Assessment of Differential Blockade by Amitriptyline and Its N -Methyl Derivative in Different Species by Different Routes

2003 ◽  
Vol 98 (6) ◽  
pp. 1484-1490 ◽  
Author(s):  
Peter Gerner ◽  
Anna E. Haderer ◽  
Mustafa Mujtaba ◽  
Yukari Sudoh ◽  
Sanjeet Narang ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Nerve Fibers ◽  
Spinal Block ◽  
Na Channel ◽  
Channel Blockers ◽  
Patch Clamp Technique ◽  
Duration Of Action ◽  
Drug Concentrations ◽  
Nerve Model

Background Increasing the duration of local anesthesia and/or creating greater differential blockade (i.e., selective block of pain-transmitting nerve fibers) has been attempted by modifying currently available agents. Most drugs show a different profile depending on the model or species studied. This study was designed to investigate the differential nerve-blocking properties of amitriptyline and its quaternary ammonium derivative in rats and sheep. Methods The Na+ channel-blocking properties of N-methyl amitriptyline were determined with the patch clamp technique in cultured GH(3) cells. Various functions (motor, nociception, proprioception-ataxia) were compared in rats (spinal and sciatic nerve blockade) and sheep (spinal blockade) with amitriptyline, N-methyl amitriptyline, lidocaine, and bupivacaine (partially from historical data). Results In vitro testing revealed N-methyl amitriptyline to be a potent Na+ channel blocker similar to amitriptyline but with a much longer duration of action. All drug concentrations tested in both the sciatic nerve model and the spinal block model produced no significant differential blockade in rats. Three of six rats in the 20-mM N-methyl amitriptyline group showed residual blockade 4 days after sciatic nerve injection. However, in the sheep spinal model, amitriptyline and in particular N-methyl amitriptyline displayed significant differential blockade at most time points. Sheep data for lidocaine and bupivacaine seemed to be more comparable to the clinical experience in humans than did rat data. Conclusions Amitriptyline and N-methyl amitriptyline are potent Na+ channel blockers and show greater differential blockade in sheep than in rats. This differential blockade in sheep is greater than that produced by lidocaine or bupivacaine.

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.

Ephedrine Blocks Rat Sciatic Nerve In Vivo  and Sodium Channels In Vitro 

2005 ◽  
Vol 103 (6) ◽  
pp. 1246-1252 ◽  
Author(s):  
Yu-Chun Hung ◽  
Yi-Chuan Kau ◽  
Anthony M. Zizza ◽  
Thomas Edrich ◽  
David Zurakowski ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Local Anesthetic ◽  
Local Anesthetics ◽  
Repeated Measures ◽  
High Frequency Stimulation ◽  
Na Channel ◽  
Patch Clamp Technique ◽  
Rat Sciatic Nerve ◽  
Lateral Incision

Background The sympathomimetic drug ephedrine has been used intrathecally as the sole local anesthetic for labor and delivery. Because ephedrine may be a useful adjuvant to local anesthetics, the authors investigated the local anesthetic properties of ephedrine in a rat sciatic nerve block model and the underlying mechanism in cultured cells stably expressing Na channels. Methods After approval of the animal protocol, the sciatic nerves of anesthetized rats were exposed by lateral incision of the thighs, 0.2 ml ephedrine at 0.25, 1, 2.5, or 5% and/or bupivacaine at 0.125% was injected, and the wound was closed. Motor and sensory/nociceptive functions were evaluated by the force achieved by pushing against a balance and the reaction to pinch, respectively. The whole cell configuration of the patch clamp technique was used to record Na currents from human embryonal kidney cells stably transfected with Nav1.4 channels. Results The nociception blockade was significantly longer than the motor blockade at test doses of 2.5 and 5% of ephedrine, or when 1% ephedrine was combined with 0.125% bupivacaine (analysis of variance with repeated measures, P < 0.001, n = 8/group). In vitro, the 50% inhibitory concentrations of ephedrine at -150 and -60 mV were 1,043 +/- 70 and 473 +/- 13 mum, respectively. High-frequency stimulation revealed a use-dependent block of 18%, similar to most local anesthetics. Conclusions Because ephedrine's properties are at least partly due to Na channel blockade, detailed histopathologic investigations are justified to determine the potential of ephedrine as an adjuvant to clinically used local anesthetics.

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.

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.

N-Butyl Tetracaine as a Neurolytic Agent for Ultralong Sciatic Nerve Block

1996 ◽  
Vol 85 (6) ◽  
pp. 1386-1394. ◽  
Author(s):  
G. K. Wang ◽  
M. Vladimirov ◽  
C. Quan ◽  
W. M. Mok ◽  
J. G. Thalhammer ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Nerve Block ◽  
Local Anesthetic ◽  
Single Injection ◽  
Nerve Fibers ◽  
Sciatic Nerve Block ◽  
Na Currents ◽  
Dependent Inhibition ◽  
Withdrawal Response

Background Neurolytic agents such as phenol (5% to 10%) and absolute alcohol have long been used clinically to destroy the pathogenic nerve regions that manifest pain. Both phenol and alcohol are highly destructive to nerve fibers. However, these agents exert only weak local anesthetic effects and therefore are difficult to administer to alert patients without pain. This report describes a tetracaine derivative that displays both local anesthetic and neurolytic properties. Studies with such a compound may lead to the design of neurolytic agents that are more effective and more easily administered than phenol and alcohol. Methods A tetracaine derivative, N-butyl tetracaine quaternary ammonium bromide, was synthesized, and its ability to elicit sciatic nerve block of sensory and motor functions in vivo was tested in rats. A single dose of 0.1 ml N-butyl tetracaine at 37 mM was injected into the sciatic notch. Transverse sections of treated sciatic nerves were subsequently examined to determine the neurolytic effect of this drug. Finally, the local anesthetic properties of N-butyl tetracaine were studied in vitro; both tonic inhibition and use-dependent inhibition of Na+ currents in neuronal GH3 cells were characterized under whole-cell voltage-clamp conditions. Results N-butyl tetracaine at 37 mM (equivalent to 1.11% tetracaine-hydrochloric acid concentration) elicited prolonged sciatic nerve block of the withdrawal response to noxious pinch in rats for more than 2 weeks. The withdrawal response was fully restored after 9 weeks. Parallel to sensory block, motor functions of the hind legs were similarly blocked by this drug. Morphologic examinations 3 and 5 weeks after a single injection of drug revealed degeneration of many sciatic nerve fibers, consistent with the results of functional tests. Finally, N-butyl tetracaine was found to be a potent Na+ channel blocker in vitro. It produced strong tonic and use-dependent inhibition of Na+ currents with a potency comparable to that of tetracaine. Conclusions A single injection of N-butyl tetracaine produces ultralong sciatic nerve block in rats. This compound possesses both local anesthetic and neurolytic properties and may prove useful as a neurolytic agent in pain management.

Development of 4-AP and TEA sensitivities in mammalian myelinated nerve fibers

1988 ◽  
Vol 60 (6) ◽  
pp. 2168-2179 ◽  
Author(s):  
D. L. Eng ◽  
T. R. Gordon ◽  
J. D. Kocsis ◽  
S. G. Waxman
Keyword(s):  
Sciatic Nerve ◽  
Action Potential ◽  
Compound Action Potential ◽  
Nerve Fibers ◽  
Repetitive Firing ◽  
Base Line ◽  
Channel Blockers ◽  
Myelinated Nerve ◽  
Sucrose Gap ◽  
Compound Action

1. The sensitivities of mammalian myelinated axons to potassium channel blockers was studied over the course of development using in vitro sucrose gap and intra-axonal recording techniques. 2. Application of 4-aminopyridine (4-AP; 1.0 mM) to young nerves led to a delay in return to base line of the sciatic nerve compound action potential and to a postspike positivity (indicative of hyperpolarization) lasting for tens of milliseconds. These effects were very much attenuated during the course of maturation. 3. Tetraethylammonium chloride (TEA; 10 mM) application alone had little effect on the waveform of the compound action potential at any age. However, the 4-AP-induced postspike positivity was blocked by TEA, Ba/+, and Cs+. This block was observed in Ca2+-free electrolyte solutions containing EGTA (1.0 mM). 4. Immature sciatic nerves (approximately 3 wk postnatal) were incubated in a potassium-free electrolyte solution containing 120 mM CsCl for up to 1 h in an attempt to replace internal potassium with cesium. When the nerves were tested in the sucrose gap chamber using solutions containing 3.0 mM CsCl substituted for KCl, the compound action potential was broadened and a prolonged depolarization appeared, but there was no postspike positivity; the CsCl effect was similar to the combined effects of 4-AP and TEA. 5. Intra-axonal recordings were obtained to study the effects of 4-AP and TEA on individual axons. In the presence of 4-AP a single stimulus led to a burst of action potentials followed by a pronounced afterhyperpolarization (AHP) in sensory fibers. The AHP was blocked by TEA. In motor fibers 4-AP application resulted in action potential broadening with no AHP. 6. Repetitive stimulation (200-500 Hz; 100 ms) was followed by a pronounced AHP in both sensory and motor fibers at all ages studied. This activity-elicited AHP was sensitive to TEA at all ages. 7. The results indicate that 4-AP and TEA sensitivity change over the course of development in rat sciatic nerve. The effects of 4-AP are much more pronounced in immature nerves than in mature nerves, suggesting that 4-AP-sensitive channels become masked as they are covered by myelin during maturation. However, the TEA-sensitive channels, demonstrable after repetitive firing, remain accessible to TEA after myelination. These channels therefore may have a nodal representation.

Clinical Investigation of Topical Antimicrobials in Healthy Volunteers

1997 ◽  
Vol 31 (1) ◽  
pp. 34-38 ◽  
Author(s):  
Jane H Langford ◽  
Shalom I Benrimoj
Keyword(s):  
Antibacterial Activity ◽  
Healthy Volunteers ◽  
Clinical Investigation ◽  
Polymyxin B ◽  
Onset Of Action ◽  
Duration Of Action ◽  
Drug Concentrations ◽  
Clinical Investigations ◽  
Forearm Skin

OBJECTIVE: To evaluate the antibacterial activity, onset of action, and duration of action of four topical antimicrobial gels containing cetrimide, bacitracin, polymyxin B sulfate, and a placebo gel. DESIGN: Multiples (1×, 2×, 4×, 8×) of minimally inhibitory in vitro drug concentrations were formulated in a gel vehicle. Antibacterial activity was evaluated using a scrub-wash methodology on artificially inoculated skin over an 8-hour study period. SETTING AND PARTICIPANTS: Healthy volunteers with intact forearm skin participated in the study. A standardized culture of Staphylococcus aureus NCTC 6571 was applied to four areas on each forearm, randomly assigned topical treatments were applied, and sites were sampled at predetermined time intervals using a surfactant wash fluid. OUTCOME MEASURES: Recovered bacteria were quantitated, allowing a comparison of antibacterial activity. RESULTS: Two-way and one-way ANOVA and a Scheffe test confirmed significant differences in antibacterial effect between the formulations containing 4 and 8 times the minimally inhibitory in vitro concentrations and placebo (p < 0.05). Duration of action was similar for all preparations; however, onset appeared to be faster with the formulations containing 4 and 8 times minimally inhibitory in vitro concentrations. CONCLUSIONS: The two topical preparations containing 4 and 8 times the minimally inhibitory in vitro concentrations of cetrimide, bacitracin, and polymyxin B sulfate demonstrated significant antibacterial activity and may have potential for further clinical investigations.

Influence of Voltage-sensitive Ca++Channel Drugs on Bupivacaine Infiltration Anesthesia in Mice

2001 ◽  
Vol 95 (5) ◽  
pp. 1189-1197 ◽  
Author(s):  
Forrest L. Smith ◽  
Richard W. Davis ◽  
Richard Carter
Keyword(s):  
Motor Block ◽  
Radiant Heat ◽  
Tail Flick ◽  
Channel Blockers ◽  
Ca Channel ◽  
Ca Channels ◽  
Duration Of Action ◽  
Bayk 8644 ◽  
Infiltration Anesthesia

Background Local anesthesia has been traditionally associated with blockade of voltage-sensitive sodium (Na(+)) channels. Yet in vitro evidence indicates that local anesthetic mechanisms are more complex than previously understood. For example, local anesthetics bind and allosterically modify 1,4-dihydropyridine-sensitive Ca(++) channels and can reduce Ca(++) influx in tissues. The current study examines the influence of voltage-sensitive Ca(++) channels in bupivacaine infiltration anesthesia. Methods Baseline tail-flick latencies to radiant heat nociception were obtained before subcutaneous infiltration of bupivacaine and Ca(++)-modulating drugs in the tails of mice. No musculature is contained in the tail that could result in motor block. The magnitude of infiltration anesthesia over time, as well as the potency of bupivacaine alone or in the presence of Ca(++)-modulating drug, was assessed by obtaining test latencies. Results The 1,4-dihydropyridine L-type Ca(++) channel agonist S(-)-BayK-8644 reduced the duration of action and potency of bupivacaine anesthesia. In opposite fashion, nifedipine and nicardipine increased the effects of bupivacaine. Neither nifedipine nor nicardipine alone elicited anesthesia. Alternatively, the phenylalkylamine L-type blocker verapamil elicited concentration-dependent anesthesia. Other Ca(++) channel subtype blockers were investigated as well. The N-, T-, P-, and Q-type channel blockers, omega-conotoxin GVIA, flunarizine, omega-agatoxin IVA, and omega-conotoxin MVIIC, respectively, were unable to modify bupivacaine anesthesia. Conclusions These results indicate that heat nociception stimulates Ca(++) influx through L-type channels on nociceptors in skin. Although other voltage-sensitive Ca(++) channels may be located on skin nociceptors, only the L-type channel drugs affected bupivacaine in the radiant heat test.

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