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A novel library of 1,3,4-thiadazoloaryl based pyrimidine-thiazole derivatives (10a-j) was synthesized and their chemical structures were confirmed by 1HNMR, 13CNMR, and mass spectral data. in silico ADME studies have demonstrated that all these compounds have a good pharmacokinetic profile. Further, these compounds were evaluated for their anticancer activity against a panel of human cancer cell lines such as prostate (PC3 and DU-145), lung (A549), and breast (MCF-7). The outcome results were compared with the standard reference as etoposide. Most of the tested compounds demonstrated remarkable anticancer activities, with IC50 values ranging from 0.01 ± 0.0017 µM to 23.6 ± 8.43 µM, where standard showed IC50 values from 1.97 ± 0.45 µM to 3.08 ± 0.135 µM, respectively. Particularly, these compounds 10a, 10b, 10c, 10d, 10e, and 10j displayed more prominent anticancer activities as etoposide. Molecular docking studies of the synthesized compounds were carried out against SARM (PDB ID: 3V49) and Abl-Tyrosine kinase (PDB ID: 1IEP), in which 10b and 10 h showed comparable dock scores of −7.3 and −7.5 against SARM (PDB ID: 3V49) and 10b and 10c −8.5 and −7.7 against Abl-Tyrosine kinase (PDB ID: 1IEP).

Nanotechnology has become the most effective and rapidly developing field in the area of material science, and silver nanoparticles (AgNPs) are of leading interest because of their smaller size, larger surface area, and multiple applications. The use of plant sources as reducing agents in the fabrication of silver nanoparticles is most attractive due to the cheaper and less time-consuming process for synthesis. Furthermore, the tremendous attention of AgNPs in scientific fields is due to their multiple biomedical applications such as antibacterial, anticancer, and anti-inflammatory activities, and they could be used for clean environment applications. In this review, we briefly describe the types of nanoparticle syntheses and various applications of AgNPs, including antibacterial, anticancer, and larvicidal applications and photocatalytic dye degradation. It will be helpful to the extent of a better understanding of the studies of biological synthesis of AgNPs and their multiple uses.

Objective: In this study, the isolation and identification of Exopolysaccharide (EPS) producing bacteria from polluted soil samples and its in vitro antioxidant activities were investigated. Methods: Isolation and identification of bacteria was investigating using 16 s rDNA genome sequencing method. Further, optimization (pH, time, and temperature), purification and characterization of EPS were performed using different (UV, FT-IR, C13-NMR and H1-NMR) methods. In addition, 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and hydrogen peroxide (H2O2) scavenging activities of EPS were performed. Results: The molecular characterization of isolated strain was confirmed as Bacillus aerophilus by 16S rDNA sequencing. The sequence was submitted to NCBI (Genbank accession number MH553072). Characterization of EPS by UV, FT-IR, C13-NMR and H1-NMR revealed the presence of hydroxyl, carbonyl, and carboxyl functional groups. SEM analysis of EPS showed a solid surface with an irregular shape. The optimum conditions for EPS production were pH 7.0, cultivation time 72 h (3.73 ± 0.211 g/L) and temperature 30 °C respectively. The yeast and sucrose extract showed higher EPS production. In addition, in vitro DPPH, H2O2 studies showed 56.6 and 67.5% of scavenging activity at 4 mg/mL of concentration. Conclusions: From this study, the novel EPS producing Bacillus aerophilus rk1 was identified. Further, the purified EPS showed good antioxidant activity.

Linezolid is a commonly prescribed antibiotic in clinical practice. Although thrombocytopenia and peripheral neuropathy are frequently encountered following prolonged administration of linezolid, lactic acidosis is a rare adverse drug reaction. We present the case of a patient on linezolid for disseminated multidrug-resistant tuberculosis who presented with vomiting, dyspnoea, hypotension and high anion gap metabolic acidosis. The initial presentation mimicked sepsis syndrome. Ketoacidosis and renal dysfunction were ruled out. There was no history of ingestion of toxins/toxic alcohols. Sepsis was unlikely because extensive radiological and microbiological testing could not identify an infection. Given the possibility of linezolid-induced lactic acidosis (LILA), linezolid was discontinued on admission. The patient's lactic acidosis resolved, and his overall condition improved. A retrospective diagnosis of LILA was thus established. LILA should be considered when patients on linezolid present with lactic acidosis and other causes for the lactic acidosis have been ruled out., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The aim of this study was to demonstrate the purpose of adding antiviral (remdesivir) to the existing steroidal (dexamethasone) therapy in treating coronavirus disease 2019 (COVID-19)., Methodology: A retrospective observational case cohort study was carried out to compare the effect of dexamethasone alone and in combination with remdesivir in treating moderate and severe COVID-19 disease. The patients were divided into 2 groups: Group 1 included patients treated with dexamethasone alone, and Group 2 included patients treated with dexamethasone and remdesivir. Levels of inflammatory markers (C-reactive protein, D- dimer and lactate dehydrogenase), World Health Organization (WHO) ordinal scale scoring, symptomatic improvement in terms of fever, cough, shortness of breath, 6-minutes' walk test and SpO2 levels on day of admission (D0), 3 days and 5 days after admission (D3 and D5), and 10 days overall outcome (determined as death, or discharge with or without Long Term Oxygenation Therapy) were collected and analyzed., Results: Addition of remdesivir to dexamethasone in treating COVID 19 did not have any additional benefits. No additional role of remdesivir is seen in combating the disease except in case of 10 days outcome. However, the better 10-day outcome associated with the use of remdesivir was thought to be due to the patients who were on mechanical ventilation in the dexamethasone treated group at the time of inclusion., Conclusions: Since a similar trend was seen in both groups, our study concluded no additional role of remdesivir in combating COVID-19., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2023 Nithish Sattoju, Santosh Gattu, Sai Sashank Merugu, Vydhika Anneboina, Sai Ram Ganapaka.)

Staphylococcus aureus causes clinical diseases ranging from mild skin infections to devastating conditions such as septic shock, endocarditis and osteomyelitis. S. aureus is a common cause of community-acquired bacteraemia. Prolonged bacteraemia may cause metastatic infection, manifesting as endocarditis, osteomyelitis and abscesses. A man in his 20s presented with a short-duration of fever and odynophagia. CT of the neck suggested a retropharyngeal abscess. Retropharyngeal abscesses are typically polymicrobial and caused by resident oral cavity flora. In the hospital, he developed shortness of breath and hypoxia. CT of the chest showed peripheral, subpleural nodular opacities raising suspicion for septic pulmonary emboli. Blood cultures demonstrated the growth of methicillin-resistant S. aureus The patient completely recovered with antibiotic therapy alone. This is a unique and rare presentation case of metastatic S. aureus bacteraemia, manifesting as a retropharyngeal abscess without any evidence of infective endocarditis on transoesophageal echocardiography., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

In this study Bacillus amyloliquefaciens RK3 was isolated from a sugar mill effluent-contaminated soil and utilised to generate a potential polysaccharide with anti-Alzheimer's activity. Traditional and molecular methods were used to validate the strain. The polysaccharide produced by B. amyloliquefaciens RK3 was purified, and the yield was estimated to be 10.35 gL -1 . Following purification, the polysaccharide was structurally and chemically analysed. The structural analysis revealed the polysaccharide consists of α-d-mannopyranose (α-d-Man p ) and β-d-galactopyranose (β-d-Gal p ) monosaccharide units connected through glycosidic linkages (i.e., β-d-Galp(1→6)β-d-Galp (1→6)β-d-Galp(1→2)β-d-Galp(1→2)[β-d-Galp(1→6)]β-d-Galp(1→2)α-d-Manp(1→6)α-d-Manp (1→6)α-d-Manp(1→6)α-d-Manp(1→6)α-d-Manp). The scanning electron microscopy and energy-dispersive X-ray spectroscopy imaging of polysaccharides emphasise their compactness and branching in the usual tubular heteropolysaccharide structure. The purified exopolysaccharide significantly impacted the plaques formed by the amyloid proteins during Alzheimer's disease. Further, the results also highlighted the potential applicability of exopolysaccharide in various industrial and pharmaceutical applications.

Background: Pharmaceutical physicians support drug development in various capacities and contribute tremendously to the healthcare system. However, there is lack of substantial information on career progression of pharmaceutical physicians in India., Materials and Methods: This cross-sectional survey involved distribution of a questionnaire via internet, to be self-administered and returned electronically from March 1, 2018, to May 31, 2018 (3 months). Respondents were pharmaceutical physicians from India., Results: Of the 410 surveyed across 32 specialties, 197 completed responses (48%) were analyzed. Top physician specialty noted was Pharmacology . Medical Advisors constituted bulk responders. Oncology and Medical Affairs were the preferred therapeutic segment and portfolio, respectively. Medical affairs also recorded the highest physician recruitment and retention figures. Majority cited a need for Pharmaceutical Medicine as a specialty curriculum in India. 'MBA' was perceived to be nonenabling for entry-level hires; sensitization through 'industry apprenticeship' was highly recommended in this regard. Better work-life balance and aversion to clinical work were top reasons for physician influx in the industry. Important challenges at workplace included diversified work and difficult colleagues . Work-related issues were a common basis for most job attritions. Annual compensation figures ranged from INR 10-20 Lakhs (at entry-level) to INR 30-40 Lakhs (at senior-manager level); however, salary dissatisfaction was prevalent (58%). Lack of information and aversion to corporate work culture were top reasons for physician hesitancy when considering career options in the pharmaceutical industry., Conclusion: A career in pharmaceutical medicine has tremendous scope for young medical graduates. One should thoroughly explore such career option and inculcate a learner-centric approach., Competing Interests: None declared., (Copyright: © 2020 Perspectives in Clinical Research.)

Aims: Recombinant PEGylated human granulocyte colony-stimulating factor (pegfilgrastim) is indicated for the reduction of chemotherapy-induced neutropenia and prevention of febrile neutropenia. Biosimilar pegfilgrastim is expected to reduce the financial burden of this complication of chemotherapy. The aim of this study was to demonstrate biosimilarity between Sandoz biosimilar pegfilgrastim and its US- and EU-approved reference biologics., Methods: Phase I, randomized, double-blind, single-dose, 3-period, 6-sequence cross-over, multicentre study to evaluate the pharmacokinetics, pharmacodynamics, safety and immunogenicity of Sandoz biosimilar pegfilgrastim with US- and EU-references in healthy adults., Results: Pharmacokinetic and pharmacodynamic similarity was demonstrated between the 3 biologics, as the 90% confidence interval for all primary pharmacokinetic and pharmacodynamic endpoint comparisons were contained within the predefined similarity margins of 0.80-1.25. Safety, immunogenicity and tolerability were also similar., Conclusions: Sandoz biosimilar pegfilgrastim demonstrated pharmacokinetic and pharmacodynamic similarity to both US- and EU-reference biologics. No meaningful differences in safety, local tolerability and immunogenicity were identified., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Vitamin A deficiency increases susceptibility to skin infection. However, the mechanisms by which vitamin A regulates skin immunity remain unclear. Here, we show that resistin-like molecule α (RELMα), a small secreted cysteine-rich protein, is expressed by epidermal keratinocytes and sebocytes and serves as an antimicrobial protein that is required for vitamin-A-dependent resistance to skin infection. RELMα was induced by microbiota colonization of the murine skin, was bactericidal in vitro, and was protected against bacterial infection of the skin in vivo. RELMα expression required dietary vitamin A and was induced by the therapeutic vitamin A analog isotretinoin, which protected against skin infection in a RELMα-dependent manner. The RELM family member Resistin was expressed in human skin, was induced by vitamin A analogs, and killed skin bacteria, indicating a conserved function for RELM proteins in skin innate immunity. Our findings provide insight into how vitamin A promotes resistance to skin infection., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Vitamin A is a dietary component that is essential for the development of intestinal immunity. Vitamin A is absorbed and converted to its bioactive derivatives retinol and retinoic acid by the intestinal epithelium, yet little is known about how epithelial cells regulate vitamin A-dependent intestinal immunity. Here we show that epithelial cell expression of the transcription factor retinoic acid receptor β (RARβ) is essential for vitamin A-dependent intestinal immunity. Epithelial RARβ activated vitamin A-dependent expression of serum amyloid A (SAA) proteins by binding directly to Saa promoters. In accordance with the known role of SAAs in regulating Th17 cell effector function, epithelial RARβ promoted IL-17 production by intestinal Th17 cells. More broadly, epithelial RARβ was required for the development of key vitamin A-dependent adaptive immune responses, including CD4 + T-cell homing to the intestine and the development of IgA-producing intestinal B cells. Our findings provide insight into how the intestinal epithelium senses dietary vitamin A status to regulate adaptive immunity, and highlight the role of epithelial cells in regulating intestinal immunity in response to diet., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Aim: This analysis compares safety data for Sandoz proposed biosimilar (LA-EP2006) and reference pegfilgrastim from a Phase I pharmacokinetic/pharmacodynamic study in healthy volunteers (HVs) and two Phase III confirmatory studies in patients with breast cancer (BC; total n = 808). Patients & methods: Baseline characteristics were summarized, and event rates of bone pain and headache calculated. Results: HVs in the Phase I pharmacokinetic/pharmacodynamic study were generally younger, with lower mean body mass index, versus BC patients in PROTECT-1/-2. Bone pain was the most frequent adverse event with similar incidences with reference versus proposed biosimilar in all studies. Conclusion: No differences in adverse events were found between Sandoz proposed biosimilar and reference pegfilgrastim, notwithstanding some differences between HVs and BC patients.

Aims: This study aimed to demonstrate that the pharmacokinetic (PK) and pharmacodynamic (PD) profile of Sandoz proposed biosimilar pegfilgrastim (LA-EP2006) matches reference pegfilgrastim (Neulasta ® ) in healthy subjects. Safety and immunogenicity were also assessed., Methods: The phase I, randomized, double-blind, two-period crossover study consisted of two treatment periods separated by an 8-week washout period. Healthy subjects aged 18-45 were randomized to either proposed biosimilar/reference pegfilgrastim or reference pegfilgrastim/proposed biosimilar. Proposed biosimilar and reference pegfilgrastim were administered on Day 1 of each treatment period (single 6 mg subcutaneous injection). Blood samples for PK/PD analysis were taken predose and ≤336 h postdose. PK/PD similarity was claimed if 90% (PK) and 95% (PD) confidence intervals (CI) for geometric mean ratios of the area under the serum concentration-time curve (AUC) from time of dosing and extrapolated to infinity (AUC 0-inf ), or to the last measurable concentration (AUC 0-last ), maximum observed serum concentration (C max ), absolute neutrophil count (ANC) area under the effect curve from the time of dosing to the last measurable concentration (AUEC 0-last ) and ANC maximum effect attributable to the therapy under investigation (E max ) were completely contained within the predefined margin (0.8 to 1.25)., Results: Overall, 169 subjects completed the study. PK/PD similarity was demonstrated; 90% CIs of geometric mean ratio of proposed biosimilar/reference for PK: AUC 0-inf (1.0559-1.2244), AUC 0-last (1.0607-1.2328), C max (1.0312-1.1909) and 95% CIs for PD (ANC): AUEC 0-last (0.9948-1.0366), E max (0.9737-1.0169) were completely contained within predefined margin of 0.8 to 1.25. Both biologics had similar safety profiles, were well tolerated and had low incidence of anti-drug antibodies. No neutralizing or clinically relevant antibodies were detected., Conclusions: PK/PD similarity of Sandoz proposed biosimilar pegfilgrastim and reference pegfilgrastim was confirmed. No clinically meaningful differences in safety, tolerability and immunogenicity were observed in healthy subjects., (© 2018 The British Pharmacological Society.)

Background: Evaluation of adverse events (AEs) in pivotal registration trials and ongoing postmarketing surveillance is important for all biologics, including biosimilars. A combined analysis of two pivotal registration studies was performed to strengthen evidence on safety for biosimilar filgrastim EP2006 in patients with breast cancer receiving myelosuppressive chemotherapy, a sensitive clinical setting to confirm biosimilarity of filgrastim., Materials and Methods: Data were combined from two phase III studies of biosimilar filgrastim EP2006. The U.S. registration study was a randomized, double-blind comparison of biosimilar and reference filgrastim in women aged ≥18 years with breast cancer, receiving (neo)adjuvant treatment with TAC (docetaxel + doxorubicin + cyclophosphamide). The European Union registration study was a single-arm, open-label study of biosimilar filgrastim in women aged ≥18 years with breast cancer receiving doxorubicin + docetaxel. Patients received filgrastim as a subcutaneous injection on day 2 of each cycle for <14 days or until the absolute neutrophil count reached 10 × 10 9 /L after the expected nadir. Results were combined for cycles 1-4., Results: A total of 277 patients received biosimilar filgrastim EP2006. Patients had a mean (± standard deviation) age of 51.1 (± 10.8) years, and 78.7% of patients had stage II or III breast cancer. A total of 46 (20.6%) patients receiving biosimilar filgrastim had AEs considered filgrastim-related. The most frequently reported filgrastim-related AEs were musculoskeletal or connective tissue disorders (15.2%), including bone pain (7.2%). One death (due to pulmonary embolism) occurred of a patient receiving biosimilar filgrastim (not considered filgrastim-related). No patient developed antidrug antibodies during the study., Conclusion: Biosimilar filgrastim has a safety profile consistent with previous filgrastim studies and is effective in preventing febrile neutropenia in patients with breast cancer., Implications for Practice: The biosimilar filgrastim EP2006 (Zarzio, Zarxio, biosimilar filgrastim-sndz) has been approved in Europe since 2009 and in the U.S. since 2015. This combined analysis of two phase III studies provides additional clinical evidence that the biosimilar filgrastim EP2006 has a safety profile consistent with previous studies of reference filgrastim and supports large postmarketing studies of EP2006 in Europe. Strengthening the evidence for biosimilar filgrastim can help improve acceptance of biosimilars and increase patient access to biologics., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Optical position-sensitive detectors (PSDs) are a non-contact method of tracking the location of a light spot. Silicon-based versions of such sensors are fabricated with standard CMOS technology, are inexpensive and provide a real-time, analog signal output corresponding to the position of the light spot. An innovative type of optical position sensor was developed using two back-to-back connected photodiodes. These so called self-balancing position-sensitive detectors (SBPSDs) eliminate the need for external readout circuitry entirely. Fabricated prototype devices demonstrate linear, symmetric coordinate characteristics and a spatial resolution of 200 μm for a 74 mm device. PSDs are commercially available only up to a length of 37 mm. Prototype devices were fabricated with various lengths up to 100 mm and can be scaled down to any size below that.

Widespread use of the chlorotriazine herbicide, atrazine, has led to serious environmental and human health consequences. Current methods of detecting atrazine contamination are neither rapid nor cost-effective. In this work, atrazine-specific single-stranded DNA (ssDNA) molecular recognition elements (MRE) were isolated. We utilized a stringent Systematic Evolution of Ligands by Exponential Enrichment (SELEX) methodology that placed the greatest emphasis on what the MRE should not bind to. After twelve rounds of SELEX, an atrazine-specific MRE with high affinity was obtained. The equilibrium dissociation constant (Kd) of the ssDNA sequence is 0.62 ± 0.21 nM. It also has significant selectivity for atrazine over atrazine metabolites and other pesticides found in environmentally similar locations and concentrations. Furthermore, we have detected environmentally relevant atrazine concentrations in river water using this MRE. The strong affinity and selectivity of the selected atrazine-specific ssDNA validated the stringent SELEX methodology and identified a MRE that will be useful for rapid atrazine detection in environmental samples.

Retinol plays a vital role in the immune response to infection, yet proteins that mediate retinol transport during infection have not been identified. Serum amyloid A (SAA) proteins are strongly induced in the liver by systemic infection and in the intestine by bacterial colonization, but their exact functions remain unclear. Here we show that mouse and human SAAs are retinol binding proteins. Mouse and human SAAs bound retinol with nanomolar affinity, were associated with retinol in vivo, and limited the bacterial burden in tissues after acute infection. We determined the crystal structure of mouse SAA3 at a resolution of 2 Å, finding that it forms a tetramer with a hydrophobic binding pocket that can accommodate retinol. Our results thus identify SAAs as a family of microbe-inducible retinol binding proteins, reveal a unique protein architecture involved in retinol binding, and suggest how retinol is circulated during infection., (Copyright © 2014, Derebe et al.)

A case-case-control study was conducted to identify independent risk factors for recovery of Escherichia coli strains producing CTX-M-type extended-spectrum β-lactamases (CTX-M E. coli) within a large Southeastern Michigan medical center. Unique cases with isolation of ESBL-producing E. coli from February 2010 through July 2011 were analyzed by PCR for blaCTX-M, blaTEM, and blaSHV genes. Patients with CTX-M E. coli were compared to patients with E. coli strains not producing CTX-M-type ESBLs (non-CTX-M E. coli) and uninfected controls. Of 575 patients with ESBL-producing E. coli, 491 (85.4%) isolates contained a CTX-M ESBL gene. A total of 319 (84.6%) patients with CTX-M E. coli (282 [74.8%] CTX-M-15 type) were compared to 58 (15.4%) non-CTX-M E. coli patients and to uninfected controls. Independent risk factors for CTX-M E. coli isolation compared to non-CTX-M E. coli included male gender, impaired consciousness, H2 blocker use, immunosuppression, and exposure to penicillins and/or trimethoprim-sulfamethoxazole. Compared to uninfected controls, independent risk factors for isolation of CTX-M E. coli included presence of a urinary catheter, previous urinary tract infection, exposure to oxyimino-cephalosporins, dependent functional status, non-home residence, and multiple comorbid conditions. Within 48 h of admission, community-acquired CTX-M E. coli (n = 51 [16%]) and non-CTX-M E coli (n = 11 [19%]) strains were isolated from patients with no recent health care contacts. CTX-M E. coli strains were more resistant to multiple antibiotics than non-CTX-M E. coli strains. CTX-M-encoding genes, especially bla(CTX-M-15) type, represented the most common ESBL determinants from ESBL-producing E. coli, the majority of which were present upon admission. Septic patients with risk factors for isolation of CTX-M E. coli should be empirically treated with appropriate agents. Regional infection control efforts and judicious antibiotic use are needed to control the spread of these organisms.