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The Journal of Headache and Pain Apr 2023The aim of this paper is to critically re-appraise the published trials assessing amitriptyline for migraine prophylaxis. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The aim of this paper is to critically re-appraise the published trials assessing amitriptyline for migraine prophylaxis.
METHODS
We report our methods and results following the Preferred Reporting Items for Systematic Reviews (PRISMA), by searching MEDLINE, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov for randomized trials of pharmacologic treatments for migraine prophylaxis. We included randomized trials that compared amitriptyline with placebo for migraine prophylaxis in adults. Our outcomes of interest were informed by the Outcome Set for preventive intervention trials in chronic and episodic migraine (COSMIG) and include the proportion of patients who experience a 50% or more reduction in migraine days per month, migraine days per month, and adverse events leading to discontinuation. We assessed risk of bias by using a modified Cochrane RoB 2.0 tool and the certainty of evidence by using the GRADE approach.
RESULTS
Our search yielded 10.826 unique records, of which three trials (n = 622) were eligible for data synthesis and analysis. We found moderate certainty evidence that amitriptyline increases the proportion of patients who experience a 50% or more reduction in monthly migraine days, compared to placebo (relative risk: 1.60 (95% CI 1.17 to 2.19); absolute risk difference: 165 more per 1,000 (95% CI 47 more to 327 more). We found moderate certainty evidence that amitriptyline increases the proportion of patients who discontinue due to adverse events compared to placebo (risk difference: 0.05 (95% CI 0.01 to 0.10); absolute risk difference: 50 more per 1,000 (95% CI 10 more to 100 more).
CONCLUSIONS
Our meta-analysis showed that amitriptyline may have a prophylactic role in migraine patients, however these results are far from robust. This warrants further large-scale research to evaluate the role of amitriptyline in migraine prevention.
Topics: Adult; Humans; Amitriptyline; Migraine Disorders; Headache; Transcription Factors
PubMed: 37038134
DOI: 10.1186/s10194-023-01573-6 -
The Journal of Physical Chemistry. B Mar 2020We investigated the loading of an amphiphilic drug, amitriptyline hydrochloride (AMT), onto sodium polyacrylate hydrogels at low ionic strength and its release at high...
We investigated the loading of an amphiphilic drug, amitriptyline hydrochloride (AMT), onto sodium polyacrylate hydrogels at low ionic strength and its release at high ionic strength. The purpose was to show how the self-assembling properties of the drug and the swelling of the gel network influenced the loading/release mechanisms and kinetics, important for the development of improved controlled-release systems for parenteral administration of amphiphilic drugs. Equilibrium studies showed that single microgels (∼100 μm) in a large solution volume underwent a discrete transition between swollen and dense states at a critical drug concentration in the solution. For single macrogels in a small solution volume, the transition progressed gradually with increasing amount of added drug, with swollen and dense phases coexisting in the same gel; in a suspension of microgels, swollen and collapsed particles coexisted. Time-resolved micropipette-assisted microscopy studies showed that drug self-assemblies accumulated in a dense shell enclosing the swollen core during loading and that a dense core was surrounded by a swollen shell during release. The time evolution of the radius of single microgels was determined as functions of liquid flow rate, network size, and AMT concentration in the solution. Mass transport of AMT in the surrounding liquid, and in the dense shell, influenced the deswelling rate during loading. Mass transport in the swollen shell controlled the swelling rate during release. A steady-state kinetic model taking into account drug self-assembly, core-shell phase separation, and microgel volume changes was developed and found to be in semiquantitative agreement with the experimental loading and release data.
Topics: Amitriptyline; Hydrogels; Kinetics; Microgels; Osmolar Concentration
PubMed: 32105083
DOI: 10.1021/acs.jpcb.0c00030 -
Arquivos de Neuro-psiquiatria Nov 2014To compare the preventive treatment benefits of amitriptyline and aerobic exercise or amitriptyline alone in patients with chronic migraine. (Randomized Controlled Trial)
Randomized Controlled Trial
UNLABELLED
To compare the preventive treatment benefits of amitriptyline and aerobic exercise or amitriptyline alone in patients with chronic migraine.
METHOD
Sixty patients, both genders, aged between 18 and 50 years, with a diagnosis of chronic migraine, were randomized in groups called amitriptyline and aerobic exercise or amitriptyline alone. The following parameters were evaluated: headache frequency, intensity and duration of headache, days of the analgesic medication use, body mass index (BMI), Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) scores.
RESULTS
In the evaluated parameters, was observed decrease in headache frequency (p=0.001), moderate intensity (p=0.048), in headache duration (p=0.001), the body mass index (p=0.001), Beck Depression Inventory (p=0.001) and Beck Anxiety Inventory scores (p=0.001), when groups were compared in the end of third month.
CONCLUSION
In this study, the amitriptyline was an effective treatment for chronic migraine, but its efficacy was increased when combined with aerobic exercise.
Topics: Adolescent; Adult; Amitriptyline; Analgesics, Non-Narcotic; Chronic Disease; Combined Modality Therapy; Exercise; Female; Humans; Male; Middle Aged; Migraine Disorders; Reproducibility of Results; Surveys and Questionnaires; Time Factors; Treatment Outcome; Young Adult
PubMed: 25410451
DOI: 10.1590/0004-282x20140148 -
Biomolecules Nov 2022SARS-CoV-2 has undergone mutations, yielding clinically relevant variants.
BACKGROUND
SARS-CoV-2 has undergone mutations, yielding clinically relevant variants.
HYPOTHESIS
We hypothesized that in SARS-CoV-2, two highly conserved Orf3a and E channels directly related to the virus replication were a target for the detection and inhibition of the viral replication, independent of the variant, using FDA-approved ion channel modulators.
METHODS
A combination of a fluorescence potassium ion assay with channel modulators was developed to detect SARS-CoV-2 Orf3a/E channel activity. Two FDA-approved drugs, amantadine (an antiviral) and amitriptyline (an antidepressant), which are ion channel blockers, were tested as to whether they inhibited Orf3a/E channel activity in isolated virus variants and in nasal swab samples from COVID-19 patients. The variants were confirmed by PCR sequencing.
RESULTS
In isolated SARS-CoV-2 Alpha, Beta, and Delta variants, the channel activity of Orf3a/E was detected and inhibited by emodin and gliclazide (IC = 0.42 mM). In the Delta swab samples, amitriptyline and amantadine inhibited the channel activity of viral proteins, with IC values of 0.73 mM and 1.11 mM, respectively. In the Omicron swab samples, amitriptyline inhibited the channel activity, with an IC of 0.76 mM.
CONCLUSIONS
We developed an efficient method to screen FDA-approved ion channel modulators that could be repurposed to detect and inhibit SARS-CoV-2 viral replication, independent of variants.
Topics: Humans; Amantadine; Amitriptyline; Ion Channels; SARS-CoV-2; Drug Evaluation, Preclinical; Drug Repositioning; COVID-19 Drug Treatment
PubMed: 36421688
DOI: 10.3390/biom12111673 -
Trials Jul 2022Irritable bowel syndrome (IBS) is a common functional bowel disorder that has a considerable impact on patient quality of life and substantial societal and health care...
Amitriptyline at low-dose and titrated for irritable bowel syndrome as second-line treatment (The ATLANTIS trial): protocol for a randomised double-blind placebo-controlled trial in primary care.
BACKGROUND
Irritable bowel syndrome (IBS) is a common functional bowel disorder that has a considerable impact on patient quality of life and substantial societal and health care resource costs. Current treatments are often ineffective. Tricyclic antidepressants have shown promise in secondary care populations but their effectiveness in a primary care setting remains unclear.
METHODS
ATLANTIS is a randomised, multi-centre, parallel-group, two-arm, double-blind, placebo-controlled trial of low-dose amitriptyline as a second-line treatment for IBS in primary care. Participants will be invited by letter, or recruited opportunistically, from general practices in three regions of England (West Yorkshire, Wessex, and West of England) and screened for eligibility. A total of 518 adult patients with IBS, who are symptomatic despite first-line therapies, will be randomised 1:1 to amitriptyline or identical placebo for 6 months. Treatment will commence at a dose of 10 mg (or one placebo tablet) daily at night, with dose titration up to a maximum of 30 mg at night, depending on side effects and response to treatment. Participant-reported assessments will be conducted at baseline and 3, 6, and 12 months post-randomisation. The primary objective is to determine the effectiveness of amitriptyline, compared with placebo, in improving participant-reported global symptoms of IBS at 6 months (using the IBS Severity Scoring System). Secondary outcomes include relief of IBS symptoms, effect on IBS-associated somatic symptoms (Patient Health Questionnaire-12), anxiety and depression (Hospital Anxiety and Depression Scale), ability to work and participate in other activities (Work and Social Adjustment Scale), acceptability and tolerability of treatment, self-reported health care use, health-related quality of life (EQ-5D-3L), and cost-effectiveness. A nested, qualitative study will explore patient and general practitioner experiences of treatments and trial participation, including acceptability, adherence, unanticipated effects, and implications for wider use of amitriptyline for IBS in primary care.
DISCUSSION
Determining the clinical and cost-effectiveness of low-dose amitriptyline as a second-line treatment for IBS in primary care will provide robust evidence to inform management decisions.
TRIAL REGISTRATION
ISRCTN ISRCTN48075063 . Registered on 7th June 2019.
Topics: Adult; Amitriptyline; Double-Blind Method; Humans; Irritable Bowel Syndrome; Multicenter Studies as Topic; Primary Health Care; Quality of Life; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 35804433
DOI: 10.1186/s13063-022-06492-6 -
Chemistry & Biology Jun 2009Neurotrophins, the cognate ligands for the Trk receptors, are homodimers and induce Trk dimerization through a symmetric bivalent mechanism. We report here that...
Neurotrophins, the cognate ligands for the Trk receptors, are homodimers and induce Trk dimerization through a symmetric bivalent mechanism. We report here that amitriptyline, an antidepressant drug, directly binds TrkA and TrkB and triggers their dimerization and activation. Amitriptyline, but not any other tricyclic or selective serotonin reuptake inhibitor antidepressants, promotes TrkA autophosphorylation in primary neurons and induces neurite outgrowth in PC12 cells. Amitriptyline binds the extracellular domain of both TrkA and TrkB and promotes TrkA-TrkB receptor heterodimerization. Truncation of amitriptyline binding motif on TrkA abrogates the receptor dimerization by amitriptyline. Administration of amitriptyline to mice activates both receptors and significantly reduces kainic acid-triggered neuronal cell death. Inhibition of TrkA, but not TrkB, abolishes amitriptyline's neuroprotective effect without impairing its antidepressant activity. Thus, amitriptyline acts as a TrkA and TrkB agonist and possesses marked neurotrophic activity.
Topics: Amitriptyline; Animals; Antidepressive Agents, Tricyclic; Apoptosis; Cell Line, Tumor; Humans; Mice; Nerve Growth Factors; Neurites; Neurons; PC12 Cells; Phosphorylation; Protein Multimerization; Rats; Receptor, trkA; Receptor, trkB; Signal Transduction
PubMed: 19549602
DOI: 10.1016/j.chembiol.2009.05.010 -
Biosensors Aug 2023A new method to transfer the standard addition procedure for concentration determination to immunoassays with non-linear calibration curves was developed. The new method...
A new method to transfer the standard addition procedure for concentration determination to immunoassays with non-linear calibration curves was developed. The new method was successfully applied to simulated data and benchmarked against a state-of-the-art algorithm, showing a significantly improved performance with improvement factors between 2 and 192. The logit function was used to transform the immunoassay signal response of test samples spiked with known analyte concentrations. The relationship between logit(signal) and log-transformed estimated total analyte concentration is linear if the estimated total analyte concentration is correct. Finally, the new method was validated experimentally using different assays in varying, relevant complex matrices, such as serum, saliva, and milk. Different concentrations of testosterone and amitriptyline between 0.05 and 3.0 µg L were quantified using a binding inhibition assay in combination with reflectometric interference spectroscopy (RIfS) as the transduction principle. The sample concentration was calculated using a numerical method. Samples could be quantified with recoveries between 70 and 118%. The standard addition method accounts for individual matrix interference on the immunoassay by spiking the test sample itself. Although the experiments were carried out using RIfS, the method can be applied to any immunoassay that meets the analytical requirements.
Topics: Algorithms; Amitriptyline; Biological Assay; Calibration; Immunoassay
PubMed: 37754083
DOI: 10.3390/bios13090849 -
Journal of Veterinary Internal Medicine 2004A prospective study was performed to determine the relative availability of buspirone and amitriptyline after oral and transdermal routes of administration in 6 adult...
A prospective study was performed to determine the relative availability of buspirone and amitriptyline after oral and transdermal routes of administration in 6 adult cats. For topical administration, drugs were compounded in a transdermal organogel containing pluronic and lecithin (PLO). Using a crossover design, each cat received a single dose of amitriptyline (5 mg) and buspirone (2.5 mg) by the transdermal and oral route of administration with at least a 2-week washout interval between drug treatments. Blood samples were obtained at 0, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours after drug administration for determination of plasma drug concentrations. Plasma concentrations of immunoreactive amitriptyline and buspirone were determined using commercial enzyme-linked immunosorbent assay (ELISA) tests. Systemic absorption of amitriptyline and buspirone administered by the transdermal route was poor compared with the oral route of administration. Until supporting pharmacokinetic data are available, veterinarians and cat owners should not rely on the transdermal route of administration for treating cats with amitriptyline or buspirone.
Topics: Administration, Cutaneous; Administration, Oral; Amitriptyline; Animals; Anti-Anxiety Agents; Antidepressive Agents, Tricyclic; Area Under Curve; Biological Availability; Buspirone; Cats; Cross-Over Studies; Eliminative Behavior, Animal; Enzyme-Linked Immunosorbent Assay; Female; Prospective Studies; Skin Absorption
PubMed: 14765730
DOI: 10.1892/0891-6640(2004)18<43:saoaab>2.0.co;2 -
The Journal of Pharmacology and... Jan 2024Inflammatory pain is caused by tissue hypersensitization and is a component of rheumatic diseases, frequently causing chronic pain. Current guidelines use a multimodal...
Assessing Dose- and Sex-Dependent Antinociceptive Effects of Cannabidiol and Amitriptyline, Alone and in Combination, and Exploring Mechanism of Action Involving Serotonin 1A Receptors.
Inflammatory pain is caused by tissue hypersensitization and is a component of rheumatic diseases, frequently causing chronic pain. Current guidelines use a multimodal approach to pain and sociocultural changes have renewed interest in cannabinoid use, particularly cannabidiol (CBD), for pain. The tricyclic antidepressant amitriptyline (AT) is approved for use in pain-related syndromes, alone and within a multimodal approach. Therefore, we investigated sex- and dose-dependent effects of CBD and AT antinociception in the 2.5% formalin inflammatory pain model. Male and female C57BL/6J mice were pretreated with either vehicle, CBD (0.3-100 mg/kg), or AT (0.1-30 mg/kg) prior to formalin testing. In the acute phase, CBD induced antinociception after administration of 30-100 mg/kg in males and 100 mg/kg in females and in the inflammatory phase at doses of 2.5-100 mg/kg in males and 10-100 mg/kg in females. In the acute phase, AT induced antinociception at 10 mg/kg for all mice, and at 0.3 mg/kg in males and 3 mg/kg in female mice in the inflammatory phase. Combining the calculated median effective doses of CBD and AT produced additive effects for all mice in the acute phase and for males only in the inflammatory phase. Use of selective serotonin 1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1 piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY-100635) maleate (0.1 mg/kg) before co-administration of CBD and AT reversed antinociception in the acute and partially reversed antinociception in the inflammatory phase. Administration of AT was found to enhance cannabinoid receptor type 1mRNA expression only in female mice. These results suggest a role for serotonin and sex in mediating cannabidiol and amitriptyline-induced antinociception in inflammatory pain. SIGNIFICANCE STATEMENT: Inflammatory pain is an important component of both acute and chronic pain. We have found that cannabidiol (CBD) and amitriptyline (AT) show dose-dependent, and that AT additionally shows sex-dependent, antinociceptive effects in an inflammatory pain model. Additionally, the combination of CBD and AT was found to have enhanced antinociceptive effects that is partially reliant of serotonin 1A receptors and supports the use of CBD within a multimodal approach to pain.
Topics: Mice; Male; Female; Animals; Cannabidiol; Serotonin; Amitriptyline; Chronic Pain; Receptor, Serotonin, 5-HT1A; Mice, Inbred C57BL; Serotonin Antagonists; Analgesics; Formaldehyde
PubMed: 38129125
DOI: 10.1124/jpet.123.001855 -
Basic & Clinical Pharmacology &... Apr 2019Amitriptyline is a tricyclic antidepressant and an inhibitor of lysosomal acid sphingomyelinase (ASM). Amitriptyline is well known for its cardiovascular side effects...
Amitriptyline is a tricyclic antidepressant and an inhibitor of lysosomal acid sphingomyelinase (ASM). Amitriptyline is well known for its cardiovascular side effects and toxicity in psychiatric patients. However, the mechanisms underlying the cardiovascular side effects of amitriptyline remain largely undefined. This study aimed to determine the effects of amitriptyline on angiogenic capability of vascular endothelial cells in physiological settings and identify its mechanism of action. The ex vivo aortic ring angiogenesis and in vitro-cultured endothelial cell tube formation assay were used to assess the effects of amitriptyline on endothelial angiogenic capability. It was demonstrated that amitriptyline impaired the angiogenesis of aortic rings, which was similar to that found in aortic rings with haploinsufficiency of the ASM gene. In cultured mouse microvascular endothelial cells (MVECs), amitriptyline impaired the proliferation and tube formation under basal condition, which were accompanied by attenuated angiogenic signalling pathways such as endothelial nitric oxide synthase, Akt and Erk1/2 pathways. Mechanistically, amitriptyline inhibited autophagic flux without affecting autophagosome biogenesis at basal condition. ASM gene silencing or autophagy inhibition mimics the inhibitory effects of amitriptyline on endothelial cell proliferation and tube formation. Collectively, our data suggest that amitriptyline inhibits endothelial cell proliferation and angiogenesis via blockade of ASM-autophagic flux axis. It is implicated that the cardiovascular side effects of amitriptyline may be associated with its inhibitory action on physiological angiogenesis.
Topics: Amitriptyline; Animals; Antidepressive Agents, Tricyclic; Aorta, Thoracic; Autophagy; Cell Proliferation; Cells, Cultured; Endothelial Cells; Gene Knockdown Techniques; Male; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Signal Transduction
PubMed: 30311396
DOI: 10.1111/bcpt.13146