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Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent single-gene disorder leading to renal failure. Current therapies are aimed to treat renal and extrarenal complications of ADPKD, but improved knowledge of the pathophysiological mechanisms leading to the generation and growth of cysts has permitted the identification of new drug candidates for clinical trials. Among these, in this review, we will examine above all the role of metformin, hypothesized to be able to activate the AMP-activated protein kinase (AMPK) pathway and potentially modulate some mechanisms implicated in the onset and the growth of the cysts.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common congenital kidney disorder, generally caused by mutations in the PKD1 and PKD2 genes, coding for polycystins 1 and 2. Its pathogenesis is accompanied by alterations of the cAMP, mTOR, MAPK/ERK, and JAK/STAT pathways. ADPKD is clinically characterized by the formation of many growing cysts with kidney enlargement and a progressive damage to the parenchyma, up to its complete loss of function, and the onset of end-stage renal disease (ESRD). The current aim of ADPKD therapy is the inhibition of cyst development and retardation of chronic kidney disease progression. Several drugs have been recently included as potential therapies for ADPKD including metformin, the drug of choice for the treatment of type 2 diabetes mellitus, according to its potential inhibitory effects on cystogenesis. In this review, we summarize preclinical and clinical evidence endorsing or rejecting metformin administration in ADPKD evolution and pathological mechanisms. We explored the biology of APDKD and the role of metformin in slowing down cystogenesis searching PubMed and Clinical Trials to identify relevant data from the database inception to December 2020. From our research analysis, evidence for metformin as emerging cure for ADPKD mainly arise from preclinical studies. In fact, clinical studies are still scanty and stronger evidence is awaited. Its effects are likely mediated by inhibition of the ERK pathway and increase of AMPK levels, which are both linked to ADPKD pathogenesis.

Status epilepticus (SE) is a neurological and medical emergency, defined as a condition resulting either from the failure of the mechanisms responsible of seizure self-limitation or from the initiation of mechanisms which lead to atypically prolonged seizures. Further than death, SE can have long-term consequences, including neuronal injury, depending on the type, cause and duration of seizures with severe associated disabilities. In Europe, SE shows an incidence rate ranging about 9 to 40/100,000/y. In adults, mortality of patients with SE is ~30%, and even higher (up to 40%) in refractory status epilepticus. To date, etiology, duration, presence of comorbidity, level of consciousness, semiology and age are the main clinical predictors of SE outcome.

Pharmaceutically purified oral cannabidiol (CBD) has been recently approved by the US Food and Drug Administration and European Medicines Agency as treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), which are severe and difficult-to-treat developmental and epileptic encephalopathies with onset in early childhood. This review will critically review the pharmacokinetic properties of CBD, the interactions with antiseizure and non-antiseizure medications, and the main tolerability and safety issues to provide guidance for its use in everyday practice. CBD is metabolized in the liver and can influence the activity of enzymes involved in drug metabolism. The best characterized drug-drug interaction is between CBD and clobazam. The most common adverse events include somnolence, gastrointestinal discomfort, and increase in serum transaminases. High-grade purified CBD oral solution represents an effective therapeutic option in patients with DS and LGS. The findings cannot be extrapolated to other cannabis-based products, synthetic cannabinoids for medicinal use and non-medicinal cannabis and CBD derivatives.

Introduction Epilepsy represents the third most common neurological disorder in the elderly. Antiseizure medications (ASMs) are often used not only to treat epilepsy but also other disorders in this age group. Many physio-pathological changes occur in body composition and organ or system functions with aging. Furthermore, drug-drug interactions (DDIs) represent a major risk considering the prevalence of polytherapy in the elderly. Areas covered Relevant studies on the pharmacokinetics of ASMs in the elderly were identified through a literature search. We have reviewed all available data on known alterations in pharmacokinetic parameters of ASMs in elderly also considering pathophysiological alterations such as renal function impairment. Finally, we have highlighted the potential risk of DDIs with some drug classes. Expert opinion Large interindividual variability also due to co-morbidities and related co-therapies makes elderly patients a not homogeneous group. Overall, a reduction in loading and maintenance doses of almost all ASMs should be considered to avoid adverse events (AEs) as well as a slow titration, following the rule 'start low and go slow'. Therapeutic drug monitoring should be performed to apply the 'individual therapeutic concentration' and implemented to overcome the age-related differences between dose and plasma concentrations, to monitor DDIs and guide dosage adjustments.

Cardiovascular (CV) disease remains the leading cause of mortality among end-stage kidney disease (ESKD) patients. Cathepsin-K (CatK), a small cysteine protease involved in bone and extracellular matrix remodeling, has recently emerged as a key-factor in the pathogenesis of various conditions predisposing to CV disease, including atherosclerosis, obesity, diabetes, and vascular calcification. In this pilot prospective study, we aimed at evaluating the clinical significance and the predictive power of CatK in a small cohort of hemodialysis (HD) patients.Cathepsin-K was measured in 54 prevalent HD patients and in 30 controls together with routine parameters. Patients were then followed up to 26 months and the time of cardiovascular death (endpoint of the study prospective phase) recorded.CatK levels were increased in the HD cohort as compared with controls (p 0.001). In HD patients, CatK was also independently correlated to PTH (β = 0.368; p = 0.001), alkaline phosphatase (β = 0.383; p 0.001), C-reactive protein (β = 0.260; p = 0.01), and white cell count (β = - 0.219; p = 0.02). After baseline assessment, patients were followed for CV death (mean follow-up 24.8 ± 3.1 months). Kaplan-Meier analysis showed a worsen survival (log-rank p = 0.04) in HD patients with CatK levels 440 pg/mL (best ROC-derived cut-off with 69.6% sensitivity and 79.8% specificity) with a crude HR (Mantel-Haenszel) of CV death of 3.46 (95% CI 1.89-13.44).In prevalent HD patients, altered CatK levels may reflect mineral dysmetabolism and inflammation, and predict CV death in the mid-term. These preliminary findings prompt the rationale for further investigations on larger cohorts to validate CatK as a biomarker for improving CV risk stratification in ESKD.

Increased expression of interleukin-6 (IL-6) both in cerebrospinal fluid (CSF) and plasma is closely associated with convulsive epilepsy and symptom severity of depression. By comparison, at present, little is known about the role of this cytokine in childhood (non-convulsive) absence epilepsy. The aim of this work was to investigate the potential effects of acute and chronic treatment with tocilizumab (TCZ, 10 and 30 mg/kg/day), on absence seizures, their development, and related psychiatric comorbidity in WAG/Rij rats. It is known that lipopolysaccharide (LPS)-induced changes in inflammatory processes increase absence epileptic activity. In order to study the central effects of TCZ, we investigated whether administration of this anti-IL-6R antibody could modulate the lipopolysaccharide (LPS) or IL-6-evoked changes in absence epileptic activity in WAG/Rij rats. Our results demonstrate that TCZ, at both doses, significantly reduced the development of absence seizures in adult WAG/Rij rats at 6 months of age (1 month after treatment suspension) compared with untreated controls, thus showing disease-modifying effects. Decreased absence seizure development at 6 months of age was also accompanied by reduced comorbid depressive-like behavior, whereas no effects were observed on anxiety-related behavior. Acute treatment with TCZ, at 30 mg/kg, had anti-absence properties lasting ~25 h. The co-administration TCZ with i.c.v. LPS or IL-6 showed that TCZ inhibited the worsening of absence seizures induced by both proinflammatory agents in the WAG/Rij rats, supporting a central anti-inflammatory-like protective action. These results suggest the possible role of IL-6 and consequent neuroinflammation in the epileptogenic process underlying the development and maintenance of absence seizures in WAG/Rij rats. Accordingly, IL-6 signaling could be a promising pharmacological target in absence epilepsy and depressive-like comorbidity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-020-00893-8) contains supplementary material, which is available to authorized users.

Mineral bone disease (MBD) is remarkably frequent among chronic hemodialysis (HD) patients. In this setting, deranged PTH levels portend an adjunctive risk of worsen outcomes. Various evidence exists demonstrating that PTH strongly induces Cathepsin-K, a cysteine protease mainly found in lysosomes of osteoclasts and macrophages which promotes bone and extracellular matrix remodelling. Cathepsin-K levels are altered in various bone disorders, systemic inflammation and even in non-advanced CKD. In this study, we tested the hypothesis of an association between Cathepsin-K, uremic-MBD and circulating PTH levels in a cohort of chronic HD patients. We measured Cathepsin-K in 85 stable chronic HD patients and dialysis vintage > 6 months by a commercially available ELISA kit and we collected routine clinical parameters, including intact PTH. Patients were further stratified according to their “on- target” or “off-target” PTH status. Cathepsin-K levels were significantly higher in HD patients than in healthy controls (p

Objective Comorbidity between epilepsy and heart diseases is frequent. Methods All drugs classified within the group of drugs for cardiovascular system according to the Anatomical Therapeutic Chemical (ATC) classification system were reviewed for their effects on seizures or epilepsy. Results Several agents showed antiseizure properties in animal models of seizures and/or in patients with epilepsy and only few were proconvulsant. Drugs with anticonvulsant effects include mecamylamine and guanfacine (antihypertensive drugs), indapamide, amiloride, furosemide and bumetanide (diuretics), fasudil (peripheral vasodilator), bioflavonoids (vasoprotective drug), propranolol (beta blocking agent), isradipine, nimodipine, verapamil and diltiazem (calcium channel blockers: CCBs), fosinopril and zofenopril (agents acting on the renin-angiotensin system), several statins, and fenofibrate (lipid-modifying agents). Drugs with proconvulsant properties in experimental models or in patients include reserpine, buflomedil, naftidrofuryl, and clonidine and propranolol at high doses. Drug-drug interactions (DDI) between antiseizure medications (ASMs) and drugs for cardiovascular system were also searched in two leading publicly accessible drug compendia. The most important DDIs occur between enzyme-inducing (EI) ASMs and ivabradine, ranolazine, macitenan and between EI-ASMs and the CCBs felodipine, nicardipine, nisoldipine, and verapamil. Simvastatin and atorvastatin are the lipid-modifying agents with more DDIs with EI-ASMs. Several pharmacodynamic interactions have been also documented. Discussion and conclusions Available data show that the treatment of patients with epilepsy and vascular comorbidities is challenging and requires the appropriate knowledge of pharmacological properties of drugs and drug interactions.

The gut microbiota seems to be implicated in the functioning and development of basic physiological processes and might also influence central neural processes, through the microbiota-gut-brain (MGB) axis. Pre- and clinical studies support the role of the microbiome in seizure modulation and in the pathogenesis of epilepsy. Acting through different interventions (PubMed and Google Scholar searches were used to compile a list of relevant publications until January 2020, using data from preclinical studies and clinical trials and gut microbiome/microbiota projects. Furthermore, we evaluate the impact of the antiepileptic drugs on gut microbiota and the influence of intestinal alterations on seizures occurrence.Investigating the MGB axis and the role of gut supplementation in epilepsy is challenging due to the numerous potential pathways and variables involved. Few studies have been performed so far and all have been limited making speculation still premature. Studies designed with the similar strictness of pharmaceutical drug development trials, performing taxa, and metabolomic analyses with standard methodologies are needed.

Background: Psoriasis is a cutaneous inflammatory condition characterized by an altered turnover of keratinocytes leading to scaly patches. Secukinumab and ixekizumab are two biologic drugs inhibiting interleukin-17. Objective: We report the first case, according to Naranjo score, of a secukinumab-induced erectile dysfunction with severe plaque psoriasis that disappeared after switching to another anti IL17 drug (ixekizumab). Methods: A 45 years old man experienced erectile dysfunction during treatment with an anti-IL17. The adverse effect appeared after 60 days of treatment with secukinumab and rapidly disappeared after discontinuation of the drug. All necessary urologic exams were carried out. Re-administration of secukinumab, due to the exacerbation of psoriasis, caused the same sexual dysfunction after 60 days. Results: Switching to ixekizumab lead to a resolution of the erectile dysfunction and a complete skin clearance. Conclusion: We describe for the first time a sexual dysfunction possibly due to secukinumab and its resolution after the switch to another similar but different drug, highlighting the potential difference between anti-IL17A drugs.

Background Resistant hypertension is highly prevalent among the general hypertensive population and the clinical management of this condition remains problematic. Different approaches, including a more intensified antihypertensive therapy, lifestyle modifications, or both, have largely failed to improve patients' outcomes and to reduce cardiovascular and renal risk. As renal sympathetic hyperactivity is a major driver of resistant hypertension, renal sympathetic ablation (renal denervation) has been recently proposed as a possible therapeutic alternative to treat this condition. Objectives We sought to evaluate the short- and long-term effects of renal denervation in individuals with resistant hypertension on clinical end points, including fatal and non-fatal cardiovascular events, all-cause mortality, hospital admissions, quality of life, blood pressure control, left ventricular hypertrophy, cardiovascular and metabolic profile, and kidney function, as well as the potential adverse events related to the procedure. Search methods We searched the following databases to 17 February 2016 using relevant search terms: the Cochrane Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ClinicalTrials.gov Selection criteria We considered randomised controlled trials (RCTs) that compared renal denervation to standard therapy or sham procedure to treat resistant hypertension, without language restriction. Data collection and analysis Two authors independently extracted data and assessed study risks of bias. We summarised treatment effects on available clinical outcomes and adverse events using random-effects meta-analyses. We assessed heterogeneity in estimated treatment effects using Chi² and I² statistics. We calculated summary treatment estimates as a mean difference (MD) or standardised mean difference (SMD) for continuous outcomes, and a risk ratio (RR) for dichotomous outcomes, together with their 95% confidence intervals (CI). Main results We found 12 eligible studies (1149 participants). In four studies, renal denervation was compared to sham procedure; one study compared a proximal ablation to a complete renal artery denervation; in the remaining, renal denervation was tested against standard or intensified antihypertensive therapy. None of the included trials was designed to look at hard clinical end points as primary outcomes. When compared to control, there was low quality evidence that renal denervation did not reduce the risk of myocardial infarction (4 studies, 742 participants; RR 1.31, 95% CI 0.45 to 3.84), ischaemic stroke (4 studies, 823 participants; RR 1.15, 95% CI 0.36 to 3.72), or unstable angina (2 studies, 201 participants; RR 0.63, 95% CI 0.08 to 5.06), and moderate quality evidence that it had no effect on 24-hour ambulatory blood pressure monitoring (ABPM) systolic BP (5 studies, 797 participants; MD 0.28 mmHg, 95% CI -3.74 to 4.29), diastolic BP (4 studies, 756 participants; MD 0.93 mmHg, 95% CI -4.50 to 6.36), office measured systolic BP (6 studies, 886 participants; MD -4.08 mmHg, 95% CI -15.26 to 7.11), or diastolic BP (5 studies, 845 participants; MD -1.30 mmHg, 95% CI -7.30 to 4.69). Furthermore, low quality evidence suggested that this procedure produced no effect on either serum creatinine (3 studies, 736 participants, MD 0.01 mg/dL; 95% CI -0.12 to 0.14), estimated glomerular filtration rate (eGFR), or creatinine clearance (4 studies, 837 participants; MD -2.09 mL/min, 95% CI -8.12 to 3.95). Based on low-quality evidence, renal denervation significantly increased bradycardia episodes compared to control (3 studies, 220 participants; RR 6.63, 95% CI 1.19 to 36.84), while the risk of other adverse events was comparable or not assessable. Data were sparse or absent for all cause mortality, hospitalisation, fatal cardiovascular events, quality of life, atrial fibrillation episodes, left ventricular hypertrophy, sleep apnoea severity, need for renal replacement therapy, and metabolic profile. The quality of the evidence was low for cardiovascular outcomes and adverse events and moderate for lack of effect on blood pressure and renal function. Authors' conclusions In patients with resistant hypertension, there is low quality evidence that renal denervation does not change major cardiovascular events, and renal function. There was moderate quality evidence that it does not change blood pressure and and low quality evidence that it caused an increaseof bradycardia episodes. Future trials measuring patient-centred instead of surrogate outcomes, with longer follow-up periods, larger sample size and more standardized procedural methods are necessary to clarify the utility of this procedure in this population.

Cenobamate (CNB) is the latest antiseizure medication (ASM) authorized for the treatment of focal-onset seizures in adults. Although the precise mechanism of action of CNB is not yet fully understood, this drug inhibits the persistent, rather than transient, voltage-gated sodium channel currents and is a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors, differently from benzodiazepines. CNB has a non-linear pharmacokinetic with a terminal half-life range of about 50/60 hours within the therapeutic dose range, which allows once daily administration. Cenobamate inhibits cytochrome P450 (CYP) 2C19 and induces CYP3A4 and 2B6, and hence can potentially interact with ASMs (eg, phenytoin, carbamazepine and clobazam) and no-ASMs drugs. In two randomized, double-blind, placebo-controlled trials in patients with focal epilepsies, CNB has shown a particularly good efficacy with a rate of seizure freedom of about 20% during the maintenance period in participants treated with the dose of 400 mg/day. The most common treatment-emergent adverse effects include central nervous system-related symptoms, like dizziness, diplopia, somnolence, and gait disturbances. Safety issues of particular interest are severe skin reactions (drug reaction with eosinophilia and systemic symptoms) and QT shortening, which contraindicates its use in subjects with familial short QT syndrome or in combination with other QT-shortening drugs. The recommended starting dose is 12.5 mg/day, which can be gradually titrated to the target dose (200 mg/day) and further increased up to 400 mg/day. There are several aspects of CNB that need to be still addressed, including the long-term efficacy and the efficacy in patients with generalized seizures. Ongoing studies will clarify these issues. The clinical relevance of the peculiar pharmacokinetics and the pattern of drug–drug interactions also require further investigation.

The Microbiota-Gut-Brain axis (MGBA) is a bidirectional communication pathway between gut bacteria and the central nervous system (CNS) (including the intestine) that exerts a profound influence on neural development, neuroinflammation, activation of stress response and neurotransmission, in addition to modulating complex behaviours, such as sociability and anxiety. Several MGBA modulating approaches are possible, such as probiotic administration. A reasonable pharmacological approach would also be the contemporarily administration of both prebiotics and postbiotics. To test this hypothesis, we probed the effects of α-lactalbumin (ALAC; a prebiotic in the dose range of 125–500 mg/kg) and sodium butyrate (NaB; a postbiotic in the dose range of 30–300 mg/kg) alone and in combination. We used two animal behavioural models of idiopathic autism, (BTBR mice) and anxiety/depression (chronic unexpected mild stress - CUMS mice) respectively, using several standard behavioural paradigms such as Three-chamber social interaction test, Marble burying assay, depression-, anxiety- and memory-tests. In BTBR autistic mice, we found that both ALAC and NaB improve animal sociability, and memory in the passive avoidance (PA); drug combination was more effective in almost all tests also reducing immobility time in the forced swimming test (FST), which was not affected by single drug administration. Similarly, in the CUMS mice, single drug administration was effective in improving: 1) depressive-like behaviour in the FST and sucrose preference test; 2) memory and learning in the PA, novel object recognition and Morris water maze tests. Drug combination was again more effective than single drug administration in most cases; however, in the CUMS model, neither single drug or combination was effective in the elevated plus maze test for anxiety. Our results suggest that in both models, ALAC and NaB combination is more effective in improving some pathological aspects of animal behaviour than single administration and that the prebiotic/postbiotic approach should be considered a reasonable approach for the manipulation of the MGBA to improve efficacy.

Liraglutide (LIR) is a novel long-lasting glucagon-like peptide-1 (GLP-1) analogue that facilitates insulin signalling and shows also neuroprotective properties in different brain disease models. In this study, we explored the potential antiepileptogenic effects of LIR in two different animal models; namely, the mouse intrahippocampal kainic acid (KA) model of temporal lobe epilepsy and the WAG/Rij rat model of absence epileptogenesis. Moreover, we evaluated LIR effects on comorbidities in various behavioural tests. Mice with kainate-induced epilepsy were treated with LIR (300 μg/kg/day s.c.) for 4 weeks after status epilepticus and then evaluated for drug effects on seizure development and behavioural alterations, whereas WAG/Rij rats were treated for 17 weeks (starting at 30 days of age, before seizure onset) with LIR (300 μg/kg/day s.c.) in order to investigate whether an early chronic treatment was able to reduce the development of absence seizures and related comorbidities. Our results indicate that LIR was effective in reducing the development of spontaneous seizures in kainate-induced epilepsy; moreover, in this model, it prevented memory impairment and related anxiety-like behaviour in the open field (OF) test while in the forced swimming test (FST), LIR displayed an apparent pro-depressant effect that was instead related to reduced endurance as confirmed by Rotarod test. In contrast, LIR was unable to modify the epileptogenic process underlying the development of absence seizures in WAG/Rij rats while being antidepressant in the FST in this strain. Our results indicate that LIR may represent a promising novel treatment to prevent and treat the epileptogenic process and its associated behavioural and cognitive alterations in some models of convulsive epilepsy characterized by neurodegeneration, since LIR effects are likely secondary to its recognized neuroprotective properties.

Introduction: Epilepsy is a common neurological disease requiring complex therapies, which are unable to achieve seizure control in 30% of patients. Poor adherence has been recognized as a possible determinant of drug-resistance. Prolonged-release formulations of antiepileptic drugs might help increase adherence and minimize side effects.Areas covered: Pregabalin (PGB) has peculiar pharmacodynamics and almost ideal pharmacokinetics, except for a short half-life and therefore requiring multiple daily dosing. PGB immediate-release (IR) is effective in focal-onset epilepsy (FOE), neuropathic pain, generalized anxiety disorder, and fibromyalgia, despite some tolerability issues, especially at higher doses. The controlled-release formulation (CR) shares PGB IR advantages and requires slight dose adjustments to guarantee bioavailability. In 2014, PGB CR (165 and 330 mg/day) failed to prove superior to placebo in a randomized placebo-controlled trial on 323 subjects with drug-resistant FOE, although it was just as tolerable. Therefore, PGB CR is not currently licensed for epilepsy.Expert opinion: Considering the disappointing results of the only controlled trial, PGB CR is unlikely to become an established epilepsy treatment anytime soon. Nevertheless, given its peculiar properties and potential advantages, PGB (in either formulation) should be further evaluated in specific populations of patients, especially fragile subjects with several comorbidities and complex polytherapies.

Epigenetic mechanisms, such as alterations in histone acetylation based on histone deacetylases (HDACs) activity, have been linked not only to normal brain function but also to several brain disorders including epilepsy and the epileptogenic process. In WAG/Rij rats, a genetic model of absence epilepsy, epileptogenesis and mild-depression comorbidity, we investigated the effects of two HDAC inhibitors (HDACi), namely sodium butyrate (NaB), valproic acid (VPA) and their co-administration, on the development of absence seizures and related psychiatric/neurologic comorbidities following two different experimental paradigms. Treatment effects have been evaluated by EEG recordings (EEG) and behavioural tests at different time points. Prolonged and daily VPA and NaB treatment, started before absence seizure onset (P30), significantly reduced the development of absence epilepsy showing antiepileptogenic effects. These effects were enhanced by NaB/VPA co-administration. Furthermore, early-chronic HDACi treatment improved depressive-like behaviour and cognitive performance 1 month after treatment withdrawal. WAG/Rij rats of 7 months of age showed reduced acetylated levels of histone H3 and H4, analysed by Western Blotting of homogenized brain, in comparison to WAG/Rij before seizure onset (P30). The brain histone acetylation increased significantly during treatment with NaB or VPA alone and more markedly during co-administration. We also observed decreased expression of both HDAC1 and 3 following HDACi treatment compared to control group. Our results suggest that histone modifications may have a crucial role in the development of epilepsy and early treatment with HDACi might be a possible strategy for preventing epileptogenesis also affecting behavioural comorbidities.

Background: Epilepsy and hypertension are common chronic conditions, both showing high prevalence in older age groups. This review outlines current experimental and clinical evidence on both direct and indirect role of hypertension in epileptogenesis and discusses the principles of drug treatment in patients with hypertension and epilepsy. Methods: We selected English-written articles on epilepsy, hypertension, stroke, and cerebrovascular disease until December, 2018. Results: Renin-angiotensin system might play a central role in the direct interaction between hypertension and epilepsy, but other mechanisms may be contemplated. Large-artery stroke, small vessel disease and posterior reversible leukoencephalopathy syndrome are hypertension-related brain lesions able to determine epilepsy by indirect mechanisms. The role of hypertension as an independent risk factor for post-stroke epilepsy has not been demonstrated. The role of hypertension-related small vessel disease in adult-onset epilepsy has been demonstrated. Posterior reversible encephalopathy syndrome is an acute condition, often caused by a hypertensive crisis, associated with the occurrence of acute symptomatic seizures. Chronic antiepileptic treatment should consider the risk of drug-drug interactions with antihypertensives. Conclusions: Current evidence from preclinical and clinical studies supports the vision that hypertension may be a cause of seizures and epilepsy through direct or indirect mechanisms. In both post-stroke epilepsy and small vessel disease-associated epilepsy, chronic antiepileptic treatment is recommended. In posterior reversible encephalopathy syndrome blood pressure must be rapidly lowered and prompt antiepileptic treatment should be initiated.

The discovery of potential antiseizure drugs (ASDs) requires the use of experimental models that can also provide a unique chance for identifying new effective molecules able to prevent and/or cure epilepsy. Most of the preclinical knowledge on epileptogenesis derives from studies performed on post-insult models that are characterized by a recognizable first insult, a silent period lasting until the onset of the first seizure and a chronic period characterized by spontaneous recurrent seizures (SRSs). At odds, genetic models, in which the first insult remains to be identified, have been poorly investigated. Among the genetic models, the WAG/Rij rat was validated as a suitable experimental model of absence epileptogenesis with neuropsychiatric symptomatology, in which, according to our previous hypothesis on SRSs onset, genes could be considered the first ‘insult’ underlying all plastic modifications supporting the occurrences of absence seizures in this strain. In fact, in several genetic models, the initial insult could be described as the mutation leading to epilepsy that, to date, remains to be defined in this strain. The silent period ends at the occurrence of the first SRS, which is approximately at 2-3 months of age in these rats and after that time the chronic phase initiates, in which, absence seizures increase over time underlying likely further epileptogenic processes. In this review, we describe both the features of this experimental model and the effects of several pharmacological treatments against epileptogenesis and its related comorbidities including depressive-like symptoms and cognitive decline.

Introduction: Cannabidiol (CBD) has antiseizure properties but no psychoactive effects. Randomized controlled trials of an oral, pharmaceutical formulation of highly purified CBD are promising; how...

Cenobamate is one of the latest antiseizure medications (ASMs) developed for the treatment of focal onset seizures in adult patients. The recommended starting dose is 12.5 mg/day, titrated gradually to the target daily dose of 200 mg, which may be increased to a maximum of 400 mg/day based on clinical response. Although the high rate of seizure freedom observed in randomized, placebo-controlled clinical trials has resulted in exciting expectations, further clinical studies are needed to better define its clinical profile. Cenobamate is characterized by a peculiar pharmacology regarding both pharmacodynamics and pharmacokinetics. The mechanism of action has only partly been described, with the drug acting on voltage-gated sodium channels through a pronounced action on persistent rather than transient currents. Cenobamate also acts as a positive allosteric modulator of GABAA receptors independently from the benzodiazepine binding site. The bioavailability of cenobamate is not influenced by other drugs, except phenytoin; it can inhibit cytochrome P450 (CYP) 2C19 and induce CYP3A4 and 2B6, and hence can potentially interact with many drugs (e.g. dose adjustments may be required for lamotrigine, carbamazepine and clobazam). The pharmacokinetics of cenobamate are not linear and dosage increases imply a disproportional increase in plasma levels, particularly at doses higher than 300 mg. The most common and dose-related adverse effects associated with cenobamate include central nervous system-related symptoms, mainly somnolence, dizziness, diplopia, and disturbances in gait and coordination. A somewhat higher incidence of adverse events has been observed in patients concomitantly treated with sodium channel blockers. The most relevant safety issues are currently represented by the risk of severe skin reactions (apparently avoidable by a slow titration) and QT shortening (the drug is contraindicated in patients with familial short QT syndrome or taking QT-shortening drugs). Overall, cenobamate is a promising ASM with an intriguing and not fully understood mechanism of action; pharmacokinetic issues need to be considered in clinical practice.

Direct oral anticoagulants (DOACs) are a more manageable alternative than vitamin K antagonists (VKAs) to prevent stroke in patients with nonvalvular atrial fibrillation and to prevent and treat venous thromboembolism. Despite their widespread use in clinical practice, there are still some unresolved issues on optimizing their use in particular clinical settings. Herein, we reviewed the current clinical evidence on uses of DOACs from pharmacology and clinical indications to safety and practical issues such as drugs and food interactions. Dabigatran is the DOAC most affected by interactions with drugs and food, although all DOACs demonstrate a favorable pharmacokinetic profile. Management issues associated with perioperative procedures, bleeding treatment, and special populations (pregnancy, renal and hepatic impairment, elderly, and oncologic patients) have been discussed. Literature evidence shows that DOACs are at least as effective as VKAs, with a favorable safety profile; data are particularly encouraging in using low doses of edoxaban in elderly patients, and edoxaban and rivaroxaban in the treatment of venous thromboembolism in oncologic patients. In the next year, DOAC clinical indications are likely to be further extended.

Background: Purified cannabidiol (CBD) was administered to highly refractory patients with Dravet (DS) or Lennox–Gastaut (LGS) syndromes in an ongoing expanded access program (EAP). Herein, we report interim results on CBD safety and seizure outcomes in patients treated for a 12-month period.Material and Methods: Thirty centers were enrolled from December 2018 to December 2019 within the open-label prospective EAP up to a maximum of 25 mg/kg per day. Adverse effects and liver function tests were assessed after 2 weeks; 1, 3, and 6 months of treatment; and periodically thereafter. Seizure endpoints were the percentage of patients with ≥50 and 100% reduction in seizures compared to baseline.Results: A total of 93 patients were enrolled and included in the safety analysis. Eighty-two patients [27 (32.9%) DS, 55 (67.1%) LGS] with at least 3 months of treatment have been included in the effectiveness analysis; median previously failed antiseizure medications was eight. Pediatric and adult patients were uniformly represented in the cohort. At 3-month follow-up, compared to the 28-day baseline period, the percentage of patients with at least a 50% reduction in seizure frequency was 40.2% (plus 1.2% seizure-free). Retention rate was similar according to diagnosis, while we found an increased number of patients remaining under treatment in the adult group. CBD was mostly coadministered with valproic acid (62.2%) and clobazam (41.5%). In the safety dataset, 29 (31.2%) dropped out: reasons were lack of efficacy [16 (17.2%)] and adverse events (AEs) [12 (12.9%)], and one met withdrawal criteria (1.1%). Most reported AEs were somnolence (22.6%) and diarrhea (11.9%), followed by transaminase elevation and loss of appetite.Conclusions: CBD is associated with improved seizure control also in a considerable proportion of highly refractory patients with DS and LGS independently from clobazam use. Overall, CBD safety and effectiveness are not dose-related in this cohort.

According to the definition of epileptogenesis, "disease modification" refers to every clinically relevant therapeutic outcome which does not necessarily prevent epilepsy onset but significantly improves the disease course by reducing seizure burden and/or decreases concomitant comorbidities. In this light, understanding comorbidities development, their characteristics, and the neurobiological causes represents a major issue both in clinical and preclinical research. This chapter is summarizing and critically evaluating the preclinical improvements over time in the study of epilepsy comorbidities reconsidering some of them according to the newer results. Furthermore, we highlight limitations and possibilities both in the methods used and in the mechanisms considered. The latter have been analysed also as potential therapeutic targets for therapy development. Finally, differences and similarities between induced epilepsy models and genetic models have been underlined in the chapter.

Introduction typical absences (TAs), are brief, generalized epileptic seizures of abrupt onset and termination clinically manifesting with impairment of awareness and associated with 3 Hz spike-wave discharges on EEG. TAs may occur in different idiopathic generalized epilepsies (IGE). Despite treatment with adequate anti-seizure medications (ASMs), TAs may persist in ~25% of subjects. This narrative review focuses on the therapeutic approach to difficult-to-treat TAs occurring in the setting of IGE. Areas covered a literature search was conducted on the topic of treatment of TAs. Expert opinion ethosuximide (ESX), valproic acid (VPA) and lamotrigine (LTG), alone or in combination, are considered the first-choice drugs. In women of childbearing potential, VPA should be avoided. Alternative therapies (benzodiazepines, levetiracetam, topiramate, or zonisamide) should be considered in subjects unresponsive to monotherapy after the exclusion of pseudo-drug resistance. Newer ASMs such as brivaracetam and perampanel seem to be promising options. Well-conducted clinical trials aimed to evaluate the efficacy of alternative monotherapy (beyond ESX, VPA or LTG) or combination of ASMs on difficult-to-treat TAs, are warranted.

Introduction: Nearly 80% of children with epilepsy have one or more chronic comorbidities that require specific drug treatments in several cases. Drug-drug interactions (DDIs) between antiseizure medications (ASMs) and all other drugs (NON-ASMs) used to treat comorbid diseases may have serious consequences. Areas covered: All potential DDIs between 27 ASMs and all NON-ASMs used for oral chronic treatment of those disorders most often comorbid with epilepsy in children were searched for drug compendia. Clinical evidence of the identified DDIs was also searched in the literature. Forty-eight drugs have been identified as potential DDIs with at least one ASM. Most important DDIs are between some ASMs and omeprazole and pantoprazole (drugs for gastrointestinal disorders), ibuprofen and cyclobenzaprine (drugs for musculoskeletal disorders), loratidine, lumacaftor/ivacaftor, montelukast, and theophylline (drugs for respiratory system), levothyroxine, liothyronine and several corticosteroids (systemic hormonal preparations), almotriptan, dihydroergotamine, ergotamine, and several antipsychotics, antidepressants and anxiolytics (drugs for nervous diseases). Clinical evidence of the predicted DDIs was found in a minority of cases. Expert opinion: Treatment of children with epilepsy should be decided considering treatment of both seizures and comorbid diseases and aimed at minimizing the risk of DDIs between ASMs and NON-ASMs.

Introduction: Status epilepticus (SE) is a neurologic and medical emergency with significant related morbidity and mortality. Hepatic or renal dysfunction can considerably affect the pharmacokinetics of drugs used for SE through a variety of direct or indirect mechanisms. Areas covered: This review aims to focus on the therapeutic management of SE in patients with hepatic or renal impairment, highlighting drugs' selection and dose changes that may be necessary due to altered drug metabolism and excretion. The references for this review were identified by searches of PubMed and Google Scholar until May 2020. Expert opinion: According to literature evidence and clinical experience, in patients with renal disease, the authors suggest considering lorazepam as the drug of choice in pre-hospital and intra-hospital early-stage SE, phenytoin in definite SE, propofol in refractory or super-refractory SE. In patients with liver disease, the authors suggest the use of lorazepam as drug of choice in pre-hospital and intra-hospital early-stage SE, lacosamide in definite SE, propofol in refractory or super-refractory SE. A list of preferred drugs for all SE stages is provided.

Epigenetic mechanisms are involved in epilepsy and chronic pain development. About that, we studied the effects of the natural histone deacetylase (HDAC) inhibitor sodium butyrate (BUT) in comparison with valproic acid (VPA) in a validated genetic model of generalized absence epilepsy and epileptogenesis. WAG/Rij rats were treated with BUT (30 mg/kg), VPA (300 mg/kg), and their combination (BUT + VPA) daily per os for 6 months. Rats were subjected at Randall–Selitto, von Frey, hot plate, and tail flick tests after 1, 3, and 6 months of treatment to evaluate hypersensitivity to noxious and non-noxiuous stimuli. Moreover, PPAR-γ (G3335 1 mg/kg), GABA-B (CGP35348 80 mg/kg), and opioid (naloxone 1 mg/kg) receptor antagonists were administrated to investigate the possible mechanisms involved in analgesic activity. The expression of NFkB, glutathione reductase, and protein oxidation (carbonylation) was also evaluated by Western blot analysis. WAG/Rij rats showed an altered pain threshold throughout the study (p < 0.001). BUT and BUT + VPA treatment reduced hypersensitivity (p < 0.01). VPA was significantly effective only after 1 month (p < 0.01). All the three receptors are involved in BUT + VPA effects (p < 0.001). BUT and BUT + VPA decreased the expression of NFkB and enhanced glutathione reductase (p < 0.01); protein oxidation (carbonylation) was reduced (p < 0.01). No effect was reported with VPA. In conclusion BUT, alone or in coadministration with VPA, is a valuable candidate for managing the epilepsy-related persistent pain.

Purpose: Interest in cannabis-based therapies has recently increased, due to the availability of cannabidiol (CBD) for the treatment of epilepsy without psychoactive effects. Therapeutic drug monitoring can prevent drug interactions and minimize drug toxicity. We evaluated a volumetric absorptive microsampling (VAMS) method combined with LC-MS/MS (liquid chromatography coupled to tandem mass spectrometry) for the quantification of CBD blood levels in patients with refractory epilepsy.Methods: Prospective observation of patients with Dravet syndrome receiving open-label, add-on GW-purified CBD (Epidyolex®) at different doses. CBD plasma samples were obtained from venipuncture and LC-MS/MS was used to measure CBD in venous and capillary blood samples collected by VAMS.Results: We enrolled five patients with a mean age of 13 (range: 4–27) years. CBD levels measured by VAMS on capillary blood did not differ from CBD levels measured in plasma by venipuncture (R2 > 0.93).Conclusion: This proof-of-concept study suggests that VAMS allows monitoring of CBD plasma levels and can offer valuable support for personalized therapy in refractory epilepsy.

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.

Objective A large number of studies have highlighted the important role of the gut microbiota in the pathophysiology of neurological disorders, suggesting that its manipulation might serve as a treatment strategy. We hypothesized that the gut microbiota participates in absence seizure development and maintenance in the WAG/Rij rat model and tested this hypothesis by evaluating potential gut microbiota and intestinal alterations in the model, as well as measuring the impact of microbiota manipulation using fecal microbiota transplantation (FMT). Methods Initially, gut microbiota composition and intestinal histology of WAG/Rij rats (a well-recognized genetic model of absence epilepsy) were studied at 1, 4, and 8 months of age in comparison to nonepileptic Wistar rats. Subsequently, in a second set of experiments, at 6 months of age, untreated Wistar or WAG/Rij rats treated with ethosuximide (ETH) were used as gut microbiota donors for FMT in WAG/Rij rats, and electroencephalographic (EEG) recordings were obtained over 4 weeks. At the end of FMT, stool and gut samples were collected, absence seizures were measured on EEG recordings, and microbiota analysis and histopathological examinations were performed. Results Gut microbiota analysis showed differences in beta diversity and specific phylotypes at all ages considered and significant variances in the Bacteroidetes/Firmicutes ratio between Wistar and WAG/Rij rats. FMT, from both Wistar and ETH-treated WAG/Rij donors to WAG/Rij rats, significantly decreased the number and duration of seizures. Histological results indicated that WAG/Rij rats were characterized by intestinal villi disruption and inflammatory infiltrates already at 1 month of age, before seizure occurrence; FMT partially restored intestinal morphology while also significantly modifying gut microbiota and concomitantly reducing absence seizures. Significance Our results demonstrate for the first time that the gut microbiota is modified and contributes to seizure occurrence in a genetic animal model of absence epilepsy and that its manipulation may be a suitable therapeutic target for absence seizure management.

Background and Aims Cathepsin-K (Cts-K) is a lysosomal cysteine protease mainly involved in bone remodeling and resorption. Although it is largely released by lung cells, osteoclasts and macrophages, increasing current evidence suggests that the parathyroids may somewhat regulate Cts-K balance. We therefore analyzed Cts-K in a cohort of 85 chronic HD patients (mean age 67+/-12, median dialysis vintage 3.2 yrs), also including some individuals who were previously parathyroidectomized. Method Cts-K serum levels were measured before a mid-week dialysis session together with standard biochemical parameters. Twenty-six healthy subjects matched for age and gender served as controls. Patients were further stratified according to whether they were parathyroidectomized or not. Results Cts-K levels were statistically higher in HD patients than in controls (median 340, IQR 170-835 vs. 190 IQR 20-120 pg/mL, p Conclusion Cathepsin-K may represent a potential candidate biomarker for diagnosing and managing MBD complications, particularly those related to parathyroid dysfunction. Its exact biological role in these conditions deserves further examination.

Background and Aims Mineral bone disease (MBD) and chronic inflammation are key triggers of the exceeding cardiovascular risk that characterizes dialysis patients. Cathepsin-K (Cts-K) is a lysosomal cysteine protease involved in bone remodeling and resorption, whose expression is promoted particularly by inflammation and whose involvement in bone and cardiovascular disorders has previously been demonstrated. We set out to undertake an exploratory, observational study to assess the possible clinical significance of Cts-K in dialysis patients. Method Eighty-five chronic HD patients (mean age 67±12, median dialysis vintage 3.2 yrs) with stable dry weight were studied. Cts-K was measured in peripheral blood samples before a mid-week dialysis session together with standard biochemical parameters. Twenty-six healthy subjects, matched with HD patients for age and gender, served as controls. Results Cts-K was statistically higher in HD patients than in controls (median 340, IQR 170-835 vs. 190 IQR 20-120 pg/mL, p Conclusion Cathepsin-K is a biomarker at the crossroads of bone and inflammatory disorders in chronic hemodialysis patients. Future research is needed to clarify the exact pathophysiological role of this protein and to test its potential usefulness as a marker for managing MBD therapy and complications.

Background: Epilepsy is one of the most common symptoms of brain tumors. It is often drug resistant and generally worsen patients' quality of life (QoL). Brain tumors release glutamate among other mediators, contributing to seizures onset, and this is accompanied by an increased AMPA receptors' expression on neuronal cells' membrane. Perampanel (PER) is a relatively new antiseizure medication (ASM) that acts as a selective non-competitive AMPA receptors' antagonist. Given its mechanism of action, we aimed to evaluate through a prospective, observational study, the efficacy and safety of PER as an add-on treatment in patients with brain tumor-related epilepsy (BTRE). The study was called PERADET. Methods: Thirty-six adult patients (intention to treat population-ITT) affected by BTRE, with uncontrolled focal-onset seizures treated with 1–3 ASMs were recruited from four Italian epilepsy centers. Perampanel was added-on, titrated from 2 mg/day up to a maximum of 12 mg/day. Tumor history and therapy, type, and seizures frequency, previous ASMs were collected at 6 and 12 months. A battery of QoL tests were administered at baseline, 6 and 12 months. The primary endpoint was to assess the efficacy of PER by calculating the percent change in seizure frequency and the responder rate. The secondary endpoints were tolerability, retention rate at 12 months, and improvement in quality of life. Results: At the end of 12 months, 21 patients (per protocol population-PP) were available for evaluation. In this population the responder rate (percentage of patients who experienced a 50% or greater reduction in seizure frequency) was 90.4 with 33.3% of patients being seizure-free. In the ITT group the responder rate at the end of 12 months was 66.6 with 25% of patients being seizure free. PER was well tolerated (30.6% of patients experienced an adverse event, none was severe; three needed a treatment interruptions). Conclusions: Our study indicate that PER may be efficacious against BTRE as suggested by its mechanism of action and our current knowledge on mechanisms of brain tumor epileptogenicity. Trial Registration Number (TRN): (Prot. n° 0008872.25-06-2019); RS 919/17.

The link between epilepsy and type 2 diabetes (T2DM) and/or metabolic syndrome (MetS) has been poorly investigated. Therefore, we tested whether a high-fat diet (HFD), inducing insulin-resistant diabetes and obesity in mice, would increase susceptibility to develop generalized seizures induced by pentylentetrazole (PTZ) kindling. Furthermore, molecular mechanisms linked to glucose brain transport and the effects of the T2DM antidiabetic drug metformin were also studied along with neuropsychiatric comorbidities. To this aim, two sets of experiments were performed in CD1 mice, in which we firstly evaluated the HFD effects on some metabolic and behavioral parameters in order to have a baseline reference for kindling experiments assessed in the second section of our protocol. We detected that HFD predisposes towards seizure development in the PTZ-kindling model and this was linked to a reduction in glucose transporter-1 (GLUT-1) expression as observed in GLUT-1 deficiency syndrome in humans but accompanied by a compensatory increase in expression of GLUT-3. While we confirmed that HFD induced neuropsychiatric alterations in the treated mice, it did not change the development of kindling comorbidities. Furthermore, we propose that the beneficial effects of metformin we observed towards seizure development are related to a normalization of both GLUT-1 and GLUT-3 expression levels. Overall, our results support the hypothesis that an altered glycometabolic profile could play a pro-epileptic role in human patients. We therefore recommend that MetS or T2DM should be constantly monitored and possibly avoided in patients with epilepsy, since they could further aggravate this latter condition.

Background Perampanel (PER) is a novel antiepileptic drug approved as an add-on therapy for focal onset seizures with or without generalization and primary generalized tonic-clonic seizures. Aim of this study was to evaluate PER efficacy and tolerability as add-on therapy in patients with drug-resistant focal onset seizures and especially temporal lobe epilepsy (TLE). Methods An observational, prospective, multicentre study on adult with drug-resistant focal epilepsy consecutively recruited from six Italian tertiary epilepsy centres. All patients received add-on PER according to indication and clinical judgement. Seizure frequency and adverse events (AEs) were recorded at 6 and 12 months after PER introduction. Results Study sample comprised 246 patients, 77 of which with TLE. Seventy-five (35.9%) out of 209 and 66 (38.8%) out of 170 patients still taking PER resulted to be responders (i.e. ≥50% of seizure frequency or seizure free) after six and 12 months, respectively. In the TLE group, 39 (57.3%) out of 68 subjects on PER after 6 months and 32 (60.4%) out of 53 subjects taking PER after 12 months were responders. Overall reported incidence of AEs was 26.1%. In 28 cases (11.3%) AEs lead/contributed to PER discontinuation. The most frequently reported AE were dizziness (14/84) and somnolence (14/84). Regarding TLE patients, 25.9% of them experienced at least one AE and discontinuation for AEs occurred in eight (10.4%). Conclusions This study confirmed the good efficacy and safety of PER for drug-resistant focal epilepsy in real-life conditions and, above all, for the first time provide its effectiveness in patients with TLE.

Type 2 diabetes mellitus (T2DM) is a risk factor for cognitive impairment. Ranolazine, an anti-ischemic drug used in the treatment of angina pectoris, has been shown to possess hypoglycemic properties in pre-clinical and clinical studies. The aim of this study was to evaluate the effects of ranolazine on glucose metabolism and cognitive function in a T2DM model of Wistar rats. Diabetes was induced by a high fat diet (HFD) and streptozotocin (STZ). The control group received a normal caloric diet (NCD) and sodium citrate buffer. Metformin, an effective hypoglycemic drug, was employed as a positive control. Animals were divided into the following groups: HFD/STZ + Ranolazine, HFD/STZ + Metformin, HFD/STZ + Vehicle, NCD + Vehicle, NCD + Ranolazine, and NCD + Metformin. Rats received ranolazine (20 mg/kg), metformin (300 mg/kg), or water, for 8 weeks. At the end of the treatments, all animals underwent to an intraperitoneal glucose tolerance test (IPGTT) and behavioral tests, including passive avoidance, novel object recognition, forced swimming, and elevate plus maze tests. Interleukin-6 plasma levels in the six treatment groups were assessed by Elisa assay. Body mass composition was estimated by nuclear magnetic resonance (NMR). Glucose responsiveness significantly improved in the HFD/STZ + Ranolazine (p &lt, 0.0001) and HFD/STZ + Metformin (p = 0.003) groups. There was a moderate effect on blood glucose levels in the NCD + Ranolazine and NCD + Metformin groups. Lean body mass was significantly increased in the HFD/STZ + Ranolazine and HFD/STZ + Metformin animals, compared to HFD/STZ + Vehicle animals. Ranolazine improved learning and long-term memory in HFD/STZ + Ranolazine compared to HFD/STZ + Vehicle (p &lt, 0.001) and ameliorated the pro-inflammatory profile of diabetic mice. These results support the hypothesis of a protective effect of ranolazine against cognitive decline caused by T2DM.

Sodiumvalproate (VPA), an antiepileptic drug, may cause dose- and time-dependent hepatotoxicity. However, its iatrogenic molecular mechanism and the rescue therapy are disregarded. Recently, it has been demonstrated that sodium butyrate (NaB) reduces hepatic steatosis, improving respiratory capacity and mitochondrial dysfunction in obese mice. Here, we investigated the protective effect of NaB in counteracting VPA-induced hepatotoxicity using in vitro and in vivo models. Human HepG2 cells and primary rat hepatocytes were exposed to high VPA concentration and treated with NaB. Mitochondrial function, lipid metabolism, and oxidative stress were evaluated, using Seahorse analyzer, spectrophotometric, and biochemical determinations. Liver protection by NaB was also evaluated in VPA-treated epileptic WAG/Rij rats, receiving NaB for 6months. NaB prevented VPA toxicity, limiting cell oxidative and mitochondrial damage (ROS, malondialdehyde, SOD activity, mitochondrial bioenergetics), and restoring fatty acid oxidation (peroxisome proliferator-activated receptor α expression and carnitine palmitoyl-transferase activity) in HepG2 cells, primary hepatocytes, and isolated mitochondria. In vivo, NaB confirmed its activity normalizing hepatic biomarkers, fatty acid metabolism, and reducing inflammation and fibrosis induced by VPA. These data support the protective potential of NaB on VPA-induced liver injury, indicating it as valid therapeutic approach in counteracting this common side effect due to VPA chronic treatment.

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.

Objective: Subjects with low levels of HDL (high-density lipoprotein) and ApoA-1 (apolipoprotein A-1) have increased risk to develop type 2 diabetes. HDL levels are an independent predictor of β-cell function and positively modulate it. Type 2 diabetes is characterized by defects in both β and α-cell function, but the effect of HDL and ApoA1 on α-cell function is unknown. Approach and Results: We observed a significant negative correlation ( r =−0.422, P P =0.006). CD1 mice treated with HDL or ApoA-1 for 3 consecutive days showed a 32% ( P P P P Conclusions: These results support the notion that HDL and ApoA-1 modulate glucagon expression and secretion by binding their cognate receptor SCARB-1, and activating the PI3K/Akt/FoxO1 signaling cascade in an in vitro α-cell model. Overall, these results raise the hypothesis that HDL and ApoA-1 may have a role in modulating glucagon secretion.

Antiepileptic drugs (AEDs) are administered orally for chronic use. Parenteral formulations might be necessary when the oral route is not feasible (e.g. an impairment of consciousness, trauma, dysphagia, gastrointestinal illness) or for treatment of seizure emergencies. At present, few intravenous (IV) formulations are available on the market.The purpose of this review is to summarize the pharmacological characteristics and clinical applications of IV medications that have been recently introduced to the armamentarium of epilepsy therapy or are currently being developed. Apart from AEDs, other compounds belonging to different pharmacological classes (e.g. diuretics, anesthetics), which have shown potential effectiveness in seizure control, are taken into consideration, and the pathophysiological premises supporting their use for epilepsy treatment are illustrated. The authors give particular focus to immunomodulatory and immunosuppressive agents, which have become the therapeutic cornerstones for immune-mediated epilepsies, despite regulatory obstacles.In several circumstances, especially in the case of seizure-related emergencies, clinical practice seems not match literature-based evidence, and several IV AEDs are still used off-label. Strong evidence derived from randomized clinical trials (RCTs) is needed to support the effectiveness and tolerability of any therapeutic approach, however common and "accepted' it may be, in order to guarantee patient safety and well-being.