Adverse Reactions to Evolocumab: Analysis of Real-World Data from EudraVigilance.

BACKGROUND: Evolocumab is a humanized immunoglobulin G2 monoclonal antibody, directed against Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9), prescribed in hypercholesterolemic patients. The safety profile of this drug is currently defined by the data of pre-authorization clinical trials. The purpose of this study is to update knowledge of the safety of evolocumab through an analysis of post-marketing real-world data on suspected adverse reactions (SARs), reported by the EudraVigilance database system. METHODS: The public version of the EudraVigilance database has been used, and only serious SARs signals were included. RESULTS: Musculoskeletal system disorders, flu-like symptoms, injection-site reactions, skin reactions, and metabolism and nutrition disorders are observed in the post-marketing surveillance, as well as being found in the pre-authorization studies. Not previously signaled in the pre-marketing studies, diarrhea was reported. Furthermore, signals related to cardiac adverse reactions, more frequently at the expense of adults in comparison to elders, were found. CONCLUSIONS: The post-marketing safety profile of evolocumab emerging from an analysis of the EudraVigilance data system indicates it is sufficiently safe but suggests the necessity for caution when it is prescribed to hyperlipidemic patients affected by heart diseases.

Effects of Physical Exercise and Motor Activity on Depression and Anxiety in Post-Mastectomy Pain Syndrome.

BACKGROUND: Chronic post-surgical pain is a condition persisting for not less than 3 months after surgical intervention. It is evaluated that 25-60% of women who underwent breast cancer excision suffer from post-mastectomy pain syndrome, and anxiety, depression, sleep disturbance, and catastrophizing. Physical activity can reduce the risk of chronic diseases and has a good impact on mood and cognitive function. The aim of this study was to estimate the influence of physical activity on the intensity of pain, depression, and anxiety in women who underwent mastectomy for breast cancer removal. METHODS: A prospective observational unicentric cohort study was performed. Patients were females who underwent unilateral or bilateral mastectomy. The Numerical Rating Scale (NRS) was used to measure pain intensity, Beck's Depression Inventory (BDI) for depression, and Generalized Anxiety Disorders-7 (GAD-7) for anxiety evaluation. Physical activity was assessed by the International Physical Activity Questionnaire (IPAQ). Interleukin (IL)-17, IL-1ß, cortisol, adrenocorticotropic hormone (ACTH), and brain-derived neurotrophic factor (BDNF) were also evaluated in the blood of patients. All evaluations were assessed 3 and 6 months after the surgery. RESULTS: Adequate physical activity reduced the intensity of pain, depression, and anxiety symptoms in women affected by post-mastectomy pain syndrome. Moreover, adequately active women showed a reduction in biomarkers of inflammation, cortisol, ACTH, and an increase of BDNF. CONCLUSIONS: Our results suggest that physical activity can improve the quality of life, reduce the intensity of pain and inflammatory markers, and be useful in the reduction of associated anxiety and depression.

Pharmacovigilance of unlicensed cannabidiol in European countries.

Cannabidiol (CBD) is a multitarget agent possessing anti-inflammatory and antioxidant properties. Unlicensed CBD gained public favor for the care of general health and well-being as well as to get comfort from inflammatory complaints, pain, anxiety, mood, and sleep disorders. Safety profile of unlicensed CBD has been not sufficiently described. For this reason, suspected adverse reactions (SARs) to CBD unlicensed products were analyzed. Serious SARs to unlicensed CBD products in EudraVigilance, a system purchased by the European Medicines Agency, were analyzed for age, sex of the patient, adverse reactions, indication for use, and concomitant drugs. Serious SARs were 18.9% of all adverse events to unlicensed CBD; they were more frequent in men and adult people and, to a less extent, in children (3-11 years). About sex, in EudraVigilance serious Individual Cases Safety Reports of SARs to CBD in men are in the largest number (58.8%) with respect to women. Unlicensed CBD was used in the 38.8% of cases for treatment of epilepsy; more frequent adverse effects were: mental disorders, hepatic disorders, and aggravation of pre-existing epilepsy. Drugs or substances more frequently associated with SARs were the antiepileptics clobazam and valproic acid, followed by cannabis. Results suggest that precautions and appropriate surveillance of adverse effects should be taken when unlicensed CBD is used.

Suspected oncologic adverse reactions associated with interleukin-23 inhibitors in EudraVigilance: Comparative study and gender distribution.

Psoriasis is a chronic inflammatory skin disease characterized by plaque formation. Interleukin (IL)-23 is upregulated in psoriatic lesions and is thought to be a major regulator of the Th17 pathway in psoriasis pathogenesis. Three monoclonal antibodies targeting the IL-23p19 subunit, guselkumab, tildrakizumab, and risankizumab, have been approved for psoriasis therapy. The balance between cytokines IL-23 and IL-12 can affect antitumor and pro-tumor immune activities, and patients with psoriasis may have higher rates of cancer than the general population. Moreover, a chronic inflammatory state typical of psoriasis may induce protumorigenic effects, however, the potential risk of malignancy in patients taking these drugs remains largely unknown. This study investigated the occurrence of malignancies as suspected adverse reactions (SARs) potentially associated with IL-23 inhibitors by analyzing real-world data from the European EudraVigilance database. Although indicatory, these real-world data seem to confirm the potential association between the IL-23 inhibitors risankizumab and tildrakizumab, and the occurrence of SARs linked to cancer in patients with psoriasis and, according to a gender perspective, they show that this relationship is asymmetrically distributed between women and men, with a clear prevalence of oncologic SARs in men.

Pharmacovigilance of Risankizumab in the Treatment of Psoriasis and Arthritic Psoriasis: Real-World Data from EudraVigilance Database.

Risankizumab is a selective, humanized immunoglobulin G1 (IgG1) monoclonal anti-body directed against interleukin (IL)-23 protein. The therapeutic indication of risankizumab is moderate-to-severe plaque psoriasis and psoriatic arthritis. The safety profile of risankizumab is currently defined by data obtained with clinical trials used for the authorization of entry into the market. The aim of this study was to expand information on the safety of risankizumab through a descriptive post-marketing analysis of real-world data regarding serious adverse reactions (SARs) to risankizumab found in the EudraVigilance database. The EudraVigilance database system, containing SARs linked to drugs not yet licensed for the market in the European Union (EU), was used. In EudraVigilance, SARs are described in single individual cases safety reports (ICSRs). More frequently reported serious SARs to risankizumab are associated with, in descending order, infections, cancer, nervous system disorders, cardiac disorders, abnormal laboratory results, pulmonary disorders, conditions aggravated, and skin disorders. Despite the classical limitations of this post-marketing study (lack of denominator, no certainty of causal relationship between the drug and the adverse reaction), analysis of real-world data related to SARs to risankizumab confirms the known safety profile of the drug but, at the same time, stimulates to further go into detail about the occurrence as adverse reactions of malignancies and their sex distribution.

Effects of Physical Exercise and Motor Activity on Oxidative Stress and Inflammation in Post-Mastectomy Pain Syndrome.

It is estimated that 10-50% of interventions can generate persistent post-surgical pain. Chronic post-mastectomy pain is a condition persisting for at least three months after surgery. It has been shown that physical activity in the cancer patient allows the improvement of the pain symptom. The aim of this study was to evaluate the effects of physical activity on the intensity and interference of chronic pain in the quality of life of women underwent mastectomy needed for breast cancer removal. The secondary objective was to measure the effects of physical activity on inflammatory and oxidative markers in the same population. A Numeric Rating Scale (NRS) was used to assess pain intensity, and Brief Inventory Pain (BIP) was used for assessing interference of pain in quality of life. Physical activity was measured with the International Physical Activity Questionnaire (IPAQ). Inflammatory mediators such as interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, c-reactive protein (CRP), and biomarkers of oxidative stress malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) were evaluated in the blood of patients. All the evaluations were performed after three and six months after surgery. Results showed that adequate physical activity can diminish intensity and interference of pain and that these effects are associated with a reduction of blood biomarkers of inflammation.

Pharmacovigilance on cannabidiol as an antiepileptic agent.

Introduction: Cannabidiol (CBD) is an active chemical contained in the plant Cannabis sativa. It is a resorcinol-based compound that crosses the blood-brain barrier without causing euphoric effects. CBD has a plethora of pharmacological effects of therapeutic interest. CBD has been authorized in the European Union as an anticonvulsant against serious infantile epileptic syndromes, but its safety profile is still not sufficiently described. Methods: With the goal of expanding information on the safety of CBD use as an antiepileptic agent beyond the most common side effects known through clinical studies, an analysis of serious case reports on suspected adverse reactions (SARs) to CBD licensed as an anti-epileptic drug found in the EudraVigilance database is reported in this article. EudraVigilance is a system purchased by the European Medicines Agency (EMA) for monitoring the safety of medicinal products marketed in Europe. Results: The most frequent serious SARs to CBD in EudraVigilance were epilepsy aggravation, hepatic disorders, lack of efficacy, and somnolence. Discussion: Based on our analysis, the following precautions should be adopted for appropriate monitoring of potential adverse effects, more attention towards possible CBD medical use as an antiepileptic: awareness of interactions with other drugs, epilepsy aggravation, and drug effectiveness.

Pharmacological Aspects and Biological Effects of Cannabigerol and Its Synthetic Derivatives.

Cannabigerol (CBG) is a cannabinoid from the plant Cannabis sativa that lacks psychotomimetic effects. Its precursor is the acidic form, cannabigerolic acid (CBGA), which is, in turn, a biosynthetic precursor of the compounds cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). CBGA decarboxylation leads to the formation of neutral cannabinoid CBG, through a chemical reaction catalyzed by heat. On the basis of the growing interest in CBG and with the aim of highlighting scientific information on this phytocannabinoid, we focused the content of this article on its pharmacokinetic and pharmacodynamic characteristics and on its principal pharmacological effects. CBG is metabolized in the liver by the enzyme CYP2J2 to produce hydroxyl and di-oxygenated products. CBG is considered a partial agonist at the CB1 receptor (R) and CB2R, as well as a regulator of endocannabinoid signaling. Potential pharmacological targets for CBG include transient receptor potential (TRP) channels, cyclooxygenase (COX-1 and COX-2) enzymes, cannabinoid, 5-HT1A, and alpha-2 receptors. Pre-clinical findings show that CBG reduces intraocular pressure, possesses antioxidant, anti-inflammatory, and anti-tumoral activities, and has anti-anxiety, neuroprotective, dermatological, and appetite-stimulating effects. Several findings suggest that research on CBG deserves to be deepened, as it could be used, alone or in association, for novel therapeutic approaches for several disorders.

Effects of Cannabidiol on Locomotor Activity.

Cannabidiol (CBD) is the second cannabinoid, in order of importance after Δ9-tetrahydrocannabinol (THC), from Cannabis sativa. Unlike THC, CBD does not cause psychotomimetic effects, and although these compounds have the same chemical formula, their pharmacological characteristics are not equivalent. Preclinical studies suggest that CBD has anti-inflammatory, analgesic, anxiolytic, antiemetic, anticonvulsant, and antipsychotic properties and influences the sleep-wake cycle. The evaluation of effects on spontaneous motor activity is crucial in experimental pharmacology, and the careful measurement of laboratory animal movement is an established method to recognize the effects of stimulant and depressant drugs. The potential influence of CBD on locomotor activity has been investigated through numerous in vivo experiments. However, there is no clear picture of the impact of CBD on these issues, even though it is administered alone for medical uses and sold with THC as a drug for pain caused by muscle spasms in multiple sclerosis, and it was recently licensed as a drug for severe forms of infantile epilepsy. On this basis, with the aim of developing deeper knowledge of this issue, scientific data on CBD's influence on locomotor activity are discussed here. We conducted research using PubMed, Scopus, Google Scholar, and a search engine for literature between January 2009 and December 2021 on life sciences and biomedical topics using the keywords "motor activity", "locomotor activity", and "locomotion" in combination with "cannabidiol". In this article, we discuss findings describing the effects on locomotor activity of the CBD precursor cannabidiolic acid and of CBD alone or in combination with THC, together with the effects of CBD on locomotor modifications induced by diseases and on locomotor changes induced by other substances.

Safety of Medical Cannabis in Neuropathic Chronic Pain Management.

Products derived from the plant Cannabis sativa are widely appreciated for their analgesic properties and are employed for the treatment of chronic neuropathic pain. Only nabiximols, a product composed of two extracts containing similar percentages of the two cannabinoids cannabidiol and delta-9-tetrahydrocannabinol, is approved by regulatory authorities for neuropathic pain and spasticity due to multiple sclerosis in many European countries and Canada. It is also included in pharmacovigilance systems monitoring the occurrence of adverse drug reactions. However, it is not the same for the great variety of other cannabis preparations widely used for medical purposes. This creates a situation characterized by insufficient knowledge of the safety of cannabis preparations and the impossibility of establishing a correct risk-benefit profile for their medical use in the treatment of chronic neuropathic pain. With the aim to explore this issue more deeply, we collected data on adverse reactions from published clinical studies reporting the use of cannabis for neuropathic relief.

Post-Mastectomy Pain: An Updated Overview on Risk Factors, Predictors, and Markers.

After breast surgery, women frequently develop chronic post-mastectomy pain (PMP). PMP refers to the occurrence of pain in and around the area of the mastectomy lasting beyond three months after surgery. The nature of factors leading to PMP is not well known. When PMP is refractory to analgesic treatment, it negatively impacts the lives of patients, increasing emotional stress and disability. For this reason, optimizing the quality of life of patients treated for this pathology has gained more importance. On the basis of the findings and opinions above, we present an overview of risk factors and predictors to be used as potential biomarkers in the personalized management of individual PMP. For this overview, we discuss scientific articles published in peer-reviewed journals written in the English language describing risk factors, predictors, and potential biomarkers associated with chronic pain after breast surgery. Our overview confirms that the identification of women at risk for PMP is fundamental to setting up the best treatment to prevent this outcome. Clinical practice can be planned through the interpretation of genotyping data, choosing drugs, and tailoring doses for each patient with the aim to provide safer and more effective individual analgesic treatment.