Dantrolene RyR2 Modulation for Dyssynchronous Cardiac Dysfunction

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Solution Overview

Problem

Current treatments for dyssynchronous cardiac dysfunction are limited, as they primarily target neurohormonal activation and fibrosis, and do not effectively address mechanical dyssynchrony, often requiring invasive surgical procedures or regional calcium cycling modifications that are not universally effective.

Innovation Solution

The chronic administration of dantrolene or its analogs, such as azumolene, to patients at risk of or with dyssynchronous cardiac dysfunction, which acts as a RyR2 modulator to resynchronize calcium cycling and prevent the development or worsening of dyssynchronous cardiac dysfunction.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If pharmacological treatments target neurohormonal activation and fibrosis, then some therapeutic effect is achieved, but mechanical dyssynchrony is not addressed

Engineering Contradiction:

Improvetherapeutic effectivenessVSAvoidability to address mechanical dyssynchrony

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent changes the pharmacological target from neurohormonal pathways to calcium cycling parameters. Dantrolene and its analogs modify the RyR2 receptor function to improve calcium release synchrony, directly addressing mechanical dyssynchrony while maintaining pharmacological (non-device) treatment approach

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent segments the treatment approach by specifically targeting the RyR2 receptor and calcium cycling mechanism separately from neurohormonal pathways. This allows simultaneous or complementary treatment of both neurohormonal activation and mechanical dyssynchrony through distinct pharmacological mechanisms

Inventive Principle:

Principle #1Segmentation

2Adaptability or versatility

If hardware devices such as cardiac resynchronizing pacemakers are implanted to address mechanical dyssynchrony, then dyssynchrony is corrected, but surgical complexity and complication risks increase

Engineering Contradiction:

Improveability to address mechanical dyssynchronyVSAvoidsurgical procedure complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent replaces the mechanical device-based solution (pacemakers, defibrillators) with a pharmacological solution. Dantrolene and its analogs achieve mechanical dyssynchrony correction through biochemical modulation of calcium release, eliminating the need for implanted hardware and associated surgeries

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The patent introduces a pharmacological intermediary (dantrolene or analogs) that mediates the correction of mechanical dyssynchrony. The drug acts as an intermediary substance that modulates RyR2 receptor function to improve calcium release synchrony, replacing the need for direct mechanical intervention through devices

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If acute administration of dantrolene is given immediately prior to cardiac arrest, then protective effect against arrhythmia is achieved, but the approach is not useful for chronic therapy due to unpredictable timing

Engineering Contradiction:

Improveprotective effect against arrhythmiaVSAvoidpredictability of administration timing

Core Design Contradiction:

ReliabilityVSLoss of time

Solution Approach 1:

The patent applies preliminary action by chronically administering dantrolene or its analogs before cardiac dysfunction or arrhythmia occurs. This continuous pre-treatment ensures the RyR2 receptors are already modulated and ready to function properly, providing protection against future arrhythmic events without requiring prediction of when they will occur

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent establishes continuity of useful action through chronic administration of dantrolene. Instead of a single acute dose, the drug is administered continuously over time to maintain steady-state levels that consistently modulate calcium cycling and prevent dyssynchrony development, making the protective effect continuous rather than intermittent

Inventive Principle:

Principle #20Continuity of useful action

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

This approach effectively resynchronizes calcium cycling, preventing the progression of dyssynchronous cardiac dysfunction and improving cardiac contractility without the need for invasive devices, as demonstrated by reduced calcium alternans ratios and improved cardiac function in preclinical models.

Implementation Method 1

Dantrolene, or a derivative, an analog, solvate or hydrate or a mixture of any of the foregoing may be useful as a RyR2 modulator to improve calcium release and/or uptake synchrony

Methodology Applied

Scientific EffectRyanodine receptor modulation:

Data Source

PatentUS11123328B2Dantrolene and analogs thereof for the chronic treatment and prevention of dyssynchronous cardiac dysfunction

Publication Date: 2021.09.21 UNIV HEALTH NETWORK

AI summary

The present disclosure relates to methods for the chronic treatment of dyssynchronous cardiac dysfunction (including non-arrhythmia cardiac dysfunction such as heart failure, cardiomyopathy, viral myocarditis, ischemia induced cardiomyopathy, ischemia, chemotherapy, pacing induced cardiomyopathy or ion channel mutation related dysfunction) and for the prevention or treatment of diseases or conditions associated with dyssynchronous cardiac dysfunction. The method comprises chronically administering to a patient an effective amount of dantrolene, or derivative or analogs thereof (such as azumolene).