Medicine in Drug Discovery最新文献

Severe aplastic anemia (SAA) is a hematological condition with high morbidity and mortality. Treatment with immunosuppressive agents is alternative treatment if bone marrow transplant is not available. Several studies reported predictors of successful treatment in patients with SAA. However, the results are not consistent and not specific to anti-thymocyte globulin and cyclosporine. This study aimed to evaluate the predictor of response to treatment in this specific regimen. This study was a retrospective cohort study. The inclusion criteria were adult patients with SAA or very SAA who received this regimen. Clinical factors predictive of response to treatment were computed. There were 92 patients met the study criteria. Of those, 56 patients (60.87%) were in a group of response to treatment. There were nine factors in the predictive model for good response to treatment. Only body mass index was independently associated with response to treatment with an adjusted odds ratio of 1.31 (95% confidence interval of 1.04, 1.67). Age or hematological laboratory factors such as lymphocyte or neutrophil count were not significant. Low body mass index may be less likely to response to immunosuppressive treatment in patients with severe or very severe aplastic anemia.

Atrial fibrillation (AF) is one of the world’s most prevalent cardiac arrhythmias. It poses a heavy burden on patients, physicians and the global healthcare system as it is one of the top leading causes of cardiovascular death. Researchers have spent numerous years conducting clinical trials to investigate the effectiveness, cost and practicality of treatment for patients suffering from AF. The primary treatment strategy for AF (acute, chronic, persistent, paroxysmal, non-valvular, nonrheumatic, and rapid) involves the use of antiarrhythmic drugs (AAD) and anticoagulant drugs (ACD) to manage heart rate and rhythm, as well as to prevent strokes. This review aims to discuss clinical trials that compared AADs (class Ia: quinidine; class Ic: flecainide, propafenone; class III: sotalol, amiodarone) and ACDs (vitamin K antagonist: warfarin; factor Xa inhibitor: apixaban, rivaroxaban; thrombin inhibitor: dabigatran) with cardiovascular surgical interventions (i.e., catheter ablation, cryoballoon ablation, ablation and DDDR pacemaker, electrical cardioversion, and left atrial appendage occlusion) to treat various types of AF in patients with a diverse history of cardiovascular diseases and medical history. This study provides a review of clinical trials on this topic and enables healthcare professionals to determine the best-suited treatment for their patients.

Self-assembly of various amphipathic copolymers is a simple method that allows the preparation of complex nanoparticles with several useful properties. Therefore, the aim of this research was to develop nanoparticles with better biocompatibility, biodegradability, and prolonged circulation time in the bloodstream to deliver drugs and genes into breast cancer tissues in a controlled and targeted manner. In this study, the copolymers PLA-chitosan- PEG -folic acid (COPA), PLA-chitosan- PEG -glucose (COPB), COPA & COPB (COPAB) and chitosan- PLA-PEG FA /Glu/VEGF/siRNA/PTX (NPsAB/siRNA/Paclitaxel) were synthesized, to control the release of paclitaxel (PTX) and siRNA and the circulation time of nanoparticles in blood. This was confirmed by ¹H NMR and FTIR spectroscopy. The particle size, zeta potential and morphology of NPsAB /siRNA/PTX were studied by DLS and TEM, respectively. The results showed that the NPsAB/siRNA/PTX had spherical morphology with particle size and zeta potential about 200 nm and −7.8 mV, respectively. In vitro cytotoxicity assay results showed that the nanoparticles had good biocompatibility and low toxicity. Also demonstrated that NPsAB in the serum medium improved the efficiency of drug and siRNA delivery more than two-fold compared to COPA, COPB, and COPAB nanoparticles. Due to results the release pattern of siRNA and PTX from NPsAB nanoparticles under an acidic environment was significantly higher than that of their release rate in a neutral medium. Therefore, due to the acidity of tumor tissue, this property of NPsAB nanoparticles seems to be useful in the treatment of cancer.

The use of small molecules in immunotherapy is a promising and rapidly growing field with the potential to revolutionize the way we treat a wide range of immunological diseases. The success stories of using small molecules in immunotherapy have been highlighted with many drugs, such as checkpoint inhibitors, which have achieved significant success in treating several types of tumors. However, despite this success, the development of small molecules for immunotherapy is still in its infancy, and there are many challenges that remain to be addressed. In a recent study, our laboratory reported the immunostimulatory effect of a small molecule (Compound A) (A). In this paper, we studied a derivative of this molecule (Compound B) (Fig. 1B). and analysed its physiochemical properties, immunological activities, and transcriptome profiling. Compound B exhibited acceptable metabolic stability and no toxicity against PBMCs. We also demonstrated that Compound B was capable of modulating the immune system by inducing pro-inflammatory cytokines and promoting T-cell proliferation. RNAseq results showed that Compound B was able to significantly upregulate genes involved in stimulating the immune response pathways. Our findings suggest that Compound B may serve as a promising therapeutic agent to modulate the immune system. The identification and validation of the molecular targets responsible for its immunological activities are underway.

Despite being the most widely prescribed and misused type of medication, opioids continue to function as robust pain relief agents; however, overdosing is a significant cause of fatalities among opioid users. The δ-opioid receptor (DOR) has immense promise in treating long-term pain by producing anxiolytic and antidepressant-like outcomes. Although DOR agonists play a crucial role, their clinical implementation is restricted because of the probable manifestation of severe, life-threatening complications. A Python-based machine learning approach was employed to develop a quantitative structure–activity relationship (QSAR) model in this study. To address this, 4217 compounds and their associated biological inhibition activities were retrieved from the gpcrdb database. The K-best features selection method revealed three key structural features such as SLOGPVSA2, Chi6ch, and S17 contributed significantly to the best model performance. Statistical analysis, K-fold cross-validation, applicability domain analysis, and external validation using 38 unseen FDA-approved drug data confirmed the robustness of the predictive model. A molecular docking study in along with Ligand–Receptor Contact Fingerprints (LRCFs) using the essential chemical interactions described for analog ligands releaved the key contact interactions of Asp 128, Tyr 129, Met 132, Trp 274, Ile 277, and Tyr 308 residues in the total binding affinities upon complexation. Our combinatorial study using regression QSAR and ligand–receptor Contact, analysis could serve in the design of more rational compounds for drug discovery targeting DOR.

Snake venom is a rich source of bioactive molecules that hold great promise for therapeutic applications. These molecules can be broadly classified into enzymes and non-enzymes, each showcasing unique medicinal properties. Noteworthy compounds such as Bradykinin Potentiating Peptides (BPP) and Three-Finger Toxins (3FTx) are showing therapeutic potential in areas like cardiovascular diseases (CVDs) and pain-relief. Meanwhile, components like snake venom metalloproteinases (SVMP), L-amino acid oxidases (LAAO), and Phospholipase A₂s (PLA₂) are paving new ways in oncology treatments. The full medicinal scope of these toxins is still emerging. In this review, we discuss drugs derived from snake venoms that address CVDs, cancer, diabetes, strokes, and pain. Further, we outline the toxin distribution across 130 snake species, categorized by their genus within the Crotalidae, Viperidae, and Elapidae families. Conclusively, we spotlight the potential of Deep Learning (DL) in discovering groundbreaking drug prospects from these toxins.

Recent decades have witnessed a paradigm shift from traditional therapy to precision medicine, which was substantially facilitated by implementing biomarker strategy. Taking the advantages of contemporary biological sciences and advanced technology, novel biomarkers are increasingly identified and validated in numerous aspects of pharmaceutical development, thus leading to the success of emerging medications for unmet clinical needs. Herein, this article presents a comprehensive update on evolving trends of biomarkers in the field, covering the applied pharmacology, therapeutic guidance/monitoring, patient stratification, toxicity detection, among others. In this light, it tends not only to improve the efficiency of drug development and the outcome of medical care, but also to optimize the entire life cycle assessment of pharmaceutical products.

Colorectal cancer (CRC), ranking as the third most common cancer globally, is associated with a high death rate. The colon, also known as the large intestine, is the site where colorectal cancer initially develops. It is a lengthy tube that facilitates the passage of digested food to the rectum and ultimately out of the body. CRC has the potential to affect other organs or regions of the body if not diagnosed or treated earlier. Delivering precise medications in a site-specific and target-oriented manner can improve chronic disease therapy in various ways. In recent years, there have been a number of innovations in nanomedicine (including chemotherapeutic medicines, biological agents, immunotherapeutic agents, and other such applications) for the treatment of various diseases, including CRC. The current review provides an up-to-date overview of the latest advancements in the field of nanomedicines and nano-based drug delivery systems for the CRC treatment. An in-depth investigation has been conducted into the study of nanomaterials such as liposomes, metal, polymeric and peptides nanomaterials, exploring their potential applications in enhancing the efficacy of both new and existing drugs. This review also focuses on the opportunities and challenges posed by nanomedicines in delivering drugs derived from natural and synthetic sources. Additionally, information on advancements and future prospects in the field of nanomedicine is provided.

Aims

Endothelial damage in acute respiratory distress syndrome (ARDS) increases capillary permeability, resulting in an increase in free lung fluid, interstitial pulmonary edema, and ventilation-perfusion imbalance. Due to their high osmolarity, Intravenous Immunoglobulin (IVIG) treatment may deepen hypoxemia by increasing lung fluid leakage. Adding furosemide to IVIG treatment in ARDS secondary to COVID-19 (CARDS) cases may increase treatment tolerance and success.

Materials and methods

In our study, we aimed to measure the effectiveness of this treatment combination in CARDS cases and to report the observed complications. Patients who were followed up in the 34-bed adult COVID intensive care unit between March 2020/2021 and who received IVIG, high-dose corticosteroid, and furosemide combination therapy were included in the study. Patients' age, gender, comorbidities, Acute Physiology, and Chronic Health Assessment II (APACHE-II), and Sequential Organ Failure Assessment (SOFA) scores were recorded. The day IVIG duration of treatment, additional medical treatments, respiratory support treatments, laboratory examinations, the percentage of involvement of lung lesions (Covid Visual Assessment Scale), clinical outcomes, and treatment complications were recorded.

Results

Combination therapy with found to improve respiratory failure in 50 % of patients. Troponin elevation was found in two patients, femoral artery embolism in one patient, and thrombosis in the femoral vein in one patient. In addition to IVIG treatment, the administration of two doses of immune plasma increased the chance of discharge (P = 0.037)

Conclusion

In severe viral ARDS refractory to standard therapy, using furosemide in addition to IVIG therapy has an acceptable side-effect profile and may increase treatment success. Furosemide given during IVIG therapy should not be considered a contraindication in every patient.

Background

Glucocorticoids (GCs) are widely used in the treatment of inflammatory liver diseases and sepsis, but GC’s various side effects on extrahepatic tissues limit their clinical benefits. Liver-targeting GC therapy may have multiple advantages over systemic GC therapy. The purpose of this study was to develop novel liver-targeting GC prodrugs as improved treatment for inflammatory liver diseases and sepsis.

Methods

A hydrophilic linker or an ultra-hydrophilic zwitterionic linker carboxylic betaine (CB) was used to bridge cholic acid (CA) and dexamethasone (DEX) to generate transporter-dependent liver-targeting GC prodrugs CA-DEX and the highly hydrophilic CA-CB-DEX. The efficacy of liver-targeting DEX prodrugs and DEX were determined in primary human hepatocytes (PHH), macrophages, human whole blood, and/or mice with sepsis induced by cecal ligation and puncture.

Results

CA-DEX was moderately water soluble, whereas CA-CB-DEX was highly water soluble. CA-CB-DEX and CA-DEX displayed highly transporter-dependent activities in reporter assays. Data mining found marked dysregulation of many GR-target genes important for lipid catabolism, cytoprotection, and inflammation in patients with severe alcoholic hepatitis. These key GR-target genes were similarly and rapidly (within 6 h) induced or down-regulated by CA-CB-DEX and DEX in PHH. CA-CB-DEX had much weaker inhibitory effects than DEX on endotoxin-induced cytokines in mouse macrophages and human whole blood. In contrast, CA-CB-DEX exerted more potent anti-inflammatory effects than DEX in livers of septic mice.

Conclusions

CA-CB-DEX demonstrated good hepatocyte-selectivity in vitro and better anti-inflammatory effects in vivo. Further test of CA-CB-DEX as a novel liver-targeting GC prodrug for inflammatory liver diseases and sepsis is warranted.