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- New delivery systems based on gellan gum nanoparticles for Parkinson Diseases TherapeuticsPublication . Rodrigues, Madalena Filipa Geada; Passarinha, Luís António Paulino; Sousa, Ângela Maria Almeida de; Cristóvão, Ana Clara BrazGlobally, there are up to 10 million people diagnosed with Parkinson's Disease, a chronic neurodegenerative disorder without a cure. Physiologically, it is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Clinically, patients with this disease reveal several motor symptoms, such as tremors, tension, and postural instability, and non-motors, such as depression and anxiety. To date, the most effective drug combination used in the treatment of Parkinson's disease is the administration of levodopa (L-Dopa) combined with catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase inhibitors to restore dopaminergic brain levels. However, the commercially available inhibitors have low capabilities to cross the blood-brain barrier and, thus, low bioavailability in the brain. Also, the prolonged use of these drugs is associated with high hepatotoxicity, which currently limits their use. Therefore, the discovery of molecules with the potential to inhibit the COMT and the development of new delivery systems for these drugs are crucial elements to improve the effectiveness of existing therapies. Using polymeric nanoparticles as antiparkinsonian drug carriers presents numerous advantages considering the current therapies. These nanosystems can cross biological barriers due to their chemical properties and small size. Furthermore, they can achieve the therapeutic target more efficiently, increasing the bioavailability of the drug in restricted environments, such as the brain. Also, the application of polysaccharides in developing this type of delivery system presents advantages such as lower economic costs and better biocompatibility and biodegradability compared to oral and intravenous therapies. The discovery of the molecules 3,4-dihydroxy-5-nitrobenzonitrile (ZINC035) and 2- bromo-3,4-dihydroxy-S-nitrobenzaldehyde (ZINC496) as new COMT inhibitors, combined with the potential of nanoparticles based on natural polymers, such as gellan and chitosan, as drug delivery systems, have proven to be the impulse for this work. In the first part of this work, an analytical method using High-Performance Liquid Chromatography (HPLC) was developed to detect and quantify these new inhibitors in brain tissue samples from adult Wistar rats. In this study, the biological samples were spiked with each inhibitor and, subsequently, analyzed using two different types of detection, in which electrochemical detection (HPLC-ECD) was more effective for biological matrices than diode-array detection (HPLC-DAD). Additionally, a study was realized using different mobile phases, varying from 9 to 18% (v/v) of the organic compound (acetonitrile) to optimize the experimental procedure time. The results obtained using an HPLC-ECD analysis system interestingly showed that the molecules under study have interaction capabilities with brain tissues, and due to their similarity with commercial inhibitors, their potential use in Parkinson's therapies has been proven. In the progress of this work, a new polymeric delivery system has been developed to improve metabolism and absorption, increasing their chemical stability, decreasing their susceptibility to enzymatic degradation, and improving bioavailability of the commercial drugs. This delivery system results from the complexation of two natural polymers with opposite charges, the gellan gum (GG) and the chitosan (CH). These polymeric complexes were formulated, testing different conditions, varying the molecular weight of chitosan (5 kDa and low molecular weight) and the ratio and concentration of the polymers (0.05-1 mg/mL). After optimization, the GG/CH systems were prepared with the inclusion of the selected COMT inhibitor (ZINC035) or L-Dopa. In order to obtain the encapsulation efficiency of the nanoparticles, a purification system was developed, testing three different methodologies (centrifugation, filtration and molecular exclusion chromatography) and varying some conditions, such as centrifugation speeds (8000- 12500 rpm), the size of filter pore (0.22 and 0.45 µm) and the elution buffers (sodium acetate, sodium chloride and phosphate-buffered saline). The best GG/CH delivery system had a size of 238.52 nm; a polydispersity index (PDI) value of 0.449 and a zeta potential (ZP) of +30.2 mV. Also, GG/CH nanoparticles loaded with ZINC035 showed a mean size of 163.5 nm; a PDI of 0.355; a zeta potential of +20.6 mV and an encapsulation efficiency of 67.04%, which are stable up to 48h after formulation. Finally, the L-Dopa-loaded delivery systems achieved a size of 177.01 nm, a PDI of 0.392, and an encapsulation efficiency of approximately 26%. Overall, the HPLC system with electrochemical detection developed in this work is an effective and innovative methodology for studying COMT inhibitors in biological tissues. Furthermore, nanoparticulate polymeric systems have unique properties that can be used according to the desired intranasal delivery application and will certainly present advantages over conventional therapies.
- Transcranial magnetic stimulation in behavioral addiction in the digital era: a systematic reviewPublication . Almeida, Inês Roseta Duarte de; Pinto, Nuno Filipe Cardoso; Patto, Maria da Assunção Morais e Cunha VazBackground The rapid evolution of digital technologies and widespread internet use in daily life have led to the emergence of behavioral addictions, such as gambling disorder (GD), internet gaming disorder (IGD), and internet addiction disorder (IAD). These conditions pose complex challenges for treatment, with conventional interventions, such as psychological and pharmacological interventions, often proving insufficient. Transcranial magnetic stimulation (TMS) has been proposed as a promising approach for treating these addictions. Aims To clarify the evidence available around the use of TMS in patients with GD (internetassociated), IGD, or IAD. Specifically, to evaluate changes in frequency and extent of the addictive behavior, craving, relapse rate, and assessment of psychosocial or other functioning domains after the intervention. Methods A comprehensive search strategy was employed across multiple bibliographic databases, including PubMed/MEDLINE, Embase, Scopus, and Web of Science. The search spanned from the inception of the databases to the search date, with no language restrictions, and required full-length articles. Additionally, Grey Literature sources such as Google Scholar were searched to identify supplementary qualifying studies, and citation searching was conducted to locate additional relevant articles. Results The search yielded 460 records, with no relevant records found in Grey Literature. After removing duplicates, 244 records remained. Screening based on eligibility criteria narrowed the focus to 15 potentially relevant articles, leading to a full-text examination. Citation searching added three more studies. Ultimately, only four articles met the criteria for inclusion in this systematic review. Of these, two involved patients diagnosed with IGD and two were related to IAD. The findings generally suggest a decrease in the severity of symptoms related to internet gaming addiction, impulsivity, cravings, anxiety and depression symptoms after the use of rTMS in the left DLPFC. Similarly, in the case of IAD, a reduction in symptom severity and cravings was observed. Conclusion Despite the promising results of using high-frequency TMS on the left-DLPFC (dorsolateral prefrontal cortex), current research on the feasibility of TMS in addressing GD, IGD and IAD is minimal. Further intervention studies are needed to fully understand the potential of TMS in ameliorating these digital dependencies.