Mepivacaine Hydrochloride

Heterocyclic compounds play a crucial role in the discovery of therapeutics. Alzheimer's disease (AD) is an unfathomable sporadic neurodegenerative disorder that involves multiple pathological pathways. The failure of current single-target small molecules to address AD's underlying causes has prompted interest in discovering multi-target directed ligands (MTDLs) to slow down the disease's progression. Herein we report the synthesis and biological evaluation of indole-piperidine amides as MTDLs for AD. The 5,6-dimethoxy-indole N-(2-(1-benzylpiperidine) carboxamide (23a) inhibits hAChE and hBACE-1 with IC₅₀ values of 0.32 and 0.39 μM, respectively. The MTDL 23a is a mixed-type inhibitor of both hAChE and hBACE-1 with K_i values of 0.26 μM and 0.46 μM, respectively. The MD simulation studies revealed that both AChE and BACE-1 experience minor conformational changes on binding with 23a. In the PAMPA-BBB assay, analog 23a demonstrated CNS permeability, indicating the possibility for future investigation in preclinical models of AD.

To determine if targeted blocking of frontal and infratrochlear nerves provided anesthesia for the approach to a frontonasal sinusotomy.

Two part study: Part 1 randomized crossover design; Part 2 proof of concept. Animals: N = 12; six each in Parts 1 and 2.

Part 1: Each horse had either frontal and infratrochlear nerve blocks or a line block performed with 2% mepivacaine hydrochloride. Mechanical nociceptive thresholds (MNT) were obtained at five sites along a proposed frontonasal sinusotomy prior to injection, and at 10, 60, and 120 min after blocking. After a 4 day washout period, the opposite procedure was performed. Order of procedure and side of face were randomized. MNTs were analyzed using mixed‐model ANOVA with p < .05. Part 2: Frontal and infratrochlear nerve blocks were performed followed by creation of a skin/periosteal incision, which was closed at 2 h. Ability to create and suture the incision, and the size of the incision were recorded.

For part 1, both line and targeted blocks resulted in at least two times an increase in median MNT values at each of the five sites, as compared to baseline MNT values (p < .0025). In Part 2, incisions could be completed in five of six horses, with median incision size of 6.5 × 5 cm.

Following frontal and infratrochlear nerve blocks, MNTs were increased along a proposed frontonasal sinusotomy, and skin incisions could be created in the majority of horses.

Frontal and infratrochlear nerve blocks provide an alternative technique to create a frontonasal sinusotomy.