Anti-ischemic Drug Research Articles

Application of hydrophilic interaction chromatography for simultaneous separation of six impurities of mildronate substance

The possibility of separating the impurities of mildronate, an antiischemic drug, by hydrophilic interaction chromatography (HILIC) was investigated on different polar stationary phases (silica, amino, cyano and zwitterionic sulfobetaine). The investigations have shown that HILIC is a useful alternative to reversed phase and ion-pair chromatography. The impact of HILIC separation conditions (acetonitrile content, buffer pH in mobile phase) on retention and selectivity has been systematically studied. Importance of these factors was found to be dependent on the structural properties of solutes. A HILIC method using a zwitterionic sulfobetaine stationary phase was developed and validated to determine six impurities in the drug substance. The method was validated in terms of specificity, limit of quantitation, limit of detection, linearity, accuracy and precision.

Ivabradine: the evidence of its therapeutic impact in angina.

Introduction:Stable angina pectoris (SAP) is a widely prevalent disease affecting 30 000 to 40 000 per million people in Europe and the US. SAP is associated with reductions in quality of life and ability to work, and increased use of healthcare resources. Ivabradine is a drug with a unique therapeutic target, the If current of the sinus node, developed for the treatment of cardiovascular diseases including SAP. It has an exclusive heart rate reducing effect, without any negative effect on left ventricular function or coronary vasodilatation.Aims:The aim of this paper is to review the evidence concerning the use of ivabradine in the treatment of SAP.Evidence review:Ivabradine is an effective antianginal and antiischemic drug, not inferior to the beta blocker atenolol and the calcium channel antagonist (CCA) amlodipine. It decreases the frequency of angina attacks and increases the time to anginal symptoms during exercise. Because of its exclusive chronotropic effect, ivabradine is not associated with the typical adverse reactions associated with beta blockers or other antianginal drugs.Clinical value:Clinical evidence shows that ivabradine is a very good antiischemic and antianginal agent, being as effective as beta blockade and CCA therapy in controlling myocardial ischemia and symptoms of stable angina. Ongoing studies will determine the potential of ivabradine to improve morbidity and mortality in coronary artery disease and heart failure.

Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts — Role of late sodium current and intracellular ion accumulation

The goal of this study was to test the hypothesis that the novel anti-ischemic drug ranolazine, which is known to inhibit late I Na, could reduce intracellular [Na +] i and diastolic [Ca 2+] i overload and improve diastolic function. Contractile dysfunction in human heart failure (HF) is associated with increased [Na +] i and elevated diastolic [Ca 2+] i. Increased Na + influx through voltage-gated Na + channels (late I Na) has been suggested to contribute to elevated [Na +] i in HF. In isometrically contracting ventricular muscle strips from end-stage failing human hearts, ranolazine (10 µmol/L) did not exert negative inotropic effects on twitch force amplitude. However, ranolazine significantly reduced frequency-dependent increase in diastolic tension (i.e., diastolic dysfunction) by ~ 30% without significantly affecting sarcoplasmic reticulum (SR) Ca 2+ loading. To investigate the mechanism of action of this beneficial effect of ranolazine on diastolic tension, Anemonia sulcata toxin II (ATX-II, 40 nmol/L) was used to increase intracellular Na + loading in ventricular rabbit myocytes. ATX-II caused a significant rise in [Na +] i typically seen in heart failure via increased late I Na. In parallel, ATX-II significantly increased diastolic [Ca 2+] i. In the presence of ranolazine the increases in late I Na, as well as [Na +] i and diastolic [Ca 2+] i were significantly blunted at all stimulation rates without significantly decreasing Ca 2+ transient amplitudes or SR Ca 2+ content. In summary, ranolazine reduced the frequency-dependent increase in diastolic tension without having negative inotropic effects on contractility of muscles from end-stage failing human hearts. Moreover, in rabbit myocytes the increases in late I Na, [Na +] i and [Ca 2+] i caused by ATX-II, were significantly blunted by ranolazine. These results suggest that ranolazine may be of therapeutic benefit in conditions of diastolic dysfunction due to elevated [Na +] i and diastolic [Ca 2+] i.

The value of stress single-photon emission computed tomography imaging performed routinely at 6 months in asymptomatic patients for predicting angiographic restenosis after successful direct percutaneous intervention for acute ST elevation myocardial infarction

The authors tested the value of stress single-photon emission computed tomography (SPECT) imaging performed systematically for detecting angiographic restenosis in asymptomatic patients who underwent direct percutaneous coronary intervention (PCI) for acute ST segment elevation myocardial infarction (STEMI). Angiographic restenosis of the infarct-related artery after direct PCI for STEMI is often silent and the strategy for follow-up evaluation of asymptomatic patients remains debated. A total of 149 patients successfully treated by direct PCI (96% stenting) for STEMI with no symptoms during the follow-up systematically underwent both rest thallium 201/stress Tc 99m setamibi myocardial perfusion imaging and coronary angiogram at 6 months. Patients were followed up for 2.5+/-0.5 years after 6 months control for cardiac events. In the 149 patients, the sensitivity, specificity, positive and negative predictive values and accuracy of SPECT imaging were 48, 61, 35, 72 and 57%, respectively, for detecting binary angiographic restenosis defined as > or =50% diameter stenosis. Whether stress testing was maximal or performed after withheld anti-ischemic drugs did not improve the results. Reversible ischemia at SPECT in the infarct territory did not predict long-term cardiac events. These data suggest a poor correlation between stress SPECT imaging and angiographic restenosis at 6 months in patients treated by direct PCI for STEMI who remain asymptomatic at follow-up. The long-term clinical prognostic value of SPECT reversible ischemia in the infarct territory appears also limited in this peculiar subset of patients. These findings should be taken into account in the strategy of the clinical follow-up of this population.

Évolution de la maladie coronaire : quelques minutes, quelques semaines, quelques décennies…

The slow progression over decades of coronary atheroma is often compensated for by arterial remodeling and collateral circulation. Coronary artery disease is therefore often asymptomatic. Sudden rupture of unstable atheromatous plaque always leads to endocoronary thrombus formation. The magnitude and the time frame of this endovascular thrombotic process determine the severity of its clinical consequences: no symptoms, exercise angina, unstable angina, acute transmural myocardial infarction, or sudden death. Two amply validated treatments have the potential to decrease both the probability and the severity of plaque rupture: statins and platelet inhibitors, which are both indicated in all cases of coronary disease. The other therapeutic tools – anti-ischemic drugs, ACE inhibitors, angioplasty, and coronary bypass – are widely used in the management of coronary disease, but their indications should be tailored to each individual clinical situation.

Cardioprotective efficacy of dinitrosyl iron complex with L-cysteine in rats in vivo

The effect ofdinitrosyl iron complex (DNIC) with L-cysteine on the hemodynamic indices and the size of myocardial infarction, which was induced by 40-min regional ischemia and subsequent 60-min reperfusion, have been studied in rats in vivo. Intravenous bolus injection of DNIC (3.1 micromol/kg body weight in 0.5 ml saline) was performed before regional ischemia; the control group was administered the same volume of saline. DNIC administration significantly decreased the mean blood pressure throughout the experiment. DNIC reduced the duration of cardiac arrhythmias to 170 +/- 10 s as against 445 +/- 30 s in control. The myocardial infraction size significantly decreased in the DNIC group compared to control (38.0 +/- 1.4 and 48.0 +/- 3.9% of the area at risk, respectively; p < 0.05). A combination of the vasodilatory effect of DNIC with the reduction of the damaging effect of cardiac ischemia and reperfusion encourage the development of hypotensive and antiischemic drugs on this class of NO donors.

Improvements in physical and mental domains of quality of life by anti-ischaemic drug and revascularisation treatment in elderly men and women with chronic angina

Background:The severity of angina is related to a reduction in global quality of life (QoL), which may be improved by anti-ischaemic treatment. It is not known, however, whether improvements relate...

Recommandations de l’Académie nationale de médecine pour la prise en charge des patients après infarctus du myocarde

The mortality rate after myocardial infarction fell sharply with the advent of reperfusion methods and the use of efficient antithrombotic and antiischemic drugs. However, new infarcts, heart failure, arrythmias and sudden death remain frequent, especially in the first two years after the initial event. Large clinical studies have defined and validated therapies for secondary prevention, but the recommended measures are not always properly implemented. Patients with and without ST elevation after myocardial infarction share the same pathophysiologic mechanism, namely atherosclerotic plaque rupture or erosion, with different degrees of superimposed thrombosis and distal embolization. Secondary prevention is the same for these two patient categories. Acute coronary syndromes are associated with an increased risk of adverse cardiovascular outcomes (new myocardial ischemia, left ventricular dysfunction or sudden death) and require aggressive secondary prevention. However, risks factors such as smoking, hypertension, obesity, hypercholesterolemia and diabetes frequently persist. In addition, medical practice does not always respect consensus guidelines. Early risk stratification is necessary to detect residual myocardial ischemia in viable myocardium. After the acute phase, the prognosis depends on the degree of left ventricular dysfunction and the extent and severity of residual ischemia. Exercise and ambulatory electrocardiography, stress echocardiography, perfusion scintigraphy using vasodilator stress, magnetic resonance imaging and coronary angiography are all useful for identifying high-risk patients. Secondary prevention should include risk factor management with lifestyle modifications such as weight reduction, a reduction in saturated fats and an increase in monounsaturated fatty acids. Smoking cessation is crucial, and regular physical activity (30 min per day at least 5 days a week) is beneficial. Cardiac rehabilitation has been shown to improve exercise tolerance and cardiovascular outcome.

New insights into bioactivation of organic nitrates, nitrate tolerance and cross-tolerance

Organic nitrates still represent a group of very effective anti-ischemic drugs used for the treatment of patients with stable angina, acute myocardial infarction and chronic congestive heart failure. Long-term therapy with organic nitrates, however, results in a rapid development of nitrate tolerance blunting their hemodynamic and antiischemic efficacy. Recent studies revealed that mitochondrial reactive oxygen species (ROS) formation and a subsequent oxidative inactivation of nitrate reductase, the mitochondrial aldehyde dehydrogenase (ALDH-2), play an important role for the development of nitrate and crosstolerance. The present review focuses firstly on the role of ALDH-2 for organic nitrate bioactivation and secondly on the role of oxidative stress in the development of tolerance and cross-tolerance (endothelial dysfunction) in response to various organic nitrates. Finally, we would like to draw the reader's attention to the protective properties of the organic nitrate pentaerithrityl tetranitrate (PETN), which, in contrast to all other organic nitrates, is able to upregulate enzymes with a strong antioxidative capacity thereby preventing tolerance and the development of endothelial dysfunction.

G.P.6.08 Comparison of the effects of chronic treatments with drugs targeting different disease-related pathways in dystrophic mdx mice

To verify the role of specific pathways activated by dystrophin absence and to identify potential pharmacotherapies against Duchenne muscular dystrophy we chronically treated (4–8weeks) exercised mdx mice with drugs acting on different targets. We first compared the phosphodiesterases inhibitor pentoxifylline (PTX; 50mg/kg/day i.p.), a wide anti-inflammatory, anti-ischemic and anti-fibrotic drug, with a potentially clinical relevant association: α-methyl-prednisolone (PDN; 1mg/kg/day i.p.) and taurine (1g/kg/day orally), to target inflammatory pathways and calcium homeostasis.

Determination of trapidil in human serum and urine by derivative UV spectrophotometry after selective solid-phase extraction

A novel analytical technique able to determine the anti-ischemic drug trapidil in human serum and urine is proposed. In order to achieve satisfactory sensitivity and selectivity, an extraction procedure was required to isolate the drug from complex matrixes such as serum and urine. A solid-phase extraction procedure was investigated to both increase the analyte concentration and eliminate the interfering molecules present in large amounts in both matrixes. Optimization of the extraction step was realized by selecting a new polymeric sorbent based on a surface-modified styrene-divinylbenzene polymer which provided fast and efficient drug extraction. Drug quantification was performed by using the third-order derivative spectra of the SPE eluates. Absorbance specific signals at (3)D(335,316) and (3)D(316) nm for urine and serum, respectively, were demonstrated to be directly proportional to drug concentration and barely affected by residual matrix interferences. Under the optimized experimental conditions the calibration plots were linear over the concentration range 0.2-50 microg mL(-1). The method was validated by analysis of a series of spiked samples. Accuracy (recovery of 95 and 94% for serum and urine, respectively) and precision (RSD below 4%) were good.

Treatment After Myocardial Infarction

Persons after myocardial infarction (MI) should have their modifiable coronary artery risk factors intensively treated. Hypertension should be treated with beta blockers and angiotensin-converting enzyme (ACE) inhibitors. The blood pressure should be reduced to <140/90 mmHg and to <130/80 mmHg in persons with diabetes or renal insufficiency. The serum low-density lipoprotein cholesterol should be reduced to <70 mg/dl with statins if necessary. Diabetics should have their hemoglobin A1c reduced to <7.0%. Aspirin or clopidogrel, beta blockers, and ACE inhibitors should be given indefinitely unless contraindications exist to the use of these drugs. Long-acting nitrates are effective antianginal and antiischemic drugs. Postinfarction patients at very high risk for sudden cardiac death should have an implantable cardioverter-defibrillator. The two indications for coronary revascularization are prolongation of life and relief of unacceptable symptoms despite optimal medical management.

Effects of anti-ischaemic drug therapy in silent myocardial ischaemia type I: the Swiss Interventional Study on Silent Ischaemia type I (SWISSI I): a randomized, controlled pilot study

To determine the effect of anti-ischaemic drug therapy on long-term outcomes of asymptomatic patients without coronary artery disease (CAD) history but silent exercise ST-depression. In a randomized multicentre trial, 263 of 522 asymptomatic subjects without CAD but at least one CAD risk factor in whom silent ischaemia by exercise ECG was confirmed by stress imaging were asked to participate. The 54 (21%) consenting patients were randomized to anti-anginal drug therapy in addition to risk factor control (MED, n = 26) or risk factor control-only (RFC, n = 28). They were followed yearly for 11.2 +/- 2.2 years. During 483 patient-years, cardiac death, non-fatal myocardial infarction, or acute coronary syndrome requiring hospitalization or revascularization occurred in 3 (12%) of MED vs. 17 (61%) of RFC patients (P < 0.001). In addition, MED patients had consistently lower rates of exercise-induced ischaemia during follow-up, and left ventricular ejection fraction remained unchanged (-0.7%, P = 0.597) in contrast to RFC patients in whom it decreased over time (-6.0%, P = 0.006). Anti-ischaemic drug therapy and aspirin seem to reduce cardiac events in subjects with asymptomatic ischaemia type I. In such patients, exercise-induced ST-segment depression should be verified by stress imaging; if silent ischaemia is documented, anti-ischaemic drug therapy and aspirin should be considered.

Effects of Percutaneous Coronary Interventions in Silent Ischemia After Myocardial Infarction

The effect of a percutaneous coronary intervention (PCI) on the long-term prognosis of patients with silent ischemia after a myocardial infarction (MI) is not known. To determine whether PCI compared with drug therapy improves long-term outcome of asymptomatic patients with silent ischemia after an MI. Randomized, unblinded, controlled trial (Swiss Interventional Study on Silent Ischemia Type II [SWISSI II]) conducted from May 2, 1991, to February 25, 1997, at 3 public hospitals in Switzerland of 201 patients with a recent MI, silent myocardial ischemia verified by stress imaging, and 1- or 2-vessel coronary artery disease. Follow-up ended on May 23, 2006. Percutaneous coronary intervention aimed at full revascularization (n = 96) or intensive anti-ischemic drug therapy (n = 105). All patients received 100 mg/d of aspirin and a statin. Survival free of major adverse cardiac events defined as cardiac death, nonfatal MI, and/or symptom-driven revascularization. Secondary measures included exercise-induced ischemia and resting left ventricular ejection fraction during follow-up. During a mean (SD) follow-up of 10.2 (2.6) years, 27 major adverse cardiac events occurred in the PCI group and 67 events occurred in the anti-ischemic drug therapy group (adjusted hazard ratio, 0.33; 95% confidence interval, 0.20-0.55; P<.001), which corresponds to an absolute event reduction of 6.3% per year (95% confidence interval, 3.7%-8.9%; P<.001). Patients in the PCI group had lower rates of ischemia (11.6% vs 28.9% in patients in the drug therapy group at final follow-up; P = .03) despite fewer drugs. Left ventricular ejection fraction remained preserved in PCI patients (mean [SD] of 53.9% [9.9%] at baseline to 55.6% [8.1%] at final follow-up) and decreased significantly (P<.001) in drug therapy patients (mean [SD] of 59.7% [11.8%] at baseline to 48.8% [7.9%] at final follow-up). Among patients with recent MI, silent myocardial ischemia verified by stress imaging, and 1- or 2-vessel coronary artery disease, PCI compared with anti-ischemic drug therapy reduced the long-term risk of major cardiac events. clinicaltrials.gov Identifier: NCT00387231.

Comparison of protective effects of trimetazidine against experimental warm ischemia of different durations: early and long-term effects in a pig kidney model

Acute renal failure (ARF) is often the consequence of an ischemia-reperfusion injury (IRI) and associated with high mortality. Warm ischemia (WI) is a crucial factor of tissue damage, and tissue destruction led by ischemia-reperfusion (I/R) can impact the early and long-term functional outcome. Trimetazidine (TMZ) is an anti-ischemic drug. Previously, we already verified its protective effect on a cold-ischemic pig kidney model by directly adding TMZ into the preservation solution (Faure JP, Baumert H, Han Z, Goujon JM, Favreau F, Dutheil D, Petit I, Barriere M, Tallineau C, Tillement JP, Carretier M, Mauco G, Papadopoulos V, Hauet T. Biochem Pharmacol 66: 2241-2250, 2003; Faure JP, Petit I, Zhang K, Dutheil D, Doucet C, Favreau F, Eugene M, Goujon JM, Tillement JP, Mauco G, Vandewalle A, Hauet T. Am J Transplant 4: 495-504, 2004). In this study, we aimed to study the potential effect of TMZ pretreatment (5 mg/kg iv 24 h before WI) on the injury caused by WI for 45, 60, and 90 min and reperfusion in a WI pig kidney model. Compared with sham-operated (control) and uninephrectomized animals (UNX), TMZ pretreatment significantly reduced deleterious effects after 45 min, and particularly 60 and 90 min, of WI by improving the recovery of renal function and minimizing the inflammatory response commonly prevalent in ischemic kidney injury. Compared with controls (control group and UNX group), it was observed that 1) hypoxia-inducible factor-1 (HIF-1alpha) expression occurred earlier and with a higher intensity in the TMZ-treated groups; 2) the reduction of IRI during the first week following reperfusion was correlated with an earlier and greater expression of stathmin, which is involved in the process of tubular repair; and 3) the tubulointerstitial fibrosis was reduced, particularly after 60 and 90 min of WI. In conclusion, TMZ made the warm-ischemic kidneys more resistant to the deleterious impact of a single episode of I/R and reduced early and long-term subsequent damage.

NEBIVOLOL IN TREATMENT OF STABLE EXERTIONAL ANGINA PECTORIS

Aim. To evaluate antianginal and antiischemic efficiency of nebivolol in patients with stable angina pectoris. Material and methods. 100 patients with ischemic heart disease showing stable exertional angina pectoris and having no contraindications to beta-blockers were studied. After 5-7 days of control period 50 randomly selected patients began to take nebivolol in initial dose of 5mg once daily and 50 patients started to take metoprolol in initial dose of 50 mg twice daily. Duration of treatment was 8 weeks. Efficiency of treatment was assessed according to the results of control treadmill assessment and control daily ECG monitoring. Results. 56-day therapy with nebivolol at a dose of 7,5 mg per day results in increase in duration of treadmill test before angina or ST depression (p&lt;0.05). Antianginal and antiischemic effect of nebivolol 7.5 mg once daily is rather similar with that of metoprolol in average daily dose of 175 mg. Nebivolol compared to metoprolol significantly (p&lt;0.05) more effectively reduces the number of silent myocardial ischemia. Conclusion. Nebivolol is an efficient antianginal and antiischemic drug for patients with stable exertional angina pectoris.

Methods of quality standardization for diumancal parent substance and related medicinal forms

Methods for the standardization of the parent substance of the original domestic antiischemic drug diumancal and its medicinal forms have been developed. Taking into account the high level of basic requirements on analytical methods and their validation for suitability in the pharmaceutical analysis of medical products, it is suggested to include HPLC, IR, and 13C NMR spectroscopy techniques into the “Identity,” “Extraneous Impurities,” and “Quantitative Determination” articles together with the well-known conventional methods. In order to ensure the reliability and specificity of determination of the content of the parent substance, the State Reference Sample (SRS) of diumancal is created and the retention times of possible impurities in diumancal are established using mixtures of 7-oxy-2-H-1-benzopyran-2-one and 7-(2-bromoethyleneoxy)-2-H-1-benzopyran-2-one. The total content of these impurities must not exceed 0.5 %. Experimental data on the analysis of impurities in diumancal are presented and optimum conditions for determining diumancal in the parent substance and related medicinal forms are established. The rated parameters of the “Identity,” “Extraneous Impurities,” and “Quantitative Determination” articles for these preparations are established, which can be used for both research and the production quality control purposes.

Polymeric Nanoparticles as Drug controlled Release Systems: A New Formulation Strategy for Drugs with Small or Large Molecular Weight

We report a study evaluating the encapsulation and release modalities from poly(D,L lactic acid) (PLA) or poly(D,L-lactide-co-glicolide) (PLGA) micro- and nano-particles of the antiischemic drug N6-cyclopentyladenosine (CPA) and bovine serum albumin (BSA), chosen as protein model. The results obtained by classical preparation methods (nanoprecipitation, single or double emulsion/solvent evaporation) of the particles were compared with those obtained by their formulation with a novel method, employing a thermosensible gel of Pluronic F-127, whose aqueous solutions can be liquid when refrigerated, but gel upon warming. Our results indicate that CPA-loaded nanoparticles, obtained by classical methods, drastically reduce their drug content showing, moreover, any control of the drug release with respect to CPA-loaded microparticles. The novel preparation method allowed us to obtain, instead, CPA encapsulation values in nanoparticles similar to those obtained for microparticles, achieving also a weak control of the drug release. Any drastic reduction of BSA particle content was obtained by decreasing their size from micro- to nano-scales, independently on the employment of classical or novel preparation methods. Moreover, the size reduction induced only a weak increase of the BSA release rate. The patterns of protein released from micro- and nano-particles obtained by the same formulation method were similar. In particular, the micro- and nano-spheres prepared by double emulsion technique showed an incomplete BSA release, characterized by an elevated burst effect followed by a very slow phase. On the other hand, the release from micro- and nano-particles obtained by the novel method was complete and quite regular, being characterized by a little burst release followed by a fast phase. These results have been related to the strong BSA distribution (observed by confocal laser scanning microscope) in the surface or in the core of microparticles obtained by the classical or novel methods, respectively.

Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine

Pathological conditions linked to imbalances in oxygen supply and demand (for example, ischaemia, hypoxia and heart failure) are associated with disruptions in intracellular sodium ([Na+]i) and calcium ([Ca2+]i) concentration homeostasis...

Structure–activity studies on the protection of Trimetazidine derivatives modified with nitroxides and their precursors from myocardial ischemia–reperfusion injury

Trimetazidine, the known anti-anginal and anti-ischemic drug, was modified by pyrroline and tetrahydropyridine nitroxides and their hydroxylamine and sterically hindered secondary amine precursors. The synthesized new compounds proved to be better superoxide scavenger molecules compared to the parent Trimetazidine in an in vitro experiment. This reactive oxygen species (ROS) scavenging activity was further supported by ischemia/reperfusion (I/R) studies on Langendorff-perfused rat hearts pretreated with Trimetazidine and with the modified Trimetazidine derivatives before ischemia. Two of the investigated compounds, containing 2,2,5,5-tetramethyl-2,5-dihydro-1 H-pyrrole and 4-phenyl-2,2,5,5-tetramethyl-2,5-dihydro-1 H-pyrrole substituents on the piperazine ring, provided significant protection from the cardiac dysfunction caused by I/R. The protective effect could be attributed to the combined anti-ischemic and antioxidant effects.