ABSTRACT
Classical local anesthetics are unsuitable to treat regional pain lasting several days due to their limited duration and systemic toxicity. Self-delivery nano systems without excipients were designed for long-term sensory blocks. 1a self-assembled into different vehicles with different fractions of intermolecular π-π stacking, transported itself into nerve cells, and released single molecules slowly to achieve long-term duration for rats' sciatic nerve block for 11.6 h in water, 12.1 h in water with CO2 and 3.4 h in NS (normal saline). After the counter ions were changed to SO42-, 1e can self-assemble into vesicles and prolong the duration to 43.2 h, which was much longer than the 3.8 h led by (s)-bupivacaine hydrocloride (0.75%). This was mainly caused by the enhancement of self-release and counter ion exchange inside nerve cells, which were affected by the gemini surfactant structure, pKa of the counter ions and π-π stacking interactions.
Subject(s)
Anesthetics, Local , Nerve Block , Rats , Animals , Sciatic Nerve/physiology , Bupivacaine , InjectionsABSTRACT
In this work, a series of water-soluble propofol prodrugs were synthesized, and their propofol release rate and pharmacodynamic characteristics were measured. We found that inserting glycolic acid as a linker between propofol and the cyclic amino acid accelerated the release of propofol from prodrugs into the plasma while preserving its safety. In animal experiments, prodrugs (3e, 3g, and 3j) were significantly better than fospropofol (the only water-soluble propofol prodrug that has been used clinically) in terms of safety, onset, and duration time of anesthesia. Their molar dose, onset time, and anesthesia duration time were comparable to those of propofol, helping to maintain the clinical benefits of propofol. The experimental results showed the potential of such compounds as water-soluble prodrugs of propofol.
