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Model-as-replica, model-as-instrument: Representational electrical power and contextual versatility inside pet designs.
Leveraging on these findings, a PEG-based suppository with a lower dose combination of tenofovir alafenamide (TAF) and EVG (8 mg each) was developed and found to achieve similar rectal drug exposures in macaques. This study establishes the utility of rectal suppositories as a promising on-demand strategy for HIV PrEP and supports their clinical development.The aim of this study was to further evaluate and optimize the Transwell® system for assessing the dissolution behavior of orally inhaled drug products (OIDPs), using fluticasone propionate as a model drug. Sample preparation involved the collection of a relevant inhalable dose fraction through an anatomical mouth/throat model, resulting in a more uniform presentation of drug particles during the subsequent dissolution test. The method differed from previously published procedures by (1) using a 0.4 µm polycarbonate (PC) membrane, (2) stirring the receptor compartment, and (3) placing the drug-containing side of the filter paper face downwards, towards the PC membrane. A model developed in silico, paired with the results of in vitro studies, suggested that a dissolution medium providing a solubility of about 5 µg/mL would be a good starting point for the method's development, resulting in mean transfer times that were about 10 times longer than those of a solution. Furthermore, the model suggested that larger donor/receptor and sampling volumes (3, 3.3 and 2 mL, respectively) will significantly reduce the so-called "mass effect". The outcomes of this study shed further light on the impact of experimental conditions on the complex interplay of dissolution and diffusion within a volume-limited system, under non-sink conditions.Osteoarthritis (OA) is a degenerative joint disease. An objective of the nanomedicine and drug delivery systems field is to design suitable pharmaceutical nanocarriers with controllable properties for drug delivery and site-specific targeting, in order to achieve greater efficacy and minimal toxicity, compared to the conventional drugs. The aim of this review is to present recent data on natural bioactive compounds with anti-inflammatory properties and efficacy in the treatment of OA, their formulation in lipid nanostructured carriers, mainly liposomes, as controlled release systems and the possibility to be intra-articularly (IA) administered. The literature regarding glycosaminoglycans, proteins, polyphenols and their ability to modify the cell response and mechanisms of action in different models of inflammation are reviewed. The advantages and limits of using lipid nanoformulations as drug delivery systems in OA treatment and the suitable route of administration are also discussed. Liposomes containing glycosaminoglycans presented good biocompatibility, lack of immune system activation, targeted delivery of bioactive compounds to the site of action, protection and efficiency of the encapsulated material, and prolonged duration of action, being highly recommended as controlled delivery systems in OA therapy through IA administration. Lipid nanoformulations of polyphenols were tested both in vivo and in vitro models that mimic OA conditions after IA or other routes of administration, recommending their clinical application.Oligonucleotide (ON) therapeutics are molecular target agents composed of chemically synthesized DNA or RNA molecules capable of inhibiting gene expression or protein function. How ON therapeutics can efficiently reach the inside of target cells remains a problem still to be solved in the majority of potential clinical applications. The chemical structure of ON compounds could affect their capability to pass through the plasma membrane. Other key factors are nuclease degradation in the extracellular space, renal clearance, reticulo-endothelial system, and at the target cell level, the endolysosomal system and the possible export via exocytosis. Several delivery platforms have been proposed to overcome these limits including the use of lipidic, polymeric, and inorganic nanoparticles, or hybrids between them. The possibility of evaluating the efficacy of the proposed therapeutic strategies in useful in vivo models is still a pivotal need, and the employment of zebrafish (ZF) models could expand the range of possibilities. In this review, we briefly describe the main ON therapeutics proposed for anticancer treatment, and the different strategies employed for their delivery to cancer cells. The principal features of ZF models and the pros and cons of their employment in the development of ON-based therapeutic strategies are also discussed.Rho-associated kinase (ROCK) activation was shown to contribute to microvascular closure, retinal hypoxia, and to retinal pigment epithelium (RPE) barrier disruption in a rat model of diabetic retinopathy. Fasudil, a clinically approved ROCK inhibitor, improved retinal perfusion and reduced edema in this model, indicating that ROCK inhibition could be a promising new therapeutic approach for the treatment of diabetic retinopathy. However, due to its short intravitreal half-life, fasudil is not suitable for long-term treatment. In this study, we evaluated a very potent ROCK1/2 inhibitor (BIRKI) in a depot formulation administered as a single intravitreal injection providing a slow release for at least four weeks. Following BIRKI intravitreal injection in old Goto-Kakizaki (GK) type 2 diabetic rats, we observed a significant reduction in ROCK1 activity in the retinal pigment epithelium/choroid complex after 8 days and relocation of ROCK1 to the cytoplasm and nucleus in retinal pigment epithelium cells after 28 days. The chronic ROCK inhibition by the BIRKI depot formulation restored retinal pigment epithelial cell morphology and distribution, favored retinal capillaries dilation, and reduced hypoxia and inner blood barrier leakage observed in the diabetic retina. No functional or morphological negative effects were observed, indicating suitable tolerability of BIRKI after intravitreous injection. In conclusion, our data suggest that sustained ROCK inhibition, provided by BIRKI slow-release formulation, could be a valuable treatment option for diabetic retinopathy, especially with regard to the improvement of retinal vascular infusion and protection of the outer retinal barrier.G-quadruplex (G4) forming DNA sequences were recently found to play a crucial role in the regulation of genomic processes such as replication, transcription and translation, also related to serious diseases. Therefore, systems capable of controlling DNA and RNA G-quadruplex structures would be useful for the modulation of various cellular events. In particular, peptides represent good candidates for targeting G-quadruplex structures, since they are easily tailored to enhance their functionality. In this work, we analyzed, by circular dichroism and synchrotron radiation circular dichroism spectroscopies, the interaction of a 25-residue peptide deriving from RHAU helicases (Rhau25) with three G-quadruplex-forming oligonucleotide sequences, in both sodium- and potassium-containing buffers, the most relevant monovalent cations in physiological conditions. The peptide displayed greater affinity for the G4 sequences adopting a parallel structure. However, it showed the ability to also interact with antiparallel or hybrid G-quadruplex structures, inducing a conformation conversion to the parallel structure. The stability of the oligonucleotide structure alone or in presence of the Rhau25 peptide was studied by temperature melting and UV denaturation experiments, and the data showed that the interaction with the peptide stabilized the conformation of oligonucleotide sequences when subjected to stress conditions.Background Nervous and muscular adverse events (NMAEs) have garnered considerable attention after the vaccination against coronavirus disease (COVID-19). However, the incidences of NMAEs remain unclear. We aimed to calculate the pooled event rate of NMAEs after COVID-19 vaccination. Methods A systematic review and meta-analysis of clinical trials on the incidences of NMAEs after COVID-19 vaccination was conducted. The PubMed, Medline, Embase, Cochrane Library, and Chinese National Knowledge Infrastructure databases were searched from inception to 2 June 2021. selleckchem Two independent reviewers selected the study and extracted the data. Categorical variables were analyzed using Pearson's chi-square test. The pooled odds ratio (OR) with the corresponding 95% confidence intervals (CIs) were estimated and generated with random or fixed effects models. The protocol of the present study was registered on PROSPERO (CRD42021240450). Results In 15 phase 1/2 trials, NMAEs occurred in 29.2% vs. 21.6% (p less then 0.001) vacciniderable measure, although life-threatening unsolicited events are rare. NMAEs should be continuously monitored during the ongoing global COVID-19 vaccination program.The recent appearance of SARS-CoV-2 is responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic and has brought to light the importance of understanding this highly pathogenic agent to prevent future pandemics. This virus is from the same single-stranded positive-sense RNA family, Coronaviridae, as two other epidemic-causing viruses, SARS-CoV-1 and MERS-CoV. During this pandemic, one crucial focus highlighted by WHO has been to understand the risk factors that may contribute to disease severity and predict COVID-19 outcomes. In doing so, it is imperative to understand the virology of SARS-CoV-2 and the immunological response eliciting the clinical manifestation and progression of COVID-19. In this review, we provide clinical data-based analyses of how multiple risk factors (such as sex, race, HLA genotypes, blood groups, vitamin D deficiency, obesity, smoking, and asthma) contribute to the inflammatory overactivation and cytokine storm (frequently seen in COVID-19 patients) with a focus on the IL-6 pathway. We also draw comparisons to the virulence and pathophysiology of SARS and MERS to establish parallels in immune response and discuss the potential for therapeutic approaches that may limit disease progression in patients with higher risk profiles than others. Moreover, we cover the latest information on approved or upcoming COVID-19 vaccines. This paper also provides perspective on emerging variants and associated opportunistic infections such as black molds and fungus that have added to mortality in some parts of the world, such as India. This compilation of existing COVID-19 studies and data will provide an excellent referencing tool for the research, clinical, and public health communities.Emerging SARS-CoV-2 variants may threaten global vaccination efforts and the awaited reduction in outbreak burden. In this study, we report a novel variant carrying the L452R mutation that emerged from a local B.1.362 lineage, B.1.362+L452R. The L452R mutation is associated with the Delta and Epsilon variants and was shown to cause increased infection and reduction in neutralization in pseudoviruses. Indeed, the B.1.362+L452R variant demonstrated a X4-fold reduction in neutralization capacity of sera from BNT162b2-vaccinated individuals compared to a wild-type strain. The variant infected 270 individuals in Israel between December 2020 and March 2021, until diminishing due to the gain in dominance of the Alpha variant in February 2021. This study demonstrates an independent, local emergence of a variant carrying a critical mutation, L452R, which may have the potential of becoming a variant of concern and emphasizes the importance of routine surveillance and detection of novel variants among efforts undertaken to prevent further disease spread.
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