Antagonists of Vitamin K-Popular Coumarin Drugs and New Synthetic and Natural Coumarin Derivatives.

Many natural coumarins and their chemically synthesized analogs and derivatives exert diverse properties, such as anticancer, antioxidant, anti-inflammatory, or anticoagulant, with the latter being of the utmost importance. The widely used warfarin, acenocoumarol, and phenprocoumon exert anticoagulant properties by inhibiting the vitamin K epoxide reductase complex. In this interdisciplinary review, we present biochemical principles of the coagulation processes and possible methods for their tuning based on the use of coumarins. We also summarize chemical methods of synthesis of coumarins and discuss structures and properties of those that have been used for a long time, as well as newly synthesized compounds. Brief information on the clinical use of coumarins and other anticoagulant drugs is given, including the severe effects of overdosing and methods for reversing their action.

ABCB1-Gen-Polymorphismus in einer polnischen Kohorte ist mit Risiko für bullöses Pemphigoid assoziiert.

HINTERGRUND UND ZIELE: Polymorphismen im ABCB1-Gen, das für das P-Glykoprotein kodiert, können die intrazelluläre Konzentration von Xenobiotika beeinflussen und so zur Entwicklung von Autoimmunerkrankungen, einschließlich des bullösen Pemphigoids (BP), beitragen. In der vorliegenden Studie sollte untersucht werden, ob in einer polnischen Kohorte die C3435T- und G2677T/A-Polymorphismen im ABCB1-Gen mit dem Risiko für ein BP assoziiert sind. PATIENTEN UND METHODIK: Die Studie umfasste 71 Patienten mit BP und 156 gesunde Probanden. Der C3435T-Polymorphismus wurde mittels PCR-RFLP bestimmt und der G2677T/A-Polymorphismus mittels Allel-spezifischer PCR. ERGEBNISSE: Es gab zwar keine Korrelation zwischen dem C3435-Polymorphismus und dem BP-Risiko, aber wir konnten eine derartige Assoziation hinsichtlich des G2677T/A-Polymorphismus nachweisen. Das relative Risiko eines BP war bei Personen mit dem 2677TA-Genotyp um mehr als den Faktor fünf erhöht (OR = 5,52; p = 0,0063) und bei Trägern des 2677TT-Genotyps mehr als verdoppelt (OR = 2,40; p = 0,0076). Mit 2,40 (p = 0,000018) war die OR bei Trägern des 2677T-Allels ebenfalls erhöht. Die höhere Prävalenz des 2677GG-Genotyps und des 2677G-Allels bei der Kontrollgruppe sowie eine OR < 1,0 (0,22 beziehungsweise 0,33) legen eine Schutzfunktion des 2677G-Allels hinsichtlich der Ausbildung eines BP nahe. SCHLUSSFOLGERUNGEN: Die Ergebnisse der vorliegenden Studie zeigen, dass der G2677T/A-Polymorphismus im ABCB1-Gen das Risiko für die Entstehung eines BP beeinflussen könnte.

ABCB1 gene is associated with the risk of bullous pemphigoid in a polish population.

BACKGROUND AND OBJECTIVES: Polymorphisms in the P-glycoprotein-encoding ABCB1 gene may affect the intracellular concentration of xenobiotics, and thus contribute to the development of autoimmune diseases, including bullous pemphigoid (BP). The objective of the present study was to investigate whether there is an association between the C3435T and G2677T/A polymorphisms in the ABCB1 gene and the risk of BP in a Polish population. PATIENTS AND METHODS: The study included 71 patients with BP and 156 healthy volunteers. Determination of the C3435T polymorphism was carried out using PCR-RFLP; the G2677T/A polymorphism, using allele-specific PCR. RESULTS: While there was no correlation between the C3435T polymorphism and the risk of BP, we did find such an association with respect to the G2677T/A polymorphism. The relative risk of BP was more than five times greater in individuals with the 2677TA genotype (OR = 5.52, p = 0.0063), and more than twice as high in carriers of the 2677TT genotype (OR = 2.40, p = 0.0076). At 2.40 (0.000018), the OR in carriers of the 2677T allele was also increased. The greater prevalence of the 2677GG genotype and the 2677G allele in the control group, as well as the OR < 1.0 (0.22 and 0.33, respectively), suggest a protective role of the 2677G allele with respect to the development of BP. CONCLUSIONS: The results of the present study indicate that the G2677T/A polymorphism in the ABCB1 gene may affect the risk of developing BP.

Assessment of release factors of b-type natriuretic peptide during the exercise test in patients with diabetes and after myocardial infarction with preserved left ventricular systolic function.

INTRODUCTION: The increased concentration of B-type natriuretic peptide (BNP) is an expression of overload of the heart, regardless of the cause. Exercise test is a helpful method of assessing the exercise tolerance and myocardial ischemia. THE AIM: The aim of the study is to determine the factors that cause the release of BNP during the exercise test. MATERIAL AND METHODS: The study included 99 patients with diabetes and after myocardial infarction with preserved left ventricular ejection fraction (EF≥40%). Before performing the exercise test (ExT) echocardiography was performed and blood sample was taken to determine BNP. Immediately after the exercise test another blood sample was taken to determine BNP. RESULTS: In 22 patients (22%) an increase in BNP ≥35pg/ml after the exercise test was observed. In patients with EF.

The effect of hypoxia on PGE2-stimulated cAMP generation in HMEC-1.

Prostaglandin E2 (PGE2) is generated in various cells, including endothelial cells, and is responsible for various functions, such as vascular relaxation and angiogenesis. Effects of PGE2 are mediated via receptors EP1-EP4, among which EP2 and EP4 are coupled to Gs protein which activates adenylate cyclase (AC) and cAMP synthesis. The aim of this work was to study the ability of human microvascular endothelial cells (HMEC-1) to synthesize cAMP in the presence of PGE2, and to determine the effect of hypoxia on the PGE2- stimulated cAMP level. It was decided to evaluate the effect of PGE2 on the secretion of VEGF, an inducer of angiogenesis. In summary, our findings show that PGE2 induces cAMP production, but hypoxia may impair PGE2-stimulated activity of the AC-cAMP signaling pathway. These results suggest that the cardioprotective effect of PGE2/EP4/cAMP may be attenuated during ischemia. Furthermore, this study indicates that the pro-angiogenic effect of PGE2 is not associated with VEGF secretion in HMEC-1 cells.

THE EFFECT OF IBUPROFEN ON bFGF, VEGF SECRETION AND CELL PROLIFERATION IN THE PRESENCE OF LPS IN HMEC-1 CELLS.

Ibuprofen belongs to the group of non-selective cyclooxygenase (COX) inhibitors, also known as traditional non-steroidal anti-inflammatory drugs (NSAIDs). Bacterial lipopolysaccharide, an inflammatory mimicking agent, is responsible for the production of prostaglandins and growth factors (VEGF and bFGF), and as inflammation and angiogenesis are closely associated with osteoarthritis, these factors play a functional role in the cardiovascular system. Therefore, the main aim of our study was to examine the effect of ibuprofen on cell viability and proliferation of HMEC-1 cells and VEGF and bFGF secretion under the inflammatory conditions. The effect of NSAID and LPS on bFGF and VEGF was analyzed by ELISA. Cell viability was measured by the MTT method and the proliferation by the [3H-thymidine test. LPS at 100 µg/mL stimulated the secretion of VEGF and bFGF by HMEC-1 cells. Ibuprofen at concentrations of 0.1 and 1 mM intensified the secretion of LPS-induced VEGF in a statistically significant manner (p < 0.05). Both concentrations of ibuprofen inhibited LPS-stimulated bFGF secretion (p < 0.05) in HMEC-1 in a concentration-dependent manner. The non-selective COX inhibitor decreased proliferation and cell viability induced by LPS in a concentration-dependent manner. The observed effects of ibuprofen on endothelial cells may further explain its effects as well as other NSAIDs on the cardiovascular system function in cardiovascular diseases.

Concurrent rho-kinase and tyrosine kinase platelet-derived growth factor inhibition in experimental pulmonary hypertension.

BACKGROUND: We hypothesized that inhibition of Rho-kinase by fasudil, together with tyrosine kinase platelet-derived growth factor (PDGF) receptor inhibition by imatinib, results in greater pulmonary arterial hypertension (PAH) improvement. METHODS: The effects of such regimens were investigated on hemodynamics, right ventricle hypertrophy, PDGF and ROCK in experimental monocrotaline (MCT)-induced pulmonary hypertension. Fourteen days after MCT injection, male rats were treated orally for another 14 days with imatinib, fasudil or their combination. RESULTS: Concurrent imatinib and fasudil administration reversed an MCT-induced increase in right ventricular pressure more than either drug alone and decreased right ventricle hypertrophy (right ventricle weight to left ventricle plus septum weight ratio) significantly. The simultaneous administration of fasudil and imatinib caused a further decrease in plasma PDGF-BB levels compared to either drug alone. CONCLUSIONS: Inhibition of Rho-kinase by fasudil in addition to tyrosine kinase PDGF inhibition by imatinib can result in further PAH improvement. Such outcome may result from additional impact of the Rho-kinase inhibitor on the decrease in PDGF-induced effects.

PPARγ, NF-κB and the UPR pathway as new molecular targets in the anti-inflammatory actions of NSAIDs: Novel applications in cancers and central nervous system diseases?

Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, diclofenac, ibuprofen, or celecoxib have a well-established and unquestionable role in the human therapeutic arsenal, but still new perspectives are being discovered. This review presents new anti-inflammatory mechanisms of NSAIDs action, other than the classical one, i.e., the inhibition of cyclooxygenase (COX) isoforms leading to the prostanoids synthesis blockage. Literature data show that this group of drugs can activate anti-inflammatory peroxisome proliferator-activated receptor gamma (PPARγ), inhibit pro-inflammatory nuclear factor-κB (NF-κB) activation or modulate the components of the unfolded protein response (UPR) pathway. These alternative pathways induced by NSAIDs may not only enhance their basic anti-inflammatory mechanism of action but also promote other effects of the drugs such as anti-cancer. It was also proved that neuroinflammation, with the involvement of NF-κB, PPARγ and the components of the UPR pathway has an essential impact on the development of central nervous system (CNS) diseases. Thus, it seems possible that these new molecular targets may expand the use of NSAIDs, e.g., in the treatment of cancers and/or CNS disorders.

The beneficial impact of fasudil and sildenafil on monocrotaline-induced pulmonary hypertension in rats: a hemodynamic and biochemical study.

Pulmonary arterial hypertension (PAH) still cannot be cured effectively, hence the search for novel treatments continues. The effects of sildenafil (25 mg/kg body weight) and fasudil (30 mg/kg body weight) given alone or in combination, on normalization of right ventricular pressure (RVP), right ventricle mass, as well as the levels of several biomarkers (HDL-C, BNP, VEGF-A), were assessed in a rat model of monocrotaline (MCT)-induced PAH. MCT (60 mg/kg body weight) induced clear PAH in male Wistar rats. After 21 days, a significant decrease in RVP accompanied by a reduction of right ventricular hypertrophy - a significant decrease in the right ventricle/left ventricle plus septum ratio - as a result of sildenafil or fasudil administration was assessed. The administration of fasudil and sildenafil alone or in combination caused a significant decrease in plasma BNP level as compared to MCT-treated rats. Fasudil alone or with sildenafil, but not sildenafil alone, significantly increased HDL-C level as compared to MCT-treated rats. Fasudil and sildenafil given alone or in combination caused a significant increase in plasma VEGF-A level as compared to rats exposed to MCT.

Concomitant administration of different doses of simvastatin with ivabradine influence on PAI-1 and heart rate in normo- and hypercholesterolaemic rats.

Ivabradine is a novel heart rate lowering agent that inhibits I(f) ionic current in the sinus node and demonstrates antiischaemic and antianginal activity. The aim of the paper was to investigate the effect its dose-dependent drug-drug interaction with simvastatin inhibitor HMGCo-A has on PAI-1 blood level, heart rate and blood pressure. The experiments were performed in hyper- and normocholesterolemic Wistar rats receiving simvastatin (1 and 20 mg × kg(-1) bw) with ivabradine (10 mg × kg(-1) bw) during a 4-week period. Ivabradine exacerbated the decrease of PAI-1 in normocholesterolemic animals receiving simvastatin at a dose of 1 mg/kg bw and was not observed to have any significant influence on the PAI-1 values in rats receiving 20 mg × kg(-1) bw simvastatin. Ivabradine, coadministered with simvastatin given at a dose of 20 mg × kg(-1) bw, significantly slowed the heart rate in normocholesterolaemic and hypercholesterolaemic groups as compared to the group receiving ivabradine alone. Conclusion. The administration of ivabradine to normocholesterolaemic and hypercholesterolaemic rats receiving simvastatin significantly exacerbated the slowing of heart rate with no effect on blood pressure. The administration of ivabradine has been shown to demonstrate different effects on PAI-1 values depending on lipid disorders.

Analysis of genetic polymorphisms of glutathione S-transferase (GSTP1, GSTM1, and GSTT1) in Polish patients with systemic sclerosis.

AIM: It is commonly assumed that a genetically determined polymorphism of xenobiotic biotransformation plays a particular role in the development of such disease entities in which chemical compounds and environmental pollutants are relevant etiologic factors. Systemic sclerosis (SSc, scleroderma) belongs to diseases of connective tissue, characterized by chronic inflammation developing on an autoimmune background. The current state of knowledge on the etiopathogenesis of autoimmune diseases indicates the existence of many factors affecting the development of the disease, including factors of the external environment. Considering all the above, a study on a role of genetic polymorphisms of glutathione S-transferase has been undertaken in which predisposition to SSc in a Polish population was assessed. METHODS: The study was carried out in 161 subjects: 61 patients with SSc and 100 healthy volunteers. A determination of the polymorphism of GSTM1 and GSTT1 was performed with a multiplex PCR (polymerase chain reaction). The GSTP1 polymorphism was determined by using the PCR restriction fragment length polymorphism. RESULTS: The risk of developing SSc was 3-fold higher for persons with the null GSTM1 and GSTT1 genotypes (odds ratio [OR] = 3.3; P = .0051). The risk for SSc was also demonstrated to be over 2.5-fold greater in the GSTP1 Ile/Val genotype individuals (OR = 2.62; P = .0037). Carriers of the GSTP1 Val variant allele had a greater than 2-fold increase in SSc risk (OR = 2.41; P = .0006). CONCLUSION: The genetic polymorphism of glutathione S-transferase may affect the risk of SSc in a Polish population.

Dose-dependent influence of two-week administration of simvastatin and metoprolol injection on the blood pressure in normocholesterolemic rats.

UNLABELLED: Beta-blockers are widely used in clinical practice. It is connected with their multiple cardiac effects: slowing heart rate, decrease of myocardial contractility and lowering of systemic blood pressure. Early use of beta-blocker in acute myocardial infarction reduces the risks of reinfarction and ventricular fibrillation. However, the above effects may be associated with the risk of cardiogenic shock. Many patients with cardiovascular diseases receiving beta-blockers are recommended to statin therapy, as well. There are several reports indicating that statins have beneficial cardiovascular effects through their broad spectrum of cholesterol-independent action. It has been revealed that statins could decrease blood pressure, as well. The aim of the study was to evaluate the influence of simvastatin in different doses and metoprolol injection on the blood pressure in normocholesterolemic rats. The experiments were performed on Wistar rats, outbred males. Simvastatin at 1, 10 and 20 mg/kg or vehicle (0.2% methylcellulose) were given intragastrically during two-week period. After two week simvastatin administration, rats were injected intraperitoneally with metoprolol at 5 mg/kg b. w. The arterial blood pressure signals were provided by Isotec pressure transducer connected to a direct current bridge amplifier and catheter was implanted into the right carotid artery. CONCLUSION: Two week administration of simvastatin in different doses to normocholesterolaemic rats does not modify metoprolol impact on the blood pressure.

Interaction between different doses of simvastatin after two-week administration and metoprolol injection on the heart rate in normocholesterolemic rats.

UNLABELLED: Heart rate slowing is the beneficial effect after beta-blocker administration in cardiac heart failure and ischemic heart disease. However, bradycardia and another cardiac disturbances after beta-blockers therapy are the most dangerous side effects. Many patients with cardiovascular diseases receiving beta-blockers are recommended to statin therapy, as well. Previous study showed that statins may desensitize beta-adrenergic signaling, in cardiac myocytes via reduction of isoprenylation of G-protein gamma-subunits. The aim of the study was to evaluate the influence of simvastatin at different doses and metoprolol injection on the heart rate in normocholesterolemic rats. The experiments were performed in Wistar rats, outbred males. Simvastatin at 1, 10 or 20 mg/kg or vehicle (0.2% methylcellulose) were given intragastrically during two-week period. After two week administration of simvastatin, rats were injected intraperitoneally with metoprolol at 5 mg/kg b.w. The heart rate signals were provided by Isotec pressure transducer connected to a direct current bridge amplifier and catheter was implanted into the right carotid artery. No changes in the baseline heart rate among all groups of the animals were observed. Metoprolol administration caused statistically significant decrease in heart rate in all groups of rats. In the control group, after metoprolol administration heart rate slowed down to 83.11 +/- 1.11% (p < 0.05) of the baseline values, in group receiving simvastatin at 1 mg/kg b.w. 82.72 +/- 5.49% (p < 0.05), in group receiving simvastatin at 10 mg/kg b.w. 85.13 +/- 4.75 (p <0.05) and in group receiving simvastatin at 20 mg/kg b.w. 85.13 +/- 4,75% (p < 0.05) of the baseline values. No significant decrease in heart rate in the control group as compared to groups receiving simvastatin in different doses was observed. No significant changes among animals receiving simvastatin in different doses were observed, as well. CONCLUSION: Two week administration of simvastatin in different doses to normocholesterolaemic rats does not modify metoprolol-induced depressing influence on the heart rate.

Haplotypes of ABCB1 1236C >T (rs1128503), 2677G >T/A (rs2032582), and 3435C >T (rs1045642) in patients with bullous pemphigoid.

Bullous pemphigoid (BP) constitutes the most prevalent disease in the group of bullous dermatoses with the autoimmune background. Some authors suggest that certain cytokines (IL-2, IFN-γ) may be transported by P-glycoprotein (P-gp), the product of the ABCB1 gene. ABCB1 polymorphism might affect not only the effectiveness of treatment with drugs that are P-gp substrates but also contribute to the development of diseases, including BP. In the present work, we resolved to conduct a haplotype analysis of ABCB1 in patients with BP and to answer the question of whether any of the haplotypes are able to affect the incidence of this entity. The study involved 71 patients with BP and 100 healthy volunteers. Determination of polymorphisms 1236C > T and 3435C > T in ABCB1 was carried out with the PCR-RFLP (Polymerase Chain Reaction-Restriction Fragment Length Polymorphism) method. The 2677G > T/A ABCB1 polymorphism was analyzed with the allele-specific PCR method. It was observed that the 1236T-2677G-3435T haplotype occurred with a statistically significantly lower frequency in patients with BP than in controls (1.4 vs. 10.0%). Carriers of this haplotype were also shown to have had a low relative risk for BP (OR = 0.13, p = 0.003). Haplotype analysis of ABCB1 conducted in patients with BP demonstrated that the 1236T-2677G-3435T haplotype may protect against development of this entity.

Statins: a new insight into their mechanisms of action and consequent pleiotropic effects.

In the recent years, 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase inhibitors have emerged as the most important class of lipid-lowering agents. Through inhibition of HMG-CoA reductase, they restrict the rate-limiting step of cholesterol synthesis resulting in up-regulation of low density lipoproteins (LDL) receptors on the cell membrane and reduction of atherogenic LDL consequences. The wide spectrum of non-lipid-mediated pleiotropic effects of statins includes: improvement of endothelial dysfunction, increased nitric oxide bioavailability, antioxidant effects, anti-inflammatory and immunomodulatory properties, stabilization of atherosclerotic plaques and inhibition of cardiac hypertrophy. Several clinical trials have demonstrated and confirmed these beneficial effects of statins in cardiovascular disorders, in primary and secondary prevention settings. Recent studies have reported that the physiological background of the widespread therapeutic efficacy of HMG-CoAreductase inhibitors involved various mechanisms, partially associated with statin impact on posttranslational modifications (e.g. prenylation process). In this review, we have focused on some of them, especially including the statin impact on the endothelial dysfunction and inflammation, peroxisome poliferator-activated receptor (PPAR), beta-adrenergic signaling, renin-angiotensin system and their possible mutual mechanistic linkage.

Genotype and haplotype analysis of ABCB1 at 1236, 2677 and 3435 among systemic sclerosis patients.

Systemic sclerosis (SSc) belongs to the group of systemic diseases of the connective tissue, which are characterized by a chronic autoimmune inflammatory process. P-glycoprotein, initially associated with the drug resistance in patients with cancer, becomes more and more often a subject of considerations in terms of its significance in the development of illnesses, including autoimmune diseases. The aim of the study was an attempt to answer the question whether there was a relationship between ABCB1 polymorphisms and morbidity of systemic sclerosis in a Polish population. The study was carried out in 61 patients with SSc and 100 healthy volunteers. Determination of polymorphisms C1236T and C3435T in ABCB1 was carried out with the PCR-RFLP (polymerase chain reaction - restriction fragment length polymorphism) method. The G2677T/A ABCB1 polymorphism was analysed with the allele-specific PCR method. No statistically significant differences were observed in the frequencies of ABCB1 genotypes and alleles between SSc patients and the control group. It was observed that haplotype 1236 C-2677 G-3435 T occurred in the group of patients with SSc statistically more frequently than in the group of healthy volunteers (25% vs. 15%; p = .032). Carriers of the haplotype demonstrated almost a twofold greater risk of SSc (OR = 1.85; p = .032). No statistically significant correlations for the other nine haplotypes were found. Presented results concerning the relationship of ABCB1 polymorphisms with susceptibility to systemic sclerosis are the first ones that were obtained in a Polish population. They imply that single nucleotide polymorphisms do not affect the risk for SSc, but the 1236 C-2677 G-3435 T haplotype might increase this risk.

Influence of simvastatin at high dose and nifedipine on hemodynamic parameters in rabbits.

Recent findings in vitro have shown that statins could reduce cardiomyocyte viability. The correlation between statin cardiotoxicity, assessed in vitro, and cardiac efficiency, investigated in vivo has not been estimated so far. The aim of the present experiment was to establish the impact of high-dose simvastatin on the hemodynamic parameters, especially on myocardium efficiency, after continuous infusion of dopamine. Moreover, hemodynamic interaction between simvastatin and nifedipine, metabolized by the same izoenzyme CYP3A4 was examined. The experiments were performed on twenty seven New Zealand white rabbits. The animals were divided into four groups receiving: 0.2% methylcellulose (MC) (control group), nifedipine, simvastatin or simvastatin + nifedipine, for 14 days (p.o.). The following hemodynamic parameters were estimated: cardiac output index (COI), heart rate (HR), systolic blood pressure (SBP), mean blood pressure (MBP), diastolic blood pressure (DBP) and total peripheral resistance index (TPRI). The registration of hemodynamic parameters was performed by Doppler method (Hugo Sachs Electronic Haemodyn). Dopamine did not cause a statistically significant increase in COI in rabbits receiving simvastatin alone or concomitantly with nifedipine. Nifedipine significantly lowered COI, BP and HR in rabbits if given simultaneously with simvastatin. In conclusion, administration of nifedipine may elicit detrimental impact on statin therapy, resulting in the worsening of cardiac performance. This may suggest another mechanism of drug-drug interaction than the one based on CYP3A4 inhibition.

Amifostine improves hemodynamic parameters in doxorubicin-pretreated rabbits.

Amifostine reduces nephrotoxicity and myelotoxicity of alkylating agents. Little is known about its role in preventing cardiotoxicity. We studied if amifostine could affect the hemodynamic parameters in doxorubicin-pretreated rabbits. The animals were divided into six groups consisting of 6 rabbits each. Group 1--doxorubicin iv 2 mg/kg of body weight 4 times every 14 days (cumulative dose 8 mg/kg); group 2--a dose of doxorubicin was 3 mg/kg (cumulative dose 12 mg/kg); groups 3 and 4--amifostine iv 30 mg/kg 15 min prior to doxorubicin 2 and 3 mg/kg, respectively, groups 5 and 6--amifostine- and physiological saline-treated controls. Two-three weeks after the last dose the animals were anesthetized and cardiac index (CI) i.e. cardiac output/body weight, and total peripheral resistance (TPR) were calculated using the method of human I(125) albumin dilution. Mean CI was 71.4 +/- 40.5 ml/min/kg in group 2, 135.8 +/- 41.2 in group 5 (p < 0.001), and 116.4 +/- 47.8 in group 6 (p < 0.001), TPR was 4.7 +/- 3.3 kPa x s/l, 1.1 +/- 1.2 (p < 0.001), and 1.9 +/- 1.1 (p < 0.001), respectively. In group 4, CI was 135.4 +/- 33.2, and TPR was 1.1 +/- 0.6. The differences in CI and TPR between groups 2 and 4 were statistically significant (p < 0.001). In conclusion, pretreatment with doxorubicin at the total dose of 12 mg/kg significantly reduced CI and increased TPR. Amifostine improved CI and TPR in doxorubicin-pretreated rabbits.

The influence of simvastatin at high dose and diltiazem on myocardium in rabbits, the biochemical study.

3-Hydroxy-3-methyl-glytaryl coenzyme A (HMG-CoA) reductase inhibitors ("statins") have been proved to be extremely useful in the management of hypercholesterolemia, as well as in prevention of primary and secondary coronary heart disease. However, they may produce rare but severe muscle-related symptoms such as myopathy and rhabdomyolysis. Recent findings in vitro have shown that statins can reduce cardiomyocyte viability. The exact mechanism of statin myotoxicity still remains unclear. Diltiazem as CYP3A4 inhibitor, is a well recognized risk factor of skeletal muscles myopathy, if co-administered with simvastatin. It is not known whether such interaction affects myocardial efficiency causing biochemical changes. The experiments were performed on thirty six New Zealand white rabbits. The animals were divided into four groups receiving: 0.2% MC (control group): diltiazem (5 mg/kg); simvastatin (50 mg/kg) or diltiazem + simvastatin, daily for 14 days (po). The following biochemical parameters were estimated: creatine kinase (CK), serum transaminases (ALT and AST), as well as myocardial injury markers: troponin I (Tnl) and creatine kinase MB (CK-MB). Simultaneous administration of simvastatin and diltiazem caused 23-fold increase (p < 0.01), in rabbit serum CK levels and 20-fold increase (p = 0.056) in TnI levels, as compared to the initial values. Also in these rabbits significant increase in CK (12411,60 vs 839.87 IU/L) and TnI (0,26 vs 0,014 ng/mL), as compared to control group were observed. Significant increase in CK (12411,60 vs 1100,92 IU/L) and TnI (0,26 vs 0,012 ng/mL), as compared to diltiazem alone were noted, too. This may suggest another mechanism of drug-drug interaction than the one based on CYP3A4 inhibition if the impact on cardiac or skeletal muscle is considered.