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British Journal of Pharmacology Jan 2022Osteoarthritis, a major cause of disability in developed countries does not have effective treatment. Activation of TLR4 and innate immune response factors contribute to...
BACKGROUND AND PURPOSE
Osteoarthritis, a major cause of disability in developed countries does not have effective treatment. Activation of TLR4 and innate immune response factors contribute to osteoarthritis progressive cartilage degradation. There are no clinically available TLR4 inhibitors. Interestingly, the antidepressant amitriptyline could block this receptor. Thus, we evaluated amitriptyline anti-TLR4 effects on human osteoarthritis chondrocytes in order to repurpose it as an inhibitor of innate immune response in joint inflammatory pathologies.
EXPERIMENTAL APPROACH
Using in silico docking analysis, RT-PCR, siRNA, elisa, proteomics and clinical data mining of drug consumption, we explored the clinical relevance of amitriptyline blockade of TLR4-mediated innate immune responses in human osteoarthritis chondrocytes.
KEY RESULTS
Amitriptyline bound TLR4 but not IL-1 receptor. Interestingly, amitriptyline binding to TLR4 inhibited TLR4- and IL-1 receptor-mediated innate immune responses in human osteoarthritis chondrocytes, synoviocytes and osteoblasts cells. Amitriptyline reduced basal innate immune responses and promoted anabolic effects in human osteoarthritis chondrocytes. Supporting its anti-innate immune response effects, amitriptyline down-regulated basal and induced expression of NLRP3, an inflammasome member from IL-1 receptor signalling linked to osteoarthritis and gout pathologies. Accordingly, mining of dissociated and aggregated drug consumption data from 107,172 elderly patients (>65 years) revealed that amitriptyline consumption was significantly associated with lower colchicine consumption associated with inflammatory gout flare treatment.
CONCLUSION AND IMPLICATIONS
Amitriptyline blocks TLR4-, IL-1 receptor and NLRP3-dependent innate immune responses. This together with clinical data amitriptyline could be repurposed for systemic or local innate immune response management in diverse joint inflammatory pathologies.
Topics: Aged; Amitriptyline; Chondrocytes; Gout; Humans; Immunity, Innate; NLR Family, Pyrin Domain-Containing 3 Protein; Osteoarthritis; Receptors, Interleukin-1; Symptom Flare Up; Toll-Like Receptor 4
PubMed: 34643941
DOI: 10.1111/bph.15707 -
European Review For Medical and... May 2024Painful peripheral diabetic neuropathy (PRDN) is a common disabling condition. Pregabalin and amitriptyline are commonly prescribed as the first-line for PPDN despite... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Painful peripheral diabetic neuropathy (PRDN) is a common disabling condition. Pregabalin and amitriptyline are commonly prescribed as the first-line for PPDN despite the contradicting recommendations. There is a need to inform the scientific community regarding first-line pain control among patients with PPDN. This meta-analysis assessed pregabalin and amitriptyline effects on PPDN.
PATIENTS AND METHODS
We searched PubMed, MEDLINE, Cochrane Library, EBSCO, and Google Scholar; the terms used were amitriptyline, pregabalin, painful diabetic neuropathy, antidepressant, gabapentinoids, quality of life, and adverse events. Boolean operators like AND, and OR were used. Six hundred and thirty-one studies were retrieved, and 37 full texts were screened. However, only six randomized controlled trials fulfilled the inclusion and exclusion criteria.
RESULTS
No significant statistical differences between amitriptyline and pregabalin regarding pain score and significant pain reduction (odd ratio, -0.82, 95% CI, -2.21-0.58, and odd ratio, 1.16, 95% CI, 0.76-1.76 respectively). Quality of life, total adverse events, and drug discontinuation were not different between the two drugs (odd ratio, 0.89, 95% CI, -2.11-3.89, odd ratio, 0.98, 95% CI, 0.52-1.85, and odd ratio, 0.51, 95% CI, 0.08-3.15, respectively).
CONCLUSIONS
No significant statistical differences between amitriptyline and pregabalin regarding their effects on pain and quality of life. The drugs showed similar total adverse events and drug withdrawal. Further larger real-world studies are needed.
Topics: Pregabalin; Amitriptyline; Humans; Diabetic Neuropathies; Analgesics; Quality of Life
PubMed: 38856135
DOI: 10.26355/eurrev_202405_36296 -
Iranian Journal of Child Neurology 2019Cyclic vomiting syndrome (CVS) is a chronic functional gastrointestinal disorder with no certain treatment. We aimed to compare the efficacy of amitriptyline and...
OBJECTIVES
Cyclic vomiting syndrome (CVS) is a chronic functional gastrointestinal disorder with no certain treatment. We aimed to compare the efficacy of amitriptyline and topiramate on prophylactic therapy of CVS.
MATERIALS & METHODS
This randomized clinical trial (registration number: IRCT2015102316844N2) was conducted during 2016 in Isfahan, central Iran. The inclusion criteria were CVS patients (based on Rome III) aging 3-15 yr with normal physical examination, no metabolic disorder, and no gastrointestinal obstruction or renal impairment. Recruited patients were divided into two groups of amitriptyline (1 mg/kg/d) and topiramate (1-2 mg/kg/d) and were followed for 3-months. The outcome was evaluated by comparing severity of attacks (monthly frequency and duration of attacks) before and after intervention.
RESULTS
Thirty-six children entered each group and two patients left the amitriptyline group. Patients and disease characteristics were similar between groups before intervention (>0.05). The frequency of attacks (standard deviation) after intervention in amitriptyline and topiramate group was 0.91 (0.40) and 1.07 (0.55), respectively (=0.368) and the duration of attacks (SD) after intervention were 3.43 (2.46) and 4.90 (3.03), respectively (=0.017). Twenty-three patients (68%) in amitriptyline group and 14 patients (39%) in topiramate group stopped having attacks after intervention (=0.016).
CONCLUSION
Amitriptyline is a better choice to reduce severity of CVS attacks compared to topiramate, in a short-term evaluation. Studies with longer follow-up are required to investigate these findings in a longer period.
PubMed: 30613204
DOI: No ID Found -
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 -
The Saudi Dental Journal Sep 2022Amitriptyline is a tricyclic antidepressant drug accustomed to treat depressive disorders. It recorded many side effects on different tissues.
BACKGROUND
Amitriptyline is a tricyclic antidepressant drug accustomed to treat depressive disorders. It recorded many side effects on different tissues.
OBJECTIVE
To investigate reaction of Albino rats' periodontium after oral administration of Amitriptyline histologically and radiographically.
METHODS
Fourteen adult male albino rats (150-200 g) were divided into two groups, control and experimental. Rats of experimental group received 10 mg⁄kg⁄day of Amitriptyline hydrochloride by oral gavage for four weeks. Mandibles were prepared for hematoxylin and eosin (H&E) and anti-osteopontin (Anti-OPN) immunohistochemistry staining. Bone mineral density was measured in mandibular alveolar bone. Statistical analysis for Anti-OPN and relative Hounsfield unit value (HU value) was performed using independent-samples -test.
RESULTS
Gingiva of experimental group showed epithelial degeneration with pyknotic nuclei and disintegration in lamina propria. Areas of separation in alveolar bone and degeneration of some regions in cementum were seen with apparent increase in periodontal ligament (PDL) thickness and its detachment from bone and cementum at some regions. Immunohistochemical examination of experimental group showed apparently increased immunopositivity in gingiva, cementocytes, osteocytes, cementum, bone matrices, fibroblasts and PDL fibers when compared to control group. Statistical analysis revealed insignificant difference of Anti-OPN area% in gingiva between both studied groups. While there was statistical significant increase of Anti-OPN area% in the other periodontium tissues and high statistical significant decrease of relative HU value in experimental group when compared to control.
CONCLUSIONS
Amitriptyline has destructive effect on periodontal tissues and statistically increases the expression of Anti-OPN in all periodontal tissues except gingiva and decreases bone mineral density.
PubMed: 36092527
DOI: 10.1016/j.sdentj.2022.06.010 -
Toxics Dec 2022Pharmaceuticals such as antidepressants are designed to be bioactive at low concentrations. According to their mode of action, they can also influence non-target...
Pharmaceuticals such as antidepressants are designed to be bioactive at low concentrations. According to their mode of action, they can also influence non-target organisms due to the phylogenetic conservation of molecular targets. In addition to the pollution by environmental chemicals, the topic of microplastics (MP) in the aquatic environment came into the focus of scientific and public interest. The aim of the present study was to investigate the influence of the antidepressant amitriptyline in the presence and absence of irregularly shaped polystyrene MP as well as the effects of MP alone on juvenile brown trout (Salmo trutta f. fario). Fish were exposed to different concentrations of amitriptyline (nominal concentrations between 1 and 1000 µg/L) and two concentrations of MP (104 and 105 particles/L; <50 µm) for three weeks. Tissue cortisol concentration, oxidative stress, and the activity of two carboxylesterases and of acetylcholinesterase were assessed. Furthermore, the swimming behavior was analyzed in situations with different stress levels. Exposure to amitriptyline altered the behavior and increased the activity of acetylcholinesterase. Moreover, nominal amitriptyline concentrations above 300 µg/L caused severe acute adverse effects in fish. MP alone did not affect any of the investigated endpoints. Co-exposure caused largely similar effects such as the exposure to solely amitriptyline. However, the effect of amitriptyline on the swimming behavior during the experiment was alleviated by the higher MP concentration.
PubMed: 36548596
DOI: 10.3390/toxics10120763 -
International Journal of Molecular... Dec 2022The facilitated activity of N-methyl-D-aspartate receptors (NMDARs) in the central and peripheral nervous systems promotes neuropathic pain. Amitriptyline (ATL) and...
The facilitated activity of N-methyl-D-aspartate receptors (NMDARs) in the central and peripheral nervous systems promotes neuropathic pain. Amitriptyline (ATL) and desipramine (DES) are tricyclic antidepressants (TCAs) whose anti-NMDAR properties contribute to their analgetic effects. At therapeutic concentrations <1 µM, these medicines inhibit NMDARs by enhancing their calcium-dependent desensitization (CDD). Li+, which suppresses the sodium−calcium exchanger (NCX) and enhances NMDAR CDD, also exhibits analgesia. Here, the effects of different [Li+]s on TCA inhibition of currents through native NMDARs in rat cortical neurons recorded by the patch-clamp technique were investigated. We demonstrated that the therapeutic [Li+]s of 0.5−1 mM cause an increase in ATL and DES IC50s of ~10 folds and ~4 folds, respectively, for the Ca2+-dependent NMDAR inhibition. The Ca2+-resistant component of NMDAR inhibition by TCAs, the open-channel block, was not affected by Li+. In agreement, clomipramine providing exclusively the NMDAR open-channel block is not sensitive to Li+. This Ca2+-dependent interplay between Li+, ATL, and DES could be determined by their competition for the same molecular target. Thus, submillimolar [Li+]s may weaken ATL and DES effects during combined therapy. The data suggest that Li+, ATL, and DES can enhance NMDAR CDD through NCX inhibition. This ability implies a drug−drug or ion−drug interaction when these medicines are used together therapeutically.
Topics: Rats; Animals; Antidepressive Agents, Tricyclic; Amitriptyline; Receptors, N-Methyl-D-Aspartate; Lithium; Calcium; Desipramine; Calcium, Dietary
PubMed: 36555818
DOI: 10.3390/ijms232416177 -
Neurotherapeutics : the Journal of the... Jan 2024While loss-of-function (LoF) variants in KCNQ2 are associated with a spectrum of neonatal-onset epilepsies, gain-of-function (GoF) variants cause a more complex...
While loss-of-function (LoF) variants in KCNQ2 are associated with a spectrum of neonatal-onset epilepsies, gain-of-function (GoF) variants cause a more complex phenotype that precludes neonatal-onset epilepsy. In the present work, the clinical features of three patients carrying a de novo KCNQ2 Y141N (n = 1) or G239S variant (n = 2) respectively, are described. All three patients had a mild global developmental delay, with prominent language deficits, and strong activation of interictal epileptic activity during sleep. Epileptic seizures were not reported. The absence of neonatal seizures suggested a GoF effect and prompted functional testing of the variants. In vitro whole-cell patch-clamp electrophysiological experiments in Chinese Hamster Ovary cells transiently-transfected with the cDNAs encoding Kv7.2 subunits carrying the Y141N or G239S variants in homomeric or heteromeric configurations with Kv7.2 subunits, revealed that currents from channels incorporating mutant subunits displayed increased current densities and hyperpolarizing shifts of about 10 mV in activation gating; both these functional features are consistent with an in vitro GoF phenotype. The antidepressant drug amitriptyline induced a reversible and concentration-dependent inhibition of current carried by Kv7.2 Y141N and G239S mutant channels. Based on in vitro results, amitriptyline was prescribed in one patient (G239S), prompting a significant improvement in motor, verbal, social, sensory and adaptive behavior skillsduring the two-year-treatment period. Thus, our results suggest that KCNQ2 GoF variants Y141N and G239S cause a mild DD with prominent language deficits in the absence of neonatal seizures and that treatment with the Kv7 channel blocker amitriptyline might represent a potential targeted treatment for patients with KCNQ2 GoF variants.
Topics: Infant, Newborn; Cricetinae; Animals; Humans; Amitriptyline; Cricetulus; CHO Cells; Gain of Function Mutation; Epilepsy; Phenotype; Seizures; KCNQ2 Potassium Channel
PubMed: 38241158
DOI: 10.1016/j.neurot.2023.10.006 -
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 -
EBioMedicine Jul 2022Prior studies have revealed remarkable phenotypic heterogeneity in KCNQ2-related disorders, correlated with effects on biophysical features of heterologously expressed...
BACKGROUND
Prior studies have revealed remarkable phenotypic heterogeneity in KCNQ2-related disorders, correlated with effects on biophysical features of heterologously expressed channels. Here, we assessed phenotypes and functional properties associated with KCNQ2 missense variants R144W, R144Q, and R144G. We also explored in vitro blockade of channels carrying R144Q mutant subunits by amitriptyline.
METHODS
Patients were identified using the RIKEE database and through clinical collaborators. Phenotypes were collected by a standardized questionnaire. Functional and pharmacological properties of variant subunits were analyzed by whole-cell patch-clamp recordings.
FINDINGS
Detailed clinical information on fifteen patients (14 novel and 1 previously published) was analyzed. All patients had developmental delay with prominent language impairment. R144Q patients were more severely affected than R144W patients. Infantile to childhood onset epilepsy occurred in 40%, while 67% of sleep-EEGs showed sleep-activated epileptiform activity. Ten patients (67%) showed autistic features. Activation gating of homomeric Kv7.2 R144W/Q/G channels was left-shifted, suggesting gain-of-function effects. Amitriptyline blocked channels containing Kv7.2 and Kv7.2 R144Q subunits.
INTERPRETATION
Patients carrying KCNQ2 R144 gain-of-function variants have developmental delay with prominent language impairment, autistic features, often accompanied by infantile- to childhood-onset epilepsy and EEG sleep-activated epileptiform activity. The absence of neonatal seizures is a robust and important clinical differentiator between KCNQ2 gain-of-function and loss-of-function variants. The Kv7.2/7.3 channel blocker amitriptyline might represent a targeted treatment.
FUNDING
Supported by FWO, GSKE, KCNQ2-Cure, Jack Pribaz Foundation, European Joint Programme on Rare Disease 2020, the Italian Ministry for University and Research, the Italian Ministry of Health, the European Commission, the University of Antwerp, NINDS, and Chalk Family Foundation.
Topics: Amitriptyline; Autistic Disorder; Epilepsy; Gain of Function Mutation; Humans; Infant, Newborn; Infant, Newborn, Diseases; KCNQ2 Potassium Channel; Language Development Disorders; Seizures
PubMed: 35780567
DOI: 10.1016/j.ebiom.2022.104130