Structure-Activity Relation of N-alkyl Tetracaine Derivatives as Neurolytic Agents for Sciatic Nerve Lesions 

1998 ◽  
Vol 88 (2) ◽  
pp. 417-428 ◽  
Author(s):  
Ging Kuo Wang ◽  
Marina Vladimirov ◽  
Hao Shi ◽  
Wai Man Mok ◽  
Johann G. Thalhammer ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Nerve Block ◽  
Local Anesthetic ◽  
Drug Application ◽  
Rapid Onset ◽  
Na Channel ◽  
Channel Blockers ◽  
Sciatic Notch ◽  
Structure Activity

Background N-butyl tetracaine has local anesthetic and neurolytic properties. An injection of this drug at the rat sciatic notch produces rapid onset and nerve impairment lasting > 1 week. This study aimed to elucidate the structure-activity relation of various tetracaine derivatives to design better neurolytic agents. Methods N-alkyl tetracaine salts (n = 2-6) were synthesized, and their ability to elicit sciatic nerve impairment of sensory and motor functions in vivo was tested in rats. A single dose (0.1 ml at 37 mM) was administered close to the sciatic nerve at the sciatic notch. Regeneration was assessed morphologically in transverse sections of treated nerves. Finally, the drug potency in blocking Na+ currents was studied under voltage-clamp conditions. Results N-ethyl and N-propyl tetracaine derivatives were non-neurolytic and elicited complete sciatic nerve block lasting 3-7 h. In contrast, N-butyl, N-pentyl, and N-hexyl tetracaine derivatives were strong neurolytic agents and elicited functional impairment of sciatic nerve for > 1 week. All derivatives were strong Na+ channel blockers, more potent than tetracaine if applied intracellularly. External drug application showed marked differences in their wash-in rate: tetracaine > N-hexyl > N-butyl > N-ethyl tetracaine. All derivatives were trapped within the cytoplasm and showed little washout within 7 min. Conclusions When n-alkylation is 4-6, n-alkyl tetracaine appeared as a strong neurolytic agent. Neurolytic derivatives retained their local anesthetic activity and elicited rapid onset of nerve block after injection. Such derivatives are potential local anesthetic-neurolytic dual agents for chemical lesions of the sciatic nerve.

N -Phenylethyl Amitriptyline in Rat Sciatic Nerve Blockade

2002 ◽  
Vol 96 (6) ◽  
pp. 1435-1442 ◽  
Author(s):  
Peter Gerner ◽  
Mustafa Mujtaba ◽  
Mohammed Khan ◽  
Yukari Sudoh ◽  
Kamen Vlassakov ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Therapeutic Range ◽  
Local Anesthetic ◽  
Na Channel ◽  
Patch Clamp Technique ◽  
Rat Sciatic Nerve ◽  
Nerve Model

Background The antidepressant amitriptyline is commonly used orally for the treatment of chronic pain, particularly neuropathic pain, which is thought to be caused by high-frequency ectopic discharge. Among its many properties, amitriptyline is a potent Na(+) channel blocker in vitro, has local anesthetic properties in vivo, and confers additional blockade at high stimulus-discharge rates (use-dependent blockade). As with other drug modifications, adding a phenylethyl group to obtain a permanently charged quaternary ammonium derivative may improve these advantageous properties. Methods The electrophysiologic properties of N-phenylethyl amitriptyline were assessed in cultured neuronal GH(3) cells with the whole cell mode of the patch clamp technique, and the therapeutic range and toxicity were evaluated in the rat sciatic nerve model. Results In vitro, N-phenylethyl amitriptyline at 10 microm elicits a greater block of Na(+) channels than amitriptyline (resting block of approximately 90% vs. approximately 15%). This derivative also retains the attribute of amitriptyline in evoking high-degree use-dependent blockade during repetitive pulses. In vivo, duration to full recovery of nociception in the sciatic nerve model was 1,932 +/- 72 min for N-phenylethyl amitriptyline at 2.5 mm (n = 7) versus 72 +/- 3 min for lidocaine at 37 mm (n = 4; mean +/- SEM). However, there was evidence of neurotoxicity at 5 mm. Conclusion N-phenylethyl amitriptyline appears to have a narrow therapeutic range but is much more potent than lidocaine, providing a block duration several times longer than any clinically used local anesthetic. Further work in animal models of neuropathic pain will assess the potential use of this drug.

scholarly journals Ultralong Peripheral Nerve Block by Lidocaine:Prilocaine 1:1 Mixture in a Lipid Depot Formulation

2006 ◽  
Vol 104 (1) ◽  
pp. 110-121 ◽  
Author(s):  
Lars Söderberg ◽  
Henrik Dyhre ◽  
Bodil Roth ◽  
Sven Björkman
Keyword(s):  
Sciatic Nerve ◽  
Nerve Block ◽  
Local Anesthetic ◽  
In Vitro Release ◽  
Sciatic Nerve Block ◽  
Depot Formulation ◽  
Duration Of Action ◽  
Depot Preparations

Background The aim of this study was to develop stable and easily injectable lipid depot preparations of local anesthetics in which the drug concentration can be varied according to desired duration of action. Methods The formulations contained a 2.0, 5.0, 10, 20, 40, 60, 80, or 100% eutectic mixture of lidocaine and prilocaine base in medium-chain triglyceride. Duration of sciatic nerve block and local neurotoxicity was investigated in rats with 2.0% lidocaine:prilocaine HCl solution and 99.5% ethanol as controls. The rate of release of local anesthetic from the site of administration and the possibility to predict in vivo depot characteristics from in vitro release data were investigated for the 20 and 60% formulations. Results The duration of sensory sciatic block was prolonged 3 times with the 20% formulation and approximately 180 times with the 60% formulation, in comparison with the 2% aqueous solution. With the 80 and 100% formulations, all animals still showed nerve block after 2 weeks. The in vivo release of local anesthetic could be approximately predicted from in vitro data for the 20% but not for the 60% formulation. The formulations of 60% or greater and ethanol showed neurotoxic effects. Conclusions The pharmaceutical properties of these formulations compare favorably with those of other depot preparations. The high-percentage ones showed the longest duration of action yet reported for sciatic nerve block in rats. The possibility of using a high-concentration local anesthetic depot formulation as an alternative to ethanol or phenol for long-term nerve blocks in chronic pain merits further investigation.

The Critical Role of Concentration for Lidocaine Block of Peripheral Nerve In Vivo 

2003 ◽  
Vol 99 (5) ◽  
pp. 1189-1197 ◽  
Author(s):  
Tadashi Nakamura ◽  
Frederique Popitz-Bergez ◽  
John Birknes ◽  
Gary R. Strichartz
Keyword(s):  
Sciatic Nerve ◽  
Peripheral Nerve ◽  
Nerve Block ◽  
Local Anesthetic ◽  
Critical Role ◽  
Longitudinal Distribution ◽  
Total Drug ◽  
Sprague Dawley ◽  
Minimal Blocking

Background The adjustment of local anesthetic dosage for peripheral nerve block must meet two basic requirements: a drug concentration sufficient to inhibit Na+ channels to the point of impulse failure and a volume of drug sufficient to expose a length of nerve longer than the "critical length" for propagation failure. This study examines the lidocaine dosage requirement, in milligrams, for functionally assayed sciatic nerve block in the rat using a fourfold range of volume corresponding to concentrations from 2 to 7 mg/ml and compares these blocks with the intraneural lidocaine content after injection of equipotent doses. Methods Lidocaine was injected percutaneously at the sciatic nerve in volumes of 0.05 ml, 0.1 ml, and 0.2 ml (all at pH 6.8), and quantitative neurobehavioral assays were conducted on male Sprague-Dawley rats weighing from 200 to 250 g. The dose requirements for 50% maximum possible effect (ED50) and for just achieving complete block (i.e., minimal blocking dose for 90% effect), the fraction of completely blocked animals, and the duration of complete block at all doses were assessed for the inhibition of three different functions: proprioception, motor, and nocifensive activities. Radiolabeled (14C) lidocaine was injected in separate experiments, and the total drug content and its longitudinal distribution were determined in nerves dissected from animals (sevoflurane anesthetized) at 10 min, the time of peak block, after injection of the E50 and minimal blocking dose for 100% effect for the three different volumes. Results For all functions, the smaller the volume, the lower was the E50, resulting in a nearly constant concentration to achieve an equivalent degree of block. Durations of block were longer, and the dose to full block was lower for the smaller injected volumes. Intraneural lidocaine, at the equipotent doses for analgesia, was not related to concentration but rather increased with increasing volume, being almost proportional to the given dose. The longitudinal spread of lidocaine was also greater with increasing volume of lidocaine solution. Conclusion Blocks of greater depth and longer duration result from injection of smaller volumes and, correspondingly, higher lidocaine concentrations containing the same dose. The corollary is that lower lidocaine doses are required to achieve the same effect when smaller volumes are injected. Curiously, when the equivalent E50 is injected, total drug taken into the nerve is less from the smaller volumes than from the larger volumes, even though the peak functional effects are equal. Total intraneural local anesthetic may not represent the effective drug in the compartment that contains nerve axons, the actual location of neural blockade.

Pharmacodynamics and Pharmacokinetics of Lidocaine in a Rodent Model of Diabetic Neuropathy

2018 ◽  
Vol 128 (3) ◽  
pp. 609-619 ◽  
Author(s):  
Werner ten Hoope ◽  
Markus W. Hollmann ◽  
Kora de Bruin ◽  
Hein J. Verberne ◽  
Arie O. Verkerk ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Diabetic Neuropathy ◽  
Nerve Block ◽  
Local Anesthetic ◽  
Local Anesthetics ◽  
Nerve Fibers ◽  
Rodent Model ◽  
Sciatic Nerve Block ◽  
Zucker Diabetic Fatty Rats

Abstract Background Clinical and experimental data show that peripheral nerve blocks last longer in the presence of diabetic neuropathy. This may occur because diabetic nerve fibers are more sensitive to local anesthetics or because the local anesthetic concentration decreases more slowly in the diabetic nerve. The aim of this study was to investigate both hypotheses in a rodent model of neuropathy secondary to type 2 diabetes. Methods We performed a series of sciatic nerve block experiments in 25 Zucker Diabetic Fatty rats aged 20 weeks with a neuropathy component confirmed by neurophysiology and control rats. We determined in vivo the minimum local anesthetic dose of lidocaine for sciatic nerve block. To investigate the pharmacokinetic hypothesis, we determined concentrations of radiolabeled (14C) lidocaine up to 90 min after administration. Last, dorsal root ganglia were excised for patch clamp measurements of sodium channel activity. Results First, in vivo minimum local anesthetic dose of lidocaine for sciatic nerve motor block was significantly lower in diabetic (0.9%) as compared to control rats (1.4%). Second, at 60 min after nerve block, intraneural lidocaine was higher in the diabetic animals. Third, single cell measurements showed a lower inhibitory concentration of lidocaine for blocking sodium currents in neuropathic as compared to control neurons. Conclusions We demonstrate increased sensitivity of the diabetic neuropathic nerve toward local anesthetics, and prolonged residence time of local anesthetics in the diabetic neuropathic nerve. In this rodent model of neuropathy, both pharmacodynamic and pharmacokinetic mechanisms contribute to prolonged nerve block duration.

Relation between Functional Deficit and Intraneural Local Anesthetic during Peripheral Nerve Block

1995 ◽  
Vol 83 (3) ◽  
pp. 583-592. ◽  
Author(s):  
F. A. Popitz-Bergez ◽  
S. Leeson ◽  
G. R. Strichartz ◽  
J. G. Thalhammer
Keyword(s):  
Steady State ◽  
Sciatic Nerve ◽  
Peripheral Nerve ◽  
Nerve Block ◽  
Local Anesthetic ◽  
Peripheral Nerve Block ◽  
Longitudinal Distribution ◽  
Functional Block

Background During peripheral nerve block, local anesthetic (LA) penetrates within and along the nerve to produce the observed functional deficits. Although much is known about the kinetics and steady-state relation for LA inhibition of impulse activity in vitro in isolated nerve, little is known about the relation between functional loss and intraneural LA content in vivo. This study was undertaken to investigate the relation of functional change to intraneural LA. Methods A sciatic nerve block was performed in rats with 0.1 ml 1% lidocaine radiolabeled with 14C. The total intraneural uptake of LA was determined at different times after injection, and the distribution of lidocaine along the nerve was assayed at different stages of functional block. Drug content was also compared with equilibrium lidocaine uptake in the isolated rat sciatic nerve. Results Total intraneural lidocaine in vivo increased to near steady-state in about 3 min, stabilizing at approximately 14.3 nmol/mg wet tissue for about 12 min before decreasing to zero at 70 min after injection. Although intraneural lidocaine was 1.6% of the injected dose during full block, only 0.3% was left when deep pain sensation returned and 0.065% was still detected when functions fully recovered. Despite these large differences in total lidocaine content, the longitudinal distribution remained constant. Intraneural lidocaine concentrations obtained at full block and partial recovery could be achieved in vitro by equilibration in 0.7-0.9 and 0.2-0.3 mM lidocaine, respectively. Conclusions During peripheral nerve block only a small amount of injected LA penetrates into the nerve. The intraneural content of LA correlates with the depth of functional block.

The Local Anesthetic Properties and Toxicity of Saxitonin Homologues for Rat Sciatic Nerve Block In Vivo

2000 ◽  
Vol 25 (1) ◽  
pp. 52-59 ◽  
Author(s):  
Daniel S. Kohane ◽  
Nu T. Lu ◽  
Arman C. Gökgöl-Kline ◽  
Maria Shubina ◽  
Yu Kuang ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Nerve Block ◽  
Local Anesthetic ◽  
Sciatic Nerve Block ◽  
Rat Sciatic Nerve

The local anesthetic properties and toxicity of saxitonin homologues for rat sciatic nerve block in vivo

2000 ◽  
Vol 25 (1) ◽  
pp. 52-59 ◽  
Author(s):  
D KOHANE ◽  
N LU ◽  
A GOKGOLKLINE ◽  
M SHUBINA ◽  
Y KUANG ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Nerve Block ◽  
Local Anesthetic ◽  
Sciatic Nerve Block ◽  
Rat Sciatic Nerve

scholarly journals Intraneural Ultrasound-guided Sciatic Nerve Block

2018 ◽  
Vol 129 (2) ◽  
pp. 241-248 ◽  
Author(s):  
Gianluca Cappelleri ◽  
Andrea Luigi Ambrosoli ◽  
Marco Gemma ◽  
Valeria Libera Eva Cedrati ◽  
Federico Bizzarri ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Nerve Block ◽  
Local Anesthetic ◽  
Sciatic Nerve Block ◽  
Effective Volume ◽  
Ultrasound Guided ◽  
Biased Coin Design ◽  
Patient Reported ◽  
Sensory Motor

Abstract What We Already Know about This Topic What This Article Tells Us That Is New Background Both extra- and intraneural sciatic injection resulted in significant axonal nerve damage. This study aimed to establish the minimum effective volume of intraneural ropivacaine 1% for complete sensory-motor sciatic nerve block in 90% of patients, and related electrophysiologic variations. Methods Forty-seven consecutive American Society of Anesthesiologists physical status I-II patients received an ultrasound-guided popliteal intraneural nerve block following the up-and-down biased coin design. The starting volume was 15 ml. Baseline, 5-week, and 6-month electrophysiologic tests were performed. Amplitude, latency, and velocity were evaluated. A follow-up telephone call at 6 months was also performed. Results The minimum effective volume of ropivacaine 1% in 90% of patients for complete sensory-motor sciatic nerve block resulted in 6.6 ml (95% CI, 6.4 to 6.7) with an onset time of 19 ± 12 min. Success rate was 98%. Baseline amplitude of action potential (mV) at ankle, fibula, malleolus, and popliteus were 8.4 ± 2.3, 7.1 ± 2.0, 15.4 ± 6.5, and 11.7 ± 5.1 respectively. They were significantly reduced at the fifth week (4.3 ± 2.1, 3.5 ± 1.8, 6.9 ± 3.7, and 5.2 ± 3.0) and at the sixth month (5.9 ± 2.3, 5.1 ± 2.1, 10.3 ± 4.0, and 7.5 ± 2.7) (P < 0.001 in all cases). Latency and velocity did not change from the baseline. No patient reported neurologic symptoms at 6-month follow-up. Conclusions The intraneural ultrasound-guided popliteal local anesthetic injection significantly reduces the local anesthetic dose to achieve an effective sensory-motor block, decreasing the risk of systemic toxicity. Persistent electrophysiologic changes suggest possible axonal damage that will require further investigation.

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