Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents) - Volume 22, Issue 1, 2024

Background: Thrombotic disease is still a major killer. Aspirin, Ticagrelor, Clopidogrel, etc. are the most widely used conventional antiplatelet drugs. The significant number of patients who are resistant to this drug shows a poor outcome. Objective: Developing a new antiplatelet agent with a stable antiplatelet effect and minimal bleeding risk is required for a patient who is resistant to antiplatelet drugs. Methods: Protein-ligand docking was performed using Autodock Vina 1.1.2 to study the interaction of 67LR with different Polyphenols. Results: Among the 18 polyphenols, thearubigin has the highest binding affinity towards 67LR and gallic acid shows the lowest binding affinity. Among the 18 molecules, the top 4 molecules from the highest to lowest binding affinity range from-10.6 (thearubigin) to -6.5 (Epigallocatechin). Conclusion: Polyphenols may inhibit platelet aggregation through 67 LR and can be an alternative treatment for Thrombotic Disease. Moreover, it will be interesting to know whether polyphenols interfere with the same pathways as aspirin and clopidogrel. Effective polyphenols could help prototype the compound development of novel antiplatelet agents.

Statin drugs have long been used as a key component of lipid-lowering therapy, which is necessary for the prevention and treatment of atherosclerosis and cardiovascular diseases. Many studies focus on finding and refining new effects of statin drugs. In addition to the main lipidlowering effect (blocking cholesterol synthesis), statin drugs have a number of pleiotropic effects, including negative effects. The main beneficial effects of statin drugs on the components of the cardiovascular system are: anti-ischemic, antithrombotic, anti-apoptotic, antioxidant, endothelioprotective, anti-inflammatory properties, and a number of other beneficial effects. Due to these effects, statin drugs are considered one of the main therapeutic agents for the management of patients with cardiovascular pathologies. To date, many review manuscripts have been published on the myotoxicity, hepatotoxicity, nephrotoxicity, neurotoxicity and diabetogenic effects of statins. However, there are no review manuscripts considering the negative effect of statin drugs on myocardial contractile cells (cardiomyocytes). The purpose of this review is to discuss the negative effects of statin drugs on cardiomyocytes. Special attention is paid to the cardiotoxic action of statin drugs on cardiomyocytes and the mechanisms of increased serum levels of cardiac troponins. In the process of preparing this review, a detailed analysis of laboratory and experimental data devoted to the study of the negative effects of statin drugs on cardiomyocytes was carried out. The literature search was carried out with the keywords: statin drugs, negative effects, mechanisms, cardiac troponins, oxidative stress, apoptosis. Thus, statin drugs can have a number of negative effects on cardiomyocytes, in particular, increased oxidative stress, endoplasmic reticulum stress, damage to mitochondria and intercalated discs, and inhibition of glucose transport into cardiomyocytes. Additional studies are needed to confirm and clarify the mechanisms and clinical consequences of the negative effects of statin drugs on cardiomyocytes.

Cardiospecific troponins are specifically localized in the troponin-tropomyosin complex and the cytoplasm of cardiac myocytes. Cardiospecific troponin molecules are released from cardiac myocytes upon their death (irreversible damage in acute coronary syndrome) or reversible damage to cardiac myocytes, for example, during physical exertion or the influence of stress factors. Modern high-sensitive immunochemical methods for detecting cardiospecific troponins T and I are extremely sensitive to minimal reversible damage to cardiac myocytes. This makes it possible to detect damage to cardiac myocytes in the early stages of the pathogenesis of many extra-cardiac and cardiovascular diseases, including acute coronary syndrome. So, in 2021, the European Society of Cardiology approved diagnostic algorithms for the acute coronary syndrome, which allow the diagnosis of acute coronary syndrome in the first 1-2 hours from the moment of admission of the patient to the emergency department. However, high-sensitive immunochemical methods for detecting cardiospecific troponins T and I may also be sensitive to physiological and biological factors, which are important to consider in order to establish a diagnostic threshold (99 percentile). One of the important biological factors that affect the 99 percentile levels of cardiospecific troponins T and I are sex characteristics. This article examines the mechanisms underlying the development of sex-specific serum levels of cardiospecific troponins T and I and the importance of sexspecific cardiospecific troponin concentrations in diagnosing acute coronary syndrome.

Chemotherapy-induced cardiotoxicity is an increasing concern and it is critical to avoid heart dysfunction induced by medications used in various cancers. Dysregulated cardiomyocyte homeostasis is a critical phenomenon of drug-induced cardiotoxicity, which hinders the cardiac tissue's natural physiological function. Drug-induced cardiotoxicity is responsible for various heart disorders such as myocardial infarction, myocardial hypertrophy, and arrhythmia, among others. Chronic cardiac stress due to drug toxicity restricts the usage of cancer medications. Anticancer medications can cause a variety of adverse effects, especially cardiovascular toxicity. This review is focused on anticancerous drugs anthracyclines, trastuzumab, nonsteroidal anti-inflammatory medications (NSAIDs), and immune checkpoint inhibitors (ICI) and associated pathways attributed to the drug-induced cardiotoxicity. Several factors responsible for enhanced cardiotoxicity are age, gender specificity, diseased conditions, and therapy are also discussed. The review also highlighted the patents assigned for different methodologies involved in the assessment and reducing cardiotoxicity. Recent advancements where the usage of trastuzumab and bevacizumab have caused cardiac dysfunction and their effects alone or in combination on cardiac cells are explained. Extensive research on patents associated with protection against cardiotoxicity has shown that chemicals like bis(dioxopiperazine)s and manganese compounds were cardioprotective when combined with other selected anticancerous drugs. Numerous patents are associated with druginduced toxicity, prevention, and diagnosis, that may aid in understanding the current issues and developing novel therapies with safer cardiovascular outcomes. Also, the advancements in technology and research going on are yet to be explored to overcome the present issue of cardiotoxicity with the development of new drug formulations.

Preventing the development of cardiovascular problems is a key objective of antihypertensive drugs. Many of the non-pressure related coronary risk factors for hypertension are thought to be connected to an increase in sympathetic activity. The sympathetic systems have N-type calcium channels at the nerve terminals that control neurotransmitter release. Cilnidipine is a unique fourth-generation calcium channel blocker with blocking action on both L-/N- type calcium channels. Several L-type calcium channel blockers (Nilvadipine, amlodipine, azelnidipine, nifedipine, etc.) have been used to treat hypertensive patients. Cilnidipine is a novel drug that exerts a hypotensive effect through vasodilation action via blocking L-type calcium channels and potent antisympathetic activity via blocking N-type calcium channels. Inhibiting N-type calcium channels might be a new approach to treating cardiovascular disorders. Therefore, it is expected that cilnidipine may respond well to complicated hypertension. The present review aims to describe the management mechanism of hypertension, and other pharmacological and physicochemical properties of cilnidipine. Cilnidipine has various other beneficial effects such as lipid-lowering effect, reduced white coat effect, improves insulin sensitivity in essential hypertensive patients, ameliorates osteoporosis in ovariectomized hypertensive rats, reduced arterial stiffness, reduced the risk of pedal edema, antinociceptive effects, neuroprotective and renal protective effect, probably through inhibition of N-type calcium channels. Cilnidipine distinguishes itself from other calcium channel blockers due to its wide range of beneficial pharmacological effects. In conclusion, cilnidipine may be more advantageous than other dihydropyridines, such as nisoldipine, amlodipine, azelnidipine, and other antihypertensive drugs.

Background: The lack of a substantial breakthrough in the treatment of diabetes, a global issue, has led to an ongoing quest for herbs that contain bioactive elements with hypoglycemic properties. Objective: To investigate the potential protective effect of Nigella sativa seeds ethanol extract and its active ingredient, thymoquinone, on streptozotocin-induced diabetic rats. Methods: To induce diabetes, the male Wistar rats were administered an intraperitoneal injection of STZ at a dosage of 90 mg/kg body weight in 0.9 percent normal saline after being fasted for 16 hours and made diabetic Group 1; 7 rats non-diabetic control (saline-treated), Group 2; 7 untreated diabetic rats, Group 3; 7 diabetic rats treated orally with N. sativa extract at a dose of 100 mg/kg body weight, Group 4; 7 diabetic rats treated orally with thymoquinone at a dose of 10 mg/kg body weight and Group 5; 7 diabetic rats treated orally with Metformin at a dose of 5 mg/kg body weight. After the treatment of 28 days, all groups were examined for body weight and biochemical alterations. Results: The results showed a significant decrease in blood glucose, urea, creatinine, uric acid, total protein, total cholesterol, low-density lipoprotein, and very low-density lipoprotein, while high-density lipoprotein was increased. Hepatic enzymes, alanine transaminase, aspartate aminotransferase, and alkaline phosphate were also normalized and significantly increased body weight. Conclusion: These preliminary findings demonstrate that the ethanol extract of N. sativa seeds and its active ingredient, thymoquinone have a protective effect against streptozotocin-induced diabetic rats. The present study opens new vistas for the use of N. sativa and its bioactive compound, thymoquinone, regarding its clinical application as a new nontoxic antidiabetic agent for managing diabetes mellitus.

Background: Digoxin poisoning commonly occurs in people treated with digoxin. It has been suggested that treatment with dantrolene may be a suitable strategy for digoxin-induced cardiotoxicity. Objective: The aim of this study was to evaluate the protective effect of dantrolene on digoxininduced cardiotoxicity in male rats. Methods: This study was approved by the ethics committee of Birjand University of Medical Sciences (Ethical number: IR.BUMS.REC.1400.067). Forty-two Wistar rats weighing between 300- 350 gr were randomly allocated to 7 groups (n = 6) as follows: Normal Saline (NS) group, Normal Saline + Ethanol (NS + ETOH) group, Normal Saline + dantrolene 10 mg/kg (NS + Dan 10) group, Digoxin (Dig) group), Digoxin + dantrolene 5 mg/kg (Dig + Dan 5) group, Digoxin + dantrolene 10 mg/kg (Dig + Dan 10) group, Digoxin + dantrolene 20 mg/kg (Dig + Dan 20) group, Dig was injected intravenously at 12 mL / h (0.25 mg / mL). Dan (5, 10 and 20 mg/kg) was injected intravenously at 5-8 min/mL. After 1 hour, blood samples were obtained from the animals' cavernous sinus and each animal's heartremoved. The blood sample was rapidly centrifuged at 2,500 rpm for 10 minutes and the serum was separated for measurement of creatine phosphokinase (CPK), potassium (K), sodium (Na), calcium (Ca), and magnesium (Mg). The samples were stored at -20®C. The heart samples were fixed in formalin 10% for histopathological evaluation. Results: K levels slightly increased in the dig group versus the NS group. A significant increase in the K levels was observed in the Dig + Dan 20 group versus the NS group (p < 0.001). Dig slightly decreased Ca levels in the treated group versus the NS group. The levels of Ca significantly increased in the Dig + Dan 10 group versus the Dig group (p < 0.05). Histological examination of the heart tissue in the dig group showed cardiomyocyte degeneration, increased edematous intramuscular space associated with hemorrhage, and congestion. Focal inflammatory cell accumulation in the heart tissue was also seen. Cardiomyocytes were clear and arranged in good order in the Dig + Dan 10 group. Conclusion: dantrolene (10 mg/kg) was cardioprotective in a model of digoxin-induced cardiotoxicity, secondary to cardiac remodeling and hyperkalemia. However, further research is necessary to determine dantrolene's cardioprotective and cardiotoxic doses in animal models.

Background: Diabetic cardiomyopathy has emerged as a major cause of cardiac fibrosis, hypertrophy, diastolic dysfunction, and heart failure due to uncontrolled glucose metabolism in patients with diabetes mellitus. However, there is still no consensus on the optimal treatment to prevent or treat the cardiac burden associated with diabetes, which urges the development of dual antidiabetic and cardioprotective cardiac therapy based on natural products. This study investigates the cardiotoxic profile of glucose and the efficacy of AGE against glucose-induced cardiotoxicity in H9c2 cardiomyocytes. Methods: The cellular metabolic activity of H9c2 cardiomyocytes under increasing glucose concentration and the therapeutic efficacy of AGE were investigated using the MTT cell cytotoxicity assay. The in vitro model was established in six groups known as 1. control, 2. cells treated with 25 μM glucose, 3. 100 μM glucose, 4. 25 μM glucose +35 μM AGE, 5. 100 μM glucose + 35 μM AGE, and 6. 35 μM AGE. Morphological and nuclear analyses were performed using Giemsa, HE, DAPI, and PI, respectively, whereas cell death was simultaneously assessed using the trypan blue assay. The antioxidant potential of AGE was evaluated by DCFH-DA assay, NO, and H202 scavenging assay. The activities of the antioxidant enzymes catalase and superoxide dismutase were also investigated. The antiglycative potential of AGE was examined by antiglycation assays, amylase zymography, and SDS PAGE. These results were then validated by in silico molecular docking and qRTPCR. Results: Hyperglycemia significantly reduced cellular metabolic activity of H9c2 cardiomyocytes, and AGE was found to preserve cell viability approximately 2-fold by attenuating oxidative, fibrosis, and apoptotic signaling molecules. In silico and qRTPCR studies confirmed that organosulfur compounds target TNF-α, MAPK, TGF-β, MMP-7, and caspase-9 signaling molecules to ameliorate glucose-induced cardiotoxicity. Conclusion: AGE was found to be an antidiabetic and cardioprotective natural product with exceptional therapeutic potential for use as a novel herb-drug therapy in the treatment of diabetic cardiomyopathy in future therapies.

Aims: The study investigated the effect of L-tartaric acid on diminazene-indiuced vasorelaxation. Background: Diminazene is known to induce vasorelaxation through the stimulation of angiotensin- converting enzyme (ACE-2). Objective: This work was designed to study the effect of L-tartaric acid on diminazene-induced vasorelaxation using an ex vivo approach. Materials and Methods: In the current investigation, the inhibitory effect of L-tartaric acid on diminazene-induced relaxation. Results: The results confirmed that L-tartaric acid was able to inhibit in a dose-dependent manner diminazene-induced vasorelaxation. Conclusion: This investigation provides important experimental evidence of the efficacy of Ltartaric acid in inhibiting diminazene-induced vasorelaxation.

Background: Reflex cardio-vascular and respiratory (CVR) alterations evoked by intraarterial instillation of nociceptive agents are termed vasosensory reflexes. Such responses elicited by optimal doses of inflammatory mediators have been described in our earlier work. Objective: The present study was designed to evaluate the interactions between subthreshold doses of inflammatory mediators on perivascular nociceptive afferents in urethane anesthetized rats. Methods: Healthy male adult rats (Charles-Foster strain) were anesthetized with an intraperitoneal injection of urethane. After anesthesia, the right femoral artery was cannulated. Respiratory movements, blood pressure, and electrocardiogram were recorded. The interactions between subthreshold doses of algogens in the elicitation of vasosensory reflex responses were studied by instillation of bradykinin (1 nM) and histamine (100 μM) into the femoral artery one after the other, in either temporal combination in separate groups of rats. The CVR responses obtained in these groups were then compared with the responses produced by 100 μM histamine and 1 nM bradykinin in saline-pretreated groups, which served as control. Results: Subthreshold doses of histamine elicited transient tachypnoeic, hyperventilatory, hypotensive, and bradycardiac responses, in rats pretreated with subthreshold doses of bradykinin [p < 0.01, two-sided Dunnett’s test] but not in saline pretreated groups [p > 0.05, two-sided Dunnett’s test]. Similar responses were elicited by bradykinin after histamine pretreatment compared to the saline-pretreated group. Furthermore, CVR responses produced by histamine in the bradykininpretreated group were greater in magnitude as compared to bradykinin-induced responses in the histamine-pretreated group [p < 0.05, two-sided Dunnett’s test]. Conclusion: The present study demonstrates that both bradykinin and histamine potentiate one another in the elicitation of vasosensory reflex responses, and bradykinin is a better potentiator than histamine at the level of perivascular nociceptive afferents in producing reflex CVR changes.