DESIGNING AND QUALITY ASPECTS OF ASEPTIC PROCESS SIMULATION

Aseptic process simulation is a crucial validation technique carried out before a new product or aseptic process is introduced in the facility and also to prove on regular intervals that the existing manufacturing operations are carried out in a state of aseptic conditions. Aseptic process simulation involves conducting aseptic production using a sterile growth medium instead of actual drug solution and excipients. The processes involved in aseptic validation include the identification of process mechanisms, variables and control methods and that also include product, component, and sterilization of equipment, sanitary facilities, environmental checks and staff training on gowning procedure. This review addresses the nature of the study involved in aseptic process simulation, speed and number of runs, runtime, the atmospheric conditions, line speed, the media used, incubating and analyzing media-filled units, data interpretation, worst-case parameters, interventions, case study on interventions and the regulatory aspects concerned with the simulation

Structure-based discovery of glycomimetic FmlH ligands as inhibitors of bacterial adhesion during urinary tract infection

Significance The emergence of multidrug-resistant bacteria, including uropathogenic Escherichia coli (UPEC), makes the development of targeted antivirulence therapeutics a critical focus of research. During urinary tract infections (UTIs), UPEC uses chaperone–usher pathway pili tipped with an array of adhesins that recognize distinct receptors with sterochemical specificity to facilitate persistence in various tissues and habitats. We used an interdisciplinary approach driven by structural biology and synthetic glycoside chemistry to design and optimize glycomimetic inhibitors of the UPEC adhesin FmlH. These inhibitors competitively blocked FmlH in vitro, in in vivo mouse UTI models, and in ex vivo healthy human kidney tissue. This work demonstrates the utility of structure-driven drug design in the effort to develop antivirulence therapeutic compounds. </jats:p

Perioperative fluid and volume management: physiological basis, tools and strategies

Fluid and volume therapy is an important cornerstone of treating critically ill patients in the intensive care unit and in the operating room. New findings concerning the vascular barrier, its physiological functions, and its role regarding vascular leakage have lead to a new view of fluid and volume administration. Avoiding hypervolemia, as well as hypovolemia, plays a pivotal role when treating patients both perioperatively and in the intensive care unit. The various studies comparing restrictive vs. liberal fluid and volume management are not directly comparable, do not differ (in most instances) between colloid and crystalloid administration, and mostly do not refer to the vascular barrier's physiologic basis. In addition, very few studies have analyzed the use of advanced hemodynamic monitoring for volume management

Synthesis and antimicrobial activity of indole isoxazolines and isoxazole derivatives

964-9702-Cinnamoyl-3-phenylindoles (chalcones) 3a-t are efficiently converted into 2-(5-aryl-4,5-dihydro-3-isoxazolyl)-3-phenylindoles 4a-t and 2-(5-aryl-3- isoxazolyl)-3-phenylindoles 6a-t. The structures of these compounds have been established on the basis or their elemental analyses and spectral (IR, 1H NMR) data. These compounds have also been tested for their antimicrobial activity

Synthesis and antimicrobial activity of 2-(4-formyl-3-pyrazolyl)-3-phenylindoles

2410-2415Vilsmeier-Haack reagent (POCl3-DMF) on reaction with hydrazones 3a-i derived from 2-acetyl-3-phenylindoles 2a-c furnishes 2-(4-formyl-3-pyrazolyl)-3-phenylindoles 4a-i. The structures of these compounds have been established on the basis of their elemental analyses and spectral (IR, 1H NMR) data. All the pyrazole derivatives 4a-i and their azines 5a-i have been tested for their antimicrobial and antifungal activities

Superparamagnetic Au-Fe₃O₄ Nanoparticles: One-Pot Synthesis, Biofunctionalization and Toxicity Evaluation

Superparamagnetic Au-Fe3O4 bifunctional nanoparticles have been synthesized using a single step hot-injection precipitation method. The synthesis involved using Fe(CO)5 as iron precursor and HAuCl4 as gold precursor in the presence of oleylamine and oleic acid. Oleylamine helps in reducing Au3+ to Au0 seeds which simultaneously oxidizes Fe(0) to form Au-Fe3O4 bifunctional nanoparticles. Triton® X-100 was employed as a highly viscous solvent to prevent agglomeration of Fe3O4 nanoparticles. Detailed characterization of these nanoparticles was performed by using x-ray powder diffraction, transmission electron microscopy, scanning tunneling electron microscopy, UV-visible spectroscopy, Mössbauer and magnetometry studies. To evaluate these nanoparticles\u27 applicability in biomedical applications, L-cysteine was attached to the Au-Fe3O4 nanoparticles and cytotoxicity of Au-Fe3O4 nanoparticles was tested using CHO cells by employing MTS assay. L-cysteine modified Au-Fe3O4 nanoparticles were qualitatively characterized using Fourier transform infrared spectroscopy and Raman spectroscopy; and quantitatively using acid ninhydrin assay. Investigations reveal that that this approach yields Au-Fe3O4 bifunctional nanoparticles with an average particle size of 80 nm. Mössbauer studies indicated the presence of Fe in Fe3+ in A and B sites (tetrahedral and octahedral, respectively) and Fe2+ in B sites (octahedral). Magnetic measurements also indicated that these nanoparticles were superparamagnetic in nature due to Fe3O4 region. The saturation magnetization for the bifunctional nanoparticles was observed to be ~74 emu g-1, which is significantly higher than the previously reported Fe3O4 nanoparticles. Mössbauer studies indicated that there was no significant Fe(0) impurity that could be responsible for the superparamagnetic nature of these nanoparticles. None of the investigations showed any presence of other impurities such as Fe2O3 and FeOOH. These Au- Fe3O4 bifunctional nanoparticles showed no significant cytotoxicity to the CHO cells up to 48 h even at concentrations of 1mg ml-1 making them suitable for biomedical applications such as local heat generators (hyperthermia) for cancer treatment and drug delivery vehicles

Inhibition of Calcium Dependent Protein Kinase 1 (CDPK1) by Pyrazolopyrimidine Analogs Decreases Establishment and Reoccurrence of Central Nervous System Disease by Toxoplasma gondii

Calcium dependent protein kinase 1 (CDPK1) is an essential enzyme in the opportunistic pathogen Toxoplasma gondii. CDPK1 controls multiple processes that are critical to the intracellular replicative cycle of T. gondii including secretion of adhesins, motility, invasion, and egress. Remarkably, CDPK1 contains a small glycine gatekeeper residue in the ATP binding pocket making it sensitive to ATP-competitive inhibitors with bulky substituents that complement this expanded binding pocket. Here we explored structure-activity relationships of a series of pyrazolopyrimidine inhibitors of CDPK1 with the goal of increasing selectivity over host enzymes, improving antiparasite potency, and improving metabolic stability. The resulting lead compound 24 exhibited excellent enzyme inhibition and selectivity for CDPK1 and potently inhibited parasite growth in vitro. Compound 24 was also effective at treating acute toxoplasmosis in the mouse, reducing dissemination to the central nervous system, and decreasing reactivation of chronic infection in severely immunocompromised mice. These findings provide proof of concept for the development of small molecule inhibitors of CDPK1 for treatment of CNS toxoplasmosis