Challenges and solutions to manufacturing of low viscosity, ultra-high concentration IgG1 drug products: From late downstream process to final fill finish processing.

Challenges in manufacturing of high concentration antibody formulations have seldom been discussed. These are observed mainly form late downstream operations where antibody gets concentrated to its final strength, to final fill finish processing and containerization of the product. Present paper summarizes challenges typically observed in manufacturing and processing of high concentration antibody products and provides turnkey solutions to these typical challenges in order to have their consistent and robust manufacturing process.

Immunogenicity of SARS-CoV-2 vaccines BBV152 (COVAXIN®) and ChAdOx1 nCoV-19 (COVISHIELD™) in seronegative and seropositive individuals in India: a multicentre, nonrandomised observational study.

Background: There are limited global data on head-to-head comparisons of vaccine platforms assessing both humoral and cellular immune responses, stratified by pre-vaccination serostatus. The COVID-19 vaccination drive for the Indian population in the age group 18-45 years began in April 2021 when seropositivity rates in the general population were rising due to the delta wave of COVID-19 pandemic during April-May 2021.

Methods: Between June 30, 2021, and Jan 28, 2022, we enrolled 691 participants in the age group 18-45 years across four clinical sites in India.

Botswana tuberculosis (TB) stakeholders broadly support scaling up next-generation whole genome sequencing: Ethical and practical considerations for Botswana and global health.

Global health agencies are increasingly promoting the scale-up of next-generation whole genome sequencing (NG-WGS) of pathogens into infectious disease control programs, including for tuberculosis (TB). However, little is known about how stakeholders in low-to-middle income countries (LMICs) understand the ethics, benefits, and risks of these proposals. We conducted a qualitative study in Greater Gaborone, Botswana to learn how TB stakeholders there viewed a potential scale-up of NG-WGS into Botswana's TB program.

Toward Consent in Molecular HIV Surveillance?: Perspectives of Critical Stakeholders.

Background: The emergence of molecular HIV surveillance (MHS) and cluster detection and response (CDR) programs as key features of the United States (US) HIV strategy since 2018 has caused major controversies. HIV surveillance programs that re-use individuals' routinely collected clinical HIV data do not require consent on the basis that the public benefit of these programs outweighs individuals' rights to opt out. However, criticisms of MHS/CDR have questioned whether expanded uses of HIV genetic sequence data for prevention reach beyond traditional public health ethics frameworks.

Transmission across non-HermitianPT-symmetric quantum dots and ladders.

A non-Hermitian (NH) region connected to semi-infinite Hermitian lattices acts either as a source or as a sink and the probability current is not conserved in a scattering typically. Even aPT-symmetric region that contains both a source and a sink does not lead to current conservation plainly. We propose a model and study the scattering across a NHPT-symmetric two-level quantum dot (QD) connected to two semi-infinite one-dimensional lattices in a special way so that the probability current is conserved.

Statistical Optimization for Coproduction of Chitinase and Beta 1, 4-Endoglucanase by Chitinolytic Paenibacillus elgii PB1 Having Antifungal Activity.

A bacterial strain PB1 with antagonistic activity against pathogenic fungi was isolated from marine soil and was identified as Paenibacillus elgii based on phenotypic and genotypic characterization. The isolate showed good antifungal activity against "Aspergillus niger (MTCC 282), Trichophyton rubrum (MTCC 791), Microsporum gypseum (MTCC 2819), Candida albicans (MTCC 227), and Saccharomyces cerevisiae (MTCC 170)". Chitinase and beta 1, 4-endoglucanase are known for their capability to degrade fungal cell wall, thus we analyzed its productivity in PB1 strain using Plackett-Burman and Central Composite Design.

Engineered mitochondrial production of monoterpenes in Saccharomyces cerevisiae.

Monoterpene indole alkaloids (MIAs) from plants encompass a broad class of structurally complex and medicinally valuable natural products. MIAs are biologically derived from the universal precursor strictosidine. Although the strictosidine biosynthetic pathway has been identified and reconstituted, extensive work is required to optimize production of strictosidine and its precursors in yeast.

Application of Combination High-Throughput Phenotypic Screening and Target Identification Methods for the Discovery of Natural Product-Based Combination Drugs.

Modern drug discovery efforts have had mediocre success rates with increasing developmental costs, and this has encouraged pharmaceutical scientists to seek innovative approaches. Recently with the rise of the fields of systems biology and metabolomics, network pharmacology (NP) has begun to emerge as a new paradigm in drug discovery, with a focus on multiple targets and drug combinations for treating disease. Studies on the benefits of drug combinations lay the groundwork for a renewed focus on natural products in drug discovery.

Production of β -cyclodextrin from pH and thermo stable Cyclodextrin Glycosyl Transferase, obtained from Arthrobacter mysorens and its evaluation as a drug carrier for Irbesartan.

Cyclodextrins (CDs) are carrier molecules produced by cyclization of α-1,4-glucans by Cyclodextrin Glycosyl Transferase (CGTase). These torus shaped molecules have hydrophobic cavity and hydrophilic shell making them useful in pharmaceutical, food, textile, pesticide and cosmetic industries. In this study, culture conditions for the production of CGTase by organism belonging to Arthrobacter genus obtained from a paddy field soil were optimized by single parameter mode.

A Fractional Factorial Design to Study the Effect of Process Variables on the Preparation of Hyaluronidase Loaded PLGA Nanoparticles.

The present study was initiated to understand the effect of PLGA concentration, PVA concentration, internal-external phase ratio, homogenization speed, and homogenization time on mean particle size, zeta potential, and percentage drug encapsulation using fractional factorial design. Using PLGA (50-50) as the carrier, hyaluronidase loaded PLGA nanoparticles were prepared using double emulsion solvent evaporation technique. The particle size was analyzed by dynamic light scattering technique and protein content by Lowry method.

A review on response of immune system in spinal cord injury and therapeutic agents useful in treatment.

Every year more than 12,000 people in US alone suffer from spinal cord injury. However, complete recovery of physical function is difficult due to multiple factors involved in disease progression. Currently available therapeutic regimens do not address all the factors concerned with the disease progression.

Discovery of N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): a highly potent, selective, and orally bioavailable inhibitor of TGF-β type I receptor kinase as cancer immunotherapeutic/antifibrotic agent.

A series of 2-substituted-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)imidazoles was synthesized and evaluated to optimize a prototype inhibitor of TGF-β type I receptor kinase (ALK5), 6. Combination of replacement of a quinoxalin-6-yl moiety of 6 with a [1,2,4]triazolo[1,5-a]pyridin-6-yl moiety, insertion of a methyleneamino linker, and a o-F substituent in the phenyl ring markedly increased ALK5 inhibitory activity, kinase selectivity, and oral bioavailability. The 12b (EW-7197) inhibited ALK5 with IC50 value of 0.

Synthesis and biological evaluation of 2-benzylamino-4(5)-(6-methylpyridin-2-yl)-5(4)-([1,2,4]triazolo[1,5-a]-pyridin-6-yl)thiazoles as transforming growth factor-β type 1 receptor kinase inhibitors.

A series of 2-benzylamino-4(5)-(6-methylpyridin-2-yl)-5(4)-([1,2,4]triazolo[1,5-a]pyridin-6-yl)thiazoles 12a-ab, 13a, 13b, and 18a-d has been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. The N-(3-fluorobenzyl)-4-(6-methylpyridin-2-yl)-5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)thiazol-2-amine (12b) inhibited ALK5 phosphorylation with an IC(50) value of 7.01 nM and showed 61% inhibition at 30 nM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct.

Oral coadministration of β-glucuronidase to increase exposure of extensively glucuronidated drugs that undergo enterohepatic recirculation.

Extensive first-pass metabolism can significantly limit a drug's oral exposure levels. In this work, we introduce an innovative approach for increasing the oral bioavailability of a drug that undergoes extensive reversible glucuronidation and enterohepatic recirculation through intraduodenal coadministration of the deconjugating enzyme β-glucuronidase. Intraduodenal administration of JNJ-10198409 (10 mg/kg) with β-glucuronidase (34,000-140,000 units/kg) to catheterized rats resulted in a significant increase (p < 0.

Synthesis and biological evaluation of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors.

A series of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)pyrazoles 14a-e, 15a-e, 17a-c, and 18a-d have been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. The 6-quinolinyl pyrazole analogue 14b inhibited ALK5 phosphorylation with IC(50) value of 0.022 μM and showed 84% inhibition at 0.

Optimization of cultural conditions for protease production by a fungal species.

Studies were carried out on a paddy soil fungal isolate identified to be a strain of Aspergillus niger from Manipal. The parameters that largely impact enzyme production viz., fermentation time, impeller speed, pH, temperature and nutrient supplements were studied.

Synergy of gatifloxacin with cefoperazone and cefoperazone-sulbactam against resistant strains of Pseudomonas aeruginosa.

Chequerboard and time-kill methods were used to compare the in vitro efficacies of the combinations gatifloxacin (GAT) with cefoperazone (CFP) and GAT with cefoperazone-sulbactam (CFP-SUL) against 58 clinical isolates of Pseudomonas aeruginosa. The combinations GAT+CFP and GAT+CFP-SUL were shown to be synergistic for 36.2 and 58.

NH3 gas sensing properties of nanocrystalline ZnO based thick films.

Zinc acetate derived precursor used in the present sol-gel synthesis of zinc oxide nanoparticles is described. The reaction product obtained before and after reflux of propanolic zinc acetate solution have been studied by UV-vis, photoluminescence and FT-IR studies which confirm the formation of oligomeric precursor Zn4O(Ac)6 (Ac=CH3COO). The formation of approximately 7 nm zinc oxide nanoparticles were confirmed by X-ray diffraction (XRD) and Transmission electron microscopic studies (TEM).

Metabolite identification by data-dependent accurate mass spectrometric analysis at resolving power of 60,000 in external calibration mode using an LTQ/Orbitrap.

Performance evaluation of accurate mass measurement by the LTQ/Orbitrap, at a resolving power of 60,000 and in external calibration mode, indicated that the Orbitrap is capable of providing high mass accuracy of <2 ppm for over 24 h post-calibration. This, together with limited trade-off between sensitivity and resolving power plus a wide dynamic range for mass accuracy, suggested that the LTQ/Orbitrap is an ideal analytical tool for structural elucidation of metabolites. The application of the LTQ/Orbitrap to identification of human liver microsomal metabolites of carvedilol was evaluated, using parent mass list triggered data-dependent multiple-stage accurate mass analysis, at a resolving power of 60,000 in external calibration mode.

Development and characterization of an immobilized human organic cation transporter based liquid chromatographic stationary phase.

Membranes from a stably transfected cell line that expresses the human organic cation 1 transporter (hOCT1) have been immobilized on the immobilized artificial membrane (IAM) liquid chromatographic stationary phase to form the hOCT1(+)-IAM stationary phase. Membranes from the parent cell line that does not express the hOCT1 were also immobilized to create the hOCT1(-)-IAM stationary phase. Columns were created using both stationary phases, and frontal displacement chromatography experiments were conducted using [(3)H]-methyl phenyl pyridinium ([(3)H]-MPP(+)) as the marker ligand and MPP(+), verapamil, quinidine, quinine, nicotine, dopamine and vinblastin as the displacers.