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.

Inferior vena cava distensibility during pressure support ventilation: a prospective study evaluating interchangeability of subcostal and trans­hepatic views, with both M­mode and automatic border tracing.

The Inferior Vena Cava (IVC) is commonly utilized to evaluate fluid status in the Intensive Care Unit (ICU),with more recent emphasis on the study of venous congestion. It is predominantly measured via subcostal approach (SC) or trans-hepatic (TH) views, and automated border tracking (ABT) software has been introduced to facilitate its assessment. Prospective observational study on patients ventilated in pressure support ventilation (PSV) with 2 × 2 factorial design. Primary outcome was to evaluate interchangeability of measurements of the IVC and the distensibility index (DI) obtained using both M-mode and ABT, across both SC and TH. Statistical analyses comprised Bland-Altman assessments for mean bias, limits of agreement (LoA), and the Spearman correlation coefficients. IVC visualization was 100% successful via SC, while TH view was unattainable in 17.4% of cases. As compared to the M-mode, the IVC-DI obtained through ABT approach showed divergences in both SC (mean bias 5.9%, LoA -18.4% to 30.2%, ICC = 0.52) and TH window (mean bias 6.2%, LoA -8.0% to 20.4%, ICC = 0.67). When comparing the IVC-DI measures obtained in the two anatomical sites, accuracy improved with a mean bias of 1.9% (M-mode) and 1.1% (ABT), but LoA remained wide (M-mode: -13.7% to 17.5%; AI: -19.6% to 21.9%). Correlation was generally suboptimal (r = 0.43 to 0.60). In PSV ventilated patients, we found that IVC-DI calculated with M-mode is not interchangeable with ABT measurements. Moreover, the IVC-DI gathered from SC or TH view produces not comparable results, mainly in terms of precision.

Morphological and Genetic Aspects for Post-Mortem Diagnosis of Hypertrophic Cardiomyopathy: A Systematic Review.

Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiovascular diseases, and it shows an autosomal dominant pattern of inheritance. HCM can be clinically silent, and sudden unexpected death due to malignant arrhythmias may be the first manifestation. Thus, the HCM diagnosis could be performed at a clinical and judicial autopsy and offer useful findings on morphological features; moreover, it could integrate the knowledge on the genetic aspect of the disease. This review aims to systematically analyze the literature on the main post-mortem investigations and the related findings of HCM to reach a well-characterized and stringent diagnosis; the review was performed using PubMed and Scopus databases. The articles on the post-mortem evaluation of HCM by gross and microscopic evaluation, imaging, and genetic test were selected; a total of 36 studies were included. HCM was described with a wide range of gross findings, and there were cases without morphological alterations. Myocyte hypertrophy, disarray, fibrosis, and small vessel disease were the main histological findings. The post-mortem genetic tests allowed the diagnosis to be reached in cases without morpho-structural abnormalities; clinical and forensic pathologists have a pivotal role in HCM diagnosis; they contribute to a better definition of the disease and also provide data on the genotype-phenotype correlation, which is useful for clinical research.

Unusual attempted suicide or covered attempted homicide? A neck stabbing case report and review of literature.

A medico-legal consult is frequently required in a clinical context in order to assess the eventual compatibility of specific wounds with a self- or hetero-infliction. Accordingly, the case of a 52-year-old man with a single, penetrating stab wound of the neck, reported as self-inflicted, is here presented. The forensic aspects, taken into account in order to determine the self- or hetero-infliction nature of the wound, are further discussed and compared to cases described in the literature.

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.

An Insight into the Role of Postmortem Immunohistochemistry in the Comprehension of the Inflammatory Pathophysiology of COVID-19 Disease and Vaccine-Related Thrombotic Adverse Events: A Narrative Review.

On 11 March 2020, the World Health Organization (WHO) declared a pandemic due to the spread of COVID-19 from Wuhan, China, causing high mortality rates all over the world. The related disease, which mainly affects the lungs, is responsible for the onset of Diffuse Alveolar Damage (DAD) and a hypercoagulability state, frequently leading to Severe Acute Respiratory Syndrome (SARS) and multiorgan failure, particularly in old and severe-critically ill patients. In order to find effective therapeutic strategies, many efforts have been made aiming to shed light on the pathophysiology of COVID-19 disease. Moreover, following the late advent of vaccination campaigns, the need for the comprehension of the pathophysiology of the fatal, although rare, thrombotic adverse events has become mandatory as well. The achievement of such purposes needs a multidisciplinary approach, depending on a correct interpretation of clinical, biochemical, biomolecular, and forensic findings. In this scenario, autopsies have helped in defining, on both gross and histologic examinations, the main changes to which the affected organs undergo and the role in assessing whether a patient is dead "from" or "with" COVID-19, not to mention whether the existence of a causal link exists between vaccination and thrombotic adverse events. In the present work, we explored the role of postmortem immunohistochemistry, and the increasingly used ancillary technique, in helping to understand the mechanism underlying the pathophysiology of both COVID-19 disease and COVID-19 vaccine-related adverse and rare effects.

MAO-A Inhibition by Metaxalone Reverts IL-1ß-Induced Inflammatory Phenotype in Microglial Cells.

Experimental and clinical studies have suggested that several neurological disorders are associated with the occurrence of central nervous system neuroinflammation. Metaxalone is an FDA-approved muscle relaxant that has been reported to inhibit monoamine oxidase A (MAO-A). The aim of this study was to investigate whether metaxalone might exert antioxidant and anti-inflammatory effects in HMC3 microglial cells. An inflammatory phenotype was induced in HMC3 microglial cells through stimulation with interleukin-1ß (IL-1ß). Control cells and IL-1ß-stimulated cells were subsequently treated with metaxalone (10, 20, and 40 µM) for six hours. IL-1ß stimulated the release of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), but reduced the anti-inflammatory cytokine interleukin-13 (IL-13). The upstream signal consisted of an increased priming of nuclear factor-kB (NF-kB), blunted peroxisome proliferator-activated receptor gamma (PPARγ), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression. IL-1ß also augmented MAO-A expression/activity and malondialdehyde levels and decreased Nrf2 mRNA expression and protein levels. Metaxalone decreased MAO-A activity and expression, reduced NF-kB, TNF-α, and IL-6, enhanced IL-13, and also increased PPARγ, PGC-1α, and Nrf2 expression. The present experimental study suggests that metaxalone has potential for the treatment of several neurological disorders associated with neuroinflammation.

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-Mortem Immunohistochemical Evidence of ß2-Adrenergic Receptor Expression in the Adrenal Gland.

The evidence from post-mortem biochemical studies conducted on cortisol and catecholamines suggest that analysis of the adrenal gland could provide useful information about its role in human pathophysiology and the stress response. Authors designed an immunohistochemical study on the expression of the adrenal ß2-adrenergic receptor (ß2-AR), a receptor with high-affinity for catecholamines, with the aim to show which zones it is expressed in and how its expression differs in relation to the cause of death. The immunohistochemical study was performed on adrenal glands obtained from 48 forensic autopsies of subjects that died as a result of different pathogenic mechanisms using a mouse monoclonal ß2-AR antibody. The results show that immunoreactivity for ß2-AR was observed in all adrenal zones. Furthermore, immunoreactivity for ß2-AR has shown variation in the localization and intensity of different patterns in relation to the original cause of death. To the best of our knowledge, this is the first study that demonstrates ß2-AR expression in the human cortex and provides suggestions on the possible involvement of ß2-AR in human cortex hormonal stimulation. In conclusion, the authors provide a possible explanation for the observed differences in expression in relation to the cause of death.

Immunohistochemical study on dystrophin expression in CAD-related sudden cardiac death: a marker of early myocardial ischaemia.

The aims of this study were to assess if dystrophin can be a tool for the forensic evaluation of sudden cardiac death due to coronary atherosclerotic disease (CAD) and particularly if it can be a marker of early myocardial ischaemia. Then in this investigation, the dystrophin was compared to C5b-9 and fibronectin to analyze if there are some differences in the expression of these proteins. Two groups of CAD-related sudden cardiac death, respectively the group 1 with gross and/or histological evidence and the group 2 with no specific histological signs of myocardial ischaemia were used. A third group formed by cases of acute mechanical asphyxiation was used as a control. The immunohistochemical staining by dystrophin, C5b-9 and fibronectin antibodies was performed. Loss of sarcolemmal dystrophin was observed in different degrees according to more or less significant histological evidence of myocardial ischaemia. Moreover, the comparison between loss of dystrophin expression and fibronectin positivity showed significant differences in group 2. The results suggested that dystrophin can be used in forensic diagnosis of CAD-related sudden cardiac death and as marker of early myocardial ischaemia.

Immunohistochemical detection of early myocardial infarction: a systematic review.

The postmortem diagnosis of early myocardial infarction is a challenge for forensic pathologists because the routine histology is neither specific. Many authors have suggested the use of the immunohistochemistry to fill the gaps in the histological diagnosis of early myocardial infarction. This review aims to analyse advances of immunohistochemical detection of early cardiac damage due to ischaemia. To this purpose, we reviewed experimental studies that investigated immunohistochemical markers and their estimated timing of expression. The review was performed according to specific inclusion and exclusion criteria, and a total of 23 studies assessing the immunohistochemical markers for the diagnosis and timing of early myocardial infarction were identified. The literature review highlights that the analysed markers are complement components, others being inflammatory mediators, cardiac cell proteins, plasma proteins, stress or hypoxia-induced factors and proteins associated with heart failure. All studies demonstrate the effectiveness of the tested markers in the early detection of myocardial infarction in both animal and human samples.

Unexpected death for Takayasu aortitis associated with coronary ostial stenosis: case report.

The differential diagnosis of vasculitis is often a difficult task due to the frequent morphological similarities that various vasculitic syndromes express when the heart is the target organ. The more the lesions are limited to the arterial tree with absent or almost silent coronary events, the less specific the anatomical and clinical frameworks. To create a series of clinical records and on the basis of these assumptions, the authors report a case concerning the sudden death of a 43-year-old woman which occurred while an ergonometric test was being carried out 28 days after the onset of the symptoms. A subsequent postmortem investigation/autopsy enabled us to detect a granulomatous aortitis process and, in particular, a coronary ostial stenosis and severe involvement of the coronary vessels which was compatible with the pathological framework of Takayasu disease.

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.

"Immunohistochemical analysis of Sigma-1 receptor (σ-1R) expression in human pineal gland in relation to different causes of death".

Sigma-1 receptor (σ-1R) modulates cellular signaling pathways, probably acting as a ligand operated chaperone. When activated, the receptor translocates from the interface mitochondrion associated membrane of the endoplasmic reticulum to the cell membrane. σ-1R was demonstrated in some brain regions, including the pineal gland, and was proposed to be involved in several cerebral processes, including neuroprotective responses against homeostasis alterations. On this basis, the immunohistochemical expression of σ-1R in human pineal glands was evaluated, with particular regard to the different causes of death. Thirty-eight pineal glands obtained from forensic autopsies were divided into five groups according to the cause of death: sudden death, drowning, fire fatality, hanging, and hemorrhagic shock, and examined with hematoxylin-eosin stain and immunohistochemistry for σ-1R. Both pinealocytes and perivascular spaces were evaluated. The pineal glands from sudden death were only mildly positive for σ-1R, while a more evident immunopositivity was observed in hanging, fire fatality, hemorrhagic shock, and drowning. These results were confirmed in a two-by-two comparison between the sudden death group and other groups. Our data demonstrate for the first time with immunohistochemical techniques the presence of σ-1R expression in the human pineal gland and propose a direct correlation between σ-1R expression and duration of the death process, in particular when hypoxic conditions and/or excessive psychological stress are present.

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.

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 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.

Risks and benefits of animal-assisted interventions for critically ill patients admitted to intensive care units.

BACKGROUND: Pets offer significant health benefits, from decreased cardiovascular risks to anxiety and post-traumatic stress improvements. Animal-assisted interventions (AAI) are not frequently practiced in the intensive care unit (ICU) for fear of health risk for critical patients because there is a hypothetical risk of zoonoses. OBJECTIVES: This systematic review aimed to collect and summarize available evidence about AAI in the ICU. The Review questions were "Do AAI improve the clinical outcome of Critically Ill Patients admitted to ICUs?" and "Are the zoonotic infections the cause of negative prognosis?". METHODS: The following databases were searched on 5 January 2023: Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, and PubMed. All controlled studies (randomized controlled, quasi-experimental, and observational studies) were included. The systematic review protocol has been registered on the International Prospective Register of Systematic Review (CRD42022344539). RESULTS: A total of 1302 papers were retrieved, 1262 after the duplicate remotion. Of these, only 34 were assessed for eligibility and only 6 were included in the qualitative synthesis. In all the studies included the dog was the animal used for the AAI with a total of 118 cases and 128 controls. Studies have high variability, and no one has used increased survival or zoonotic risk as outcomes. CONCLUSIONS: The evidence on the effectiveness of AAIs in ICU settings is scarce and no data are available on their safety. AAIs use in the ICU must be considered experimental and follow the related regulation until further data will be available. Given the potential positive impact on patient-centered outcomes, a research effort for high-quality studies seems to be justified.

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.