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Per H. Rosenberg - One of the best experts on this subject based on the ideXlab platform.

  • intravenous lipid emulsion entraps Amitriptyline into plasma and can lower its brain concentration an experimental intoxication study in pigs
    Basic & Clinical Pharmacology & Toxicology, 2013
    Co-Authors: Juho A Heinonen, Erik Litonius, Janne T. Backman, Per H. Rosenberg
    Abstract:

    Intravenous lipid emulsion has been suggested as treatment for severe intoxications caused by lipophilic drugs, includ- ing tricyclic antidepressants. We investigated the effect of lipid infusion on plasma and tissue concentrations of Amitriptyline and haemodynamic recovery, when lipid was given after Amitriptyline distribution into well-perfused organs. Twenty anaesthetized pigs received Amitriptyline intravenously 10 mg/kg for 15 min. Thirty minutes later, in random fashion, 20% Intralipid (Lipid group) or Ringer's acetate (Control group) was infused 1.5 ml/kg for 1 min. followed by 0.25 ml/kg/min. for 29 min. Arterial and venous plasma Amitriptyline concentrations and haemodynamics were followed till 75 min. after Amitriptyline infusion. Then, frontal brain and heart apex samples were taken for Amitriptyline measurements. Arterial plasma total Amitriptyline concentrations were higher in the Lipid than in the Control group (p < 0.03) from 20 min. on after the start of the treatment infusions. Lipid emulsion reduced brain Amitriptyline concentration by 25% (p = 0.038) and Amitriptyline concentration ratios brain/arterial plasma (p = 0.016) and heart/arterial plasma (p = 0.011). There were no differences in ECG parameters and no severe cardiac arrhythmias occurred. Two pigs developed severe hypotension during the lipid infusion and were given adrenaline. In conclusion, lipid infusion, given not earlier than after an initial Amitriptyline tissue distribution, was able to entrap Amitriptyline back into plasma from brain and possibly from other highly perfused, lipid-rich tissues. In spite of the entrapment, there was no difference in haemodynamics between the groups. Intravenous lipid emulsion is recommended for the treatment of severe local anaesthetic toxicity in several countries, includ-

  • intravenous lipid emulsion entraps Amitriptyline into plasma and can lower its brain concentration an experimental intoxication study in pigs
    Basic & Clinical Pharmacology & Toxicology, 2013
    Co-Authors: Juho A Heinonen, Erik Litonius, Janne T. Backman, Pertti J Neuvonen, Per H. Rosenberg
    Abstract:

    Intravenous lipid emulsion has been suggested as treatment for severe intoxications caused by lipophilic drugs, including tricyclic antidepressants. We investigated the effect of lipid infusion on plasma and tissue concentrations of Amitriptyline and haemodynamic recovery, when lipid was given after Amitriptyline distribution into well-perfused organs. Twenty anaesthetized pigs received Amitriptyline intravenously 10 mg/kg for 15 min. Thirty minutes later, in random fashion, 20% Intralipid(®) (Lipid group) or Ringer's acetate (Control group) was infused 1.5 ml/kg for 1 min. followed by 0.25 ml/kg/min. for 29 min. Arterial and venous plasma Amitriptyline concentrations and haemodynamics were followed till 75 min. after Amitriptyline infusion. Then, frontal brain and heart apex samples were taken for Amitriptyline measurements. Arterial plasma total Amitriptyline concentrations were higher in the Lipid than in the Control group (p < 0.03) from 20 min. on after the start of the treatment infusions. Lipid emulsion reduced brain Amitriptyline concentration by 25% (p = 0.038) and Amitriptyline concentration ratios brain/arterial plasma (p = 0.016) and heart/arterial plasma (p = 0.011). There were no differences in ECG parameters and no severe cardiac arrhythmias occurred. Two pigs developed severe hypotension during the lipid infusion and were given adrenaline. In conclusion, lipid infusion, given not earlier than after an initial Amitriptyline tissue distribution, was able to entrap Amitriptyline back into plasma from brain and possibly from other highly perfused, lipid-rich tissues. In spite of the entrapment, there was no difference in haemodynamics between the groups.

  • no antidotal effect of intravenous lipid emulsion in experimental Amitriptyline intoxication despite significant entrapment of Amitriptyline
    Basic & Clinical Pharmacology & Toxicology, 2012
    Co-Authors: Erik Litonius, Tomohisa Niiya, Pertti J Neuvonen, Per H. Rosenberg
    Abstract:

    Intravenous lipid emulsion has been used in the resuscitative treatment of intoxications caused by local anaesthet- ics and tricyclic antidepressants with seemingly beneficial results. We studied the effect of intravenous lipid emulsion on the plasma concentration of Amitriptyline and haemodynamic recovery in a pig model of Amitriptyline intoxication. Twenty pigs were anaesthetized (1% isoflurane in 21% O2) and given Amitriptyline 15 mg ⁄ kg intravenously for 15 min. In random fashion immediately thereafter, either 20% lipid emulsion (ClinOleic � , Lipid group) or Ringer's acetate (Control group) was infused for 30 min.; first 1.5 ml ⁄ kg for 1 min., followed by 0.25 ml ⁄ kg ⁄ min. for 29 min. The Amitriptyline concentration in total and lipid-poor plasma and haemodynamic parameters were measured until 30 min. after the infusions. Lipid infusion prevented the decrease in plasma total Amitriptyline concentration, resulting in a 90% higher (p < 0.001) total concentration and signifi- cantly (p = 0.014) lower free fraction of plasma Amitriptyline in the Lipid group (1.1%) compared with the Control group (3.0%) at 30 min. Haemodynamic recovery from the intoxication as measured by heart rate, arterial pressure or cardiac output was similar in both groups. However, five pigs in the Lipid group and two pigs in the Control group died. In conclusion, a marked entrapment of Amitriptyline by intravenous lipid emulsion was observed but this did not improve the pigs' haemody- namic recovery from severe Amitriptyline intoxication. Care should be exercised in the antidotal use of lipid emulsion until controlled human studies indicate its efficacy and safety.

Erik Litonius - One of the best experts on this subject based on the ideXlab platform.

  • intravenous lipid emulsion entraps Amitriptyline into plasma and can lower its brain concentration an experimental intoxication study in pigs
    Basic & Clinical Pharmacology & Toxicology, 2013
    Co-Authors: Juho A Heinonen, Erik Litonius, Janne T. Backman, Per H. Rosenberg
    Abstract:

    Intravenous lipid emulsion has been suggested as treatment for severe intoxications caused by lipophilic drugs, includ- ing tricyclic antidepressants. We investigated the effect of lipid infusion on plasma and tissue concentrations of Amitriptyline and haemodynamic recovery, when lipid was given after Amitriptyline distribution into well-perfused organs. Twenty anaesthetized pigs received Amitriptyline intravenously 10 mg/kg for 15 min. Thirty minutes later, in random fashion, 20% Intralipid (Lipid group) or Ringer's acetate (Control group) was infused 1.5 ml/kg for 1 min. followed by 0.25 ml/kg/min. for 29 min. Arterial and venous plasma Amitriptyline concentrations and haemodynamics were followed till 75 min. after Amitriptyline infusion. Then, frontal brain and heart apex samples were taken for Amitriptyline measurements. Arterial plasma total Amitriptyline concentrations were higher in the Lipid than in the Control group (p < 0.03) from 20 min. on after the start of the treatment infusions. Lipid emulsion reduced brain Amitriptyline concentration by 25% (p = 0.038) and Amitriptyline concentration ratios brain/arterial plasma (p = 0.016) and heart/arterial plasma (p = 0.011). There were no differences in ECG parameters and no severe cardiac arrhythmias occurred. Two pigs developed severe hypotension during the lipid infusion and were given adrenaline. In conclusion, lipid infusion, given not earlier than after an initial Amitriptyline tissue distribution, was able to entrap Amitriptyline back into plasma from brain and possibly from other highly perfused, lipid-rich tissues. In spite of the entrapment, there was no difference in haemodynamics between the groups. Intravenous lipid emulsion is recommended for the treatment of severe local anaesthetic toxicity in several countries, includ-

  • intravenous lipid emulsion entraps Amitriptyline into plasma and can lower its brain concentration an experimental intoxication study in pigs
    Basic & Clinical Pharmacology & Toxicology, 2013
    Co-Authors: Juho A Heinonen, Erik Litonius, Janne T. Backman, Pertti J Neuvonen, Per H. Rosenberg
    Abstract:

    Intravenous lipid emulsion has been suggested as treatment for severe intoxications caused by lipophilic drugs, including tricyclic antidepressants. We investigated the effect of lipid infusion on plasma and tissue concentrations of Amitriptyline and haemodynamic recovery, when lipid was given after Amitriptyline distribution into well-perfused organs. Twenty anaesthetized pigs received Amitriptyline intravenously 10 mg/kg for 15 min. Thirty minutes later, in random fashion, 20% Intralipid(®) (Lipid group) or Ringer's acetate (Control group) was infused 1.5 ml/kg for 1 min. followed by 0.25 ml/kg/min. for 29 min. Arterial and venous plasma Amitriptyline concentrations and haemodynamics were followed till 75 min. after Amitriptyline infusion. Then, frontal brain and heart apex samples were taken for Amitriptyline measurements. Arterial plasma total Amitriptyline concentrations were higher in the Lipid than in the Control group (p < 0.03) from 20 min. on after the start of the treatment infusions. Lipid emulsion reduced brain Amitriptyline concentration by 25% (p = 0.038) and Amitriptyline concentration ratios brain/arterial plasma (p = 0.016) and heart/arterial plasma (p = 0.011). There were no differences in ECG parameters and no severe cardiac arrhythmias occurred. Two pigs developed severe hypotension during the lipid infusion and were given adrenaline. In conclusion, lipid infusion, given not earlier than after an initial Amitriptyline tissue distribution, was able to entrap Amitriptyline back into plasma from brain and possibly from other highly perfused, lipid-rich tissues. In spite of the entrapment, there was no difference in haemodynamics between the groups.

  • no antidotal effect of intravenous lipid emulsion in experimental Amitriptyline intoxication despite significant entrapment of Amitriptyline
    Basic & Clinical Pharmacology & Toxicology, 2012
    Co-Authors: Erik Litonius, Tomohisa Niiya, Pertti J Neuvonen, Per H. Rosenberg
    Abstract:

    Intravenous lipid emulsion has been used in the resuscitative treatment of intoxications caused by local anaesthet- ics and tricyclic antidepressants with seemingly beneficial results. We studied the effect of intravenous lipid emulsion on the plasma concentration of Amitriptyline and haemodynamic recovery in a pig model of Amitriptyline intoxication. Twenty pigs were anaesthetized (1% isoflurane in 21% O2) and given Amitriptyline 15 mg ⁄ kg intravenously for 15 min. In random fashion immediately thereafter, either 20% lipid emulsion (ClinOleic � , Lipid group) or Ringer's acetate (Control group) was infused for 30 min.; first 1.5 ml ⁄ kg for 1 min., followed by 0.25 ml ⁄ kg ⁄ min. for 29 min. The Amitriptyline concentration in total and lipid-poor plasma and haemodynamic parameters were measured until 30 min. after the infusions. Lipid infusion prevented the decrease in plasma total Amitriptyline concentration, resulting in a 90% higher (p < 0.001) total concentration and signifi- cantly (p = 0.014) lower free fraction of plasma Amitriptyline in the Lipid group (1.1%) compared with the Control group (3.0%) at 30 min. Haemodynamic recovery from the intoxication as measured by heart rate, arterial pressure or cardiac output was similar in both groups. However, five pigs in the Lipid group and two pigs in the Control group died. In conclusion, a marked entrapment of Amitriptyline by intravenous lipid emulsion was observed but this did not improve the pigs' haemody- namic recovery from severe Amitriptyline intoxication. Care should be exercised in the antidotal use of lipid emulsion until controlled human studies indicate its efficacy and safety.

Ardeshir Talebi - One of the best experts on this subject based on the ideXlab platform.

  • A study on the mechanisms involving the anti-inflammatory effect of Amitriptyline in carrageenan-induced paw edema in rats.
    European Journal of Pharmacology, 2011
    Co-Authors: Hossein Sadeghi, Valiolla Hajhashemi, Mohsen Minaiyan, Ahmad Movahedian, Ardeshir Talebi
    Abstract:

    Anti-inflammatory effects of antidepressants have been reported in some studies, but the mechanisms underlying these effects remain unknown. Amitriptyline, a tricyclic antidepressant, is widely used in the management of psychological disorders and various types of pain, including neuropathic pain or fibromyalgia. In our previous work, we found the role of supraspinal mechanisms in the anti-inflammatory effect of Amitriptyline. In the line of the indicated study, we sought to evaluate the effects of intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) application of Amitriptyline in the carrageenan-induced paw edema in rats in more details. Our findings confirmed that i.p. (40 and 80 mg/kg) and i.c.v. (100 μg/rat) injection of Amitriptyline inhibited carrageenan-induced inflammation at different times. We also found that both i.p. and i.c.v. Amitriptyline significantly decreased migration of polymorphonuclear (PMN) leucocytes into the site of inflammation, according to pathological evidence and the activity of myeloperoxidase (MPO). Furthermore, i.p. Amitriptyline at the applied doses markedly reduced interleukin (IL)-1β and tumor necrosis factor (TNF)-α levels in the paw treated with carrageenan. Our results also showed that i.c.v. Amitriptyline noticeably decreased the concentration of IL-1β in the inflamed paws. The TNF-α levels reduced in the i.c.v. group, even though these reductions were not statistically significant. These results confirmed the anti-inflammatory effects of systemic and central Amitriptyline in the carrageenan-induced paw edema in rats, and demonstrated that these effects mediated mostly through the inhibition of PMN cells migration and release of IL-1β and TNF-α into the site of inflammation.

  • the role of central mechanisms in the anti inflammatory effect of Amitriptyline on carrageenan induced paw edema in rats
    Clinics, 2010
    Co-Authors: Valiolla Hajhashemi, Mohsen Minaiyan, Ahmad Movahedian, Hossein Sadeghi, Ardeshir Talebi
    Abstract:

    OBJECTIVE: The present study was designed to further investigate the effect of Amitriptyline, a classical tricyclic antidepressant, on carrageenan-induced paw edema in rats. METHODS: First, Amitriptyline was administered intraperitoneally (i.p.) at doses of 20, 40 and 80 mg kg-1, 30 min before subplantar injection of carrageenan. Second, Amitriptyline was given intracerebroventriculary or intrathecally at doses of 25, 50 and 100 μg/rat, 30 min prior to carrageenan challenge. Third, the effect of adrenergic receptor antagonists such as propranolol (10 mg kg-1, i.p.), prazosin (4 mg kg-1, i.p.) and yohimbine (10 mg kg-1, i.p.) and an opioid receptor antagonist (naloxone, 4 mg kg-1, i.p.) on the anti-inflammatory effect of Amitriptyline (40 mg kg-1, i.p.) was investigated. RESULTS: Our data confirm that intraperitoneally administered Amitriptyline exhibits a marked anti-inflammatory effect on carrageenan-induced paw edema in rats 4 h postcarrageenan challenge (P < 0.001). Intracerebroventricular (i.c.v.) administration of Amitriptyline also reduced the development of paw edema at 4 h postcarrageenan (P < 0.001), but intrathecal (i.t.) application of Amitriptyline failed to alter the degree of paw swelling. Furthermore, the applied antagonists did not modify the anti-inflammatory effect of Amitriptyline. CONCLUSION: These results support the view that Amitriptyline has a considerable anti-inflammatory effect on carrageenan-induced paw edema in rats and suggest that at least a part of this property could be mediated through supraspinal sites. Moreover, it seems unlikely that the investigated adrenergic and opioid receptors have a significant role in this effect of Amitriptyline.

Juho A Heinonen - One of the best experts on this subject based on the ideXlab platform.

  • intravenous lipid emulsion entraps Amitriptyline into plasma and can lower its brain concentration an experimental intoxication study in pigs
    Basic & Clinical Pharmacology & Toxicology, 2013
    Co-Authors: Juho A Heinonen, Erik Litonius, Janne T. Backman, Per H. Rosenberg
    Abstract:

    Intravenous lipid emulsion has been suggested as treatment for severe intoxications caused by lipophilic drugs, includ- ing tricyclic antidepressants. We investigated the effect of lipid infusion on plasma and tissue concentrations of Amitriptyline and haemodynamic recovery, when lipid was given after Amitriptyline distribution into well-perfused organs. Twenty anaesthetized pigs received Amitriptyline intravenously 10 mg/kg for 15 min. Thirty minutes later, in random fashion, 20% Intralipid (Lipid group) or Ringer's acetate (Control group) was infused 1.5 ml/kg for 1 min. followed by 0.25 ml/kg/min. for 29 min. Arterial and venous plasma Amitriptyline concentrations and haemodynamics were followed till 75 min. after Amitriptyline infusion. Then, frontal brain and heart apex samples were taken for Amitriptyline measurements. Arterial plasma total Amitriptyline concentrations were higher in the Lipid than in the Control group (p < 0.03) from 20 min. on after the start of the treatment infusions. Lipid emulsion reduced brain Amitriptyline concentration by 25% (p = 0.038) and Amitriptyline concentration ratios brain/arterial plasma (p = 0.016) and heart/arterial plasma (p = 0.011). There were no differences in ECG parameters and no severe cardiac arrhythmias occurred. Two pigs developed severe hypotension during the lipid infusion and were given adrenaline. In conclusion, lipid infusion, given not earlier than after an initial Amitriptyline tissue distribution, was able to entrap Amitriptyline back into plasma from brain and possibly from other highly perfused, lipid-rich tissues. In spite of the entrapment, there was no difference in haemodynamics between the groups. Intravenous lipid emulsion is recommended for the treatment of severe local anaesthetic toxicity in several countries, includ-

  • intravenous lipid emulsion entraps Amitriptyline into plasma and can lower its brain concentration an experimental intoxication study in pigs
    Basic & Clinical Pharmacology & Toxicology, 2013
    Co-Authors: Juho A Heinonen, Erik Litonius, Janne T. Backman, Pertti J Neuvonen, Per H. Rosenberg
    Abstract:

    Intravenous lipid emulsion has been suggested as treatment for severe intoxications caused by lipophilic drugs, including tricyclic antidepressants. We investigated the effect of lipid infusion on plasma and tissue concentrations of Amitriptyline and haemodynamic recovery, when lipid was given after Amitriptyline distribution into well-perfused organs. Twenty anaesthetized pigs received Amitriptyline intravenously 10 mg/kg for 15 min. Thirty minutes later, in random fashion, 20% Intralipid(®) (Lipid group) or Ringer's acetate (Control group) was infused 1.5 ml/kg for 1 min. followed by 0.25 ml/kg/min. for 29 min. Arterial and venous plasma Amitriptyline concentrations and haemodynamics were followed till 75 min. after Amitriptyline infusion. Then, frontal brain and heart apex samples were taken for Amitriptyline measurements. Arterial plasma total Amitriptyline concentrations were higher in the Lipid than in the Control group (p < 0.03) from 20 min. on after the start of the treatment infusions. Lipid emulsion reduced brain Amitriptyline concentration by 25% (p = 0.038) and Amitriptyline concentration ratios brain/arterial plasma (p = 0.016) and heart/arterial plasma (p = 0.011). There were no differences in ECG parameters and no severe cardiac arrhythmias occurred. Two pigs developed severe hypotension during the lipid infusion and were given adrenaline. In conclusion, lipid infusion, given not earlier than after an initial Amitriptyline tissue distribution, was able to entrap Amitriptyline back into plasma from brain and possibly from other highly perfused, lipid-rich tissues. In spite of the entrapment, there was no difference in haemodynamics between the groups.

Peter Gerner - One of the best experts on this subject based on the ideXlab platform.

  • assessment of differential blockade by Amitriptyline and its n methyl derivative in different species by different routes
    Anesthesiology, 2003
    Co-Authors: Peter Gerner, Anna Haderer, Mustafa Mujtaba, Yukari Sudoh, Sanjeet Narang, Salahadin Abdi, Venkatesh Srinivasa, C Pertl, Ging Kuo Wang
    Abstract:

    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.

  • Amitriptyline for prolonged cutaneous analgesia in the rat
    Anesthesiology, 2002
    Co-Authors: Mohammed A Khan, Peter Gerner
    Abstract:

    BACKGROUND Amitriptyline has been reported to be a more potent local anesthetic than bupivacaine. In keeping with the objective of identifying drugs for prolonged cutaneous analgesia, the authors compared the cutaneous analgesic effectiveness of Amitriptyline and bupivacaine in rats. METHODS Rats were subcutaneously injected on shaved dorsal skin. The skin wheal raised after injection of 0.6 ml of various concentrations of either Amitriptyline or bupivacaine with and without epinephrine (1:200,000) was marked. Inhibition of the cutaneous trunci muscle reflex was evaluated quantitatively by the fraction of times a total of six pinpricks applied to the marked area failed to elicit a nocifensive motor response compared with control responses. No responses out of six pinpricks was defined as 100% maximum possible effect. RESULTS Complete recovery from the cutaneous analgesia elicited by 0.05% and 0.5 Amitriptyline versus 0.05 and 0.5% bupivacaine occurred in 9.9 +/- 0.2 and 19.3 +/- 0.4 h versus 2.2 +/- 0.1 and 16.1 +/- 0.2 h, respectively (mean +/- SE). Addition of epinephrine increased this duration to 14.1 +/- 0.1 and 21.4 +/- 0.2 h versus 3.2 +/- 0.1 and 17.0 +/- 0.3 h, respectively. Complete nociceptive blockade after coinjection of 0.25% Amitriptyline, 0.25% bupivacaine, and epinephrine lasted 24 +/- 0.5 h, and complete recovery from this block took 33 +/- 0.5 h. Areas under the percent maximum possible effect versus time curve were 1,770 +/- 24 and 1,471 +/- 50% h for 0.5% Amitriptyline and bupivacaine with epinephrine, respectively, whereas this value was 2,836 +/- 62% h for the coinjected 0.25% Amitriptyline, 0.25% bupivacaine, and epinephrine admixture. CONCLUSION Amitriptyline is a longer-acting local anesthetic compared with bupivacaine for cutaneous infiltration. Its analgesic effectiveness is significantly enhanced by epinephrine. Coinjection of Amitriptyline and bupivacaine with epinephrine enhances the analgesic duration of both drugs.

  • Amitriptyline versus bupivacaine in rat sciatic nerve blockade
    Anesthesiology, 2001
    Co-Authors: Peter Gerner, Mustafa G Mujtaba, Catherine J Sinnott
    Abstract:

    BACKGROUND Amitriptyline, a tricyclic antidepressant, is frequently used orally for the management of chronic pain. To date there is no report of Amitriptyline producing peripheral nerve blockade. The authors therefore investigated the local anesthetic properties of Amitriptyline in rats and in vitro. METHODS Sciatic nerve blockade was performed with 0.2 ml Amitriptyline or bupivacaine at selected concentrations, and the motor, proprioceptive, and nociceptive blockade was evaluated. Cultured rat GH3 cells were externally perfused with Amitriptyline or bupivacaine, and the drug affinity toward inactivated and resting Na+ channels was assessed under whole-cell voltage clamp conditions. In addition, use-dependent blockade of these drugs at 5 Hz was evaluated. RESULTS Complete sciatic nerve blockade for nociception was obtained with Amitriptyline for 217 +/- 19 min (5 mM, n = 8, mean +/- SEM) and for 454 +/- 38 min (10 mM, n = 7) versus bupivacaine for 90 +/- 13 min (15.4 mM, n = 6). The time to full recovery of nociception for Amitriptyline was 353 +/- 12 min (5 mM) and 656 +/- 27 min (10 mM) versus 155 +/- 9 min for bupivacaine (15.4 mM). Amitriptyline was approximately 4.7-10.6 times more potent than bupivacaine in binding to the resting channels (50% inhibitory concentration [IC50] of 39.8 +/- 2.7 vs. 189.6 +/- 22.3 microM) at - 150 mV, and to the inactivated Na+ channels (IC50 of 0.9 +/- 0.1 vs. 9.6 +/- 0.9 microM) at -60 mV. High-frequency stimulation at 3 microM caused an additional approximately 14% blockade for bupivacaine, but approximately 50% for Amitriptyline. CONCLUSION Amitriptyline is a more potent blocker of neuronal Na+ channels than bupivacaine in vivo and in vitro. These findings suggest that Amitriptyline could extend its clinical usefulness for peripheral nerve blockade.