Cardiovascular Adverse Drug Reactions of Anti-Calcitonin Gene-Related Peptide Monoclonal Antibodies for Migraine Prevention: An Analysis from the European Spontaneous Adverse Event Reporting System.

INTRODUCTION: Anti-calcitonin gene-related peptide monoclonal antibodies (anti-CGRP-mAbs) have recently been approved for the prevention of migraine, and their safety profile is not fully characterized. OBJECTIVE: The aim of this study was to evaluate the adverse drug reactions (ADRs) of anti-CGRP-mAbs through the analysis of individual case safety reports (ICSRs) collected in the EudraVigilance (EV) database, with a specific focus on cardiovascular (CV) ADRs. METHODS: Data on ICSRs recorded between July 2018 and December 2022 in the EV database, involving one of the anti-CGRP-mAbs for migraine prevention-erenumab (ERE), galcanezumab (GMB), fremanezumab (FMB), and eptinezumab (EPT)-were included in the analysis. All ICSRs reporting at least one CV ADR, as identified within the MedDRA® System Organ Classes (SOCs) "cardiac disorders" or "vascular disorders," were selected for the analysis. The frequency of disproportionate reporting was expressed as the reporting odds ratio (ROR) with its 95% confidence interval (CI), to evaluate the frequency of reporting of CV ADRs for each anti-CGRP-mAb compared with all other monoclonal antibodies (mAbs). A case-by-case analysis was conducted paying particular attention to serious CV ADR reports, focusing on the type of seriousness, age group, sex, and concomitant drugs. RESULTS: A total of 9441 ICSRs were recorded in the EV database from 2018 to 2022, of which more than half were related to ERE (58.9%), followed by GMB (21.4%), FMB (19.0%), and EPT (0.7%). CV ICSRs accounted for 1205 cases (12.8%), with a total of 1599 CV ADRs. The CV ICSRs were mainly related to female patients (82.6%) aged 18-64 years (73.4%). Of the reported CV ADRs, 67.5% were considered serious. Among the total number of ICSRs related to each anti-CGRP-mAb, those associated with FMB had a higher percentage of CV ADRs (n = 253; 14.1%), followed by ERE (n = 707; 12.7%), EPT (n = 8; 12.7%), and GMB (n = 237; 11.7%). A higher frequency of reporting hypertension was shown for ERE (ROR = 1.45; 95% CI = 1.14-1.85). Pallor was mainly observed with FMB (5.00; 1.68-14.89), as well as deep vein thrombosis (3.86; 1.57-9.51), hot flush (2.16; 1.43-3.25), and palpitations (1.48; 1.05-2.08). Atrial fibrillation (2.36; 1.02-5.46) and myocardial infarction (2.21; 1.37-3.58) were mostly reported for GMB. CONCLUSION: The analysis of anti-CGRP-related CV ADRs was consistent with the information reported in the literature. However, hypertension with ERE, atrial fibrillation and myocardial infarction with GMB, as well as pallor, deep vein thrombosis, hot flush, and palpitations with FMB were not reported in the Summary of Product Characteristics (SmPCs). Considering this, more post-marketing analyses are needed to improve knowledge on the CV safety profiles of anti-CGRP-mAbs, especially for the last approved medication, EPT.

Neuropsychiatric adverse drug reactions with oral tyrosine kinase inhibitors in metastatic colorectal cancer: an analysis from the FDA Adverse Event Reporting System.

Introduction: New oral tyrosine kinase inhibitors (TKIs) are approved for metastatic colorectal cancer (mCRC). The aim of this study was to assess the neuropsychiatric adverse drug reactions (ADRs) of these drugs reported in the FDA Adverse Event Reporting System (FAERS) database. Methods: All reports with regorafenib (REG) and encorafenib (ENC) as the primary suspect, and reported in the FAERS between 2012 and 2022, were collected. A descriptive and disproportionality analyses were conducted. Results: Out of 4,984 cases, 1,357 (30.2%) reported at least one neuropsychiatric ADR. New potential signals for REG included neuropathy peripheral (n = 265; reporting odds ratio, ROR = 19.48, 95% confidence interval, CI 95% = 17.52-22.47; information component, IC = 2.89, IC025-IC075 = 2.77-3.02), hyperesthesia (n = 18; ROR = 12.56, CI 95% = 7.90-19.96; IC = 2.25, IC025-IC075 = 1.79-2.72), taste disorder (n = 41; ROR = 9.91, CI 95% = 7.29-13.49; IC = 2.18, IC025-IC075 = 1.88-2.49), poor quality sleep (n = 18; ROR = 6.56, CI 95% = 4.13-10.42; IC = 1.74, IC025-IC075 = 1.27-2.20), altered state of consciousness (n = 15; ROR = 5.50, CI 95% = 3.31-9.14; IC = 1.57, IC025-IC075 = 1.06-2.07), depressed mood (n = 13; ROR = 1.85, CI 95% = 1.07-3.19; IC = 0.58, IC025-IC075 = 0.04-1.13) and insomnia (n = 63; ROR = 1.48, CI 95% = 1.15-1.89; IC = 0.38, IC025-IC075 = 0.13-0.63). For ENC comprised depressed mood (n = 4; ROR = 5.75, CI 95% = 2.15-15.39; IC = 1.74, IC025-IC075 = 0.76-2.73) and cognitive disorders (n = 3; ROR = 4.71, CI 95% = 1.51-14.66; IC = 1.54, IC025-IC075 = 0.41-2.68). Discussion: This study identified new unknown potential neuropsychiatric ADRs. Further investigations are required to better define the neurotoxicity of TKIs in mCRC patients.

Renal Disorders with Oral Tyrosine Kinase Inhibitors in Metastatic Colorectal Cancer: An Analysis from the FDA Adverse Event Reporting System Database.

BACKGROUND: this study assessed the nephrotoxicity of regorafenib (REG) and encorafenib (ENC) in metastatic colorectal cancer (mCRC) through an analysis of reports from the US Food and Drug Administration's Adverse Event Reporting System (FAERS) database. METHODS: descriptive and disproportional analyses were performed for all reports using ENC and REG as the primary suspect. RESULTS: A total of 379 reports had at least one renal adverse drug reaction (ADR), and these ADRs were mainly related to REG (93.1%). Potential safety signals for REG included chromaturia (n = 44; ROR = 12.00, CI 95% = 8.92-16.16; IC = 2.36, IC025-IC075 = 2.06-2.66), hydronephrosis (10; 8.70, 4.67-16.19; 1.85, 1.23-2.47), nephrotic syndrome (7; 5.73, 2.73-12.03; 1.47, 0.73-2.21), renal impairment (53; 4.16, 3.17-5.45; 1.39, 1.12-1.66), dysuria (19; 3.06, 1.95-4.81; 1.06, 0.61-1.52), renal failure (38; 1.66, 1.20-2.28; 0.49, 0.17-0.81), and acute kidney injury (AKI) (43; 1.46, 1.08-1.97; 0.37, 0.07-0.67). For ENC, consistent disproportionalities were observed for AKI (n = 11; ROR = 3.79, CI 95% = 2.09-6.90; IC = 1.32, IC025-IC075 = 0.72-1.91) and dysuria (4; 6.50, 2.43-17.39; 1.86, 0.88-2.85). CONCLUSIONS: these findings highlight some not extensively reported renal ADRs that require further investigations to better characterize the safety profiles of REG and ENC in patients with mCRC.

Neuropsychiatric Adverse Drug Reactions with Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors: An Analysis from the European Spontaneous Adverse Event Reporting System.

Tyrosine kinase inhibitors (TKIs) are widely used in gastrointestinal stromal tumors (GISTs). The aim of this study is to evaluate the reporting frequency of neuropsychiatric adverse drug reactions (ADRs) for TKIs through the analysis of European individual case safety reports (ICSRs). All ICSRs collected in EudraVigilance up to 31 December 2021 with one TKI having GISTs as an indication (imatinib (IM), sunitinib (SU), avapritinib (AVA), regorafenib (REG), and ripretinib (RIP)) were included. A disproportionality analysis was performed to assess the frequency of reporting for each TKI compared to all other TKIs. The number of analyzed ICSRs was 8512, of which 57.9% were related to IM. Neuropsychiatric ADRs were reported at least once in 1511 ICSRs (17.8%). A higher reporting probability of neuropsychiatric ADRs was shown for AVA. Most neuropsychiatric ADRs were known, except for a higher frequency of lumbar spinal cord and nerve root disorders (reporting odds ratio, ROR 4.46; confidence interval, CI 95% 1.58-12.54), olfactory nerve disorders (8.02; 2.44-26.33), and hallucinations (22.96; 8.45-62.36) for AVA. The analyses of European ICSRs largely confirmed the safety profiles of TKIs in GISTs, but some ADRs are worthy of discussion. Further studies are needed to increase the knowledge of the neuropsychiatric disorders of newly approved TKIs.

Safety profile of tyrosine kinase inhibitors used in non-small-cell lung cancer: An analysis from the Italian pharmacovigilance database.

Introduction: Non-small cell lung cancer (NSCLC) is often caused by molecular alterations that can be detected by predictive biomarkers including mutations or amplifications of several genes. Several tyrosine kinase inhibitors (TKIs) have been approved in Europe by the European Medicines Agency (EMA) for NSCLC. The aim of this study was to analyze the onset of adverse drug reactions (ADRs) related to TKIs in NSCLC through a spontaneous reporting system (SRS) database. Methods: All ADR reports having as suspected drug afatinib (AFT), alectinib (ALEC), brigatinib (BRG), ceritinib (CER), crizotinib (CRIZ), erlotinib (ERL), gefitinib (GEF), lorlatinib (LORL), nintedanib (NTB), and osimertinib (OSI) recorded into the Report Reazioni Avverse dei Medicinali (RAM) system database for national data and into the Italian SRS database for Sicilian data and collected from 2006 to 2021 have been evaluated. A descriptive analysis of basal demographic and drug-related characteristics was performed. A case-by-case methodology was conducted paying particular attention to all serious ADR reports collected in Sicily, focusing on type of seriousness, age, sex, concomitant drugs, and comorbidities. Results: Of the 3,048 Italian reports, most of ADRs were related to ERL (n = 1,448), followed by AFT (n = 435) and GEF (n = 366). ADR reports were slightly more frequent in females (52.2%) and in the age group >65 years (53.0%). A higher number of cases were related to skin disorders (n = 1,766; 57.9%), followed by gastrointestinal disorders (n = 1,024; 33.6%), general disorders and administration site conditions (n = 536; 17.6%), and infections (n = 483; 15.8%). The case-by-case assessment of Sicilian ADRs showed that 33 cases were serious (12.5%) and mainly involved ERL (n = 17; 51.5%), occurring in males with a higher onset of respiratory diseases (30.3%) such as respiratory failure, interstitial lung disease and dyspnea. Discussion: The analysis of spontaneous ADR reports of TKIs confirmed, in general, well-known risks, which often include skin, gastrointestinal, general, liver, and respiratory diseases as well as infections. However, more attention should be paid to the occurrence of serious life-threatening ADRs including respiratory failure, interstitial lung disease, and cardiogenic shock, especially in young patients.

Adverse Drug Reactions with Drugs Used in Multiple Sclerosis: An Analysis from the Italian Pharmacovigilance Database.

Given the importance of inflammation at the onset of multiple sclerosis (MS), therapy is mainly based on the use of anti-inflammatory drugs including disease modifying therapies (DMTs). Considering the recent approval of some DMTs, pharmacovigilance becomes a fundamental tool for the acquisition of new safety data. The aim of the study was to analyze adverse drug reactions (ADRs) related to the use of drugs approved for MS. All national publicly-available aggregated ADR reports recorded from 2002 to 2020 into the Reports of Adverse Reactions of Medicines (RAM) system and all complete Sicilian data reported into the Italian spontaneous reporting system (SRS) database having as suspected drugs interferon ß-1a (IFN ß-1a), interferon ß-1b (IFN ß-1b), peginterferon ß-1a (PEG-IFN ß-1a), glatiramer acetate (GA), natalizumab (NTZ), fingolimod (FNG), teriflunomide (TRF), dimethyl fumarate (DMF), alemtuzumab (Alem), ocrelizumab (OCZ), or cladribine (Cladr), were collected. Descriptive analyses of national, publicly-available aggregated data and full-access regional data were performed to assess demographic characteristics and drug-related variables followed by a more in-depth analysis of all Sicilian ADRs with a case-by-case assessment and a disproportionality analysis of unexpected ADRs. A total of 13,880 national reports have been collected from 2002 to 2020: they were mainly not serious ADRs (67.9% vs. 26.1%) and related to females (71.7% vs. 26.3%) in the age group 18-65 years (76.5%). The most reported ADRs were general and administration site conditions (n = 6,565; 47.3%), followed by nervous (n = 3,090; 22.3%), skin (n = 2,763; 19.9%) and blood disorders (n = 2,180; 15.7%). Some unexpected Sicilian ADRs were shown, including dyslipidemia for FNG (n = 10; ROR 28.5, CI 14.3-59.6), NTZ (n = 5; 10.3, 4.1-25.8), and IFN ß-1a (n = 4; 8.7, 3.1-24.1), abortion and alopecia for NTZ (n = 9; 208.1, 73.4-590.1; n = 3; 4.9, 1.5-15.7), and vitamin D deficiency for GA (n = 3; 121.2, 30.9-475.3). Moreover, breast cancer with DMF (n = 4, 62.8, 20.5-191.9) and hypothyroidism with Cladr (n = 3; 89.2, 25.9-307.5) were also unexpected. The reporting of drugs-related ADRs in MS were mostly reported in the literature, but some unknown ADRs were also found. However, further studies are necessary to increase the awareness about the safety profiles of new drugs on the market.

Adverse Drug Reactions with HER2-Positive Breast Cancer Treatment: An Analysis from the Italian Pharmacovigilance Database.

BACKGROUND: Anti-HER2 therapy has evolved in the last years and an important role in this transformation was that of monoclonal antibodies and tyrosine kinase inhibitors. Considering their extended use in clinical practice, some toxicity problems have been highlighted around these drugs. OBJECTIVE: To analyze the onset of adverse drug reactions (ADRs) related to the use of HER2-positive breast cancer treatments through a spontaneous reporting system (SRS) database. METHODS: All ADR reports having as suspected drug trastuzumab, pertuzumab, lapatinib, or trastuzumab emtansine (TDM-1), recorded into the Report Reazioni Avverse dei Medicinali (RAM) system database for national data and into the Italian SRS database for Sicilian data and collected from 2006 to 2020 have been evaluated. A descriptive analysis of basal demographic and drug-related characteristics was performed. A case-by-case methodology was conducted paying particular attention to the serious ADR reports collected in Sicily, focusing on type of seriousness, age, sex, concomitant drugs, comorbidities, time to onset (TTO), and time to resolution (TTR). RESULTS: Of the 3609 Italian reports, 65.6% were related to trastuzumab (n = 2367), followed by pertuzumab, TDM-1, and lapatinib. Almost all reports occurred in female patients (94.3%) and were most frequent in the age group 18-65 years (69.6%). A higher number of cases were related to general disorders and administration site conditions (n = 1079; 29.9%), gastrointestinal disorders (n = 1037; 28.7%), skin disorders (n = 821; 22.7%), and blood disorders (n = 599; 16.6%). Cases involving trastuzumab and pertuzumab mainly reported general disorders (n = 788; 33.3% and n = 194; 32.1%, respectively) while more than half of the reports associated with lapatinib were related to gastrointestinal (n = 184; 59.7%) and skin diseases (n = 146; 47.4%). Regarding TDM-1, 40% of reports had at least one ADR belonging to blood and lymphatic system disorders. The case-by-case assessment of Sicilian ADR reports showed that 40 cases were serious (33.3%), with a median TTO of 37 (6-97) days. Serious ADR reports mainly involved the onset of thrombocytopenia (n = 8; 20.0%), diarrhea (n = 6; 15.0%), asthenia and cardiac failure (both with n = 5; 12.5%), vomiting, hypersensitivity, and ejection fraction decreased (all with n = 4; 10.0%) and stomatitis (n = 3: 7.5%). CONCLUSION: This study is fundamentally consistent with results from the literature. Given the serious clinical condition of breast cancer and taking into account the importance of preventing some clinically relevant ADRs related to the use of anti-HER2 therapy, further analyses are essential to better describe the safety profile of these target therapies.

Management of High Cardiovascular Risk in Diabetic Patients: Focus on Low Density Lipoprotein Cholesterol and Appropriate Drug Use in General Practice.

This study aimed to evaluate the management of high cardiovascular risk (CVr) in the patients with diabetes by exploring the prescribing behavior in a setting of general practitioners (GPs). A retrospective cohort study was carried out using the data recorded between 2018 and 2020 in the clinical database of 10 GPs. Diabetes was defined using the International Classification of Diseases (ICD-9-CM) coding (250*) or using the laboratory parameters (hyperglycemia condition: ≥126 mg/dL). A cohort was described stratifying by demographic, clinical and therapeutic characteristics, and laboratory tests. Both the CVr and statin prescriptions were evaluated; adherence to statin therapy (medication possession ratio, MPR ≥ 80) was calculated in accordance with the low-density lipoprotein cholesterol (LDL-C) target. The multivariate logistic regression models with adjusted odds ratios (ORs) and the corresponding 95% Confidence Intervals (CIs) were calculated to identify the predictors of lipid modifying agents use and achieved target therapy; moreover, glucose-lowering drugs use was evaluated. Out of 13,206 people screened, 1,851 (14.0%) patients were affected by diabetes mellitus (DM), and 1,373 were identified at high/very high CVr. Of them, 1,158 (84.3%) had at least one measurement of LDL-C, and 808 (58.8%) received a prescription with at least one lipid-lowering drug (LLD). The patients at high/very high CVr treated or not treated with LLD, reached the LDL-C target in 24.0 and 10.3%, respectively (p < 0.001). Furthermore, 34.6% of patients treated with high intensity LLDs and adherent to therapy showed the LDL-C values below the therapeutic target. Out of 1,373 patients at high/very high CVr, 958 (69.8%) had at least one prescription of glucose-lowering drugs. Of them, 52.0% (n = 498) were prescribed not in agreement with the current guidelines. More specifically, 392 patients (40.9%) were treated with metformin only, while the remaining 106 (11.1%) were treated with metformin together with hypoglycemic agents other than glucagon-like peptide-1 receptor agonists (GLP1-RA) or sodium-glucose-transporter 2 (SGLT2) inhibitors. Our results suggest the urgent need to improve the management of patients with diabetes at high and very high CVr in the real life, to reduce the burden of diabetes on the health system.

A standardized extract of Opuntia ficus-indica (L.) Mill and Olea europaea L. improves gastrointestinal discomfort: A double-blinded randomized-controlled study.

Gastrointestinal discomfort (GD), which often includes gastroesophageal reflux disease (GERD), is a common disorder in healthy adults affecting 40% of the worldwide population. The symptoms related to GD can have a negative impact on the quality of life (QoL). Current treatments for GERD are associated with side effects. We conducted a randomized double-blind placebo-controlled trial to assess the effect of a standardized extract of Opuntia ficus-indica L. cladodes and Olea europaea L. leaves on the symptoms and QoL of healthy adults with GD. One hundred healthy participants with GD were enrolled in the study and divided into two groups: 60 participants taking verum (400 mg/day) and 40 taking the placebo for 8 weeks. The Gastrointestinal Quality of Life index (GIQLI) and GERD Symptom Assessment Scale (GSAS) questionnaires were administered at the beginning of the study and after 4 and 8 weeks. The group treated with verum experienced a statistically significant improvement of GIQLI and GSAS scores (p < .001). Moreover, the effect size measured revealed a clinical significance. A day-dependent improvement of symptoms was also observed. The standardized extract represents a fast, effective, and well-tolerated treatment for improving symptoms related to GD and GERD.

Nutraceuticals against Oxidative Stress in Autoimmune Disorders.

Antioxidant mechanisms are constituted of enzymes, endogenous, and non-enzymatic, exogenous, which have the role of counterbalancing oxidative stress. Intake of these compounds occurs in the diet. Vegetables, plants, and fruits contain a wide range of alkaloids, polyphenols, and terpenoids which are called "phytochemicals". Most of these substances are responsible for the positive properties of fruits and vegetables, which are an essential part of a healthy life with roles in ameliorating chronic illnesses and favoring longevity. Nutraceuticals are substances contained in a food or fragment of it influencing health with positive effects on health helping in precenting or treating disorders. We conducted a review illustrating the principal applications of nutraceuticals in autoimmune disorders. Literature reported several studies about exogenous dietary antioxidant supplementation in diverse autoimmune diseases such as rheumatoid arthritis, lupus, diabetes, and multiple sclerosis. In these pathologies, promising results were obtained in some cases. Positive outcomes were generally associated with a reduction of oxidative stress parameters and a boost to antioxidant systems, and sometimes with anti-inflammatory effects. The administration of exogenous substances through food derivates or dietary supplements following scientific standardization was demonstrated to be effective. Further bias-free and extended studies should be conducted that include ever-increasing oxidative stress biomarkers.

Efficacy and safety of the syrup "KalobaTUSS®" as a treatment for cough in children: a randomized, double blind, placebo-controlled clinical trial.

BACKGROUND: Acute cough in children often causes discomfort to children and parents, reducing their quality of life. Despite the extensive utilization of over-the-counter remedies for cough, the efficacy of most of these treatments in children has not been confirmed. METHODS: We conducted a randomized, double blind, placebo-controlled clinical trial of 106 children with acute cough to evaluate the efficacy and safety of KalobaTUSS®, a paediatric cough syrup based on acacia honey and on Malva sylvestris extract, Inula helenium extract, Plantago major extract, and Helichrysum stoechas extract by using a validated 6 points Likert scale. RESULTS: Children were orally treated with KalobaTUSS® or placebo for 8 days. Children receiving KalobaTUSS® showed an early and significant reduction in night-time and day-time cough scores measured using a specific scale and a shorter duration of cough than children treated with the placebo. CONCLUSIONS: KalobaTUSS® is well tolerated and produces positive effects by reducing the severity and shortening the duration of cough in children. TRIAL REGISTRATION: Clinicaltrials.gov no. NCT04073251 . Retrospectively registered.

Cannabinoids, Blood-Brain Barrier, and Brain Disposition.

Potential therapeutic actions of the cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are based on their activity as analgesics, anti-emetics, anti-inflammatory agents, anti-seizure compounds. THC and CBD lipophilicity and their neurological actions makes them candidates as new medicinal approaches to treat central nervous system (CNS) diseases. However, they show differences about penetrability and disposition in the brain. The present article is an overview about THC and CBD crossing the blood-brain barrier (BBB) and their brain disposition. Several findings indicate that CBD can modify the deleterious effects on BBB caused by inflammatory cytokines and may play a pivotal role in ameliorating BBB dysfunction consequent to ischemia. Thus supporting the therapeutic potential of CBD for the treatment of ischemic and inflammatory diseases of CNS. Cannabinoids positive effects on cognitive function could be also considered through the aspect of protection of BBB cerebrovascular structure and function, indicating that they may purchase substantial benefits through the protection of BBB integrity. Delivery of these cannabinoids in the brain following different routes of administration (subcutaneous, oral, and pulmonary) is illustrated and commented. Finally, the potential role of cannabinoids in drug-resistance in the clinical management of neurological or psychiatric diseases such as epilepsy and schizophrenia is discussed on the light of their crossing the BBB.

Preclinical and Clinical Evidence Supporting Use of Cannabidiol in Psychiatry.

BACKGROUND: Cannabidiol (CBD) is a major chemical compound present in Cannabis sativa. CBD is a nonpsychotomimetic substance, and it is considered one of the most promising candidates for the treatment of psychiatric disorders. OBJECTIVE: The aim of this review is to illustrate the state of art about scientific research and the evidence of effectiveness of CBD in psychiatric patients. METHODS: This review collects the main scientific findings on the potential role of CBD in the psychiatric field, and results of clinical trials carried out on psychiatric patients are commented. A research was conducted in the PUBMED, SCOPUS, and ScienceDirect databases using combinations of the words cannabidiol, psychiatry, and neuropsychiatric. RESULTS: Preclinical and clinical studies on potential role of CBD in psychiatry were collected and further discussed. We found four clinical studies describing the effects of CBD in psychiatric patients: two studies about schizophrenic patients and the other two studies carried out on CBD effects in patients affected by generalized social anxiety disorder (SAD). CONCLUSION: Results from these studies are promising and suggest that CBD may have a role in the development of new therapeutic strategies in mental diseases, and they justify an in-depth commitment in this field. However, clinical evidence we show for CBD in psychiatric patients is instead still poor and limited to schizophrenia and anxiety, and it needs to be implemented with further studies carried out on psychiatric patients.