Amitriptyline neurotoxicity: dose-related pathology after topical application to rat sciatic nerve.
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BACKGROUND: Amitriptyline is a tricyclic antidepressant drug used systemically for the management of neuropathic pain. Antidepressants, as a class of drugs with direct neurologic actions, are becoming widely used for the management of chronic pain, although their mechanisms are not entirely understood. Amitriptyline exerts potent effects on reuptake of norepinephrine and serotonin and blocks alpha 2A adrenoreceptors and N-methyl-D-aspartate receptors. Because amitriptyline is also a particularly potent blocker of sodium channels and voltage-gated potassium and calcium channels, it has been recommended as a long-acting local anesthetic agent. Unfortunately, amitriptyline has significant toxic side effects in the central nervous system and cardiovascular system that are dose-related to its systemic administration. Therefore, before amitriptyline can be used clinically as a local anesthetic agent, it should be thoroughly explored with respect to its direct neurotoxic effect in the peripheral nervous system. METHODS: The left sciatic nerve of Sprague-Dawley rats (12/ group) received a single topical amitriptyline dose of 0.625, 1.25, 2.5, or 5 mg; a saline group (n = 2) was used as control. Neuropathologic evaluations were conducted in separate animals (n = 4) 1, 3, and 7 days later. RESULTS: Amitriptyline topically applied in vivo to rat sciatic nerve causes a dose-related neurotoxic effect. Drug doses of 0.625-5 mg all caused Wallerian degeneration of peripheral nerve fibers, with the number of affected fibers and the severity of the injury directly related to the dose. CONCLUSION: Because the effective local anesthetic dose is within this dose range, the authors strongly recommend that amitriptyline not be used as a local anesthetic agent. (+info)
Allele-specific change of concentration and functional gene dose for the prediction of steady-state serum concentrations of amitriptyline and nortriptyline in CYP2C19 and CYP2D6 extensive and intermediate metabolizers.
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BACKGROUND: Recently, new polymorphisms were described in connection with intermediate and ultrarapid CYP2D6 metabolism. These may allow a much desired prediction of metabolic activity within the extensive metabolizer group. The functional consequences are still being discussed with few data available for clinical patients. METHODS: We conducted a prospective, blinded two-center study seeking correlations between CYP2C19 (*2,*3, and *4; conventional PCR) and CYP2D6 genotypes (*1 to *10, *35, and *41; real-time and multiplex PCR) and drug concentrations (Emit and HPLC) in 50 Caucasians receiving amitriptyline (AT; 75 mg twice a day). RESULTS: Eighteen CYP2C19 heterozygotes (*1/*2) had higher AT (P = 0.033) and lower nortriptyline (NT; P = 0.059) concentrations than 30 homozygotes (*1/*1). For CYP2D6, we calculated two new indices, i.e., the allele-specific change of concentration on identical background (ASCOC) and a quantitative functional gene dose. The ASCOC describes the change in NT concentration attributable to a mutant allele compared with the wild type. We found significantly higher concentrations for alleles *4 (95.6%; P <0.0001), *10 (63.3%; P <0.001), and *41 (39.8%; P <0.0001) but not for *2 and *35. Assigning of semiquantitative gene doses of 0, 0.5, or 1 to each allele instead of applying the current classification system (predicted phenotypes: 3 intermediate metabolizers, 46 extensive metabolizers, and 1 ultrarapid metabolizer) produced significant NT concentration differences: gene doses of 0.5 (n =3), 1 (n = 14), 1.5 (n = 11), 2 (n = 21) and 3 (n = 1; P <0.00001). CONCLUSIONS: AT and NT concentrations can be predicted within the group of CYP2D6 extensive metabolizers. The ASCOC provides substantial advantages compared with current methods of analysis. CYP2D6 but not CYP2C19 correlates with the sum of both concentrations used to guide AT therapy. (+info)
Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats.
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5-Hydroxytryptamine (serotonin) (5-HT) and norepinephrine (NE) are implicated in modulating descending inhibitory pain pathways in the central nervous system. Duloxetine is a selective and potent dual 5-HT and NE reuptake inhibitor (SNRI). The ability of duloxetine to antagonize 5-HT depletion in para-chloramphetamine-treated rats was comparable with that of paroxetine, a selective serotonin reuptake inhibitor (SSRI), whereas its ability to antagonize NE depletion in alpha-methyl-m-tyrosine-treated rats was similar to norepinephrine reuptake inhibitors (NRIs), thionisoxetine or desipramine. In this paradigm, duloxetine was also more potent than other SNRIs, including venlafaxine or milnacipran and amitriptyline. Low doses of the SSRI paroxetine or the NRI thionisoxetine alone did not have an effect on late phase paw-licking pain behavior in the formalin model of persistent pain; however, when combined, significantly attenuated this pain behavior. Duloxetine (3-15 mg/kg intraperitoneal) significantly attenuated late phase paw-licking behavior in a dose-dependent manner in the formalin model and was more potent than venlafaxine, milnacipran, and amitriptyline. These effects of duloxetine were evident at doses that did not cause neurologic deficits in the rotorod test. Duloxetine (5-30 mg/kg oral) was also more potent and efficacious than venlafaxine and milnacipran in reversing mechanical allodynia behavior in the L5/L6 spinal nerve ligation model of neuropathic pain. Duloxetine (3-30 mg/kg oral) was minimally efficacious in the tail-flick model of acute nociceptive pain. These data suggest that inhibition of both 5-HT and NE uptake may account for attenuation of persistent pain mechanisms. Thus, duloxetine may have utility in treatment of human persistent and neuropathic pain states. (+info)
A strategy to decrease the use of risky drugs in the elderly.
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Many medications that are safe in most patients pose serious risks in older patients, including functional decline, delirium, falls, and poorer outcomes. We describe our institution's program of "academic detailing," designed to reduce the use of three high-risk drugs in elderly patients. (+info)
Differential effects of two types of antidepressants, amitriptyline and fluoxetine, on anorectal motility and visceral perception.
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BACKGROUND: Although antidepressants are used for functional gastrointestinal disorders, the mechanisms of their effects on gut are incompletely understood. AIM: To assess the effects of two types of antidepressants (tricyclic, serotoninergic) on anorectal motility and visceral perception. METHODS: A placebo-controlled, randomized, double-blind, crossover study was performed in 12 healthy male volunteers who received a single oral dose of amitriptyline (80 mg), fluoxetine (40 mg) or placebo. Drug effects were assessed using phasic isobaric distensions of the rectum with an electronic barostat (11 levels from 1 to 51 mmHg) 4 h after drug intake. Maximal rectal volume and pressure, mean and residual pressures at upper anal canal, mean pressure at lower anal canal, defecation sensation (5-level scale) and visceral perception (visual analogue scale) were recorded at each level of distending pressure. RESULTS: Ten subjects completed the study. Compared with placebo, neither amitriptyline nor fluoxetine modified rectal compliance or visceral perception. Compared with placebo, antidepressants significantly reduced mean and residual pressures at upper anal canal (-18%, P = 0.0019, and -27%, P = 0.0002, respectively, for amitriptyline; -26%, P = 0.0001, and -33%, P = 0.0001, respectively, for fluoxetine) whereas only amitriptyline significantly reduced mean pressure at lower anal canal (-16%, P = 0.0008). CONCLUSION: Both antidepressants similarly relaxed the internal anal sphincter, probably through a non-specific mechanism, without modifying visceral perception. Only amitriptyline relaxed the external anal sphincter. (+info)
Contralateral effect of amitriptyline and bupivacaine for sciatic nerve block in an animal model of inflammation.
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BACKGROUND: Using a carrageenan inflammation rat model, we evaluated two experimental approaches to prolong sciatic nerve block on contralateral hyperalgesia. Method. We performed ipsilateral sciatic nerve block on the inflamed hind paw with bupivacaine-loaded microspheres suspended in dexamethasone (bupivacaine 12.5 mg) and with amitriptyline (6.25 and 12.5 mg) as ultralong-acting local anaesthetics. Bupivacaine (1.25 mg) was used as long-acting local anaesthetic and saline was used as a control. The sixth group received amitriptyline 6.25 mg intraperitoneally (n=10 for each group). RESULTS: The duration of ipsilateral nerve block was 2 h for bupivacaine, 7 h for amitriptyline 6.25 mg, 11 h for amitriptyline 12.5 mg and 21 h for bupivacaine-loaded microspheres in suspension with dexamethasone. Whereas contralateral hyperalgesia was not observed during block produced by bupivacaine-loaded microspheres, contralateral hyperalgesia was observed with sciatic nerve block using amitriptyline. CONCLUSIONS: Because of the differential effect observed on the contralateral side, the mechanism underlying the prolongation of ipsilateral block with amitriptyline may not result only from a prolonged Na(+) channel blockade but might be explained by a local toxic effect or lack of systemic actions. (+info)
Application of copper (II) in spectrophotometric determination of some drugs of aliphatic amine nature.
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Anhydrous copper(II) acetate was applied to spectrophotometric determination of amitriptilline, doxepin and lignocaine in acetone solutions. The developed method was employed for determining these substances in pharmaceutical preparations. The obtained results has indicated both high precision and accuracy of the method. (+info)
Amitriptyline or not, that is the question: pharmacogenetic testing of CYP2D6 and CYP2C19 identifies patients with low or high risk for side effects in amitriptyline therapy.
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BACKGROUND: Amitriptyline has been replaced in many countries by alternative and more expensive drugs based on claims of improved tolerability and toxicity and despite slightly reduced efficacy. Preliminary studies indicate that adverse effects could be linked to polymorphisms of drug-metabolizing enzymes, but information on their clinical impact remains scanty and includes mainly case reports. We conducted a prospective blinded two-center study seeking correlations between CYP2C19 and CYP2D6 genotypes, drug concentrations, adverse events, and therapy response. METHODS: Fifty Caucasian inpatients with at least medium-grade depressive disorder received amitriptyline at a fixed dose of 75 mg twice a day. Blood samples for concentration monitoring of amitriptyline and nortriptyline were taken weekly until discharge along with evaluations of depression (Hamilton Depression Scale and Clinical Global Impression Scale) and side effect (Dosage Record and Treatment Emergent Symptoms Scale; DOTES) scores. RESULTS: In a ROC analysis, nortriptyline but not amitriptyline concentrations correlated with side effects (DOTES sum score >or=5; area under the curve, 0.733; P = 0.008). Carriers of two functional CYP2D6 alleles had a significantly lower risk of side effects than carriers of only one functional allele (12.1% vs 76.5%; P = 0.00001). The lowest risk was observed for carriers of two functional CYP2D6 alleles combined with only one functional CYP2C19 allele [0 of 13 (0%) vs 9 of 11 (81.8%) for the high-risk group; P = 0.00004]. We found no correlations between drug concentrations or genotypes and therapeutic response. CONCLUSIONS: Combined pharmacogenetic testing for CYP2D6 and CYP2C19 identifies patients with low risk for side effects in amitriptyline therapy and could possibly be used to individualize antidepressive regimens and reduce treatment cost. Identification of genotypes associated with slightly reduced intermediate metabolism may be more important than currently anticipated. It could also be the key to demonstrating cost-effectiveness for CYP2D6 genotyping in critical dose drugs. (+info)