New agents in development

2011 ◽  
pp. 100-121
Author(s):  
Gino A Vena ◽  
Nicoletta Cassano
Keyword(s):  
New Agents

Review about structure and evaluation of reactivators of Acetylcholinesterase inhibited with neurotoxic organophosphorus compounds

2020 ◽  
Vol 27 ◽  
Author(s):  
José Daniel Figueroa-Villar ◽  
Elaine C. Petronilho ◽  
Kamil Kuca ◽  
Tanos C. C. Franca
Keyword(s):  
Organophosphorus Compounds ◽  
Chemical Warfare Agents ◽  
Nerve Impulse ◽  
Limited Capacity ◽  
New Agents ◽  
Long Time ◽  
Warfare Agents ◽  
Comprehensive Search ◽  
Pharmacology And Toxicology ◽  
The Many

Background: Neurotoxic chemical warfare agents can be classified as some of the most dangerous chemicals for humanity. The most effective of those agents are the organophosphates (OPs) capable of restricting the enzyme acetylcholinesterase (AChE), which in turn controls the nerve impulse transmission. When AChE is inhibited by OPs, its reactivation can be usually performed through cationic oximes. However, until today it has not been developed one universal defense agent, with complete effective reactivation activity for AChE inhibited by any of the many types of existing neurotoxic OPs. For this reason, before treating people intoxicated by an OP, it is necessary to determine the neurotoxic compound that was used for contamination, in order to select the most effective oxime. Unfortunately, this task usually requires a relative long time, raising the possibility of death. Cationic oximes also display a limited capacity of permeating the blood-brain barrier (BBB). This fact compromises their capacity of reactivating AChE inside the nervous system. Methods: We performed a comprehensive search on the data about OPs available on the scientific literature today in order to cover all the main drawbacks still faced in the research for the development of effective antidotes against those compounds. Results: Therefore, this review about neurotoxic OPs and the reactivation of AChE, provides insights for the new agents’ development. The most expected defense agent is a molecule without toxicity and effective to reactivate AChE inhibited by all neurotoxic OPs. Conclusion: To develop these new agents it is necessary the application of diverse scientific areas of research, especially theoretical procedures as computational science (computer simulation, docking and dynamics); organic synthesis; spectroscopic methodologies; biology, biochemical and biophysical information; medicinal chemistry, pharmacology and toxicology.

MODERN FEATURES OF FORMATION OF NEW AGENTS OF YOUTH POLITICAL SOCIALIZATION

2020 ◽  
Vol 15 (2) ◽  
pp. 99-109
Author(s):  
M.A. BURDA ◽  
◽  
A.R. GORCHAKOVA ◽  
N.S. STRIGINA ◽  
◽  
...  
Keyword(s):  
Political Socialization ◽  
New Agents

Rebellious Tin Ore Processing with New Agents for Nonferrous and Noble Metal Recovery

2019 ◽  
Vol 55 (5) ◽  
pp. 832-838 ◽  
Author(s):  
T. N. Matveeva ◽  
V. V. Getman ◽  
M. V. Ryazantseva ◽  
A. Yu. Karkeshkina ◽  
L. B. Lantsova
Keyword(s):  
Noble Metal ◽  
Metal Recovery ◽  
New Agents ◽  
Ore Processing

New agents for thromboprotection

2015 ◽  
Vol 35 (04) ◽  
pp. 338-350 ◽  
Author(s):  
L. Labberton ◽  
E. Kenne ◽  
T. Renné
Keyword(s):  
Current Knowledge ◽  
Thrombus Formation ◽  
Coagulation Cascade ◽  
Factor Xii ◽  
Bleeding Tendency ◽  
New Agents ◽  
Mechanistic Basis ◽  
Normal Hemostasis ◽  
Coagulation Pathway

SummaryBlood coagulation is essential for hemostasis, however excessive coagulation can lead to thrombosis. Factor XII starts the intrinsic coagulation pathway and contact-induced factor XII activation provides the mechanistic basis for the diagnostic aPTT clotting assay. Despite its function for fibrin formation in test tubes, patients and animals lacking factor XII have a completely normal hemostasis. The lack of a bleeding tendency observed in factor XII deficiency states is in sharp contrast to deficiencies of other components of the coagulation cascade and factor XII has been considered to have no function for coagulation in vivo. Recently, experimental animal models showed that factor XII is activated by an inorganic polymer, polyphosphate, which is released from procoagulant platelets and that polyphosphate-driven factor XII activation has an essential role in pathologic thrombus formation. Cumulatively, the data suggest to target polyphosphate, factor XII, or its activated form factor XIIa for anticoagulation. As the factor XII pathway specifically contributes to thrombosis but not to hemostasis, interference with this pathway provides a unique opportunity for safe anticoagulation that is not associated with excess bleeding.The review summarizes current knowledge on factor XII functions, activators and inhibitors.

scholarly journals Sub-Inhibitory Concentrations of Ciprofloxacin Alone and Combinations with Plant-Derived Compounds against P. aeruginosa Biofilms and Their Effects on the Metabolomic Profile of P. aeruginosa Biofilms

Antibiotics ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 414
Author(s):  
Didem Kart ◽  
Tuba Reçber ◽  
Emirhan Nemutlu ◽  
Meral Sagiroglu
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Inhibitory Concentration ◽  
Molecular Level ◽  
Metabolomic Profile ◽  
Gene Expressions ◽  
New Agents ◽  
Qrt Pcr ◽  
Metabolomic Approach

Introduction: Alternative anti-biofilm agents are needed to combat Pseudomonas aeruginosa infections. The mechanisms behind these new agents also need to be revealed at a molecular level. Materials and methods: The anti-biofilm effects of 10 plant-derived compounds on P. aeruginosa biofilms were investigated using minimum biofilm eradication concentration (MBEC) and virulence assays. The effects of ciprofloxacin and compound combinations on P. aeruginosa in mono and triple biofilms were compared. A metabolomic approach and qRT-PCR were applied to the biofilms treated with ciprofloxacin in combination with baicalein, esculin hydrate, curcumin, and cinnamaldehyde at sub-minimal biofilm inhibitory concentration (MBIC) concentrations to highlight the specific metabolic shifts between the biofilms and to determine the quorum sensing gene expressions, respectively. Results: The combinations of ciprofloxacin with curcumin, baicalein, esculetin, and cinnamaldehyde showed more reduced MBICs than ciprofloxacin alone. The quorum sensing genes were downregulated in the presence of curcumin and cinnamaldehyde, while upregulated in the presence of baicalein and esculin hydrate rather than for ciprofloxacin alone. The combinations exhibited different killing effects on P. aeruginosa in mono and triple biofilms without affecting its virulence. The findings of the decreased metabolite levels related to pyrimidine and lipopolysaccharide synthesis and to down-regulated alginate and lasI expressions strongly indicate the role of multifactorial mechanisms for curcumin-mediated P. aeruginosa growth inhibition. Conclusions: The use of curcumin, baicalein, esculetin, and cinnamaldehyde with ciprofloxacin will help fight against P. aeruginosa biofilms. To the best of our knowledge, this is the first study of its kind to define the effect of plant-based compounds as possible anti-biofilm agents with low MBICs for the treatment of P. aeruginosa biofilms through metabolomic pathways.

scholarly journals 1443. Activity of Ceftazidime-Avibactam against Carbapemenase-negative Carbapenem-resistant Enterobacterales (CRE) Isolates from US Hospitals

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S725-S725
Author(s):  
Mariana Castanheira ◽  
Timothy B Doyle ◽  
Cory Hubler ◽  
Rodrigo E Mendes ◽  
Helio S Sader
Keyword(s):  
Resistance Mechanisms ◽  
Chemical Diversity ◽  
Services Research ◽  
New Agents ◽  
E Coli ◽  
Department Of Health ◽  
Carbapenem Resistant ◽  
Center Research ◽  
Research Grant

Abstract Background Most CRE isolates in US hospitals produce KPC enzymes, but some do not carry carbapenemases. We investigated the prevalence, resistance mechanisms and activity of ceftazidime-avibactam and comparator agents against CRE that did not carry carbapenemase genes from US hospitals. Additionally, meropenem-resistant isolates were tested for meropenem-vaborbactam. Methods A total of 28,904 Enterobacterales isolates were collected in 70 US hospitals during 2016-2018, and susceptibility tested by reference broth microdilution. Meropenem-vaborbactam was tested using lyophilized panels following the manufacturer’s instructions. CRE isolates were submitted to whole genome sequencing for the screening of b-lactamase genes, multilocus sequence typing, changes in outer membrane protein (OMP) genes and AmpC expression levels. Results A total of 304 (1.1%) CREs were observed in the study period and 45 (14.8%) isolates did not carry carbapenemases. These isolates were mainly Klebsiella aerogenes, Enterobacter cloacae and Klebsiella pneumoniae (11, 11 and 10 isolates, respectively), but also included 5 other species. Acquired b-lactamase genes were detected among 17 isolates and blaCTX-M-15 was the most common (13 isolates). All K. aerogenes and 10 E. cloacae did not carry acquired b-lactamase genes. Ceftazidime-avibactam (100% susceptible) inhibited all isolates at the current breakpoint, followed by tigecycline and amikacin (> 80% susceptible). Other comparators were not active against non-carbapenemase-producing CRE. Nine of 35 meropenem-resistant isolates displayed meropenem-vaborbactam MIC values of ≥ 8 mg/L (nonsusceptible). Further analysis showed that 23 isolates had disruption of OmpC/OmpK36, 4 had disrupted OmpF/OmpK35 and 13 had both OMP genes disrupted. Additionally, 7 isolates had elevated AmpC expression among 17 isolates tested. Among 7 E. coli, 4 were ST131 and only 2 of 10 K. pneumoniae were clonal complex 11. Conclusion Therapy options for treatment of infections caused by CRE were very limited until recent approval of new agents with activity against these isolates. Ceftazidime-avibactam demonstrated full in vitro activity against all carbapenemase-negative CRE carrying multiple resistance mechanisms. Disclosures Mariana Castanheira, PhD, 1928 Diagnostics (Research Grant or Support)A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Amplyx Pharmaceuticals (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Timothy B. Doyle, Allergan (Research Grant or Support)Allergan (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Cory Hubler, Allergan (Research Grant or Support) Rodrigo E. Mendes, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Basilea Pharmaceutica International, Ltd (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Pfizer (Research Grant or Support) Helio S. Sader, MD, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Melinta (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support)

scholarly journals 833. Characteristics and Utilization Patterns of Colistin Compared with Newer Agents in Gram-Negative Infections

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S457-S457
Author(s):  
Stephen Marcella ◽  
Casey Doremus ◽  
Roger Echols
Keyword(s):  
Patient Characteristics ◽  
Total Hospital Cost ◽  
Healthcare Database ◽  
New Agents ◽  
Antibiotic Resistant ◽  
Gram Negative ◽  
Days Of Therapy ◽  
New Antibiotics ◽  
The Usa ◽  
Utilization Patterns

Abstract Background Colistin has resurfaced in light of Gram-negative (GN) resistance. New antibiotics to treat antibiotic resistant GN infections (eg, ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam [new agents]), have recently been approved but their use vs colistin is unclear. We compared the overall use of colistin and new agents from 2014 to 2018 in patient days on therapy (PDOT). Methods Data on non-cystic fibrosis patients from the Premier Healthcare Database was used. PDOT was tabulated quarterly for Premier hospitals and projected to the US population. A subset of data from 2016 to 2018 with microbiologically confirmed GN (MCGN) infections was selected for adult inpatients receiving ≥3 days of therapy with colistin, new agents, carbapenems, or extended-spectrum cephalosporins. The index infection was defined either as the first carbapenem-resistant (CR) or -sensitive infection if no CR infection occurred. Patients could be treated with ≥1 antibiotic per infection. Utilization was examined by pathogen and patient characteristics. Results PDOT with colistin decreased from 2015 to 2018, while new agents have increased (Figure). During 2015–2018, colistin and any of 3 new agents were used by 3,320 and 5,781 inpatients, respectively, of whom, 649 (20%) and 1,284 (22%) had MCGN pathogens. Colistin-treated patients were sicker than patients treated with new agents (Table), underlying renal disease was present in 34.5% vs 36.3 %, and median length of stay of 17 vs 15 days, respectively. Mean total hospital cost was $93,815 vs $84,013 for colistin and new agents, respectively. Mortality was greater in colistin patients (18% vs 12%; p< 0.0001). CR infections constituted similar proportions of colistin and new agent use (79% vs 75%). Colistin accounted for 15.2% of CR Acinetobacter treatments and 9.7% of CR Enterobacterales (CRE) treatments compared with 4.5% and 12.8%, respectively, for new agents. Figure. Projected Inpatient PDOT Table. Conclusion Colistin use has decreased simultaneously with the introduction and increased use of new agents in the USA. Colistin was used more frequently in sicker patients and for Acinetobacter spp. infections than for CRE infections. Patients on colistin have worse outcomes, probably due to baseline differences in their health status. Disclosures Stephen Marcella, MD, Shionogi Inc. (Employee) Casey Doremus, MS, Shionogi Inc. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant)

scholarly journals Potential impact of biocide adaptation on selection of antibiotic resistance in bacterial isolates

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Engy Elekhnawy ◽  
Fatma Sonbol ◽  
Ahmed Abdelaziz ◽  
Tarek Elbanna
Keyword(s):  
Antibiotic Resistance ◽  
Cross Resistance ◽  
Main Body ◽  
Bacterial Isolates ◽  
New Agents ◽  
Biocidal Products ◽  
Potential Impact ◽  
Emergence Of Resistance ◽  
Vital Factor ◽  
Selection Of

Abstract Background Antibiotic resistance in pathogenic bacterial isolates has increased worldwide leading to treatment failures. Main body Many concerns are being raised about the usage of biocidal products (including disinfectants, antiseptics, and preservatives) as a vital factor that contributes to the risk of development of antimicrobial resistance which has many environmental and economic impacts. Conclusion Consequently, it is important to recognize the different types of currently used biocides, their mechanisms of action, and their potential impact to develop cross-resistance and co-resistance to various antibiotics. The use of biocides in medical or industrial purposes should be monitored and regulated. In addition, new agents with biocidal activity should be investigated from new sources like phytochemicals in order to decrease the emergence of resistance among bacterial isolates.

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