Aromatic-Cationic Peptides for Ischemia-Reperfusion No-Reflow

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Solution Overview

Problem

Current treatments for ischemia/reperfusion tissue injury, particularly the no-reflow phenomenon, are inadequate in effectively preventing or treating anatomic zones of no re-flow, which lead to poor clinical outcomes due to microvascular obstruction and reduced tissue perfusion.

Innovation Solution

Administration of therapeutically effective amounts of aromatic-cationic peptides, such as D-Arg-2′,6′-Dmt-Lys-Phe-NH2 or its pharmaceutically acceptable salts, to prevent or treat anatomic zones of no re-flow by improving tissue perfusion and reducing microvascular damage during ischemia/reperfusion events.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional treatments are used for ischemia/reperfusion injury, then basic reperfusion can be achieved, but anatomic zones of no re-flow persist leading to poor clinical outcomes

Engineering Contradiction:

Improveclinical outcomesVSAvoidno-reflow phenomenon

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The aromatic-cationic peptide is administered before the no-reflow phenomenon develops during reperfusion. The peptide pre-conditiones the microvasculature by reducing endothelial cell swelling and microvascular obstruction in advance, thereby preventing the formation of anatomic zones of no re-flow and improving clinical outcomes.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The aromatic-cationic peptide acts as a mediator between the reperfusion process and the microvasculature. It specifically targets and reduces endothelial cell swelling and microvascular obstruction, thereby facilitating improved tissue perfusion and preventing no-reflow without requiring direct mechanical intervention on the vessels.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If epicardial artery patency is restored, then coronary flow can be re-established, but microvascular obstruction and no-reflow zones persist

Engineering Contradiction:

Improvecoronary flow restorationVSAvoidtissue perfusion

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The aromatic-cationic peptide specifically targets the microvascular level rather than acting only at the epicardial artery level. By locally reducing endothelial cell swelling and microvascular obstruction in the microcirculation, it ensures that tissue perfusion is improved throughout the myocardium, not just at the macrovascular level.

Inventive Principle:

Principle #3Local quality

3Speed

If reperfusion is performed without peptide treatment, then blood flow can be restored, but microvascular injury and infarct size increase

Engineering Contradiction:

Improveblood flow restorationVSAvoidmicrovascular injury

Core Design Contradiction:

SpeedVSObject-affected harmful factors

Solution Approach 1:

The aromatic-cationic peptide is administered before reperfusion to pre-protect the microvasculature against injury. It reduces endothelial cell swelling and microvascular obstruction in advance, thereby counteracting the harmful effects of reperfusion-induced microvascular injury and reducing infarct size.

Inventive Principle:

Principle #9Preliminary anti-action

Data Source

PatentUS10322159B2Methods for the prevention or treatment of no-reflow following ischemia/reperfusion injury

Publication Date: 2019.06.18 STEALTH BIOTHERAPEUTICS INC

AI summary

The invention provides methods of preventing or treating cardiac ischemia-reperfusion injury in a mammalian subject. The methods provide administering aromatic-cationic peptides in effective amounts to prevent or treat an anatomic zone of no re-flow in mammalian subjects. The methods comprise administering to the subject an effective amount of an aromatic-cationic peptide to subjects in need thereof.