Elucidation of the Role of TRPV1, VEGF-A, TXA2, Redox Homeostasis, and Inflammatory Cascades in Protection against Cold Injuries by Herbosomal-Loaded PEG-Poloxamer Topical Formulation.

High-altitude regions, cold deserts, permafrost regions, and the polar region have some of the severest cold conditions on earth and pose immense perils of cold injuries to exposed individuals. Accidental and unintended exposures to severe cold, either unintentionally or due to occupational risks, can greatly increase the risk of serious conditions including hypothermia, trench foot, and cold injuries like frostbite. Cold-induced vasoconstriction and intracellular/intravascular ice crystal formation lead to hypoxic conditions at the cellular level. The condition is exacerbated in individuals having inadequate and proper covering and layering, particularly when large area of the body are exposed to extremely cold environments. There is a paucity of preventive and therapeutic pharmacological modalities that have been explored for managing and treating cold injuries. Given this, an efficient modality that can potentiate the healing of frostbite was investigated by studying various complex pathophysiological changes that occur during severe cold injuries. In the current research, we report the effectiveness and healing properties of a standardized formulation, i.e., a herbosomal-loaded PEG-poloxamer topical formulation (n-HPTF), on frostbite. The intricate mechanistic pathways modulated by the novel formulation have been elucidated by studying the pathophysiological sequelae that occur following severe cold exposures leading to frostbite. The results indicate that n-HPTF ameliorates the outcome of frostbite, as it activates positive sensory nerves widely distributed in the epidermis transient receptor potential vanilloid 1 (TRPV1), significantly (p < 0.05) upregulates cytokeratin-14, promotes angiogenesis (VEGF-A), prominently represses the expression of thromboxane formation (TXA2), and significantly (p < 0.05) restores levels of enzymatic (glutathione reductase, superoxide dismutase, and catalase) and nonenzymatic antioxidants (glutathione). Additionally, n-HPTF attenuates oxidative stress and the expression of inflammatory proteins PGF-2α, NFκB-p65, TNF-α, IL-6, IL-1ß, malondialdehyde (MDA), advanced oxidative protein products (AOPP), and protein carbonylation (PCO). Masson's Trichrome staining showed that n-HPTF stimulates cellular proliferation, and increases collagen fiber deposition, which significantly (p < 0.05) promotes the healing of frostbitten tissue, as compared to control. We conclude that protection against severe cold injuries by n-HPTF is mediated via modulation of pathways involving TRPV1, VEGF-A, TXA2, redox homeostasis, and inflammatory cascades. The study is likely to have widespread implications for the prophylaxis and management of moderate-to-severe frostbite conditions.

Novel formulation development from Ophiocordyceps sinensis (Berk.) for management of high-altitude maladies.

Ophiocordyceps sinensis (Berk.) is a fungus closely related to medicinal mushroom, which belongs to the family Ophiocordycipitaceae. It is a well-known and rich herbal source of bioactive active constituents. The medicinal mushroom has garnered worldwide attention owing to its multifarious bioactivities. This mushroom grows on the larva of ghost moths (Hepialidae) and produces fruiting bodies, which serve as a vital natural source of medicine and supplementary diets. On account of the diverse pharmacological and bioactive constituents present in O. sinensis, it has been established as a potential antioxidant, anticancer, antibacterial, anti-proliferative, anti-inflammatory agent that has been successfully used for treating several health issues, including hypoxia-related problems encountered by mountaineers, pilgrims, tourists and soldiers occurring at high-altitude regions such as acute mountain sickness (AMS), high-altitude pulmonary edema (HAPE), high-altitude cerebral edema (HACE), frostbite, chilblains, hypothermia, etc. The most important pharmacologically active compounds present in the O. sinensis include nucleobases and its derivatives (adenosine, cordycepin, 3-deoxyadenosine, AMP, GMP, UMP, guanosine, uridine), polysaccharides (mannose, glucose, galactose, rhamnose, arabinose, xylose, galactose), proteins, peptides and steroids. This article focuses on the various research endeavors undertaken to scientifically establish the medicinal properties of O. sinensis, highlighting the various principally active compounds, their pharmacological action, drug designing and development and future perspective for various health benefits.

A Critique of Computer Simulation Software's Used in Pharmacokinetics and Pharmacodynamics Analysis.

BACKGROUND: In the pharmaceutical sectors, the computer plays a crucial role as a commander of all the theoretical aspects and provides a workbench to improve the overall quality of pharmaceutical research and development. The aim of this article is to provide a computational approach to the development of numerous technology of computer software in the field of clinical pharmacokinetics. The computational technique practised by clinical pharmacist and scientist with the applied knowledge and skills in dealing with clinical pharmacokinetics problems can be applied in routine clinical practices. METHODS: To solve the various complicated pharmacokinetic equations and modeling of pharmacokinetic processes, various software were used like Population pharmacokinetics, Individual pharmacokinetics, Absorption, Distribution, Metabolism, and Excretion (ADME) pharmacokinetics, in - silico pharmacokinetics like Window-Based Non-linear model fitting (WinNonlin), Statistical Analysis Software (SAS), Non-linear Mixed Effects Modelling (NONMEM), PK Solution etc. Results: Various software's which was described in this paper help in the development of experimental study designs, statistical treatment of data and various simulation studies, etc. A robust software solution should be easy to use and address the three main parts of the PK-PD workflow like data management, analysis, and reporting. PK-PD software's allow researchers to predict ADME properties of new drug entity. For the study of the pharmacokinetic, the best software is WINBUGS where there is no limitation of dimensional array and size of the problem. The best software to be used for individual pharmacokinetics is T.D.M.S in which, we can apply Bayesian and least square method for curve fitting and it can be used for both linear and non-linear pharmacokinetic data. CONCLUSION: Various software were discussed here. This software not only help in knowing the history of the software but also help in gaining more knowledge about pharmacokinetics and pharmacodynamics simulation. Different software such as population pharmacokinetic, individual pharmacokinetic and others discussed in this article will help in the reporting and analyzing of data. The important points to be considered while selecting the software is also discussed which will help in easy accessing of software.

Hybrid nanoparticles for the topical delivery of norfloxacin for the effective treatment of bacterial infection produced after burn.

The present study was designed to investigate the solubility and penetrability of norfloxacin after the topical application of developed lipid-polymer hybrid nanoparticle (LPN) formulation. The core shell of the LPNs formulation was composed of poly (lactic-co-glycolic acid) that is highly lipophilic in nature, thus control the release of drug. The developed formulations were characterised for size, shape (transmission electron microscopy [TEM], scanning electron microscopy [SEM], and atomic force microscopy), entrapment efficiency, Fourier transform infra-red (FTIR) spectroscopy, differential scanning calorimetry (DSC) and thermo gravimetric analysis (TGA). Moreover, in vitro skin permeation studies were performed to determine release profile of the drug. Norfloxacin loaded nanoparticles retained there antimicrobial efficacy against Staphylococcus aureus and Pseudomonas aeruginosa. Stability study was suggested that the suitable storage condition should be at 4 ± 2 °C/60 ± 5% RH for the LPNs. Therefore, these nanoparticles showed a safe and effective long-lasting approach for long treatment of bacterial infections due to burn.

Lipid-polymer hybrid nanoparticles: Development & statistical optimization of norfloxacin for topical drug delivery system.

Poly lactic acid is a biodegradable, biocompatible, and non-toxic polymer, widely used in many pharmaceutical preparations such as controlled release formulations, parenteral preparations, surgical treatment applications, and tissue engineering. In this study, we prepared lipid-polymer hybrid nanoparticles for topical and site targeting delivery of Norfloxacin by emulsification solvent evaporation method (ESE). The design of experiment (DOE) was done by using software to optimize the result, and then a surface plot was generated to compare with the practical results. The surface morphology, particle size, zeta potential and composition of the lipid-polymer hybrid nanoparticles were characterized by SEM, TEM, AFM, and FTIR. The thermal behavior of the lipid-polymer hybrid nanoparticles was characterized by DSC and TGA. The prepared lipid-polymer hybrid nanoparticles of Norfloxacin exhibited an average particle size from 178.6 ± 3.7 nm to 220.8 ± 2.3 nm, and showed very narrow distribution with polydispersity index ranging from 0.206 ± 0.36 to 0.383 ± 0.66. The surface charge on the lipid-polymer hybrid nanoparticles were confirmed by zeta potential, showed the value from +23.4 ± 1.5 mV to +41.5 ± 3.4 mV. An Antimicrobial study was done against Staphylococcus aureus and Pseudomonas aeruginosa, and the lipid-polymer hybrid nanoparticles showed potential activity against these two. Lipid-polymer hybrid nanoparticles of Norfloxacin showed the %cumulative drug release of 89.72% in 24 h. A stability study of the optimized formulation showed the suitable condition for the storage of lipid-polymer hybrid nanoparticles was at 4 ± 2 °C/60 ± 5% RH. These results illustrated high potential of lipid-polymer hybrid nanoparticles Norfloxacin for usage as a topical antibiotic drug carriers.