PLA2 Inhibitors for Early Sepsis Stabilization
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Solution Overview
Problem
Current methods for treating sepsis and acute inflammatory syndromes, such as systemic inflammatory response syndrome (SIRS) and acute respiratory distress syndrome (ARDS), are limited by the need for early antibiotic administration, which can be ineffective in pre-diagnostic settings, especially in remote or resource-limited areas, and lack effective diagnostics for front-line medics, leading to prolonged treatment times and increased risk of infection.
Innovation Solution
The use of PLA2 inhibitors, such as varespladib and metalloprotease inhibitors, like prinomastat, in combination with antibiotics to prevent or mitigate the effects of toxins and stabilize patients before diagnosis, improving antibiotic performance and reducing the risk of sepsis and ARDS, particularly in pre-hospital and early hospital settings.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Loss of time
If antibiotics are administered early in pre-diagnostic settings, then treatment timing is improved, but effectiveness deteriorates due to inability to select appropriate antibiotics without confirmed diagnosis
Solution Approach 1:
The patent applies preliminary action by administering PLA2 inhibitors and metalloprotease inhibitors before antibiotic therapy in pre-diagnostic sepsis settings. These enzymes inhibitors are given upfront to block pathogenic enzymatic activity immediately, while antibiotic selection is subsequently guided by culture results. This sequential approach ensures timely intervention without compromising antibiotic effectiveness, as the enzymes inhibitors provide immediate protection while diagnostic information is obtained.
2Productivity
If antibiotics are administered without confirmed diagnosis, then treatment speed is improved, but appropriateness deteriorates leading to increased resistance and inappropriate use
Solution Approach 1:
The patent uses PLA2 inhibitors and metalloprotease inhibitors as intermediary agents that bridge the gap between immediate treatment needs and delayed antibiotic selection. These enzymes inhibitors act as mediators by providing immediate therapeutic effect against pathogenic enzymes while the appropriate antibiotic is being selected based on culture results. This intermediary approach enables fast treatment initiation without committing to potentially inappropriate antibiotic therapy, thereby reducing antibiotic resistance development.
3Reliability
If PLA2 inhibitors and metalloprotease inhibitors are used in combination with antibiotics, then treatment effectiveness is improved, but treatment complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the treatment protocol into distinct phases: (1) immediate administration of PLA2 inhibitors and metalloprotease inhibitors to block enzymatic pathogenesis, and (2) subsequent administration of culture-guided antibiotics to target specific pathogens. This segmented approach simplifies the overall complexity by clearly separating the immediate protective intervention from the targeted antimicrobial therapy, making the combined regimen more manageable and implementable in clinical settings.
Data Source
AI summary
The present invention relates to the early treatment, including pre-diagnosis treatment, of sepsis and acute inflammatory syndromes such as systemic inflammatory response syndrome (SIRS) by PLA2 and metalloprotease inhibitors to improve the performance of antibiotics and outcomes prior to and after confirmation of the diagnosis of sepsis and/or SIRS in a patient or subject. Additional embodiments include methods of treating sepsis, anthrax and severe acute respiratory syndrome coronavirus (SARS and SARS-CoV2) and related inflammatory syndromes and compositions, including pharmaceutical compositions and blood sample compositions. In further embodiments, the present invention is directed to embodiments which evidence that LY315920, LY333013 and related sPLA2 inhibitors are particularly effective COVID-19/cytokine release syndrome therapeutics-prophylactics. In embodiments, the PLA2 inhibitor is varespladib (LY315920), methyl varespladib (LY333013), AZD2716-(R)-3-(5′-benzyl-2′-carbamoyl-[1,1′-biphenyl-3-yl)-2-methylpropanoic acid—as a racemic mixture or separately, as the “R” enantiomer), AZD Compound 4 (3-(5′-Benzyl-2′-carbamoylbiphenyl-3-yl)propanoic acid) and LY433771 ((9-[(phenyl)methyl]-5-carbamoylcarbazol-4-yl) oxyacetic acid), a pharmaceutically acceptable salt thereof or a mixture thereof. In embodiments, the metalloprotease inhibitor is Prinomastat, Batimastat, marimastat or vorinostat dosed alone or in combination with preferred sPLA2 inhibitors for the treatment of infection, inflammatory and wound conditions arising from various causes. Methods and compositions for achieving accelerated. treatment of wounds and burns, anthrax metalloprotease toxin (lethal factor) driven complications, ARDS, neo-natal and pediatric acute respiratory distress syndrome (neo-natal/pediatric ARDS), including, meconium aspiration syndrome are also disclosed.