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American Family Physician Jun 2006
Review
Topics: Aged; Amitriptyline; Antidepressive Agents, Tricyclic; Diabetic Neuropathies; Humans; Male; Neuralgia
PubMed: 16770921
DOI: No ID Found -
The Acid Sphingomyelinase Inhibitor Amitriptyline Ameliorates TNF-α-Induced Endothelial Dysfunction.Cardiovascular Drugs and Therapy Feb 2024Inflammation associated endothelial cell (EC) dysfunction is key to atherosclerotic disease. Recent studies have demonstrated a protective role of amitriptyline in...
PURPOSE
Inflammation associated endothelial cell (EC) dysfunction is key to atherosclerotic disease. Recent studies have demonstrated a protective role of amitriptyline in cardiomyocytes induced by hypoxia/reoxygenation. However, the mechanism by which amitriptyline regulates the inflammatory reaction in ECs remains unknown. Thus, the aim of this study was to investigate whether amitriptyline protects against inflammation in TNF-α-treated ECs.
METHODS
HUVECs were incubated with amitriptyline (2.5 μM) or TNF-α (20 ng/ml) for 24 h. EdU, tube formation, transwell, DHE fluorescence staining, and monocyte adhesion assays were performed to investigate endothelial function. Thoracic aortas were isolated from mice, and vascular tone was measured with a wire myograph system. The levels of ICAM-1, VCAM-1, MCP-1, phosphorylated MAPK and NF-κB were detected using western blotting.
RESULTS
Amitriptyline increased the phosphorylation of nitric oxide synthase (eNOS) and the release of NO. Amitriptyline significantly inhibited TNF-α-induced increases in ASMase activity and the release of ceramide and downregulated TNF-α-induced expression of proinflammatory proteins, including ICAM-1, VCAM-1, and MCP-1 in ECs, as well as the secretion of sICAM-1 and sVCAM-1. TNF-α treatment obviously increased monocyte adhesion and ROS production and impaired HUVEC proliferation, migration and tube formation, while amitriptyline rescued proliferation, migration, and tube formation and decreased monocyte adhesion and ROS production. Additionally, we demonstrated that amitriptyline suppressed TNF-α-induced MAPK phosphorylation as well as the activity of NF-κB in HUVECs. The results showed that the relaxation response of aortic rings to acetylcholine in the WT-TNF-α group was much lower than that in the WT group, and the sensitivity of aortic rings to acetylcholine in the WT-TNF-α group and WT-AMI-TNF-α group was significantly higher than that in the WT-TNF-α group.
CONCLUSION
These results suggest that amitriptyline reduces endothelial inflammation, consequently improving vascular endothelial function. Thus, the identification of amitriptyline as a potential strategy to improve endothelial function is important for preventing vascular diseases.
Topics: Animals; Mice; Humans; NF-kappa B; Intercellular Adhesion Molecule-1; Tumor Necrosis Factor-alpha; Human Umbilical Vein Endothelial Cells; Amitriptyline; Reactive Oxygen Species; Vascular Cell Adhesion Molecule-1; Sphingomyelin Phosphodiesterase; Acetylcholine; Inflammation; Vascular Diseases
PubMed: 36103099
DOI: 10.1007/s10557-022-07378-0 -
Carcinogenesis Sep 2009NKX2-1 is a homeodomain transcription factor that is critical for genesis of the thyroid and transcription of the thyroid-specific genes. Nkx2-1-thyroid-conditional...
NKX2-1 is a homeodomain transcription factor that is critical for genesis of the thyroid and transcription of the thyroid-specific genes. Nkx2-1-thyroid-conditional hypomorphic mice were previously developed in which Nkx2-1 gene expression is lost in 50% of the thyroid cells. Using this mouse line as compared with wild-type and Nkx2-1 heterozygous mice, a thyroid carcinogenesis study was carried out using the genotoxic carcinogen N-bis(2-hydroxypropyl)-nitrosamine (DHPN), followed by sulfadimethoxine (SDM) or the non-genotoxic carcinogen amitrole (3-amino-1,2,4-triazole). A significantly higher incidence of adenomas was obtained in Nkx2-1-thyroid-conditional hypomorphic mice as compared with the other two groups of mice only when they were treated with DHPN + SDM, but not amitrole. A bromodeoxyuridine incorporation study revealed that thyroids of the Nkx2-1-thyroid-conditional hypomorphic mice had >2-fold higher constitutive cell proliferation rate than the other two groups of mice, suggesting that this may be at least partially responsible for the increased incidence of adenoma in this mouse line after genotoxic carcinogen exposure. Thus, NKX2-1 may function to control the proliferation of thyroid follicular cells following damage by a genotoxic carcinogen.
Topics: Adenoma; Amitrole; Animals; Carcinogens; Female; Genes, ras; Hyperplasia; Male; Mice; Nitrosamines; Nuclear Proteins; Pituitary Gland; Sulfadimethoxine; Thyroid Neoplasms; Thyroid Nuclear Factor 1; Transcription Factors
PubMed: 19581346
DOI: 10.1093/carcin/bgp167 -
Cleveland Clinic Journal of Medicine Aug 2005Interstitial cystitis is more common than previously thought and is often diagnosed only when pain, frequency, and urgency become continuous and severe. Its diagnosis is... (Review)
Review
Interstitial cystitis is more common than previously thought and is often diagnosed only when pain, frequency, and urgency become continuous and severe. Its diagnosis is straightforward, and effective therapies are available. Physicians should keep the diagnosis of interstitial cystitis in mind for all patients presenting with pelvic pain or urinary symptoms.
Topics: Amitriptyline; Cystitis, Interstitial; Disease Progression; Humans; Hydroxyzine; Primary Health Care
PubMed: 16122055
DOI: 10.3949/ccjm.72.8.698 -
Journal of Forensic Sciences Sep 2021For years, a number of professional groups have warned forensic and clinical toxicologists against calculating an administered dose of a drug based on postmortem blood...
For years, a number of professional groups have warned forensic and clinical toxicologists against calculating an administered dose of a drug based on postmortem blood drug concentrations. But to date, there has been limited information as to how unreliable these dose calculations may actually be. Using amitriptyline as a model drug, this study used empirically determined pharmacokinetic variables for amitriptyline from clinical studies coupled with clinical overdoses (where the individual survived), and death case studies (ascribed to amitriptyline toxicity) in which the dose of amitriptyline was known. Using these data, standard pharmacokinetic equations, and general error propagation, it was possible to estimate the accuracy of calculated doses of amitriptyline, compared with the doses that were consumed. As was expected in postmortem cases, depending on the pharmacokinetic equation used, the accuracy (mean +128% to +2347%) and precision (SD ± 383% to 3698%) were too large to allow reliable estimations of the dose of amitriptyline consumed prior to death based on postmortem blood drug concentrations. This work again reinforces that dose calculations from postmortem blood drug concentrations are unreliable.
Topics: Amitriptyline; Drug Dosage Calculations; Forensic Toxicology; Humans; Pharmacokinetics; Postmortem Changes
PubMed: 34302366
DOI: 10.1111/1556-4029.14801 -
BMJ Case Reports Jul 2022A massive tricyclic overdose of 10 g of amitriptyline resulted in cardiovascular collapse with multiple episodes of ventricular tachycardia and ventricular fibrillation...
A massive tricyclic overdose of 10 g of amitriptyline resulted in cardiovascular collapse with multiple episodes of ventricular tachycardia and ventricular fibrillation despite aggressive attention to current recommended therapy of sodium bicarbonate and hypertonic saline, and correction of electrolytes. Second-line antiarrhythmic therapies failed to reduce the recurrent deterioration to malignant ventricular rhythms. Progression to extracorporeal support was avoided by the use of a titrated esmolol infusion. We discuss the physiological rationale by which esmolol may prevent tachyarrhythmia and fibrillation in severe amitriptyline toxicity.
Topics: Amitriptyline; Antidepressive Agents, Tricyclic; Arrhythmias, Cardiac; Humans; Propanolamines; Tachycardia, Ventricular
PubMed: 35868803
DOI: 10.1136/bcr-2021-248373 -
In Vivo (Athens, Greece) 2022Amitriptyline is a major tricyclic antidepressant that is also used to relieve chronic orofacial pain. Recently, alterations in gut flora due to various antidepressants...
BACKGROUND/AIM
Amitriptyline is a major tricyclic antidepressant that is also used to relieve chronic orofacial pain. Recently, alterations in gut flora due to various antidepressants have been demonstrated. However, it remains unknown how antidepressants affect the oral environment, including microbiota and innate immunity. The aim of this study was to investigate the effects of amitriptyline on oral microflora and antimicrobial peptides.
MATERIALS AND METHODS
Sprague-Dawley rats were intraperitoneally injected with amitriptyline for 2 weeks. The DNA extracted from the oral swabs were used to perform 16SrRNA sequencing to evaluate the oral microbiome. Quantitative RT-PCR was performed to evaluate the mRNA levels of antimicrobial peptides in the buccal tissues.
RESULTS
No significant differences in salivary flow rates were observed between the amitriptyline and control groups. Taxonomic analysis showed significant alterations in bacteria such as Corynebacterium, Rothia, and Porphyromonas due to amitriptyline administration. The beta diversity showed significant differences between the amitriptyline and control groups. Additionally, the predicted metagenome functions were significantly different between the two groups. The mRNA expression levels of antimicrobial peptides in the amitriptyline group were significantly higher as compared to controls.
CONCLUSION
Systemic administration of amitriptyline may affect the oral environment, including oral microbes and innate immunity in the oral mucosa.
Topics: Amitriptyline; Animals; Antidepressive Agents; Gastrointestinal Microbiome; Rats; Rats, Sprague-Dawley
PubMed: 36099099
DOI: 10.21873/invivo.12939 -
Systematic Reviews Mar 2020Unwanted anticholinergic effects are both underestimated and frequently overlooked. Failure to identify adverse drug reactions (ADRs) can lead to prescribing cascades...
BACKGROUND
Unwanted anticholinergic effects are both underestimated and frequently overlooked. Failure to identify adverse drug reactions (ADRs) can lead to prescribing cascades and the unnecessary use of over-the-counter products. The objective of this systematic review and meta-analysis is to explore and quantify the frequency and severity of ADRs associated with amitriptyline vs. placebo in randomized controlled trials (RCTs) involving adults with any indication, as well as healthy individuals.
METHODS
A systematic search in six electronic databases, forward/backward searches, manual searches, and searches for Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval studies, will be performed. Placebo-controlled RCTs evaluating amitriptyline in any dosage, regardless of indication and without restrictions on the time and language of publication, will be included, as will healthy individuals. Studies of topical amitriptyline, combination therapies, or including < 100 participants, will be excluded. Two investigators will screen the studies independently, assess methodological quality, and extract data on design, population, intervention, and outcomes ((non-)anticholinergic ADRs, e.g., symptoms, test results, and adverse drug events (ADEs) such as falls). The primary outcome will be the frequency of anticholinergic ADRs as a binary outcome (absolute number of patients with/without anticholinergic ADRs) in amitriptyline vs. placebo groups. Anticholinergic ADRs will be defined by an experienced clinical pharmacologist, based on literature and data from Martindale: The Complete Drug Reference. Secondary outcomes will be frequency and severity of (non-)anticholinergic ADRs and ADEs. The information will be synthesized in meta-analyses and narratives. We intend to assess heterogeneity using meta-regression (for indication, outcome, and time points) and I statistics. Binary outcomes will be expressed as odds ratios, and continuous outcomes as standardized mean differences. Effect measures will be provided using 95% confidence intervals. We plan sensitivity analyses to assess methodological quality, outcome reporting etc., and subgroup analyses on age, dosage, and duration of treatment.
DISCUSSION
We will quantify the frequency of anticholinergic and other ADRs/ADEs in adults taking amitriptyline for any indication by comparing rates for amitriptyline vs. placebo, hence, preventing bias from disease symptoms and nocebo effects. As no standardized instrument exists to measure it, our overall estimate of anticholinergic ADRs may have limitations.
SYSTEMATIC REVIEW REGISTRATION
Submitted to PROSPERO; assignment is in progress.
Topics: Adult; Amitriptyline; Drug-Related Side Effects and Adverse Reactions; Humans; Meta-Analysis as Topic; Systematic Reviews as Topic; United States
PubMed: 32183872
DOI: 10.1186/s13643-020-01296-8 -
The Cochrane Database of Systematic... Jul 2011Abdominal pain-related functional gastrointestinal disorders (FGIDs) are among the most common medical problems in paediatric medicine. Frequently, physicians prescribe... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Abdominal pain-related functional gastrointestinal disorders (FGIDs) are among the most common medical problems in paediatric medicine. Frequently, physicians prescribe antidepressants as a second-line treatment for children and adolescents with FGIDs. To date, the evidence on the benefits and harms of antidepressants for the treatment of abdominal pain-related FGIDs has not been assessed systematically.
OBJECTIVES
The primary objectives were to conduct a systematic review to evaluate the efficacy and safety of antidepressants for the treatment of abdominal pain-related FGIDs in children and adolescents.
SEARCH STRATEGY
We searched The Cochrane Library, PubMed, EMBASE, IPA, CINAHL, PsycINFO, ISI Web of Science, Biosis Previews and the International Clinical Trials Registry Platform of the World Health Organization with appropriate filters (from inception to January 31, 2011).
SELECTION CRITERIA
For efficacy we included double-blind, randomised controlled trials (RCTs) of antidepressants for treatment of abdominal pain-related FGIDs in children and adolescents 18 years or younger. Open-label and uncontrolled experimental studies, as well as observational studies were eligible for the assessment of harms. The minimum study duration was 4 weeks. The minimum study size was 30 participants.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed all abstracts and full text articles, and rated the risk of bias for included studies. Data were extracted independently by one author and checked for accuracy by another author. Data were analysed using RevMan 5.
MAIN RESULTS
Two RCTs (123 participants), both using amitriptyline, met the pre-specified inclusion criteria. These studies provided mixed findings on the efficacy of amitriptyline for the treatment of abdominal pain-related FGIDs. The larger, publicly-funded study reported no statistically significant difference in efficacy between amitriptyline and placebo in 90 children and adolescents with FGIDs after 4 weeks of treatment. On intention-to-treat (ITT)- analysis, 59% of the children reported feeling better in the amitriptyline group compared with 53% in the placebo group (RR 1.12; 95% CI: 0.77 to 1.63; P = 0.54). The risk of bias for this study was rated as low.The second RCT enrolled 33 adolescents with irritable bowel syndrome. Patients receiving amitriptyline experienced greater improvements in the primary outcome, overall quality of life, at weeks 6, 10, and 13 compared with those on placebo (P= 0.019, 0.004, and 0.013, respectively). No effect estimates were calculated for the quality of life outcome because mean quality of life scores and standard deviations were not reported. For most secondary outcomes no statistically significant differences between amitriptyline and placebo could be detected. The risk of bias for this study was rated as unclear for most items. However, it was rated as high for other bias due to multiple testing. The results of this study should be interpreted with caution due to the small number of patients and multiple testing.The larger study reported mild adverse events including fatigue, rash and headache and dizziness. On ITT analysis, 4% of the amitriptyline group experienced at least one adverse event compared to 2% of the placebo group. There was no statistically significant difference in the proportion of patients who experienced at least one adverse event (RR 1.91; 95% CI 0.18 to 20.35; P = 0.59). The smaller study reported no adverse events. The methods of adverse effects assessment was poorly reported in both studies and no clear conclusions on the risks of harms of amitriptyline can be drawn.
AUTHORS' CONCLUSIONS
Clinicians must be aware that for the majority of antidepressant medications no evidence exists that supports their use for the treatment of abdominal pain-related FGIDs in children and adolescents. The existing randomised controlled evidence is limited to studies on amitriptyline and revealed no statistically significant differences between amitriptyline and placebo for most efficacy outcomes. Amitriptyline does not appear to provide any benefit for the treatment of FGIDs in children and adolescents. Studies in children with depressive disorders have shown that antidepressants can lead to substantial, sometimes life-threatening adverse effects. Until better evidence evolves, clinicians should weigh the potential benefits of antidepressant treatment against known risks of antidepressants in paediatric patients.
Topics: Abdominal Pain; Adolescent; Amitriptyline; Antidepressive Agents, Tricyclic; Child; Gastrointestinal Diseases; Humans; Irritable Bowel Syndrome; Randomized Controlled Trials as Topic
PubMed: 21735420
DOI: 10.1002/14651858.CD008013.pub2 -
Psychopharmacology Bulletin Jun 2018Due to the stringent regulatory environment for therapeutics, common side-effects of drugs in the general population are largely well-documented. This is however less...
Due to the stringent regulatory environment for therapeutics, common side-effects of drugs in the general population are largely well-documented. This is however less the case with certain patient subgroups who may exhibit significant adverse responses to therapeutics that are otherwise well-tolerated. We report a case of psychosis induced by exposure to a commonly prescribed drug to treat muscle spasms and associated pain cyclobenzaprine (Flexeril®). Cyclobenzaprine is structurally very similar to tricyclic anti-depressants, such as amyltriptine. While it is well known that agitation caused by cyclobenzaprine is not an uncommon occurrence in the elderly, there have also been sporadic reports of significant psychosis in association with the use of cyclobenzaprine in younger patients. We report a case of reversible mania in a susceptible 44-year-old patient with a lengthy history of mild borderline personality and bipolar disorder. Shortly after being treated with cyclobenzaprine for pain due to a minor injury, this patient exhibited significant signs of mania although these signs were readily reversible upon termination of the treatment with cyclobenzaprine. The patient's severe adverse reaction to this normally innocuous drug adds weight to the notion that there is reason for caution with its prescription for potentially susceptible patient subgroups.
Topics: Adult; Amitriptyline; Antidepressive Agents, Tricyclic; Bipolar Disorder; Borderline Personality Disorder; Female; Humans; Muscle Relaxants, Central; Psychoses, Substance-Induced; Tranquilizing Agents
PubMed: 30618472
DOI: No ID Found