Disease-Modifying Therapies (DMTs) in Pregnant and Lactating Women with Multiple Sclerosis: Analysis of Real-World Data from EudraVigilance Database.

(1) Background: The purpose of study was to compare the safety profile of glatiramer with natalizumab, alemtuzumab and ocrelizumab in pregnant and lactating women affected by multiple sclerosis (MS). (2) Methods: Individual case safety reports (ICSRs) were retrieved from the European spontaneous reporting system database (EudraVigilance). The reporting odds ratios (RORs) were computed to compare the reporting probability of events between natalizumab, alemtuzumab and ocrelizumab vs. glatiramer. (3) Results: A total of 1236 ICSRs reporting at least one DMT as a suspected drug were selected. More adverse drug reactions (ADRs) unrelated to pregnancy and breastfeeding (n = 1171; 32.6%) were reported than ADRs specific to pregnancy and breastfeeding (n = 1093; 30.4%). The most frequently reported unrelated ADR was MS relapse. Alemtuzumab and natalizumab seem to have a lower reporting probability of MS relapse compared to glatiramer (ROR 0.17, 95% CI 0.07-0.45 and ROR 0.34, 95% CI 0.20-0.57). Among pregnancy- and breastfeeding-related ADRs, the first most reported event was spontaneous abortion (n = 321; 8.9%). Natalizumab and ocrelizumab were associated with a higher reporting probability of spontaneous abortion compared to glatiramer (ROR 2.22, 95% CI 1.58-3.12; ROR 2.18, 95% CI 1.34-3.54, respectively), while alemtuzumab had a lower reporting frequency (ROR 0.32, 95% CI 0.17-0.60). (4) Conclusions: This study did not suggest any strong or new insights for DMTs in this special subpopulation. However, further studies need to be performed.

Which is the top player for the cardiovascular safety? ibrutinib vs. obinutuzumab in CLL.

Introduction: Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, is authorized for the treatment of chronic lymphocytic leukemia (CLL). This study aims to explore the cardiac safety profile of ibrutinib in comparison with obinutuzumab. Methods: A retrospective pharmacovigilance study was conducted on data retrieved from the European pharmacovigilance database (Eudravigilance) from 1 January 2014 to 30 September 2022. To compare the reporting frequency of cardiovascular events among ibrutinib, obinutuzumab, and the combination of both. Results: A total of 2 291 CV cases were retrieved, of which 1965 were related to ibrutinib, 312 to obinutuzumab, and 14 to the combination. Most cases referred to patients aged ≥65 years (N = 1,454; 63.47%) and male (N = 1,497; 65.34%). Most cases were serious (N = 2,131; 93.02%). The most reported events were: atrial fibrillation (N = 913; 31.31%) and haemorrhage (N = 201; 6.89%). A higher reporting frequency of CV events was found when ibrutinib was compared to obinutuzumab (ROR, 3.22; 95% CI, 2.89-3.60) or combination (ROR, 1.77; 95% CI, 1.11-2.83). A lower reporting was observed when obinutuzumab was compared to combination (ROR, 0.55; 95% CI, 0.34-0.88). Discussion: A higher reporting frequency of CV events in patients exposed to ibrutinib in comparison with obinutuzumab was found. Further studies are needed to better explore the safety of ibrutinib.

What Is the Role of Nutraceutical Products in Cancer Patients? A Systematic Review of Randomized Clinical Trials.

Chemotherapy represents the main pharmacological cancer treatment. Recently, positive effects emerged with the combination of anticancer therapy and nutraceutical products. The aim of this systematic review is to collect and synthesize the available scientific evidence regarding the potential effects of nutraceuticals on cancer cells. A systematic literature search of randomized clinical trials of nutraceutical products in patients with cancer published up to 15 December 2022 was conducted using three data sources: Embase, PubMed, and Web of Science. The effect of high-dose isoflavone supplements on prostate cancer resulted in stabilization or reduction of PSA concentrations in 50% of isoflavone group patients six months after treatment. High doses of vitamin D supplementation plus chemotherapy in patients with advanced or metastatic colorectal cancer showed a median PFS of 13.0 months (95% CI, 10.1-14.7 months) for 49 patients. The effect of vitamin D supplementation on markers of inflammatory level and antioxidant capacity in women with breast cancer showed a significant increase in serum vitamin D concentration (28 ± 2.6 to 39 ± 3.5; p = 0.004) after 8 weeks of treatment. In conclusion, nutraceutical supplements represent a potentially growing sector and can be utilized in medical treatment or nutrition to provide integrated medical care.

Immune-related adverse events and immune checkpoint inhibitors: a focus on neurotoxicity and clinical management.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) represent an innovative therapeutic approach of oncologic diseases. In Europe, this therapeutic class currently includes eight agents: ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, cemiplimab, durvalumab and dostarlimab. Despite their proved clinical benefits, they can induce immune-related adverse events (irADRs), that can also involve the nervous system. AREAS COVERED: Despite their rarity, neurological irADRs related to ICI-treatments can lead to serious and dangerous complications, highlighting the importance of a strict monitoring of patients. This review aims to summarize the safety profile of ICIs, focusing on their possible neurotoxicity and their management. EXPERT OPINION: Considering the clinical relevance of ICIs-induced irADRs and that the underlying mechanisms are still not completely understood, the use of ICIs requires extensive safety monitoring. Before to prescribe immunotherapy, oncologists should identify possible individual risk factors that may favor the onset of irADRs. Oncologists and general practitioners should inform and educate patients about the specific toxicities of immunological checkpoint inhibitors, including nervous ones. They should be carefully monitored at least 6 months after the end of treatment. ICIs-related nervous toxicities require a multidisciplinary management, in which neurologists and clinical pharmacologists should participate.

Do peripheral neuropathies differ among immune checkpoint inhibitors? Reports from the European post-marketing surveillance database in the past 10 years.

Although the immunotherapy advent has revolutionized cancer treatment, it, unfortunately, does not spare cancer patients from possible immune-related adverse events (irAEs), which can also involve the peripheral nervous system. Immune checkpoint inhibitors (ICIs), blocking cytotoxic T-lymphocyteassociated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed cell death ligand 1 (PD-L1), can induce an immune imbalance and cause different peripheral neuropathies (PNs). Considering the wide range of PNs and their high impact on the safety and quality of life for cancer patients and the availability of large post-marketing surveillance databases, we chose to analyze the characteristics of ICI-related PNs reported as suspected drug reactions from 2010 to 2020 in the European real-world context. We analyzed data collected in the European pharmacovigilance database, Eudravigilance, and conducted a systematic and disproportionality analysis. In our study, we found 735 reports describing 766 PNs occurred in patients treated with ICIs. These PNs included Guillain-Barré syndrome, Miller-Fisher syndrome, neuritis, and chronic inflammatory demyelinating polyradiculoneuropathy. These ADRs were often serious, resulting in patient disability or hospitalization. Moreover, our disproportionality analysis revealed an increased reporting frequency of PNs with tezolizumab compared to other ICIs. Guillain-Barré syndrome is a notable potential PN related to ICIs, as it is associated with a significant impact on patient safety and has had unfavorable outcomes, including a fatal one. Continued monitoring of the safety profile of ICIs in real-life settings is necessary, especially considering the increased frequency of PNs associated with atezolizumab compared with other ICIs.

Safety profile of sodium glucose co-transporter 2 (SGLT2) inhibitors: A brief summary.

A new therapeutic class of oral agents firstly used for the treatment of type 2 diabetes mellitus is represented by gliflozines or sodium-glucose co-transporter 2 (SGLT2) inhibitors. SGLT2 inhibitors might be effective alone or in combination with any other drugs. This therapeutic class currently includes five agents: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin. SGLT2 inhibitors prevent the renal reabsorption of filtered glucose and sodium by blocking the SGLT2 co-transporters in the proximal convoluted renal tubule, facilitating glucose excretion in the urine (glycosuria) and lowering blood glucose levels. SGLT2 inhibitors have also shown to have pleiotropic effects and determine cardiovascular and renal prevention, thus leading to an extension of their therapeutic indication to include the heart failure. Despite their clinical benefits, warnings about adverse events have been implemented by Regulatory Agencies in the product's information since their introduction to the market. In particular, SGLT2 inhibitors have shown a strong impact on a high number of risk factors. They can cause hypoglycaemia, hypotension, lower limb amputation, fractures, genito-urinary infections, and diabetic ketoacidosis with different frequencies of onset. Despite some of these events are rare, they can lead to serious and dangerous complications, highlighting the importance of a strict monitoring of patients. Overall, SLGT-2 inhibitors are effective antidiabetic drugs with favorable advantages in renal and cardiovascular protection, and with a generally well-tolerated safety profile. This review aims to summarize the safety profile of SGLT2 inhibitors available in the market.

Utilizing clinical pharmacology in the drug repurposing arena: a look into COVID-19.

INTRODUCTION: Drug repurposing represented an important contribution in the management of COVID-19, becoming the first line of defense to mitigate the effects of the new coronavirus. In a brief time, drug repurposing (DR) provided potentially effective and already available drugs for COVID-19, while specific therapies against SARS-CoV-2 and/or vaccines were developing. Identifying repurposed drugs requires a multidisciplinary approach, where clinical pharmacology represents the missing piece of the puzzle. AREAS COVERED: Nowadays, clinical pharmacology is recognized as a discipline at the core of translational science, whose activities lead to the identification of the right drug for the right patient. In the context of the COVID-19 pandemic, its role in drug development and therapy choice has been decisive and itself repositioned. In this review, we tried to highlight the important role of clinical pharmacology in the identification and evaluation of possible repurposed drugs for COVID-19. EXPERT OPINION: We believe that clinical pharmacology had an important role in identifying patient-oriented therapy during the COVID-19 pandemic. In this context, DR was just one of the challenges for clinical pharmacology, which proved that this discipline is ready to respond to future threats.

Capillary leak syndrome following COVID-19 vaccination: Data from the European pharmacovigilance database Eudravigilance.

Capillary leak syndrome (CLS) emerged as new adverse event after immunization (AEFI) associated to COVID-19 vaccination. CLS is a rare condition characterized by increased capillary permeability, resulting in hypoalbuminemia, hypotension, and edema mainly in the upper and lower limbs. Our pharmacovigilance study aims to evaluate the CLS onset following receipt of COVID-19 mRNA vaccines (mRNA-1273 and BNT162b2) compared to viral vector vaccines (Ad26.COV2-S and ChAdOx1-SARS-COV-2). We carried a cross-sectional study using all Individual Case Safety Reports (ICSRs) reporting a COVID-19 vaccine as suspected drug and CLS as AEFI, which were collected in the pharmacovigilance database EudraVigilance from January 1st, 2021, to January 14th, 2022. We applied the Reporting Odds Ratio (ROR) 95% CI for the disproportionality analysis. During our study period, CLS was described as AEFI in 84 out of 1,357,962 ICRs reporting a vaccine COVID-19 as suspected drug and collected in the EV database. Overall, the ICSR reported by CLS were mainly related to the viral vector COVID-19(ChAdOx1-SARS-COV-2 = 36; Ad26.COV2-S = 9). The mRNA COVID-19 vaccines were reported in 39 ICSRs (BNT162b2 =33; mRNA-1273 =6). Majority of ICSRs were reported by healthcare professionals (71.4%). Majority of the patients were adult (58.3%) and the female gender accounted in more than 65% of ICSRs referred both to classes vaccines. In particular, women were more represented in ICSRs referred to mRNA-1273 (83.3%) and to ChAdOx1-SARS-COV-2 (72.2%). The CLS outcome was more frequently favorable in mRNA ICSRs (33,3%) than the viral vector ones (13.3%). Among the ICSRs reporting CLS with unfavorable outcome, we found also 9 fatal cases (BNT162b2 = 1; ChAdOx1-SARS-COV-2 = 4; Ad26.COV2-S = 4). From disproportionality analysis emerged a lower CLS reporting probability after vaccination with mRNA vaccines compared to viral vector-based ones (ROR 0.5, 95% CI 0.3-0.7; p <0.001).Our findings, even if subject to the limitations of spontaneous reporting systems, suggest a small but statistically significant safety concern for CLS following receipt of COVID-19 viral vector vaccines, in particular with Ad26.COV2-S. Cytokine-release following T-cell activation could be involved in CLS occurrence, but a precise mechanism has been not yet identified. COVID-19 vaccines remain attentive as possible triggers of CLS.

Neurological Manifestations Related to Immune Checkpoint Inhibitors: Reverse Translational Research by Using the European Real-World Safety Data.

Immune checkpoint inhibitors (ICIs) are widely used improving clinical outcomes in many cancer patients. However, they can induce serious consequences, like neurological immune-related adverse drug reactions (NirADRs). Although these are rare complications, they can be serious with important impact on patients' quality of life. Our purpose is to describe these adverse events observed in the European clinical practice context. We carried out a descriptive analysis of individual case safety reports (ICSRs) related to ICIs collected until February 7, 2020, in the European spontaneous reporting database, EudraVigilance, and reported nervous disorders as suspect adverse drug reactions (ADRs). NirADRs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA). In order to identify a hypothetical different reporting probability of the NirADR types between the ICI classes, we carried out a disproportionality analysis. The reporting odds ratio (ROR) with 95% CI was computed comparing the different ICI classes to each other based on their pharmacological target [the cytotoxic T-lymphocyte antigen-4 (CTLA-4), the programmed death-1 (PD-1) or its ligand (PD-L1)]. Finally, we researched in the literature the hypothesized mechanisms, which could explain the onset of these ICI-related neurological complications. Overall, we found 4,875 cases describing 6,429 ICI-related suspected NirADRs. ICI-related neurotoxicities include a wide range of central and peripheral events. These were mainly related to anti-PD-1 agents and occurred in male patients (59%). Our analysis confirmed a gender difference of NirADRs. Twenty-three percent of the events (comprising myasthenia gravis, neuropathy peripheral, and cerebral infarction) had unfavorable fallouts, including fatal outcome (7%). Majority of the NirADRs were categorized as "Neurological disorders NEC" HLGTs MedDRA (2,076; 32%). In 1,094 cases (22%), more NirADRs overlapped with other neurologic complications. An interesting overlapping of myasthenia gravis with myositis or myocarditis emerged. From our disproportionality analysis, an increased reporting probability of peripheral neuropathies and headaches emerged with ipilimumab when compared to anti-PD-1 and anti-PD-L1 agents. However, neuromuscular disorders were more probably reported with anti-PD-1. Several pathogenic mechanisms, including neuronal damage by T cells and autoantibodies and/or cytokine-mediated inflammation processes, have been hypothesized. However, the pathogenesis of these ICI-related complications is not completely understood. Considering the recent marketing authorizations of ICIs, further studies are strongly needed to monitor their neurologic safety profile.

Happy air®, a successful school-based asthma educational and interventional program for primary school children.

BACKGROUND: To investigate whether an active partnership between schools, parents, and pediatricians can improve the management of asthma and quality of life of children with asthma. METHODS: A comprehensive asthma program (Happy Air®), based on a strong family-physician-school relationship, was carried out over a period of 3 years in six primary schools (2765 children). This program provides educational intervention to families, school staff, and students, as well as the administration of written questionnaires to identify children with asthma, asthma diagnosis and management, and, last but not least, extracurricular activities to improve respiratory and psychological conditions. Quality of life of children and parents, at the beginning and end of the program, was assessed using PedsQL™ 4.0 (Pediatric Quality of Life Inventory) measurement model. RESULT: Asthma was diagnosed in 135 children, of which 37 (27%) were diagnosed de novo. In all children, both single item and total clinical asthma scores showed a significant increase (p < .001) at the end of the Happy Air® program. The average scores of both the total PedsQL™ 4.0 and the four Scales were significantly increased (p < .001). CONCLUSION: Happy Air® is a model for a strategy of education- and school-based intervention for children with asthma and their families. This multi-action program for diagnosis, clinical follow-up, education, self-management, and quality-of-life control aims to minimize the socioeconomic burden of asthma disease.