Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents) - Volume 19, Issue 1, 2021

Introduction: Acute porphyrias cause life-threatening attacks of neurovisceral non-specific symptoms, so this condition mimics many acute medical and psychiatric diseases. The disease is very misdiagnosed, probably due to its low incidence and non-pathognomonic symptoms, this delays the effective treatment onset. Early diagnosis and treatment highly improve the prognosis and can prevent the development of neuropathic manifestations. Methods: We assembled a systematic review, following the PRISMA guidelines and using Pubmed as our database. Our aim was to show some peculiarities among patients that present neurological manifestations in acute porphyria attack. We obtained the patients’ age, sex, clinical presentation, eurological manifestations and porphyria type of 16 patients. We also evaluated the time between symptoms onset and neurological manifestations. The average age was 28,4 ± 11,1; 50% of patients were male. Results: AIP was the most prevalent porphyria type. The average time between symptoms onset and neurological manifestations was of 9,53 ± 11,6 days. Abdominal pain; nausea and vomiting and psychiatric manifestations were the most common symptoms preceding neurological attacks. Seizures and consciousness disturbance were the most prevalent findings within an attack. We also presenting a case to illustrate how difficult this diagnosis can be.

In this era of potent medications and interventional cardiovascular (CV) procedures, the importance of beginning with and including Therapeutic Lifestyle Changes (TLC) is frequently forgotten. A major goal of this review article is to show and emphasize that modification of CV risk with nonmedication approaches makes an essential contribution to CV risk reduction. Available information on TLC and modifiable CV risk factors was reviewed and assessed. Modifiable major CV risk factors include diabetes mellitus, hypertension, hyperlipidemia, tobacco abuse, obesity, stress, and a sedentary lifestyle. Age as a major CV risk factor is, of course, not susceptible to modification. A contribution to the control of CV risk factors can occur without the start of medications and there is proof of benefit for beginning with a non-pharmacological approach. TLC can benefit all of the major modifiable CV risk factors and there is good evidence for the additional benefit of supervised and group TLC. TLC includes physical activity, diet, and smoking cessation. Evidence for the benefits of TLC in reducing CV disease events is well established. However, medications must be added in those patients with higher CV risk to obtain maximum cholesterol reduction (lower is better for the low-density lipoprotein cholesterol) and good blood pressure control. • The benefit of TLC is frequently forgotten in this era of potent medications and invasive procedures. The benefits of diet and physical activity are emphasized with supporting data. Many motivated patients can prolong their lives significantly by dedication to TLC. • Therapeutic Lifestyle Change (TLC) especially encompasses increased physical activity, a healthy diet, and smoking cessation. • There is extensive proof for the benefit of TLC in contributing to cardiovascular (CV) disease prevention. • CV diseases have strong metabolic and inflammatory components, both of which can be improved by TLC.

Aims: This study aimed to assess the effect of Scorzanera undulata on plasma lipid profile. Background: Scorzanera undulata (S. undulata) is a medicinal plant popularly used in the Moroccan pharmacopeia as traditional medicine, particularly to treat diabetes mellitus. Objective: The purpose of this study was to explore the effects of aqueous extract of Scorzanera undulata tubers (AERSU) on lipid profile and atherogenic indices in Wistar rats. Biochemical parameters such as Total Cholesterol (TC), triglycerides (TG), and low-and high-density lipoproteins-cholesterol (LDL and HDL) were assessed. Furthermore, the in vitro antioxidant activity of AERSU was also evaluated. Methods: The effect of tubers aqueous extract (AERSU) of S. undulata (20 mg/kg) on plasma lipid profile was investigated in normal and streptozotocin (STZ)-induced diabetic rats. The aqueous extract was tested for its in vitro antioxidant activity. Besides, cardiovascular parameters were estimated. Results: Treatment with AERSU significantly improved the weight in diabetic rats and decreased plasma cholesterol, triglycerides, and LDL lipoproteins levels. Furthermore, the extract had a favorable impact on the Atherogenic Index (AI) and Coronary Risk Index (CRI). In addition, AERSU seems to possess a potent in vitro antioxidant activity. Conclusion: The study demonstrates that aqueous Scorzanera undulate extract exhibits antidyslipidemic and antioxidant activities.

Aims: The aim of the study was to study the antidiabetic effect of Traganum nudatum in an animal model of diabetes. Background: Traganum nudatum (T. nudatum) is a medicinal plant widely used in folk medicine by the Moroccan population to treat various diseases including diabetes. Objective: The objective of the study was to evaluate the antihyperglycemic and hypoglycemic of the aqueous Traganum nudatum extract in normal and streptozotocin-induced diabetic rats. Methods: Normal and streptozotocin-induced diabetic rats were treated orally by the extract of Traganum nudatum (T. nudatum) at a dose of 50 mg/kg. The blood glucose levels were determined for 6 hours and 15 days during this treatment. The oral glucose tolerance and phytochemical tests and the analysis of histopathological changes of the liver were performed. The antioxidant activity of aqueous T. nudatum extract was also assessed using the method of trapping of free radical 2,2- diphenyl-1 picrylhydrazyl (DPPH). Results: T. nudatum Aerial Part Aqueous Extract (TNAPAE) reduced the blood glucose levels in both normal and diabetic rats. The results demonstrated that TNAPAE treatment exhibited a significant hypoglycemic effect without altering the body weight. In addition, a noticeable influence on glucose tolerance was also observed after TNAPAE treatment. Moreover, TNAPAE was able to exhibit a beneficial effect on the histological structure of the liver. Finally, a potential antioxidant effect has been shown in vitro. Conclusion: In conclusion, this study demonstrates the antihyperglycemic and hypoglycemic effects of T. nudatum in rats supporting its traditional use for the management of diabetes.

Aim: Aromatherapy products, hydrosol beverages and distillates containing essential oils are widely used for cardiovascular conditions. Investigation of the possible activity of their major constituents with the cardiovascular-related receptors may lead to developing new therapeutics. It also may prevent unwanted side effects and drug-herb interactions. Materials and Methods: A list of 243 volatile molecules (mainly monoterpene and sesquiterpene) was prepared from a literature survey in Scopus and PubMed (2000-2019) on hydrosols and essential oils which are used for Cardiovascular Diseases (CVD) and its risk factors (diabetes mellitus and hyperlipidemia). The PDB files of the receptors (229 native PDB files) included alpha-glucosidase, angiotensin- converting enzymes, beta-2 adrenergic receptor, glucocorticoid, HMG-CoA reductase, insulin, mineralocorticoid, potassium channel receptors and peroxisome proliferator-activated receptoralpha, were downloaded from Protein Data Bank. An in silico study using AutoDock 4.2 and Vina in parallel mode was performed to investigate possible interaction of the molecules with the receptors. Drug likeliness of the most active molecules was investigated using DruLiTo software. Results: Spathulenol, bisabolol oxide A, bisabolone oxide, bergapten, bergamotene, dill apiole, pcymene, methyl jasmonate, pinocarveol, intermedeol, α-muurolol, S-camphor, ficusin, selinen-4-ol, iso-dihydrocarveol acetate, 3-thujanone, linanool oxide and cadinol isomers made a better interaction with some of the named receptors. All of the named molecules had an acceptable dug likeliness except for α-bergamotene. In addition, all of the named molecules had the ability to pass the bloodbrain barrier and it is possible to produce unwanted side effects. Conclusion: Some ingredients of essential oils might be active on cardiovascular-related receptors.

Background: Drug-drug interactions are undesirable, as they reduce drug bioavailability. Drug-reagent interactions in biochemical tests may directly affect the accuracy of test results. Objective: The aim of the present study was to investigate the impact of drug-reagent interactions of drugs used in cardiology on different cardiac markers (troponin I, Nt-proBNP, CK-MB mass, CK, AST, and LDH) and the D-dimer test. Methods: Eleven drugs (enoxaparin, tirofiban hydrochloride monohydrate, diltiazem, glyceryl trinitrate, metoprolol, epinephrine, heparin sodium, atropine sodium, furosemide, norepinephrine tartrate, and amiodarone HCl) were tested in an interference study. The interference protocol was applied to the control material of troponin I, CK-MB mass, Nt-proBNP, CK, AST, LDH tests with 11 different drugs and performed with analyzers. Cardiac Markers Plus Control (Bio-Rad, Irvine, CA, USA; Lot: 23662) materials were used to assess the impact of drug-reagent interactions on the accuracy of tests of cardiac markers based on immunoassay methods. The bias rate, defined as the extent of deviation from the target value (bias %), in the interference study was calculated in each test. Results: For all 11 drugs, positive interference in the range of 43.58% to 130.06% occurred in the CK-MB mass test, whereas positive interference in the range of 11.98% to 107.44% occurred in the troponin I test. All the drugs, except enoxaparin sodium, led to negative interference in the range of - 84.21 to -29.6% in the Nt-proBNP test. In the D-dimer test, amiodarone HCl and diltiazem caused interference (122.87% and 28.08%, respectively). The percentage of interference caused by the other drugs ranged from -1.27% to 11.44%. Minimal deviations in the target values (between -3.31% and 3.86%) were observed in the CK, AST, and LDH tests measured using spectrophotometric methods. Conclusion: Parenteral drugs used in cardiology can significantly interfere with troponin I, CK-MB mass, Nt-proBNP, and D-dimer tests in the analytical phase because of drug-reagent interactions. Minimal deviations in the CK, AST, and LDH tests were observed using spectrophotometric methods. Thus, changes in test results may be due to drug interference rather than the treatment itself. Clinicians should consider the possibility of drug interference in cases of doubtful cardiac test results that do not comply with the diagnosis.

Background: Chronotherapeutics, the drug delivery based on circadian rhythm, is recently gaining much attention worldwide. Various diseases like asthma, hypertension, and arthritis show the circadian variation that demands time scheduled drug release for effective drug action. Therefore, the pulsatile drug delivery system has been designed to confer preprogrammed drug delivery. Objective: In the present study, a ‘3 Cap’ pulsatile drug delivery system has been developed, optimized, and characterized in order to achieve the floating and pulsatile release of ramipril. Methods: An optimal response surface design was employed to investigate the effect of isopropanol: formaldehyde vapors for varying time on drug release from the capsules. ‘3 Cap’ pulsatile drug delivery system was evaluated in terms of floating time, density, the effect of gastric flow rate, and type of dissolution apparatus on drug release. Results: Independent variables exhibited a significant effect on the drug release of the prepared formulations. Results showed that time between the release of fractions of dose increased with an increase in formaldehyde: isopropanol ratio and duration of exposure to formaldehyde vapors with no effect of gastric flow rate. Conclusion: The results of the designed system revealed that an optimum exposure of 1:2 of isopropanol: formaldehyde vapors for sixty minutes resulted in the desired release of second pulse of dose after a predetermined lag time of 5 hours as desired. ‘3Cap’ system was successful in achieving floating and pulsed release of hypertensive drug opening a ‘new lease of life’ to the existing drug molecule.

Aims: The study aimed to evaluate the antihyperlipidemic and antioxidant activities of Matricaria pubescens. Background: Matricaria pubescens (Desf.) Shultz belongs to Asteraceae family and it is commonly used traditionally for handling diabetes mellitus. Objective: The objective of this study was to assess the antioxidant activity of Matricaria pubescens (Desf.) Shultz and its effect on lipid and lipoprotein profile in normal and streptozotocin-induced diabetic rats. Methods: The effect of repeated (7 days of treatment) oral administration of the aqueous extracts of aerial part of Matricaria pubescens (MPAE) at a dose of 40 mg/kg on lipid and lipoprotein profile was examined in normal and streptozotocin-induced diabetic rats. Furthermore, a preliminary phytochemical screening and the quantification of phenolic, flavonoid and tannin contents as well as the antioxidant activity using two methods (FRAP and ABTS) were carried out. Results: MPAE demonstrated a potent antidyslipidemic effect in diabetic rats by reducing serum levels of triglycerides, total cholesterol and Low-Density Lipoprotein (LDL). In addition, the results showed that the extract is rich in several phytochemical compounds and revealed an important antioxidant activity. Conclusion: In summary, this study proved that Matricaria pubescens (Desf.) Shultz. has a favorable effect on diabetic dyslipidemia.

Objective: Pioglitazone (PG) is used to control high blood sugar in patients with type 2 diabetes mellitus. PG acts as a peroxisome proliferator-activated receptor γ agonist. In addition to the insulin-sensitizing effect, PG possesses anti-inflammatory effect. In this study, the protective effect of PG was evaluated against DNA damage induced by ionizing radiation in healthy human lymphocytes. Methods: The microtubes containing human whole blood were treated with PG at various concentrations (1-50 μM) for three hours. Then, the blood samples were irradiated with X-ray. Lymphocytes were cultured for determining the frequency of micronuclei as a genotoxicity biomarker in binucleated lymphocytes. Results: The mean percentage of micronuclei was significantly increased in human lymphocytes when exposed to IR, while it was decreased in lymphocytes pre-treated with PG. The maximum reduction in the frequency of micronuclei in irradiated lymphocytes was observed at 5 μM of PG treatment (48% decrease). Conclusion: The anti-inflammatory property suggested the mechanism action of PG for protecting human lymphocytes against genotoxicity induced by ionizing radiation.

Background: Coronary Artery Disease (CAD), which is a multifactorial genetic disease, is known as one of the most common causes of death worldwide. In this regard, X-ray Repair Cross-Complementing group 1 (XRCC1), a DNA repair protein involved in Single-Strand Breaks (SSBs), and Base Excision Repair (BER) pathways have been reported to be responsible for the efficient repair of single strand breaks and damaged bases in DNA. Objectives: In the current study, we analyzed Arg399Gln (rs25487), which is one of the most common polymorphisms of XRCC1 gene that might be associated with the increased risk for CAD. Methods: This case-control study was performed to investigate the relationship between this polymorphism and CAD development. In this study, 290 patients and 216 controls were diagnosed by cardiac angiography and then screened for the above-mentioned polymorphism using Restriction Fragment Length Polymorphisms (RFLP) method. Results: The frequency of the GA genotype of XRCC1 Arg399Gln (rs25487) was significantly higher in CAD patients compared to the controls (p=0.002, OR: 1.21, 95% CI: 1.06-1.37). Moreover, its dominant mode (AA + GA) genotype had a 1.851-fold increase in the risk of CAD (p = 0.005). Conclusion: Our findings demonstrated that Arg399Gln polymorphism of XRCC1 (rs25487) has a significant relationship with CAD and also plays a probable predisposing role in that. Our results support the role of DNA damages and the malfunctions of DNA repair system in the patients with CAD.

Immune thrombocytopenia is an immune condition where antibodies are produced against platelets. Eltrombopag is a thrombopoietin receptor agonist that stimulates and promotes platelet production approved for treating thrombocytopenia in patients with chronic immune thrombocytopenia, where other treatments such as corticosteroids, splenectomy or immunoglobulins are inadequate. The aim of this meta-analysis was to evaluate the efficacy and safety of the eltrombopag in adults and children with immune thrombocytopenia. We included 7 studies with a total of 765 patients (606 adults and 159 children). We evaluated the number of patients that achieved a post-treatment platelet count equal or above 50x10⁹/L (primary result-target) without the need of rescue treatment for at least 4 weeks. Our data showed that patients who received eltrombopag were almost 4 times more probable in achieving the primary target when compared to patients who received placebo (RR 3.84, 95% CI 2.39 to 6.14; I² = 46%). The number of patients needed rescue treatment and the number of bleeding incidents were reduced in the group that received eltrombopag when compared to those who received placebo (RR 0.40, 95% CI 0.25 to 0.62; I² = 40%) (RR 0.74, 95% CI 0.62 to 0.89; I² = 68%). The total number of side effects did not statistically differ between the two groups (RR 0.99, 95% CI 0.90 to 1.08; I² = 14%). Our findings were similar to previously published studies and confirm that eltrombopag is safe and efficient in immune thrombocytopenia. However, more clinical trials are needed in order to enhance our findings.

Background and Aims: Anemia is a common complication of heart failure and Chronic Kidney Disease (CKD). Sacubitril-valsartan is a novel therapy for the treatment of chronic Heart Failure with a reduced Ejection Fraction (HFrEF). We have evaluated the short-term effects of sacubitril- valsartan on the anemia of CRS. Methods: The study group comprised 39 patients with HFrEF, who were followed-up for three months. The study is a retrospective analysis of clinical data. Data of 3 months’ and baseline visits were recorded including plasmatic creatinine, glomerular filtration rate, cystatin C, kaliemia, haemoglobin, pro-BNP, and albuminuria. Results: In all, 34 patients ended the follow-up. Mean sacubitril-valsartan dosage at baseline was 101 ± 62 mg/day and 126 ± 59 mg/day at end. Mean hemoglobin increased from 12.2 ± 1.1 g/dl at baseline to 12.9 ± 1.0 g/dl (p = 0.001,). Prevalence of anemia was 64.7% (95%CI, 47.9-78.5%) at baseline and 38.4 (95%CI, 23.9-55.0%) after the follow-up (p = 0.016). Serum cystatin C levels decreased from 2.71 ± 1.0 to 2.48 ± 1.0 mg/l (p = 0.028). Serum K levels remained unchanged (baseline 4.94 ± 0.60, three months visit 4.94 ± 0.61 mmol/l, p = 0.998). Conclusion: Sacubitril-valsartan improves anemia in CRS patients. An improvement in serum cystatin levels was observed. Few untoward effects were detected. These findings should be confirmed in wider clinical trials.