Medicine in Drug Discovery最新文献

Among all diseases, cancer has the highest fatality rate in the world. Conventional therapies have come a long way, but they still are not a panacea for cancer. Nanotechnology-based compositions of several nanoparticles (NPs) hold promise as a cancer therapy. The co-delivery of amphiphilic molecules is feasible with lipid-polymer hybrid nanoparticles (LPHNPs). Increased encapsulation of pharmaceuticals with a regulated release profile is made possible by the physical benefits of polymers and the resembling features of lipids. For increased cytotoxicity against cancer, LPHNPs have been created for the co-transport of phytochemicals and other chemotherapeutic medicines. Specifically, LPHNPs are used as carrier systems to deliver drugs to tumour locations in a regulated fashion. This method makes use of the biocompatibility of lipids and the structural advantages of polymers to provide controlled drug administration. Co-loaded LPHNPs demonstrated improved cytotoxicity, and the incorporation of phytochemicals into various medications resulted in enhanced chemo-sensitization of carcinomas. The shortcomings of existing nano-delivery systems and the benefits of LPHNPs have been discussed in this review.

Multidrug resistance (MDR) poses a severe threat to human health. The existence of efflux pumps primarily contributes to resistance in Gram-negative bacterial infections. Efflux pump inhibitors (EPIs) can potentially improve the efficacy of antibiotics and reduce bacterial pathogenicity by inhibiting the mechanism of these pumps. Here we report Bac-EPIC, a web interface consisting of AcrA_Ipred, and AcrB_Ipred tools, can aid in the identification of potential EPIs that might bind to AcrAB-TolC pump subunits, alter its structure in vivo, prevent efflux, and enhance antibiotic efficacy in Escherichia coli (E. coli) and other Gram-negative bacteria. The web server is developed by collecting and archiving structural moieties from literature-reported EPIs. The web interface can be utilized in decision-making upon structural similarity-based screening on whether a compound should be examined experimentally or disregarded. It takes the SMILES format of chemical structure as an input. Users can also draw the 2D structure and get the output report of the possible structural similarity profile, similarity percentage, and the active moieties in the compound. The designed web interface is publicly accessible for in silico efflux pump inhibition prediction, at http://14.139.62.46/AcrAB_Ipred/. Overall, the webserver increases the diversity of EPIs, and proposes mechanistic insights to understand and regulate the efflux pump assembly & its function, ultimately aiding in fight against antibiotic resistance.

Exosomes are vital for cellular communication and the transfer of materials between cells. Recently, it has been shown that nanoparticles may be used as diagnostic indicators and as a potential medicine delivery strategy due to their nanoscale size and capacity to carry biological components to target cells. Exosomes have the potential to be an appealing and practical approach for drug administration in cancer treatment due to their biocompatibility, high stability, favoured tumour homing, and adjustable targeting efficacy. While exosomes have properties that make them useful for transporting bioactive compounds, the gap between our present understanding of exosome biology and the most optimal condition for their use remains. The rationale for using exosomes as a drug delivery strategy, their production and purification, bioengineering and targeting, uptake and distribution, efficacy, immune response, and other factors will all be discussed in this study. Modern methods are required for observing, categorising, and sorting exosome diversity. Improvements in nanotechnology and our knowledge of exosome biology will undoubtedly speed up the field's medical uses.

Microemulsions are a promising drug delivery system that can be used to enhance the bioavailability, solubility, and therapeutic efficacy of hydrophilic drugs. The downside of hydrophilic drugs is the poor solubility in lipid-based media; therefore, they require frequent dosing or high doses to achieve the therapeutic level. This may lead to unintended adverse effects and poor patient compliance Microemulsions can improve drug delivery by incorporating hydrophilic drugs within a thermodynamically stable and transparent oil-in-water emulsion. This can optimize the drug's solubility and permeability, leading to enhanced bioavailability and therapeutic efficacy. This review provides an insight to various routes of administration for delivering hydrophilic drugs using microemulsion. It will explore the use of microemulsion for oral, nasal, transdermal, and ocular delivery. The review also discusses the advantages, disadvantages and the physicochemical properties associated with each one of it. Overall, the article aims to provide a comprehensive overview of the use of microemulsions as a drug delivery system for hydrophilic drugs administered via different routes.

Abrocitinib stands as a targeted therapy, functioning as an inhibitor of Janus kinase (JAK) 1. This pharmaceutical advancement has been meticulously crafted to address the challenges of moderate to severe atopic dermatitis (AD), a prevalent skin ailment in developed nations. Introduced in 2022, Abrocitinib emerged as a cutting-edge addition to its therapeutic category, gaining approval for utilization within the United States. Diverging from its predecessors in the realm of moderate to severe AD treatment, Abrocitinib distinguishes itself through its heightened specificity. Moreover, its tablet formulation facilitates straightforward administration, offering diverse dosage options. An additional noteworthy feature is its applicability to individuals aged 12 and above, making it an option for alleviating symptoms in this demographic. Within this comprehensive assessment, key aspects such as the biological target of the drug, developmental strategies, mode of operation, pharmacokinetics, pharmacodynamics, clinical trial insights, contraindications, potential interactions with other medications, and adverse reactions are examined. In light of the overarching perspective and available clinical evidence, Abrocitinib emerges as a promising orally bioavailable therapeutic, authorized for treating AD. Notably, it gained its initial approval in Japan for patients aged 12 years and older, marking a significant advancement in the realm of dermatological care.

The discovery and implementation of antibiotics led to a better prognosis for infectious diseases. Fluoroquinolones are a family of antibiotics with a broad spectrum of action and antibacterial effectiveness. Because bacterial strains have increased their resistance to antibiotics, the World Health Organization has reported an urgent need to develop new active molecules. Our research group has therefore focused on deriving different compounds from fluoroquinolones. A fluoroquinolone derivatized in complex with boron, labeled 7a, was found to have good antibacterial potential. The objective of this research was to evaluate the in vitro and in vivo antimicrobial effect of the derivatized 7a on K. pneumoniae (clinical isolates) strains. The Kirby-Bauer inhibition technique generated average inhibition areas of 8.24 ± 1.239 cm². For the minimum inhibitory concentration and minimum bactericidal concentration, macrodilutions of 7a compound were performed, obtaining 1 μg/mL in both determinations. For the in vivo model, Balb/c mice were infected intratracheally with K. pneumoniae; the animals were treated daily with ciprofloxacin (80 mg/kg/day) or 7a (80 mg/kg/day). The animals were sacrificed on the seventh day post-infection and hematoxylin and eosin staining was done on the lungs to evaluate the percentage of pneumonia. It was found that 7a significantly reduced the generation of pneumonia (5.96% of pneumonic tissue was found) while the untreated infected group generated 71.70% of pneumonic lung tissue. Compound 7a is an antimicrobial agent capable of inhibiting in vitro development of a Gram-negative (K. pneumoniae) bacterial strain. In addition, 7a is effective in treating acute pneumonia induced by K. pneumoniae in a murine model.

In the etiology of nosocomial infections, the leading role belongs to such microorganisms as Staphylococcus aureus. Insufficient effectiveness of antimicrobial chemotherapy and practical absence of drugs with an antibiofilm activity encourage the development of new remedies. The study presents results on antibiofilm activity of the adamantane derivative 1-[4-(1-adamantyl)phenoxy]-3-(N-benzyl,N-dimethylamino)-2-propanol chloride (KVM-97) against methicillin-resistant S. aureus (MRSA) and the effect of this agent on the expression genes that provide regulatory and biosynthetic functions of biofilms. The ability of adamantane derivative to affect S. aureus biofilms was tested by microtiter dish biofilm formation assay. The effect of KVM-97 on expression level of genes icaA, icaD, icaR, agrA, sarA, clfB, fib, fnbB, ebpS, and eno was detected by the real-time PCR. The KVM-97 inhibits the formation of S. aureus biofilms at 5.0 MIC by 95.1 % and at 0.5 MIC – by 22.4 %. Under the action of KVM-97, destruction of the mature biofilms was not detected. It inhibits expression of the icaADBC operon and agrA gene, as well as stimulates a transcriptional activity of the icaR regulator. Subinhibitory concentrations of the KVM-97 significantly inhibit the expression of clfB, fib, fnbB, ebpS, and eno, but does not change the sarA gene expression. Thus, 1-[4-(1-adamantyl)phenoxy]-3-(N-benzyl,N-dimethylamino)-2-propanol chloride shows pronounced antibiofilm activity against MRSA at the early stages of the biofilm forming. This effect may be relating to influence on the expression of genes that regulate adhesion to the substrate and formation of S. aureus biofilms.

Cancer patients have a shorter life expectancy because of metastasis, which is the dynamic chain of events that leads to the spread of tumour cells to distant places inside the body. Cancer's development, spread, metastasis, and treatment all involve fluid mechanics in some way. Cancer cells and their associated components take advantage of the body's many fluid systems as a means of dissemination throughout the body and colonisation of distant organs. Cancerous tissues rely on the blood supply for oxygen and nutrition, metastasis to other organs, and medication delivery. Cancer cells' ability to travel from the main tumour, extravasate, and seed metastases can be enhanced by exploiting the flow mechanics of the blood and lymphatic circulatory systems. Cancer cell survival in the circulation and the regulation of organotropic seeding patterns are affected by flow rates, channel size, and shear stress. Therefore, cancer cells not only use these fluids as a mode of transport throughout the body, but also as a fertile ground to seed distant metastases by taking advantage of the fundamental physical forces among these fluids. Metastasis, tumor growth, & nanoparticle-mediated medication delivery is all under the control of multiscale flow-structure interaction processes, whereas an increase in interstitial pressure is caused by the tumour vasculature's irregularity and leakiness. This Review discusses the role that fluids play in metastasis, including the forces and stresses that are utilised by circulating tumour cells & tumour-associated factors. Given the intriguing concerns raised by the role of physiological fluids and their mechanics in the biology of the metastatic cascade, gaining insight into this process may reveal a novel strategy for intercepting cancer cells on their route.

Only 5% of orphan diseases have approved drugs, leading to a high demand for new treatment. As a result, pharmaceutical companies have shifted their focus of drug development to orphan diseases. This study conducted a database search to analyze the modality and development strategy of orphan drugs approved by the Food and Drug Administration from 2011 to 2022. The analysis showed that the modalities used for orphan drugs have diversified with increasing emergence of nucleic acid drugs, gene therapies, cell therapies, antibody drugs including next-generation antibodies, and engineered proteins, suggesting that modality diversification enhances the drug development for orphan diseases that are otherwise challenging to treat with conventional drugs. The ratio of orphan drugs targeting only a single disease has increased, likely due to the emergence of gene-specific treatments such as nucleic acid drugs and gene therapies. Moreover, this study found that orphan drugs using different modalities have been competitively developed with the same mechanism of action targeting only a single orphan disease in recent years. In several cases, small-molecule drugs with unique characteristics offer advantages such as dosing convenience and non-genetic patient coverage over nucleic acid drugs, antibody drugs, and gene therapy. These trends suggest the importance of modality technology development and advancement of small molecule optimization technology for future orphan drug development.

Atrial fibrillation (AF) is a life-changing and life-threatening cardiac electropathological condition, especially in patients with prior history of cardiovascular diseases. This multifaceted condition is one of the top 5 leading causes of cardiovascular death with a rapidly increasing prevalence and death rate. From inception till now, numerous clinical trials have been conducted to explore novel therapeutic targets and strategies along with pre-existing treatments for patients suffering from atrial fibrillation. The pharmacotherapy approach to treat AF (acute, chronic, persistent, paroxysmal, non-valvular, nonrheumatic, and rapid) comprises mainly antiarrhythmic drugs (AAD) and anticoagulant drugs (ACD) for rate and rhythm control along with the prevention of strokes. This narrative review aims to discuss monotherapeutic clinical trials that compared AADs (class II: carvedilol and xamoterol; class III: amiodarone; class IV: verapamil, diltiazem, and nifedipine) and ACDs (vitamin K antagonist: warfarin; factor Xa inhibitor: apixaban; factor IIa and Xa inhibitor: heparin) with cardiac glycoside (digoxin), angiotensin II receptor antagonist (telmisartan), platelet inhibitor (indobufen), anti-convulsant (magnesium sulfate), anti-inflammatory (aspirin), and antipyretic drugs (aspirin) to treat various types of AF in patients with a diverse history of cardiovascular diseases. This study provides a review of all clinical trials on this topic and provides a comparative chart for healthcare professionals to determine the best-suited treatment for their patients.