TRPV1 Agonists for Selective Vasoconstriction in Septic Shock
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for septic shock, such as angiotensin II infusion, are ineffective in maintaining blood pressure while preserving flow to critical organs like the spleen and kidney, and are associated with adverse thromboembolic events and high mortality rates.
Innovation Solution
Administration of TRPV1 agonists, such as capsaicin or vanillotoxins, to increase and maintain systolic blood pressure by constricting arterioles, which are selectively expressed in small arteries of vital organs, thereby avoiding impairment of blood flow to these organs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stress or pressure
If vasoconstrictor drugs (adrenergic/dopamine agonists) are administered to increase blood pressure, then blood pressure is improved, but blood flow to vital organs (spleen and kidney) is compromised
Solution Approach 1:
The patent applies local quality by using TRPV1 agonists that selectively constrict arterioles in non-vital tissues while preserving blood flow to vital organs. The TRPV1 receptor is differentially expressed in the vasculature, with higher density in non-vital tissues, allowing selective vasoconstriction in those areas while maintaining perfusion to organs with lower TRPV1 expression like the kidney and spleen.
2Stress or pressure
If angiotensin II is administered to control blood pressure, then blood pressure is improved, but thromboembolic events are exacerbated and mortality remains high
Solution Approach 1:
The patent employs parameter changes by switching from angiotensin II (which acts on AT1 receptors) to TRPV1 agonists. This pharmacological parameter change eliminates the pro-coagulant effects associated with angiotensin II while maintaining blood pressure control through a different mechanism of action on TRPV1 receptors in vascular smooth muscle.
3Stress or pressure
If standard vasoconstrictors are used to treat hypotensive shock, then blood pressure increases, but effectiveness is lost in many patients
Solution Approach 1:
The patent introduces TRPV1 agonists as an intermediary substance with a novel mechanism of action. Instead of using conventional adrenergic or dopaminergic pathways that may be desensitized or ineffective in septic shock, the TRPV1 agonist activates a different receptor system that remains effective in refractory cases of hypotensive shock.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
TRPV1 agonists effectively stabilize blood pressure in septic shock by promoting vasoconstriction in a targeted manner, reducing the risk of thromboembolic events and improving survival rates compared to existing treatments.
Implementation Method 1
TRPV1 agonists, such as capsaicin or vanillotoxins, to increase and maintain systolic blood pressure by constricting arterioles
Data Source
AI summary
Provided herein are methods of stabilizing blood pressure in severe sepsis/septic shock and other types of distributive shock using TRPV1 agonists. Also provided are pharmaceutical formulations for increasing blood pressure in septic shock the formulation including at least one TRPV1 agonist in a dosage form for parenteral administration, wherein the TRPV1 agonist is selected from capsaicin, daphane TRPV1 agonists, vanillotoxin, N-oleoyl dopamine, N-arachidonyl dopamine, BrP-LPA, and derivatives and analogues thereof. Also provided are TRPV1 agonists co-lyophilized with adrenergic agonists and/or angiotensins in a dosage form for reconstitution and parenteral administration.