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BMC Ophthalmology Aug 2023To evaluate the efficacy of 1% and 2% rebamipide clear solution in the treatment of dry eye disease (DED). (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
To evaluate the efficacy of 1% and 2% rebamipide clear solution in the treatment of dry eye disease (DED).
METHODS
Two hundred twenty patients with DED were randomly assigned to one of three groups: the 1% rebamipide, 2% rebamipide, or placebo (eye drops containing the same ingredients, except for the active components). Each eye drop was instilled four times daily for 12 weeks. Changes in tear film break-up time (TBUT), corneal and conjunctival staining score, Schirmer 1 test, and the Ocular Surface Disease Index (OSDI) from baseline to 12-week visit between the study groups were compared for efficacy assessment.
RESULTS
The mean age of study patients was 43.8±14.2 years. The 1% and 2% rebamipide groups showed greater improvement in TBUT (1.99±1.87 and 2.02±2.21 s) at 12 weeks from baseline than the placebo group (1.25±2.93 s). The 2% rebamipide group showed greater improvement in the corneal staining score (- 3.15±2.00) at 12 weeks from baseline than the placebo group (- 2.85±1.80). The 1% and 2% rebamipide groups showed improvement in Schirmer 1 test (1.27±3.86 and 1.50±4.14 mm) at 12 weeks of treatment, but not the placebo group (0.55±2.99 mm). Both the rebamipide groups and the placebo group showed significantly improved OSDI after treatment for 12 weeks; however, there was no significant difference among the three groups.
CONCLUSIONS
1% and 2% rebamipide clear solutions are an effective therapeutic option for improving TBUT and tear volume, and stabilizing the corneal staining score in DED.
Topics: Humans; Adult; Middle Aged; Dry Eye Syndromes; Quinolones; Ophthalmic Solutions; Alanine; Tears
PubMed: 37537533
DOI: 10.1186/s12886-023-03004-1 -
Drug Design, Development and Therapy 2021Parkinson's therapeutic interventions are only symptomatic. An optimal treatment should therefore address the largest number of motor and non-motor symptoms, to manage... (Review)
Review
INTRODUCTION
Parkinson's therapeutic interventions are only symptomatic. An optimal treatment should therefore address the largest number of motor and non-motor symptoms, to manage patients at best. Safinamide is one of the most recent approved drugs for fluctuating patients, in add-on to levodopa, that remains the gold standard treatment. It has a unique mechanism of action, both dopaminergic (as MAO-B inhibitor) and glutamatergic (through Na channel blockade). Results from Phase III trials, post-hoc analyses and real-life experiences suggest a beneficial effect on motor (such as tremor, bradykinesia, rigidity and gait) and non-motor (pain, mood, sleep) symptoms.
AREAS COVERED
Here, the authors discuss clinical efficacy and safety of safinamide, identifying the patients' profiles that could benefit most. A search in PubMed was performed in September 2020, with no time limits. Publications' abstracts were reviewed.
CONCLUSION
Safinamide is peculiar due to its double mechanism of action. Its benefits in improving motor functions and fluctuations, and some non-motor symptoms, could have a valuable impact on patients' quality of life (QoL), together with its safety profile.
Topics: Alanine; Animals; Antiparkinson Agents; Benzylamines; Drug Therapy, Combination; Humans; Levodopa; Monoamine Oxidase Inhibitors; Parkinson Disease; Quality of Life; Treatment Outcome
PubMed: 34140766
DOI: 10.2147/DDDT.S302673 -
Proceedings of the National Academy of... Dec 2022Most diazotrophs fix nitrogen only under nitrogen-limiting conditions, for example, in the presence of relatively low concentrations of NH (0 to 2 mM). However, T27...
Most diazotrophs fix nitrogen only under nitrogen-limiting conditions, for example, in the presence of relatively low concentrations of NH (0 to 2 mM). However, T27 exhibits an unusual pattern of nitrogen regulation of nitrogen fixation, since although nitrogenase activities are high under nitrogen-limiting conditions (0 to 3 mM NH) and are repressed under conditions of nitrogen sufficiency (4 to 30 mM NH), nitrogenase activity is reestablished when very high levels of NH (30 to 300 mM) are present in the medium. To further understand this pattern of nitrogen fixation regulation, we carried out transcriptome analyses of T27 in response to increasing ammonium concentrations. As anticipated, the genes were highly expressed, either in the absence of fixed nitrogen or in the presence of a high concentration of NH (100 mM), but were subject to negative feedback regulation at an intermediate concentration of NH (10 mM). Among the differentially expressed genes, , encoding alanine dehydrogenase (ADH1), was highly expressed in the presence of a high level of NH (100 mM). Mutation and complementation experiments revealed that is required for nitrogen fixation at high ammonium concentrations. We demonstrate that alanine, synthesized by ADH1 from pyruvate and NH, inhibits GS activity, leading to a low intracellular glutamine concentration that prevents feedback inhibition of GS and mimics nitrogen limitation, enabling activation of transcription by the nitrogen-responsive regulator GlnR in the presence of high levels of extracellular ammonium.
Topics: Alanine Dehydrogenase; Nitrogen Fixation; Ammonium Compounds; Alanine; Nitrogen; Pyruvic Acid; Nitrogenase
PubMed: 36459643
DOI: 10.1073/pnas.2215855119 -
Drug Discoveries & Therapeutics 2020The outbreak of SARS-CoV-2 rapidly spread across China and worldwide. Remdesivir had been proposed as a promising option for treating coronavirus disease 2019... (Review)
Review
The outbreak of SARS-CoV-2 rapidly spread across China and worldwide. Remdesivir had been proposed as a promising option for treating coronavirus disease 2019 (COVID-19). We provided a rapid review to critically assess the potential anti-coronavirus effect of remdesivir on COVID-19 and other coronaviruses based on the most up-to-date evidence. Even though remdesivir was proposed as a promising option for treating COVID-19 based on laboratory experiments and reports from compassionate use, its safety and effect in humans requires high-quality evidence from well-designed and adequately-powered clinical trials for further clarification.
Topics: Adenosine Monophosphate; Alanine; Animals; Antiviral Agents; Betacoronavirus; COVID-19; Clinical Trials as Topic; Coronavirus Infections; Drug Evaluation, Preclinical; Humans; Middle East Respiratory Syndrome Coronavirus; Pandemics; Pneumonia, Viral; Severe acute respiratory syndrome-related coronavirus; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 32378648
DOI: 10.5582/ddt.2020.01015 -
Selective Alanine Transporter Utilization Creates a Targetable Metabolic Niche in Pancreatic Cancer.Cancer Discovery Jul 2020Pancreatic ductal adenocarcinoma (PDAC) evolves a complex microenvironment comprised of multiple cell types, including pancreatic stellate cells (PSC). Previous studies...
Pancreatic ductal adenocarcinoma (PDAC) evolves a complex microenvironment comprised of multiple cell types, including pancreatic stellate cells (PSC). Previous studies have demonstrated that stromal supply of alanine, lipids, and nucleotides supports the metabolism, growth, and therapeutic resistance of PDAC. Here we demonstrate that alanine cross-talk between PSCs and PDAC is orchestrated by the utilization of specific transporters. PSCs utilize SLC1A4 and other transporters to rapidly exchange and maintain environmental alanine concentrations. Moreover, PDAC cells upregulate SLC38A2 to supply their increased alanine demand. Cells lacking SLC38A2 fail to concentrate intracellular alanine and undergo a profound metabolic crisis resulting in markedly impaired tumor growth. Our results demonstrate that stromal-cancer metabolic niches can form through differential transporter expression, creating unique therapeutic opportunities to target metabolic demands of cancer. SIGNIFICANCE: This work identifies critical neutral amino acid transporters involved in channeling alanine between pancreatic stellate and PDAC cells. Targeting PDAC-specific alanine uptake results in a metabolic crisis impairing metabolism, proliferation, and tumor growth. PDAC cells specifically activate and require SLC38A2 to fuel their alanine demands that may be exploited therapeutically..
Topics: Adenocarcinoma; Alanine; Carcinoma, Pancreatic Ductal; Humans; Metabolic Networks and Pathways; Signal Transduction; Tumor Microenvironment
PubMed: 32341021
DOI: 10.1158/2159-8290.CD-19-0959 -
SLAS Discovery : Advancing Life... Dec 2020COVID-19 respiratory disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has rapidly become a global health issue since it emerged in... (Review)
Review
COVID-19 respiratory disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has rapidly become a global health issue since it emerged in December 2019. While great global efforts are underway to develop vaccines and to discover or repurpose therapeutic agents for this disease, as of this writing only the nucleoside drug remdesivir has been approved under Emergency Use Authorization to treat COVID-19. The RNA-dependent RNA polymerase (RdRP), a viral enzyme for viral RNA replication in host cells, is one of the most intriguing and promising drug targets for SARS-CoV-2 drug development. Because RdRP is a viral enzyme with no host cell homologs, selective SARS-CoV-2 RdRP inhibitors can be developed that have improved potency and fewer off-target effects against human host proteins and thus are safer and more effective therapeutics for treating COVID-19. This review focuses on biochemical enzyme and cell-based assays for RdRPs that could be used in high-throughput screening to discover new and repurposed drugs against SARS-CoV-2.
Topics: Adenosine Monophosphate; Alanine; Amides; Antiviral Agents; Drug Discovery; Enzyme Inhibitors; High-Throughput Screening Assays; Humans; Middle East Respiratory Syndrome Coronavirus; Pyrazines; RNA-Dependent RNA Polymerase; SARS-CoV-2; Viral Proteins; Virus Replication; COVID-19 Drug Treatment
PubMed: 32660307
DOI: 10.1177/2472555220942123 -
Microbiology and Molecular Biology... Aug 2020The Rid (YjgF/YER057c/UK114) protein superfamily was first defined by sequence homology with available protein sequences from bacteria, archaea, and eukaryotes (L.... (Review)
Review
The Rid (YjgF/YER057c/UK114) protein superfamily was first defined by sequence homology with available protein sequences from bacteria, archaea, and eukaryotes (L. Parsons, N. Bonander, E. Eisenstein, M. Gilson, et al., Biochemistry 42:80-89, 2003, https://doi.org/10.1021/bi020541w). The archetypal subfamily, RidA (reactive intermediate deaminase A), is found in all domains of life, with the vast majority of free-living organisms carrying at least one RidA homolog. In over 2 decades, close to 100 reports have implicated Rid family members in cellular processes in prokaryotes, yeast, plants, and mammals. Functional roles have been proposed for Rid enzymes in amino acid biosynthesis, plant root development and nutrient acquisition, cellular respiration, and carcinogenesis. Despite the wealth of literature and over a dozen high-resolution structures of different RidA enzymes, their biochemical function remained elusive for decades. The function of the RidA protein was elucidated in a bacterial model system despite (i) a minimal phenotype of mutants, (ii) the enzyme catalyzing a reaction believed to occur spontaneously, and (iii) confusing literature on the pleiotropic effects of RidA homologs in prokaryotes and eukaryotes. Subsequent work provided the physiological framework to support the RidA paradigm in by linking the phenotypes of mutants lacking to the accumulation of the reactive metabolite 2-aminoacrylate (2AA), which damaged metabolic enzymes. Conservation of enamine/imine deaminase activity of RidA enzymes from all domains raises the likelihood that, despite the diverse phenotypes, the consequences when RidA is absent are due to accumulated 2AA (or a similar reactive enamine) and the diversity of metabolic phenotypes can be attributed to differences in metabolic network architecture. The discovery of the RidA paradigm in laid a foundation for assessing the role of Rid enzymes in diverse organisms and contributed fundamental lessons on metabolic network evolution and diversity in microbes. This review describes the studies that defined the conserved function of RidA, the paradigm of enamine stress in , and emerging studies that explore how this paradigm differs in other organisms. We focus primarily on the RidA subfamily, while remarking on our current understanding of the other Rid subfamilies. Finally, we describe the current status of the field and pose questions that will drive future studies on this widely conserved protein family to provide fundamental new metabolic information.
Topics: Alanine; Amino Acids; Aminohydrolases; Bacteria; Bacterial Proteins; Eukaryota; Gene Expression Regulation, Bacterial; Hydrocarbons, Aromatic; Imines; Metabolic Networks and Pathways; Salmonella enterica; Stress, Physiological; Substrate Specificity; Uracil
PubMed: 32669283
DOI: 10.1128/MMBR.00024-20 -
Infection Feb 2022This review was aimed to synthesise the best available evidence on the effectiveness and safety of remdesivir in the treatment of moderate to severe COVID-19. (Meta-Analysis)
Meta-Analysis Review
PURPOSE
This review was aimed to synthesise the best available evidence on the effectiveness and safety of remdesivir in the treatment of moderate to severe COVID-19.
METHOD
Randomised controlled trials (RCTs) and observational studies reporting the effectiveness and safety of remdesivir were searched via databases and other sources from December 2019 to December 2020. Two independent reviewers performed literature screening, data extraction and assessment of risk bias. Seven studies involving 3686 patients were included.
RESULTS
Treatment with remdesivir was associated with an increase in clinical recovery rate by 21% (RR 1.21; 95% CI 1.08-1.35) on day 7 and 29% (RR 1.29; 95% CI 1.22-1.37) on day 14. The likelihoods of requiring high-flow supplemental oxygen and invasive mechanical ventilation in the remdesivir group were lower than in the placebo group by 27% (RR 0.73; 95% CI 0.54-0.99) and 47% (RR 0.53; 95% CI 0.39-0.72), respectively. Remdesivir-treated patients showed a 39% (RR 0.61; 95% CI 0.46-0.79) reduction in the risk of mortality on day 14 compared to the control group; however, there was no significant difference on day 28. Serious adverse effects (SAEs) were significantly less common in patients treated with remdesivir, with an absolute risk difference of 6% (RD -0.06; 95% CI -0.09 to -0.03).
CONCLUSION
Despite conditional recommendation against its use, remdesivir could still be effective in early clinical improvement; reduction of early mortality and avoiding high-flow supplemental oxygen and invasive mechanical ventilation among hospitalised COVID-19 patients. Remdesivir was also well tolerated without significant SAEs compared to placebo, yet available evidence from clinical studies support the need to conduct close monitoring.
Topics: Adenosine Monophosphate; Alanine; Humans; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34331674
DOI: 10.1007/s15010-021-01671-0 -
Molecules (Basel, Switzerland) Mar 2023We report the short synthesis of novel -nucleoside Remdesivir analogues, their cytotoxicity and an in vitro evaluation against SARS-CoV-2 (CoV2). The described compounds...
We report the short synthesis of novel -nucleoside Remdesivir analogues, their cytotoxicity and an in vitro evaluation against SARS-CoV-2 (CoV2). The described compounds are nucleoside analogues bearing a nitrogen heterocycle as purine analogues. The hybrid structures described herein are designed to enhance the anti-CoV2 activity of Remdesivir. The compounds were evaluated for their cytotoxicity and their anti-CoV2 effect. We discuss the impact of combining both sugar and base modifications on the biological activities of these compounds, their lack of cytotoxicity and their antiviral efficacy.
Topics: Humans; SARS-CoV-2; COVID-19; COVID-19 Drug Treatment; Antiviral Agents; Alanine
PubMed: 36985586
DOI: 10.3390/molecules28062616 -
Frontiers in Public Health 2020Coronaviruses are enveloped positive-sense RNA viruses with an unusual large RNA genome and a unique replication mechanism, which are characterized by club-like spikes... (Review)
Review
Coronaviruses are enveloped positive-sense RNA viruses with an unusual large RNA genome and a unique replication mechanism, which are characterized by club-like spikes that protrude from their surface. An outbreak of a novel coronavirus 2019 infection has posed significant threat to the health and economies in the whole world. This article reviewed the viral replication, pathogenicity, prevention and treatment strategies. With a lack of approved treatment options for this virus, alternative approaches to control the spread of disease is in urgent need. This article also covers some management strategies which may be applied to this virus outbreak. Ongoing clinical studies related to possible treatments for COVID-19, potential vaccines, and alternative medication such as natural compounds are also discussed.
Topics: Adenosine Monophosphate; Alanine; Antimalarials; Antiviral Agents; COVID-19; Humans; Hydroxychloroquine; Public Health; Vaccines; Virus Replication
PubMed: 32733837
DOI: 10.3389/fpubh.2020.00281