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Drug Safety Aug 2023Time- and resource-demanding activities related to processing individual case safety reports (ICSRs) include manual procedures to evaluate individual causality with the...
Developing an Artificial Intelligence-Guided Signal Detection in the Food and Drug Administration Adverse Event Reporting System (FAERS): A Proof-of-Concept Study Using Galcanezumab and Simulated Data.
INTRODUCTION
Time- and resource-demanding activities related to processing individual case safety reports (ICSRs) include manual procedures to evaluate individual causality with the final goal of dismissing false-positive safety signals. Eminent experts and a representative from pharmaceutical industries and regulatory agencies have highlighted the need to automatize time- and resource-demanding procedures in signal detection and validation. However, to date there is a sparse availability of automatized tools for such purposes.
OBJECTIVES
ICSRs recorded in spontaneous reporting databases have been and continue to be the cornerstone and the most important data source in signal detection. Despite the richness of this data source, the incessantly increased amount of ICSRs recorded in spontaneous reporting databases has generated problems in signal detection and validation due to the increase in resources and time needed to process cases. This study aimed to develop a new artificial intelligence (AI)-based framework to automate resource- and time-consuming steps of signal detection and signal validation, such as (1) the selection of control groups in disproportionality analyses and (2) the identification of co-reported drugs serving as alternative causes, to look to dismiss false-positive disproportionality signals and therefore reduce the burden of case-by-case validation.
METHODS
The Summary of Product Characteristics (SmPC) and the Anatomical Therapeutic Chemical (ATC) classification system were used to automatically identify control groups within and outside the chemical subgroup of the proof-of-concept drug under investigation, galcanezumab. Machine learning, specifically conditional inference trees, has been used to identify alternative causes in disproportionality signals.
RESULTS
By using conditional inference trees, the framework was able to dismiss 20.00% of erenumab, 14.29% of topiramate, and 13.33% of amitriptyline disproportionality signals on the basis of purely alternative causes identified in cases. Furthermore, of the disproportionality signals that could not be dismissed purely on the basis of the alternative causes identified, we estimated a 15.32%, 25.39%, and 26.41% reduction in the number of galcanezumab cases to undergo manual validation in comparison with erenumab, topiramate, and amitriptyline, respectively.
CONCLUSION
AI could significantly ease some of the most time-consuming and labor-intensive steps of signal detection and validation. The AI-based approach showed promising results, however, future work is needed to validate the framework.
Topics: United States; Humans; Artificial Intelligence; Drug-Related Side Effects and Adverse Reactions; Adverse Drug Reaction Reporting Systems; United States Food and Drug Administration; Amitriptyline; Topiramate; Databases, Factual
PubMed: 37300636
DOI: 10.1007/s40264-023-01317-0 -
The Journal of Trauma and Acute Care... Aug 2021Traumatic brain injury (TBI) is common in civilians and military personnel. No potential therapeutics have been evaluated to prevent secondary injury induced by the...
BACKGROUND
Traumatic brain injury (TBI) is common in civilians and military personnel. No potential therapeutics have been evaluated to prevent secondary injury induced by the hypobaric hypoxia (HH) environment integral to postinjury aeromedical evacuation (AE). We examined the role of allopurinol, propranolol, adenosine/lidocaine/magnesium (ALM), or amitriptyline administration prior to simulated flight following murine TBI.
METHODS
Mice underwent TBI and were given allopurinol, propranolol, amitriptyline, or ALM prior to simulated AE or normobaric normoxia (NN) control. Heart rate (HR), respiratory rate, and oxygen saturation (Spo2) were recorded throughout simulated AE. Mice were sacrificed at 24 hours, 7 days, or 30 days. Serum and cerebral cytokines were assessed by enzyme-linked immunosorbent assay. Motor function testing was performed with Rotarod ambulation. Immunohistochemistry was conducted to examine phosphorylated tau (p-tau) accumulation in the hippocampus at 30 days.
RESULTS
While all treatments improved oxygen saturation, propranolol, amitriptyline, and allopurinol improved AE-induced tachycardia. At 24 hours, both propranolol and amitriptyline reduced tumor necrosis factor alpha levels while allopurinol and ALM reduced tumor necrosis factor alpha levels only in NN mice. Propranolol, amitriptyline, and ALM demonstrated lower serum monocyte chemoattractant protein-1 7 days after AE. Both amitriptyline and allopurinol improved Rotarod times for AE mice while only allopurinol improved Rotarod times for NN mice. Propranolol was able to reduce p-tau accumulation under both HH and NN conditions while ALM only reduced p-tau in hypobaric hypoxic conditions.
CONCLUSION
Propranolol lowered post-TBI HR with reduced proinflammatory effects, including p-tau reduction. Amitriptyline-induced lower post-TBI HR and improved functional outcomes without affecting inflammatory response. Allopurinol did not affect vital signs but improved late post-TBI systemic inflammation and functional outcomes. Adenosine/lidocaine/magnesium provided no short-term improvements but reduced p-tau accumulation at 30 days in the HH cohort. Allopurinol may be the best of the four treatments to help prevent short-term functional deficits while propranolol may address long-term effects.
LEVEL OF EVIDENCE
Basic science article.
Topics: Adenosine; Air Ambulances; Allopurinol; Amitriptyline; Animals; Brain; Brain Chemistry; Brain Injuries, Traumatic; Cytokines; Disease Models, Animal; Emergency Medical Services; Lidocaine; Magnesium; Male; Mice; Mice, Inbred C57BL; Propranolol; Rotarod Performance Test
PubMed: 33938511
DOI: 10.1097/TA.0000000000003259 -
Revista de Neurologia Apr 2022Neuropathic pain (NP) is difficult to treat due to the heterogeneity of causes, symptoms and underlying mechanisms. It constitutes a great medical need that is not... (Review)
Review
INTRODUCTION
Neuropathic pain (NP) is difficult to treat due to the heterogeneity of causes, symptoms and underlying mechanisms. It constitutes a great medical need that is not covered, and has a high number of therapeutic failures in recent randomized clinical trials.
DEVELOPMENT
This narrative review presents an update on the pharmacological treatment of NP with emphasis on the new published clinical guidelines, new drugs in development, and the new challenges that arise in the therapeutic management of this entity.
CONCLUSIONS
First-line drugs proposed include tricyclic antidepressants (particularly amitriptyline), serotonin and norepinephrine reuptake inhibitors (particularly duloxetine), pregabalin, and gabapentin. However, the latest recommendations are still relevant and the most recent clinical studies even question the role of pregabalin as a first-line treatment. Therefore, we consider that periodic updates of the clinical guidelines in NP are necessary to better guide our daily clinical practice and rationalize the use of all available therapeutic options. Furthermore, the expansion of knowledge in NP has generated a series of challenges, such as the development of new drugs based on pathophysiological mechanisms investigated in animals, and the development of optimal therapeutic approaches in clinical trials, based more on personalized than etiological approaches.
Topics: Amitriptyline; Analgesics; Animals; Antidepressive Agents, Tricyclic; Gabapentin; Humans; Neuralgia; Pregabalin
PubMed: 35383875
DOI: 10.33588/rn.7408.2021381 -
Journal of Veterinary Pharmacology and... Jul 2020The purpose of this study was to evaluate the pharmacokinetics of oral amitriptyline in horses. Oral amitriptyline (1 mg/kg) was administered to six horses. Blood...
The purpose of this study was to evaluate the pharmacokinetics of oral amitriptyline in horses. Oral amitriptyline (1 mg/kg) was administered to six horses. Blood samples were collected from jugular and lateral thoracic vein at predetermined times from 0 to 24 hr after administration. Plasma concentrations were determined by high-performance liquid chromatography and analyzed using noncompartmental methods. Pharmacodynamic parameters including heart rate, respiration rate, and intestinal motility were evaluated, and electrocardiographic examinations were performed in all subjects. The mean maximum plasma concentration (C ) of amitriptyline was 30.7 ng/ml, time to maximum plasma concentration (T ) 1-2 hr, elimination half-life (t ) 17.2 hr, area under plasma concentration-time curve (AUC) 487.4 ng ml hr , apparent clearance (Cl/F) 2.6 L hr kg , and apparent volume of distribution (Vd/F) 60.1 L/kg. Jugular vein sampling overestimated the amount of amitriptyline absorbed and should not be used to study uptake following oral administration. Heart rate and intestinal motility showed significant variation (p < .05). Electrocardiography did not provide conclusive results. Further studies are required to discern if multiple dose treatment would take the drug to steady state as expected, consequently increasing plasma concentrations.
Topics: Administration, Oral; Amitriptyline; Animals; Antidepressive Agents, Tricyclic; Area Under Curve; Female; Half-Life; Horses; Male
PubMed: 32339314
DOI: 10.1111/jvp.12870 -
Andrology Nov 2022Rat isolated vas deferens releases 6-nitrodopamine (6-ND), and the spasmogenic activity of this novel catecholamine is significantly reduced by tricyclic compounds such...
BACKGROUND
Rat isolated vas deferens releases 6-nitrodopamine (6-ND), and the spasmogenic activity of this novel catecholamine is significantly reduced by tricyclic compounds such as amitriptyline, desipramine, and carbamazepine and by antagonists of the α -adrenergic receptors such as doxazosin, tamsulosin, and prazosin.
OBJECTIVES
To investigate the liberation of 6-ND by human epididymal vas deferens (HEVDs) and its pharmacological actions.
METHODS
The in vitro liberation of 6-ND, dopamine, noradrenaline, and adrenaline from human vas deferens was evaluated by LC-MS/MS. The contractile effect of the catecholamines in HEVDs was investigated in vitro. The action of tricyclic antidepressants was evaluated on the spasmogenic activity ellicited by the catecholamines and by the electric-field stimulation (EFS). The tissue was also incubated with the inhibitor of nitric oxide (NO) synthase L-NAME and the release of catecholamines and the contractile response to EFS were assessed.
RESULTS
6-ND is the major catecholamine released from human vas deferens and its synthesis/release is inhibited by NO inhibition. The spasmogenic activity elicited by EFS in the human vas deferens was blocked by tricyclic antidepressants only at concentrations that selectively antagonize 6-ND induced contractions of the human vas deferens, without affecting the spasmogenic activity induced by dopamine, noradrenaline, and adrenaline in this tissue. Incubation of the vas deferens with L-NAME reduced both the 6-ND release and the contractions induced by EFS.
DISCUSSION AND CONCLUSION
6-ND should be considered a major endogenous modulator of human vas deferens contractility and possibly plays a pivotal role in the emission process of ejaculation. It offers a novel and shared mechanism of action for tricyclic antidepressants and α -adrenergic receptor antagonists.
Topics: Adrenergic Antagonists; Amitriptyline; Animals; Antidepressive Agents, Tricyclic; Carbamazepine; Chromatography, Liquid; Desipramine; Dopamine; Doxazosin; Epinephrine; Humans; Male; Muscle Contraction; Muscle, Smooth; NG-Nitroarginine Methyl Ester; Nitric Oxide; Norepinephrine; Prazosin; Rats; Receptors, Adrenergic; Tamsulosin; Tandem Mass Spectrometry; Vas Deferens
PubMed: 35934935
DOI: 10.1111/andr.13263 -
Comparative Biochemistry and... Nov 2023Many studies have demonstrated that microplastics (MPs) can combine with various coexisting chemical pollutants, increasing their bioavailability and changing the...
Many studies have demonstrated that microplastics (MPs) can combine with various coexisting chemical pollutants, increasing their bioavailability and changing the combined toxicity to organisms. However, information on the combined effects of MPs and amitriptyline (AMI, a widely used tricyclic antidepressant) on aquatic species is still limited. In this study, we exposed zebrafish to MPs (2-μm polystyrene beads, 0.44 mg/L), AMI (2.5 μg/L), and their mixture for 7 days and investigated the alternation in their behaviors and ocular oxidative stress. As a result, combined exposure to MPs and AMI could significantly elevate locomotor activity, increase the frequency and duration of shoaling behavior in zebrafish, and alter their post-stimulation behaviors. Although combined exposure to MPs and AMI exhibited stronger behavioral toxicity than individual exposure, no significant interactive effects on the behavioral traits were detected, suggesting that the combined behavioral toxicity appeared to be an additive effect. However, their combined exposure to MPs or AMI significantly decreased the ocular levels of SOD, CAT, and GSH in zebrafish, with significant interaction effects on the CAT activity and GSH content. Significant correlations between some post-stimulation behavioral traits and ocular levels of SOD, CAT, and GSH in zebrafish were detected, suggesting that ocular oxidative stress induced by combined exposure to MPs and AMI may play an important role in their behavioral toxicity.
Topics: Animals; Microplastics; Amitriptyline; Zebrafish; Plastics; Water Pollutants, Chemical; Oxidative Stress; Superoxide Dismutase
PubMed: 37586580
DOI: 10.1016/j.cbpc.2023.109717 -
Semergen 2019We provide an updated review of the pharmacological treatment of neuropathic pain, with emphasis on the latest evidence-based recommendations. Drugs proposed as first... (Review)
Review
We provide an updated review of the pharmacological treatment of neuropathic pain, with emphasis on the latest evidence-based recommendations. Drugs proposed as first line include tricyclic antidepressants (particularly amitriptyline), serotonin-noradrenaline reuptake inhibitors (particularly duloxetine), pregabalin and gabapentin. Second-line treatments include 5% lidocaine medicated plasters and capsaicin 8% patches, only for peripheral neuropathic pain and tramadol; whereas potent opioids and botulinum toxin A (for peripheral neuropathic pain) are considered third-line treatments. Future perspectives include the development of new drugs and a more personalised therapeutic approach, which is made possible by recent progress in the assessment and understanding of neuropathic pain.
Topics: Algorithms; Humans; Neuralgia; Practice Guidelines as Topic
PubMed: 31337589
DOI: 10.1016/j.semerg.2019.05.008 -
Current Drug Safety 2022Pregabalin is used in the treatment of neuropathic pain of various etiologies and as an adjuvant in epilepsy. Blockade of the α2δ subunit of L and N-type Ca-channels... (Review)
Review
BACKGROUND
Pregabalin is used in the treatment of neuropathic pain of various etiologies and as an adjuvant in epilepsy. Blockade of the α2δ subunit of L and N-type Ca-channels is its main mechanism of neurotropic action. Compared to other antiepileptics like phenytoin, valproate and lamotrigine, and other neuropathic pain medications such as amitriptyline and duloxetine, pregabalin has a relatively favorable safety profile and hence is a drug of choice for many geriatricians.
CASE PRESENTATION
Here we describe a case of maculopapular rash induced by pregabalin in an older man, which resolved with withdrawal of the offending drug and conservative management.
CONCLUSION
We have also conducted a literature review of similar cases and highlighted the clinical patterns and management strategies for pregabalin-induced skin rashes.
Topics: Aged; Amitriptyline; Analgesics; Anticonvulsants; Exanthema; Humans; Male; Neuralgia; Pregabalin
PubMed: 35264095
DOI: 10.2174/1574886317666220309143913 -
Translational Psychiatry Feb 2021Antidepressant medications are known to modulate the central nervous system, and gut microbiota can play a role in depression via microbiota-gut-brain axis. But the...
Antidepressant medications are known to modulate the central nervous system, and gut microbiota can play a role in depression via microbiota-gut-brain axis. But the impact of antidepressants on gut microbiota function and composition remains poorly understood. Thus this study assessed the effect of serotonin reuptake inhibitor antidepressant fluoxetine (Flu) and tricyclic antidepressant amitriptyline (Ami) administration on gut microbiota composition, diversity, and species abundance, along with microbial function in a chronic unpredictable mild stress (CUMS)-induced depression rat model. Oral administration of Ami and Flu significantly altered the overall gut microbiota profile of CUMS-induced rats, as assessed using the permutational multivariate analysis of variance test. At the phylum level, 6-week of antidepressant treatment led to a decreased Firmicutes/Bacteroidetes ratio due to an enhanced Bacteroidetes and reduced Firmicutes relative abundance. Flu was more potent than Ami at altering the Firmicutes and Bacteroidetes levels in the CUMS rats. At the family level, both antidepressants significantly increased the abundance of Porphyromonadaceae. However, an increased Bacteroidaceae level was significantly associated with Ami, not Flu treatment. Furthermore, at the genus level, an increase in the relative abundance of Parabacteroides, Butyricimonas, and Alistipes was observed following Ami and Flu treatment. Subsequent metagenomics and bioinformatics analysis further indicated that Ami and Flu likely also modulated metabolic pathways, such as those involved in carbohydrate metabolism, membrane transport, and signal transduction. Additionally, both antidepressants affected antibiotic resistome, such as for aminoglycoside (aph3iiiA), multidrug (mdtK, mdtP, mdtH, mdtG, acrA), and tetracycline (tetM) resistance in CUMS rats. These data clearly illustrated the direct impact of oral administration of Flu and Ami on the gut microbiome, thus set up the foundation to reveal more insights on the therapeutic function of the antidepressants and their overall contribution to host health.
Topics: Amitriptyline; Animals; Antidepressive Agents; Fluoxetine; Gastrointestinal Microbiome; Rats; Stress, Psychological
PubMed: 33602895
DOI: 10.1038/s41398-021-01254-5