Fernanda S. Tonin

Neuroprotective effects of peroxisome proliferator-activated receptor alpha and gamma agonists in model of parkinsonism induced by intranigral 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine.

A large body of evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists may improve some of the pathological features of Parkinsons disease (PD). In the present study, we evaluated the effects of the PPAR-α agonist fenofibrate (100mg/kg) and PPAR-γ agonist pioglitazone (30mg/kg) in a rat model of parkinsonism induced by intranigral 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP). Male Wistar rats were pretreated with both drugs for 5 days and received an infusion of MPTP. The experiments were divided into two parts. First, 1, 7, 14, and 21 days after surgery, the animals were submitted to the open field test. On days 21 and 22, the rats were subjected to the forced swim test and two-way active avoidance task. In the second part of the study, 24h after neurotoxin administration, immunohistochemistry was performed to assess tyrosine hydroxylase activity. The levels of dopamine and its metabolites in the striatum were determined using high-performance liquid chromatography, and fluorescence detection was used to assess caspase-3 activation in the substantia nigra pars compacta (SNpc). Both fenofibrate as pioglitazone protected against hypolocomotion, depressive-like behavior, impairment of learning and memory, and dopaminergic neurodegeneration caused by MPTP, with dopaminergic neuron loss of approximately 33%. Fenofibrate and pioglitazone also protected against the increased activation of caspase-3, an effector enzyme of the apoptosis cascade that is considered one of the pathological features of PD. Thus, PPAR agonists may contribute to therapeutic strategies in PD.

PPAR-α agonist fenofibrate protects against the damaging effects of MPTP in a rat model of Parkinson's disease

Parkinsons disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The etiology and pathogenesis of PD are still unknown, however, many evidences suggest a prominent role of oxidative stress, inflammation, apoptosis, mitochondrial dysfunction and proteosomal dysfunction. The peroxisome proliferator-activated receptor (PPAR) ligands, a member of the nuclear receptor family, have anti-inflammatory activity over a variety of rodents models for acute and chronic inflammation. PPAR-α agonists, a subtype of the PPAR receptors, such as fenofibrate, have been shown a major role in the regulation of inflammatory processes. Animal models of PD have shown that neuroinflammation is one of the most important mechanisms involved in dopaminergic cell death. In addition, anti-inflammatory drugs are able to attenuate toxin-induced parkinsonism. In this study we evaluated the effects of oral administration of fenofibrate 100mg/kg 1h after infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the SNpc. First, we assessed the motor behavior in the open field for 24h, 7, 14 and 21 days after MPTP. Twenty-two days after surgery, the animals were tested for two-way active avoidance and forced swimming for evaluation regarding cognitive and depressive parameters, respectively. Twenty-three days after infusion of the toxin, we quantified DA and turnover and evaluated oxidative stress through the measurement of GSH (glutathione peroxidase), SOD (superoxide dismutase) and LOOH (hydroperoxide lipid). The data show that fenofibrate was able to decrease hypolocomotion caused by MPTP 24h after injury, depressive-like behavior 22 days after the toxin infusion, and also protected against decreased level of DA and excessive production of reactive oxygen species (ROS) 23 days after surgery. Thus, fenofibrate has shown a neuroprotective effect in the MPTP model of Parkinsons disease.

Safety of interferon-free therapies for chronic hepatitis C: a network meta-analysis

Interferon‐free (IFN‐free) therapies for hepatitis C virus (HCV) have been developed to provide more effective, tolerable and safer therapeutic strategies. To date, no network meta‐analysis (NMA) evaluating the safety profile of these regimens has been performed. This systematic review and NMA aimed to evaluate safety outcomes of IFN‐free treatment options for chronic hepatitis C.

The nonsteroidal antiinflammatory drug piroxicam reverses the onset of depressive-like behavior in 6-OHDA animal model of Parkinson’s disease

Depression is one of the most common psychiatric symptoms in patients with Parkinsons disease (PD). Some authors have reported that depression is characterized by activation of the inflammatory response. Animal models of PD also present with depressive-like behavior, such as increased immobility time in the modified forced swim test and anhedonia-like behavior in the sucrose preference test. Considering the potential neuroprotective effect of nonsteroidal antiinflammatory drugs in neurodegenerative diseases, the objective of the present study was to investigate the effects of piroxicam on depressive-like behavior in male Wistar rats lesioned with 6-hydroxydopamine (6-OHDA) in the substantia nigra (SN). Antidepressant-like effects were observed after prolonged administration of piroxicam for 21days. In the forced swim test, the 6-OHDA+saline group exhibited significant reductions in swimming time and increased immobility time compared with the sham+saline. In the sucrose preference test, the 6-OHDA+piroxicam group exhibited no reduction of sucrose preference compared with the sham+saline, with significant effects of treatment and time and a significant treatment×time interaction. 5-Hydroxytryptamine (5-HT) levels significantly decreased in the hippocampus in the 6-OHDA+saline group and not changed in the 6-OHDA+piroxicam group when compared with the sham+saline on day 21. In conclusion, 21-day treatment with piroxicam reversed the onset of depressive-like behavior and prevented the reduction of hippocampal 5-HT levels.

Efficacy and safety of amphotericin B lipid‐based formulations—A systematic review and meta‐analysis

Invasive fungal infections, an important cause of mortality, are primarily treated using amphotericin B, which is available in different formulations, both conventional and lipid‐based (liposomal, lipid complex, colloidal dispersion and Intralipid® infusion). The aim of our study was to determine the efficacy and safety of conventional amphotericin B vs its lipid‐based formulations. A systematic review followed by pairwise meta‐analysis was performed, including randomised controlled trials (RCTs) that evaluated the use of lipid‐based amphotericin B in patients with any degree of immunosuppression and susceptibility to invasive fungal infection. An electronic search was conducted using PubMed, Scopus, Web of Science and Scielo databases. Extracted outcomes were related to efficacy (cure) and safety (incidence of adverse events). Results were evaluated and meta‐analyses were performed. Twenty‐three RCTs were identified (n=2677 participants) for meta‐analysis. No significant differences between conventional amphotericin B and any of the five formulations evaluated were observed, with regard to the efficacy analysis. With respect to the adverse events of nephrotoxicity, fever, chills and vomiting, all lipid formulations presented better profiles than the conventional formulation. The present systematic review and meta‐analysis showed that conventional amphotericin B presents the same efficacy profile as lipid‐based formulations, although the latter were associated with a safer profile.

Impact of Natural Juice Consumption on Plasma Antioxidant Status: A Systematic Review and Meta-Analysis

Background: Oxidative stress may lead to overproduction of reactive species and a decrease in antioxidant defenses, resulting in chronic diseases such as diabetes and cancer. The consumption of natural compounds with an antioxidant profile may be a preventive alternative. Therefore, we aimed to obtain evidence regarding the potential antioxidant activity of juices in human plasma. Methods: A systematic review and meta-analysis was performed, which included randomized controlled trials that compared the use of fruit or vegetable juices vs. placebo or other beverages. An electronic search was conducted in PubMed, Scopus, International Pharmaceutical Abstracts, and SciELO. The outcome measures extracted were related to antioxidant status, e.g., vitamin C, superoxide dismutase (SOD), and catalase (CAT) levels and reduction in malondialdehyde (MDA) and antioxidant capacity measured as TEAC. Results: Twenty-eight trials were identified (n = 1089), of which 16 were used for meta-analysis. No significant differences were observed between juices and placebo with regard to TEAC, SOD, and CAT. However, juices were superior to control in enhancing vitamin C and reducing MDA. Conclusions: Natural juices are possible candidates for the management of oxidative stress. The effects of juices should be further investigated by conducting larger and well-defined trials of longer duration.

Ledipasvir/sofosbuvir with or without ribavirin for the treatment of chronic hepatitis C genotype 1: a pairwise meta-analysis

Ledipasvir with sofosbuvir (LED/SOF) for the treatment of patients infected with genotype 1 hepatitis C virus can be used with or without ribavirin (RBV). RBV is well known to promote significant adverse events (AE). The aim of this study was to compare the efficacy and safety of treatment with LED/SOF, with or without RBV, in patients infected with hepatitis C virus genotype 1.

Rapid virological response of telaprevir and boceprevir in a Brazilian cohort of HCV genotype 1 patients: a multicenter longitudinal study.

Background Chronic hepatitis C is a major public health issue, but there is a gap in the literature regarding the effectiveness and safety of direct-acting antiviral agents in the Brazilian population. The main aim of this study was to describe the effectiveness of boceprevir and telaprevir in patients treated at public health care institutions in Brazil. Materials and methods A prospective longitudinal and multicenter study was conducted in five centers in the State of Paraná between September 2014 and June 2016. Data regarding effectiveness and safety were collected from medical records of patients treated with boceprevir or telaprevir. The effectiveness outcome comprised the rapid virological response (RVR). Multivariate analysis was performed to verify the influence of independent variables (ie, age, gender, baseline viral load) on RVR achievement. Results Data were collected from 117 patients with chronic hepatitis C virus (HCV) genotype 1 infection. Fifteen patients received treatment with boceprevir and 102 received telaprevir. The mean age was 51.6 years, 64.1% were male, 44.4% were infected with HCV subtype 1a, 62.4% had a high baseline viral load (≥800,000 IU/mL) and 33% were cirrhotic. Furthermore, 79.5% of patients achieved RVR (26.7% in the boceprevir group and 87.3% in the telaprevir group). Multivariate analysis demonstrated that the type of protease inhibitor (boceprevir or telaprevir) and the baseline viral load had an influence on the RVR rate (odds ratio [OR] =0.011; 95% confidence interval [CI]: 0.001–0.119; P<0.001/OR =13.004; 95% CI: 1.522–111.115; P=0.019, respectively). Conclusion In this longitudinal multicenter cohort study conducted from the Brazilian perspective, differences were found in the RVR rates, favoring telaprevir over boceprevir for genotype 1 HCV-infected patients. In addition, the baseline viral load was associated with RVR achievement in both evaluated groups. As RVR is also reported in the literature as a predictor of the sustained virological response (SVR), further analyses of RVR as predictor of SVR outcomes should be further evaluated in Brazil.

Efficacy and safety of amphotericin B formulations: a network meta-analysis and a multicriteria decision analysis.

Despite its broad spectrum, conventional amphotericin B (AB) is associated with serious adverse events. Lipid‐based formulations may offer safer options. We aimed to synthesize the evidence of efficacy and safety of AB formulations.

A network meta-analysis of primary prophylaxis for invasive fungal infection in haematological patients

Antifungal prophylaxis is an option to reduce the incidence of invasive fungal infection (IFI) in haematological patients. To date, no network meta‐analysis (NMA) of high‐quality evidence (double‐blind randomized controlled trials) has been performed on this subject. This systematic review and NMA aimed to evaluate the safety and efficacy of different antifungal agents used for prophylaxis of IFI in patients with haematological disorders.