Ranolazine: An Old Drug with Emerging Potential; Lessons from Pre-Clinical and Clinical Investigations for Possible Repositioning

Ischemic heart disease is a significant public health problem with high mortality and morbidity. Extensive scientific investigations from basic sciences to clinics revealed multilevel alterations from metabolic imbalance, altered electrophysiology, and defective Ca2+/Na+ homeostasis leading to lethal arrhythmias. Despite the recent identification of numerous molecular targets with potential therapeutic interest, a pragmatic observation on the current pharmacological R&D output confirms the lack of new therapeutic offers to patients. By contrast, from recent trials, molecules initially developed for other fields of application have shown cardiovascular benefits, as illustrated with some anti-diabetic agents, regardless of the presence or absence of diabetes, emphasizing the clear advantage of “old” drug repositioning. Ranolazine is approved as an antianginal agent and has a favorable overall safety profile. This drug, developed initially as a metabolic modulator, was also identified as an inhibitor of the cardiac late Na+ current, although it also blocks other ionic currents, including the hERG/Ikr K+ current. The latter actions have been involved in this drug’s antiarrhythmic effects, both on supraventricular and ventricular arrhythmias (VA). However, despite initial enthusiasm and promising development in the cardiovascular field, ranolazine is only authorized as a second-line treatment in patients with chronic angina pectoris, notwithstanding its antiarrhythmic properties. A plausible reason for this is the apparent difficulty in linking the clinical benefits to the multiple molecular actions of this drug. Here, we review ranolazine’s experimental and clinical knowledge on cardiac metabolism and arrhythmias. We also highlight advances in understanding novel effects on neurons, the vascular system, skeletal muscles, blood sugar control, and cancer, which may open the way to reposition this “old” drug alone or in combination with other medications.

EFFECT OF TRIMETAZIDINE ON HEART PARAMETERS IN PATIENTS AFTER VIRAL PNEUMONIA WITH A TEST WITH A FIXED RESPIRATORY RATE

Статья посвящена оценке динамики традиционных показателей вариабельности ритма сердца (ВРС) на фоне терапии триметазидином у больных с кардиальной патологией после перенесенной коронавирусной пневмонии при использовании методики темпа дыхания. Выполнен анализ анамнестических, клинико-лабораторных и микробиологических показателей 50 лиц мужского пола с диагнозом стабильной стенокардией напряжения II функционального класса, после перенесенной коронавирусной пневмонии с использованием аппаратно-программных комплексов. При использовании пробы с ФТД у пациентов с ИБС после перенесенной коронавирусной пневмонии на фоне терапии триметазидином было выявлено два типа реакции: первый - позитивный достоверный прирост параметров вариабельности ритма сердца, второй - U-образный вид изменения показателей ВРС: снижение при проведении методики в 6 секунд и дальнейший рост при 12 секундах. Клиническая значимость методики ФТД достаточно велика, она позволяет доктору по динамике показателей ВРС: СВВР - показатель средней взвешенной вариации ритмограммы, SDNN - показатель суммарного эффекта вегетативной регуляции кровообращения, рассуждать об адекватности восстановительного периода у постковидных пациентов с ИБС и проводить коррекцию тактики лечения. Триметазидин является эффективным антиангинальным средством в комплексной терапии пациентов со стабильной стенокардией после перенесенной коронавирусной пневмонии. На фоне лечения выявлено уменьшение числа эпизодов, а также времени ишемической депрессии, что несомненного благоприятно для пациента. При исходно низком показателе СВВР добавление триметазидина в комплексную терапию ИБС может свидетельствовать о восстановлении дисбаланса вегетативной нервной системы Purpose: to evaluate the change in heart rate variability (HRV) indicators during treatment with trimetazidine in patients with coronavirus pneumonia after coronavirus pneumonia using a fixed respiratory rate test (FTD). Material and methods. A comparative analysis of anamnestic, clinical, laboratory and microbiological indicators of 50 men with stable exertional angina of II functional class (NYHA FC) after suffering coronavirus pneumonia using hardware and software systems was carried out. Results. When using a test with PTD in patients with coronavirus pneumonia after suffering from coronavirus pneumonia during therapy with trimetazidine, two types of reaction were revealed: the first was a positive significant increase in heart rate variability parameters, the second was a U-shaped type of change in HRV parameters: a decrease in 6-second breathing and further growth with 12-second breathing. Conclusion. The practical significance of the test with FTD is quite large, it allows the doctor, by the type of change in HRV parameters: SDNN - the total effect of autonomic regulation of blood circulation, SVVR - the average weighted variation of the rhythmogram, to talk about the adequacy of the rehabilitation process of postcovid patients with IHD and to correct the treatment tactics. Trimetazidine is an effective antianginal agent in the complex treatment of patients with stable angina pectoris after suffering from coronavirus pneumonia. Against the background of therapy, there is a decrease in the number of episodes, the time of ischemic depression, which is a favorable factor. With an initially low value of SVVR, the addition of trimetazidine to the complex therapy of ischemic heart disease may indicate the restoration of a disturbed vegetative balance

Identification of hit compounds with anti-schistosomal activity on in vitro generated juvenile worms in cell-free medium

Background Anthelminthic treatment options against schistosomiasis are limited. The current treatment relies almost exclusively on a single drug, praziquantel (PZQ). As a consequence, the development of resistance to PZQ and limited activity of PZQ against earlier development stages are respectively a risk and a limitation to achieving the goals of the new WHO roadmap towards elimination. For the discovery of new chemical starting points, the in vitro drug screening on Schistosoma mansoni (S. mansoni) against newly transformed schistosomula (NTS) is still the most predominant approach. The use of only NTS in the initial screening limits sensitivity to potential new compounds which are predominantly active in later developmental stages. Using our recently described highly standardized, straightforward and reliable culture method that generates high rates of juvenile worms, we aimed to repurpose a subset of the NCATS Pharmaceutical Collection (340 compounds) to identify new hits with an in vitro worm culture assay. Methodology/Principal findings Cercariae were mechanically transformed into skin-stage (SkS) schistosomula and continuously cultured for 3–6 weeks to the liver stage (LiS). A commercial source of serum was identified, and decrease of NTS/well along with optimal drug testing conditions was established to test compounds on early and late LiS worms. The library was screened in 96-well format assays using praziquantel (PZQ) as a positive control. Primary screening allowed a 5.9% hit rate and generated two confirmed hits on adult worms; a prophylactic antianginal agent and an antihistaminic drug. Conclusion With this standardized and reliable in vitro assay, important S. mansoni developmental stages up to LiS worms can be generated and cultured over an extended period. When exposed to a subset of the National Center for Advancing Translational Sciences (NCATS) Pharmaceutical Collection, 3 compounds yielded a defined anti-schistosomal phenotype on juvenile worms. Translation of activity on perfused adult S. mansoni worms was achieved only for perhexiline (a prophylactic antianginal agent) and astemizole (an antihistaminic drug).

Withdrawal of prenylamine: perspectives on pharmacological, clinical and regulatory outcomes following the first QT-related casualty

Prenylamine, an antianginal agent marketed since early 1960, became the first casualty of QT interval related proarrhythmias in 1988 when it was withdrawn from the market. The period of its synthesis and marketing is of particular interest since it antedated, first, any serious clinical safety concern regarding drug-induced prolongation of the QT interval which was, in fact, believed to be an efficient antiarrhythmic mechanism; second, the first description of torsade de pointes as a unique proarrhythmia, typically associated with prolonged QT interval; and third, the discovery and recognition of calcium antagonism as an important cardiovascular therapeutic strategy. This review, 30 years almost to the day following its withdrawal, provides interesting perspectives on clinical, pharmacological and regulatory outcomes that followed. Prenylamine underscored torsadogenic potential of other early antianginal drugs on the market at that time and identified QT-related proarrhythmias as a much wider major public health issue of clinical and regulatory concern. This resulted in various guidelines for early identification of this potentially fatal risk. Application of these guidelines would have readily identified its proarrhythmic potential. Prenylamine also emphasized differences in drug responses between men and women which subsequently galvanized extensive research into sex-related differences in pharmacology. More importantly, however, investigations into the mechanisms of its action paved the way to developing modern safe and effective calcium antagonists that are so widely used today in cardiovascular pharmacotherapy.

Switching from Nitrate Therapy to Ranolazine in Patients with Coronary Artery Disease Receiving Phosphodiesterase Type-5 Inhibitors for Erectile Dysfunction

Coronary artery disease (CAD) and erectile dysfunction (ED) frequently coexist. The introduction of phosphodiesterase type-5 (PDE-5) inhibitors has revolutionized medical management of organic ED; however, in patients with angina pectoris, a common symptom of CAD, coadministration of PDE-5 inhibitors and nitrates has been implicated in CAD-related deaths following sexual activity. The mechanism of action of PDE-5 inhibitors results in a potential cumulative drop in blood pressure (BP); thus, these agents are contraindicated in patients receiving nitrates. Beta-blockers and calcium channel antagonists are considered the mainstays of antianginal therapy, but may not be tolerated by all patients. Ranolazine is an antianginal agent that produces minimal reductions in heart rate and BP. Here we report three cases of men with CAD, chronic angina, and concomitant ED. We describe our treatment approach in these patients, using ranolazine as a potential substitute to nitrate therapy.

Nicorandil-Induced Hyperkalemia in a Uremic Patient

Nicorandil is an antianginal agent with nitrate-like and ATP-sensitive potassium channel activator properties. After activation of potassium channels, potassium ions are expelled out of the cells, which lead to membrane hyperpolarization, closure of voltage-gated calcium channels, and finally vasodilation. We present a uremic case suffering from repeated junctional bradycardia, especially before hemodialysis. After detailed evaluation, nicorandil was suspected to be the cause of hyperkalemia which induced bradycardia. This case reminds us that physicians should be aware of this potential complication in patients receiving ATP-sensitive potassium channel activator.