Therapeutic Combination for Brain Ischemia Treatment
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Solution Overview
Problem
Current treatments for brain ischemia and ischemia-reperfusion injury are limited, with existing therapies failing to effectively address oxidative stress and reperfusion injury, particularly in diabetic patients, due to the complexity of disease pathomechanisms and comorbidities, and the lack of effective pharmacological interventions.
Innovation Solution
A therapeutic combination of NADPH oxidase inhibitors, nitric oxide synthase inhibitors, and soluble guanylate cyclase agonists is developed, which targets specific molecular interactions and pathways to inhibit oxidative stress and promote neuroprotection, using a multi-target network pharmacology approach to synergistically reduce infarct size, stabilize the blood-brain barrier, and improve neurological outcomes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If thrombolysis by tissue plasminogen activator is used to restore blood flow, then mortality in acute ischemic stroke is reduced, but the treatment has a narrow time window, high cost, and risk of bleeding complications
Solution Approach 1:
The invention segments the stroke treatment into two distinct phases: (1) reperfusion phase using thrombolysis/thrombectomy to restore blood flow, and (2) neuroprotection phase using the multi-component composition to prevent reperfusion injury. This segmentation allows each treatment to be optimized for its specific phase without the constraints of the other.
Solution Approach 2:
The neuroprotective composition is designed to be administered in preparation for or concurrent with reperfusion therapy, providing preliminary protection against the anticipated reperfusion injury. This preliminary action expands the effective time window by protecting brain tissue before the actual reperfusion event occurs.
2Reliability
If thrombectomy is performed to restore blood flow in proximal large artery occlusions, then reperfusion is achieved, but the procedure is limited to specific patient groups and requires high expertise
Solution Approach 1:
The neuroprotective composition acts as an intermediary that bridges the gap between reperfusion therapy and tissue protection. It mediates the transition from ischemic damage to recovered function by protecting against reperfusion injury, thereby extending the benefits of reperfusion to patients who would otherwise be ineligible due to timing or comorbidities.
3Reliability
If reperfusion is restored to ischemic brain tissue, then blood supply is recovered, but oxidative stress and reperfusion injury cause additional tissue damage
Solution Approach 1:
The composition converts the harmful oxidative stress and inflammation that normally accompany reperfusion into a beneficial protective effect. By pre-treating with antioxidants, anti-inflammatory agents, and NADPH oxidase inhibitors, the harmful reperfusion process is transformed into a controlled, protected reperfusion that restores blood flow without causing damage.
Solution Approach 2:
The neuroprotective composition applies preliminary anti-action by administering agents that counteract the anticipated harmful effects of reperfusion before they occur. The antioxidants, anti-inflammatory drugs, and NADPH oxidase inhibitors are given in advance to neutralize the oxidative stress and inflammation that will inevitably follow reperfusion, thereby preventing tissue damage.
4Object-affected harmful factors
If antioxidants are administered to prevent reperfusion injury, then oxidative stress might be reduced, but high doses cause indiscriminate effects and ROS cannot reach sufficient concentrations at the ischemic site
Solution Approach 1:
The invention uses a composite multi-component formulation that combines antioxidants, anti-inflammatory agents, and NADPH oxidase inhibitors in specific ratios and dosages. This composite approach provides synergistic protection, where each component contributes to a overall effect greater than the sum of individual parts, achieving reliable neuroprotection without the need for excessively high doses of single agents.
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
The combination significantly reduces infarct size, stabilizes the blood-brain barrier, improves neurological function, and increases survival in animal models of ischemic stroke, while avoiding the toxicity associated with glucose, demonstrating a synergistic and mechanism-based therapeutic effect.
Implementation Method 1
at least one NADPH oxidase inhibitor
Implementation Method 2
at least one nitric oxide synthase inhibitor
Implementation Method 3
at least one soluble guanylate cyclase agonist
Data Source
AI summary
The present invention relates to a therapeutic combination comprising two or three of at least one NADPH oxidase inhibitor, at least one nitric oxide synthase inhibitor and at least one soluble guanylate cyclase agonist. More specifically, the invention relates to said therapeutic combination for use in the prevention or treatment of brain ischemia or for use in the prevention or treatment of ischemia-reperfusion injury. The invention also relates to a pharmaceutical composition comprising two or three of at least one NADPH oxidase inhibitor, at least one nitric oxide synthase inhibitor and at least one soluble guanylate cyclase agonist, and to said pharmaceutical composition for use in the prevention or treatment of brain ischemia or for use in the prevention or treatment of ischemia-reperfusion injury.