Current Pharmaceutical Design - Volume 29, Issue 23, 2023

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) represent a novel class of hypolipidemic drugs, providing an additional therapeutic option over conventional hypolipidemic treatments. Given the constantly lowering recommended LDL-C goals, low goal achievement rate and low compliance with treatment, new hypolipidemic drug classes may substantially contribute to residual risk reduction for atherosclerotic cardiovascular disease (ASCVD). This review aims to summarize contemporary evidence on the clinical role of PCSK9i in ASCVD prevention. PubMed and MEDLINE databases were searched for keywords in studies on PCSK9i and ASCVD. Approved PCSK9i are the monoclonal antibodies (Mabs), evolocumab and alirocumab, targeting PCSK9, and inclisiran, a small interfering RNA inhibiting PSCK9 synthesis. Overall, PCSK9i effectively reduced LDL-C and other atherogenic lipoproteins, including apolipoprotein B and lipoprotein( a) primarily. PSCK9i Mabs improved imaging markers reflecting coronary atherosclerotic plaque vulnerability and reduced ASCVD events in high-risk patients after short-term treatment (< 3 years follow-up). They are currently indicated as a third-line treatment for secondary prevention and primary prevention in patients with familial hypercholesterolemia at high risk of not achieving their LDL-C goals. Patients with higher baseline ASCVD risk receive greater benefits from PCSK9i. Recent evidence suggests that evolocumab was effective and safe after long-term treatment. Ongoing trials investigate new therapeutic indications for PCSK9i while their cost-effectiveness is still being considered. PCSK9i is a novel hypolipidemic drug class currently indicated for reducing residual risk in secondary ASCVD prevention and high-risk patients.

Coronary artery disease remains a condition with high prevalence and detrimental effects on the quality of life of affected individuals. Its most frequent manifestation, stable angina pectoris, may be challenging to manage despite the available antianginal pharmacotherapy and adequate risk factor control, especially in subjects not amenable to revascularization. In the direction of refractory angina pectoris, several approaches have been developed over the years with varying degrees of success. Among the most recognized techniques in managing angina is enhanced external counterpulsation, which utilizes mechanical compression of the lower extremities to increase blood flow to the heart. Moving to coronary sinus reduction, it leads to an increase in coronary sinus backward pressure, ultimately augmenting myocardial blood flow redistribution to ischemic regions and ameliorating chronic angina. Clinical trial results of the above-mentioned techniques have been encouraging but are based on small sample sizes to justify their widespread application. Other interventional approaches, such as transmyocardial laser revascularization, extracorporeal shockwave myocardial revascularization, and spinal cord stimulation, have been met with either controversial or negative results, and their use is not recommended. Lastly, angiogenic therapy with targeted intramyocardial vascular endothelial growth factor injection or CD34+ cell therapy may be beneficial and warrants further investigation. In this review, we summarize the current knowledge in the field of angina management, highlighting the potential and the gaps in the existing evidence that ought to be addressed in future larger-scale, randomized studies before these techniques can be safely adapted in the clinical practice of patients with refractory angina pectoris

Coronary artery disease (CAD) is the leading cause of morbidity and mortality in Western societies, despite the significant advances that have improved primary and secondary prevention. Hence, several novel biomarkers have been identified as potential diagnostic and therapeutic targets which could improve outcomes even when traditional risk factors are well-controlled. Lipoprotein (a) [Lp(a)] has pro-atherogenic, pro-thrombotic, and pro-inflammatory properties, and its levels are relatively constant and genetically predetermined. Several epidemiological studies have associated high Lp(a) with increased risk for acute coronary syndromes (ACS) even when other CAD risk factors are included in the multivariate analysis. However, until recently, specific therapeutic options targeting Lp(a) were not associated, and thus, Lp(a) is currently used as a risk and treatment modifying biomarker with guidelines suggesting the intensified treatment of low-density lipoprotein in intermediate- to-high-risk patients with increased Lp(a) levels. Lately, specific treatment options targeting Lp(a) have become available and include antisense oligonucleotides and small-interfering RNA, which induce a robust reduction of Lp(a). Results of ongoing phase-3 trials will answer whether Lp(a) will become a biomarker specifically treated to reduce the burden of cardiovascular mortality. The scope of this review article is to present the current evidence regarding the use of Lp(a) as a biomarker, predictive of increased CAD risk, and to discuss the future perspectives on pharmaceutical reduction of Lp(a) as a therapeutic target in high-risk patients.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in individuals with diabetes mellitus (DM). Although benefit has been attributed to the strict control of hyperglycemia with traditional antidiabetic treatments, novel antidiabetic medications have demonstrated cardiovascular (CV) safety and benefits by reducing major adverse cardiac events, improving heart failure (HF), and decreasing CVD-related mortality. Emerging data underline the interrelation between diabetes, as a metabolic disorder, and inflammation, endothelial dysfunction, and oxidative stress in the pathogenesis of microvascular and macrovascular complications. Conventional glucose-lowering medications demonstrate controversial CV effects. Dipeptidyl peptidase- 4 inhibitors have not only failed to prove to be beneficial in patients with coronary artery disease, but also their safety is questionable for the treatment of patients with CVD. However, metformin, as the first-line option for type 2 DM (T2DM), shows CVD protective properties for DM-induced atherosclerotic and macrovascular complications. Thiazolidinedione and sulfonylureas have questionable effects, as evidence from large studies shows a reduction in the risk of CV events and deaths, but with an increased rate of hospitalization for HF. Moreover, several studies have revealed that insulin monotherapy for T2DM treatment increases the risk of major CV events and deaths from HF, when compared to metformin, although it may reduce the risk of myocardial infarction. Finally, this review aimed to summarize the mechanisms of action of novel antidiabetic drugs acting as glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors that show favorable effects on blood pressure, lipid levels, and inflammation, leading to reduced CVD risk in T2DM patients.

Objective: This study aimed to determine the effectiveness and safety of 5 mg olanzapine (OLZ) in preventing vomiting and nausea caused by carboplatin chemotherapy. Methods: All patients with malignant tumors (n = 113) who underwent Carboplatin (AUC ≥ 5) treatment were randomly categorized into two groups: the standard group (n = 57) and the OLZ regimen (n = 56). The major endpoints of the trial were the TC (total control) between two groups during the OP (Overall phase, 0-120 hours), DP (delayed phase, 25-120 hours), and AP (acute phase, 0-24 hours). The secondary endpoints were the CR (complete response) and TP (total protection) during AP, OP, and DP. The time of first vomiting was compared between the two groups using Kaplan-Meier curves. The impact of CINV on the quality of life was assessed by the Functional Living Index-Emesis (FLIE). OLZ-related side effects were also recorded. Results: (1) The primary endpoint TC rates were more favorable in the OLZ regimen group than in the standard group during the AP 87.50% (49/56) vs. 63.15% (36/57) P = 0.003, OP 62.50% (35/56) vs. 31.57% (18/57) P = 0.001, and DP 64.28% (36/56) vs. 33.33% (19/57) P = 0.001. (2) The secondary endpoints TP were 82.14% (46/56) vs. 63.15% (36/57), P = 0.024, 83.92% (47/56) vs. 63.15% (36/57). P = 0.012 during the DP and OP. There was no statistical significance during AP between the two groups. The CR rates were not statistically different between the two groups during the three periods, P > 0.05; (3) The first vomiting time in the OLZ group was delayed compared with the standard group (P = 0.248). The effect on life quality (score ≥ 108) assessed by FLIE was 62.50% vs. 43.48% between the two groups, P < 0.05. The primary side effects of OLZ are fatigue (85%) and somnolence (75%). The primary side effects of the standard group are fatigue (77%) and loss of appetite (85%). Conclusion: The 5 mg OLZ-based triple antiemetic regimen is effective and safe in preventing vomiting and nausea induced by Carboplatin.

Background: All the current antifungal azoles have one substituted nitrogen atom in their imidazole or triazole rings. In this study, eleven imine and amine derivatives of imidazole, in which both nitrogen atoms of the imidazole ring are unsubstituted, were designed and synthesized. Materials and Methods: Imine derivatives were prepared by condensation of imidazole-4-carboxaldehyde with appropriate amines, and then in the next step, using sodium borohydride, the imines were reduced to amine derivatives. Docking studies reveal unsubstituted nitrogen atom of the imidazole ring coordinated well with the heme molecule of the receptor. In vitro, antimicrobial evaluation was tested on Candida albicans, E. coli, and Staphylococcus aureus. Results: Based on the results of the antimicrobial study, compound 10, which contains 4-chlorobenzyl moiety, proved to be the most potent compound against Candida albicans, and it was more active than the reference drug fluconazole and showed comparable activity to amphotericin B. Compounds 10 and 11 and compounds 8, 10 and 11 showed significant responses against E. coli and Staphylococcus aureus respectively. Conclusion: It is concluded that compound 10 can be acted as a new lead compound to find new azoles antifungal.