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.

• Klíčová slova
• dysrhythmia, heart failure, hypertension, myocardial infarction, stroke,
• MeSH
• alkaloidy škodlivé účinky   MeSH
• amfetaminy škodlivé účinky   MeSH
• antiarytmika škodlivé účinky   MeSH
• antiflogistika nesteroidní škodlivé účinky   MeSH
• beta blokátory škodlivé účinky   MeSH
• blokátory kalciových kanálů škodlivé účinky   MeSH
• cévní mozková příhoda farmakoterapie   MeSH
• digoxin škodlivé účinky   MeSH
• hormony škodlivé účinky   MeSH
• kardiovaskulární nemoci chemicky indukované   farmakoterapie   MeSH
• kardiovaskulární systém účinky léků   MeSH
• kokain škodlivé účinky   MeSH
• lidé MeSH
• protinádorové látky škodlivé účinky   MeSH
• srdeční frekvence účinky léků   MeSH
• steroidy škodlivé účinky   MeSH
• vaskulární endoteliální růstový faktor A MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• alkaloidy MeSH
• amfetaminy MeSH
• antiarytmika MeSH
• antiflogistika nesteroidní MeSH
• beta blokátory MeSH
• blokátory kalciových kanálů MeSH
• cathinone MeSH Prohlížeč
• digoxin MeSH
• hormony MeSH
• kokain MeSH
• protinádorové látky MeSH
• steroidy MeSH
• vaskulární endoteliální růstový faktor A MeSH

OBJECTIVES: Rutin, quercetin-3-O-rutinoside, a natural flavonol glycoside, has shown various in vitro benefits with potential use treating human diseases, especially cardiovascular system disorders. Antioxidant properties are assumed to underlie the majority of these benefits. Yet rutin pro-oxidant properties have been reported as well. Our research group has recently shown aggravating effects on isoprenaline (ISO)-induced cardiotoxicity in Wistar:Han rats after 24 hours. METHODS: This study was designed to examine in more detail the reasons for the negative effects of rutin (11.5 and 46 mg/kg, i.v.) after administration of ISO (100 mg/kg, s.c.) in rats within 2 hours of continuous experiment and in the H9c2 cardiomyoblast-derived cell line. RESULTS: Like our previous findings, rutin did not (11.5 or 46 mg/kg, i.v.) reduce the ISO-induced mortality within 2 hours although the lower dose significantly reduced cardiac troponin T (cTnT) and partly improved the histological findings. In contrast, the higher dose increased the mortality in comparison with solvent (1.26% w/v sodium bicarbonate). This was not caused by any specific haemodynamic disturbances. It appears to be associated with oxidative stress as rutin enhanced intracellular reactive oxygen species formation in vitro and had the tendency to increase it in vivo. CONCLUSIONS: Rutin, likely due to its pro-oxidative effects, can exacerbate catecholamine cardiotoxicity depending on the dose used.

• Klíčová slova
• Catecholamine, Flavonoid, H9c2 cell line, Isoprenaline, Reactive oxygen species, Rutin, Wistar rat,
• MeSH
• buněčné linie MeSH
• dinoprost analogy a deriváty   krev   MeSH
• elektrokardiografie MeSH
• glutathion krev   MeSH
• injekce intravenózní MeSH
• isoprenalin škodlivé účinky   MeSH
• Kaplanův-Meierův odhad MeSH
• kardiotoxicita etiologie   mortalita   MeSH
• myokard patologie   MeSH
• potkani Wistar MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• rutin aplikace a dávkování   škodlivé účinky   farmakokinetika   MeSH
• srdce účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 8-epi-prostaglandin F2alpha MeSH Prohlížeč
• dinoprost MeSH
• glutathion MeSH
• isoprenalin MeSH
• reaktivní formy kyslíku MeSH
• rutin MeSH

Iron and copper release participates in the myocardial injury under ischemic conditions and hence protection might be achieved by iron chelators. Data on copper chelation are, however, sparse. The effect of the clinically used copper chelator D-penicillamine in the catecholamine model of acute myocardial injury was tested in cardiomyoblast cell line H9c2 and in Wistar Han rats. D-Penicillamine had a protective effect against catecholamine-induced injury both in vitro and in vivo. It protected H9c2 cells against the catecholamine-induced viability loss in a dose-dependent manner. In animals, both intravenous D-penicillamine doses of 11 (low) and 44 mg/kg (high) decreased the mortality caused by s.c. isoprenaline (100 mg/kg) from 36% to 14% and 22%, respectively. However, whereas the low D-penicillamine dose decreased the release of cardiac troponin T (specific marker of myocardial injury), the high dose resulted in an increase. Interestingly, the high dose led to a marked elevation in plasma vitamin C. This might be related to potentiation of oxidative stress, as suggested by additional in vitro experiments with D-penicillamine (iron reduction and the Fenton reaction). In conclusion, D-penicillamine has protective potential against catecholamine-induced cardiotoxicity; however the optimal dose selection seems to be crucial for further application.

• MeSH
• buněčné linie MeSH
• chelátory železa farmakologie   MeSH
• deferoxamin farmakologie   MeSH
• ionty MeSH
• kardiotonika chemie   farmakologie   MeSH
• katecholaminy MeSH
• koncentrace vodíkových iontů MeSH
• myokard patologie   MeSH
• penicilamin chemie   farmakologie   MeSH
• potkani Wistar MeSH
• troponin T metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• železo metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chelátory železa MeSH
• deferoxamin MeSH
• ionty MeSH
• kardiotonika MeSH
• katecholaminy MeSH
• penicilamin MeSH
• troponin T MeSH
• železo MeSH

Cancer cells have a high iron requirement and many experimental studies, as well as clinical trials, have demonstrated that iron chelators are potential anti-cancer agents. The ligand, 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT), demonstrates both potent anti-neoplastic and anti-retroviral properties. In this study, Bp4eT and its recently identified amidrazone and semicarbazone metabolites were examined and compared with respect to their anti-proliferative activity towards cancer cells (HL-60 human promyelocytic leukemia, MCF-7 human breast adenocarcinoma, HCT116 human colon carcinoma and A549 human lung adenocarcinoma), non-cancerous cells (H9c2 neonatal rat-derived cardiomyoblasts and 3T3 mouse embryo fibroblasts) and their interaction with intracellular iron pools. Bp4eT was demonstrated to be a highly potent and selective anti-neoplastic agent that induces S phase cell cycle arrest, mitochondrial depolarization and apoptosis in MCF-7 cells. Both semicarbazone and amidrazone metabolites showed at least a 300-fold decrease in cytotoxic activity than Bp4eT towards both cancer and normal cell lines. The metabolites also lost the ability to: (1) promote the redox cycling of iron; (2) bind and mobilize iron from labile intracellular pools; and (3) prevent 59Fe uptake from 59Fe-labeled transferrin by MCF-7 cells. Hence, this study demonstrates that the highly active ligand, Bp4eT, is metabolized to non-toxic and pharmacologically inactive analogs, which most likely contribute to its favorable pharmacological profile. These findings are important for the further development of this drug candidate and contribute to the understanding of the structure-activity relationships of these agents.

• MeSH
• buněčná smrt účinky léků   MeSH
• buněčné linie MeSH
• chelátory železa chemie   farmakologie   MeSH
• kontrolní body fáze S buněčného cyklu účinky léků   MeSH
• lidé MeSH
• metabolické sítě a dráhy účinky léků   MeSH
• mitochondrie metabolismus   patologie   MeSH
• nádorové buněčné linie MeSH
• oxidace-redukce účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• semikarbazony chemie   metabolismus   farmakologie   toxicita   MeSH
• thiosemikarbazony chemie   metabolismus   farmakologie   toxicita   MeSH
• železo chemie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone MeSH Prohlížeč
• chelátory železa MeSH
• protinádorové látky MeSH
• reaktivní formy kyslíku MeSH
• semikarbazony MeSH
• thiosemikarbazony MeSH
• železo MeSH

Salicylaldehyde isonicotinoyl hydrazone (SIH) is a lipophilic, tridentate iron chelator with marked anti-oxidant and modest cytotoxic activity against neoplastic cells. However, it has poor stability in an aqueous environment due to the rapid hydrolysis of its hydrazone bond. In this study, we synthesized a series of new SIH analogs (based on previously described aromatic ketones with improved hydrolytic stability). Their structure-activity relationships were assessed with respect to their stability in plasma, iron chelation efficacy, redox effects and cytotoxic activity against MCF-7 breast adenocarcinoma cells. Furthermore, studies assessed the cytotoxicity of these chelators and their ability to afford protection against hydrogen peroxide-induced oxidative injury in H9c2 cardiomyoblasts. The ligands with a reduced hydrazone bond, or the presence of bulky alkyl substituents near the hydrazone bond, showed severely limited biological activity. The introduction of a bromine substituent increased ligand-induced cytotoxicity to both cancer cells and H9c2 cardiomyoblasts. A similar effect was observed when the phenolic ring was exchanged with pyridine (i.e., changing the ligating site from O, N, O to N, N, O), which led to pro-oxidative effects. In contrast, compounds with long, flexible alkyl chains adjacent to the hydrazone bond exhibited specific cytotoxic effects against MCF-7 breast adenocarcinoma cells and low toxicity against H9c2 cardiomyoblasts. Hence, this study highlights important structure-activity relationships and provides insight into the further development of aroylhydrazone iron chelators with more potent and selective anti-neoplastic effects.

• MeSH
• aldehydy chemie   farmakologie   toxicita   MeSH
• antioxidancia chemie   farmakologie   MeSH
• buněčné linie MeSH
• chelátory železa chemie   farmakologie   MeSH
• hydrazony chemie   farmakologie   toxicita   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• myoblasty účinky léků   MeSH
• oxidační stres účinky léků   MeSH
• peroxid vodíku toxicita   MeSH
• protinádorové látky chemie   toxicita   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aldehydy MeSH
• antioxidancia MeSH
• chelátory železa MeSH
• hydrazony MeSH
• peroxid vodíku MeSH
• protinádorové látky MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Prohlížeč

Thiosemicarbazones (TSCs) are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resistance to clinically used chemotherapeutics. In the current study, 35 novel TSCs of 6 different classes were designed using a combination of retro-fragments that appear in other TSCs. Additionally, di-substitution at the terminal N4 atom, which was previously identified to be critical for potent anti-cancer activity, was preserved through the incorporation of an N4-based piperazine or morpholine ring. The anti-proliferative activity of the novel TSCs were examined in a variety of cancer and normal cell-types. In particular, compounds 1d and 3c demonstrated the greatest promise as anti-cancer agents with potent and selective anti-proliferative activity. Structure-activity relationship studies revealed that the chelators that utilized "soft" donor atoms, such as nitrogen and sulfur, resulted in potent anti-cancer activity. Indeed, the N,N,S donor atom set was crucial for the formation of redox active iron complexes that were able to mediate the oxidation of ascorbate. This further highlights the important role of reactive oxygen species generation in mediating potent anti-cancer activity. Significantly, this study identified the potent and selective anti-cancer activity of 1d and 3c that warrants further examination.

• MeSH
• biologický transport účinky léků   MeSH
• kyselina askorbová metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• oxidace-redukce účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• racionální návrh léčiv * MeSH
• thiosemikarbazony chemická syntéza   chemie   farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• železo chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kyselina askorbová MeSH
• protinádorové látky MeSH
• thiosemikarbazony MeSH
• železo MeSH

SIGNIFICANCE: Anthracyclines (doxorubicin, daunorubicin, or epirubicin) rank among the most effective anticancer drugs, but their clinical usefulness is hampered by the risk of cardiotoxicity. The most feared are the chronic forms of cardiotoxicity, characterized by irreversible cardiac damage and congestive heart failure. Although the pathogenesis of anthracycline cardiotoxicity seems to be complex, the pivotal role has been traditionally attributed to the iron-mediated formation of reactive oxygen species (ROS). In clinics, the bisdioxopiperazine agent dexrazoxane (ICRF-187) reduces the risk of anthracycline cardiotoxicity without a significant effect on response to chemotherapy. The prevailing concept describes dexrazoxane as a prodrug undergoing bioactivation to an iron-chelating agent ADR-925, which may inhibit anthracycline-induced ROS formation and oxidative damage to cardiomyocytes. RECENT ADVANCES: A considerable body of evidence points to mitochondria as the key targets for anthracycline cardiotoxicity, and therefore it could be also crucial for effective cardioprotection. Numerous antioxidants and several iron chelators have been tested in vitro and in vivo with variable outcomes. None of these compounds have matched or even surpassed the effectiveness of dexrazoxane in chronic anthracycline cardiotoxicity settings, despite being stronger chelators and/or antioxidants. CRITICAL ISSUES: The interpretation of many findings is complicated by the heterogeneity of experimental models and frequent employment of acute high-dose treatments with limited translatability to clinical practice. FUTURE DIRECTIONS: Dexrazoxane may be the key to the enigma of anthracycline cardiotoxicity, and therefore it warrants further investigation, including the search for alternative/complementary modes of cardioprotective action beyond simple iron chelation.

• MeSH
• antioxidancia chemie   farmakologie   MeSH
• antracykliny škodlivé účinky   chemie   farmakologie   MeSH
• chelátory škodlivé účinky   chemie   farmakologie   MeSH
• kardiotonika škodlivé účinky   chemie   farmakologie   MeSH
• kovy škodlivé účinky   MeSH
• lidé MeSH
• myokard metabolismus   MeSH
• oxidace-redukce MeSH
• oxidační stres * MeSH
• protinádorové látky škodlivé účinky   chemie   farmakologie   MeSH
• razoxan škodlivé účinky   chemie   farmakologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• signální transdukce * MeSH
• srdce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antioxidancia MeSH
• antracykliny MeSH
• chelátory MeSH
• kardiotonika MeSH
• kovy MeSH
• protinádorové látky MeSH
• razoxan MeSH
• reaktivní formy kyslíku MeSH