How effective are ionization state-based QSPKR models at predicting pharmacokinetic parameters in humans?

Optimizing the pharmacokinetics (PK) of a drug candidate to support oral dosing is a key challenge in drug development. PK parameters are usually estimated from the concentration-time profile following intravenous administration; however, traditional methods are time-consuming and expensive. In recent years, quantitative structure-pharmacokinetic relationship (QSPKR), an in silico tool that aims to develop a mathematical relationship between the structure of a molecule and its PK properties, has emerged as a useful alternative to experimental testing. Due to the complex nature of the various processes involved in dictating the fate of a drug, the development of adequate QSPKR models that can be used in real-world pre-screening situations has proved challenging. Given the crucial role played by a molecule's ionization state in determining its PK properties, this work aims to build predictive QSPKR models for PK parameters in humans using an ionization state-based strategy. We divide a high-quality dataset into clusters based on ionization state at physiological pH and build global and ion subset-based 'local' models for three major PK parameters: plasma clearance (CL), steady-state volume of distribution (VDss), and half-life (t1/2). We use a robust methodology developed in our lab entitled 'EigenValue ANalySis' that accounts for the stereospecificity in drug disposition and use the support vector machine algorithm for model building. Our findings suggest that categorizing compounds in accordance with ionization state does not result in improved QSPKR models. The narrow ranges in the endpoints along with redundancies in the data adversely affect the ion subset-based QSPKR models. We suggest alternative approaches such as elimination route-based models that account for drug-transporter interactions for CL and chemotype-specific QSPKR for VDss.

Early life thymectomy induces arterial dysfunction in mice.

Aging of the arteries is characterized by increased large artery stiffness and impaired endothelium-dependent dilation. We have previously shown that in old (22-24 month) mice T cells accumulate within aorta and mesentery. We have also shown that pharmacologic and genetic deletion of these T cells ameliorates age-related arterial dysfunction. These data indicate that T cells contribute to arterial aging; however, it is unknown if aged T cells alone can induce arterial dysfunction in otherwise young mice. To produce an aged-like T cell phenotype, mice were thymectomized at three-weeks of age or were left with their thymus intact. At 9 months of age, thymectomized mice exhibited greater proportions of both CD4 + and CD8 + memory T cells compared to controls in the blood. Similar changes were observed in the T cells accumulating in the aorta and mesentery. We also observed greater numbers of proinflammatory cytokine producing T cells in the aorta and mesentery. The phenotypic T cell changes in the blood, aorta and mesentery of thymectomized mice were similar to those observed when we compared young (4-6 month) to old thymus intact mice. Along with these alterations, compared to controls, thymectomized mice exhibited augmented large artery stiffness and greater aortic collagen deposition as well as impaired mesenteric artery endothelium dependent dilation due to blunted nitric oxide bioavailability. These results indicate that early life thymectomy results in arterial dysfunction and suggest that an aged-like T cell phenotype alone is sufficient to induce arterial dysfunction in otherwise young mice.

A Smartphone-Based Assessment of Hearing Impairment among Students of a Medical College, Delhi, India- A Cross-Sectional Study.

Introduction: The burden of hearing impairment in India is substantially high, largely preventable, and avoidable. The present study aimed to estimate the prevalence of hearing impairment using a smartphone-based tool among medical students and to study the factors associated, including personal audio device usage in a medical college hospital in Delhi, India. Material and Methods: We conducted a cross-sectional study among undergraduate medical students. The study participants were enrolled via. Stratified random sampling. We assessed hearing impairment via-HearWHO application with scores ranging from a minimum of 0 to a maximum of 100 with categorization into i) above 75 ii) 50-75 iii) below 50. A p-value less than 0.05 was considered statistically significant. Results: A total of 96 study participants were included, with the mean age of study participants as 20.3±1.4 years. On assessment with HearWHO, 36 (37.5%) were in the category of score above 75, 51 (53.1%) in score category 50-75, and 9 (9.4%) in score below 50. The overall mean score of the hearing assessment was 68.9±13.4 (Range: 12 to 94). Among the earphone device users, 27.1% do not comply with volume alerts on user devices. Conclusion: Among the study population, 9.4% of the study participants were likely to be having hearing loss and 53.1% should be screened regularly for hearing impairment. Addressing hearing loss remains crucial among the young population, especially the medical professionals, which is feasible and imperative in the current scenario.

Functionalised-biomatrix for wound healing and cutaneous regeneration: future impactful medical products in clinical translation and precision medicine.

Skin tissue engineering possesses great promise in providing successful wound injury and tissue loss treatments that current methods cannot treat or achieve a satisfactory clinical outcome. A major field direction is exploring bioscaffolds with multifunctional properties to enhance biological performance and expedite complex skin tissue regeneration. Multifunctional bioscaffolds are three-dimensional (3D) constructs manufactured from natural and synthetic biomaterials using cutting-edge tissue fabrication techniques incorporated with cells, growth factors, secretomes, antibacterial compounds, and bioactive molecules. It offers a physical, chemical, and biological environment with a biomimetic framework to direct cells toward higher-order tissue regeneration during wound healing. Multifunctional bioscaffolds are a promising possibility for skin regeneration because of the variety of structures they provide and the capacity to customise the chemistry of their surfaces, which allows for the regulated distribution of bioactive chemicals or cells. Meanwhile, the current gap is through advanced fabrication techniques such as computational designing, electrospinning, and 3D bioprinting to fabricate multifunctional scaffolds with long-term safety. This review stipulates the wound healing processes used by commercially available engineered skin replacements (ESS), highlighting the demand for a multifunctional, and next-generation ESS replacement as the goals and significance study in tissue engineering and regenerative medicine (TERM). This work also scrutinise the use of multifunctional bioscaffolds in wound healing applications, demonstrating successful biological performance in the in vitro and in vivo animal models. Further, we also provided a comprehensive review in requiring new viewpoints and technological innovations for the clinical application of multifunctional bioscaffolds for wound healing that have been found in the literature in the last 5 years.

Thermomechanical Analysis of Isora Nanofibril Incorporated Polyethylene Nanocomposites.

The research on cellulose fiber-reinforced nanocomposites has increased by an unprecedented magnitude over the past few years due to its wide application range and low production cost. However, the incompatibility between cellulose and most thermoplastics has raised significant challenges in composite fabrication. This paper addresses the behavior of plasma-modified polyethylene (PE) reinforced with cellulose nanofibers extracted from isora plants (i.e., isora nanofibrils (INFs)). The crystallization kinetics of PE-INF composites were explained using the Avrami model. The effect of cellulose nanofillers on tuning the physiochemical properties of the nanocomposite was also explored in this work. The increase in mechanical properties was due to the uniform dispersion of fillers in the PE. The investigation on viscoelastic properties confirmed good filler-matrix interactions, facilitating the stress transfer.

Extraction of Nanochitin from Marine Resources and Fabrication of Polymer Nanocomposites: Recent Advances.

Industrial sea food residues, mainly crab and shrimp shells, are considered to be the most promising and abundant source of chitin. In-depth understanding of the biological properties of chitin and scientific advancements in the field of nanotechnology have enabled the development of high-performance chitin nanomaterials. Nanoscale chitin is of great economic value as an efficient functional and reinforcement material for a wide range of applications ranging from water purification to tissue engineering. The use of polymers and nanochitin to produce (bio) nanocomposites offers a good opportunity to prepare bioplastic materials with enhanced functional and structural properties. Most processes for nanochitin isolation rely on the use of chemical, physical or mechanical methods. Chitin-based nanocomposites are fabricated by various methods, involving electrospinning, freeze drying, etc. This review discusses the progress and new developments in the isolation and physico-chemical characterization of chitin; it also highlights the processing of nanochitin in various composite and functional materials.

Novel core-shell dextran hybrid nanosystem for anti-viral drug delivery.

Zidovudine (AZT) is an antiviral drug extensively used for combating the global pandemic- HIV/AIDS. However, its uses are overshadowed by its short half -life, poor aqueous solubility and inability to cross physiological barriers. This study highlights a nanosystem consisting of dextran and stearic acid for AZT delivery. This hybrid nanoparticle was prepared by double emulsion solvent evaporation method. The morphological analysis of the prepared nanoparticles was carried out by transmission electron microscopy (TEM) and structural analysis through FTIR spectroscopy. Haemolysis, blood cell aggregation and cytotoxicity evaluations were also performed. These biological evaluations indicated that the nanoparticles were compatible and fluorescence microscopy studies demonstrated increased cellular internalization of drug loaded hybrid nanoparticles when compared with free drug molecules. The experimental outcomes indicate that the prepared nanoparticles are highly biocompatible haemocompatible and effective in getting internalized into cells of neural origin. These results highlight the feasibility and efficacy of the hybrid nanoparticles for effective delivery of zidovudine.

Potential molecular mimicry between the human endogenous retrovirus W family envelope proteins and myelin proteins in multiple sclerosis.

Multiple sclerosis is an autoimmune disease caused by the destruction of the myelin sheath in the central nervous system. The major target molecules for the immune response are the myelin basic protein, myelin oligodendrocyte glycoprotein and proteolipid protein but the aetiology of the disease is as yet poorly understood. The HLA Class II allele DRB1*1501 in particular as well as DRB5*0101 and the expression of human endogenous retroviral envelope proteins have been linked to multiple sclerosis but the molecular mechanisms relating these remain to be elucidated. We hypothesised that cross-reactive peptide epitopes in retroviral envelope proteins and myelin proteins that can be presented by the two Class II DR molecules may play a role in initiating multiple sclerosis. Sequence homologies between retroviral envelope and myelin proteins and in silico predictions of peptides derived from them that are able to bind to the two Class II alleles were examined to test the hypothesis. The results support the hypothesis that molecular mimicry in peptide epitopes from envelope proteins of the HERV-W family of endogenous retroviruses and myelin proteins is possible and could potentially trigger multiple sclerosis. Mimicry between syncytin-1, a HERV-W envelope protein that is expressed during placentation, and myelin proteins may also explain the higher prevalence of multiple sclerosis in women. Experiments to test the ability of the identified peptide epitopes to activate TH cells are required to confirm the present findings.

Polymer sutures for simultaneous wound healing and drug delivery - A review.

Drug delivery using suitable polymeric devices has gathered momentum in the recent years due to their remarkable properties. The versatility of polymeric materials makes them reliable candidates for site targeted drug release. Among them biodegradable sutures has received considerable attention because they offer great promises in the realm of drug delivery. Sutures have been found to be an effective strategy for the delivery of antibacterial agents or anti-inflammatory drugs to the surgical site. Recent developments yielded sutures with improved mechanical properties, but designing sutures with all the desirable properties is still under investigation. This review is an attempt to analyze the recent developments pertaining to biologically active sutures emphasizing their potential as drug delivery vehicle.

In silico optimization of pharmacokinetic properties and receptor binding affinity simultaneously: a 'parallel progression approach to drug design' applied to ß-blockers.

The present work exploits the potential of in silico approaches for minimizing attrition of leads in the later stages of drug development. We propose a theoretical approach, wherein 'parallel' information is generated to simultaneously optimize the pharmacokinetics (PK) and pharmacodynamics (PD) of lead candidates. ß-blockers, though in use for many years, have suboptimal PKs; hence are an ideal test series for the 'parallel progression approach'. This approach utilizes molecular modeling tools viz. hologram quantitative structure activity relationships, homology modeling, docking, predictive metabolism, and toxicity models. Validated models have been developed for PK parameters such as volume of distribution (log Vd) and clearance (log Cl), which together influence the half-life (t1/2) of a drug. Simultaneously, models for PD in terms of inhibition constant pKi have been developed. Thus, PK and PD properties of ß-blockers were concurrently analyzed and after iterative cycling, modifications were proposed that lead to compounds with optimized PK and PD. We report some of the resultant re-engineered ß-blockers with improved half-lives and pKi values comparable with marketed ß-blockers. These were further analyzed by the docking studies to evaluate their binding poses. Finally, metabolic and toxicological assessment of these molecules was done through in silico methods. The strategy proposed herein has potential universal applicability, and can be used in any drug discovery scenario; provided that the data used is consistent in terms of experimental conditions, endpoints, and methods employed. Thus the 'parallel progression approach' helps to simultaneously fine-tune various properties of the drug and would be an invaluable tool during the drug development process.