Redox and apoptotic potential of novel ruthenium complexes in rat blood and heart.

Ruthenium(II) complexes offer the potential for lower toxicity compared with platinum(II) complexes. Our study aimed to compare cardiotoxicity of [Ru(Cl-tpy)(en)Cl][Cl], [Ru(Cl-tpy)(dach)Cl][Cl], [Ru(Cl-tpy)(bpy)Cl][Cl], cisplatin, and saline through assessment of redox status and relative expression of apoptosis-related genes. A total of 40 Wistar albino rats were divided into five groups. Ruthenium groups received a single dose of complexes intraperitoneally (4 mg/kg/week) for a 4-week period; cisplatin group received cisplatin (4 mg/kg/week) and control group received saline (4 mL/kg/week) in the same manner as ruthenium groups. In collected blood and heart tissue samples, spectrophotometric determination of oxidative stress biomarkers was performed. The relative expression of apoptosis-related genes (Bcl-2, Bax, and caspase-3) in hearts was examined by real-time polymerase chain reaction. Our results showed that systemic and cardiac pro-oxidative markers (thiobarbituric acid reactive substances and nitrite) were significantly lower in ruthenium groups compared with cisplatin group, while concentrations of antioxidative parameters (catalase, superoxide dismutase, and oxidized glutathione) were significantly higher. Ruthenium administration led to significantly lower gene expression of Bax and caspase-3 compared with cisplatin-treated rats, while Bcl-2 remained unchanged. Applied ruthenium complexes have less pronounced potential for induction of oxidative stress-mediated cardiotoxicity compared with cisplatin. These findings may help for future studies that should clarify the mechanisms of cardiotoxicity of ruthenium-based metallodrugs.

The perfusion of cisplatin and cisplatin structural analogues through the isolated rat heart: The effects on coronary flow and cardiodynamic parameters.

The therapeutic use of cisplatin for the treatment of solid tumours is associated with organ toxicity. Amongst those, the cardiotoxicity is an occasional but very serious and severe side effect. To prevent or reduce these negative effects, many cisplatin analogues have been synthesized and evaluated in terms of being a less toxic and more effective agent. In present study, we examined the effects of cisplatin and its three analogues in the isolated rat heart to determine whether changes in the structure of the platinum complexes (changing of carrier ligands - ethylenediamine; 1,2-diaminocyclohexane; 2,2':6',2''-terpyridine) can influence their cardiotoxic effects. The results of our research indicate that the introduction of aromatic rings in the structure of the platinum complexes has a negative influence on the heart function. Conversely, the other two examined complexes had less negative effects on heart function compared to cisplatin. Our findings may be of interest for a possible synthetic strategy of introducing a carrier ligand that will exert a less cardiotoxic effect.

Cisplatin and cisplatin analogues perfusion through isolated rat heart: the effects of acute application on oxidative stress biomarkers.

Drug-induced oxidative stress can occur in numerous tissues and organ systems (liver, kidney, ear, nervous system, and cardiovascular system). Cancer therapy with cisplatin is associated with side effects to which oxidative stress may contribute. We have compared the influences of cisplatin (reference compound) and its' analogues (dichloro(1,2-diaminocyclohexane)platinum(II) and chloro(2,2':6',2″-terpyridine)platinum(II)) in a model of isolated rat heart using the Langendorff technique. The production of oxidative stress biomarkers, antioxidant enzymes, myocardial damage, and expression of Bax, OH-1, and SODs were studied. Cisplatin and the analogues were perfused at concentration of 10-6 and 10-5 M during 30 min. The results of this study showed that examined platinum complexes had different ability to induce oxidative stress of isolated perfused rat heart. Varying the carrier ligands, such as 1,2-diaminocyclohexane and 2,2':6',2″-terpyridine, related to amino ligands (cisplatin) directly influenced the strength to induce production of oxidative stress biomarkers. Introducing 2,2':6',2″-terpyridine ligands provoked the smallest changes in antioxidant enzymes activity, lipid peroxidation, and expression of heme oxygenase-1, that undoubtedly indicated that this complex had the lowest impact on redox status in heart tissue. These findings may be useful in synthesis of novel platinum analogues with lower potential for oxidative stress induction. However, the fact that platinum complexes could induce toxic effects in the heart by other mechanisms should be taken into the consideration.

Platinum Complexes-Induced Cardiotoxicity of Isolated, Perfused Rat Heart: Comparison of Pt(II) and Pt(IV) Analogues Versus Cisplatin.

We have compared the cardiotoxicity of five platinum complexes in a model of isolated rat heart using the Langendorff technique. These effects were assessed via coronary flow (CF) and cardiac functional parameters. cis-Diamminedichloroplatinum(II) (cisplatin, CDDP), dichloro-(1,2-diaminocyclohexane)platinum(II) (Pt((II))DACHCl2), dichloro-(ethylenediamine)platinum(II) (Pt((II))ENCl2), tetrachloro-(1,2-diaminocyclohexane)platinum(IV) (Pt((IV))DACHCl4) and tetrachloro-(ethylenediamine)platinum(IV) (Pt((II))ENCl4) were perfused at increasing concentrations of 10(-8), 10(-7), 10(-6), 10(-5) and 10(-4) M during 30 min. In this paper, we report that cisplatin-induced dose-dependent effects on cardiac contractility and coronary flow both manifested as decrease in cardiac contractile force (dP/dt)max, heart rate and significant reduction in CF. Pt((II))ENCl2, Pt((IV))ENCl2 and Pt((IV))DACHCl4 did induce dose-dependent response only in case of CF. Our results could be also important for better understanding dose-dependent side effects of potential metal-based anticancer drugs.

Risk factors for lethal outcome in patients with delirium tremens - psychiatrist's perspective: a nested case-control study.

BACKGROUND: The aim was to identify potential risk factors for lethal outcome in patients with delirium tremens (DT) treated in the psychiatric setting. METHODS: In a nested case-control study, a total of 190 medical records of patients with DT hospitalized at the Psychiatric Clinic in Serbia between 2002 and 2011 were reviewed and analyzed. The characteristics of patients who died (cases) were compared with those who survived (controls). For each case, two controls (matched for age, gender, and year of hospitalization) were randomly chosen. RESULTS: Significant differences between cases and controls were found for serum potassium levels (p < 0.001), the number of hospitalizations (p < 0.001), and duration of hospitalization (p < 0.001). A significant association with lethal outcome was found for serum potassium levels even in the normal range (adjusted odds ratio 40.52; 95% CI 1.20, >1,000.00; p = 0.004). CONCLUSIONS: Even though the number and duration of psychiatric hospitalizations were identified as factors determining survival after admission for DT, only serum potassium levels were found to be significant. Patients with an increase in potassium (or absence of hypokalemia) may require more intensive treatment. Monitoring of serum levels of potassium is important not only as an indicator for replacement but also as an indicator of maladaptation.

Toxic effects of palladium compounds on the isolated rat heart.

Taken into consideration limited data about effects of palladium on cardiovascular system, the aim of our study was to compare toxicity of inorganic and organic palladium compounds on the isolated rat heart. The hearts (total number n=30, 6 for each experimental group) excised from Wistar albino rats, male sex, age 8 weeks, and body mass 180-200 g, were retrogradely perfused according to the Langendorff technique at constant perfusion pressure (70 cm H2O). After the insertion of sensor in the left ventricle, the parameters of heart function: maximum rate of left ventricular pressure development (dP/dt max), systolic left ventricular pressure (SLVP), diastolic left ventricular pressure (DLVP), mean blood pressure (MBP) and heart rate (HR)), were continuously registered. The experiments were performed during control conditions, and in the presence of perfusion with incresing concentration of the following: (triethanolamine (TEA), triethanolamine acetate (TEAA), palladium(II)chloride (PdCl2), and trans-dichlorobis(triethanolamine-N)palladium(II) complex (trans-[PdCl2(TEA)2])) started every 30 minutes (30, 60, 90, 120 minute). dP/dt max was not affected significantly by either TEAA, TEA, PdCl2 or Pd complex. SLVP was, also, not affected significantly by either TEAA, TEA, PdCl2, or Pd complex. DLVP was significantly decreased by both TEAA and PdCl2, while TEA and Pd complex did not show significant effect. MBP was significantly decreased only by PdCl2, while TEAA, TEA and Pd complex did not show significant effect. HR was significantly decreased by all compounds- PdCl2, TEAA, TEA and Pd complex. In our study, inorganic palladium compound (PdCl2) induced clear depression of the isolated rat heart contractility, manifested as drop in diastolic and mean blood pressure , and as decrease of the heart rate. On the other hand, it seems that palladium, when bound in an organic compound (linked to TEA in Pd complex), does not contribute significantly to cardio-toxicity in our experimental conditions.

Human platelets perfusion through isolated guinea-pig heart: the effects on coronary flow and oxidative stress markers.

Present study was designed to evaluate effect of perfusion with human platelets reach plasma (PRP) on coronary flow (CF) and oxidative stress markers in coronary vascular bed of the isolated guinea-pig heart. In coronary venous effluent the following oxidative stress markers were estimated: nitrite as a measure of nitric oxide (NO) production, superoxide anion (O2(-)), and index of lipid peroxidation (TBARS). Isolated guinea-pig hearts (n = 6, b.m. 250-300 g) were perfused according to a Langendorff's technique at different (30, 70, and 120 cmH2O) coronary perfusion pressures (CPP). Samples were collected at control conditions and during perfusion with platelets rich plasma (PRP) obtained either from healthy volunteers or from patients with acute myocardial infarction (PRP (AMI)) with/or without previous inhibition of NO synthase (NOS) by Nomega-nitro-L-arginine monomethyl ester (L-NAME, 30 micromol/l). PRP and PRP (AMI) perfusion induced reduction of CF and all evaluated oxidative stress parameters. The reduction of CF was more potentiated in PRP (AMI) as in PRP group, while oxidative stress parameters where significantly decreased only in PRP (AMI). In addition, previous blockade of NOS by L-NAME potentiated these effects only in PRP (AMI) group. It can be concluded that non-activated and activated platelets interact with coronary endothelium in similar way, with more significant influence of activated platelets on CF and oxidative stress markers.

Aromatic interactions in unusual backbone nitrogen-coordinated zinc peptide complexes: a crystallographic and spectroscopic study.

A series of zinc complexes with dipeptide ligands of the type Dpg-Xaa was synthesized, where Dpg is dipicolylglycine and Xaa is phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp), 2-naphthylalanine (Nal), or glycine (Gly). It was shown that aromatic interactions promote the unusual coordination of an anionic peptide backbone nitrogen atom to zinc. This binding mode was, for the first time, characterized by X-ray structure analyses of the electrically neutral complexes [(Dpg-Phe)(-H)Zn], [(Dpg-Tyr)(-H)Zn], [(Dpg-Trp)(-H)Zn], and [(Dpg-Nal)(-H)Zn]. The pKa values for amide nitrogen deprotonation were determined by 1H NMR titrations {[(Dpg-Phe)Zn], 7.17; [(Dpg-Tyr)Zn], 6.85; [(Dpg-Trp)Zn], 6.85; [(Dpg-Nal)Zn], 6.64; [(Dpg-Gly)Zn], 8.54}. It was calculated that aromatic interactions contribute ca. -8 to -11 kJ/mol of stabilizing free enthalpy changes in the derivatives with aromatic amino acid side chains. These are the first quantitative data obtained for crystallographically characterized metal complexes. A comparison with the literature shows that it is difficult to distinguish between pi-cation attraction and pi-pi stacking. However, it is evident that modification of small peptides with synthetic pyridine ligands enhances their ability to stabilize secondary structures by noncovalent interactions. This is an important consideration for the design of biomimetic metallopeptides.

[Effects of platelet single passage on coronary circulation in the isolated guinea-pig heart: focus on the L-arginine: nitric oxide system]. / Efekat jednokratne pasaze trombocita na koronarnu cirkulaciju izolov anog srca zamorceta: fokus na l-arginin:NO sistem.

INTRODUCTION: In order to evaluate endothelial response to platelet single passage through coronary vascular bed, experiments on isolated guinea-pig hearts perfused by the Langendorff method at constant pressure were performed. MATERIAL AND METHODS: Platelet single passage was performed with platelet-rich plasma obtained from healthy volunteers, as well as from patients with acute myocardial infarction. Hearts, isolated from guinea-pigs of either sex were perfused with Krebs-Hensenleit buffer. After a stabilization period of 30 minutes at 70 cm H2O, coronary perfusion pressure decreased to 30 cm H2O and increased to 120 cm H2O. After basic protocol, hearts were perfused with PRP, PRP-AMI alone or in combination with nitric oxide synthase inhibitor, N(omega)-nitro-L arginine methyl ester (L-NAME)--30 M, and nitrite outflow (NO2-) was measured. RESULTS: Basal (at 70 cm H2O) coronary flow (CF) and NO2- was 4.71+/-0.43 ml/min and 0.55+/-0.13 nmol/min/g wt. PRP induced significant decrease of CF at all values of CPP (from 32% at 30 cm H2O to 27% at 120 cm H2O), with parallel NO2- reduction (from 25% to 28%). When L-NAME, 30 M was added, PRP was much less effective: CF was reduced from 13% to 5%, with parallel changes of NO2- (reduction of 10% at all CPP values). PRP-AMI induced higher degree of CF reduction (from 42% to 44%) with NO2 reduction from 23% to 35%. PRP-AMI after applied L-NAME induced also less CF-reduction (from 18% to 12%), with similar NO2- reduction (from 18% to 12%). CONCLUSION: Our findings show that effects of platelet single passage through coronary vascular bed should be affected by NO in isolated guinea-pig hearts.