Antianginal Drugs Research Articles

Ranolazine Interacts Antagonistically with Some Classical Antiepileptic Drugs-An Isobolographic Analysis.

Ranolazine, an antianginal and antiarrhythmic drug blocking slow inactivating persistent sodium currents, is described as a compound with anticonvulsant potential. Since arrhythmia often accompanies seizures, patients suffering from epilepsy are frequently co-treated with antiepileptic and antiarrhythmic drugs. The aim of this study was to evaluate the effect of ranolazine on maximal-electroshock (MES)-induced seizures in mice as well as interactions between ranolazine and classical antiepileptic drugs in this model of epilepsy. Types of pharmacodynamic interactions were established by isobolographic analysis of obtained data. The main findings of the study were that ranolazine behaves like an antiseizure drug in the MES test. Moreover, ranolazine interacted antagonistically with carbamazepine, phenytoin, and phenobarbital in the proportions of 1:3 and 1:1. These interactions occurred pharmacodynamic, since ranolazine did not change the brain levels of antiepileptic drugs measured in the fluorescence polarization immunoassay. Ranolazine and its combinations with carbamazepine, phenytoin, and phenobarbital did not impair motor coordination evaluated in the chimney test. Unfortunately, an attempt to conduct a passive avoidance task (evaluating long-term memory) resulted in ranolazine-induced delayed lethality. In conclusion, ranolazine exhibits clear-cut anticonvulsant properties in the MES test but interacts antagonistically with some antiepileptic drugs. The obtained results need confirmation in clinical studies. The mechanisms of ranolazine-induced toxicity require specific explanation.

How efficacious are traditional Chinese medicine injections in treating angina pectoris? A network meta-analysis of randomized controlled trials

Ethnopharmacological relevanceOver 50 million adults in China suffer from angina pectoris, which are often treated with traditional Chinese medicine injections (TCMIs). However, the efficacies of TCMIs and conventional drugs as determined by randomized controlled trials (RCTs) were not rigorously compared with one another by network meta-analysis (NMA). This PRISMA-compliant NMA aimed to compare the efficacy and assess the evidence strengths of 24 TCMIs in treating adults with angina pectoris of RCTs. Materials and methodsFollowing the protocol (PROSPERO registration number CRD42018117720), the RCTs that compared any TCMI with another TCMI or conventional drug on outcome measures including symptomatic and electrocardiography improvements were included. The quality of included RCTs was assessed with the Cochrane's risk of bias 2 tool. Frequentist statistical analyses were performed, including NMA, pairwise meta-analysis (PMA), subgroup analysis, sensitivity analysis, meta-regression, and publication bias analysis. The certainty of evidence was assessed with the GRADE approach. ResultsTotally, 556 eligible RCTs with 57015 participants were identified while the quality of all but five included RCTs was poor. The significant efficacy estimates and insignificant heterogeneity assessment from PMA and NMA indicated that nearly all TCMIs were more efficacious than conventional treatments for angina pectoris. Adequate subgroup and sensitivity analyses found the robust and consistent results. However, the evidence strengths of meta-analyses were assessed as very low to low due to the high risk of RCTs. The comprehensive efficacy estimates suggested that 4 TCMIs (HH, Honghua injection; HHH, Honghua Huangsesu injection; GLP, Gualoupi injection; and SM, Shenmai injection) was the best anti-anginal drugs for adults with angina pectoris. ConclusionTCMIs appear to be efficacious for angina pectoris, although evidence evaluation of high-quality RCTs of TCMIs would be necessary. In particular, randomization and blinding procedures of the RCTs should be explicated to meet the CONSORT requirements.

OPTIMAL MEDICAL THERAPY: FOR SYMPTOMS CONTROL

One of the main objectives in the treatment of chronic coronary artery disease is to improve quality of life, by controlling the symptoms of angina, which are often limiting. To perform this task, the physician must offer the patient what we call optimal medical therapy, which includes education on lifestyle modifications, control of risk factors and comorbidities, pharmacological treatment and, in selected cases, myocardial revascu-larization. The initial drug therapy usually consists of one or two classes of antianginal drugs plus secondary prevention medications. A significant proportion of patients do not satisfactorily achieve the goal of controlling the symptoms of angina, many of which for not receiving a truly optimal medical therapy, with maximum tolerated doses of antianginal drugs, in combination therapy, according to the individual characteristics of each patient. There is strong evidence indicating that all classes of antianginals have similar efficacy in the treatment of angina and myocardial ischemia and, nevertheless, none of them reduce cardiovascular events, except for beta-blockers in patients with left ventricular dysfunction or recent myocardial infarction. There is no definition of which drug or combination is optimal, and there is no evidence to support the use of the terms “first- and second-line” drugs in the treatment of angina. We suggest, therefore, that the best strategy should be individualized, choosing the antianginal drug according to the patients’ clinical charac-teristics and comorbidities.

REABILITAÇÃO CARDÍACA BASEADA EM EXERCÍCIO NA ANGINA REFRATÁRIA: EXPERIÊNCIA UNICÊNTRICA

Refractory angina (RA) is a chronic clinical condition characterized by angina pectoris, which occurs as a result of myocardial ischemia, unresponsive to conventional medical treatment (i.e. control of cardiovascular risk factors and other clinical conditions, in addition to antianginal drugs), which is not eligible for coronary interventions. Patients with RA evolve with great functional limitation due to pain and consequent loss of quality of life, and their improvement is the focus of treatment. Exercise-based cardiac rehabilitation (CR) is an adjuvant therapy that effectively promotes secondary prevention in patients with coronary artery disease, but it is rarely prescribed for patients with refractory angina due to concerns about adverse events during exercise, related to triggering ischemia myocardial infarction at low thresholds. In this review, we address the experience obtained with the management of patients with RA in a reference center for the treatment of RA, especially related to exercise-based CR. Some peculiarities in the evaluation and prescription of training in patients with RA and their understanding are important to promote greater safety and efficacy of physical exercise in this population.

Central Composite Design for the Development of Trimetazidine Dihydrochloride-Loaded Fast Dissolving Film

A fast-dissolving dosage form is an approach used to improve therapeutic efficacy and bioavailability by avoiding the first-pass metabolism of the cargo. Besides, the approach causes rapid cargo absorption from the pre-gastric area which may outcome in the quick inception of action. The trimetazidine dihydrochloride (TDC) is an anti-anginal drug and there is a prerequisite to provide fast onset of action to treat angina. Therefore, the present work was aimed to prepare and evaluate fast-dissolving oral films (FDOF) of TDC to provide fast onset of action. The FDOF is prepared by using the solvent casting method and it was optimized by employing a central composite statistical design. The two independent variables such as HPMC K4M and PEG 400 are the film-forming polymers which are evaluated at three levels. The dependent variables selected as folding endurance, disintegration time, and % drug release. The formulation was prepared and optimized the batch F-4 showed the least disintegration time (19 s) and the highest drug release (98.55±7.90%). Moreover, the ex-vivo mucus permeation study showed better permeation and satisfying physicochemical properties. As per the above results, we conclude that the prepared formulation could be a novel dosage form to improve drug delivery and patient compliance.

Abstract 14023: Myocardial Perfusion Abnormalities: A Potential Biomarker for Ventricular Arrhythmias in Hypertrophic Cardiomyopathy Young Patients?

Introduction: Despite progress in the field, risk stratification for sudden death in patients with hypertrophic cardiomyopathy (HCM) remains challenging. Although ventricular arrhythmias (VA) account for most of these events, the mechanisms responsible for cardiac arrest in HCM are not understood. Hypothesis: Abnormalities in myocardial perfusion may create an arrhythmogenic substrate in HCM patients. Methods/ Results: A 12-year-old boy was admitted to our department after an out-of-hospital cardiac arrest, with documented ventricular fibrillation while running. A non-obstructive asymmetric HCM was diagnosed with echocardiography (max LV wall thickness 32 mm). He had one conventional risk factor for SCD. Genetic testing revealed a heterozygous state for a MYH7 variation: p.Glu500Ala (NM_000257.3:c.1499A>C). This variation was classified as “probably pathogenic” (class 4 according to ACMG). His father and his 15-year-old brother were heterozygous for the same variant and were asymptomatic. The brother displayed a similar HCM phenotype. The patient received an implantable defibrillator and suffered from appropriate exercise-related shocks within 6-months despite sotalol therapy (160 mg bid). Because the VA occurred always when the patient was engaged in vigorous physical activity despite beta blocker and since he could not refrain from physical activity, thallium-201 myocardial scintigraphy was performed. To further understand the arrhythmogenic phenotype, his brother underwent the same investigation. Significant uptake perfusion defects in both initial and delayed images were evident in the proband (15%) but not in the asymptomatic brother. Treatment with antianginal drug (amlodipine 5 mg/day) was initiated. With 10 mg/day amlodipine was associated with a significant improvement of the scintigraphy (6% versus 15% perfusion defect). At a follow-up of 12 months, there was no recurrence of VA. Conclusions: Regarding HCM patients, the present report 1) strengthens the hypothesis that myocardial perfusion defects may identify patients at risk for VA, 2) suggests that tailored anti-ischemic prescription may be useful, and 3) underscores the need of prospective studies quantifying ischemia in HCM patients with exercise-induced VF.

Updates on Pharmacologic Management of Microvascular Angina.

Microvascular angina (MVA), historically called cardiac syndrome X, refers to angina with nonobstructive coronary artery disease. This female-predominant cardiovascular disorder adds considerable health-related costs due to repeated diagnostic angiography and frequent hospital admissions. Despite the high prevalence of this diagnosis in patients undergoing coronary angiography, it is still a therapeutic challenge for cardiologists. Unlike obstructive coronary artery disease, with multiple evidence-based therapies and management guidelines, little is known regarding the management of MVA. During the last decade, many therapeutic interventions have been suggested for the treatment of MVA. However, there is a lack of summarization tab and update of current knowledge about pharmacologic management of MVA, mostly due to unclear pathophysiology. In this article, we have reviewed the underlying mechanisms of MVA and the outcomes of various medications in patients with this disease. Contrary to vasospastic angina in which normal angiogram is observed as well, nitrates are not effective in the treatment of MVA. Beta-blockers and calcium channel blockers have the strongest evidence of improving the symptoms. Moreover, the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, estrogen, and novel antianginal drugs has had promising outcomes. Investigations are still ongoing for vitamin D, omega-3, incretins, and n-acetyl cysteine, which have resulted in beneficial initial outcomes. We believe that the employment of the available results and results of the future large-scale trials into cardiac care guidelines would help reduce the global cost of cardiac care tremendously.

Nicorandil mitigates amiodarone-induced pulmonary toxicity and fibrosis in association with the inhibition of lung TGF-β1/PI3K/Akt1-p/mTOR axis in rats.

The long-term side effect of the antiarrhythmic drug, amiodarone (AMIO), such as lung toxicity, remains a critical clinical issue. The previous knowledge denotes diverse antioxidant, anti-inflammatory, and antifibrotic properties of the anti-anginal drug, nicorandil (NI). Therefore, we aimed to investigate the possible protective effect of NI on pulmonary tissue remodelling following AMIO-induced lung toxicity. The included rats were assigned into four equal groups (n=8): (1) control, (2) control group that received NI 10mg kg-1 day-1 , (3) model group that received AMIO in a dose of 60 mg kg-1 day-1 , and (4) treated group (AMIO-NI) that were treated with AMIO plus NI as shown above. Drug administration continued for 10 weeks. AMIO resulted in deteriorated (p < 0.001) pulmonary functions accompanied by respiratory acidosis. AMIO showed an obvious histological injury score with intense collagen deposition, disturbed nitric oxide synthase enzymes (NOS/iNOS), and increased alpha smooth muscle actin expression. Furthermore, AMIO upregulated the transforming growth factor (TGF-β1)/phosphoinositide-3 kinase (PI3K)-Akt1-p/mammalian target of rapamycin (mTOR) axis, which determined the possible mechanism of AMIO on pulmonary remodelling. NI treatment significantly (p < 0.001) prevented the AMIO-induced lung toxicity, as well as inhibited the TGF-β1/PI3K/Akt1-p/mTOR axis in the lung tissue of rats. The results were confirmed by an in-vitro study. CONCLUSION: The current results revealed that NI was effective in preserving the lung structure and functions. Amelioration of the oxidative stress and modulation of TGF-β1/PI3K/Akt1-p/mTOR have been achieved. This study suggests NI administration as a preventive therapy from the serious pulmonary fibrosis side effect of AMIO.

The place of diltiazem in the treatment of patients with stable angina in concomitant bronchial asthma

Introduction. In the treatment of stable angina in patients with concomitant bronchial asthma (BA), the bronchopulmonary system may be adversely affected by a number of drugs. Diltiazem may be the drug of choice when antianginal therapy with a pulseslowing effect is required, but β-blockers are contraindicated.Aim of the study. To compare the antianginal, pulse-slowing and vasoprotective effects of the calcium antagonist (CA) diltiazem, the calcium antagonist verapamil and the cardioselective beta-adrenoblocker (BAB) bisoprolol in the treatment of stable angina (SA) patients with concomitant BA.Materials and methods. The study included 60 patients with stable angina II-III FC with concomitant mild or moderate persistent BA. The patients were divided into three groups of 20 patients depending on antianginal drugs: Group 1 received betaadrenoblocker bisoprolol, Group 2 – calcium antagonist verapamil, Group 3 – calcium antagonist diltiazem. All patients underwent cardiography (Doppler EchoCG), external respiration function (ERF), endothelium-dependent vasodilation (EDVD) study at baseline and after 2, 4, 6 weeks of treatment.Results. No negative dynamics of FEV1 was found in patients of all groups during the study of ERF after 6 weeks of treatment. There was a statistically significant increase in FEV1 after 6 weeks of treatment in group 3 patients receiving diltiazem (p = 0.032). There was a statistically significant decrease in HR in all three groups during treatment, but in group 2 the dynamics were significantly lower when treated with verapamil. Analysis of mPAP of patients showed that it decreased in all groups after 6 weeks of treatment, but significant dynamics was noted only in Group 3. EDVD test after 6 weeks of treatment revealed positive dynamics, with a statistically significant increase in the index registered in patients of groups 1 and 3.Conclusions. In treatment of patients with stable angina with mild and intermediate persistent disease without exacerbation, antianginal therapy with the calcium antagonist diltiazem has marked antianginal, pulse-slowing action, has vasoprotective effect on the small and large circulatory vessels, improves the parameters of bronchial permeability.

Formation of antianginal pharmacotherapy in the historical aspect. From theoretical background to practical effect

Angina pectoris is the most common form of chronic coronary insufficiency, treatment of which consists in reducing the number, duration and severity of anginal pains, as well as improving the prognosis: preventing the development of cardiovascular complications such as acute myocardial infarction, life-threatening rhythm disturbances and congestive heart failure. The treatment of coronary artery disease (CAD) has recently undergone significant changes. This is primarily due to the wide introduction into clinical practice of surgical and endovascular methods of myocardial blood flow restoration, which have moved the use of pharmacological of antianginal agents to the background. Despite this, the clinic continues to feel the need for drugs with anti-ischemic properties. This is due to the fact that there is a group of patients who, for various reasons, cannot undergo revascularization of the heart. This is due to the fact that there is a group of patients who, for various reasons, cannot undergo cardiac revascularization. These include individuals with morphological features of the coronary bed, technical obstacles to surgery, increasing number of cases of diabetic microangiopathy as a cause of myocardial ischemia, frequent recurrence of angina after coronary angioplasty. Finally, today we are not yet able to meet all the needs for myocardial revascularization. Thus, the clinical interest in antianginal therapy remains. The present review shows analysis of usage medications with various pharmacological properties in patients with angina in the historical aspect since the second half of the IX century, evolution of the researchers’ ideas about the mechanism of antianginal action, the amount of drugs used. A brief characteristic of modern antianginal drugs presented in the recommendations of the European Society of Cardiologists last revision (2019) is given.

Safety and efficacy of ranolazine in hypertrophic cardiomyopathy: Real-world experience in a National Referral Center

ObjectivesWe assessed the efficacy and safety of ranolazine in real-world patients with hypertrophic cardiomyopathy (HCM). BackgroundRanolazine is an anti-anginal drug that inhibits the late phase of the inward sodium current. In a small prospective trial, ranolazine reduced the arrhythmic burden and improved biomarker profile in HCM patients. However, systematic reports reflecting real-world use in this setting are lacking. MethodsChanges in clinical and instrumental features, symptoms and arrhythmic burden were evaluated in 119 patients with HCM before and during treatment with ranolazine at a national referral centre for HCM. ResultsPatients were treated with ranolazine for 2 [1–4] years; 83 (70%) achieved a dosage ≥1000 mg per day. Treatment interruption was necessary in 24 patients (20%) due to side effects (n = 10, 8%) or disopyramide initiation (n = 8, 7%). Seventy patients (59%) were treated with ranolazine for relief of angina. Among them, 51 (73%) had total symptomatic relief and 47 patients (67%) showed ≥2 Canadian Cardiovascular society (CCS) angina grade improvement. Sixteen patients (13%) were treated for recurrent ventricular arrhythmias, including 4 with a clear ischemic trigger, who experienced no further arrhythmic episodes while on ranolazine. Finally, 33 patients (28%) were treated for heart failure associated with severe diastolic dysfunction: no symptomatic benefit could be observed in this group. ConclusionRanolazine was safe and well tolerated in patients with HCM. The use of ranolazine may be considered in patients with HCM and microvascular angina.

ПРИМЕНЕНИЕ АТОРВАСТАТИНА В СОВРЕМЕННОЙ КАРДИОЛОГИИ ДЛЯ СНИЖЕНИЯ РИСКОВ ИШЕМИЧЕСКОЙ БОЛЕЗНИ СЕРДЦА

Abstract. This article discusses issues regarding the use of drugs of the statin group for the prevention of diseases of the cardiovascular system, namely the use of atorvastatin in the prevention of coronary artery disease. The study involved 80 patients. at the same time, 65 participants in the study suffered from coronary artery disease, they were diagnosed with angina pectoris of functional class 2, 15 people were potentially healthy, all participants had a common average age and gender characteristics. All patients included in the study were divided into two groups: main and control. The first group received atorvastatin as therapy for IHD, the second group received standard IHD therapy, which included beta-blockers, antianginal drugs, etc. The results of the study were evaluated after 6 weeks and six months. An auxiliary instrumental method was the veloergometric test, as the most optimal option relative to others. This technique was used to verify the ischemic heart disease. To conduct a veloergometric test, the Cardiovit AT-10 apparatus was used, which allows you to gradually increase the load. The study included several stages, each stage assumed a 3-minute load. The load power was determined by a number of factors, such as weight, height of the patient, comorbidities, and age. In the first group, there is a clear positive trend and changes in the lipid profile, which persist for six months. In patients of the second group, such dynamics were not reliably detected. Also, all patients with coronary heart disease underwent a determination of the correspondence of biological age to chronological age. In this case, a formula based on the results of a well ergometric study was used.

The Safety of Nicorandil Therapy and the Relationship with Treatment Adherence in Patients with Stable Angina Pectoris (According to the NIKEA Observational Study)

The working group of the NIKEA study: Reznik I.I. (Ekaterinburg), Akulina E.N. (Ekaterinburg), Ezhov A.V. (Izhevsk), Shinkareva S.I. (Izhevsk), Grebnev S.A. (Izhevsk), Skibitsky V.V. (Krasnodar), Kudryashov E.A. (Krasnodar), Fendrikova A.V. (Krasnodar), Skibitsky A.V. (Krasnodar), Matyushin G.V. (Krasnoyarsk), Nemik D.B. (Krasnoyarsk), Pitaev R.R. (Krasnoyarsk), Altaev V.D. (Krasnoyarsk), Samokhvalov E.V. (Krasnoyarsk), Stolbikov Y.Y.. (Krasnoyarsk), Voronina V.P. (Moscow), Lerman O.V. (Moscow), Gaisenok O.V. (Moscow), Dmitrieva N.A. (Moscow), Zagrebelny A.V. (Moscow), Zakharova A.V. (Moscow), Balashov I.S. (Moscow), Leonov A.S. (Moscow), Sladkova T.A. (Moscow), Zelenova T.I. (Moscow), Shestakova G.N. (Moscow), Kolganova E.V. (Moscow), Maksimova M.A. (Moscow), Kuimov A.D. (Novosibirsk), Moskalenko I.V. (Novosibirsk), Shurkevich A.A. (Novosibirsk), Nechaeva G.I. (Omsk), Loginova E.N. (Omsk), Gudilin V.A. (Omsk), Mitroshina T.N. (Orel), Zhuravleva L.L. (Orel), Lobanova G.N. (Orel), Luneva M.M. (Orel), Libis R.A. (Orenburg), Kondratenko V.Yu. (Orenburg), Chesnikova A.I. (Rostov-on-Don), Kalacheva N.M. (Rostov-on-Don), Kolomatskaya O.O. (Rostov-on-Don), Dubishcheva N.F. (Rostov-on-Don), Romadina G.V. (Rostov-on-Don), Chugunova I.B. (Rostov-on-Don), Skarzhinskaya N.S. (Rostov-on-Don), Dobrynina N.V. (Ryazan), Yakushin S.S. (Ryazan), Bulanov A.V. (Ryazan), Trofimova Ya.M. (Ryazan), Nikolaeva A.S. (Ryazan), Sokolova L.A. (St. Petersburg), Savinova E.B. (St. Petersburg), Ievskaya E.V. (St. Petersburg), Vasilyeva L.B. (St. Petersburg), Gomova T.A. (Tula), Zubareva L.A. (Tula), Berberfish L.D. (Tula), Gorina G.I. (Tula), Nadezhkina K.N. (Tula), Yunusova K.N. (Tula), Nikitina V.F. (Tula), Dabizha V.G. (Tula), Renko I.E. (Tula), Soin I.A. (Tula)Aim. To analyze the adverse events (AEs) of nicorandil therapy based on the results of an observational study of NIKEA, to assess the relationship between the occurrence of AEs treatment and adherence to it in patients with stable angina pectoris.Material and methods. The study included 590 people who had nicorandil added to the basic therapy of coronary artery disease (CAD). The followup period averaged 21 months. There were two visits of 1 and 3 months of follow-up (V1 and V3), and after 21 months, by telephone contact (PhC21), it was possible to obtain information about 524 patients (89% response), 509 of whom were alive. Information about the treatment adherence and AEs of nicorandil was collected during V1, V3 and at PhC21.Results. Out of 590 people, 402 (68.1%) patients started treatment with nicorandil. During 21 months of follow-up, 35 AEs were registered in 34 patients. There were no serious AEs associated with taking medications in the study. The most frequent AEs of treatment with nicorandil were hypotension and headache, which led to non-adherence to therapy in 94% and 42% of cases, respectively. The majority of AEs (24 out of 35) occurred during the first three months of nicorandil treatment. Both any AEs of drug therapy and AEs of nicorandil therapy, on average, increase the chance of non-adherence to the recommended treatment by 3 times (p=0.004).Conclusion. The results of the NIKEA study confirmed the good safety of nicorandil in patients with stable angina pectoris, the absence of serious adverse events associated with taking this antianginal drug. The most frequent nicorandil AEs were hypotension and headache. Any AEs of therapy increase the chance of patients' non-adherence by 3 times.

Statistically designed novel ranolazine-loaded ethosomal transdermal gel for the treatment of angina pectoris

Ranolazine (RZ) is a newer novel anti-anginal drug with poor solubility and high permeability features. The current research work focused on the statistical design and development of RZ-loaded ethosome as a novel carrier through entrapment and in silico binding affinity studies using molecular docking. The study investigates the prospect of ethosomes as lipid nano-carrier in the form of vesicles for the transdermal enhancement of RZ. The affinity studies of RZ with Phospholipon 90H (PL90H) and a copolymer cholesterol signified the importance of cholesterol in the entrapment of drug in polar region of lipid bilayer in ethosomal vesicle with binding affinity −10.2 kcal/mol that enhanced drug solubility and absorption. In the absence of copolymer, the drug entrapped in non-polar tail with significantly less binding affinity −1.9 kcal/mol. Based on this finding the effective RZ-loaded ethosome compositions were designed and optimized. The Box-Behnken Design (BBD) was applied to fabricate ethosomes with changing amounts of phospholipon PL90H, hydroethanol, and cholesterol. The influence of independent variables PL90H (A), hydroethanol solution (B), and cholesterol (C) on vesicle size (nm), and % entrapment efficiency (%EE) was studied. The optimized ethosome formulation (R4) containing drug in ethosomal vesicle, evaluated using FTIR and XRD techniques, revealed a change in its physical state. Results demonstrated composition R4 with PL90H (100 mg) and hydroethanol (40% w/v) was embedded into Carbopol 934P gel to screen drug permeation and skin irritation. The ethosomal suspension (R4) was demonstrated with ethosome size 165.71 ± 2.73 nm, zeta potential −36.63 ± 2.78 mV, and %EE 80.21 ± 1.27. The optimized ethosomal suspension recorded release of RZ through dialysis membrane against RZ-loaded plain gel; was superior sustained over 24 h. The drug release from ethosomal gel followed a combination of Higuchi and Peppas model. RZ ethosomal gel tested using MTT assay manifested enhanced cytotoxic potential of RZ on H9C2-mouse cardiomyoblast cell line. Incorporation of vesicles into the gel leads to significant improvement in its stability. The present study demonstrates the prospective of ethosomal vesicles in delivering RZ across transdermal layers with the least skin irritation potential proclaiming its better safety, efficacy, and patient compliance.

Pharmacologic modulation of intracellular Na+ concentration with ranolazine impacts inflammatory response in humans and mice

Changes in Ca2+ influx during proinflammatory stimulation modulates cellular responses, including the subsequent activation of inflammation. Whereas the involvement of Ca2+ has been widely acknowledged, little is known about the role of Na+. Ranolazine, a piperazine derivative and established antianginal drug, is known to reduce intracellular Na+ as well as Ca2+ levels. In stable coronary artery disease patients (n = 51) we observed reduced levels of high-sensitive C-reactive protein (CRP) 3 mo after the start of ranolazine treatment (n = 25) as compared to the control group. Furthermore, we found that in 3,808 acute coronary syndrome patients of the MERLIN-TIMI 36 trial, individuals treated with ranolazine (1,934 patients) showed reduced CRP values compared to placebo-treated patients. The antiinflammatory effects of sodium modulation were further confirmed in an atherosclerotic mouse model. LDL-/- mice on a high-fat diet were treated with ranolazine, resulting in a reduced atherosclerotic plaque burden, increased plaque stability, and reduced activation of the immune system. Pharmacological Na+ inhibition by ranolazine led to reduced express of adhesion molecules and proinflammatory cytokines and reduced adhesion of leukocytes to activated endothelium both invitro and invivo. We demonstrate that functional Na+ shuttling is required for a full cellular response to inflammation and that inhibition of Na+ influx results in an attenuated inflammatory reaction. In conclusion, we demonstrate that inhibition of Na+-Ca2+ exchange during inflammation reduces the inflammatory response in human endothelial cells invitro, in a mouse atherosclerotic disease model, and in human patients.

Assessment of the Quality of Drug Therapy in Patients with Stable Coronary Artery Disease in the Second Stage of the ALIGN Study

Aim. To assess adjusted pharmacotherapy for prescribing drugs of the main classes, according to clinical guidelines, and achieving target levels of lowdensity lipoprotein cholesterol (LDL-C) in patients with stable coronary heart disease (CHD).Material and methods. Of the 73 patients included in the ALIGN study, 64 patients (53 males and 11 females; mean age 68,2±9,4 years) with stable coronary artery disease attended a second visit (3 months after the initial treatment adjustment). Prescribed drug therapy, its compliance with clinical guidelines, achievement of lipid profile and blood pressure (BP) targets were studied in all patients.Results. An increase in the frequency of taking beta-blockers (p=0.002), lipid-lowering drugs (p=0.008) by patients was found during the second visit. The proportion of patients taking all 4 groups of drugs according to clinical guidelines (statins, antiplatelet agents, beta-blockers, angiotensinconverting enzyme inhibitors / angiotensin II receptor blockers) increased from 44% to 65.5% (p&lt;0.001) after correction of therapy, as well as an increase in the proportion of patients taking 1 antianginal drug in the presence of exertional angina from 75% to 89% (p&lt;0.001) was found. About 90% of hypertensive patients achieved the target level of systolic blood pressure (p&lt;0.001). Achievement of the target level of cholesterol low density lipoprotein (&lt;1.8 mmol/l) during the second visit was found in half of the patients (p=0.004).Conclusion. Despite the initial correction of drug therapy by the staff of the cardiology department, the prescribed treatment for patients with stable coronary artery disease did not in all cases comply with clinical guidelines due to insufficient adherence of doctors and insufficient adherence of patients to prescribed medical recommendations.Working group of the register PROFILE: Voronina V. P., Dmitrieva N. A., Komkova N. A., Zagrebelny A.V., Kutishenko N.P., Lerman O.V., Lukina Yu. V., Tolpygina S.N., Martsevich S.Yu.

Case Report on chronic cardiac failure &amp; hyperthyroidism &amp; bronchial asthma

Heart failure is a long-term, development of a progressive ailment when the The heart’s muscle cannot to sufficient blood pump to meet the body’s needs for oxygen and blood. Essentially, The heart cannot do it to withstand the stress. A 75 year old women admitted in AVBR hospital with the chief complaints breathlessness , cough, fever, pain in thoracic region , hypertension, etc. During her hospital stay, the patient received the patient’s major therapeutic intervention and was treated with intravenous anti-anginal medicines, injection antiemetics, NSAIDs,etc .Categories : anti anginal drugs , Injection antiemetics, NSAID’s, etc

Comparison of pharmacokinetic parameters of ranolazine between diabetic and non-diabetic rats.

Objective(s):Diabetes mellitus (DM) affects the pharmacokinetics of drugs. Ranolazine is an antianginal drug that is prescribed in DM patients with angina. We decided to evaluate the effect of DM on the pharmacokinetics of ranolazine and its major metabolite CVT-2738 in rats.Materials and Methods:Male rats were divided into two groups: DM (induced by 55 mg/kg Streptozotocin (STZ)) and non-DM. All animals were treated with 80 mg/kg of ranolazine for 7 continuous days. The blood samples were collected immediately at 0 (prior to dosing), 1, 2, 3, 4, 8, and 12 hr after administration of the 7th dose of ranolazine. Serum ranolazine and CVT-2738 concentrations were determined using the high-performance liquid chromatography (HPLC) method. Pharmacokinetic parameters were calculated using a non-compartmental model and compared between the two groups.Results:The peak serum concentration (Cmax) and area under the curve (AUC) of ranolazine significantly decreased in DM compared with non-DM rats. DM rats showed significantly higher volumes of distribution (Vd) and clearance (CL) of ranolazine than non-DM rats. DM did not affect Ke, Tmax, and T1/2 of ranolazine. The concentration of metabolite was lower than the HPLC limit of detection (LOD).Conclusion:It was found that streptozotocin-induced DM increased Vd and CL of ranolazine, thereby decreasing the AUC of the drug. Therefore, dosage adjustment may be necessary for DM patients, which requires further clinical studies.

Local Anesthetics via Multicomponent Reactions.

Local anesthetics occupy a prime position in clinical medicine as they temporarily relieve the pain by blocking voltage-gated sodium channels. However, limited structural diversity, problems with the efficiency of syntheses and increasing toxicity, mean that alternative scaffolds with improved chemical syntheses are urgently needed. Here, we demonstrate a multicomponent reaction (MCR)-based approach both towards the synthesis of commercial local anesthetics and towards novel derivatives as potential anesthesia candidates via scaffold hopping. The reactions are efficient and scalable, and several single-crystal structures have been obtained. In addition, our methodology has been applied to the synthesis of the antianginal drug ranolazine, via an Ugi three-component reaction. Representative derivatives from our libraries were evaluated as neuronal activity inhibitors using local field potential recordings (LFPs) in mouse hippocampal brain slices and showed very promising results. This study highlights new opportunities in drug discovery targeting local anesthetics.

Upregulation of neuronal progranulin mediates the antinociceptive effect of trimetazidine in paclitaxel-induced peripheral neuropathy: Role of ERK1/2 signaling

Neuronal progranulin (PGRN) overexpression is an endogenous adaptive pain defense following nerve injury. It allows the survival of injured neurons to block enhanced nociceptive responses. Trimetazidine (TMZ) is widely used by cardiac patients as an anti-anginal drug, reflecting its anti-ischemic property. TMZ promotes axonal regeneration of sciatic nerves after crush injury. This study explored the interplay between PGRN and extracellular signal-regulated kinases (ERK1/2) to address mechanisms underlying neuropathic pain alleviation following paclitaxel (PTX) administration. Rats were given four injections of PTX (2 mg/kg, i.p.) every other day. Two days after the last dose, rats received TMZ (25 mg/kg) with or without the ERK inhibitor, PD98059, daily for 21 days. TMZ preserved the integrity of myelinated nerve fibers, as evidenced by an obvious reduction in axonal damage biomarkers. Accordingly, it alleviated PTX-evoked thermal, cold, and mechanical hyperalgesia/allodynia. TMZ also promoted ERK1/2 phosphorylation with a profound upsurge in PGRN content. These effects were associated with a substantial increase in Notch1 receptor gene expression and a prominent anti-inflammatory effect with a marked increase in mRNA expression of secretory leukocyte protease inhibitor. Further, TMZ decreased oxidative stress and caspase-3 activity in the sciatic nerve. Conversely, co-administration of PD98059 completely abolished these beneficial effects. Thus, the robust antinociceptive effect of TMZ is largely attributed to upregulating PGRN and Notch1 receptors via ERK1/2 activation.