Biology subjects

Avedissian, S. N.

Publications and source records attributed to Avedissian, S. N..

4 recordsLinked to original sources

bioRxiv2025

Late treatment initiation leads to reduced antiviral potency

The timing of initiation is critical in antiviral treatment and viral dynamic (VD) modeling is a powerful tool to study the within-host viral load changes and evaluate antiviral treatment effects using mathematical equations. Previous simulation studies have shown that early treatment initiation is critical to maximize the therapeutic response in antiviral treatment in an acute viral infection such as influenza and SARS-CoV-2. A recent experimental study demonstrated that late therapy initiation can lead to diminished antiviral potency. However, most VD model simulations with varying treatment initiation time accounted only for the effect of initiation condition (i.e., state of different cell populations when the therapy started), the loss of drug potency has been under-investigated. This may overestimate the antiviral effect, potentially resulting in suboptimal dose selection. To this end, we aimed to characterize relationship between the drug potency (EC50) and the timing of drug addition, using nirmatrelvir and GS-441524 against SARS-CoV-2 as an example. Viral load data were obtained from in vitro experiments with various drug concentrations and treatment initiated between 0 to 3 days post infection. EC50 values were fitted for each treatment initiation group and were found to vary with the timing of treatment initiation in both drugs. Also, a VD model with time-varying EC50 provided better fits than a constant EC50 model (BIC = 1667.90 vs. 1677.84). Further simulations also indicated that a constant EC50 model overestimated the antiviral efficacy when treatment started late. These findings highlighted the importance of considering EC50 shift when optimizing dosage regimens for patients presenting late.

pharmacology and toxicology↗

bioRxiv2024

TISSUE-SPECIFIC METABOLOMIC REPROGRAMMING DETERMINES THE DISEASE PATHOPHYSIOLOGY OF SARS-COV-2 VARIANTS IN HAMSTER MODEL

Despite significant effort, a clear understanding of host tissue-specific responses and their implications for immunopathogenicity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant infection has remained poorly defined. To shed light on the interaction between organs and specific SARS-CoV-2 variants, we sought to characterize the complex relationship among acute multisystem manifestations, dysbiosis of the gut microbiota, and the resulting implications for SARS-CoV-2 variant-specific immunopathogenesis in the Golden Syrian Hamster (GSH) model using multi-omics approaches. Our investigation revealed increased viremia in diverse tissues of delta-infected GSH compared to the omicron variant. Multi-omics analyses uncovered distinctive metabolic responses between the delta and omicron variants, with the former demonstrating dysregulation in synaptic transmission proteins associated with neurocognitive disorders. Additionally, delta-infected GSH exhibited an altered fecal microbiota composition, marked by increased inflammation-associated taxa and reduced commensal bacteria compared to the omicron variant. These findings underscore the SARS-CoV-2-mediated tissue insult, characterized by modified host metabolites, neurological protein dysregulation, and gut dysbiosis, highlighting the compromised gut-lung-brain axis during acute infection. TeaserIn hamsters at acute infection, SARS-CoV-2 variant-specific metabolic responses and gut dysbiosis dysregulate synaptic transmission proteins.

systems biology↗

bioRxiv2019

Evaluation of Dose Fractionated Polymyxin B on Acute Kidney Injury: A Translational In Vitro Model

The polymyxins are last-line defense for highly resistant infections. Nephrotoxicity, however, is a dose-limiting factor. Yet, approaches to mitigate nephrotoxicity are poorly defined. This study aimed to investigate the impact of dose fractionated (once, twice and thrice daily) polymyxin B (PB) on acute kidney injury (AKI) in a pre-clinical model. Secondarily, we aimed to describe the pharmacokinetic (PK) profile of PB. Sprague-Dawley rats were assigned to experimental groups with different dosing intervals but constant total daily exposure (12 mg/kg/day into single, twice daily, and thrice daily doses) and controls received normal saline subcutaneously over 3 days. Blood and urine samples were collected, and kidneys were harvested at necropsy. A three-compartment model best described the data and Bayesian observed vs. predicted concentration demonstrated bias, imprecision, and R2 of 0.129 mg/L, 0.729 mg2/L2 and 0.652, respectively. PB exposure (i.e. AUC24h) were similar across treatment groups over time (p=0.87). As a representative, urinary KIM-1 were elevated on days 1 and 2 for experimental groups compared to controls, and thrice daily group experienced the most KIM-1 increase [mean increase (95% CI) day 1 from day -1, 4.44 (0.89, 8.00) ng/mL; p=0.018] as compared to control [mean increase (95% CI) day 1 from day -1, 0.03 (-0.42, 0.49) ng/mL; p=0.99]. Correspondingly, significant histopathological damage was observed with the same group (p=0.013) (controls as a referent). Our findings suggested that fractionating the PB dose thrice daily resulted in the most injury in a rat model.

pharmacology and toxicology↗

bioRxiv2019

Urinary biomarker and histopathological evaluation of vancomycin and piperacillin-tazobactam nephrotoxicity in comparison with vancomycin in a rat model and a confirmatory cellular model

IntroductionVancomycin and piperacillin tazobactam (VAN+TZP) are two of the most commonly utilized antibiotics in the hospital setting and are reported in clinical studies to increase acute kidney injury (AKI). However, no clinical study has demonstrated that synergistic toxicity occurs, only that serum creatinine (SCr) increases with VAN+TZP. The purpose of this study was to assess biologic plausibility by quantifying kidney injury between VAN, TZP, and VAN+TZP treatments using a translational rat model of AKI and rat kidney epithelial cell studies.\n\nMethods(i) Male Sprague-Dawley rats (n=32) received either saline, VAN 150 mg/kg/day intravenously, TZP 1400 mg/kg/day via intraperitoneal injection, or VAN+TZP. Animals were placed in metabolic cages pre-study and on drug dosing days 1-3. Urinary biomarkers and histopathology were analyzed. (ii) Cellular injury of VAN+TZP was assessed in serum-deprived rat kidney cells (NRK-52E) using an alamarBlue(R) viability assay. Cells were incubated with antibiotics VAN, TZP, cefepime, and gentamicin alone or combined with the same drugs plus VAN 1 mg/mL.\n\nResultsIn the VAN-treated rats, urinary KIM-1 and clusterin were increased on days 1, 2, and 3 compared to controls (P<0.001). Elevations were seen only after 3 days of treatment with VAN+TZP (P<0.001 KIM-1, P<0.05 clusterin). Histopathology was only elevated in the VAN group when compared to TZP as a control (P=0.04). Results were consistent across biomarkers and histopathology suggesting that adding TZP did not worsen VAN induced AKI and may even be protective. In NRK-52E cells, VAN alone caused moderate cell death with high doses (IC5048.76 mg/mL). TZP alone did not cause cellular death under the same conditions. VAN+TZP was not different from VAN alone in NRK-52E cells (P>0.2).\n\nConclusionsVAN+TZP does not cause more kidney injury than VAN alone in a rat model of VIKI or in rat kidney epithelial cells.

pharmacology and toxicology↗