Cardiovascular & hematological disorders drug targets最新文献

Background: Elevated levels of lipoprotein(a) have been linked to an increased risk of Atherosclerotic Cardiovascular Disease (ASCVD). Conventional lipid-lowering medications have modest to no impact on Lp(a) levels. Emerging RNA-based modalities significantly decrease Lp(a) by silencing the apo(a) mRNA at the post-transcriptional level. Pelacarsen (TQJ230) is a GalNAc-conjugated novel Antisense Oligonucleotide (ASO) that selectively inhibits apo(a) synthesis in hepatocytes.

Objective: This updated review aims to elucidate the mechanism of action, pharmacokinetics, clinical efficacy, and safety profile of Pelacarsen (TQJ230), with a focused appraisal of its potential role in the prevention of Atherosclerotic Cardiovascular Disease (ASCVD).

Methodology: We conducted a literature search on PubMed, Google Scholar, and Scopus using keywords such as "Pelacarsen", "antisense oligonucleotide" OR "ASO", and "lipoprotein(a)" from inception to March 2025.

Results: Pelacarsen demonstrated a dose-dependent sustained reduction in Lp(a) levels, achieving up to a 97% reduction at the highest dose in Phase 1 and 2 trials. It was well-tolerated with a favorable safety profile. Phase 3 trials are underway to provide robust data on its long-term safety and impact on Atherosclerotic Cardiovascular Disease (ASCVD) outcomes.

Conclusion: Pelacarsen (TQJ230) is a potent Lp(a)-lowering agent with promising efficacy and a favorable safety profile. However, its definitive role in reducing atherosclerotic cardiovascular events remains to be established. Ongoing Phase 3 trials will be critical in determining whether its lipid-lowering effects translate into meaningful long-term cardiovascular outcomes.

Introduction: Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder marked by insulin resistance and impaired insulin secretion. Effective glycemic management is critical for preventing problems, which can be achieved through Oral Hypoglycemic Agents (OHAs). Metformin is the first-line drug due to its insulin-sensitizing effects, while other classes, such as sulfonylureas, meglitinides, DPP-4 inhibitors, SGLT2 inhibitors, thiazolidinediones, and α-glucosidase inhibitors, serve complementary roles. Evolving treatment strategies increasingly favour combination therapies to increase outcomes.

Methods: The review involved an extensive search of scientific databases and relevant literature, including studies published to date in PubMed, Science Direct, and Google Scholar. Type 2 Diabetes Mellitus (T2DM), oral hypoglycaemic agents, pharmacoeconomics, insulin sensitivity, SGLT2 inhibitors, and Thiazolidinediones were among the search phrases used. The selected papers were carefully evaluated for methodological soundness and the significance of their results.

Results: There is an increased prescribing of fixed-dose combinations, such as metforminvildagliptin, which has led to better adherence and control. Regional differences in costs have an impact on the accessibility of drugs. SGLT2 and GLP-1 drugs provide cardiovascular and renal effects, whereas DPP-4 drugs produce limited results. The difference in pharmacokinetics and a certain decline of β-cells may require the prescription of an individualized treatment, combination therapy, or the introduction of insulin over time.

Discussion: The current inclination to fixed-dose combinations improves compliance and glycemic control. Regional inequity is affected by the differences in costs. Better results in the use of SGLT2 and GLP-1 drugs favor their application in vulnerable patients, whereas the DDP-4 blocking agent is more appropriate in milder patient populations. Individualized treatment programs are a necessity, even with impaired β-cell functioning, which necessitates intensification of the therapy or insulin.

Conclusion: Optimizing T2DM management requires a personalized approach that integrates clinical efficacy, safety, and cost into account. Regular prescription audits and targeted pharmacoeconomic strategies are vital for equitable access and long-term disease control worldwide.

Introduction: Anticoagulants are used frequently in the treatment of cardiac and thrombotic disorders, but they can sometimes lead to life-threatening conditions. Plants consist of various bioactive molecules; hence, the extracts of their different part possess various pharmacological activities. Allamanda schottii is notable for its richness in terms of secondary metabolites. The protease in this plant helps to reduce the clot with minimal or no side effects.

Methods: In the present study, we used leaves of Allamanda schottii that were processed for extraction. The Ultrasonic Assisted Extraction (UAE) method was used. Preliminary phytochemical analysis was performed using reagent-based phytochemical testing, estimation of total phenolic content, and evaluation of antioxidant activity using the DPPH and FRAP methods. For the evaluation of in-vitro anticoagulant activity, clot lysis, prothrombin time (PT), and activated partial thromboplastin time (aPTT) were assessed in female Wistar rats. Additionally, in vivo anticoagulant activity was evaluated by measuring clotting time and using the Tail Bleeding Assay. Furthermore, major organs of rats were extracted for histopathology to assess hemorrhagic events.

Result: The results demonstrated the anticoagulant potential of the plant extracts, with significant prolongation of clotting times observed at higher concentrations: PT (90.33 s and 84.00 s), aPTT (175.50 s and 174.33 s), and clotting time (121.00 s and 123.00 s).

Discussion: The UAE approach is a rapid method for extracting chemical components from plant cells, facilitating the identification of phytocompounds with diverse pharmacological properties. It involves an extraction technique and appropriate solvent selection, with the aqueous extract playing a crucial role. The studied plant possesses antioxidant potential, with methanolic extracts exhibiting favorable IC50 values. Statistical analysis showed a significant difference in all groups compared to the control group, with p < 0.001.

Conclusion: Allamanda schottii comprises a variety of constituents, and a range of secondary metabolites exhibit distinct medicinal properties. The antioxidant and clot lysis potential of this plant indicates its significant efficacy, suggesting the potential for discovering new antioxidant and anticoagulant compounds.

Introduction: Menopause is known as a stage in a woman's natural life cycle in which menstrual periods permanently stop with developing age. This review aims to review the modulating mechanistic effects of resveratrol (RSV) on cardiometabolic changes associated with menopause.

Methods: To identify published studies before January 12, 2025, a comprehensive search was conducted across various electronic databases, such as Web of Science, PubMed/MEDLINE, Embase, Scopus, and the Cochrane Library. Based on the study's objectives, two reviewers independently performed data extraction to ensure accuracy and reduce bias. The extracted data were subsequently reviewed.

Results: RSV has reductive effects on blood pressure, improves endothelial function, and enhances insulin-stimulated glucose uptake. It also decreases fasting blood glucose levels, insulin levels, total cholesterol, triglycerides, and adipocyte hypertrophy. Increased estradiol levels correlate with improved cerebrovascular function and enhanced neurovascular coupling. However, the effects on body weight, body mass index (BMI), and lipid metabolism are inconsistent; some studies reported reductions in fat volume and changes in thermogenesis-related gene expression. Moreover, total antioxidant capacity (TAC) and malondialdehyde (MDA) levels increase. While RSV demonstrates potential benefits for vascular function and metabolic regulation, further research is necessary to determine its long-term efficacy.

Discussion: The findings align with existing evidence on RSV's vascular and metabolic benefits, underscoring its complementary therapeutic potential. Limitations, like bioavailability, differences in patient characteristics, and inconsistent lipid outcomes, call for standardized and long-term studies.

Conclusion: RSV, as a phytoestrogen, increases estrogen levels in the intervention groups. RSV shows potential effects in modulating the most studied menopausal cardio-metabolic changes.

Introduction: Traditional risk reduction strategies like diet, exercise, and existing lipid- lowering medications have minimal impact on Lp(a) levels. Recent therapies targeting Lp(a) at the level of mRNA transcription of apo(a) or binding of apo(a) to apoB-100 have demonstrated substantial reductions of Lp(a). Lepodisiran is a GalNAc-conjugated small interfering RNA (siRNA) developed to inhibit LPA transcription, reducing apo(a) synthesis and circulating Lp(a) levels. This is an updated review of the mechanism of action, pharmacokinetics, clinical efficacy, and safety of Lepodisiran, as well as its effects on lipoprotein(a), with potential applications in treating patients with elevated cardiovascular risk.

Methods: We conducted a literature search on PubMed, Google Scholar, and Scopus using keywords such as "Lepodisiran," "small interfering RNA therapies," and "lipoprotein(a)".

Results: Lepodisiran demonstrated a dose-dependent and sustained reduction in Lp(a) levels, achieving a maximum reduction of up to 97% at the highest dose in a Phase 1 trial. A Phase 2 placebo-controlled trial similarly showed robust and durable decline in Lp(a) with a favorable safety profile.

Discussion: Lepodisiran is a promising therapy, with sustained Lp(a) reduction and good safety. Ongoing phase 3 trials are poised to provide robust data on its long-term safety, clinical efficacy, and impact on Atherosclerotic Cardiovascular Disease (ASCVD) outcomes.

Conclusion: Lepodisiran demonstrates potent and sustained reductions in Lp(a) levels with a favorable safety profile, making it a promising therapeutic candidate for Lp(a)-mediated cardiovascular risk. Ongoing long-term outcome studies are essential to confirm its clinical benefit.

Introduction: Cardiovascular disorders (CVDs) remain the leading cause of global mortality, surpassing other chronic illnesses. An alarming rise in CVD-related deaths, particularly among younger populations, has intensified research efforts to better understand the disease and its complications. Among these, myocardial fibrosis plays a central role in the development of cardiac dysfunction and heart failure. Given its multifactorial nature, diverse therapeutic strategies are required to manage its progression effectively.

Methods: A comprehensive literature review was conducted using databases such as PubMed, Scopus, Elsevier, and ClinicalTrials.gov. Only peer-reviewed, English-language studies focusing on molecular mechanisms and therapeutic strategies for myocardial fibrosis were included. Irrelevant, non-English, and non-peer-reviewed sources were excluded. Data from selected preclinical and clinical investigations were qualitatively synthesized.

Results: Myocardial fibrosis arises from various pathological conditions, including ischemia, hyperlipidemia, and genetic disorders, which promote maladaptive cardiac remodeling. Although traditional treatments such as RAAS inhibitors and β-blockers offer symptomatic relief, they do not halt disease progression. Recent evidence suggests that multiple molecular pathways are involved in the development of fibrosis, opening opportunities to explore alternative therapeutic targets.

Discussion: Due to its complex pathophysiology, myocardial fibrosis cannot be addressed by monotherapy alone. Anti-TGF-β agents have emerged as promising candidates, alongside newer therapies like SGLT2 inhibitors and MMP inhibitors. Additionally, regenerative approaches, such as stem cell and gene therapy, offer future avenues, though technical and safety challenges accompany them.

Conclusion: Myocardial fibrosis remains a critical contributor to heart failure, and current treatments are insufficient to reverse its course. A multifaceted therapeutic approach targeting different molecular mechanisms holds the key to improved clinical outcomes. Continued translational research is crucial for advancing emerging therapies from bench to bedside.

Background: The t(15;17)(q22;q21) is a well-known cytogenetic abnormality in acute promyelocytic leukemia (APL) and has defined management and better outcomes compared to other acute myeloid leukemia subtypes. Acute myeloid leukemia (AML) with t(15;17)(q21;p11.2) cytogenetic abnormality and associated B2M::RARA molecular abnormality has not been previously reported.

Case presentation: The patient reported here was a 48-year-old female who presented with generalized weakness, with no lymphadenopathy or organomegaly. Further evaluation for pancytopenia revealed a diagnosis of AML confirmed by immunophenotyping using flow cytometry. Conventional karyotyping revealed a complex karyotype with the presence of 48, XX, add(1)(q44), +der(1), del(3)(q12q21), del(5)(q31), del(6)(q21), t(15;17)(q21;p11.2), +21[cp20]. Fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) for PML-RARA t(15;17)(q24;q21) were negative, and next-generation sequencing (NGS) revealed TP53 mutation and B2M-RARA fusion. The patient was managed with a hypomethylating agent plus venetoclax (VEN) therapy.

Conclusion: t(15;17)(q21;p11.2) is a novel cytogenetic abnormality in AML, along with the B2M-RARA fusion, and warrants thorough evaluation to rule out APL.

Introduction: Acute coronary syndrome (ACS) is a leading cause of death, and clopidogrel resistance remains a major challenge in its treatment. This study aims to determine the impact of CYP2C19 genetic variants on clopidogrel resistance (CR) and major adverse cardiovascular events (MACEs) in Vietnamese patients undergoing percutaneous coronary intervention (PCI).

Methods: We carried out a descriptive cross-sectional study, supplemented by a prospective longitudinal follow-up, on 113 ACS patients undergoing PCI with drug-eluting stent implantation at the Department of Cardiology, Military Hospital 103, from January 2015 to May 2018. We excluded patients with a decreased platelet count (< 100 × 10^9/L), a decreased estimated glomerular filtration rate (< 15 mL/min), ongoing bleeding, coagulation disorders, planned or recent surgery, or a coexisting malignancy. CR was defined as platelet aggregation ≥ 46%. The Amplification Refractory Mutation System (ARMS)-PCR was used to determine the CYP2C19 genotype and phenotype. Causes leading to patient readmission, such as angina, recurrent acute myocardial infarction, stroke, or death within 30 days, were recorded as MACEs.

Results: The rate of CR was 29.9% (33/113 patients), and the incidence of MACEs was 15.9% (18/113 patients). The frequencies of CYP2C192 and CYP2C193 polymorphisms, as well as the PM CYP2C19 phenotype, were higher in the CR and MACE groups compared to those without these characteristics (p = 0.24, 0.006, and < 0.001, respectively). The PM CYP2C19 phenotype was predictive of 30-day MACEs in ACS patients undergoing PCI with stent implantation (p < 0.001).

Discussion: Our findings demonstrate a strong association between CYP2C19 PM phenotypes and increased risks of both clopidogrel resistance and 30-day MACEs in Vietnamese ACS patients undergoing PCI. These results underscore the clinical significance of CYP2C19 genotyping in optimizing antiplatelet therapy and enhancing outcomes in this patient population.

Conclusion: PM CYP2C19 phenotypes were associated with an increased risk of CR and MACEs in Vietnamese patients undergoing PCI with stent implantation.

Introduction: Sacubitril/valsartan (SAC/VAL) is a combination medication primarily used to treat heart failure with reduced ejection fraction (HFrEF). This randomized controlled trial (RCT) assessed the impacts of SAC/VAL compared with valsartan (VAL) on left ventricular (LV) remodeling, clinical outcomes, and cardiac function in patients with HFrEF.

Methods: A single-blinded run-in phase and a double-blinded treatment phase were conducted at Imam Hospital (Ahvaz, Iran) among 106 patients (SAC/VAL group: n=54; VAL group=52). Patients were randomly assigned to receive a combination of SAC/VAL (up-titrated to the target dosage of 200 mg, twice daily) or VAL (up-titrated to 160 mg, twice daily) for a six-month of intervention. Patients' clinical, demographic, and echocardiographic data were collected before and after the intervention.

Results: After a six-month intervention, statistically significant mean differences were detected in various echocardiographic parameters (e.g., LV end-systolic volume, LV ejection fraction, and LV end-diastolic volume) within each group and between the two groups. Significant mean differences were noted in the six-minute walk test, serum levels of blood urea nitrogen, aspartate aminotransferase, sodium, creatinine, alanine aminotransferase, N-terminal pro-B-type natriuretic peptide, and scores of the Kansas City Cardiomyopathy questionnaire in post-intervention assessments within each group and between the two groups (P <0.05). There was a substantial within-group difference in the frequency of the New York Heart Association (NYHA) functional class from pre- to post-intervention (P <0.05).

Discussion: This study revealed that SAC/VAL exhibited superior efficacy compared to VAL. However, the follow-up period was relatively short, and the potential risks associated with the prolonged administration of this medication have not been thoroughly evaluated.

Conclusion: This RCT indicated that the combination of SAC/VAL had better therapeutic effects than VAL on LV remodeling, clinical outcomes, and cardiac function in patients with ischemic HFrEF. These findings may help refine treatment priorities for patients with HFrEF and improve the quality of their care.

Clinical trial registration number: IRCT20240117060713N1.

Introduction: Immune thrombocytopenia (ITP) is an autoimmune condition characterized by reduced platelet counts due to increased peripheral destruction and impaired platelet generation. An estimated incidence of ITP is 2 to 5 cases per 100,000 individuals in the general population. While mucocutaneous bleeding is common, life-threatening complications, such as spontaneous lingual hematoma and intracerebral hemorrhage (ICH), are extremely rare. Rapid progression of lingual haematomas might compromise airway function and necessitate immediate medical intervention. It is well established that most patients with ITP respond to first-line therapy; however, severe bleeding events, such as intracerebral hemorrhage, occur in less than 1% of cases and are associated with significant morbidity and mortality.

Case presentation: A 21-year-old male with a 6-month history of chronic ITP and poor compliance with therapy presented with a 2-day history of progressive reddish discoloration and swelling of the tongue. The clinical examination revealed stable vital signs and a remarkable general and systemic evaluation. The relevant blood routine showed a critically low platelet count at 8×103/μL, with normal coagulation parameters. No other bleeding manifestations were noted. Four hours after admission, the patient developed generalized tonic-clonic seizures and altered sensorium. Computed tomography (CT) of the head revealed an ICH. He was managed with single- donor platelet transfusions, intravenous anti-epileptics, pulse corticosteroid therapy, eltrombopag, and supportive care. The patient demonstrated a favorable clinical response, characterized by a rising platelet count and resolution of symptoms. He was discharged in stable condition with counseling on therapy adherence.

Conclusion: The present case emphasizes the rarely yet life-threatening complication of inadequately managed ITP, such as spontaneous lingual hematoma and intracranial haemorrhage. It highlights the vital significance of therapy adherence and timely interdisciplinary intervention to avert disastrous consequences. Timely detection and intervention are crucial for positive outcomes in these intricate cases.