Medicine in Drug Discovery最新文献

Purpose

Glaucoma is the leading cause of irreversible visual loss in the world. The present study was designed to evaluate the beneficial effects of crocin, as a supplement, in the management of primary open-angle glaucoma (POAG).

Methods

In total, 50 POAG patients within the age range of 30–71 years with intraocular pressure (IOP) between 12 and 21 mmHg were entered into the study, and ultimately, 40 patients (49 eyes) finished the clinical trial. The participants were randomly divided into crocin and placebo groups. Patients in the crocin group received a 15 mg crocin tablet per day for four months while others, in the placebo group, received a placebo tablet per day for four months besides the main medications during the study. After four months, all patients underwent a two-month washout period. The IOP level and optical coherence tomography of the retinal nerve fiber layer (RNFL), cup-to-disc ratio (CDR), and the best-corrected visual acuity (BCVA), as the secondary outcomes, were measured at baseline, as well as four and six months later.

Results

The IOP value decreased significantly in the crocin group after four (P = 0.0001) and six months (P = 0.003). The difference in CDR changes after four and six months was significant between the two groups (P = 0.00009). The crocin and placebo groups did not have a statistically significant difference regarding the changes in BCVA values and RNFL thickness (P = 0.092); however, the optical coherence tomography results showed stable conditions in the retinal nerve fiber layer.

Conclusion

This study indicated that administration of crocin, as a potent neuroprotective and antioxidant ingredient of saffron, could be useful as a supplement for the prevention of the POAG progression.

Idiopathic pulmonary fibrosis (IPF) is a life-threatening and progressive interstitial lung disease. Healthy pulmonary tissues were replaced by an altered extracellular matrix (ECM) and destroyed the alveolar architecture, which led to the disruption of gas exchange, decreased lung compliance, and ultimately led to the failure of respiration and death. IPF is associated with dyspnoea and cough, eventually impairing the quality of a large population worldwide, with the incidence rate increasing drastically with age. The IPF involves a complex pathophysiology; thus, it is necessary to understand the precise molecular mechanism for lung fibrosis to develop novel therapeutic options. Different kinases, including p38 mitogen-activated protein kinase, JNK (c-Jun N-terminal kinase), and SAPKs (Stress-activated protein kinases), were ubiquitously expressed in numerous variety of cells and were activated in response to inflammatory stimuli, cellular environmental stress, and stimuli for apoptosis. After many failed drugs for IPF in clinical trials, two drugs, namely nintedanib and pirfenidone, were approved, which helped to slow the disease progression. However, the prognosis of IPF remains poor, which leads to continuing the search for better drugs, targeting to either reduce or halt the disease progression. The current review summarises the pathophysiology, signaling, and role of different kinases, therapeutic interventions, investigational therapies, and biomarkers for IPF. A better understanding of the pathophysiology of IPF will be helpful to understand disease mechanisms, discovering potential biomarkers, and development of effective therapeutics to handle patients.

Hypertension is a common disease in clinical practice. Calcium channel blocker (CCB) is an effective antihypertensive agent. There is inconsistent data of an association of CCB and breast cancer in literatures particularly in breast cancer cytology. This study aimed to evaluate this association by a case-control design. The inclusion criteria were adult patients with an age of 18 years or over, diagnosed as hypertension, with a result of mammogram. Those who were pregnant, had no pathological results, or had breast mass prior to diagnosis of hypertension were excluded. Cases defined if the pathological report of any types of breast cancer, while controls were those with benign breast mass. Factors associated with breast cancer were calculated by logistic regression analysis. There were 299 patients met the study criteria. Of those, 100 patients (33.4 %) were in the case group or breast cancer group. There were three factors independently associated with breast cancer. CCB treatment had adjusted odds ratio of 2.25 (95 % confidence interval of 1.36, 3.77), while age of 50 years old or over and hormonal therapy also independently associated with breast cancer with adjusted odds ratios of 3.41 and 2.91, respectively. The CCB group had significantly higher proportion of ductal breast cancer than those who did not take CCB (42.5 % vs 23.8 %, p < 0.001). CCB treatment may be associated with breast cancer especially ductal carcinoma in this study population.

The transcriptome of a cell governs the overall cellular expression of proteins, hence, targeting mRNA holds promise as a therapeutic strategy in the field of drug discovery. RNA therapeutics especially, antisense oligonucleotide (ASO) technology, have gained tremendous pace in the last few decades with many of the ASOs being evaluated in various clinical phases and several ASO-based drugs are currently marketed after FDA approval. Several chemical modifications in the nucleic acid backbone of ASOs have led to improved properties of ASOs, such as oligonucleotide stability, enhanced affinity, and better pharmacokinetics contributing to their therapeutic success. ASOs interfere with the translation process either by RNase H-mediated mRNA cleavage or by posing steric hindrance in the translation machinery. Further, the cellular delivery of ASOs has always remained questionable, however, with the advancements in the delivery approaches, it is now feasible to achieve better target specific cellular delivery. In this review, we provide comprehensive insights into antisense oligonucleotide therapeutics, their various modifications, the mechanisms involved, different strategies for their delivery, and the utility of ASOs against several bacterial diseases.

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.