Comprehensive review of cardiovascular toxicity of drugs and related agents.

Cardiovascular diseases are a leading cause of morbidity and mortality in most developed countries of the world. Pharmaceuticals, illicit drugs, and toxins can significantly contribute to the overall cardiovascular burden and thus deserve attention. The present article is a systematic overview of drugs that may induce distinct cardiovascular toxicity. The compounds are classified into agents that have significant effects on the heart, blood vessels, or both. The mechanism(s) of toxic action are discussed and treatment modalities are briefly mentioned in relevant cases. Due to the large number of clinically relevant compounds discussed, this article could be of interest to a broad audience including pharmacologists and toxicologists, pharmacists, physicians, and medicinal chemists. Particular emphasis is given to clinically relevant topics including the cardiovascular toxicity of illicit sympathomimetic drugs (e.g., cocaine, amphetamines, cathinones), drugs that prolong the QT interval, antidysrhythmic drugs, digoxin and other cardioactive steroids, beta-blockers, calcium channel blockers, female hormones, nonsteroidal anti-inflammatory, and anticancer compounds encompassing anthracyclines and novel targeted therapy interfering with the HER2 or the vascular endothelial growth factor pathway.

Allergy-like immediate reactions with herbal medicines in children: A retrospective study using data from VigiBase®.

BACKGROUND: The use of herbal medicines in children and the general population is continually on the rise with an overall herbal lifetime and current use ranging between 0.8%-85.5% and 2.2%-8.9%, respectively. Although acute hypersensitivity reactions are generally considered to be rare, little knowledge exists on the frequency and type of these reactions especially in specific populations like children. OBJECTIVES: To assess the patterns of acute hypersensitivity reactions to herbal medicines reported to the WHO global individual case safety report (ICSR) database VigiBase® in children. STUDY DESIGN: From the original VigiBase® extract for the time between 1968 and 2014, we included all reports with adverse drug reactions (ADR) associated with herbal medicines in children where WHO-ART reaction terms were indicative of acute hypersensitivity reactions. RESULTS: VigiBase® contained 2646 ICSRs with 14 860 distinct adverse reactions reported in association with herbal medicine in children. Among those, 79 cases with 107 allergy-like reactions met our inclusion criteria. The most commonly reported WHO-ART terms were urticaria or rash/rash erythematous (59.8%), and allergic reaction (8.4%). The most frequently reported suspected herbal medicines were mixed herbal products (51.4%), Hedera helix (15.0%), and Echinacea purpurea (5.6%). Most frequent routes of administration were oral (75.9%), topical (8.9%), and rectal (3.8%). Over 30% of cases were reported in the age group from 7 to 12 years. The majority of reports were received from Germany (29.1%), Thailand (21.5%), and Australia (11.4%). CONCLUSION: VigiBase® contains a considerable number of acute hypersensitivity reactions in children associated with herbal medicines, including life-threatening reactions such as anaphylactic shock.

In vitro copper-chelating properties of flavonoids.

Copper is an indispensable trace element for human body and the association between a disruption of copper homeostasis and a series of pathological states has been well documented. Flavonoids influence the human health in a complex way and the chelation of transient metal ions indisputably contributes to their mechanism of the action, however, the information about their copper-chelating properties have been sparse. This in vitro study was thus aimed at the detailed examination of flavonoids-copper interactions by two spectrophotometric assays at four (patho)physiologically relevant pH conditions (4.5-7.5), with the emphasis on the structure-activity relationship. The tested flavonoids were compared with the clinically used copper chelator, trientine. Most of the 26 flavonoids chelated copper ions, however, in a variable extent. Only flavones and flavonols were able to form stable complexes with both cupric and cuprous ions. The 3-hydroxy-4-keto group and 5,6,7-trihydroxyl group represented the most efficient chelation sites in flavonols and flavones, respectively, and the 2,3-double bond was essential for the stable copper chelation. Interestingly, the 3´,4´-dihydroxyl (catechol) group was associated only with a weak activity. Although none of the tested flavonoids were more potent than trientine at physiological or slightly acidic conditions, 3-hydroxyflavone, kaempferol and partly baicalein surpassed trientine at acidic conditions. Conclusively, flavonoids containing appropriate structural features were efficient copper chelators and some of them were even more potent than trientine under acidic conditions.

Evaluation of the antioxidant activity of several naturally occurring coumarins and their synthesized analogues by "ferric reducing antioxidant power" assay.

Coumarins have attracted intense interest in recent years because of their diverse pharmacological properties. According to our continuing investigations of biological effects of several coumarins, the structure-antioxidant activity relationships (SARs) of six naturally occurring coumarins and their 16 synthesized analogues were established. For this purpose, the very reliable colorimetric assay (ferric reducing antioxidant power) modified to be used in 96-well microplates was used. This approach, which determines the reducing capacity of tested compounds directly, has previously been used for the determination of SARs of flavonoids, but has not been used for SAR determination of coumarins. It is known that the biological properties and consequently, therapeutic application of simple coumarins depends upon the pattern of substitution. It was established that 7,8-dihydroxy- and 6,7-dihydroxy-4-methylcoumarins have shown excellent ferric-reducing properties.

In vitro platelet antiaggregatory properties of 4-methylcoumarins.

Platelets play a crucial role in physiological haemostasis. However, in coronary arteries damaged by atherosclerosis, enhanced platelet aggregation, with subsequent thrombus formation, is a precipitating factor in acute myocardial infarction. Current therapeutic approaches are able to reduce approximately one quarter of cardiovascular events, but they are associated with an increased risk of bleeding and in some resistant patients are not efficient. Some coumarins possess antiplatelet activity and, due to their additional antioxidant effects, may be promising drugs for use in combination with the present therapeutic agents. The aim of this study was to analyse a series of simple 4-methylcoumarins for their antiplatelet activity. Human plasma platelet suspensions were treated with different aggregation inducers [arachidonic acid (AA), collagen and ADP] in the presence of the 4-methylcoumarins. Complementary experiments were performed to explain the mechanism of action. 5,7-Dihydroxy-4-methylcoumarins, in particular those containing a lipophilic side chain at C-3, reached the activity of acetylsalicylic acid on AA-induced aggregation. Other tested coumarins were less active. Some of the tested compounds mildly inhibited either collagen- or ADP-induced aggregation. 5,7-Dihydroxy-4-methylcoumarins did not interfere with the function of thromboxane synthase, but were competitive antagonists of thromboxane A(2) receptors and inhibited cyclooxygenase-1 as well. 5,7-Dihydroxy-4-methylcoumarins appear to be promising candidates for the extension of the current spectrum of antiplatelet drugs.

Iron reduction potentiates hydroxyl radical formation only in flavonols.

Flavonoids, substantial components of the human diet, are generally considered to be beneficial. However, they may possess possible pro-oxidative effects, which could be based on their reducing potential. The aims of this study were to evaluate the ability of 26 flavonoids to reduce ferric ions at relevant pH conditions and to find a possible relationship with potentiation of hydroxyl radical production. A substantial ferric ions reduction was achieved under acidic conditions, particularly by flavonols and flavanols with the catecholic ring B. Apparently corresponding bell-shaped curves displaying the pro-oxidant effect of flavonols quercetin and kaempferol on iron-based Fenton reaction were documented. Several flavonoids were efficient antioxidants at very low concentrations but rather inefficient or pro-oxidative at higher concentrations. Flavonols, morin and rutin were progressively pro-oxidant, while 7-hydroxyflavone and hesperetin were the only flavonoids with dose-dependent inhibition of hydroxyl radical production. Conclusively, administration of flavonoids may lead to unpredictable consequences with few exceptions.

Alkaloids from some amaryllidaceae species and their cholinesterase activity.

Alkaloid extracts of four Amaryllidaceae species were studied with respect to their acetylcholinesterase and butyrylcholinesterase inhibitory activity and alkaloid patterns. Twenty-one alkaloids were determined by GC/MS, and seventeen of them identified from their mass spectra and retention times. The GC/MS analysis of the alkaloid extract of Nerine filamentosa is the first phytochemical investigation of this species. Promising erythrocytic acetylcholinesterase inhibitory activity was demonstrated by the alkaloid extracts of Narcissus poeticus var recurvus, Nerine filifolia and N. filamentosa (IC(50,HuAChE) = 6.0 +/- 0.1 microg/mL; IC(50,HuAChE) = 18.5 +/- 0.8 microg/mL, IC(50,HuAChE) = 21.6 +/- 1.1 microg/mL). The most potent inhibitory activity against serum butyrylcholinesterase was shown by extracts of Sternbergia lutea and Nerinefilamentosa (IC(50,HuBuChE) = 3.7 +/- 0.1 microg/mL; IC(50.HuBuChE) = 13.0 +/- 0.7 microg/mL).

Analysis of Amaryllidaceae alkaloids from Chlidanthus fragrans by GC-MS and their cholinesterase activity.

The underivatized alkaloid mixture extracted from the bulbs of Chlidanthus fragrans Herb. was investigated by capillary GC/MS for the first time. Fifteen known Amaryllidaceae alkaloids of five structure types were identified. The main alkaloids were tazzetine (9, tazettine-type), chlidanthine (2, galanthamine-type), belladine (8, belladine-type) and lycorine (12, lycorine-type). The alkaloid extract from the bulbs showed promising human blood acetylcholinesterase (IC50 = 20.1 +/- 2.9 microg/mL) and human plasma butyrylcholinesterase (IC50 = 136.8 +/- 6.9 microg/mL) inhibitory activity.

In vitro analysis of iron chelating activity of flavonoids.

Flavonoids have been demonstrated to possess miscellaneous health benefits which are, at least partly, associated with iron chelation. In this in vitro study, 26 flavonoids from different subclasses were analyzed for their iron chelating activity and stability of the formed complexes in four patho/physiologically relevant pH conditions (4.5, 5.5, 6.8, and 7.5) and compared with clinically used iron chelator deferoxamine. The study demonstrated that the most effective iron binding site of flavonoids represents 6,7-dihydroxy structure. This site is incorporated in baicalein structure which formed, similarly to deferoxamine, the complexes with iron in the stoichiometry 1:1 and was not inferior in all tested pH to deferoxamine. The 3-hydroxy-4-keto conformation together with 2,3-double bond and the catecholic B ring were associated with a substantial iron chelation although the latter did not play an essential role at more acidic conditions. In agreement, quercetin and myricetin possessing all three structural requirements were similarly active to baicalein or deferoxamine at the neutral conditions, but were clearly less active in lower pH. The 5-hydroxy-4-keto site was less efficient and the complexes of iron in this site were not stable at the acidic conditions. Isolated keto, hydroxyl, methoxyl groups or an ortho methoxy-hydroxy groups were not associated with iron chelation at all.

In vitro interactions of coumarins with iron.

Coumarins are a large group of natural substances with diverse pharmacological properties that may predetermine some of them for the prevention and/or treatment of cardiovascular diseases and also other pathologies. Free iron participates in the production of reactive oxygen species (ROS) and plays an important role in the pathogenesis of cardiovascular diseases. Therefore, chelation of iron may attenuate some ROS consequences, but on the other hand, reduction of ferric ions to ferrous ones is unfavourable and leads to intensification of ROS production. In this study, we have examined the interaction of iron with coumarins which has been rarely analyzed. A series of naturally occurring and chemically synthesized 4-methylcoumarins were analyzed for their ferrous and total iron-chelating properties and compared with standard iron chelator deferoxamine. The iron chelation activity was assessed by a simple spectrophotometric approach based on the specific indicator for ferrous ions--ferrozine. The methodology was also extended for the measurement of total iron. Among the tested coumarins, ortho-dihydroxyderivatives were the most potent iron chelators and 7,8-dihydroxy-4-methylcoumarin even reached the efficiency of deferoxamine in neutral pH. However, these ortho-dihydroxycoumarins did not bind iron firmly in acidic conditions (e.g., in acute myocardial infarction) and, moreover, they reduced ferric ions that could lead to intensification of the Fenton chemistry. Other tested coumarins did not substantially chelate iron with the exception of ortho-diacetoxycoumarins. Conclusively, the use of iron-chelating coumarins in acidic conditions may be disadvantageous in contrast to neutral conditions.

New antioxidant flavonoid isolated from Leuzea carthamoides.

A new natural flavonoid patuletin 3'-beta-xylofuranoside was isolated from Leuzea carthamoides leaves. The antioxidant activity of this compound was evaluated by the DPPH radical assay and ferric reducing antioxidant power (FRAP) assay, and the results were compared with those for trolox and quercetin. DPPH radical scavenging activity of the tested compounds was expressed by the parameter EC50: patuletin 3'-beta-xylofuranoside (56.0 microM), trolox (27.8 microM), and quercetin (25.3 microM). The ferric reducing activity of the compounds was demonstrated as FRAP values at 4 and 60 min: patuletin 3'-beta-xylofuranoside (28.4 microM, 35.8 microM), trolox (19.3 microM, 20.2 microM), and quercetin (54.3 microM, 79.9 microM). The structure/activity relationship of the flavonoid is also discussed. The results indicate significant antioxidant potency of patuletin 3'-beta-xylofuranoside.

Free-radical scavenging activity of some European boletales.

The ethanol extracts of 47 mushroom species from the order Boletales were tested for their free radical scavenging activities by means of the DPPH free-radical scavenging and hydrogen peroxide-induced luminol chemiluminescence assays. In the DPPH radical scavenging test, 26 species gave EC50 values of less than 1 mg/mL. The highest activity was exhibited by Gyrodon lividus (0.05 mg/mL). However, in the hydrogen peroxide-induced luminol chemiluminescence assay, only 4 species had EC50 values of less than 1 mg/mL, with the highest activity being exhibited by Strobilomyces floccopus (0.26 mg/mL). When compared with known antioxidants, all the mushroom extracts exhibited relatively low activity in both assays. The free radical scavenging results appeared to be correlated with the total phenol contents of the extracts.

Evaluation of antioxidant activity of some common mosses.

The antioxidant activity of ethanol extracts of Atrichum undulatum, Polytrichum formosum (Polytrichaceae), Pleurozium schreberi (Entodontaceae) and Thuidium tamariscinum (Thuidiaceae) was evaluated by an electrochemical method (cyclic voltammetry) and standard photometric methods: Fe(III) to Fe(II) reducing power, nitric oxide scavenging (NO) assay and simulation of Fenton-type reaction by nonsite-specific (NSSOH) and site-specific (SSOH) hydroxyl radical-mediated 2-deoxy-D-ribose degradation inhibition. The total content of phenols was determined by the Folin-Ciocalteau reagent. All tested species showed antioxidant effects lower than the positive control, caffeic acid. The extracts of A. undulatum and P. formosum contained the highest content of phenols and were the most effective in Fe(III) to Fe(II) reducing power, cyclic voltammetry and SSOH assay. By contrast, only the extract of Pl. schreberi showed activity in the NSSOH assay. A. undulatum and T. tamariscinum extracts were the most active in the NO assay. The results suggest that the extracts of A. undulatum and P. formosum possess stronger antioxidant activity than those of Pl. scheberi and T. tamariscinum, but they affect the Fenton-type reaction mainly by iron chelation.

Evaluation of natural substances from Evolvulus alsinoides L. with the purpose of determining their antioxidant potency.

In recent years, great attention has been given to the search for natural compounds or extracts with the purpose of medical use. Evolvulus alsinoides L. (Convolvulaceae) is a plant used in traditional medicine of East Asia in many indications and has known nootropic and anti-inflammatory activity. However, the bioactive constituents have been described poorly in the literature. Four substances isolated from the ethanol extract of E. alsinoides by means of polyamide and Silica-gel chromatography are reported here. Their molecular structures were determined using NMR analyses. There were identified as scopoletin, umbelliferone, scopolin and 2-methyl-1,2,3,4-butanetetrol. The quantity of these substances was determined using HPLC-UV and GC-FID detection. Antioxidant activity of the isolated substances was measured by DPPH assay using the SIA method. Antioxidant activity and total phenolic content of the prepared fractions are also described. The prepared fractions and isolated substances did not exhibit any significant activity in DPPH test.

Condensed and hydrolysable tannins as antioxidants influencing the health.

Natural polyphenols are a wide class of secondary plant metabolites and represent an abundant antioxidant component of human diet. An important, but often neglected group of natural polyphenols, are tannins. This review offers a general description of chemistry of both hydrolysable and condensed tannins (proanthocyanidins), the mechanisms of their antioxidation action, like free radical scavenging activity, chelation of transition metals, inhibition of prooxidative enzymes and lipid peroxidation. The mechanisms of action of antibacterial, antiviral, anticarcinogenic, cardiovascular system preventing, and antiinflammatory effects as well as the absorption, metabolic fate and positive in vivo effects of tannins are enclosed.

Evaluation of natural antioxidants of Leuzea carthamoides as a result of a screening study of 88 plant extracts from the European Asteraceae and Cichoriaceae.

In recently, there has been a great interest in natural antioxidants as bioactive components of food, nutraceuticals or potential drugs against several diseases. In our study, 88 extracts from various parts of plants from European Asteraceae and Cichoriaceae were assayed for radical scavenging activity by means of DPPH (1,1-diphenyl-2-picryl hydrazyl radical) test using the SIA (Sequential injection analysis) method developed for this purpose in our laboratory. DPPH radical scavenging activity of all tested plant extracts was evaluated according to the IC(50) parameter. 29 extracts exhibited IC(50) value lower than 0.1 mg/mL. The leaves of Leuzea carthamoides (IC(50) = 0.046 mg/mL) were chosen as the most promising sample for a subsequent phytochemical study, which resulted in isolation of seven natural compounds, namely, 4',5,7-trihydroxy-6-methoxyflavone (hispidulin) (1), 5, 7, 3', 4'- tetrahydroxyflavanone (eriodictyol) (2), 3',4',5,7-pentahydroxy-6-methoxyflavonol (patuletin) (3), eriodictyol-7-beta-glucopyranoside (4), 6-hydroxykaempferol-7-O-(6''-O-acetyl-beta-D-glucopyranoside) (5), 4-hydroxybenzoic acid (6) and 3,4-dihydroxybenzoic acid (protocatechuic acid) (7). Antioxidant activity of the isolated compounds was evaluated by DPPH test and ferric reducing antioxidant power (FRAP) test and compared with trolox and quercetin. Both tests evaluated the flavonoid (5) as the most active antioxidant. This result was confirmed by comparison with known data concerning the structure/activity relationships of flavonoids.

High-performance liquid chromatography analysis of four Leuzea carthamoides flavonoids.

A simple and sensitive high-performance liquid chromatography method for the determination of four Leuzea carthamoides flavonoids, namely eriodictyol, patuletin, eriodictyol-7-beta-glucopyranoside, and 6-hydroxykaempferol-7-O-(6"-O-acetyl-beta-D-glucopyranoside), is presented. Using this method, quantitative composition of flavonoids ranged from 0.011% to 0.574% in dried plant material was determined. This method could be used in the future for the quantitative evaluation of major phenolic compounds in L. carthamoides.

Antioxidant and free radical scavenging activities of five moss species.

Total phenolic content, reducing power, antioxidant and free radical scavenging activities of ethanol extracts of five mosses were determined in vitro. No correlation between the total phenolic content and antioxidant or scavenging activities was found.

Phototoxic activity of a thiophene polyacetylene from Leuzea carthamoides.

The thiophene polyacetylene (E)-1-[5-(hept-5-en-1,3-diynyl)-2-thienyl]ethan-1,2-diol, isolated from the roots of Leuzea carthamoides, showed phototoxic activity in the assay systems of histidine photo-oxidation, Artemia and Tubifex assays. The effects were compared with the standard photosensitizer xanthotoxin.

Use of molybdate as novel complex-forming selector in the analysis of polyhydric phenols by capillary zone electrophoresis.

Molybdate was examined as a complex-forming additive to the CE background electrolytes (BGE) to affect the selectivity of separation of polyhydric phenols such as flavonoids (apigenin, hyperoside, luteolin, quercetin and rutin) and hydroxyphenylcarboxylic acids (ferulic, caffeic, p-coumaric and chlorogenic acid). Effects of the buffer concentrations and pH and the influence of molybdate concentration on the migration times of the analytes were investigated. In contrast to borate (which is a buffering and complex-forming agent generally used in CE at pH > or =9) molybdate forms more stable complexes with aromatic o-dihydroxy compounds and hence the complex-formation effect is observed at considerably lower pH. Model mixtures of cinnamic acid, ferulic acid, caffeic acid and 3-hydroxycinnamic acid were separated with 25 mM morpholinoethanesulfonic acid of pH 5.4 (adjusted with Tris) containing 0.15 mM sodium molybdate as the BGE (25 kV, silica capillary effective length 45 cm x 0.1mm I.D., UV-vis detection at 280 nm). With 25 mM 2-hydroxy-3-[4-(2-hydroxyethyl)-1-piperazinyl]propanesulphonic acid/Tris of pH* 7.4 containing 2mM sodium molybdate in aqueous 25% (v/v) methanol as the BGE mixtures of all the above mentioned flavonoids, p-coumaric acid and chlorogenic acid could be separated (the same capillary as above, UV-vis detection at 263 nm). The calibration curves (analyte peak area versus concentration) were rectilinear (r>0.998) for approximately 8-35 microg/ml of an analyte (with 1-nitroso-2-naphthol as internal standard). The limit of quantification values ranged between 1.1 mg l(-1) for p-coumaric acid and 2.8 mg l(-1) for quercetin. The CE method was employed for the assay of flavonoids in medicinal plant extracts. The R.S.D. values ranged between 0.9 and 4.7% (n=3) when determining luteolin (0.08%) and apigenin (0.92%) in dry Matricaria recutita flowers and rutin (1.03%) and hyperoside (0.82%) in dry Hypericum perforatum haulm. The recoveries were >96%.