Reversible Neuromuscular Blockade Agents via Thiol Reversal
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Solution Overview
Problem
Current neuromuscular blockade agents used in surgery can cause prolonged paralysis of muscles, including the diaphragm, requiring mechanical respiration and posing challenges for post-surgical recovery.
Innovation Solution
Development of novel neuromuscular blockade agents, specifically compounds of formula (I), which induce reversible neuromuscular blockade upon administration, allowing for rapid reversal with thiol compounds like L-cysteine or glutathione, facilitating safe and efficient surgical procedures.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional neuromuscular blockade agents are used, then effective surgical paralysis is achieved, but prolonged paralysis including diaphragm paralysis occurs requiring mechanical respiration
Solution Approach 1:
The patent introduces a thiol compound as an intermediary substance that reverses the neuromuscular blockade. The thiol compound mediates the termination of the blocking effect by reacting with the neuromuscular blocking agent, thereby restoring muscle function. This resolves the contradiction by adding a reversing mechanism without compromising the initial blocking effectiveness.
Solution Approach 2:
The patent modifies the chemical structure of conventional neuromuscular blocking agents by introducing specific substituents (R1-R14, m1-m4, n1-n2, p1-p2) that create compounds with reversible binding characteristics. These structural parameter changes enable the agents to be reversed by thiol compounds while maintaining their blocking effectiveness during surgery.
2Ease of operation
If neuromuscular blockade agents are used during surgery, then patient immobilization is achieved, but extended mechanical respiration support is required post-surgery
Solution Approach 1:
The thiol compound serves as a mediator to rapidly terminate the neuromuscular blockade effect after surgery. By administering the thiol compound, surgeons can quickly restore muscle function and breathing, significantly reducing the time patients require mechanical respiration support and accelerating post-surgical recovery.
Solution Approach 2:
The patent establishes a preliminary reversible binding mechanism in the drug design, where the neuromuscular blocking agent is structurally configured to be reversibly bound by thiol compounds. This preliminary design ensures that the blockade can be quickly terminated when needed, reducing recovery time without compromising surgical immobilization.
3Reliability
If conventional neuromuscular blocking agents are administered, then surgical paralysis is achieved, but rapid reversal is not possible
Solution Approach 1:
The thiol compound acts as a chemical intermediary that rapidly reverses the neuromuscular blockade through specific chemical reactions. This intermediary mechanism enables fast reversal of paralysis while maintaining the reliability of the initial blocking effect during surgery, directly addressing the speed-reversal need.
Solution Approach 2:
The patent introduces specific chemical parameter changes in the neuromuscular blocking agent structure (substituents R1-R14, ring structures with m1-m4 and n1-n2) that create high-affinity binding sites for thiol compounds. These parameter changes enable rapid reversible binding kinetics, allowing fast termination of the blocking effect when thiol compounds are administered.
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 novel agents provide effective neuromuscular blockade with the option for rapid reversal, minimizing the duration of mechanical respiration and enhancing post-surgical recovery by using thiol compounds to quickly terminate the neuromuscular blockade.
Implementation Method 1
the neuromuscular blockade is reversible by administration to the patient of an effective amount of a thiol compound
Data Source
AI summary
The invention provides neuromuscular blockade agents of the non-depolarizing type with few if any circulatory effects. Compounds of the invention include bis(isoquinolylalkanol) diesters of fumaric, maleic, succinic, and acetylenedicarboxylic acids; compositions suitable for parenteral administration of these compounds as a surgical adjunct to anesthesia, and methods of preparation of the compounds. Compounds of the invention can produce neuromuscular blockade of short or intermediate duration, which for various compounds can be reversed by administration of a thiol compound such as L-cysteine, D-cysteine or glutathione. For various compounds of the invention, the neuromuscular blockade effect can be reversed quickly, efficiently, and without notable side-effects.