Pharmacokinetic and pharmacodynamic herb-drug interactions-part I. Herbal medicines of the central nervous system.

Unlike conventional drug substances, herbal medicines are composed of a complex of biologically active compounds. Therefore, the potential occurrence of herb-drug interactions is even more probable than for drug-drug interactions. Interactions can occur on both the pharmacokinetic and pharmacodynamic level. Herbal medicines may affect the resulting efficacy of the concomitantly used (synthetic) drugs, mainly on the pharmacokinetic level, by changing their absorption, distribution, metabolism, and excretion. Studies on the pharmacodynamic interactions of herbal medicines and conventional drugs are still very limited. This interaction level is related to the mechanism of action of different plant constituents. Herb-drug interactions can cause changes in drug levels and activities and lead to therapeutic failure and/or side effects (sometimes toxicities, even fatal). This review aims to provide a summary of recent information on the potential drug interactions involving commonly used herbal medicines that affect the central nervous system (Camellia, Valeriana, Ginkgo, Hypericum, Humulus, Cannabis) and conventional drugs. The survey databases were used to identify primary scientific publications, case reports, and secondary databases on interactions were used later on as well. Search keywords were based on plant names (botanical genera), officinal herbal drugs, herbal drug preparations, herbal drug extracts.

Proposed mechanisms of action of herbal drugs and their biologically active constituents in the treatment of coughs: an overview.

Various medicinal plants find their use in cough treatment, based on traditions and long-term experience. Pharmacological principles of their action, however, are much less known. Herbal drugs usually contain a mixture of potentially active compounds, which can manifest diverse effects. Expectorant or antitussive effects, which can be accompanied by others, such as anti-inflammatory or antibacterial, are probably the most important in the treatment of coughs. The aim of this review is to summarize the current state of knowledge of the effects of medicinal plants or their constituents on cough, based on reliable pharmacological studies. First, a comprehensive description of each effect is provided in order to explain the possible mechanism of action in detail. Next, the results related to individual plants and substances are summarized and critically discussed based on pharmacological in vivo and in vitro investigation.

Natural Products for the Prevention and Treatment of Common Cold and Viral Respiratory Infections.

The common cold is generally considered a usually harmless infectious disease of the upper respiratory pathway, with mostly mild symptoms. However, it should not be overlooked, as a severe cold can lead to serious complications, resulting in hospitalization or death in vulnerable patients. The treatment of the common cold remains purely symptomatic. Analgesics as well as oral antihistamines or decongestants may be advised to relieve fever, and local treatments can clear the airways and relieve nasal congestion, rhinorrhea, or sneezing. Certain medicinal plant specialties can be used as therapy or as complementary self-treatment. Recent scientific advances discussed in more detail in this review have demonstrated the plant's efficiency in the treatment of the common cold. This review presents an overview of plants used worldwide in the treatment of cold diseases.

Combination Therapy of Carnosic Acid and Methotrexate Effectively Suppressed the Inflammatory Markers and Oxidative Stress in Experimental Arthritis.

BACKGROUND: Combination therapy with methotrexate (MTX) is the most common therapeutic strategy used for the treatment of patients with rheumatoid arthritis (RA). In this study, we combined the natural compound carnosic acid (CA) with MTX to reduce inflammation and oxidative stress in adjuvant arthritis (AA). METHODS: AA was induced in 6-8 rats per group. MTX was administrated twice a week at a dose of 0.3 mg/kg b.w., while CA was administered daily at a dose of 100 mg/kg both in monotherapy and in combination with MTX. Plasma samples were collected on the 14th, 21st, and 28th day. Body weight and hind paw volume were measured once a week. RESULTS: We found that, mainly, the CA + MTX combination significantly reduced the hind paw swelling, the levels of IL-17A, MMP-9, and MCP-1 in plasma, and GGT activity in joint homogenates. The mRNA expression of HO-1, catalase, and IL-1ß in the liver were significantly improved by CA + MTX only. Our results indicate that adding CA to MTX treatment could be a good therapeutic option for patients suffering from RA. CONCLUSIONS: The addition of CA to methotrexate treatment significantly improved its efficacy in decreasing the development of AA by inhibiting the markers of inflammation and oxidative stress.

Treatment of Gastrointestinal Disorders-Plants and Potential Mechanisms of Action of Their Constituents.

The worldwide prevalence of gastrointestinal diseases is about 40%, with standard pharmacotherapy being long-lasting and economically challenging. Of the dozens of diseases listed by the Rome IV Foundation criteria, for five of them (heartburn, dyspepsia, nausea and vomiting disorder, constipation, and diarrhoea), treatment with herbals is an official alternative, legislatively supported by the European Medicines Agency (EMA). However, for most plants, the Directive does not require a description of the mechanisms of action, which should be related to the therapeutic effect of the European plant in question. This review article, therefore, summarizes the basic pharmacological knowledge of synthetic drugs used in selected functional gastrointestinal disorders (FGIDs) and correlates them with the constituents of medicinal plants. Therefore, the information presented here is intended as a starting point to support the claim that both empirical folk medicine and current and decades-old treatments with official herbal remedies have a rational basis in modern pharmacology.

Betalains in Edible Fruits of Three Cactaceae Taxa-Epiphyllum, Hylocereus, and Opuntia-Their LC-MS/MS and FTIR Identification and Biological Activities Evaluation.

Epiphyllum, Hylocereus, and Opuntia plants belong to the Cactaceae family. They are mostly known as ornamental plants but also for their edible fruits, which can potentially be sources of betalains, such as betanin, a natural pigment used in the food industry, e.g., under the European label code E 162. The aim of this work was the identification of betalains (using LC-MS/MS), evaluation of total betalain content (spectrophotometrically), analysis of functional groups (using FT-IR), evaluation of antioxidant activity (using DPPH, ABTS, FRAP, DCFH-DA, and reducing power methods) and evaluation of antimicrobial activity (S. aureus, E. coli, and C. albicans) in fruits of Epiphyllum, Hylocereus, and Opuntia taxa. A total of 20 betalains were identified in the studied Cactaceae fruits. The Epiphyllum pink hybrid had the highest values of total betalains amongst all samples. The highest antioxidant activity was observed in the Epiphyllum pink hybrid, in Opuntia zacuapanensis and O. humifusa fruits. The antimicrobial activity assay showed that cacti fruits were not able to effectively inhibit the growth of E. coli, S. aureus, or C. albicans. Our results prove that these fruits are good sources of natural pigments-betalains. They do not contain toxic compounds in significant amounts and they exhibit antioxidant activity.

Characterization of Phenolic Compounds and Antiproliferative Effects of Salvia pomifera and Salvia fruticosa Extracts.

The phenolic compounds of methanolic extracts of Salvia pomifera and Salvia fruticosa were identified by liquid chromatography tandem mass spectrometry. Carnosic acid and its metabolite carnosol were the most abundant terpene phenolic compounds of S. fruticosa, while they were completely absent in S. pomifera. The main terpene phenolic constituent of S. pomifera was 12-O-methylcarnosic acid and its mass/mass fragmentation pathway was explained. The detailed mechanism of carnosic acid oxidation to carnosol was suggested. The effects of Salvia extracts and/or carnosic acid, the main diterpene phenolic component of S. fruticosa, on the proliferation and cell cycle of two melanoma cell lines (A375, Mel JuSo) and human fibroblast cell line (HFF) were investigated by MTT assay, PI-exclusion assay and flow cytometry cell cycle analysis. Extract of S. fruticosa more efficiently than S. pomifera extract reduced the proliferation of the human melanoma cells. Carnosic acid showed the most significant effect. The first evidence that carnosic acid affects microtubule dynamics and arrests the cell cycle in the G2/M phase was provided. Collectively, our results demonstrate that these two Salvia species are plants of medicinal interest with perspective for further investigation. Carnosic acid could be the compound responsible for the biological activities of S. fruticosa extracts.

Ginkgo biloba Food Supplements on the European Market - Adulteration Patterns Revealed by Quality Control of Selected Samples.

The aim of this study was to prove whether Ginkgo biloba food supplements on the European market comply with pharmaceutical quality, and whether their composition satisfies the European Pharmacopoeia criteria. Medicinal products containing a standardised Ginkgo leaf extract are used for the improvement of cognitive impairment and quality of life in mild dementia. Further, Ginkgonis folium is used for the treatment of peripheral circulation disorders. Pharmacopoeial Ginkgo dry extract contains 22.0 - 27.0% flavonoids and 5.4 - 6.6% terpene lactones (ginkgolides, bilobalide). In addition to its widespread use as an herbal medicine (herbal medicinal product), the same extract can be an ingredient in food supplements. The content of active secondary metabolites was quantified in a number of European food supplements containing Ginkgo dry extract or Ginkgo leaf. Flavonoids were quantified using a modified pharmacopoeial HPLC-UV method, and terpene lactones (ginkgolides A, B, C, and bilobalide) using LC-MS/MS. Some Ginkgo leaf supplement samples were also analysed by microscopy. The quality of food supplements on the European market is dubious. In this paper, we present selected examples of several methods of adulteration and falsification, including higher/lower doses of Ginkgo dry extract or Ginkgo leaf than declared and the addition of undeclared extraneous materials. These examples reveal several patterns in the manufacturing of adulterated products.

Ferulaldehyde Improves the Effect of Methotrexate in Experimental Arthritis.

Methotrexate (MTX) is still the gold standard for treatment of rheumatoid arthritis (RA). The therapeutic efficacy of low-dose of MTX can be increased by its combination with a natural substance, ferulaldehyde (FRA). The aim of this study was to evaluate the effect FRA and MTX administered alone or in combination in adjuvant arthritis. The disease was induced to Lewis male rats by intradermal injection, which contains a suspension of heat-inactivated Mycobacterium butyricum in incomplete Freund's adjuvant. The experiment of 28 days included: healthy animals, arthritic animals, arthritic animals with administration of FRA at the oral daily dose of 15 mg/kg, arthritic animals with administration of MTX at the oral dose of 0.3 mg/kg twice a week, and arthritic animals administered with FRA and MTX. FRA in monotherapy decreased significantly only the level of interleukin-1ß (IL-1ß) and matrix metalloproteinase-9 in plasma. Combination of FRA and low-dose MTX was more effective than MTX alone when comparing body weight, hind paw volume, arthritic score, plasmatic levels of IL-1ß, activity of γ-glutamyl transferase, and relative mRNA expression of IL-1ß in the spleen. Therefore, the combination treatment was the most effective. The obtained results are interesting for future possible innovative therapy of patients with RA.

[Phenolic compounds in leaves insertions of Mentha × villosa Huds. cv. Snezná]. / Fenolové látky v listových inzerciách Mentha × villosa Huds. cv. Snezná.

Lamiaceae plants mostly accumulate active ingredients in their leaves. The subfamily Nepetoideae, including the genus Mentha L., is characterized by the presence of essential oil and antioxidant phenolics, chiefly hydroxycinnamic acids with predominance of rosmarinic acid, and flavonoids. Mentha × piperita and M. spicata are the most broadly used mints in both medicine and industry, while M. x villosa is less known in our country. Herbal drugs in the form of leaves are usually analysed unpartitioned, while single leaves insertions have only been studied occasionally. Therefore, the aim of this work was the quantification of the active compounds content in the leaves pairs of Mentha × villosa Huds. cv. Snezná, using pharmacopoeial methods: total hydroxycinnamic derivatives expressed as rosmarinic acid (THD) and luteolin-type flavonoids. THD content ranged from 6.7% to 9.4% in the leaves pairs water extracts, and from 6.6% to 14.0% in methanol extracts. Flavonoids contents, expressed as luteolin-7-O-glucoside, ranged from 4.0% to 8.8% in water extracts, and from 4.0% to 10.5% in methanol extracts. Antioxidant activity (DPPH) expressed as SC50 ranged from 10.2 to 16.9 µg.ml-1 (drug dry weight) in water extracts, and from 10.7 to 21.6 µg.ml-1 in methanol extracts. The highest content of phenolic compounds as well as the highest antioxidant activity were found to be in the top sheet, while the lowest content of phenolic compounds and lowest antioxidant activity were detected in the leaves of the middle stem part.Key words: Mentha × villosa Huds cv. Snezná hydroxycinnamic derivatives rosmarinic acid luteolin-7-O-glucoside DPPH.

Elemental analysis of Ginkgo biloba leaf samples collected during one vegetation period.

The object of our work was the identification and quantification of inorganic elements in Ginkgo biloba L. leaves (Ginkgonis folium, Ginkgoaceae) by X-ray fluorescence analysis. The plant material was obtained from a 50-years-old female tree at the Comenius University Botanical Garden (Bratislava, Slovakia). Leaves were collected from early May to late September, with the last sample consisting of fallen leaves. The elements analyzed were: phosphorus, sulfur, potassium, calcium, scandium, iron, zinc, yttrium, molybdenum, tellurium, samarium, gadolinium, dysprosium, iridium, thallium and lead. The amounts of the monitored heavy metals were below the limits specified in Ph. Eur. 7 and PhS 1.

Safety assessment of botanicals and botanical preparations used as ingredients in food supplements: testing an European Food Safety Authority-tiered approach.

This article describes results obtained by testing the European Food Safety Authority-tiered guidance approach for safety assessment of botanicals and botanical preparations intended for use in food supplements. Main conclusions emerging are as follows. (i) Botanical ingredients must be identified by their scientific (binomial) name, in most cases down to the subspecies level or lower. (ii) Adequate characterization and description of the botanical parts and preparation methodology used is needed. Safety of a botanical ingredient cannot be assumed only relying on the long-term safe use of other preparations of the same botanical. (iii) Because of possible adulterations, misclassifications, replacements or falsifications, and restorations, establishment of adequate quality control is necessary. (iv) The strength of the evidence underlying concerns over a botanical ingredient should be included in the safety assessment. (v) The matrix effect should be taken into account in the safety assessment on a case-by-case basis. (vi) Adequate data and methods for appropriate exposure assessment are often missing. (vii) Safety regulations concerning toxic contaminants have to be complied with. The application of the guidance approach can result in the conclusion that safety can be presumed, that the botanical ingredient is of safety concern, or that further data are needed to assess safety.

Antifungal activity of Mahonia aquifolium extract and its major protoberberine alkaloids.

The crude extract of Mahonia aquifolium (Berberidaceae) stem bark and its components berberine, palmatine and jatrorrhizine were screened for their inhibitory activity against a variety of dermatophytes and two Candida species of human origin using the in vitro dilution agar plate method. Jatrorrhizine was found to be the most effective against all fungal species tested (MIC ranges from 62.5 to 125 micro g/mL), while the crude extract, berberine, and palmatine exhibited only marginal activity (MIC 500 to >/= 1000 micro g/mL). Dermatophytes were more susceptible to jatrorrhizine than yeasts, and Scopulariopsis brevicaulis appeared the least sensitive species to all the compounds tested. The effects of the alkaloids were compared with those of fluconazole and bifonazole for which the MIC ranges were 12.5 to >100 micro g/mL. Our results suggest that jatrorrhizine may serve as a leading compound for further studies to develop new antifungal agents with highly potent antifungal activity and low host toxicity.

Antimutagenic potential of homoisoflavonoids from Muscari racemosum.

The potential antimutagenic effect of the plant extract of Muscari racemosum bulbs, rich on 3-benzylidene-4-chromanones, was evaluated on three genetic model organisms. The mixture of three homoisoflavonoids was applied together with diagnostic mutagens in the Ames assay on four bacterial strains Salmonella typhimurium TA97, TA98, TA100, TA102, in the toxicity and mutagenicity/antimutagenicity assay on the yeast strain Saccharomyces cerevisiae D7, and in the simultaneous phytotoxicity and clastogenicity/anticlastogenicity assay on Vicia sativa (L.). The extract exerted antimutagenic and anticlastogenic effects due to the presence of homoisoflavonoids, which may be included in the group of natural antimutagens. This genotoxicological study suggests that homoisoflavonoids from M. racemosum (L.) owing to antimutagenic and anticlastogenic properties are of great pharmacological importance, and might be beneficial for prevention of cancer.

Potential antimutagenic activity of berberine, a constituent of Mahonia aquifolium.

BACKGROUND: As part of a study aimed at developing new pharmaceutical products from natural resources, the purpose of this research was twofold: (1) to fractionate crude extracts from the bark of Mahonia aquifolium and (2) to evaluate the strength of the antimutagenic activity of the separate components against one of the common direct-acting chemical mutagens. METHODS: The antimutagenic potency was evaluated against acridine orange (AO) by using Euglena gracilis as an eukaryotic test model, based on the ability of the test compound/fraction to prevent the mutagen-induced damage of chloroplast DNA. RESULTS: It was found that the antimutagenicity of the crude Mahonia extract resides in both bis-benzylisoquinoline (BBI) and protoberberine alkaloid fractions but only the protoberberine derivatives, jatrorrhizine and berberine, showed significant concentration-dependent inhibitory effect against the AO-induced chloroplast mutagenesis of E. gracilis. Especially berberine elicited, at a very low dose, remarkable suppression of the AO-induced mutagenicity, its antimutagenic potency being almost three orders of magnitude higher when compared to its close analogue, jatrorrhizine. Possible mechanisms of the antimutagenic action are discussed in terms of recent literature data. While the potent antimutagenic activity of the protoberberines most likely results from the inhibition of DNA topoisomerase I, the actual mechanism(s) for the BBI alkaloids is hard to be identified. CONCLUSIONS: Taken together, the results indicate that berberine possesses promising antimutagenic/anticarcinogenic potential that is worth to be investigated further.

Effect of Mahonia aquifolium active compounds on interleukin-8 production in the human monocytic cell line THP-1.

The effect of the crude extract and of two alkaloid fractions prepared from Mahonia aquifolium on interleukin-8 (IL-8) production in the lipopolysaccharide (LPS)-stimulated human monocytic cell line THP-1 was studied. The production of IL-8 by cells stimulated with 20 ng/ml LPS after 48 h treatment with 20 microg/ml crude extract was inhibited by about 30 %. LPS-stimulated cells treated with 0.1 microg/ml bisbenzylisoquinoline alkaloid fraction exhibited a 40% inhibition of IL-8 production in comparison with control cells. The fraction of protoberberine alkaloids had no significant inhibitory activity. Weak or no inhibition of IL-8 production was found after treatment with 0.5 microg/ml of protoberberine alkaloids berberine and jatrorrhizine and with berbamine from the group of BBI alkaloids. In contrast, the production was inhibited after treatment with BBI alkaloids baluchistine (about 20%) and aromoline (up to 30%).

The influence of the harvest cut height on the quality of the herbal drugs Melissae folium and Melissae herba.

Variability in both the content and quality of essential oil was observed in herb and leaf drugs in dependence on the harvest cut height of lemon balm (Melissa officinalis L. cv. Citra). Three different cuts were carried out on the respective plants. The oil content in the herb was highest in the top third (0.13 % V/m), satisfactory in the herb including both the top and middle thirds (0.08 % V/m) and lowest in the whole herb (0.06 % V/m). The oil content in the leaves of the respective herbs was in the range 0.39 % - 0.14 % V/m (top third part - whole aerial part). The percentage of citrals, linalool and beta-caryophyllene in essential oil decreased in the basipetal direction, whilst the amounts of beta-caryophyllene oxide and citronellal increased in the same direction. Citrals (A and B): 55.79 % in the top third part of the herb, 48.46 % in the whole herb, 59.74 % and 56.87 % in the leaves from that parts, respectively. Similarly, beta-caryophyllene: 5.01 %, 3.87 %, 6.97 %, 5.13 %; beta-caryophyllene oxide: 17.19 %, 24.07 %, 15.64 %, 17.82 %; citronellal: 2.73 %, 5.51 %, 2.82 %, 6.44 %.