Benzonatate as a local anesthetic

Introduction Benzonatate is an FDA-approved antitussive agent that resembles tetracaine, procaine, and cocaine in its chemical structure. Based on structural similarities to known local anesthetics and recent findings of benzonatate exerting local anesthetic-like effects on voltage-gated sodium channels in vitro, we hypothesized that benzonatate will act as a local anesthetic to yield peripheral nerve blockade. Methods Benzonatate was injected at the sciatic nerve of Sprague-Dawley rats. Sensory and motor blockade were assessed using a modified hot plate test and a weight-bearing test, respectively. Additionally, the effect of co-injection with tetrodotoxin and Tween 80 (a chemical permeation enhancer) was examined. Myotoxicity of benzonatate was assessed in vivo by histological analysis. Results Benzonatate produced a concentration-dependent sensory and motor nerve blockade with no appreciable systemic effects. Co-injection with tetrodotoxin or Tween 80 produced prolongation of sensory nerve blockade. Histologic assessment showed significant inflammation and myotoxicity from benzonatate injection, even at low concentrations. Conclusion This study demonstrates that benzonatate does act as a local anesthetic at the peripheral nerve, with sensory and motor nerve blockade. Benzonatate interacts with tetrodotoxin and Tween 80 to prolong nerve blockade. However, benzonatate causes significant myotoxicity, even at subtherapeutic concentrations

Formulations injected at the sciatic nerve.

IntroductionBenzonatate is an FDA-approved antitussive agent that resembles tetracaine, procaine, and cocaine in its chemical structure. Based on structural similarities to known local anesthetics and recent findings of benzonatate exerting local anesthetic-like effects on voltage-gated sodium channels in vitro, we hypothesized that benzonatate will act as a local anesthetic to yield peripheral nerve blockade.MethodsBenzonatate was injected at the sciatic nerve of Sprague-Dawley rats. Sensory and motor blockade were assessed using a modified hot plate test and a weight-bearing test, respectively. Additionally, the effect of co-injection with tetrodotoxin and Tween 80 (a chemical permeation enhancer) was examined. Myotoxicity of benzonatate was assessed in vivo by histological analysis.ResultsBenzonatate produced a concentration-dependent sensory and motor nerve blockade with no appreciable systemic effects. Co-injection with tetrodotoxin or Tween 80 produced prolongation of sensory nerve blockade. Histologic assessment showed significant inflammation and myotoxicity from benzonatate injection, even at low concentrations.ConclusionThis study demonstrates that benzonatate does act as a local anesthetic at the peripheral nerve, with sensory and motor nerve blockade. Benzonatate interacts with tetrodotoxin and Tween 80 to prolong nerve blockade. However, benzonatate causes significant myotoxicity, even at subtherapeutic concentrations.</div

Quantification of tissue reaction.

(A) Inflammation and (B) myotoxicity scores of animals injected at the sciatic nerve with benzonatate and bupivacaine. Equieffective concentrations have the same shading. Data are medians with 25th and 75th percentiles, n = 4 for all groups. * p < 0.05 for the comparison of equieffective concentrations by Mann-Whitney U test.</p

Tissue toxicity of benzonatate: Inflammation and myotoxicity scores.

Tissue toxicity of benzonatate: Inflammation and myotoxicity scores.</p

Quantification of tissue reaction represented by a box and whisker plot.

(a) Inflammation and (b) myotoxicity scores of animals injected at the sciatic nerve with benzonatate and bupivacaine. Equieffective concentrations have the same shading. Data are medians with 25th and 75th percentiles, n = 4 for all groups. Note that the median value (bar) overlaps with the 25th or 75th percentiles (box) for multiple data points. * P (DOCX)</p

Formulations injected at the sciatic nerve.

IntroductionBenzonatate is an FDA-approved antitussive agent that resembles tetracaine, procaine, and cocaine in its chemical structure. Based on structural similarities to known local anesthetics and recent findings of benzonatate exerting local anesthetic-like effects on voltage-gated sodium channels in vitro, we hypothesized that benzonatate will act as a local anesthetic to yield peripheral nerve blockade.MethodsBenzonatate was injected at the sciatic nerve of Sprague-Dawley rats. Sensory and motor blockade were assessed using a modified hot plate test and a weight-bearing test, respectively. Additionally, the effect of co-injection with tetrodotoxin and Tween 80 (a chemical permeation enhancer) was examined. Myotoxicity of benzonatate was assessed in vivo by histological analysis.ResultsBenzonatate produced a concentration-dependent sensory and motor nerve blockade with no appreciable systemic effects. Co-injection with tetrodotoxin or Tween 80 produced prolongation of sensory nerve blockade. Histologic assessment showed significant inflammation and myotoxicity from benzonatate injection, even at low concentrations.ConclusionThis study demonstrates that benzonatate does act as a local anesthetic at the peripheral nerve, with sensory and motor nerve blockade. Benzonatate interacts with tetrodotoxin and Tween 80 to prolong nerve blockade. However, benzonatate causes significant myotoxicity, even at subtherapeutic concentrations.</div

Representative light microscopy of hematoxylin/eosin-stained sections of nerves (n), muscles (m), and surrounding tissues at the site of injection.

Tissues were collected 4 days after injection with equieffective concentrations of benzonatate and bupivacaine. Infl: Inflammation. Mtox: Myotoxicity. Nec: Necrosis.</p

Characterization of benzonatate.

(A) chemical structure of benzonatate (B) LC-MS of benzonatate used in this study.</p

Effect of co-administration of benzonatate (Benz, 12.4 mM) with TTX (30 μM) or T80 (23 mM).

(A) frequency of successful sensory nerve block (B) duration of sciatic sensory and motor nerve block. Data are medians with 25th and 75th percentiles, n = 8 per group except benzonatate administration with n = 12 (note that administration of T80 alone resulted in no sensory or motor block for all animals). Duration of nerve block were compared by a Kruskal-Wallis test (p = 0.0001) with post-hoc pairwise comparison with Bonferroni correction (p<0.01 for sensory and motor blockade following co-administration of benzonatate and TTX compared to benzonatate alone).</p

Targeted siRNA Nanoparticles for Mammary Carcinoma Therapy

Non-viral, polymeric-based, siRNA nanoparticles (NPs) have been proposed as promising gene delivery systems. Encapsulating siRNA in targeted NPs could confer improved biological stability, extended half-life, enhanced permeability, effective tumor accumulation, and therapy. In this work, a peptide derived from apolipoprotein B100 (ApoB-P), the protein moiety of low-density lipoprotein, was used to target siRNA-loaded PEGylated NPs to the extracellular matrix/proteoglycans (ECM/PGs) of a mammary carcinoma tumor. siRNA against osteopontin (siOPN), a protein involved in breast cancer development and progression, was encapsulated into PEGylated poly(d,l-lactic-co-glycolic acid) (PLGA) NPs using the double emulsion solvent diffusion technique. The NPs obtained possessed desired physicochemical properties including ~200 nm size, a neutral surface charge, and high siOPN loading of ~5 &#181;g/mg. ApoB-P-targeted NPs exhibited both enhanced binding to isolated ECM and internalization by MDA-MB-231 human mammary carcinoma cells, in comparison to non-targeted NPs. Increased accumulation of the targeted NPs was achieved in the primary mammary tumor of mice xenografted with MDA-MB-231 mammary carcinoma cells as well as in the lungs, one of the main sites affected by metastases. siOPN NPs treatment resulted in significant inhibition of tumor growth (similar bioactivity of both formulations), accompanied with significant reduction of OPN mRNA levels (~40% knockdown of mRNA levels). We demonstrated that targeted NPs possessed enhanced tumor accumulation with increased therapeutic potential in mice models of mammary carcinoma