal properties and as a dietary supplement, its use is increasing in Western countries. It is thought that its beneficial properties are a function of its antioxidant potency. The study investigated the chemistry and antioxidant properties of four commercial E. officinalis fruit extracts in order to determine if there are any qualitative-quantitative differences. All extracts produced positive responses in the total phenol, total flavonoid and total tannin assays. The presence of predominantly (poly)phenolic analytes, e.g. ellagic and gallic acids and corilagin, was confirmed by RP-HPLC coupled with photodiode array detection. Despite ascorbic acid being a major constituent of E. officinalis fruits, the furanolactone could not be identified in one of the samples. The extracts demonstrated varying degrees of antioxidative efficacy. The extract designated IG-3 was consistently amongst the most effective extracts in the iron(III) reduction and 1,1-diphenyl-2-picrylhydrazyl and superoxide anion radical scavenging assays while the extract designated IG-1 demonstrated the best hydroxyl radical scavenging activity. All extracts appeared to be incapable of chelating iron(II) at realistic concentrations.

Animal-derived medicinal products in Russia: Current nomenclature and specific aspects of quality control.

ETHNOPHARMACOLOGICAL RELEVANCE: Animal-derived medicinal products (ADMP) had been extensively used in Russia and became a part of officinal medicine in 1778. AIM OF THE STUDY: The aim of the current review was to analyse the ADMPs authorised in the Russian Federation and to identify specific aspects of quality evaluation of these medicinal products. MATERIALS AND METHODS: Information of ADMPs was extracted from the online State Register of Medicinal Products of the Russian Federation. At the next stage, we systematically searched library catalogues, E-library.ru, Medline/PubMed, Scopus, Web of Science and Google Scholar databases to find data related to ADMP quality evaluation, clinically proven efficacy and safety. RESULTS: For classification of ADMP, we propose an approach based on the raw material used: ADMPs derived from marine organisms, ADMPs from cattle and pigs and ADMPs from other terrestrial animals. The majority of ADMPs authorised in Russia are produced by local manufacturers. ADMPs are available in dosage forms of solution for parenteral administration (35% of all products) and lyophilisates for parenteral use (19%), tablets and capsules (17% and 11%, respectively), ointments (5%) and powders (3%). ADMPs belong to the following pharmacotherapeutic groups: medicines for tissue regeneration and repair stimulators (30%), digestive enzyme products (22%), anticoagulants (17%), proteolytic agents (6%) and medicines for the treatment of chronic prostatitis (5%). The most important approaches to standardisation of ADMPs are implementation of modern requirements for registration dossiers, development of risk-oriented approaches for evaluation of impurities, elaboration of advanced instrumental and in vitro test methods capable of replacing in vivo methods and harmonisation of the potency units used for standardisation. CONCLUSIONS: The key features of ADMPs that help them retain their leading position in the pharmaceutical market are as follows: (i) their unique composition usually represented by a complex of biologically active substances; (ii) a high degree of affinity of the active ingredient of an ADMP to the human body and (iii) proved safety and clinical efficiency. Variability in the quality of raw ingredients, epidemiological situation and other conditions pose additional challenges for the development of ADMPs and for the standardisation.

Separation and free radical-scavenging activity of major curcuminoids of Curcuma longa using HPTLC-DPPH method.

A direct HPTLC assay was developed for the determination of total curcuminoids and three individual curcuminoids, curcumin, demethoxycurcumin and bisdemethoxycurcumin. In addition, a new procedure was developed to separate and quantitative the free radical-scavenging activity of individual compounds from the rhizome of Curcuma longa L. (Zingiberaceae) based on the combination of HPTLC with a diode array detector (DAD) and post chromatographic DPPH(*) radical derivatisation. It was established that both individual curcuminoids and the extract of C. longa were capable of scavenging DPPH(*) radicals. From the estimated ID(50) values, it can be seen that the order of activity was curcumin > demethoxycurcumin > bisdemethoxycurcumin >> ascorbic acid. However, the ID(50) values of curcuminoids were not significantly different. The data indicates the presence of a synergistic mechanism of antiradical activity of curcuminoids.

A new tridecapeptide with an octaarginine vector has analgesic therapeutic potential and prevents morphine-induced tolerance.

A growing body of evidence suggests that peptides may possess analgesic effects without tolerance development. The synthetic tetrapeptide Tyr-d-Arg-Phe-Gly-NH2 was modified with the inclusion of a (d-Arg)8 vector to prevent the action of endopeptidase and to increase the duration of the analgesic action of the tetrapeptide when administered orally. The aim of this study was to estimate the analgesic efficacy of the tetrapeptide with (d-Arg)8 (tridecapeptide, TDP) in experimental models of acute and chronic pain. The analgesic effects of TDP were estimated using a model of acute visceral pain in mice (writhing test) and a model of chronic neuropathic pain (chronic constriction injury (CCI) of the sciatic nerve) in rats. The intravenous administration of morphine (0.32-1mg/kg) and TDP (0.32-1.8mg/kg) produced significant dose-related antinociceptive effects in the writhing test. The potency of TDP after i.g. administration was lower than that after i.v. administration but comparable with that of i.g. morphine. In the CCI model, TDP (0.1, 1 and 10mg/kg, i.g.) induced marked analgesia with repeated administration without any signs of tolerance. The single administration of TDP after morphine treatment (7days) produced a significant analgesic effect in morphine-tolerant rats, indicating the absence of cross-tolerance between these two drugs. The combined administration of TDP and morphine resulted in the reduction of analgesic tolerance to morphine. The absence of cross-tolerance to morphine and the ability to prevent morphine tolerance allows this compound to be a prospective candidate for chronic pain therapy. In order to find the target receptors for TDP, a docking study was performed. It was found that the molecule can bind to the NMDA receptor using electrostatic, hydrogen bonding and hydrophobic interactions.

Effect of lipid-based suspension of Epimedium koreanum Nakai extract on sexual behavior in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Herba of Epimedium koreanum is used in traditional Chinese and Korean herbal medicine as a potent enhancer of erectile function. Icariin, the main active component of Epimedium koreanum, possesses many biological effects, such as improving cardiovascular function, hormone regulation, immunological function modulation, and anti-tumor activity. AIM OF THE STUDY: This study supports the traditional use of extracts from Epimedium species in erectile dysfunction. MATERIALS AND METHODS: The Epimedium koreanum dry extract was suspended in wheat germ oil using lecithin and bee wax for oral administration. The effect of oral administration of two compositions (E-01 and E-02) standardized by their icariin content on the number of complete intromissions, the number of ejaculations, and the latent period of ejaculation (LPE) in rats were evaluated. E-01 and E-02 were administered orally for 10 days to the experimental animals. The control animals received olive oil for 10 days. On day 10, 0.5h after the dose was administered to male rats, one virgin female rat was placed with one male rat. RESULTS: The number of complete intromissions increased to 23.3+/-2.6 in the E-01 and E-02 group (dose 300 mg/kg body weight) (b.wt) and to 20.1+/-2.3 in the E-02 group (dose 750 mg/kg b.wt) compared with 15.2+/-2.4 in the control group of aged rats. The number of ejaculations increased from 1.1+/-0.3 in the control-aged group to 2.6+/-0.4 in the E-01 group. The LPE of male rats was 14.2+/-1.8 min in the control-aged group. The LPE of the aged group was reduced to 9.8+/-1.5 min, 9.8+/-1.6 min, and 11.4+/-1.8 min when treated with E-01 at a dose of 300 mg/kg b.wt, and E-02 at a dose of 300 mg/kg b.wt and 750 mg/kg b.wt, respectively. CONCLUSION: It was established that oral administration of lipid-based suspension of dry extract of Epimedium koreanum in wheat germ oil improved erectile function of aged rats.

Traditional and Current Food Use of Wild Plants Listed in the Russian Pharmacopoeia.

Historically Russia can be regarded as a "herbophilious" society. For centuries the multinational population of Russia has used plants in daily diet and for self-medication. The specificity of dietary uptake of medicinal plants (especially those in the unique and highly developed Russian herbal medical tradition) has remained mostly unknown in other regions. Based on 11th edition of the State Pharmacopoeia of the USSR, we selected 70 wild plant species which have been used in food by local Russian populations. Empirical searches were conducted via the Russian-wide applied online database E-library.ru, library catalogs of public libraries in St-Petersburg, the databases Scopus, Web of Science, PubMed, and search engine Google Scholar. The large majority of species included in Russian Pharmacopoeia are used as food by local population, however, aerial parts are more widely used for food. In this review, we summarize data on medicinal species published in Russia and other countries that are included in the Russian Pharmacopoeia and have being used in food for a long time. Consequently, the Russian Pharmacopoeia is an important source of information on plant species used traditionally at the interface of food and medicine. At the same time, there are the so-called "functional foods", which denotes foods that not only serves to provide nutrition but also can be a source for prevention and cure of various diseases. This review highlights the potential of wild species of Russia monographed in its pharmacopeia for further developing new functional foods and-through the lens of their incorporation into the pharmacopeia-showcases the species' importance in Russia.

Comparative stability of dimeric and monomeric pigments extracted from sea urchin Strongylocentrotus droebachiensis.

Ultraviolet-visible spectroscopy and UPLC-DAD-MS were used for analysis of stability of ethanol solutions of ethylidene-6,6'-bis(2,3,7-trihydroxynaphthazarin) (ENZ), spinochrome dimer (SDM) and spinochrome D (SD) that were isolated from Strongylocentrotus droebachiensis. In the freshly prepared solution, the concentration of ENZ at pH 6.0 was at 6 fold less comparing to pH 1.6. The increase of pH up to 4.0 resulted to increase of SD concentration and to decrease of SDM concentration. After 48 h storage, both dimers showed the highest stability at pH 1.6, while the elevation of the pH solution up to 6.0 activates degradation of SDM and ENZ at 1.3 and 3.6 fold correspondingly. The concentration of SD after 48 h storage at the pH 1.6 was at two-fold less comparing to the initial concentration, and at the pH 6.0 - at 4 fold less. This study contributes to increasing the knowledge on the stability of the spinochrome pigments.

Pharmacokinetics and Tissue Disposition of Nanosystem-Entrapped Betulin After Endotracheal Administration to Rats.

BACKGROUND AND OBJECTIVES: Betulin is a triterpene extracted from the cork layer of the outer bark of Betula spp. It has a wide spectrum of pharmacological activities, including being lung protective; however, its bioavailability is low. To increase its bioavailability, betulin was entrapped in a nanosystem (BN). In this study, we investigated the pharmacokinetics and tissue distribution of nanosystem-entrapped betulin after single dose endotracheal administration to rats. METHOD: Betulin was nanosystem-entrapped using a solvent exchange technique. The surface morphology and size of the nanosystem were characterized by transmission electron microscopy and dynamic light scattering. The plasma and tissue concentrations of betulin were determined using a validated high-performance liquid chromatography method. RESULTS: The highest concentration of betulin was found in lungs and liver, and the lowest in the heart. Betulin did not penetrate highly vascularized tissues or tissue with an average degree of vascularization, nor did it cross the blood-brain barrier. Tissue availability in the lungs was 1.3 times higher for BN than for free betulin. Betulin was detected in the bloodstream at 15 min after administration of BN compared with only at 1 h after administration of free betulin. Penetration of betulin in the liver tissue was characterized by a high degree of intensity both for BN and free betulin. Betulin in the heart tissue was detected in much smaller quantities than in the liver. CONCLUSION: Entrapment of betulin in nanosystem form shows promise as a novel strategy in the treatment of pulmonary diseases.

Chemical composition and in vitro antioxidant evaluation of commercial water-soluble willow herb (Epilobium angustifolium L.) extracts.

Five commercially available water-soluble extracts prepared from the aerial parts of Epilobium angustifolium L. (Onagraceae) were screened for antioxidant-related properties in a battery of six in vitro assays. Total phenol content and qualitative-quantitative analyses were also carried out. The extracts demonstrated varying degrees of efficacy in each screen. Two extracts, denoted as nonfermented and Tver, were the most effective toward reducing iron(III), scavenging 1,1-diphenyl-2-picrylhydrazyl free radicals, inhibiting hydroxyl radical-catalyzed bovine brain-derived phospholipid degradation, and non-site- and site-specific hydroxyl radical-catalyzed 2-deoxy-D-ribose degradation. The activity profile of the extracts changed, however, when their iron(II) chelating ability was assessed. The nonfermented and Tver extracts were not as effective iron(II) chelators as the extract denoted as Lotos. All the extracts contained Folin-Ciocalteu-reactive substances, which was confirmed by the presence of predominantly polar phenolic analytes (i.e., hydroxylated benzoic acid derivatives and flavonoids).

Aralia elata var. mandshurica (Rupr. & Maxim.) J.Wen: An overview of pharmacological studies.

PURPOSE: Aralia elata var. mandshurica (Rupr. & Maxim.) J.Wen syn. A. mandshurica Rupr. & Maxim is evaluated for its medicinal application. The aim of this study is to analyze pharmacological studies on A. elata var. mandshurica published until December 2015. METHODS: The information regarding the chemistry, safety, effectiveness, and pharmacological and clinical effects of A. elata was systematically collected from the scientific literature through library catalogs; online services such as E-library.ru, Medline/PubMed, Scopus, Web of Science, and Google Scholar. RESULTS: A. elata is often considered an example of a medicinal plant used in Chinese, Korean, and Japanese traditional medicine. However, the contemporary applications of Aralia in officinal medicine result primarily from a large number of pharmacological and clinical investigations carried out in the former USSR in the mid-20th century. Since the 1950s, medicinal preparations from radices of A. elata and radices of A. mandshurica have secured an established position within Russian/USSR medicine as evidenced by the inclusion of the drug in recent editions of the National Pharmacopoeia of the USSR and in the Register of Medicinal Preparations of Russia. Pharmacological studies on animals have shown that Aralia increases physical working capacity and affords a stress-protective effect against a broad spectrum of harmful factors including cold stress, immobilization, UV irradiation, and low air pressure. The phytoadaptogen exerts an effect on the central nervous, reproductive, immune, respiratory, and gastrointestinal systems; the metabolic syndrome including hypolipidemic and antidiabetic effects; and blood coagulation. Together with general properties of adaptogens, Aralia has its own specificity, which manifests in cardioprotective and antiarrhythmic activities. Studies on isolated organs, cells, and enzymes have revealed that Aralia preparations exhibit antioxidant activities and enhance sarcoplasmic reticulum Ca2+-ATPase activity, inhibit endoplasmic reticulum stress-associated apoptosis markers (GRP78, CHOP, Caspase-12, and JNK), and increase phosphorylation of STAT3 and Bcl2/Bax ratio; they also show cytotoxic activities against some tumor cell lines; affect NF-κB and PPARs activities; and regulate biosynthesis of pro-inflammatory cytokines and inflammation-related protein expression, tissue respiration, and oxygen consumption. In healthy subjects, Aralia increases mental performance, working capacity, and endurance of movement. Numerous clinical trials have shown the efficiency of Aralia preparations in patients with traumatic brain injury (accompanied with asthenic syndrome and neurotic reactions, depression, neurasthenia, and psychasthenia), neurological diseases (accompanied with astheno-depressive and astheno-hypochondriasis syndromes), myasthenia syndrome (accompanied with chronic post-influenza arachnoiditis), and arterial hypotension. Aralia tincture and "Saparal" are useful as antiviral remedies. Radioprotective properties of Aralia have been reported in pregnant women. Synergistic antiobesity effect was reported for the combination of A. mandshurica and Engelhardtia chrysolepis extracts and antidiabetic effect for the combination of Aralia and glipizide. Promising stress-relieving effects of Aralia are reported for professionals whose work requires a high level of attention. Its proposed ability to moderate stress-induced damage and dysfunction in the cardiovascular tissue might make Aralia the adaptogen of choice among patients with higher risk for cardiovascular diseases. Because Aralia extract administration appears to affect plasma glucose level and hepatic lipid accumulation and ameliorate hyperinsulinemia, it might also provide benefits and be the adaptogen of choice for patients with obesity and diabetes. CONCLUSION: This review describes the considerable diversity of pharmacological effects of A. elata reported in numerous studies carried out in the former USSR and other countries, which have been confirmed over >47 years of use of the plant as an official medicinal remedy. The knowledge discussed in this review can be applied to the expansion of the use of this high-value plant in the pharmacotherapy of European and other countries and for the further discovery of new drugs based on the secondary metabolites of this plant. Modern approaches in mechanisms of action, including a study of gene expression profiling, suggest the most up-to-date challenges for the future research of Aralia.