Publications by authors named "Giovambattista De Sarro"

295 Publications

Increased efficacy of combining prebiotic and postbiotic in mouse models relevant to autism and depression.

Neuropharmacology 2021 Sep 4;198:108782. Epub 2021 Sep 4.

System and Applied [email protected] Magna Grecia, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy.

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.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108782DOI Listing
September 2021

Direct-acting antivirals inducing HCV-RNA sustained suppression improve Xerophthalmia in HCV-infected patients.

Curr Rev Clin Exp Pharmacol 2021 Sep 3. Epub 2021 Sep 3.

Department of Health Science, School of Medicine, University of Catanzaro, Operative Unit of Clinical Pharmacology, Mater Domini University Hospital, Catanzaro, Italy.

Background: Hepatitis C virus (HCV) infection represents a global problem, and it is related to both hepatic and extra-hepatic manifestations (e.g., xerophthalmia). New direct-acting antivirals (DAAs), IFN-free treatments, are commonly used to manage HCV infection. However, the impact of new DAAs on dry eyes (xerophthalmia) is lacking. In this study, we evaluated its incidence in HCV patients and the effect of DAAs on this manifestation.

Methods: We performed an observational open-label non-randomized study in HCV patients from 01 April 2018 to 01 June 2020.

Results: Patients who satisfied the inclusion criteria underwent clinical and laboratory evaluation, Schirmer's test, and Break-up time test. Enrolled patients were divided in two groups: Group 1: HCV patients with xerophthalmia: 24 patients (16 male and 8 female), HCV-RNA 2,685,813 ± 1,145,698; Group 2: HCV patients without xerophthalmia: 35 patients (19 male and 16 female), HCV-RNA 2,614,757 ± 2,820,433. The follow-ups (3 and 6 months after the enrollment) documented an improvement in both eyes' manifestations and HCV-infection (HCV-RNA undetected).

Conclusion: In conclusion, in this study, we reported that xerophthalmia could appear in HCV patients, and DAAs treatment reduces this manifestation without the development of adverse drug reactions.
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http://dx.doi.org/10.2174/2772432816666210903150454DOI Listing
September 2021

Biomarkers in unstable carotid plaque: Physiopathology and Prediction.

Cardiovasc Hematol Agents Med Chem 2021 Sep 1. Epub 2021 Sep 1.

Department of Health Science, School of Medicine, University of Catanzaro, Catanzaro, Italy.

Aims: To study the role of cytokines and vascular inflammatory biomarkers in unstable carotid plaque.

Background: Clinical studies showed that not only the degree of stenosis but also the type of carotid plaque can be responsible for ipsilateral ischemic stroke.

Objective: The objective of this study is to suggest a role for vulnerable carotid atherosclerotic disease in the occurrence of ischemic stroke.

Methods: PubMed, Embase, Cochrane library, and reference lists have been used to evaluate articles published until February 15, 2021.

Results: Several factors may be involved in unstable plaque. Clinical studies support the involvement of brain inflammatory biomarkers as well as cytokines in the unstable carotid plaque.

Conclusions: Biomarkers could help to stratify patients with a vulnerable carotid plaque and to personalize the drug treatment. In this review, we briefly discuss the characteristics of vulnerable plaque and the role of biomarkers in the vulnerable carotid plaque.
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http://dx.doi.org/10.2174/1871525719666210901131509DOI Listing
September 2021

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

Med Pharm Rep 2021 Jul 29;94(3):289-297. Epub 2021 Jul 29.

Department of Health Sciences, University "Magna Græcia" of Catanzaro, Italy.

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.
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http://dx.doi.org/10.15386/mpr-1897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357365PMC
July 2021

Autosomic dominant polycystic kidney disease and metformin: Old knowledge and new insights on retarding progression of chronic kidney disease.

Med Res Rev 2021 Jul 30. Epub 2021 Jul 30.

Department of Health Sciences, Renal Unit, "Magna Graecia" University, Catanzaro, Italy.

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.
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http://dx.doi.org/10.1002/med.21850DOI Listing
July 2021

Data Recorded in Real Life Support the Safety of Nattokinase in Patients with Vascular Diseases.

Nutrients 2021 Jun 13;13(6). Epub 2021 Jun 13.

Department of Health Science, School of Medicine, University of Catanzaro, Clinical Pharmacology and Pharmacovigilance Unit, Mater Domini University Hospital, 88100 Catanzaro, Italy.

Nattokinase (NK) is a serine protease enzyme with fibrinolytic activity. Even if it could be used for the treatment of several diseases, no data have been published supporting its use patients who underwent vascular surgery. In this study, we evaluated both the efficacy and the safety of nattokinase (100 mg/day per os) in patients admitted to vascular surgery. Patients were of both sexes, >18 years of age, with vascular diseases (i.e., deep vein thrombosis, superficial vein thrombosis, venous insufficiency), and naïve to specific pharmacological treatments (anticoagulants or anti-platelets). Patients were divided into three groups. Group 1: patients with deep vein thrombosis, treated with fondaparinux plus nattokinase. Group 2: patients with phlebitis, treated with enoxaparin plus nattokinase. Group 3: patients with venous insufficiency after classical surgery, treated with nattokinase one day later. During the study, we enrolled 153 patients (age 22-92 years), 92 females (60.1%) and 61 males (39.9%;), and documented that nattokinase was able to improve the clinical symptoms ( < 0.01) without the development of adverse drug reactions or drug interactions. Among the enrolled patients, during follow-up, we did not record new cases of vascular diseases. Attention to patients' clinical evolution, monitoring of the INR, and timely and frequent adjustment of dosages represent the cornerstones of the safety of care for patients administered fibrinolytic drugs as a single treatment or in pharmacological combination. Therefore, we can conclude that the use of nattokinase represents an efficient and safe treatment able to both prevent and treat patients with vascular diseases.
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http://dx.doi.org/10.3390/nu13062031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231931PMC
June 2021

Direct Oral Anticoagulants: From Randomized Clinical Trials to Real-World Clinical Practice.

Front Pharmacol 2021 26;12:684638. Epub 2021 May 26.

Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.

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.
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http://dx.doi.org/10.3389/fphar.2021.684638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188985PMC
May 2021

Neuron-specific enolase serum levels in COVID-19 are related to the severity of lung injury.

PLoS One 2021 19;16(5):e0251819. Epub 2021 May 19.

Department of Health Science, School of Medicine, Operative Unit of Clinical Pharmacology, Mater Domini University Hospital, University of Catanzaro, Catanzaro, Italy.

The multifunctional role of neuron-specific enolase (NSE) in lung diseases is well established. As the lungs are greatly affected in COVID-19, we evaluated serum NSE levels in COVID-19 patients with and without dyspnea. In this study, we evaluated both SARS-CoV-2-infected and uninfected patients aged >18 years who were referred to hospitals in Catanzaro, Italy from March 30 to July 30, 2020. Epidemiological, clinical, and radiological characteristics, treatment, and outcome data were recorded and reviewed by a trained team of physicians. In total, 323 patients (178 men, 55.1% and 145 women, 44.9%) were enrolled; of these, 128 were COVID-19 patients (39.6%) and 195 were control patients (60.4%). Westergren's method was used to determine erythroid sedimentation rate. A chemiluminescence assay was used for measurement of interleukin-6, procalcitonin, C-reactive protein, and NSE. We detected significantly higher NSE values (P<0.05) in COVID-19 patients than in controls. Interestingly, within the COVID-19 group, we also observed a further significant increase in dyspnea (Dyspnea Scale and Exercise score: 8.2 ± 0.8; scores ranging from 0 to 10, with higher numbers indicating very severe shortness of breath). These data provide the background for further investigations into the potential role of NSE as a clinical marker of COVID-19 progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251819PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133450PMC
June 2021

Darbepoetin alfa reduces cell death due to radiocontrast media in human renal proximal tubular cells.

Toxicol Rep 2021 31;8:816-821. Epub 2021 Mar 31.

Department of "Health Sciences", Nephrology Unit, "Magna Graecia" University, I-88100, Catanzaro, Italy.

The hypersialylated erythropoiesis stimulating agent (ESA) darbepoetin alfa was developed for the treatment of anemia, and has also been reported to have other nonerythropoietic effects. This study outlines one such effect against the toxicity of the radiocontrast medium (RCM) sodium diatrizoate (NaD) in human renal proximal tubular (HK-2) cells in vitro. Using a standard cell viability assay, we observed that pre-incubation of HK-2 cells with darbepoetin (at concentrations of 0.25and 1.0 μg/mL) for 2.5 h prior to addition of NaD (75 mg I/mL, for 2 h) reduced the decrease in cell viability due to the RCM, assayed 22 h after removal of the NaD, whilst maintaining the cells incubated with darbepoetin. Western blot analysis showed that darbepoetin reduced the phosphorylation of c-Jun N-terminal kinases (JNK)1/2 over a period of 1 h incubation with NaD, but did not have an obvious effect on several other targets associated with cell death/survival. However, incubation of HK-2 cells with darbepoetin for a further 22 h after prior exposure to NaD (75 mg I/mL, for 2 h) and subsequent immunoblotting showed that darbepoetin: caused recovery of the activity (phosphorylation) of pro-proliferative/survival signalling molecules, such as Akt (Ser473), STAT (signal transducer and activator of transcription)3(Tyr705); decreased activation of the pro-apoptotic transcription factor FOXO3a by increasing its phosphorylation at Thr32; decreased phosphorylation (activation) of p38 Mitogen activated protein kinase; and reduced poly(ADP-ribose)polymerase (PARP)-1 cleavage. In summary, we present here a beneficial nonerythropoietic effect of darbepoetin alfa against radiocontrast-induced toxicity together with modulation of signalling molecules that play a crucial role in determining cell fate.
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http://dx.doi.org/10.1016/j.toxrep.2021.03.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044868PMC
March 2021

Assessing knowledge and attitudes toward epilepsy among schoolteachers and students: Implications for inclusion and safety in the educational system.

PLoS One 2021 2;16(4):e0249681. Epub 2021 Apr 2.

Science of Health Department, University Magna Graecia, Catanzaro, Italy.

Several studies have evidenced inadequate knowledge about epilepsy and inappropriate seizure management, influencing quality of life and social inclusion of patients with epilepsy. Aim of the study was to estimate the knowledge and the attitudes toward epilepsy in schoolteachers and students in Italy. Custom-designed and validated questionnaires in Italian on general and specific knowledge, and social impact of epilepsy have been administered in a random sample of schoolteachers and students. Overall, 667 schoolteachers and 672 students have been included. Among teachers and students, consider epilepsy a psychiatric disorder (16.8% and 26.5%) or an incurable disease (43.9% and 33%). The 47.5% of teachers declared to be unable to manage a seizing student, 55.8% thought it requires specific support and 21.6% reported issues in administer antiseizure medications in school. Healthcare professionals should have an active role in the educational system, dispelling myths, preparing educators and students with appropriate attitudes in the event of a seizure and prevent over limitations in patients with epilepsy. These findings highlight still poor knowledge and attitudes about epilepsy among teachers and students although the 99.4% claimed to have heard/read something about epilepsy. Therefore, improving existing dedicated educational/training interventions could be necessary.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249681PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018618PMC
April 2021

Analgesic and Anti-Inflammatory Effects of Perampanel in Acute and Chronic Pain Models in Mice: Interaction With the Cannabinergic System.

Front Pharmacol 2020 1;11:620221. Epub 2021 Feb 1.

Department of Pharmacy, University of Naples Federico II, Naples, Italy.

Pain conditions, such as neuropathic pain (NP) and persistent inflammatory pain are therapeutically difficult to manage. Previous studies have shown the involvement of glutamate receptor in pain modulation and in particular same of these showed the key role of the AMPA ionotropic glutamate receptor subtype. Antiseizure medications (ASMs) are often used to treat this symptom, however the effect of perampanel (PER), an ASM acting as selective, non-competitive inhibitor of the AMPA receptor on the management of pain has not well been investigated yet. Here we tested the potential analgesic and anti-inflammatory effects of PER, in acute and chronic pain models. PER was given orally either in acute (5 mg/kg) or repeated administration (3 mg/kg/d for 4 days). Pain response was assessed using models of nociceptive sensitivity, visceral and inflammatory pain, and mechanical allodynia and hyperalgesia induced by chronic constriction injury to the sciatic nerve. PER significantly reduced pain perception in all behavioral tests as well as CCI-induced mechanical allodynia and hyperalgesia in acute regimen (5 mg/kg). This effect was also observed after repeated treatment using the dose of 3 mg/kg/d. The antinociceptive, antiallodynic and antihyperalgesic effects of PER were attenuated when the CB antagonist AM251 (1 mg/kg/i.p.) was administered before PER treatment, suggesting the involvement of the cannabinergic system. Moreover, analyses showed that PER significantly increased CB receptor expression and reduced inflammatory cytokines (i.e. TNFα, IL-1β, and IL-6) in the spinal cord. In conclusion, these results extend our knowledge on PER antinociceptive and antiallodynic effects and support the involvement of cannabinergic system on its mode of action.
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http://dx.doi.org/10.3389/fphar.2020.620221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883473PMC
February 2021

Blood-brain barrier dysfunction and extension of time window for thrombolysis: a limitation not evaluated.

Curr Vasc Pharmacol 2021 Feb 3. Epub 2021 Feb 3.

University of Catanzaro, Clinical Pharmacology Unit, Mater Domini University Hospital - Chair of Pharmacology, Department of Health Science, School of Medicine, Catanzaro. Italy.

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http://dx.doi.org/10.2174/1570161119666210203144947DOI Listing
February 2021

First evidence of altered microbiota and intestinal damage and their link to absence epilepsy in a genetic animal model, the WAG/Rij rat.

Epilepsia 2021 02 11;62(2):529-541. Epub 2021 Jan 11.

System and Applied [email protected] Magna Grecia ([email protected]) Research Center, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy.

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.
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http://dx.doi.org/10.1111/epi.16813DOI Listing
February 2021

Pain Modulation in WAG/Rij Epileptic Rats (A Genetic Model of Absence Epilepsy): Effects of Biological and Pharmacological Histone Deacetylase Inhibitors.

Front Pharmacol 2020 3;11:549191. Epub 2020 Dec 3.

Department of Pharmacy, University of Naples Federico II, Naples, Italy.

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 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- (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 ( < 0.001). BUT and BUT + VPA treatment reduced hypersensitivity ( < 0.01). VPA was significantly effective only after 1 month ( < 0.01). All the three receptors are involved in BUT + VPA effects ( < 0.001). BUT and BUT + VPA decreased the expression of NFkB and enhanced glutathione reductase ( < 0.01); protein oxidation (carbonylation) was reduced ( < 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.
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http://dx.doi.org/10.3389/fphar.2020.549191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745735PMC
December 2020

Management of status epilepticus in patients with liver or kidney disease: a narrative review.

Expert Rev Neurother 2020 Dec 28:1-14. Epub 2020 Dec 28.

Regional Epilepsy Centre, Great Metropolitan "Bianchi-Melacrino-Morelli" Hospital, Reggio, Italy.

: 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.: 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.: 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.
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http://dx.doi.org/10.1080/14737175.2021.1862649DOI Listing
December 2020

The risk of polypharmacy and potentially inappropriate drugs in residential care dementia patients: tips from the PharE study.

Aging Clin Exp Res 2021 Jul 23;33(7):1909-1917. Epub 2020 Nov 23.

Chair of Pharmacology, School of Medicine, University Magna Graecia, Catanzaro, Italy.

Aims: The aims of the present study, conducted in two regions of Italy, Calabria and Piedmont, were to assess the use of inappropriate drugs according to the Beers Criteria and to study the possible drug-drug interactions.

Methods: Data were obtained retrospectively from 972 residential care patients between 2016 and 2018. Mean age was 82.4 ± 8.4 years, with a prevalence of women (64.8%). Activities of daily living, instrumental activities of daily living, Mini-Mental State Examination, Cumulative Illness Rating Scale, Neuropsychiatric Inventory Scale and number and kind of drugs were recorded. A classification of potential inappropriate drugs was made according to the Beers criteria. Data were collected through an Excel file able to gather the main information. In the case of suspected adverse event, Naranjo Scale was applied. The study of possible drug-drug interactions was made by Micromedex 2.0.

Results: Functional and cognitive impairments, comorbidities and number of drugs were assessed. The bivariate relationship between number of drugs and glomerular filtration rate assessed by CKD-EPI showed that the higher was the number of drugs used, the worst was kidney function assessment (p = 0.0001). The most frequent inappropriate drugs were anticholinergic drugs, tricyclics antidepressants, long-half-life benzodiazepines, antipsychotics and proton pump inhibitors.

Conclusions: These data are very interesting and show the need for an accurate choice of drugs in elderly people and for starting a wise deprescribing procedure.
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http://dx.doi.org/10.1007/s40520-020-01719-5DOI Listing
July 2021

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

PLoS One 2020 3;15(11):e0241575. Epub 2020 Nov 3.

Science of Health Department, School of Medicine, University Magna Graecia, Catanzaro, Italy.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241575PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608898PMC
December 2020

HDL (High-Density Lipoprotein) and ApoA-1 (Apolipoprotein A-1) Potentially Modulate Pancreatic α-Cell Glucagon Secretion.

Arterioscler Thromb Vasc Biol 2020 12 22;40(12):2941-2952. Epub 2020 Oct 22.

Department of Clinical and Molecular Medicine, University of Rome-Sapienza, Italy (G.S.).

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 (=-0.422, <0.0001) between HDL levels and fasting glucagon in a cohort of 132 Italian subjects. In a multivariable regression analysis including potential confounders such as age, sex, BMI, triglycerides, total cholesterol, fasting and 2-hour postload glucose, and fasting insulin, the association between HDL and fasting glucagon remained statistically significant (β=-0.318, =0.006). CD1 mice treated with HDL or ApoA-1 for 3 consecutive days showed a 32% (<0.001) and 23% (<0.05) reduction, respectively, in glucagon levels following insulin-induced hypoglycemia, compared with controls. Treatment of pancreatic αTC1 clone 6 cells with HDL or ApoA-1 for 24 hours resulted in a significant reduction of glucagon expression (<0.04) and secretion (<0.01) after an hypoglycemic stimulus and increased Akt (RAC-alpha serine/threonine-protein kinase) and FoxO1 (forkhead/winged helix box gene, group O-1) phosphorylation. Pretreatment with Akt inhibitor VIII, PI3K (phosphatidylinositol 3-kinase) inhibitor LY294002, and HDL receptor SCARB-1 (scavenger receptor class B type 1) inhibitor BLT-1 (block lipid transport-1) restored αTC1 cell response to low glucose levels.

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.
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http://dx.doi.org/10.1161/ATVBAHA.120.314640DOI Listing
December 2020

Treatment patterns, health resource consumption, and costs of patients with migraine in an Italian real-world setting.

Curr Med Res Opin 2020 12 26;36(12):1991-1998. Epub 2020 Oct 26.

CliCon Srl Health, Economics & Outcomes Research, Ravenna, Italy.

Objective: This study aimed to describe the demographic and clinical characteristics of migraineurs prescribed ≥1 migraine prophylactic therapy, and to analyze their therapeutic pathways, healthcare resource consumption, and related costs.

Methods: This retrospective analysis was based on administrative databases from two regions and three local health units in Italy. Adult patients with ≥1 discharge diagnosis for migraine or ≥1 prescription for migraine-specific drugs, or ≥1 emergency room visit for migraine from 1 January 2010 to 31 December 2016 were included if they had received ≥1 migraine prophylactic therapy between 1 January 2011 and 31 December 2015 (enrollment period). The first date of the last migraine prophylactic treatment was considered as the index date (ID). Patients were characterized 1-year prior ID and followed-up for 1 year afterwards.

Results: Of the 166,362 identified migraineurs, 32,794 (mean age: 45.9 ± 13.9 years, 19.2% male) who received migraine prophylaxis were included in the analysis. At ID, 31,629 patients had received 1 prophylactic treatment with antidepressants (51.2%), neuromodulators (28.1%), beta blockers (12.4%), other migraine preparations (7.8%), and botulinum toxin A (0.5%). Focusing on patients with one prophylactic treatment at ID, 85.4% did not have any previous therapeutic failures whereas 14.6% had ≥1 previous failure. During follow-up, 5% of patients made a therapeutic switch after a mean period of 103.4 ± 97.9 days. Total mean annual cost for patients receiving migraine prophylaxis was 1193.64€ during characterization and 1303.86€ during follow-up periods.

Conclusion: This real-world study gave insights on the characterization of migraineurs and patterns of prophylaxis utilization in Italian clinical settings, showing an underuse of prophylactic agents.
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http://dx.doi.org/10.1080/03007995.2020.1835850DOI Listing
December 2020

The Art of Safe and Judicious Deprescribing in an Elderly Patient: A Case Report.

Geriatrics (Basel) 2020 Sep 21;5(3). Epub 2020 Sep 21.

Department of Health Science, School of Medicine, University "Magna Graecia" Catanzaro, 88100 Catanzaro, Italy.

Prescription for inappropriate drugs can be dangerous to the elderly due to the increased risk of adverse drug reactions and drug-interactions. In this manuscript, we report the complexity of polypharmacy and the possible harmful consequences in an old person. An 81-year-old man with a clinical history of diabetes, blood hypertension, non-valvular atrial fibrillation, chronic obstructive pulmonary disease, osteoarthritis, anxiety, and depression, was admitted to our attention for cognitive disorders and dementia. Brain magnetic resonance imaging showed parenchymal atrophy with lacunar state involving thalami and internal capsules. Neuropsychological tests revealed cognitive impairment and a depressed mood. History revealed that he was taking 11 different drug severy day with a potential risk of 55 drug-drug interactions. Therefore, risperidone, chlorpromazine, -demethyl-diazepam, and L-DOPA/carbidopa were gradually discontinued and citicoline (1g/day), cholecalciferol (50,000 IU once a week), and escitalopram (5 mg/day) were started. Furthermore, he started a program of home rehabilitation. During the follow-up, three months later, we recorded an improvement in both mood and cognitive tests, as well as in walking ability. The present case report shows the need for a wise prescription and deprescribing in older people.
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http://dx.doi.org/10.3390/geriatrics5030057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554853PMC
September 2020

Contribution of Predictive and Prognostic Biomarkers to Clinical Research on Chronic Kidney Disease.

Int J Mol Sci 2020 Aug 14;21(16). Epub 2020 Aug 14.

Renal Unit, Department of Health Sciences, "Magna Graecia" University of Catanzaro, I-88100 Catanzaro, Italy.

Chronic kidney disease (CKD), defined as the presence of albuminuria and/or reduction in estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m, is considered a growing public health problem, with its prevalence and incidence having almost doubled in the past three decades. The implementation of novel biomarkers in clinical practice is crucial, since it could allow earlier diagnosis and lead to an improvement in CKD outcomes. Nevertheless, a clear guidance on how to develop biomarkers in the setting of CKD is not yet available. The aim of this review is to report the framework for implementing biomarkers in observational and intervention studies. Biomarkers are classified as either prognostic or predictive; the first type is used to identify the likelihood of a patient to develop an endpoint regardless of treatment, whereas the second type is used to determine whether the patient is likely to benefit from a specific treatment. Many single assays and complex biomarkers were shown to improve the prediction of cardiovascular and kidney outcomes in CKD patients on top of the traditional risk factors. Biomarkers were also shown to improve clinical trial designs. Understanding the correct ways to validate and implement novel biomarkers in CKD will help to mitigate the global burden of CKD and to improve the individual prognosis of these high-risk patients.
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http://dx.doi.org/10.3390/ijms21165846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461617PMC
August 2020

Cathepsin-K is a potential cardiovascular risk biomarker in prevalent hemodialysis patients.

Int Urol Nephrol 2021 Jan 13;53(1):171-175. Epub 2020 Aug 13.

Renal Unit, "Magna Graecia" University, Campus Salvatore Venuta, Viale Europa, Catanzaro, 88100, Italy.

Purpose: 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.

Methods: 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.

Results: 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).

Conclusions: 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.
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http://dx.doi.org/10.1007/s11255-020-02602-yDOI Listing
January 2021

Metabolic Alterations Predispose to Seizure Development in High-Fat Diet-Treated Mice: the Role of Metformin.

Mol Neurobiol 2020 Nov 12;57(11):4778-4789. Epub 2020 Aug 12.

Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, Viale Europa e Germaneto, 88100, Catanzaro, Italy.

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.
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http://dx.doi.org/10.1007/s12035-020-02062-6DOI Listing
November 2020

Pharmacokinetic considerations about antiseizure medications in the elderly.

Expert Opin Drug Metab Toxicol 2020 Oct 25;16(10):983-995. Epub 2020 Sep 25.

Science of Health Department, School of Medicine, University of Catanzaro, Italy.

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.
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http://dx.doi.org/10.1080/17425255.2020.1806236DOI Listing
October 2020

Pharmaco-utilization of biologic drugs in patients affected by psoriasis, psoriatic arthritis and ankylosing spondylitis in an Italian real-world setting.

Expert Rev Pharmacoecon Outcomes Res 2020 Oct 23;20(5):491-497. Epub 2020 Aug 23.

CliCon S.r.l., Health, Economics & Outcomes Research , Ravenna, Italy.

Background: As primary aim the study evaluated the monthly average dose for biologic drugs used for psoriasis (PSO), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) in real-world settings.

Methods: This retrospective analysis was based on administrative databases of Italian Entities. Adult patients diagnosed PSO, PsA or AS with ≥1 prescription of biologic drugs indicated for these diseases were included during 01/01/2011 - 30/06/2017. Monthly average dose and persistence were evaluated during 6-months after inclusion (follow-up).

Results: Overall, 6,179 patients prescribed biologic drugs were included: 2,373 represented the 1.1% of PSO-patients, 2,756 the 37.4% of PsA-patients, 1,050 the 17.8% of AS-patients. Monthly average dose was: 69 mg (PSO), 73 mg (PsA), 70 mg (AS) for adalimumab; 152 mg (PSO), 155 mg (PsA), 147 mg (AS) for etanercept; 140 mg (PSO), 133 mg (PsA), 166 mg (AS) for infliximab; 255 mg (PSO), 183 mg (PsA), 154 mg (AS) for secukinumab. Persistance to adalimumab was 76%(PSO), 78%(PsA), 74%(AS); with etanercept 77% in each disease-cohort; with infliximab 67%(PSO), 71%(PsA), 88%(AS); with secukinumab 91%(PSO) and 85%(PsA).

Conclusion: The study described real-world dosing patterns of biologics indicated for PSO, PsA, or AS, suggesting a trend of monthly average dose generally lower than the dosage indicated in the datasheet.
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http://dx.doi.org/10.1080/14737167.2020.1800456DOI Listing
October 2020

IL-6 Receptor Blockade by Tocilizumab Has Anti-absence and Anti-epileptogenic Effects in the WAG/Rij Rat Model of Absence Epilepsy.

Neurotherapeutics 2020 10;17(4):2004-2014

Science of Health Department, School of Medicine and Surgery, Magna Græcia University of Catanzaro, Viale Europa - Germaneto, 88100, Catanzaro, Italy.

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.
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http://dx.doi.org/10.1007/s13311-020-00893-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851197PMC
October 2020

Increased circulating Cathepsin-K levels reflect PTH control in chronic hemodialysis patients.

J Nephrol 2021 Apr 12;34(2):451-458. Epub 2020 Jul 12.

Department of Medical and Surgical Sciences-Renal Unit, "Magna Graecia" University, Campus Salvatore Venuta, Viale Europa, 88100, Catanzaro, Italy.

Background: 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.

Methods: 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.

Results: Cathepsin-K levels were significantly higher in HD patients than in healthy controls (p < 0.0001) and were independently associated with alkaline phosphatase (β = 0.37; p < 0.001), PTH (β = 0.30; p = 0.02) and C-reactive protein (β = 0.24; p = 0.008) levels. Cathepsin-K was also higher in patients with off-target PTH as compared to those with controlled PTH levels (230 [40-420] vs. 3250 [820-4205] pg/mL; p < 0.0001). At ROC analyses, Cathepsin-K levels were able to identify off-target PTH and parathyroidectomized patients (AUCs 0.85 [95% CI 0.71-0.98] and 0.97 [95% CI 0.92-0.99], respectively).

Conclusion: In chronic HD patients, Cathepsin-K associates with PTH levels, raising the intriguing hypothesis that this protein represents a causal link between mineral and inflammatory complications and could be tested as a candidate biomarker of MBD severity and PTH balance.
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http://dx.doi.org/10.1007/s40620-020-00801-5DOI Listing
April 2021

Histopathological findings in a COVID-19 patient affected by ischemic gangrenous cholecystitis.

World J Emerg Surg 2020 07 2;15(1):43. Epub 2020 Jul 2.

Digestive Surgery Unit, Department of Science of Health, "Magna Graecia" University, Catanzaro, Italy.

Background: Since its first documentation, a novel coronavirus (SARS-CoV-2) infection has emerged worldwide, with the consequent declaration of a pandemic disease (COVID-19). Severe forms of acute respiratory failure can develop. In addition, SARS-CoV-2 may affect organs other than the lung, such as the liver, with frequent onset of late cholestasis. We here report the histological findings of a COVID-19 patient, affected by a tardive complication of acute ischemic and gangrenous cholecystitis with a perforated and relaxed gallbladder needing urgent surgery.

Case Presentation: A 59-year-old Caucasian male, affected by acute respiratory failure secondary to SARS-CoV-2 infection was admitted to our intensive care unit (ICU). Due to the severity of the disease, invasive mechanical ventilation was instituted and SARS-CoV-2 treatment (azithromycin 250 mg once-daily and hydroxychloroquine 200 mg trice-daily) started. Enoxaparin 8000 IU twice-daily was also administered subcutaneously. At day 8 of ICU admission, the clinical condition improved and patient was extubated. At day 32, patient revealed abdominal pain without signs of peritonism at examination, with increased inflammatory and cholestasis indexes at blood tests. At a first abdominal CT scan, perihepatic effusion and a relaxed gallbladder with dense content were detected. The surgeon decided to wait and see the evolution of clinical conditions. The day after, conditions further worsened and a laparotomic cholecystectomy was performed. A relaxed and perforated ischemic gangrenous gallbladder, with a local tissue inflammation and perihepatic fluid, was intraoperatively met. The gallbladder and a sample of omentum, adherent to the gallbladder, were also sent for histological examination. Hematoxylin-eosin-stained slides display inflammatory infiltration and endoluminal obliteration of vessels, with wall breakthrough, hemorrhagic infarction, and nerve hypertrophy of the gallbladder. The mucosa of the gallbladder appears also atrophic. Omentum vessels also appear largely thrombosed. Immunohistochemistry demonstrates an endothelial overexpression of medium-size vessels (anti-CD31), while not in micro-vessels, with a remarkable activity of macrophages (anti-CD68) and T helper lymphocytes (anti-CD4) against gallbladder vessels. All these findings define a histological diagnosis of vasculitis of the gallbladder.

Conclusions: Ischemic gangrenous cholecystitis can be a tardive complication of COVID-19, and it is characterized by a dysregulated host inflammatory response and thrombosis of medium-size vessels.
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http://dx.doi.org/10.1186/s13017-020-00320-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330255PMC
July 2020

Does screening for adverse effects improve health outcomes in epilepsy? A randomized trial.

Neurology 2020 07 29;95(3):e239-e246. Epub 2020 Jun 29.

From the Clinical Pharmacology Unit (V.F., G.G., E.P.), University of Pavia; IRCCS Mondino Foundation (V.F., C.F., C.A.G., E.P.), Pavia; Epilepsy Center (M.P.C.), San Paolo Hospital, Milan; Magna Graecia University (G.D.S.), Catanzaro; School of Hospital Pharmacy (G.F.), University of Milan; Epilepsy Center (A.L.N.), Neurology Hospital "Amaducci," University of Bari; Unit of Neurology (E.R.), Usl Centro Toscana Health Authority, Prato; University of Foggia (L.M.S.); Epilepsy Center (S.S.), Federico II University, Naples; and IRCCS (P.T.), Institute of Neurological Sciences of Bologna and Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.

Objective: To determine whether systematic screening for adverse effects of antiepileptic drugs (AEDs) reduces toxicity burden and improves health-related quality of life in patients with epilepsy.

Methods: Consecutive patients with uncontrolled seizures aged ≥16 years and a high Adverse Event Profile (AEP) score were randomized to 2 groups and followed up for 18 months at 11 referral centers. AEP scores were made available to treating physicians at all visits in the intervention group, but not in the control group. Co-primary endpoints were changes in AEP scores and Quality of Life Inventory for Epilepsy-31 (QOLIE-31) scores.

Results: Of 809 enrolled patients able to complete the AEP questionnaire, 222 had AEP scores ≥45 and were randomized to the intervention (n = 111) or control group (n = 111). A total of 206 patients completed the 18-month follow-up. Compared with baseline, AEP scores decreased on average by 7.2% at 6 months, 12.1% at 12 months, and 13.8% at 18 months in the intervention group ( < 0.0001), and by 7.7% at 6 months, 9.2% at 12 months, and 12.0% at 18 months in controls ( < 0.0001). QOLIE-31 scores also improved from baseline to final visit, with a mean 20.7% increase in the intervention group and a mean 24.9% increase in the control group ( < 0.0001). However, there were no statistically significant differences in outcomes between groups for the 2 co-primary variables.

Conclusions: Contrary to findings from a previous study, systematic screening for adverse effects of AEDs using AEP scores did not lead to a reduced burden of toxicity over usual physician treatment.

Italian Medicines Agency Aifa Identifier: FARM52K2WM_003.

Clinicaltrialsgov Identifier: NCT03939507 (registered retrospectively in 2019; the study was conducted during the 2006-2009 period and registration of clinical trials was not a widely established practice when this study was initiated).

Classification Of Evidence: This study provides Class II evidence that the additional collection of formal questionnaires regarding adverse effects of AEDs does not reduce toxicity burden over usual physician treatment.
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http://dx.doi.org/10.1212/WNL.0000000000009880DOI Listing
July 2020

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

Curr Med Res Opin 2020 09 27;36(9):1457-1463. Epub 2020 Jul 27.

Science of Health Department, School of Medicine, University of Catanzaro, Catanzaro, 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;  = .88), IFX (51/308;  = .54), ADA (28/125;  = .40) and VED (6/73;  = .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.
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http://dx.doi.org/10.1080/03007995.2020.1786681DOI Listing
September 2020
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