Current pharmaceutical design最新文献

Alzheimer's disease (AD) is a debilitating condition that significantly affects the elderly. Early diagnosis is not only critical for improving patient outcomes but also directly influences the success of emerging therapeutic interventions. A therapeutic strategy targeting only one pathogenic mechanism is unlikely to be very effective, as there is increasing evidence that AD does not have a single pathogenic cause. Therefore, combining medications or developing therapies that address multiple pathways may be beneficial. Most clinical trials can be classified under added therapy rather than combination therapy. Effective treatment of AD likely requires targeting multiple mechanisms, such as amyloid-beta (Aβ) and tau pathology. However, many medications face challenges, including poor solubility, low permeability, and the inability to cross the blood- -brain barrier (BBB). This is where nanocarriers come into play, as they can be loaded with these medications to facilitate targeted drug delivery. This approach enhances the pharmacokinetic profile of drugs in both the blood and the brain. Therefore, this paper provides a concise overview of the use of various nanocarriers loaded with drug combinations for treating AD.

Introduction: Chronic Kidney Disease (CKD) is recognized as a major global public health problem. Dialysis is the mainstay of treatment for patients with end-stage renal disease and can prolong survival in patients with CKD. As patient survival increases, the treatment of complications becomes more important. CKD-mineral and bone disorders (CKD-MBD) and renal anemia are common complications in patients with CKD. Cinacalcet is a calcimimetic for the treatment of Secondary Hyperparathyroidism (SHPT) in adult dialysis patients, which regulates the synthesis and secretion of parathyroid hormone by increasing the sensitivity of calcium-sensitive receptors. This retrospective study evaluated the efficacy of cinacalcet in dialysis patients.

Method: Forty-seven patients on dialysis with elevated parathyroid hormone were included. The selected patients have regular follow-up visits in our outpatient clinic and regular use of cinacalcet for no less than 6 months.

Result: During the 6-month efficacy evaluation phase, cinacalcet not only reduced the levels of the intact parathyroid hormone (iPTH, P ≤ 0.05), serum calcium (P ≤ 0.01), and Ca×P (P ≤ 0.05) but also reduced weekly erythropoietin dosage (P ≤ 0.01) and erythropoietin resistance index (ERI, P ≤ 0.05).

Conclusion: While controlling SHPT in patients with CKD, cinacalcet reduced EPO resistance and improved renal anemia. In conclusion, cinacalcet not only decreased the levels of the iPTH, serum calcium, and Ca×P but also reduced weekly EPO dosage and ERI levels. Controlling SHPT in patients with CKD, cinacalcet also reduced ERI and improved renal anemia.

Background: In vascular tissue, macrophages and inflammatory cells produce the enzyme lipoprotein- associated phospholipase A2 (Lp-PLA2). Treatment with fibrates decreases Lp-PLA2 levels in individuals with obesity and metabolic syndrome; however, these findings have not been fully clarified.

Objective: The goal of this study was to investigate the possible effects of fibrate therapy on Lp-PLA2 mass and activity through a meta-analysis of clinical trials.

Methods: Web of Science, PubMed, Scopus, Google Scholar, and ClinicalTrials.gov databases were searched using MeSH terms and keywords. Randomized controlled trials (RCT) evaluating the effect of statins on Lp- PLA2 mass and/or activity were included in the meta-analysis. Quantitative data were analyzed using a random- effects model and the generic inverse variance method.

Results: The meta-analysis of 10 clinical trials indicated that fibrate treatment has no significant effect on Lp- PLA2 mass (fibrate vs. placebo/nothing = WMD: -3.29 ng/ml, 95% CI: -21.35, 14.78, p = 0.72; fibrate vs. active control = WMD: -1.08 ng/ml, 95% CI: -51.38, 49.22, p = 0.97); Lp-PLA2 activity (fibrate vs. active control = WMD: 0.84 nmol/ml/min, 95% CI: -0.17, 1.84, p = 0.10); HDL-LpPLA2 activity (fibrate vs. active control = WMD: 0.77 nmol/ml/min, 95% CI: -0.33, 1.88, p = 0.17); and secretory PLA2 (fibrate vs. active control = WMD: 0.37 ng/ml, 95% CI: -1.22, 1.97, p = 0.65). Also, the results of the sensitivity analysis were robust for all these parameters.

Conclusion: In conclusion, fibrate therapy did not reduce the mass and activity of Lp-PLA2.

Aims: This study aims to identify and evaluate promising therapeutic proteins and compounds for breast cancer treatment through a comprehensive database search and molecular docking analysis.

Background: Breast cancer (BC), primarily originating from the terminal ductal-lobular unit of the breast, is the most prevalent form of cancer globally. In 2020, an estimated 2.3 million new cases were reported, resulting in approximately 685,000 deaths. Mutations in the BRCA1 and BRCA2 genes are well-established in hereditary breast cancer. The identification of effective therapeutic proteins for BC remains a complex and evolving area of research.

Objective: This study aims to identify and evaluate promising therapeutic proteins and compounds specific to breast cancer through a comprehensive database search and molecular docking analysis.

Methods: A rigorous search was conducted within the National Cancer Institute (NCI), NCI Metathesaurus, SIGnaling Network Open Resource (SIGNOR), Human Protein Atlas (HPA), and the Human Phenotype Ontology (HPO) to shortlist proteins linked to BC (CUI C0678222). Recent studies were reviewed to understand the administration of CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) combined with endocrine therapy for HR-positive and HER2-negative breast cancer. Anticancer compound libraries available at ZINC and PubChem were analyzed. Compounds were evaluated based on their binding energies with CDK4 protein, a rationally selected druggable target.

Results: Key proteins linked to breast cancer were identified through database searches. Proliferation, apoptosis, and G1/S transition pathways were frequently found dysregulated in breast cancer. ZINC13152284 exhibited the strongest binding energy at -10.9 Kcal/mol, followed by ZINC05492794 with a binding energy of -10.4 Kcal/mol. Preexisting drugs showed lower binding energies with the CDK4 protein.

Conclusion: The study highlights the importance of drug repurposing as a strategy for the safe and effective treatment of breast cancer. Synthetic inhibitors often cause severe side effects, emphasizing the need for novel targets and compounds with better therapeutic profiles. Molecular docking identified promising compounds from the ZINC database, suggesting potential new avenues for breast cancer therapy.

Background: In recent years, sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as a valuable treatment for type 2 diabetes (T2D) and heart failure. Despite these medications seeming to be safe in older people, the literature about SGLT2i and frailty is still limited. This study aims to evaluate whether SGLT2i use is associated with increased survival in older adults and if frailty can affect the findings.

Material and methods: We enrolled over 65 patients admitted to the Geriatrics Wards at the University Hospital 'P. Giaccone' in Palermo, Italy, between December 2022 and May 2023. After 12 months of follow-up, various outcomes were assessed, including mortality, hospitalization, glycemic dysregulation, urinary tract infections, and falls. The association between SGLT2i use and mortality was analyzed and reported as hazard ratios (HRs) with their 95% confidence intervals (CIs).

Results: A total of 80 patients were included in the study (mean age 79.5 ± 8.5 years; 50% were women). Patients using SGLT2i had a higher prevalence of T2D (p = 0.02) and cirrhosis (p = 0.001). After adjusting for potential confounders, SGLT2i use was significantly associated with a reduced mortality risk (HR = 0.53; 95% CI: 0.20-0.93; p = 0.02). When stratified by the presence of multidimensional frailty, SGLT2i use was significantly associated with a lower risk of mortality in frail patients (HR = 0.27; 95% CI: 0.06-0.88; p = 0.008), but not in robust ones.

Conclusion: In older frail patients, the use of SGLT2i is associated with reduced mortality after 12 months of follow-up. Further larger studies are needed to evaluate the role of these medications in older adults.

Molecular hydrogen (H2) is considered a biological antioxidant. Hydrogen-rich Water (HRW) is regular water that contains dissolved H2 and has become more widely used in recent years. This review summarizes the basic research and clinical applications of HRW consumption to support its use for daily health and clinical treatment. The biological effects of HRW include reducing oxidative stress, exerting antiinflammatory effects, regulating glucose and lipid metabolism, protecting mitochondrial function, and regulating apoptosis. Hypotheses about the mechanisms of H2 include the direct scavenging of toxic free radicals, the Fe-porphyrin biosensor hypothesis, the effect of H2 on biological enzymes, the lipoprotein regulation of H2, and H2 acting on the intestinal barrier. Clinically, HRW has been used for adjuvant treatment, disease prevention, and quality of life improvement. In the future, more in-depth studies and large-scale clinical trials are needed.

Hemophilia A (HA) is an inherited condition that is characterized by a lack of coagulation factor VIII (FVIII), which is needed for blood clotting. To produce recombinant factor VIII (rFVIII) for treatment, innovative methods are required. This study presents a thorough examination of the genetic engineering and biotechnological methods that are essential for the production of this complex process. Multiple host cells, such as animal, microbial, and human cell lines, are examined. Cultivating genetically modified cells enables the production of rFVIII, with further changes after protein synthesis, such as glycosylation, taking place in eukaryotic cells to guarantee correct folding. The extraction and purification of rFVIII require advanced methods, including affinity chromatography, to improve the purity of the protein. The purified protein undergoes rigorous quality control, which includes Sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDSPAGE) analysis, to assess its identity, purity, and functioning. The scalability of this approach allows for the synthesis of significant amounts of rFVIII for therapeutic purposes. Optimization strategies include modifying B-domain-deleted (BDD) FVIII, including introns in FVIII complementary DNA (cDNA) sequences to boost synthesis and storage, and making changes to chaperone-binding areas to optimize protein release. Furthermore, the search for a modified form of FVIII that has a longer duration of action in the body shows potential for enhancing the effectiveness of synthetic FVIII and progressing the treatment of hemophilia A. Future research should focus on improving the treatment of hemophilia A by developing a variant of FVIII that has increased stability and reduced immunogenicity.

Background: The metal oxide nanoparticles possess unique properties such as biological compatibility, superior reactivity, and capacity to develop reactive oxygen species, due to this they have drawn significant interest in cancer treatment. The various MONPs such as cerium oxide, Copper oxide, Iron oxide, Titanium dioxide, and Zinc oxide have been investigated for several types of cancers including brain, breast, cervical, colon, leukemia, liver, lung, melanoma, ovarian, and prostate cancers. However, traditional physiochemical synthetic methods for MONPs commonly include toxic materials, a major concern that raises questions regarding their biocompatibility and safety.

Objective: This study aims to investigate the role of plant phytoconstituents in the development of MONPs via green synthesis and explore the therapeutic effectiveness of MONPs in treating several types of cancer. Primarily, it examines the potential of plant phytoconstituents (phenolic compounds, flavonoids, glycosides, alkaloids, etc.) in the development of MONPs as well as their improved ability to target numerous types of cancer.

Methods: A systemic search was conducted on recent literature, focusing on developing green MONPs by utilizing plants' phytoconstituents (plant extracts). The study of plant phytochemicals (present in different parts of a plant such as leaves, flowers, stems, peels, and roots) and their role in the synthesis of green metal oxide nanoparticles as well as their anticancer activity against several types of cancers was analyzed. Also focusing on their anticancer mechanism that involves ROS production, generates oxidative stress, and apoptosis leads to cancer inhibition.

Results: Phytochemicals-mediated metal oxide nanoparticle synthesis revealed many advantages such as improved biological compatibility and enhanced sensitivity towards cancer cells. Phytochemicals present in plant extracts act as natural capping, reducing, and stabilizing agents, enhancing nanoparticle synthesis which leads to synergistic anticancer activity. Additionally, the natural antioxidant and anticancer activity of various phytochemicals enhances the therapeutic potential of metal oxide nanoparticles, producing them more effective against ROS-generated apoptosis and showing negligible toxicity towards normal cells.

Conclusion: The utilization of plant phytochemicals in metal oxide nanoparticle production presents a safe, eco-friendly, sustainable, and effective approach to developing effective and safer cancer nanomedicines. Green synthesis not only increases anticancer activity but also decreases the biocompatibility problems associated with the physiochemical synthetic approach. Further research needs to concentrate on improving this synergy to create a targeted phytochemical-based metal oxide nanoparticle for cancer therapeutics.

Scutellarein, a flavone found in the perennial herb Scutellaria baicalensis, has a wide range of pharmacological actions, such as antioxidant, anti-inflammatory, and neuroprotective. Increasing evidence has emphasized the developing significance of scutellarein in several neurological illnesses, such as Alzheimer's and Parkinson's disease, cerebral ischemia, and neuroblastoma. This review is centered on the molecular processes that underlie the neuroprotective properties of scutellarein in various neurological disorders, as indicated by recent pre-clinical research. Furthermore, it critically examines the potential challenges and advantages of scutellarein inclusion within the range of treatments for neurological disorders.

Amyloid beta (Aβ) dyshomeostasis is considered the main biological aberration in Alzheimer's Disease (AD) pathology. The interplay between Aβ formation and clearance is predominantly modulated by a disintegrin and a metalloproteinase 10 (ADAM10, α-secretase) and β-site APP Cleaving Enzyme 1 (BACE1), the two pivotal enzymes in both non-amyloidogenic/amyloidogenic and amyloidolytic pathways. Emerging evidence suggests that aberrations in ADAM10 and BACE1 expression, activity, and function in the brain of AD patients also manifest in peripheral fluids, suggesting their potential as blood-based biomarkers for AD diagnosis. This review provides a comprehensive overview of the literature by exploring the roles of ADAM10 and BACE1 in AD, spanning from their involvement as pathological AD drivers to their potential utility as promising biomarkers.