Cenobamate enhances the anticonvulsant effect of other antiseizure medications in the DBA/2 mouse model of reflex epilepsy.

Clinical studies documented that cenobamate (CNB) has a marked efficacy compared to other antiseizure medications (ASMs) in reducing focal seizures. To date, different aspects of CNB need to be clarified, including its efficacy against generalized seizures. Similarly, the pattern of drug-drug interactions between CNB and other ASMs also compels further investigation. This study aimed to detect the role of CNB on generalized seizures using the DBA/2 mouse model. We have also studied the effects of an adjunctive CNB treatment on the antiseizure properties of some ASMs against reflex seizures. The effects of this adjunctive treatment on motor performance, body temperature, and brain levels of ASMs were also evaluated. CNB was able to antagonize seizures in DBA/2 mice. CNB, at 5 mg/kg, enhanced the antiseizure activity of ASMs, such as diazepam, clobazam, levetiracetam, perampanel, phenobarbital, topiramate, and valproate. No synergistic effects were observed when CNB was co-administered with some Na+ channel blockers. The increase in antiseizure activity was associated with a comparable intensification in motor impairment; however, the therapeutic index of combined treatment of ASMs with CNB was more favorable than the combination with vehicle except for carbamazepine, phenytoin, and oxcarbazepine. Since CNB did not significantly influence the brain levels of the ASMs studied, we suggest that pharmacokinetic interactions seem not probable. Overall, this study shows the ability of CNB to counteract generalized reflex seizures in mice. Moreover, our data documented an evident synergistic antiseizure effect for the combination of CNB with ASMs including phenobarbital, benzodiazepines, valproate, perampanel, topiramate, and levetiracetam.

A new emergency during the latest phase of the COVID-19 pandemic: access to healthcare services by patients with non-communicable diseases.

Background: The aim of our study was to investigate the impact of the COVID-19 pandemic on the healthcare and the disease management of patients affected by non-communicable diseases (NCDs), by exploring, specifically, the obstacles encountered in the access to healthcare services during the latest phase of the pandemic. Methods: This cross-sectional study was carried out among subjects attending the anti-SARS-CoV2 vaccination clinic in a Teaching Hospital of Southern Italy. To be included in the study, subjects had to be affected by at least one NCD, such as diabetes, hypertension, respiratory and heart diseases, renal and liver chronic conditions, immunodeficiency disorders due to cancer, or being kidney or liver transplant recipients. Results: Among the 553 subjects who completed the questionnaire, the 39.4% (95% IC = 35.3-43.6) experienced obstacles in the access to healthcare services in the six months prior to the enrollment. The most frequent canceled/postponed healthcare services were the visits for routine checks for NCDs (60.6, 95% IC = 53.9-67), control visits of more complex diseases as cancer or transplantation (17.3, 95% IC = 12.6-22.8), and scheduled surgery (11.5, 95% IC = 7.7-16.4). The patients who experienced canceled/postponed healthcare services were significantly more likely to suffer from 3 or more NCDs (p = 0.042), to be diabetics (p = 0.038), to have immunodeficiency disorders (p = 0.028) and to have consulted GP at least once (p = 0.004). Conclusion: Our results appear to be fundamental for guiding the choices of providers in order to concentrate organizational efforts to recover and reschedule missed appointments, where applicable, of the most fragile patients by virtue of age and chronic conditions.

Ranolazine Attenuates Brain Inflammation in a Rat Model of Type 2 Diabetes.

Recent studies suggest a pathogenetic association between metabolic disturbances, including type 2 diabetes (T2DM), and cognitive decline and indicate that T2DM may represent a risk factor for Alzheimer's disease (AD). There are a number of experimental studies presenting evidence that ranolazine, an antianginal drug, acts as a neuroprotective drug. The aim of the present study was to evaluate the effects of ranolazine on hippocampal neurodegeneration and astrocytes activation in a T2DM rat model. Diabetes was induced by a high fat diet (HFD) and streptozotocin (STZ) injection. Animals were divided into the following groups: HFD/STZ + Ranolazine, HFD/STZ + Metformin, HFD/STZ + Vehicle, NCD + Vehicle, NCD + Ranolazine and NCD + Metformin. The presence of neurodegeneration was evaluated in the hippocampal cornus ammonis 1 (CA1) region by cresyl violet staining histological methods, while astrocyte activation was assessed by western blot analysis. Staining with cresyl violet highlighted a decrease in neuronal density and cell volume in the hippocampal CA1 area in diabetic HFD/STZ + Vehicle rats, while ranolazine and metformin both improved T2DM-induced neuronal loss and neuronal damage. Moreover, there was an increased expression of GFAP in the HFD/STZ + Vehicle group compared to the treated diabetic groups. In conclusion, in the present study, we obtained additional evidence supporting the potential use of ranolazine to counteract T2DM-associated cognitive decline.

Biologics for Inflammatory Bowel Disease in Clinical Practice: A Calabria (Southern Italy) Prospective Pharmacovigilance Study.

BACKGROUND: The use of immune-modifying biological agents has markedly changed the clinical course and the management of Inflammatory bowel diseases (IBDs). Active post-marketing surveillance programs are fundamental to early recognize expected and unexpected adverse events (AEs), representing a powerful tool to better determine the safety profiles of biologics in a real-world setting. METHODS: This study aimed to identify the occurrence of AEs and therapeutic failures linked to biological drugs used in gastroenterology units during a prospective pharmacovigilance program in Southern Italy. Patients affected by IBDs and treated with a biologic agent, from 1 January 2019, to 31 December 2021 (study period) in three gastroenterology units were enrolled. RESULTS: Overall, 358 patients with a diagnosis of active Crohn's disease or ulcerative colitis satisfying inclusion criteria have been enrolled. Infliximab (IFX) was the most administered drug at the index date (214; 59.8%), followed by Adalimumab (ADA; 89; 24.9%), Golimumab (GOL; 37; 10.3%), Vedolizumab (VDZ; 17; 4.7%) and Ustekimumab (UST; 1; 0.3%). Seventy-three patients (20.4%) experienced at least one AE, while 62 patients (17.3%) had therapeutic ineffectiveness. No serious AEs were reported in the follow-up period in the enrolled patients. AEs have been described with IFX (50/214; p = 0.47), GOL (7/37; p = 0.78), ADA (13/89; p = 0.18), and VDZ (3/17; p = 0.52), no AEs have been noticed with UST (0/1). CONCLUSIONS: Based on the low rate of AEs observed and withdrawal from treatment, our data seem to corroborate the favorable beneficial/risk profile of biologics for IBDs.

Real-World Safety Profile of Biologics Used in Rheumatology: A Six-Year Observational Pharmacovigilance Study in the Calabria Region.

Background: The introduction of biological agents into the clinical armamentarium has modified the management of moderate-severe inflammatory arthritis (IA). However, these drugs can lead to serious adverse events (SAEs) and unpredictable adverse events (AEs) that are difficult to detect in pre-marketing clinical trials. This pharmacovigilance project aimed to study the AEs associated with biologics use in rheumatology. Methods: The current investigation is a multicenter, prospective, observational cohort study based on the Calabria Biologics Pharmacovigilance Program. Patients treated with one biologic agent from January 2016 to January 2022 were enrolled. Results: Overall, 729 (86.3%) of a total of 872 patients did not develop AEs or SAEs, whereas 143 (16.4%) patients experienced at least one AE, of which 16 (1.8%) had at least one SAE. The most common AEs were administration site conditions followed by gastrointestinal, nervous system and skin disorders. We reported a total of 173 switches and 156 swaps. Switches mainly occurred for inefficacy (136; 77.7%), whereas only 39 (22.3%) were due to the onset of an AE. Primary/secondary failure was the most frequent reason for swaps (124, 79%), while AEs onset led to 33 (21%) swaps. Conclusions: This study supports the validity of our program in monitoring and detecting AEs in the rheumatological area, confirming the positive beneficial/risk ratio of biologics.

Pediatric Drug Safety Surveillance: A 10-Year Analysis of Adverse Drug Reaction Reporting Data in Calabria, Southern Italy.

INTRODUCTION: The paucity of pediatric clinical trials has led to many medicines frequently prescribed to children without a license for use in pediatrics, resulting in an increased risk of adverse drug reactions. Pharmacovigilance databases remain, among others, a valuable tool for evaluating pediatric drug safety in the real-life setting. OBJECTIVE: We aimed to characterize pediatric adverse drug reactions reported in the Italian Pharmacovigilance database coming from the Calabria region (Southern Italy) over 10 years. METHODS: All Individual Case Safety Reports (ICSRs) concerning individuals aged under 18 years were extracted from 2010 to 2019. Duplicate and vaccine ICSRs were excluded. The remaining ICSRs were analyzed with respect to patients' demographic data, suspected drugs, and category of adverse drug reactions across different age groups. RESULTS: Among 6529 selected ICSRs, 395 pediatric ICSRs corresponding to 556 adverse drug reactions were analyzed. From 2010 to 2015, an increasing number of ICSRs were observed, but the reporting rate decreased after 2015. The highest proportion of ICSRs concerned children and adolescents. Around 52% of ICSRs involved boys: a trend observed in all age groups excluding newborns. Sixty ICSRs were serious and among them, 75% required hospitalization mainly in children and adolescents. Most of the ICSRs were issued by physicians (64.1%), followed by other healthcare professionals (22.5%) and pharmacists (9.9%). Anti-infective agents for systemic use and skin disorders were, respectively, the most frequently reported drug group and adverse drug reaction category. CONCLUSIONS: This study provides an overview of adverse drug reactions reported in the pediatric population of the Calabria region and emphasizes the need for strengthening the surveillance in specific age subgroups and on given drugs in relation to their pattern of use.

Vaccinations Status against Vaccine-Preventable Diseases and Willingness to Be Vaccinated in an Italian Sample of Frail Subjects.

BACKGROUND: Study aim was to investigate the vaccination status against vaccine-preventable diseases (VPD) of frail adults during the SARS-CoV-2 pandemic and, for those subjects eligible for at least one vaccine, with respect to the recommended vaccination in line with the Italian National Vaccination Prevention Plane (NPVP), to explore the willingness to be vaccinated. METHODS: A cross-sectional study was carried out among adults aged ≥ 60, immunocompromised or subjects affected by chronic conditions. RESULTS: Among the 427 participants, a vaccination coverage rate lower than the targets for all the vaccines considered was found. Of those, 72.6% of subjects stated their willingness to receive recommended vaccinations, and 75.2% of the respondents stated that the advice to undergo vaccinations was received by the General Practitioner (GP). In a multivariable logistic regression model, higher odds of recommended VPD vaccination uptake (defined as having two or more of the recommended vaccinations) were associated with the willingness towards recommended VPD vaccination (Odds Ratio = 3.55, 95% Confidence Interval: 1.39 to 9.07), university education (OR = 2.03, 95% CI: 1.03 to 3.97), but having another person in the household (OR = 0.52, 95% CI: 0.28 to 0.97), and history of oncological disease (OR = 0.39, 95% CI: 0.18 to 0.87) were predictive of lower odds of vaccination uptake. In another multivariable model, higher odds of willingness to receive vaccines were associated with kidney disease (OR = 3.3, 95% CI: 1.01 to 10.5), perceived risk of VPD (OR = 1.9, 95% CI: 1.02 to 3.3), previous influenza vaccination (OR = 3.4, 95% CI: 1.8 to 6.5), and previous pneumococcal vaccination (OR = 3.1, 95% CI: 1.3 to 7.7), but increasing age (OR = 0.93 per year, 95% CI: 0.91 to 0.97), working (OR = 0.40, 95% CI: 0.20 to 0.78), and fear of vaccine side effects (OR = 0.38, 95% CI: 0.21 to 0.68) were predictive of lower odds of willingness to receive vaccines. CONCLUSIONS: Despite specific recommendations, vaccination coverage rates are far below international targets for frail subjects. Reducing missed opportunities for vaccination could be a useful strategy to increase vaccination coverage in frail patients during the routine checks performed by GPs and specialists.

Liraglutide chronic treatment prevents development of tolerance to antiseizure effects of diazepam in genetically epilepsy prone rats.

Glucagon-like peptide-1 (GLP-1) is a hormone that can regulate several neuronal functions. The modulation of GLP-1 receptors emerged as a potential target to treat several neurological diseases, such as epilepsy. Here, we studied the effects of acute and chronic treatment with liraglutide (LIRA), in genetically epilepsy prone rats (GEPR-9s). We have also investigated the possible development of tolerance to antiseizure effects of diazepam, and how LIRA could affect this phenomenon over the same period of treatment. The present data indicate that an acute treatment with LIRA did not diminish the severity score of audiogenic seizures (AGS) in GEPR-9s. By contrast, a chronic treatment with LIRA has shown only a modest antiseizure effect that was maintained until the end of treatment, in GEPR-9s. Not surprisingly, acute administration of diazepam reduced, in a dose dependent manner, the severity of the AGS in GEPR-9s. However, when diazepam was chronically administered, an evident development of tolerance to its antiseizure effects was detected. Interestingly, following an add-on treatment with LIRA, a reduced development of tolerance and an enhanced diazepam antiseizure effect was observed in GEPR-9s. Overall, an add-on therapy with LIRA demonstrate benefits superior to single antiseizure medications and could be utilized to treat epilepsy as well as associated issues. Therefore, the potential use of GLP1 analogs for the treatment of epilepsy in combination with existing antiseizure medications could thus add a new and long-awaited dimension to its management.

Serological Response to SARS-CoV-2 Messenger RNA Vaccine: Real-World Evidence from Italian Adult Population.

BACKGROUND: This study aims to investigate the extent of the BNT162b2 mRNA vaccine-induced antibodies against SARS-CoV-2 in a large cohort of Italian subjects belonging to the early vaccinated cohort in Italy. METHODS: A prospective study was conducted between December 2020 and May 2021. Three blood samples were collected for each participant: one at the time of the first vaccine dose (T0), one at the time of the second vaccine dose, (T1) and the third 30 days after this last dose (T2). RESULTS: We enrolled 2591 fully vaccinated subjects; 16.5% were frail subjects, and 9.8% were over 80 years old. Overall, 98.1% of subjects were seropositive when tested at T2, and 76.3% developed an anti-S IgG titer ≥4160 AU/mL, which is adequate to develop viral neutralizing antibodies. Seronegative subjects at T1 were more likely to remain seronegative at T2 or to develop a low-intermediate anti-S IgG titer (51-4159 AU/mL). CONCLUSIONS: In summary, vaccination leads to detectable anti-S IgG titer in nearly all vaccine recipients. Stratification of the seroconversion level could be useful to promptly identify high-risk groups who may not develop a viral neutralizing response, even in the presence of seroconversion, and therefore may remain at higher risk of infection, despite vaccination.

Real-life burden of adverse reactions to biological therapy in inflammatory bowel disease: a single-centre prospective case series.

BACKGROUND/AIM: Biologics represent a key therapeutic option in inflammatory bowel disease (IBD), but are associated with several side effects. Post-marketing surveillance, through a spontaneous adverse drug reactions (ADRs) monitoring system, is essential to assess the safety profile of biologics. The aim of the study was to prospectively evaluate the occurrence of ADRs in IBD patients treated with biologics from a single centre in Southern Italy. METHODS: Data from patients with Crohn's Disease (CD) and Ulcerative Colitis (UC) who underwent biological therapy were prospectively collected. ADRs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA®). RESULTS: Overall, 68 (54% male, 68% with UC and 32% with CD) biologic-naïve IBD patients underwent biological therapy. Mean follow-up was 11.7 ± 6.2 months. As a results of switches, for 68 patients we obtained 96 biologic prescriptions. Overall, 45 ADRs occurred in 36 (53%) patients, distributed as follows (ADRs/prescriptions): 19/37 with IFX-Remicade, 5/12 with IFX-Remsima, 8/9 with GOL, 11/26 with ADA, and 2/12 with VDZ. Mild ADRs were 29 (64%), moderate 15 (34%) and 1 (2%) severe. General disorders and administration related reactions were the most frequent ADRs (35%), followed by skin and subcutaneous tissue disorders (20%), infections (15%), musculoskeletal (11%), respiratory (6%) blood (4%), gastrointestinal (4%), and vascular disorders (2%). In 9 cases (20%) the ADRs resulted in definitive discontinuation of biologic therapy. CONCLUSION: In a prospective cohort of IBD patients, more than half experienced ADRs during biologic therapy. General disorders and administration related reactions were the most common ADRs, while infections were less common and rarely led to discontinuation of therapy. Findings underline the importance of surveillance in management of IBD patients during biologic therapy and implementing safety protocols with data from real-life settings.

Vaccination coverage among health-care workers: pre-post intervention study to assess impact of an on-site vaccination-dedicated clinic.

BACKGROUND: Several studies have revealed low vaccinations coverage among health-care workers (HCWs) for all vaccinations. The aim of our study was to evaluate the impact of the implementation of an on-site vaccination-dedicated clinic on the vaccination coverage rates of HCWs. RESEARCH DESIGN AND METHODS: A quasi-experimental pre-post intervention study was carried out among undergraduate and postgraduate students attending medical and health-care professions schools. RESULTS: We enrolled 804 students, 404 in the control and 400 in the experimental group. A significantly higher increase of vaccination coverage in the experimental group than in the control group for all the investigated vaccinations (p < 0.001) was found. The odds of adherence to vaccinations in the experimental group, compared to the control group, ranged from 6.9-fold (95% CI 3.51-13.44) to 18.9-fold (95% CI 10.85-32.96). The increase in the coverage rate in the control group was between 2.5% and 3.5%, whereas in the experimental group, higher increases were found, ranging from 34.8% to 71%. CONCLUSIONS: The extraordinary increase in the adherence to HCWs recommended vaccinations found in the study seems to indicate a significant role of enabling factors in the complex process of decision-making and implementation of health-related behaviors.

Obesity, Blood Pressure, and Intraocular Pressure: A Cross-Sectional Study in Italian Children.

INTRODUCTION: Several studies in the adult population have shown that obesity is an independent risk factor for elevated intraocular pressure (IOP), whereas data in the paediatric population are sparse and controversial. The purpose of the present study is to investigate the relationship between body mass index (BMI), blood pressure (BP), and IOP in healthy school children. METHODS: The survey was conducted among a random sample of 8-year-old Italian students. Data were collected on their health status and behaviours related to obesity (physical activity, food and drinking habits, etc.). Physical examinations, conducted at school, included measurements of height, weight, BP, and IOP. RESULTS: Five hundred and seventy-six subjects were recruited (92.8% response rate); 42.4% were overweight or obese, 58.9% consumed inadequate daily servings of fruit and vegetables, and 87.5% were involved in sedentary activities. Elevated BP/hypertension (HTN) affected 3.6% and high IOP was revealed in 12.5% of the children. In the multivariate analysis, elevated BP/HTN was the only significant determinant of ocular HTN (OR 5.36, 95% CI 1.95-14.73, p = 0.001). CONCLUSIONS: Our results show that high IOP affects 12.5% of 8-year-old school children and appears to be associated with high BP related to a high BMI.

Safety profile of biologic drugs for psoriasis in clinical practice: An Italian prospective pharmacovigilance study.

Psoriasis is an inflammatory and chronic skin disorder associated with physical and psychological burden impairing patients' quality of life. In the last decade, biologic drugs have widely changed treatment of moderate-severe psoriasis and their number is increasing overtime. To early identify expected/unexpected adverse events (AEs) with biologic treatments, pharmacovigilance programs are needed. We designed a post-marketing active pharmacovigilance program to monitor and analyse AEs and/or serious adverse events (SAEs) reports. All consecutive patients treated with one biologic drug during a two-years period and satisfying inclusion criteria have been enrolled in five Dermatology tertiary units. Demographic and clinical features of patients, type of treatment used, therapy discontinuation, failures, switch/swap to another biologic, and possible onset of AEs were collected. Overall, 512 patients with a diagnosis of psoriasis (286; 55.9%) or arthropathic psoriasis (226; 44.1%) have been enrolled. Eighty-two (16%) patients with AEs and 5 (1%) with SAEs have been identified. Further, 59 (11.5%) had a primary/secondary failure (mainly on infliximab and etanercept). The adverse events and SAEs were reported with golimumab (4/12), adalimumab (32/167), infliximab (9/48), etanercept (31/175) and ustekinumab (11/73), no adverse events have occurred with secukinumab (0/37). Infliximab and etanercept were significantly associated with primary/secondary failures, whereas no differences have been highlighted for AEs insurgence. On the other hand, ustekinumab seems to be associated with a low rate of AEs (p = 0.01) and no adverse events or failures have been reported with secukinumab (p = 0.04 and 0.03, respectively). Our study, even though limited by a small sample size and a brief follow-up period, provide useful data on widely used biologic drugs and their tolerability, discontinuation rate and the incurrence of severe adverse events. Further studies are necessary to include the recently approved biologic drugs and to increase the sample size for more detailed analysis.

Safety profiles of biologic agents for inflammatory bowel diseases: a prospective pharmacovigilance study in Southern Italy.

INTRODUCTION: Inflammatory bowel diseases (IBDs) are a public health issue with over 3.5 million patients in Europe, but the advent of several biologic agents has completely changed their management. Pharmacovigilance is needed to early detect expected/unexpected adverse events (AEs) to assess the safety of drugs in a real-world setting. Aim of this prospective pharmacovigilance study was to evaluate the occurrence of AEs in patients treated with biologic drugs in gastroenterology units in Southern Italy. METHODS: All consecutive patients treated with one biologic drug during a 2-years period (2017-2018) in six gastroenterology tertiary units and satisfying inclusion criteria were enrolled. Demographic and clinical characteristics of patients, type of treatment used, therapy discontinuation, failures, switch/swap to another biologic, and possible onset of AEs were collected. Adverse events have been compared to the number of AEs reported in the same centres in the two years before the protocol. RESULTS: Overall, 623 patients (253 females) with Crohn's disease (352; 56.5%) or ulcerative colitis (271; 43.5%) have been included. Infliximab (IFX) was the most commonly used (308, 49.4%), followed by adalimumab (ADA; 215, 34.5%), vedolizumab (VED; 73, 11.7%), golimumab (GOL; 26, 4.2%) and ustekinumab (UST; 0.2%). Ninety-two patients have experienced AEs (14.8%) and 10 serious adverse events (SAEs) (1.6%) were recorded. Adverse events and SAEs have been reported with GOL (7/26; p = .88), IFX (51/308; p = .54), ADA (28/125; p = .40) and VED (6/73; p = .11), no AEs occurred with UST (0/1). CONCLUSION: Overall, considering the low rate of AEs reported and discontinuation from therapy, our data seems to confirm the positive beneficial/risk ratio of biologic treatment for IBDs and provide useful data on biologic drugs in gastroenterology.

Is There Any Opportunity to Provide an HBV Vaccine Booster Dose Before Anti-Hbs Titer Vanishes?

Whether the primary Hepatitis B vaccination confers lifelong protection is debated. The aim of the study was to assess the effectiveness of booster doses in mounting a protective HBV immune response in subjects vaccinated 18-20 years earlier. The study population consisted of vaccinated students attending medical and healthcare professions schools. A booster dose was offered to subjects with a <10 mIU/mL anti-HBs titer. The post-booster anti-HBs titer was evaluated after four weeks. The subjects with a <10 mIU/mL post-booster anti-HBs titer, received a second and third dose of the vaccine and after one month they were retested. A <10 mIU/mL anti-HBs titer was found in 35.1% of the participants and 92.2% of subjects that were boosted had a ≥10 mIU/mL post-booster anti-HBs titer, whereas 7.8% did not mount an anamnestic response. A low post-booster response (10-100 mIU/mL anti-HBs) was significantly more likely in subjects with a <2.00 mIU/mL pre-booster titer compared to those with a 2.00-9.99 mIU/mL pre-booster titer. The anamnestic response was significantly related to the baseline anti-HBs levels. A booster dose of the HBV vaccine may be insufficient to induce an immunological response in subjects with undetectable anti-HBs titers. A booster dose might be implemented when an anamnestic response is still present.

Safety Profile of Biologics Used in Rheumatology: An Italian Prospective Pharmacovigilance Study.

Post-marketing surveillance activities are essential to detect the risk/benefit profile of biologic disease-modifying antirheumatic drugs (bDMARDs) in inflammatory arthritis. The aim of this study was to evaluate adverse events (AEs) in patients treated with bDMARDs in rheumatology during a prospective pharmacovigilance study from 2016 to 2018. Descriptive statistical analyses were performed to evaluate bDMARDs-related variables of patients without AEs/failures vs patients with AEs and failures. The risk profile among biologics was assessed by comparing patients treated with each bDMARD to patients treated with etanercept. A total of 1155 patients were enrolled, mostly affected by rheumatoid arthritis (46.0%). AEs and failures were experienced by 8.7% and 23.3%, respectively. The number of comorbidities significantly influenced the onset of AEs, while anxiety-depressive, gastrointestinal disease, and fibromyalgia influenced onset of failures. The probability of developing an AE was significantly lower in patients treated with secukinumab, while the probability of developing treatment failure was significantly lower in patients treated with golimumab, secukinumab and tocilizumab. A total of 216 AEs were reported (25.5% serious), mostly regarding infections (21.8%), musculoskeletal (17.6%) and skin (16.2%) disorders. Serious AEs included neutropenia (12.7%), lymphocytosis (9.1%) and uveitis (7.3%). The obtained results revealed known AEs but real-world data should be endorsed for undetected safety concerns.

Perampanel chronic treatment does not induce tolerance and decreases tolerance to clobazam in genetically epilepsy prone rats.

Tolerance to some therapeutic effects of antiepileptic drugs may account for the development of pharmacoresistance in patients with epilepsy. In the present study, following oral acute pretreatment with the new antiepileptic drug perampanel (0.1, 0.3, 1 or 3 mg/kg), we observed that the drug significantly and dose-dependently attenuated the seizure phases (clonus and tonus) of audiogenic seizures in genetically epilepsy prone rats (GEPR-9 s), a genetic model of reflex generalized epilepsy. In addition, the GEPR-9 s were administered orally with perampanel (1 or 3 mg/kg) once daily for 10 weeks in order to study the possible development of tolerance, and when animals were subjected to auditory stimulation we observed that the ED50 values against clonus or tonus were not significantly different from those observed after single administration. Furthermore, the duration of anticonvulsant effects observed between 60 min and 9 h following oral administration of perampanel (1 mg/kg) were similar in acute and after chronic treatment. In another group of experiments, clobazam (0.75, 1.5, 3, 6, 9, 12 and 15 mg/kg) after acute administration was able to dose-dependently reduce the severity of the audiogenic seizures in GEPR-9 s. When clobazam (6 or 12 mg/kg) was administered alone for 10 consecutive weeks a clear development of tolerance to its anticonvulsant effects within approximately seven weeks was observed. In addition, we observed that when clobazam (6 mg/kg) was co-administered with perampanel (1 mg/kg), the latter drug was able to attenuate the development of tolerance to the antiseizure activity of clobazam. The present data indicate that both perampanel and clobazam are effective against audiogenic seizures, however, clobazam effects are hampered by the development of tolerance. Furthermore, concomitant treatment with perampanel slows development of tolerance to the anticonvulsant effects of clobazam in GEPR-9 s.

The potential role of cannabinoids in epilepsy treatment.

INTRODUCTION: Epilepsy is one of the world's oldest recognized and prevalent neurological diseases. It has a great negative impact on patients' quality of life (QOL) as a consequence of treatment resistant seizures in about 30% of patients together with drugs' side effects and comorbidities. Therefore, new drugs are needed and cannabinoids, above all cannabidiol, have recently gathered attention. Areas covered: This review summarizes the scientific data from human and animal studies on the major cannabinoids which have been of interest in the treatment of epilepsy, including drugs acting on the endocannabinoid system. Expert commentary: Despite the fact that cannabis has been used for many purposes over 4 millennia, the development of drugs based on cannabinoids has been very slow. Only recently, research has focused on their potential effects and CBD is the first treatment of this group with clinical evidence of efficacy in children with Dravet syndrome; moreover, other studies are currently ongoing to confirm its effectiveness in patients with epilepsy. On the other hand, it will be of interest to understand whether drugs acting on the endocannabinoid system will be able to reach the market and prove their known preclinical efficacy also in patients with epilepsy.

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model.

One of the major challenges in the epilepsy field is identifying disease-modifying drugs in order to prevent or delay spontaneous recurrent seizure onset or to cure already established epilepsy. It has been recently reported that fingolimod, currently approved for the treatment of relapsing-remitting multiple sclerosis, has demonstrated antiepileptogenic effects in 2 different preclinical models of acquired epilepsy. However, to date, no data exist regarding the role of fingolimod against genetic epilepsy. Therefore, we have addressed this issue by studying the effects of fingolimod in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats, a well-established genetic model of absence epilepsy, epileptogenesis, and neuropsychiatric comorbidity. Our results have demonstrated that an early long-term treatment with fingolimod (1 mg/kg/day), started before absence seizure onset, has both antiepileptogenic and antidepressant-like effects in WAG/Rij rats. However, these effects were transitory, as 5 months after treatment discontinuation, both absence seizure and depressive like-behavior returned to control levels. Furthermore, a temporary reduction of mTOR signaling pathway activity, indicated by reduced phosphorylated mammalian target of rapamycin and phosphorylated p70S6k levels, and by increased phosphorylated Akt in WAG/Rij rats of 6 months of age accompanied the transitory antiepileptogenic effects of fingolimod. Surprisingly, fingolimod has demonstrated longer-lasting positive effects on cognitive decline in this strain. This effect was accompanied by an increased acetylation of lysine 8 of histone H4 (at both 6 and 10 months of age). In conclusion, our results support the antiepileptogenic effects of fingolimod. However, the antiepileptogenic effects were transitory. Moreover, fingolimod might also have a positive impact on animal behavior and particularly in protecting the development of memory decline.