Hepatic injury and hepatic failure adverse events in 3,4-methylenedioxymethamphetamine users reported to the FDA Adverse Event Reporting System.

3,4-Methylenedioxymethamphetamine (MDMA) is being investigated in controlled clinical trials for use as an adjunct medication treatment for post-traumatic stress disorder. MDMA is metabolized by N-demethylation, primarily by CYP2D6, to its main inactive metabolite, 4-hydroxy-3-methoxymethamphetamine. It is also metabolized to a lesser extent by CYP1A2, CYP2B6, and CYP3A4 to its active metabolite, 3,4-methylenedioxyamphetamine. Considering the extensive hepatic metabolism and excretion, MDMA use in psychiatry raises concerns over drug-induced liver injury (DILI), a rare but dangerous event. Majority of the drugs withdrawn from the market for liver injury caused death or transplantation at frequencies under 0.01%. Unfortunately, markers for liver injury were not measured in most published clinical trials. At the same time, no visible DILI-related symptoms and adverse events were observed. Idiosyncratic DILI cases are rarely registered during clinical trials due to their rare nature. In this study, we surveyed a larger, over 1,500, and a more diverse set of reports from the FDA Adverse Event Reporting System and found 23 cases of hepatic injury and hepatic failure, in which MDMA was reported to be taken in addition to one or more substances. Interestingly, 22 out of 23 cases had one or more listed drugs with a known DILI concern based on the FDA's DILIrank dataset. Furthermore, only one report had MDMA listed as the primary suspect. Considering the nearly 20 million doses of MDMA used annually, this single report is insufficient for establishing a significant association with DILI.

Thyroid Hyperplasia and Neoplasm Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists in the Food and Drug Administration Adverse Event Reporting System: Retrospective Analysis.

Background: Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are one of the most commonly used drugs for type 2 diabetes mellitus. Clinical guidelines recommend GLP-1 RAs as an adjunct to diabetes therapy in patients with chronic kidney disease, presence or risk of atherosclerotic cardiovascular disease, and obesity. The weight loss observed in clinical trials has been explored further in healthy individuals, putting GLP-1 RAs on track to be the next weight loss treatment. Objective: Although the adverse event profile is relatively safe, most GLP-1 RAs come with a labeled boxed warning for the risk of thyroid cancers, based on animal models and some postmarketing case reports in humans. Considering the increasing popularity of this drug class and its expansion into a new popular indication, a further review of the most recent postmarketing safety data was warranted to quantify thyroid hyperplasia and neoplasm instances. Methods: GLP-1 RA patient reports from the US Food and Drug Administration (FDA) Adverse Event Reporting System database were analyzed using reporting odds ratios and 95% CIs. Results: In this study, we analyzed over 18 million reports from the US FDA Adverse Event Reporting System and provided evidence of significantly increased propensity for thyroid hyperplasias and neoplasms in patients taking GLP-1 RA monotherapy when compared to patients taking sodium-glucose cotransporter-2 (SGLT-2) inhibitor monotherapy. Conclusions: GLP-1 RAs, regardless of indication, are associated with an over 10-fold increase in thyroid neoplasm and hyperplasia adverse event reporting when compared to SGLT-2 inhibitors.

Co-occurring infections in cancer patients treated with checkpoint inhibitors significantly increase the risk of immune related adverse events.

Therapeutic antibodies designed to target immune checkpoint proteins such as PD-1, PD-L1, and CTLA-4 have been applied in the treatment of various tumor types, including small and non-small cell lung cancers, melanoma, renal cell carcinoma, and others. These treatments combat cancers by reactivating CD8 cytotoxic T-cells. Nevertheless, this unique targeted mode of action was found to be associated with a broader range of immune-related adverse events, irAEs, affecting multiple physiological systems. Depending on their severity, these irAEs often necessitate the suspension or discontinuation of treatment and, in rare instances, may lead to fatal consequences. In this study we investigated over eighty thousand adverse event reports of irAEs in patients treated with PD-1, PD-L1, and CTLA-4 inhibitors. FDA Adverse Event Reporting System MedWatch submissions were used as the data source. These therapeutics included pembrolizumab, nivolumab, cemiplimab, avelumab, durvalumab, atezolizumab, and ipilimumab. The data analysis of these reports revealed a statistically significant association of immune related adverse events, including serious and life-threatening events in patients who experienced infectious disease during treatment. Additionally, the association trend was preserved across all the three classes of checkpoint inhibitors and each of the seven individual therapeutic agent cohorts.

Thyroid hyperplasia and neoplasm adverse events associated with GLP-1 receptor agonists in FDA Adverse Event Reporting System.

Glucagon receptor-like peptide receptor agonists, GLP-1 RAs, are one of the most commonly used drugs for type-2 diabetes mellitus. The clinical guidelines recommend GLP-1 RAs as adjunct to diabetes therapy in patients with chronic kidney disease, presence or risk of atherosclerotic cardiovascular disease, obesity, and other cardiometabolic conditions. The weight loss seen in clinical trials has been explored further in healthy individuals, putting GLP-1 RAs on track to be the next weight loss treatment. Although the adverse event profile is relatively safe, most GLP-1 RAs come with a labeled black boxed warning of the risk of thyroid cancers, based on animal models and some postmarketing case reports in humans. Considering the increasing popularity of this drug class and its expansion into a new popular indication, a further review of most recent postmarketing safety data is warranted to quantify thyroid hyperplasia and neoplasms instances. In this study we analyzed over eighteen million reports from United States Food and Drug Administration Adverse Event Reporting System and identified 17,653 relevant GLP-1 RA monotherapy reports to provide the evidence of significantly increased propensity for thyroid hyperplasias and neoplasms in patients taking GLP-1 RA as monotherapy when compared to patients taking sodium-glucose cotransporter-2 inhibitor monotherapy.

Concomitant medications associated with ischemic, hypertensive, and arrhythmic events in MDMA users in FDA adverse event reporting system.

3,4-Methylenedioxymethamphetamine (MDMA) is currently being investigated as an adjunctive treatment to therapy for posttraumatic stress and other anxiety related disorders in clinical trials. Within the next few years MDMA-assisted therapy is projected for approval by regulatory authorities. MDMA's primary mechanism of action includes modulation of monoamine signaling by increasing release and inhibiting reuptake of serotonin, norepinephrine, and, to a lesser extent, dopamine. This pharmacology affects sympathomimetic physiology. In controlled trials, special attention has been given to cardiovascular adverse events (AEs), because transient increases in heart rate and blood pressure have been observed during the MDMA-assisted therapy sessions. Finding and quantifying the potential drivers of cardiac AEs in clinical trials is difficult since only a relatively small number of participants have been included in these studies, and a limited set of allowed concomitant drugs has been studied. In this study a more diverse set of reports from the FDA Adverse Event Reporting System was surveyed. We found 17 cases of cardiovascular AEs, in which the individuals had taken one or more substances in addition to MDMA. Interestingly, all of those concomitant medications and illicit substances, including opioids, stimulants, anticholinergics, and amphetamines, had been previously associated with cardiovascular AEs. Furthermore, in none of the reports MDMA was marked as the primary suspect.

Anti-TNF-α therapy induced psoriasis in rheumatoid arthritis patients according to FDA postmarketing surveillance data.

Rheumatoid arthritis, RA, is a chronic autoimmune disease characterized by joint pain, tenderness, swelling, and stiffness. This disease affects nearly 1% of the world population. RA predominates in females and typically develops between the ages of 30 and 50 years. Common therapeutics for the treatment of RA include immune system suppressants such as tumor necrosis factor, or TNF, inhibitors. There is growing concern related to multiple clinical cases reporting an unexpected onset of psoriasis following the use of TNF inhibitors. This adverse event is counterintuitive since some tumor necrosis factor inhibitors are indicated for the treatment of plaque psoriasis. In this study, we analyzed over 880 thousand postmarketing safety reports from patients being treated for RA with a single therapeutic and provided evidence for a statistically significant association of psoriasis adverse events with TNF inhibitor use as compared to methotrexate. Additionally, we quantified the reported odds ratios and their 95% confidence intervals between four individual TNF inhibitors and found that the degree of association with psoriasis was variable among the drugs studied, with certolizumab pegol exhibiting the highest reported risk.

Retrospective analysis of clinical trial safety data for pembrolizumab reveals the effect of co-occurring infections on immune-related adverse events.

Biologics targeting PD-1, PD-L1, and CTLA-4 immune checkpoint proteins have been used in a variety of tumor types including small and non-small cell lung cancers, melanoma, and renal cell carcinoma. Their anti-tumor activity is achieved through amplifying components of the patient's own immune system to target immune response evading cancer cells. However, this unique mechanism of action causes a range of immune related adverse events, irAEs, that affect multiple physiological systems in the body. These irAEs, depending on severity, often cause suspension or discontinuation of therapy and, in rare cases, may lead to fatal outcomes. In this study we focused on pembrolizumab, a PD-1 inhibitor currently approved for multiple types of cancer. We analyzed over ten thousand adverse event reports from Keynote clinical trials of pembrolizumab for various cancer indications with or without co-occurring infections, and observed a statistically significant 80% increase in the risk of developing an irAE in subjects with infections.

Common osteoporosis drug associated with increased rates of depression and anxiety.

Osteoporosis affects over 10 million Americans over 50. Bisphosphonate therapy, mainly alendronate, is amongst the most prescribed treatments for the disease. The use of alendronate and other bisphosphonates has been associated with depressive symptoms in recent case reports. In this study we quantified this association by analyzing over 100,000 adverse events reports from the Food and Drug Administration Adverse Events Reporting System (FAERS) and the World Health Organization's (WHO) global database for adverse drug reactions, ADRs, VigiAccess. We found that alendronate therapy is significantly associated with depression and anxiety when compared to other first-line osteoporosis treatments. The reported risk of depressive ADRs was found to be over 14-fold greater in patients taking alendronate under the age of 65 and over fourfold greater for patients over 65 compared to the control. Several hypotheses concerning the molecular mechanism of the observed association of alendronate and depressive symptoms were discussed.

Postmarketing safety surveillance data reveals protective effects of botulinum toxin injections against incident anxiety.

Randomized controlled trials (RCTs) have shown an antidepressant effect of glabellar botulinum toxin (BoNT) injections. In the FDA Adverse Event Reporting System (FAERS) database, BoNT injection is associated with reduced incidence rates of depression across various non-psychiatric indications, which confirms the previous findings independently of specific expectations to an antidepressant effect of BoNT. The rationale of using BoNT to treat depression is to interrupt proprioceptive body feedback that may reinforce negative emotions. Negative emotions also occur in other mental disorders, suggesting a transdiagnostic therapeutic potential of BoNT in psychiatry. Here we report an analysis of the FAERS database, in which we found that, compared to alternative treatments, BoNT injections were associated with lower incidence of anxiety symptoms and related disorders. Among seven indications/injection sites, we found this protective effect of BoNT in cosmetic use/facial muscles, migraine/facial and head muscles, spasms and spasticity/upper and lower limbs, torticollis and neck pain/neck muscles, and sialorrhea/parotid and submandibular glands (reporting odds ratios 0.79-0.27). These findings are encouraging for possible future RCTs on the use of BoNT as a treatment for anxiety and related disorders.

Myocarditis occurrence with cancer immunotherapy across indications in clinical trial and post-marketing data.

Antibodies targeting the PD-1, PD-L1, and CTLA-4 immune checkpoint axis have been used in a variety of tumor types. They achieve anti-tumor activity through activating the patient's own immune system to target immune response evading cancer cells. However, this unique mechanism of action may cause immune-related adverse events, irAEs. One of these irAEs is myocarditis which is associated with an alarming mortality rate. In this study we presented clinical cases of myocarditis from safety trial datasets submitted to the U.S. Food and Drug Administration, FDA. Additionally, we analyzed over fourteen million FDA Adverse Event Reporting System, FAERS, submissions. The statistical analysis of the FAERS data provided evidence of significantly increased reporting of myocarditis in patients administered immune checkpoint inhibitors alone, in combination with another immune checkpoint inhibitor, the kinase inhibitor axitinib, or chemotherapy, for all cancer types, when compared to patients administered chemotherapy. All combination therapies led to further increased reporting odds ratios of myocarditis. We further analyzed the occurrence of myocarditis by stratifying the reports into sub-cohorts based on specific cancer types and treatment/control groups in major cancer immunotherapy efficacy trials and confirmed the observed trend for each cohort.

Concomitant drugs associated with increased mortality for MDMA users reported in a drug safety surveillance database.

3,4-Methylenedioxymethamphetamine (MDMA) is currently being evaluated by the Food and Drug Administration (FDA) for the treatment of post-traumatic stress disorder (PTSD). If MDMA is FDA-approved it will be important to understand what medications may pose a risk of drug-drug interactions. The goal of this study was to evaluate the risks due to MDMA ingestion alone or in combination with other common medications and drugs of abuse using the FDA drug safety surveillance data. To date, nearly one thousand reports of MDMA use have been reported to the FDA. The majority of these reports include covariates such as co-ingested substances and demographic parameters. Univariate and multivariate logistic regression was employed to uncover the contributing factors to the reported risk of death among MDMA users. Several drug classes (MDMA metabolites or analogs, anesthetics, muscle relaxants, amphetamines and stimulants, benzodiazepines, ethanol, opioids), four antidepressants (bupropion, sertraline, venlafaxine and citalopram) and olanzapine demonstrated increased odds ratios for the reported risk of death. Future drug-drug interaction clinical trials should evaluate if any of the other drug-drug interactions described in our results actually pose a risk of morbidity or mortality in controlled medical settings.

Reported Cases of Serotonin Syndrome in MDMA Users in FAERS Database.

3,4-Methylenedioxymethamphetamine (MDMA), is investigated as a treatment for post-traumatic stress disorder and other anxiety-related conditions in multiple placebo-controlled and open label studies. MDMA-assisted therapy is projected for approval by the United States Food and Drug Administration (FDA) and other regulatory agencies worldwide within the next few years. MDMA is a monoamine releaser and uptake inhibitor affecting serotonin, potentially increasing the risk of serotonin syndrome (SS). No instances of SS have occurred in clinical trials. The relatively small number of patients in controlled trials warranted a survey of FDA Adverse Event Reporting System data for the occurrence of SS in a larger database. We found 20 SS cases in people exposed to MDMA, all of which had also taken one or more substances with serotonergic properties in addition to MDMA, including amphetamines, stimulants, and opioids. There were no cases of SS associated with MDMA where MDMA was the sole reported compound taken.

Cardiac adverse events associated with chloroquine and hydroxychloroquine exposure in 20 years of drug safety surveillance reports.

Chloroquine (CQ) and hydroxychloroquine (HCQ) are on the World Health Organization's List of Essential Medications for treating non-resistant malaria, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In addition, both drugs are currently used off-label in hospitals worldwide and in numerous clinical trials for the treatment of SARS-CoV-2 infection. However, CQ and HCQ use has been associated with cardiac side effects, which is of concern due to the higher risk of COVID-19 complications in patients with heart related disorders, and increased mortality associated with COVID-19 cardiac complications. In this study we analyzed over thirteen million adverse event reports form the United States Food and Drug Administration Adverse Event Reporting System to confirm and quantify the association of cardiac side effects of CQ and HCQ. Additionally, we identified several confounding factors, including male sex, NSAID coadministration, advanced age, and prior diagnoses contributing to drug related cardiotoxicity. These findings may help guide therapeutic decision making and ethical trial design for COVID-19 treatment.

Postmarketing safety surveillance data reveals antidepressant effects of botulinum toxin across various indications and injection sites.

The World Health Organization estimates the number of people suffering from depression to be over 264 million. Current monoamine transmission modulating therapeutics, even with proper adherence and acceptable tolerability, are not effective for nearly one third of the patients, leading clinicians to explore other therapeutic options such as electroconvulsive therapy, transcranial magnetic stimulation, ketamine infusions, and, more recently, glabellar botulinum toxin, BoNT, injections. The scale and mechanism of antidepressant action of BoNT is unclear and maybe hypothetically attributed to the disruption of proprioceptive facial feedback reinforcing negative emotions. Here we verify the antidepressant effect of botulinum toxin by analysis of over 40 thousand BoNT treatment reports out of thirteen million postmarketing safety reports in the FDA Adverse Event Reporting System, FAERS. The results of the analysis indicate that patients who received BoNT injections to treat hyperhidrosis, facial wrinkles, migraine prophylaxis, spasticity, and spasms, had a significantly lower number of depression reports when compared to patients undergoing different treatments for the same conditions. These findings suggest that the antidepressant effect of BoNT is significant, and, surprisingly, is observed for a broad range of injection sites.

Proton-pump inhibitor use is associated with a broad spectrum of neurological adverse events including impaired hearing, vision, and memory.

Proton-pump inhibitors, PPIs, are considered effective therapy for stomach acid suppression due to their irreversible inhibition of the hydrogen/potassium pump in the gastric parietal cells. They are widely prescribed and are considered safe for over-the-counter use. Recent studies have shown an association between PPI use and Alzheimer dementia, while others have disputed that connection. We analyzed over ten million United States Food and Drug Administration Adverse Event Reporting System reports, including over forty thousand reports containing PPIs, and provided evidence of increased propensity for memory impairment among PPI reports when compared to histamine-2 receptor antagonist control group. Furthermore, we found significant associations of PPI use with a wide range of neurological adverse reactions including, migraine, several peripheral neuropathies, and visual and auditory neurosensory abnormalities.

Divergent mechanisms for regulating growth and development after imaginal disc damage in the tobacco hornworm, Manduca sexta.

Holometabolous insects have been able to radiate to vast ecological niches as adults through the evolution of adult-specific structures such as wings, antennae and eyes. These structures arise from imaginal discs that show regenerative capacity when damaged. During imaginal disc regeneration, development has been shown to be delayed in the fruit fly Drosophila melanogaster, but how conserved the delay-inducing mechanisms are across holometabolous insects has not been assessed. The goal of this research was to develop the hornworm Manduca sexta as an alternative model organism to study such damage-induced mechanisms, with the advantage of a larger hemolymph volume enabling access to the hormonal responses to imaginal disc damage. Upon whole-body X-ray exposure, we noted that the imaginal discs were selectively damaged, as assessed by TUNEL and Acridine Orange stains. Moreover, development was delayed, predominantly at the pupal-to-adult transition, with a concomitant delay in the prepupal ecdysteroid peak. The delays to eclosion were dose dependent, with some ability for repair of damaged tissues. We noted a shift in critical weight, as assessed by the point at which starvation no longer impacted developmental timing, without a change in growth rate, which was uncoupled from juvenile hormone clearance in the body. The developmental profile was different from that of D. melanogaster, which suggests species differences may exist in the mechanisms delaying development.

Retrospective analysis reveals significant association of hypoglycemia with tramadol and methadone in contrast to other opioids.

Tramadol is one of the most commonly used analgesics worldwide, classified as having a low abuse potential by U.S. Drug Enforcement Agency, and often recommended in pain management guidelines. Its pain-relieving mechanism of action is attributed to mild µ-opioid receptor agonism, serotonin and norepinephrine mediated nociception modulation, and N-methyl-D-aspartate receptor, NMDAR, antagonism. However, recent case reports and case-control studies have shown an association between tramadol use and hypoglycemia. The growing concern over increasing tramadol use and unexpected side effects warranted a further comparative and quantitative analysis of tramadol adverse reactions. In this study we analyzed over twelve million reports from United States Food and Drug Administration Adverse Event Reporting System and provided evidence of increased propensity for hypoglycemia in patients taking tramadol when compared to patients taking other opioids, serotonin-norepinephrine reuptake inhibitors, and drugs affecting NMDAR activity. Additionally, we identified that only methadone from the opioid cohort behaves similarly to tramadol and has an association with hypoglycemia.

Analysis of postmarketing safety data for proton-pump inhibitors reveals increased propensity for renal injury, electrolyte abnormalities, and nephrolithiasis.

Proton pump inhibitors, PPIs, are widely prescribed and sold globally. Although initially intended for time-limited treatment of acute disorders, such as gastric ulcers and esophagitis, PPIs are now commonly used for prolonged durations and are considered safe for over the counter access. Recent studies have raised concern over associations between PPI use and acute kidney injury, chronic kidney disease, end-stage renal disease, and electrolyte abnormalities. The growing concern over potentially serious adverse drug reactions warrants an evaluation of post marketing surveillance data. In this study of over ten million FDA Adverse Event Reporting System records, we provided evidence of kidney injury and electrolyte imbalances in an alarming number of patients taking PPIs. Additionally, we assessed differences between specific PPIs and observed significant electrolyte and renal abnormalities for each individual drug with varying magnitudes.