In view of the role of sEH (soluble epoxide hydrolase) in hypertension, we have developed a rigorously validated pharmacophore model containing one HBA (Hydrogen Bond Acceptor), two HY (Hydrophobic) and one RA (Ring Aromatic) features. The model was used as a query to search the NCI (National Cancer Institute) and Maybridge database leading to retrieval of many compounds which were sorted on the basis of predicted activity, fit value and Lipinski’s violation. The selected compounds were docked into the active site of enzyme soluble epoxide hydrolase. Potential interactions were observed between the features of the identified hits and the amino acids present in the docking site. The three selected compounds were subjected to in vitro evaluation using enzyme- based assay and the isolated rat aortic model followed by cytotoxicity studies. The results demonstrate that the identified compounds are potent, safe and novel soluble epoxide hydrolase inhibitors.

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In recent years, the drug repositioning strategy has gained considerable attention in the drug discovery process that involves establishing new therapeutic uses of already known drugs. In line with this, we have identified digoxin a cardiac glycoside, as a potent inhibitor of soluble epoxide hydrolase (sEH) enzyme employing in silico high throughput screening protocols and further confirmed using in vitro cell‐free sEH inhibitory assay and in vivo preclinical studies in rodents for its repurposing in hyperalgesia, inflammation, and related disorders. Oral administration of digoxin at dose 0.2 mg/kg significantly reduced (p < .0001) the allodynia in mice induced by using hot plate (3.6 ± 1.9) and tail‐flick test (7.58 ± 0.9). In addition, digoxin at a dose of 0.2 mg/kg showed marked reduction (94%, p < .0001) in acetic acid‐induced abdominal contraction in rats. Further, digoxin also demonstrated antipyretic activity (37.04 ± 0.2, p < .0001) and showed notable reduction (0.60 ± 0.06) in carrageenan‐induced paw edema in rats. Also, the histopathological evaluation revealed that digoxin treatment attenuated the edema, neutrophil infiltration, and alveolar septal thickening in lung tissue. These findings are novel and highlight the newer insights towards repurposing digoxin as a new lead in the treatment of hyperalgesia, inflammation, and related disorders.

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Liposomes nowadays have become preferential drug delivery system, since it provides facilitating properties to drugs such as improved therapeutic index of encapsulated drug, target and controlled drug delivery, and less toxicity. However, conventional liposomes have shown some disadvantages such as less drug loading capacity, poor retention, clearance by kidney or reticuloendothelial system, and less release of hydrophilic drugs. Thus, to overcome these disadvantages recently, scientists have explored new approaches and methods viz. ligand conjugation, polymer coating, and liposomes-hybrid including surface-modified liposomes, biopolymer-incorporated liposomes, guest-in-cyclodextrin-in-liposome, liposome-in-hydrogel, liposome-in-film, and liposome-in-nanofiber, etc. These approaches have been shown to improve the physiochemical and pharmacokinetic properties of encapsulated drugs. Lately, Pharmacokinetic-pharmacodynamic (PK–PD) computational modeling has emerged as a beneficial tool for analyzing the impact of formulation- and system-specific factors on the target disposition and therapeutic efficacy of liposomal drugs. There has been an increasing number of liposome-based therapeutic drugs, both FDA approved and undergoing clinical trials having application in anticancer, Alzheimer's, diabetes, and glaucoma. To meet the continuous demand of health sectors and to produce the desired product, it is important to perform pharmacokinetic studies. This review focuses on the physical, physicochemical, and chemical factors of drugs that influence the target delivery of drugs. It also explains various physiological barriers such as systemic clearance, and extravasation. A novel approach, liposomal-hybrid complex: an innovative approach as a vesicular drug delivery system to overcome limited membrane permeability and bioavailability has been discussed in the review. Moreover, this review highlights the pharmacokinetic considerations and challenges of poorly absorbed drugs along with the applications of a liposomal delivery system in improving PKPD in various diseases such as cancer, Alzheimer's, diabetes, and glaucoma.

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BackgroundTylophora indica (Burm. f.) Merr is a climbing perennial plant reported in Indian traditional system of medicine for its use in allergy and asthma. However, only few scientific studies have been performed in the past to validate its antiasthmatic potential.ObjectivesThe present study deals with investigation of airway smooth muscle relaxant and antiasthmatic potential of extract and subsequent fractions prepared from T. indica.MethodsThe most active fraction of T. indica leaves selected through bio‐guided activity was subjected to liquid chromatography‐mass spectrometry (LC–MS) analysis for chemical profiling. The binding affinity of identified compounds in fraction towards M3 and H1 receptors was determined by molecular docking study. F‐2 (chloroform fraction prepared from methanolic extract of T. indica leaves) was examined for its smooth muscle relaxant properties using isolated trachea of guinea‐pig. Further, F‐2 was evaluated through in vivo studies employing ovalbumin‐induced asthma model in guinea‐pigs.ResultsF‐2 was found most effective in bioassay‐guided fractionation. Characterization by LC–MS analysis revealed presence of five major bioactive compounds in F‐2 that showed good docking interactions with M3 and H1 receptors. The ex vivo study demonstrated that F‐2 could significantly relax tracheal rings via targeting multiple signalling pathways videlicet, namely, noncompetitive antagonism of the histamine and muscarinic receptors, β2‐adrenergic stimulation and activation of soluble guanylyl cyclase. In in vivo studies, F‐2 ameliorated airway hyperresponsiveness and decreased broncho alveolar lavage fluid (BALF) levels of inflammatory cytokines and immunoglobulin E (IgE).ConclusionThese results confirm the traditional use of T. indica as an antiasthmatic agent which are evidenced through ex vivo, in silico and in vivo studies.