The Phenotypic/Genotypic Profile of OXA-10-like harboring, Carbapenem-Resistant Pseudomonas aeruginosa : Using Validated Pharmacokinetic/Pharmacodynamic in vivo Models to Further Evaluate Enzyme Functionality and Clinical Implications

2021 ◽  
Author(s):  
Christian M. Gill ◽  
Adrian Brink ◽  
Chun Yat Chu ◽  
Jennifer Coetzee ◽  
George Dimopoulos ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Clinical Implications ◽  
In Vivo Models ◽  
Carbapenem Resistant ◽  
Enzyme Functionality ◽  
Dose Dependent ◽  
Genotypic Profile

In vitro MICs and in vivo pharmacodynamics of ceftazidime and cefepime human-simulated regimens (HSR) against mCIM-positive P. aeruginosa harboring different OXA-10-like subtypes were described. The murine thigh model assessed ceftazidime (2g q8h HSR) and cefepime (2g and 1g q8h HSR). Phenotypes were similar despite possessing OXA-10-like subtypes with differing spectra. Ceftazidime produced ≥1-log 10 kill in all isolates. Cefepime activity was dose-dependent and MIC driven. This approach may be useful in assessing implications of β-lactamase variants.

Antimicrobial and antibiofilm activities of meropenem loaded-mesoporous silica nanoparticles against carbapenem-resistant Pseudomonas aeruginosa

2021 ◽  
pp. 088532822110038
Author(s):  
Mohammad Yousef Memar ◽  
Mina Yekani ◽  
Hadi Ghanbari ◽  
Edris Nabizadeh ◽  
Sepideh Zununi Vahed ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Mesoporous Silica ◽  
Silica Nanoparticles ◽  
Mesoporous Silica Nanoparticles ◽  
Carbapenem Resistant ◽  
Toxicity In Vitro ◽  
Different Levels

The aims of the present study were the determination of antimicrobial and antibiofilm effects of meropenem-loaded mesoporous silica nanoparticles (MSNs) on carbapenem resistant Pseudomonas aeruginosa ( P. aeruginosa) and cytotoxicity properties in vitro. The meropenem-loaded MSNs had shown antibacterial and biofilm inhibitory activities on all isolates at different levels lower than MICs and BICs of meropenem. The viability of HC-04 cells treated with serial concentrations as MICs and BICs of meropenem-loaded MSNs was 92–100%. According to the obtained results, meropenem-loaded MSNs display the significant antibacterial and antibiofilm effects against carbapenem resistant and biofilm forming P. aeruginosa and low cell toxicity in vitro. Then, the prepared system can be an appropriate option for the delivery of carbapenem for further evaluation in vivo assays.

scholarly journals Multicenter Evaluation of Ceftazidime-Avibactam and Ceftolozane-Tazobactam Inhibitory Activity against Meropenem-Nonsusceptible Pseudomonas aeruginosa from Blood, Respiratory Tract, and Wounds

2017 ◽  
Vol 61 (10) ◽  
Author(s):  
Mordechai Grupper ◽  
Christina Sutherland ◽  
David P. Nicolau
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Inhibitory Activity ◽  
Clinical Utility ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Broth Microdilution ◽  
Content Type ◽  
Carbapenem Resistant

ABSTRACT The recent escalation of occurrences of carbapenem-resistant Pseudomonas aeruginosa has been recognized globally and threatens to erode the widespread clinical utility of the carbapenem class of compounds for this prevalent health care-associated pathogen. Here, we compared the in vitro inhibitory activity of ceftazidime-avibactam and ceftolozane-tazobactam against 290 meropenem-nonsusceptible Pseudomonas aeruginosa nonduplicate clinical isolates from 34 U.S. hospitals using reference broth microdilution methods. Ceftazidime-avibactam and ceftolozane-tazobactam were active, with ceftolozane-tazobactam having significantly higher inhibitory activity than ceftazidime-avibactam. The heightened inhibitory activity of ceftolozane-tazobactam was sustained when the site of origin (respiratory, blood, or wound) and nonsusceptibility to other β-lactam antimicrobials was considered. An extensive genotypic search for enzymatically driven β-lactam resistance mechanisms revealed the exclusive presence of the VIM metallo-β-lactamase among only 4% of the subset of isolates nonsusceptible to ceftazidime-avibactam, ceftolozane-tazobactam, or both. These findings suggest an important role for both ceftazidime-avibactam and ceftolozane-tazobactam against carbapenem-nonsusceptible Pseudomonas aeruginosa. Further in vitro and in vivo studies are needed to better define the clinical utility of these novel therapies against the increasingly prevalent threat of multidrug-resistant Pseudomonas aeruginosa.

scholarly journals Ochratoxin A Induces Oxidative Stress in HepG2 Cells by Impairing the Gene Expression of Antioxidant Enzymes

Toxins ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 271
Author(s):  
Enrique García-Pérez ◽  
Dojin Ryu ◽  
Chan Lee ◽  
Hyun Jung Lee
Keyword(s):  
Oxidative Stress ◽  
Ochratoxin A ◽  
Hepg2 Cells ◽  
Mrna Level ◽  
Dependent Manner ◽  
In Vivo Models ◽  
Dose Dependent ◽  
And Oxidative Stress

Ochratoxin A (OTA) is a mycotoxin frequently found in raw and processed foods. While it is considered a possible human carcinogen, the mechanism of action remains unclear. OTA has been shown to be hepatotoxic in both in vitro and in vivo models and oxidative stress may be one of the factors contributing to its toxicity. Hence, the effect of OTA on human hepatocellular carcinoma, HepG2 cells, was investigated on oxidative stress parameters. The cytotoxicity of OTA on HepG2 was time- and dose-dependent within a range between 0.1 and 10 µM; while 100 μM of OTA increased the intracellular reactive oxygen species (ROS) in a time-dependent manner. Additionally, the levels of glutathione (GSH) were increased by 9.7% and 11.3% at 10 and 100 nM of OTA, respectively; while OTA at 100 μM depleted GSH by 40.5% after 24 h exposure compared with the control. Finally, the mRNA level of catalase (CAT) was downregulated by 2.33-, 1.92-, and 1.82-fold after cells were treated with 1, 10, and 10 μM OTA for 24 h, respectively; which was linked to a decrease in CAT enzymatic activity. These results suggest that oxidative stress is involved in OTA-mediated toxicity in HepG2 cells.

scholarly journals OP0034 STP938, A NOVEL, POTENT AND SELECTIVE INHIBITOR OF CTP SYNTHASE 1 (CTPS1) DEMONSTRATES EFFICACY IN RODENT MODELS OF INFLAMMATION AND ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 18.1-19
Author(s):  
H. Asnagli ◽  
A. Novak ◽  
L. Birch ◽  
R. Lane ◽  
N. Minet ◽  
...  
Keyword(s):  
B Cell ◽  
Therapeutic Potential ◽  
Selective Inhibitor ◽  
Dependent Manner ◽  
Human Pbmcs ◽  
Small Molecular Weight ◽  
In Vivo Models ◽  
Dose Dependent

Background:The final rate-limiting step in pyrimidine synthesis is the conversion of UTP to CTP which is catalyzed by cytidine triphosphate synthase 1 (CTPS1) or CTPS2. A hypomorphic mutation in the CTPS1 gene has highlighted the essential and non-redundant role of CTPS1 in T and B lymphocyte proliferation1. These patients exhibit no effects on non-hematopoietic tissues. Thus, selective inhibition of CTPS1 represents a novel targeted approach to dampen pathological T- and B-cell lympho-proliferation. STP938 is an orally bioavailable, small molecular weight, selective inhibitor of CTPS1 developed by Step Pharma.Objectives:To demonstrate the in vitro effects of CTPS1 inhibition on T and B cell proliferation and the therapeutic potential of STP938 using in vivo models of disease.Methods:The in vitro anti-proliferative activity of STP938 was investigated using cell lines and primary human PBMCs. STP938 was assessed in vivo using the DTH-KLH rat model and the mouse collagen-induced arthritis (CIA) model. For the KLH-DTH model, Lewis rats were immunized with KLH, a week later, challenged locally at the ear with KLH antigen, ear swelling was assessed after 24 hours. Blood samples were collected for detection of KLH-specific IgG levels at day 8. STP938 was given orally one-hour prior to immunization and then b.i.d. for 7 days. For the CIA model, DBA-1 mice were immunized with Collagen type II and complete Freund’s adjuvant and received a booster immunization three weeks later. STP938 was administered to mice developing signs of arthritis from Day 28 to 45 orally daily b.i.d.Results:STP938 inhibited in vitro proliferation of HEKwt but not HEK-CTPS1KO cells as well as Jurkat and human PBMCs. STP938 demonstrated a significant and dose-dependent inhibition of KLH-specific T and B cell responses in vivo. STP938 significantly reduced the disease severity in the CIA model in a dose-dependent manner as determined by clinical and histopathological readouts.Conclusion:Our preliminary in vitro and in vivo results indicate that inhibition of CTPS1 specifically blocks proliferation of cells derived from the lymphocyte lineage and reduces the T cell driven inflammatory response. These data highlight the therapeutical potential of STP938 in treating patients with autoimmune diseases such as rheumatoid arthritis.References:[1]Martin et al, JCI Insight. 2020, 12;5(5):133880Disclosure of Interests:Hélène ASNAGLI Employee of: Step Pharma, Andrew Novak: None declared, Louise Birch Shareholder of: Step Pharma, Rebecca Lane: None declared, Norbert Minet Employee of: employee as Ph D student under CIFRE grant, David Laughton: None declared, Pascal George Shareholder of: Step Pharma, Geoffroy de Ribains Shareholder of: as former employee of Step Pharma, Employee of: former employee of Step Pharma, Sylvain Latour: None declared, Alain Fischer: None declared, Tim Bourne Shareholder of: UCB, Step Pharma, Sitryx Therapeutics, Consultant of: a range of biotech companies, Employee of: former employee of Step Pharma and Sitryx Therapeutics, Andrew Parker Employee of: Step Pharma

scholarly journals In vivo Fitness of Acinetobacter baumannii Strains in Murine Infection Is Associated with International Lineage II-rep-2 and International Lineage III Clones Showing High Case Fatality Rates in Human Infections

2020 ◽  
Vol 8 (6) ◽  
pp. 847
Author(s):  
Amir Nutman ◽  
Jonathan Lellouche ◽  
Ziv Lifshitz ◽  
Rivka Glick ◽  
Yehuda Carmeli
Keyword(s):  
Acinetobacter Baumannii ◽  
Case Fatality ◽  
Growth Curves ◽  
Thigh Muscle ◽  
Day Case ◽  
In Vivo Models ◽  
Carbapenem Resistant ◽  
Human Infections

We previously reported that the 14-day case fatality rate (CFR) in patients with carbapenem-resistant Acinetobacter baumannii (CRAB) bacteremia varied between infecting clones. Here, we evaluated the in vitro and in vivo fitness of CRAB blood isolates belonging to clones with low CFR (< 32% 14-day mortality) and high CFR (65% 14-day mortality). Fitness was measured in vitro using a growth curve assay and in vivo using murine thigh muscle and septicemia models of infection. Our sample included 38 CRAB isolates belonging to two clones with low CFR (international lineage (IL)-II-rep-1, n = 13 and IL-79, n = 6) and two clones with high CFR (IL-III, n = 9 and IL-II-rep-2, n = 10). In in vitro growth curves, mean lag time, generation time and maximal growth varied between clones but could not discriminate between the high and low CFR clones. In the in vivo models, bacterial burdens were higher in mice infected with high CFR clones than in those infected with low CFR clones: in thigh muscle, 8.78 ± 0.25 vs. 7.53 ± 0.25 log10CFU/g, p < 0.001; in infected spleen, 5.53 ± 0.38 vs. 3.71 ± 0.35 log10CFU/g, p < 0.001. The thigh muscle and septicemia model results were closely correlated (r = 0.93, p < 0.01). These results suggest that in vivo but not in vitro fitness is associated with high CFR clones.

Soluble Thrombomodulin Purified from Human Urine Exhibits a Potent Anticoagulant Effect In Vitro and In Vivo

1995 ◽  
Vol 73 (05) ◽  
pp. 805-811 ◽  
Author(s):  
Yasuo Takahashi ◽  
Yoshitaka Hosaka ◽  
Hiromi Niina ◽  
Katsuaki Nagasawa ◽  
Masaaki Naotsuka ◽  
...  
Keyword(s):  
Human Urine ◽  
Specific Activity ◽  
Anticoagulant Activity ◽  
Rabbit Lung ◽  
Soluble Thrombomodulin ◽  
Molecular Weights ◽  
Dose Dependent Fashion ◽  
Dose Dependent

SummaryWe examined the anticoagulant activity of two major molecules of soluble thrombomodulin purified from human urine. The apparent molecular weights of these urinary thrombomodulins (UTMs) were 72,000 and 79,000, respectively. Both UTMs showed more potent cofactor activity for protein C activation [specific activity >5,000 thrombomodulin units (TMU)/mg] than human placental thrombomodulin (2,180 TMU/mg) and rabbit lung thrombomodulin (1,980 TMU/mg). The UTMs prolonged thrombin-induced fibrinogen clotting time (>1 TMU/ml), APTT (>5 TMU/ml), TT (>5 TMU/ml) and PT (>40 TMU/ml) in a dose-dependent fashion. These effects appeared in the concentration range of soluble thrombomodulins present in human plasma and urine. In the rat DIC model induced by thromboplastin, administration of UTMs by infusion (300-3,000 TMU/kg) restored the hematological abnormalities derived from DIC in a dose-dependent fashion. These results demonstrate that UTMs exhibit potent anticoagulant and antithrombotic activities, and could play a physiologically important role in microcirculation.

Melatonin modifies tumor hypoxia and metabolism by inhibiting HIF-1α and energy metabolic pathway in the in vitro and in vivo models of breast cancer

2019 ◽  
Vol 2 (4) ◽  
pp. 83-98 ◽  
Author(s):  
André De Lima Mota ◽  
Bruna Vitorasso Jardim-Perassi ◽  
Tialfi Bergamin De Castro ◽  
Jucimara Colombo ◽  
Nathália Martins Sonehara ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Carbonic Anhydrases ◽  
In Vivo Models ◽  
Ca Ix ◽  
Gene And Protein Expression

Breast cancer is the most common cancer among women and has a high mortality rate. Adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can modify these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects, exhibits important anti-tumor actions which may associate with modification of hypoxia and Warburg effect. In this study, we have evaluated the action of melatonin on tumor growth and tumor metabolism by different markers of hypoxia and glucose metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer model. In an in vitro study, gene and protein expressions of these markers were evaluated by quantitative real-time PCR and immunocytochemistry, respectively. The effects of melatonin were also tested in a MDA-MB-231 xenograft animal model. Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and tumor growth in Balb/c nude mice (p <0.05). The treatment significantly decreased HIF-1α gene and protein expression concomitantly with the expression of GLUT1, GLUT3, CA-IX and CA-XII (p <0.05). These results strongly suggest that melatonin down-regulates HIF-1α expression and regulates glucose metabolism in breast tumor cells, therefore, controlling hypoxia and tumor progression. 

Current Challenges in the Development of Vaccines and Drugs Against Emerging Vector-borne Diseases

2019 ◽  
Vol 26 (16) ◽  
pp. 2974-2986 ◽  
Author(s):  
Kwang-sun Kim
Keyword(s):  
New Host ◽  
In Vivo Models ◽  
Vector Borne Diseases ◽  
Novel Drugs ◽  
Huge Impact ◽  
Tick Borne Disease ◽  
Vector Borne ◽  
Living Organisms

Vectors are living organisms that transmit infectious diseases from an infected animal to humans or another animal. Biological vectors such as mosquitoes, ticks, and sand flies carry pathogens that multiply within their bodies prior to delivery to a new host. The increased prevalence of Vector-Borne Diseases (VBDs) such as Aedes-borne dengue, Chikungunya (CHIKV), Zika (ZIKV), malaria, Tick-Borne Disease (TBD), and scrub typhus has a huge impact on the health of both humans and livestock worldwide. In particular, zoonotic diseases transmitted by mosquitoes and ticks place a considerable burden on public health. Vaccines, drugs, and vector control methods have been developed to prevent and treat VBDs and have prevented millions of deaths. However, development of such strategies is falling behind the rapid emergence of VBDs. Therefore, a comprehensive approach to fighting VBDs must be considered immediately. In this review, I focus on the challenges posed by emerging outbreaks of VBDs and discuss available drugs and vaccines designed to overcome this burden. Research into promising drugs needs to be upgraded and fast-tracked, and novel drugs or vaccines being tested in in vitro and in vivo models need to be moved into human clinical trials. Active preventive tactics, as well as new and upgraded diagnostics, surveillance, treatments, and vaccination strategies, need to be monitored constantly if we are to manage VBDs of medical importance.

Potential for Treatment of Neurodegenerative Diseases with Natural Products or Synthetic Compounds that Stabilize Microtubules

2020 ◽  
Vol 26 (35) ◽  
pp. 4362-4372
Author(s):  
John H. Miller ◽  
Viswanath Das
Keyword(s):  
Natural Products ◽  
Neurodegenerative Diseases ◽  
In Vivo Models ◽  
Synthetic Compounds ◽  
Stabilizing Agents ◽  
Animal Models Of Disease ◽  
Model Studies ◽  
Models Of Disease

No effective therapeutics to treat neurodegenerative diseases exist, despite significant attempts to find drugs that can reduce or rescue the debilitating symptoms of tauopathies such as Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, amyotrophic lateral sclerosis, or Pick’s disease. A number of in vitro and in vivo models exist for studying neurodegenerative diseases, including cell models employing induced-pluripotent stem cells, cerebral organoids, and animal models of disease. Recent research has focused on microtubulestabilizing agents, either natural products or synthetic compounds that can prevent the axonal destruction caused by tau protein pathologies. Although promising results have come from animal model studies using brainpenetrant natural product microtubule-stabilizing agents, such as paclitaxel analogs that can access the brain, epothilones B and D, and other synthetic compounds such as davunetide or the triazolopyrimidines, early clinical trials in humans have been disappointing. This review aims to summarize the research that has been carried out in this area and discuss the potential for the future development of an effective microtubule stabilizing drug to treat neurodegenerative disease.

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