196 research outputs found
Dopaminergic system modulation, behavioral changes, and oxidative stress after neonatal administration of pyrethroids
Pyrethroids are a class of insecticides involved in different neurological disorders. They cross the blood–brain barrier and exert
their effect on dopaminergic system, contributing to the burden of oxidative stress in Parkinson’s disease through several pathways.
The aim of the present study was to evaluate the effect of neonatal exposition to permethrin and cypermethrin (1/10 of DL50) in rats
from the eighth to the fifteenth day of life. Open-field studies showed increased spontaneous locomotor activity in the groups treated
with permethrin and the one treated with cypermethrin, while a higher number of center entries and time spent in the center was
observed for the cypermethrin-treated group. Lower dopamine and higher homovanillic acid levels were measured in the striatum
from both treated groups. A reduction of blood glutathione peroxidase content was measured, while no change in blood superoxide
dismutase was observed. Carbonyl group formation increased in striatum, but not in erythrocytes. Lipid peroxidation occurred in
erythrocytes, but not in striatum. No changes in fluidity at different depths of plasma membrane were measured in striatum or
erythrocytes. The activation of monocyte NADPH oxidase by phorbol esters (PMA) shows that superoxide anion production was
reduced in the pyrethroid-treated groups compared to the control group. Our studies suggest that neonatal exposition to permethrin or
cypermethrin induces long-lasting effects after developmental exposure giving changes in open-field behaviors, striatal monoamine
level, and increased oxidative stress. Although the action of pyrethroids on various target cells is different, a preferential interaction
with the extracellular side of plasma membrane proteins can be observed
Event Detection in Optical Signals via Domain Adaptation
Data-driven models trained in an end-to-end manner can reliably detect events within optical signals. Unfortunately, event detection models poorly generalize when monitoring signals collected from devices with different acquisition procedures. We overcome this limitation by presenting a novel domain adaptation solution for event detection networks that enables inference across multiple types of devices. Rather than training a black-box detection network, we decouple event localization and classification tasks. Localization is performed by the Interval Proposal Algorithm (IPA), which leverages signal processing techniques to localize candidate events and derive context features. These events are then standardized and fed to a feature extractor to obtain morphological features. By combining domain-specific context features with domain-invariant morphological features, the classifier achieves good generalization capabilities through different domains. Our method can successfully detect events in OTDR traces achieving a [email protected] of 75.33% on traces from the source domain and generalizing well ([email protected] of 69.27%) on traces from the target domain, despite being trained solely from the source domain
Population pharmacokinetics and pharmacodynamic target attainment of isavuconazole against aspergillus fumigatus and aspergillus flavus in adult patients with invasive fungal diseases: Should therapeutic drug monitoring for isavuconazole be considered as mandatory as for the other mold-active azoles?
Isavuconazole is a newer broad-spectrum triazole approved for the treatment of invasive fungal disease. The objective of this study was to conduct a population pharmacokinetic and pharma-codynamic analysis of isavuconazole in a retrospective cohort of hospitalized patients. A nonlinear mixed-effect approach with Monte Carlo simulations was conducted to assess the probability of target attainment (PTA) of an area under the concentration–time curve (AUC24 h )/minimum inhibitory concentration (MIC) ratio of 33.4 (defined as efficacy threshold against A. fumigatus and A. flavus) associated with a maintenance dose (MD) of 100, 200 and 300 mg daily after loading. The cumulative fraction of response (CFR) against the EUCAST MIC distributions of A. fumigatus and A. flavus was calculated as well. The proportion of trough concentrations (Ctrough ) exceeding a defined threshold of toxicity (>5.13 mg/L) was estimated. A total of 50 patients, with a median age of 61.5 years, pro-vided 199 plasma isavuconazole concentrations. Invasive pulmonary aspergillosis was the prevalent type of infection and accounted for 80% (40/50) of cases. No clinical covariates were retained by the model. With the standard MD of 200 mg daily, CFRs were always ≥90% during the first two months of treatment. The risk of Ctrough < 1.0 mg/L was around 1%, and that of Ctrough > 5.13 mg/L was 27.7 and 39.2% at 28 and 60 days, respectively, due to isavuconazole accumulation over time. Our findings suggest that TDM for isavuconazole should not be considered as mandatory as for the other mold-active azoles voriconazole and posaconazole
Ibuprofen and Lipoic Acid Diamide as Co-Drug with Neuroprotective Activity: Pharmacological Properties and Effects in β-Amyloid (1–40) Infused Alzheimer's Disease Rat Model
Both oxidative stress and inflammation are elevated in brains of Alzheimer's disease patients, but their pathogenic significance still remains unclear. Current evidence support the hypothesis that non-steroidal anti-inflammatory drugs (NSAIDs) and antioxidant therapy might protect against the development of Alzheimer's disease, and ibuprofen has the strongest epidemiological support. In the present work our attention was focused on (R)-α-lipoic acid considered as a potential neuroprotective agent in Alzheimer's disease therapy. In particular, we investigated a new co-drug (1) obtained by joining (R)-α-lipoic acid and ibuprofen via a diamide bond, for evaluating its potential to antagonize the deleterious structural and cognitive effects of β-amyloid (1–40) in an infused Alzheimer's disease rat model. Our results indicated that infusion of β-amyloid (1–40) impairs memory performance through a progressive cognitive deterioration; however, ibuprofen and co-drug 1 seemed to protect against behavioural detriment induced by simultaneous administration of β-amyloid (1–40) protein. The obtained data were supported by the histochemical findings of the present study: β-amyloid protein was less expressed in 1-treated than in ibuprofen and (R)-α-lipoic acid alone-treated cerebral cortex. Taken together, the present findings suggest that co-drug 1 treatment may protect against the cognitive dysfunction induced by intracerebroventricular infusion of β-amyloid (1–40) in rats. Thus, co-drug 1 could prove useful as a tool for controlling Alzheimer's disease-induced cerebral amyloid deposits and behavioural deterioration
Correlates of hepatic stiffness by FibroScan© in a multicentric Italian cohort of HIV-infected patients
Rapid and persistent selection of the K103N mutation as a majority quasispecies in a HIV1-patient exposed to efavirenz for three weeks: a case report and review of the literature
<p>Abstract</p> <p>Introduction</p> <p>Selection of the K103N mutation is associated with moderately reduced in vitro fitness of HIV. Strains bearing K103N in vivo tend to persist, even in the absence of additional drug pressure, as minority quasispecies, often undetectable in genotyping resistance testing assays, performed at standard conditions. Here, we report on the rapid and long lasting selection of a K103N bearing strain as the dominant quasispecies after very short exposure to efavirenz in vivo.</p> <p>Case presentation</p> <p>A 55-year-old Caucasian man was switched to efavirenz, zidovudine and lamivudine in February 2003, while on viral suppression in his first-line highly active anti-retroviral treatment regimen. One month later, he reported inconsistent adherence and his viremia level was 5700 c/mL. He did not attend further checkups until September 2005, when his viral load was 181,000 c/mL. The patient reported interrupting his medications approximately three weeks after simplification. The genotyping resistance testing assay was performed both on HIV RNA and HIV DNA from plasma, yielding an identical pattern with the isolate presence of the K103N mutation in the prevalent strain.</p> <p>Conclusion</p> <p>Persistence of the K103N mutation as a majority quasispecies may ensue after a very short exposure to efavirenz. Our case would therefore suggest that the presence of the K103N mutation should always be ruled out by genotyping resistance testing assays, even after minimal exposures to efavirenz.</p
L-dopa and dopamine-(R)-alpha-lipoic acid conjugates as multifunctional codrugs with antioxidant properties
A series of multifunctional codrugs (1-4), obtained by joining L-Dopa (LD) and dopamine (DA) with
(R)-R-lipoic acid (LA), was synthesized and evaluated as potential codrugs with antioxidant and iron-chelating
properties. These multifunctional molecules were synthesized to overcome the pro-oxidant effect associated
with LD therapy. The physicochemical properties, together with the chemical and enzymatic stabilities of
synthesized compounds, were evaluated in order to determine both their stability in aqueous medium and
their sensitivity in undergoing enzymatic cleavage by rat and human plasma to regenerate the original drugs.
The new compounds were tested for their radical scavenging activities, using a test involving the Fe (II)-
H2O2-induced degradation of deoxyribose, and to evaluate peripheral markers of oxidative stress such as
plasmatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the plasma.
Furthermore, we showed the central effects of compounds 1 and 2 on spontaneous locomotor activity of
rats in comparison with LD-treated animals. From the results obtained, compounds 1-4 appeared stable at
a pH of 1.3 and in 7.4 buffered solution; in 80% human plasma they were turned into DA and LD. Codrugs
1-4 possess good lipophilicity (log P > 2 for all tested compounds). Compounds 1 and 2 seem to protect
partially against the oxidative stress deriving from auto-oxidation and MAO-mediated metabolism of DA.
This evidence, together with the “in vivo” dopaminergic activity and a sustained release of the parent drug
in human plasma, allowed us to point out the potential advantages of using 1 and 2 rather than LD in
treating pathologies such as Parkinson’s disease, characterized by an evident decrease of DA concentration
in the brain
Synthesis and study of L-dopa-glutathione codrugs as new anti-Parkinson agents with free radical scavenging properties
Codrugs linking L-Dopa and sulfur-containing antioxidants: new pharmacological tools against Parkinson’s Disease
A series of multifunctional codrugs (1-6) were synthesized to overcome the pro-oxidant effect associated with L-dopa (LD) therapy. Target compounds release LD and dopamine (DA) in human plasma after enzymatic hydrolysis, displaying an antioxidant effect superior to that of N-acetylcysteine (NAC). After intracerebroventricular injection of codrug 4, the levels of DA in the striatum were higher than those in LD-treated groups, indicating that this compound has a longer half-life in brain than LD
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