Oral Administration Of Amitriptyline Research Articles

Amitriptyline efficacy in decreasing implant-induced foreign body reaction.

Beyond its actions on the nervous system, amitriptyline (AM) has been shown to lower inflammatory, angiogenic, and fibrogenic markers in a few pathological conditions in human and in experimental animal models. However, its effects on foreign body reaction (FBR), a complex adverse healing process, after biomedical material implantation are not known. We have evaluated the effects of AM on the angiogenic and fibrogenic components on a model of implant-induced FBR. Sponge disks were implanted subcutaneously in C57BL/6 mice, that were treated daily with oral administration of AM (5 mg/kg) for seven consecutive days in two protocols: treatment was started on the day of surgery and the implants were removed on the seventh day after implantation and treatment started 7 days after implantation and the implants removed 14 after implantation. None of the angiogenic (vessels, Vascular endothelial growth factor (VEGF), and interleukin-1β (IL-1β) or fibrogenic parameters (collagen, TGF-β, and fibrous capsule) and giant cell numbers analyzed were attenuated by AM in 7-day-old implants. However, AM was able to downregulate angiogenesis and FBR in 14-day-old implants. The effects of AM described here expands its range of actions as a potential agent capable of attenuating fibroproliferative processes that may impair functionality of implantable devices.

Comparison of activated charcoal and sodium polystyrene sulfonate resin efficiency on reduction of amitriptyline oral absorption in rat as treatments for overdose and toxicities.

Objective(s):Comparative in vivo studies were carried out to determine the adsorption characteristics of amitriptyline (AMT) on activated charcoal (AC) and sodium polystyrene sulfonate (SPS). AC has been long used as gastric decontamination agent for tricyclic antidepressants and SPS has showed to be highly effective on in-vitro drugs adsorption.Materials and Methods:Sprague-Dawley male rats were divided into six groups. Group I: control, group II: AMT 200 mg/kg as single dose orally, group III and IV: AC 1g/kg as single dose orally 5 and 30 min after AMT administration respectively, and group 5 and 6: SPS 1 g/kg as single dose orally 5 and 30 min after AMT administration, respectively. 60 min after oral administration of AMT (Tmax of AMT determined in rats), Cmax plasma levels were determined by a validated GC-Mass method.Results:The Cmax values for groups II to IV were determined as 1.1, 0.5, 0.6, 0.1 and 0.3 µg/ml, respectively.Conclusion:AC and SPS could significantly reduce Cmax of AMT when administrated either 5 or 30 min after AMT overdose (P<0.05). However, SPS showed to be more effective than AC in reducing Cmax when was administrated immediately (5 min) after AMT overdose. The results suggest a more efficient alternative to AC for AMT and probably other TCA overdoses.

Systematic review of topical amitriptyline for the treatment of neuropathic pain.

Neuropathic pain is a common disorder for which patients seek treatment. The most common causes of neuropathic pain are diabetes, herpetic infection and chemotherapy-induced neuropathy. Oral administration of amitriptyline has traditionally been used for treating neuropathic pain; however, it has dose-related anticholinergic effects, which may limit its use in some individuals. Pharmacotherapeutic agents that are commonly used to treat neuropathic pain include antidepressants, anticonvulsants, opioids and opioid-like substances, and topical medications. The objective of this paper is to review the effectiveness of topical amitriptyline in patients with neuropathic pain. We utilized the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to provide a systematic and transparent reporting method. The literature search was performed using PubMed (1966 through October 2014) applying the MeSH 'amitriptyline' and 'drug administration, topical' and 'neuropathy'. Web of Science (1945 through October 2014) was searched using the text words 'amitriptyline' and 'neuropathy'. Bibliographies of retrieved articles were scanned for relevant articles. Cochrane databases were also searched for methods to treat neuropathic pain. Broad subject headings, including 'neuropathic pain', were used to search the database for review articles. All data sources in English and in humans were considered for inclusion. Topical application of amitriptyline has the theoretical advantage of local effects with fewer systemic side effects. The clinical trials and case reports describing the use of topical amitriptyline we reviewed show mixed results concerning the efficacy and the presence of adverse reactions. Controlled clinical trials reveal that topical amitriptyline is not effective in treating neuropathic pain. The uncontrolled clinical trials did support efficacy of topical amitriptyline; however, the data from these trials may be biased due to the nature of the study design. Finally, there have been several case reports that claim patients achieved pain relief with the use of topical amitriptyline. Data from these cases are limited due to the fact that there were no controls to which the amitriptyline treatments could be compared, and the majority of the patients in these cases were on other analgesics. Although there are reports that describe the benefits of topical amitriptyline for neuropathic pain, data from evidence-based controlled clinical trials do not support efficacy in patients who use topical amitriptyline for neuropathic pain control.

Quantitative Determination of Amitriptyline and Its Metabolite in Rat Plasma by Liquid Chromatography-tandem Mass Spectrometry

Incrementally Modified Drug (IMD), Yuhan Research Institute 416-1, Gyeonggi-do, KoreaReceived February 21, 2012, Accepted March 26, 2012A rapid, specific, and reliable LC-MS/MS-based bioanalytical method was developed and validated in ratplasma for the simultaneous quantitation of amitriptyline and its metabolite nortriptyline. Chromatographicseparation of these analytes was achieved on a Gemini C18 column (50 × 4.60 mm, 5 µm) using reversed-phasechromatography. The mobile phase was an isocratic solvent system consisting of 1% formic acid in water andmethanol (10:90, v/v), at a flow rate of 0.2 mL/min. The analytical range was set as 0.1-500 ng/mL foramitriptyline and 0.08-500 ng/mL for nortriptyline using a 200 µL plasma sample. The accuracy and precisionof the assay were in accordance with FDA regulations for the validation of bioanalytical methods. Thevalidated method was successfully applied to a pharmacokinetic study in six rats after oral administration ofamitriptyline (15 mg/kg). This method allows laboratory scientists to rapidly determine amitriptyline andnortriptyline concentrations in plasma.Key Words : Amitriptyline, Nortriptyline, LC-MS/MS, Quantitation, PharmacokineticsIntroductionAmitriptyline is a typical tricyclic antidepressant (TCA)used for the treatment of major depression since the 1960s. Itinduces a specific pharmacodynamic effect primarily byblocking presynaptic uptake of amines (norepinephrine,dopamine, and serotonin). Amitriptyline metabolism involveshepatic microsomal enzymes (mainly CYP2C19 and CYP3A4)that demethylate the aliphatic side chain, generating thepharmacologically active metabolite nortriptyline.

Pharmacokinetics of Amitriptyline and One of Its Metabolites, Nortriptyline, in Rats: Little Contribution of Considerable Hepatic First-Pass Effect to Low Bioavailability of Amitriptyline Due to Great Intestinal First-Pass Effect

Pharmacokinetics of amitriptyline and nortriptyline were evaluated after intravenous (2.5-10 mg/kg) and oral (10-100 mg/kg) administration of amitriptyline to rats. The hepatic, gastric, and intestinal first-pass effects of amitriptyline were also measured at a dose of 10 mg/kg. The areas under the plasma concentration-time curve (AUCs) of amitriptyline were dose-proportional following both intravenous and oral administration. After oral administration of amitriptyline, approximately 1.50% of the dose was not absorbed, the extent of absolute oral bioavalability (F) was approximately 6.30%, and the hepatic and intestinal first-pass effects of amitriptyline were approximately 9% and 87% of the oral dose, respectively. Although the hepatic first-pass effect was 78.9% after absorption into the portal vein, the value was only 9% of the oral dose due to considerable intestinal first-pass effect in rats. The low F of amitriptyline in rats was primarily attributable to considerable intestinal first-pass effect. This study proves the little contribution of considerable hepatic first-pass effect to low F of amitriptyline due to great intestinal first-pass effect in rats. The lower F value of amitriptyline in rats than that in humans (46 +/- 48%) was due to grater metabolism of amitriptyline in rats' liver and/or small intestine.

Amitriptyline Treatment Under Chronic Stress Conditions: Effect on Circulating Catecholamines and Anxiety in Early Maternally Separated Rats

The aim of this work was to determine the effect of amitriptyline (AMI) on peripheral outcomes such as plasma epinephrine (E) and norepinephrine (NE) concentration and anxiety-like behavior displayed in the plus maze test in adult male Wistar rats under variable chronic stress and daily oral administration of AMI (5 mg/kg). Animals were previously isolated from the mother for 4.5 hr every day for the first 3 weeks of life. Administration of the antidepressant AMI reduced anxiety-like behavior in animals submitted only to chronic stress but not in early maternally separated (MS) subjects or in animals subjected to the two types of stresses.

Blood Concentrations of Amitriptyline and Its Metabolite in Rats after Acute Oral Administration of Amitriptyline

Amitriptyline (AMT), a tricyclic antidepressant that is a dibenzocycloheptadine derivative, is frequently used. However, the case reports of AMT-related fatalities are increased, nowadays, due to the low levels of toxic and fatal concentration in blood. So, this study was carried out to determine the concentrations of AMT and its demethylated metabolite, nortriptyline (NTR), after acute single oral administration of AMT in rats. Blood samples were collected five times from the ophthalmic venous plexus at 0, 1, 2, 4, and 8 h after acute single oral administration of AMT in toxic doses of 10 (Group I) or 20 mg/kg (Group II), and the concentrations of AMT and NTR and the mean ratios of AMT to NTR (AMT/NTR) in the blood were periodically determined at designated times. The blood concentrations of AMT and NTR were identified and quantitated by gas chromatography with thermionic specific detection and gas chromatography-mass spectrometry after solid-phase extraction with a Clean Screen DAU column. The peak blood concentrations of AMT and NTR in Group I were 0.34 and 0.28 microg/mL, respectively, and those of AMT and NTR in Group II were 0.59 and 0.43 microg/mL, respectively, and were reached at 1 h after single oral administration.

Amitriptyline-induced constipation in cynomolgus monkeys is beneficial for the evaluation of laxative efficacy.

In an attempt to create an animal model of constipation in monkeys, amitriptyline was administered to cynomolgus monkeys at doses of 10-160 mg/kg body weight via a nasogastric tube. Normal control monkeys excreted feces frequently throughout the day. Monkeys treated with amitriptyline at doses of 10-40 mg/kg showed delays in feces excretion. The 60 mg/kg treated monkeys for the most part did not excrete feces during the 24 h after amitriptyline administration. The 80 and 120 mg/kg treated monkeys did not excrete feces until 24 h from administration of amitriptyline, and also showed prolonged crouching and lethargy. On the other hand, 160 mg/kg treated monkeys died within 24 h after administration. We therefore felt that the optimal dose for creating constipation in the monkeys was 60 mg/kg. We tested the appropriateness of this amitriptyline-induced constipated monkey model by observing the effects of a new laxative, the herbal medicine ND-10 and the commercially available laxative bisacodyl. Control monkeys (those not receiving ND-10 or bisacodyl) treated with 60 mg/kg amitriptyline did not excrete feces up to 32 h after amitriptyline administration in 2 of 3 monkeys. However, all monkeys treated with one tablet of ND-10 excreted feces. Also, in 4 monkeys administrated with bisacodyl, 3 excreted feces. In this study, we confirmed that constipation can be caused in cynomolgus monkeys by oral administration of amitriptyline. This model may also be useful for the evaluation of laxatives.

P-1-5 - Effect of gender, age and smoking on doses and plasma levels of neuroleptics in schizophrenia

Pharmacokinetics of amitriptyline and nortriptyline were evaluated after intravenous (2.5–10 mg/kg) and oral (10–100 mg/kg) administration of amitriptyline to rats. The hepatic, gastric, and intestinal first-pass effects of amitriptyline were also measured at a dose of 10 mg/kg. The areas under the plasma concentration–time curve (AUCs) of amitriptyline were dose-proportional following both intravenous and oral administration. After oral administration of amitriptyline, approximately 1.50% of the dose was not absorbed, the extent of absolute oral bioavalability (F) was approximately 6.30%, and the hepatic and intestinal first-pass effects of amitriptyline were approximately 9% and 87% of the oral dose, respectively. Although the hepatic first-pass effect was 78.9% after absorption into the portal vein, the value was only 9% of the oral dose due to considerable intestinal first-pass effect in rats. The low F of amitriptyline in rats was primarily attributable to considerable intestinal first-pass effect. This study proves the little contribution of considerable hepatic first-pass effect to low F of amitriptyline due to great intestinal first-pass effect in rats. The lower F value of amitriptyline in rats than that in humans (46 ± 48%) was due to grater metabolism of amitriptyline in rats’ liver and/or small intestine

P-1-9 - No age-related change in platelet tritiated paroxetine binding in humans

Pharmacokinetics of amitriptyline and nortriptyline were evaluated after intravenous (2.5–10 mg/kg) and oral (10–100 mg/kg) administration of amitriptyline to rats. The hepatic, gastric, and intestinal first-pass effects of amitriptyline were also measured at a dose of 10 mg/kg. The areas under the plasma concentration–time curve (AUCs) of amitriptyline were dose-proportional following both intravenous and oral administration. After oral administration of amitriptyline, approximately 1.50% of the dose was not absorbed, the extent of absolute oral bioavalability (F) was approximately 6.30%, and the hepatic and intestinal first-pass effects of amitriptyline were approximately 9% and 87% of the oral dose, respectively. Although the hepatic first-pass effect was 78.9% after absorption into the portal vein, the value was only 9% of the oral dose due to considerable intestinal first-pass effect in rats. The low F of amitriptyline in rats was primarily attributable to considerable intestinal first-pass effect. This study proves the little contribution of considerable hepatic first-pass effect to low F of amitriptyline due to great intestinal first-pass effect in rats. The lower F value of amitriptyline in rats than that in humans (46 ± 48%) was due to grater metabolism of amitriptyline in rats’ liver and/or small intestine