Effective Antianginal Drug Research Articles

Platelet reactivity in patients with coronary artery disease on treatment with ivabradine and clopidogrel: The PLATIVA study

The combination of aspirin and clopidogrel remains the most frequent dual antiplatelet therapy in patients with acute coronary syndrome or undergoing percutaneous coronary intervention. Clopidogrel, a P2Y12 adenosine diphosphate (ADP) platelet receptor inhibitor requires transformation by cytochrome P450 (CYP) in the liver to produce an active metabolite. On the other hand, ivabradine is an effective antianginal drug that is also metabolized by the CYP enzyme, acting as a weak inhibitor. Our aim is to evaluate the impact of ivabradine on platelet reactivity in patients receiving clopidogrel and to evaluate the possible pharmacodynamic interactions between them. This is a prospective, observational, post-authorization pharmacodynamic study including patients treated with aspirin and clopidogrel and initiating ivabradine. Patients with platelet abnormalities and those treated with anticoagulants or other CYP inhibitors were excluded. A platelet aggregation test was performed at baseline before the first dose of ivabradine and repeated after 4 weeks of treatment. The primary endpoint was inhibition of platelet aggregation (IPA) after 20 mM ADP stimulation. A total of 34 patients were initially recruited; eight patients were excluded, leaving 25 patients for final analysis. All patients had chronic ischemic heart disease. The maximum ivabradine dosage of 7.5 mg twice daily was achieved in seven patients (28%). After 4 weeks of treatment with ivabradine, no significant differences were found in maximal platelet aggregation from baseline, as assessed with 20 μM ADP stimulation. In addition, no significant difference in IPA from baseline was detected after stimulation with ADP 5 μM, arachidonic acid, thrombin receptor-activated peptide 25 μM, and platelet reactivity index. Ivabradine did not alter antiplatelet response to clopidogrel in patients treated concomitantly with both drugs.

Мультисистемный эффект цитопротекции

The anti-ischemic and pleiotropic effects of a drug from the group of myocardial cytoprotectors – trimetazidine are discussed in the article. Currently, trimetazidine is recommended by experts of the scientific medical community as an effective antianginal drug for the treatment of patients of different ages diagnosed with stable angina. Trimetazidine, a reversible competitive inhibitor of 3-ketoacyl coenzyme A thiolase, has a good safety and tolerability profile, improves physical performance in patients with stable angina pectoris and ischemic cardiomyopathy, and is considered as an agent that affects the energy metabolism of cells under conditions of ischemia, optimizing the use of oxygen myocardium due to increased aerobic glycolysis and a decrease in the intensity of oxidation of free fatty acids. The results of the VASCO-angina study allow us to consider a daily dose of trimetazidine 70 mg as a standard therapeutic dose in the treatment of patients with coronary artery disease. The KARDIOKANON study confirmed the clinical equivalence of the original and reproducible drug trimetazidine – Deprenorm® SR (manufactured by Canonpharm Production, Russia) in the secondary prevention of coronary artery disease and its complications. Pleiotropic effects: anti-atherosclerotic, anti-inflammatory, nephroprotective, neuroprotective, allow expanding the use of trimetazidine in clinical practice. Keywords: coronary artery disease, angina pectoris, metabolism, ischemia, trimetazidine For citation: Larina VN. Multisystem effect of cytoprotection. Consilium Medicum. 2021; 23 (1): 93–98. DOI: 10.26442/20751753.2021.1.200732

Ivabradine: A Unique and Intriguing Medication for Treating Cardiovascular Disease.

There has been much research linking elevated resting heart rate to cardiovascular morbidity and mortality. Based on these findings, a lower resting heart rate would be of theoretical benefit in patients with cardiovascular disease. From a pathophysiologic perspective, a lower resting heart rate would be of particular benefit in patients with ischemic heart disease and/or heart failure. Although β-blockers and nondihydropyridine calcium channel blockers are effective at lowering heart rate, they have many other pharmacologic effects that may not be desirable in some patients, such as negative inotropy. Ivabradine is a drug designed to lower heart rate without any other demonstrable pharmacologic effects; in other words, a pure heart rate-lowering drug. It functions by blocking the hyperpolarization-activated cyclic nucleotide gated channels (f-channels) specific for the sinoatrial node and disrupting If ion current flow. This effectively prolongs diastolic depolarization and slows firing in the sinoatrial node, which lowers heart rate. The effects of ivabradine are most pronounced at higher heart rates (use-dependence), which is important in minimizing the development of symptomatic bradycardia. Clinical trials have demonstrated ivabradine to be an effective antianginal drug both alone and in combination with β-blocker therapy, although it has not been shown to produce a demonstrable effect on reducing major adverse cardiovascular events. In patients with heart failure, ivabradine has demonstrated many hemodynamic benefits, but its effect on clinical outcomes have been mixed and dependent on baseline heart rate, ie, the drug may be of benefit with higher baseline heart rates, but detrimental with low baseline heart rates. The adverse effects of ivabradine are not uncommon, but are rarely severe and include visual disturbances, bradycardia, and atrial fibrillation. Although ivabradine is a very interesting new agent, its variable benefits in large-scale clinical trials leave its exact place in therapy still somewhat nebulous. Unanswered questions include which patient populations would benefit most from this drug, and which concomitant medications would produce the best clinical outcomes when used with ivabradine.

Liquid Chromatographic Resolution of Fendiline and Its Analogues on a Chiral Stationary Phase Based on (+)-(18-Crown-6)-2,3,11,12-tetracarboxylic Acid

Fendiline, an effective anti-anginal drug for the treatment of coronary heart diseases, and its sixteen analogues were resolved on a CSP based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid. Fendiline was resolved quite well with the separation factor (α) of 1.25 and resolution (RS) of 1.55 when a mobile phase consisting of methanol–acetonitrile–trifluoroacetic acid–triethylamine at a ratio of 80/20/0.1/0.5 (v/v/v/v) was used. The comparison of the chromatographic behaviors for the resolution of fendiline and its analogues indicated that the 3,3-diphenylpropyl group bonded to the secondary amino group of fendiline is important in the chiral recognition and the difference in the steric bulkiness between the phenyl group and the methyl group at the chiral center of fendiline is also important in the chiral recognition.

Search of substances with the cardioprotective activity in the series of derivatives of halogenides 1-alkyl- and carboxyalkyl-4-ylideneamino-1,2,4-triazole

In spite of achievements in the sphere of highly effective drugs creation for treating cardiovascular diseases the problem is still urgent since mortality is high because of these diseases, and it takes the 2-nd – 3-d place among the population of industrially developed countries. In the Research and Production Association “Pharmatron” a new approach concerning creation of new effective anti-anginal drugs has been developed; it is a chemical modification of position 1 and 4 of 1,2,4-triazole molecule by introduction of the structural fragments of the most active medicines and structures imitating sites of adrenergic receptors. Bromides of 1-(alkyl) carboxyalkyl-4-ylideneamino-1,2,4-triazole have been synthesized at the Pharmaceutical Chemistry department of Zaporizhzhia State Medical University under the supervision of professor I.A.Mazur. The cardioprotective activity of 12 compounds – derivatives of 1-carboxyalkyl-4-ylideneamino-1,2,4-triazole bromides and 1-alkyl-4-ylidenamino-1,2,4-triazole bromides has been investigated. The experiments were conducted in 510 white outbred male rats weighing 120-130 g from the mouse bank of the Institute of Pharmacology and Toxicology of the AMS of Ukraine. Determination of acute toxicity of the compounds investigated was conducted according to Kerber method. It has been found that LD50 of these compounds when introduced intraabdominally to rats is within 29.5-295 mg/kg. It allows to refer the compounds under research to the III and IV classes of toxicity (moderate or low toxic). The model of acute myocardial infarction in rats was used for studying the cardioprotective activity of the compounds, the infarction was modeled by staged introduction of isadrin and pituitrin. It has been found that intraabdominal introduction of 8 compounds of 12 ones in the dose of 1/100 LD50 to rats with myocardial infarction leads to decrease of hyperenzymemia of cardiospecific isoenzymes of creatine phosphokinase (MB CPK) and lactate dehydrogenase (LDH-1), which play the role of biochemical markers of the myocardium damage, and decrease of electrophysiological marker ΣΔST during electrocardiography. The structural fragments of the molecule, which play a determinative role in manifestation of the cardioprotective effect of such series as β-phenylethyl, carboxy propyl, octyl in position 1 and the presence of amino- and n-methoxybensilidenamino-groups in position 4, have been revealed. It has been determined that compound MT significantly exceeds the therapeutical efficacy of metoprolol by decrease of MB CPK and LDH-1 activity in the blood serum of rats with myocardial infarction, as well as decrease of ECG ST amplitude.

EFFICACY OF NEBIVOLOL IN TREATMENT OF WOMEN WITH CORONARY HEART DISEASE

Aim. Evaluation of clinical efficacy and tolerability of beta-blockers in premenopausal women with stable angina. Material and methods. The anaysis of 43-55 years old premenopausal 50 women with stable angina was performed. Therapy included enalapril 2,5-10 mg daily, betaadrenoblocker in 1 group (23 persons) – 5-10 mg of bisoprolol daily, and in 2 group (27 pers.) nebivolol 2,5-5 mg daily (Nebilet®, “Berlin-Chemie/A. Menarini”, Germany), acetylsalycilic acid 100 mg daily during 6 months. The studies done were veloergometry, long-lasting ECG monitoring, echocardiography and also the test with reactive hyperemia on brachial artery. Severity of anxiety-depressive syndrome was evaluated usin hospital scale of anxiety and depression, and the severity of climacteric disorders – by the M. Kuppermann index. Results. With the therapy all patients self-reported improvement of their condition: in 80% there was a decrease of angina functional class, more significant in the second group. Also there was decrease of climacteric symptoms salience as anxiety-depressive disorders, especially in nebivolol group. By the results of ECG monitoring, i. e. frequency of rhythm dosirders (supraventricular and ventricular arrhythmias) there was lower quantity of episodes, more significant in nebivolol group. All groups showed an increase of basal brachial artery diameter, more significant in the 2nd group. Also we marked the changes in central hemodynamics parameters and sctructure-functional parameters of the left ventricle in both groups. Conclusion. Nebilet® in saily dose as 2,5-5 mg is an effective antianginal drug in women with CHD and stable angina pectoris. Under Nebilet® action there is improvement of systolic and diastolic functions of the left ventricle myocardium. With Nebilet® women with stable angina significantly increase exercise tolerance and there is a decrease of climacteric and anxiety-depressive syndrome.

Long-Term Use of Short- and Long-Acting Nitrates in Stable Angina Pectoris

Long-acting nitrates are effective antianginal drugs during initial treatment. However, their therapeutic value is compromised by the rapid development of tolerance during sustained therapy, which means that their clinical efficacy is decreased during long-term use. Sublingual nitroglycerin (NTG), a short-acting nitrate, is suitable for the immediate relief of angina. In patients with stable angina treated with oral long-acting nitrates, NTG maintains its full anti-ischemic effect both after initial oral ingestion and after intermittent long-term oral administration. However, NTG attenuates this effect during continuous treatment, when tolerance to oral nitrates occurs, and this is called cross-tolerance. In stable angina long-acting nitrates are considered third-line therapy because a nitrate-free interval is required to avoid the development of tolerance. Nitrates vary in their potential to induce the development of tolerance. During long-lasting nitrate therapy, except pentaerythritol tetranitrate (PETN), one can observe the development of reactive oxygen species (ROS) inside the muscular cell of a vessel wall, and these bind with nitric oxide (NO). This leads to decreased NO activity, thus, nitrate tolerance. PETN has no tendency to form ROS, and therefore during long-term PETN therapy, there is probably no tolerance or cross-tolerance, as during treatment with other nitrates.

Drug treatment of stable angina pectoris in the elderly: defining the place of calcium channel antagonists.

Chronic stable angina pectoris (CSAP) resulting from coronary artery disease (CAD) is common in elderly patients, and significantly reduces their quality of life. Myocardial revascularisation procedures in this age group entail significant risks, largely related to comorbidities rather than advanced age itself. Coronary artery anatomy is more likely to be technically unsuitable for revascularisation and angina more resistant to drug treatment. Therefore, elderly patients often take combinations of antianginal drugs. Calcium channel antagonists (CCAs) are effective antianginal drugs first introduced for clinical use in the late 1970's. They reduce myocardial ischaemia by both causing vasodilatation of coronary resistance vessels and reducing cardiac workload (negative inotropic effect). However, adverse effects related to abrupt arterial vasodilatation limited the tolerability of these short acting 'first generation' drugs (nifedipine, verapamil and diltiazem). Furthermore, short acting nifedipine may occasionally increase both the frequency of angina pectoris and mortality in patients with CAD. Since then, long acting formulations of first generation agents and new chemical entities (second and third generation drugs) have been developed. These are well tolerated and effective at attenuating both myocardial ischaemia and the frequency and severity of angina pectoris in most patients with stable CAD. Current guidelines on the drug treatment of CSAP propose that beta-adrenoceptor antagonists (beta-blockers) should be used as first line medication primarily for their prognostic benefits, and that CCAs need only be introduced if beta-blockers are not tolerated, contraindicated or ineffective. Despite this, there is a wealth of evidence from clinical trials that demonstrate equal antianginal efficacy for CCAs and beta-blockers. The presence of chronic heart failure and prior myocardial infarction are clear indications for the use of beta-blockers in preference to CCAs for the treatment of CSAP. However, in patients with both CSAP and hypertension, second and third generation CCAs may offer prognostic benefits of similar magnitude to those provided by beta-blockers. Therefore, antianginal drug therapy must be tailored to the individual needs and comorbidities of each elderly patient.

A comparison of nicorandil with isosorbide mononitrate in elderly patients with stable coronary heart disease: The SNAPE study

Nicorandil, a potassium channel opener, is an effective antianginal drug, but its therapeutic evaluation is still limited. Objective The efficacy and safety of nicorandil compared with isosorbide mononitrate (ISMN) was evaluated in the treatment of elderly patients (≥65 years) with stable angina pectoris and a positive exercise test result (≥0.1 mV ST-segment depression). Methods and Results In a multicenter, double-blind, double-dummy, controlled trial, 194 patients were randomly assigned to 10 mg nicorandil twice daily or 20 mg ISMN twice daily. For the evaluation of ischemic variables, a symptom-limited bicycle exercise test was performed after 1 week of placebo treatment and after 4 weeks of nicorandil or ISMN treatment. Clinical assessment for safety and side effects occurred at 2-week intervals. One hundred seventy-eight patients were analyzed on an intent-to-treat basis and 145 were terminated from the study per protocol (efficacy analysis). During treatment, within both treatment groups exercise testing revealed a significant postponement of the onset of ischemia (nicorandil, P <.01; ISMN, P =.03) and angina (P ≤.03 for both) and a decrease of maximum ST depression (ISMN, P <.002) compared with baseline. There were no differences between the groups for both intent-to-treat and efficacy analysis, with the exception of the rate-pressure product, which was increased (P =.03) in the nicorandil group. Safety and well-being variables were not different between groups, but the frequency of angina decreased (P =.02) in the ISMN group. Conclusions These data suggest that, although nicorandil seems to be as safe and effective as ISMN for the treatment of stable angina in elderly patients, ISMN may be superior to nicorandil for the symptomatic treatment of daily angina in this patient population.

Contemporary approaches in medical management of patients with stable coronary artery disease

CAD continues to be the principal cause of mortality in the United States, and the largest group of patients with CAD are those with stable angina. Among this group of patients, the most common manifestation of CAD is presence of transient episodes of myocardial ischemia. The presence of transient ischemia and not the severity of angina has been found to be associated with poor clinical outcome in patients with stable CAD. As part of a global treatment strategy for patients with stable CAD, changes in lifestyle and modification of coronary risk factors should be emphasized as an integral part of treatment. Conventional antianginal therapy is quite effective in controlling anginal attacks. Currently, several drugs and therapeutic strategies are available for the treatment of patients with angina (see Table 5). Nitrates are highly effective antianginal drugs with complex beneficial actions in patients with CAD, but their usefulness is limited by development of tolerance during long-term use. When clinically indicated, the use of nitrates should be supplemented with another longer-acting antianginal drug, such as a beta-blocker or a calcium channel blocker. Based on the available data, beta-blockers, when tolerated, seem to be the most effective antianginal drugs for most patients with stable CAD. Beta-blockers are also the most effective anti-ischemic drugs that reduce the magnitude of myocardial ischemia detected during routine daily activities. Calcium channel blockers are also effective vasodilators and good antianginal drugs. The clinician should become familiar with the different actions that this heterogeneous group of drugs has on the heart and vessels. This knowledge allows the clinician to choose the appropriate combination of different antianginal drugs for patients on an individualized basis. It is also critical to develop the treatment strategy by carefully taking into account other associated medical conditions that are frequently encountered in patients with CAD.

The recent development and the present status of K+ channel opener

The development of vasodilator drugs that open the K+ channels in blood vessels has been of great academic and practical interest. The discoveries of the ATP-sensitive K+ channel and the glibenclamide-sensitive K+ channel have promoted these interests. In relation to this channel, the cardioprotective effectiveness of a K+ channel opener (Aprikalim) in doses that did not change haemodynamics or collateral blood flow were demonstrated in infarct dog heart. The effects were antagonized by glibenclamide. Thus, ATP-sensitive K+ channels seem to play an important role in this effect. Clinical evaluations of the K+ channel openers are reviewed. The hypotensive effects of the drugs are well-recognized. At present, however, the clinical usefulness of K+ channel openers has not been accepted widely, because of their side-effects including reflex tachycardia, edema, flushing and headache. An approach to reduce these side-effects is critical if these K+ channel openers are to be used as good hypotensive drugs. The K+ channel opener nicorandil has been evaluated as a highly effective antianginal drug. It seems likely that the clinical benefits of nicorandil result from both its K+ channel opening properties and its ability to stimulate smooth muscle guanylate cyclase. Clinical data on the pure-selective K+ channel opener cromakalim (lemakalim) as an antianginal drug is limited. However, on the basis of the vasodilator profile of this drug, it is expected to be useful for this purpose. The application of K+ channel openers to treat other disorders such as bladder instability is limited because of its hypotensive action.

Historical aspects of nitrate therapy.

The exciting story of the development of nitrates as drugs in clinical medicine is briefly reviewed. Glyceryl trinitrate (nitroglycerin) was synthesised by Sombrero in 1847. Amyl nitrite was discovered a few years later and was used by Guthrie in 1859. The first report on the action of glyceryl trinitrate and amyl nitrite was published by Brunton in 1867, and further papers were published by Murell in 1879. Organic nitrates appeared in the 1930s. Krantz and co-workers synthesised and used mannide dinitrate, which was longer acting than the nitrates that had been used previously. Research on a similar drug, isosorbide dinitrate, was initiated by Porjé in Stockholm. The drug was first marketed in Sweden in 1946. Isosorbide dinitrate was independently synthesised in the United States by Harris and colleagues in the 1950s. The drug was used fairly extensively on both sides of the Atlantic. However, there was a temporary decrease in popularity around 1970 when Needleman and colleages reported oral nitrates to be of questionable value, as they underwent rapid biotransformation during first-pass metabolism in the liver. This opinion was later altered and today the drug enjoys worldwide acceptance in different formulations. Also, in recent years one of the active metabolites, isosorbide 5-mononitrate, has been marketed as an effective antianginal drug.

Molsidomine &amp;ndash; an Effective Antianginal Drug

The antianginal efficacy of molsidomine (single oral dose of 2 mg), a new antianginal drug, was evaluated in 12 patients with coronary artery disease in a double-blind randomized placebo-controlled study by bicycle ergometry. Besides the standard ergometric parameters, the myocardial efficiency index (MEI) was determined from the ratio of the maximum workload (kgm/min) to double product (mm Hg X min) X 10(-2), normalized for body surface area. Compared to placebo, molsidomine decreased positive exercise tests by 50%, pain response by 66%, and the magnitude of ST depression by 43%. Furthermore, the onset of ergometric positive response was delayed, with an increase in maximum workload achieved (+21%), total work performed (+43%), and duration of exercise (+28%). MEI also increased from 0.98 +/- 0.43 to 1.18 +/- 0.44 (p less than 0.005), due to a significant increase in maximal workload without a parallel increase in double product. These findings suggest that molsidomine is an effective antianginal drug and improves myocardial efficiency in patients with angina due to coronary artery disease.

Verapamil versus placebo in relieving stable angina pectoris.

Verapamil and placebo were compared in patients with stable, effort-induced angina. Single-blind dose titration (240, 360 and 480 mg/day) preceded a double-blind crossover. Among the 18 patients who completed graded exercise stress tests with reproducible pretreatment effort-limiting angina, exercise duration increased from 348 +/- 127 seconds (SD) before treatment to 494 +/- 182 seconds after verapamil (p less than 0.001), but did not change after placebo. Compared with placebo, verapamil reduced the weekly number of anginal episodes from 4.54 +/- 5.03 to 2.44 +/- 3.30 (p less than 0.05) and reduced nitroglycerin consumption from 3.46 +/- 5.30 to 1.55 +/- 2.89 tablets per week (p less than 0.05). Of 26 patients who completed the single-blind dose titration, 16 were improved (greater than 1 minute) at a dosage of 240 or 360 mg/day. No patient improved (greater than 1 minute) on 480 mg/day who had not already improved on a lower dose, but side effects requiring reduction in dosage occurred in seven patients receiving 480 mg of verapamil per day. Verapamil is an effective antianginal drug that appears most efficacious at a dose of 360 mg/day, but side effects are common at a dose of 480 mg/day.

Evaluation of the beta-blocking drug acebutolol in angina pectoris

The effects of the beta-adernergic blocking drug acebutolol were studied in 23 patients with angina pectoris and angiographically documented coronary artery disease. Patients were evaluated clinically, by graded treadmill testing and by 24-hour Holter monitoring in the control state, after 2 weeks treatment with placebo, and after 2 weeks treatment with 600 mg. and then 1,200 mg. of acebutolol. Acebutolol (in a daily dose of 600 mg.) was an effective antianginal drug: the number of clinical attacks of angina pectoris (p < 0.001) and the consumption of sublingual nitrate decreased (p < 0.01), there was a significant increase in the treadmill effort tolerance as measured by the time to appearance of ischemic ECG changes (p < 0.001) and the total work performed (p < 0.001), and there was also a significant decrease in ischemic ST segment depression on 24-hour Holter monitoring. Treatment with 1,200 mg. acebutolol was associated with a further decrease in heart rate and a further improvement in effort tolerance on treadmill testing (p < 0.05). On the large dose of the drug, however, there was no further clinical improvement, and no further improvement on 24-hour ECG monitoring; several patients complained of weakness and fatigue. Graded treadmill testing was an excellent objective method for assessing physical effort tolerance and its improvement after treatment with the beta-blocking drug. Twenty-four-hour Holter monitoring was a useful and complementary test, especially in patients who stopped exercising on the treadmill because of fatigue or weakness, and especially for assessing the efficacy of beta-blockade in controlling emotionally induced tachyacrdia and ischemia in the patient's own daily environment.

Effect of Sublingual Pentrinitrol on Exercise Tolerance in Angina Pectoris

The effects of 10 mg sublingual pentrinitrol and placebo on the exercise tolerance of 20 patients with angina pectoris were compared. The ten patients who received pentrinitrol had increases in exercise times and metabolic oxygen equivalents (METs) 15 and 60 minutes after administration, whereas no change occurred in ten comparable patients receiving placebo. Pentrinitrol produced lower preexercise systolic blood pressures and systolic blood pressures at point of angina. An increase in heart rate offset the effect of the reduced systolic blood pressure on double product (systolic blood pressure times heart rate). Sublingual pentrinitrol is an effective antianginal drug for at least 60 minutes.