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Drug Discovery Today Jan 2019Chemical-stimuli-responsive nanotherapeutics have gained great interest in drug delivery and diagnosis applications. These nanotherapeutics are designed to respond to...
Chemical-stimuli-responsive nanotherapeutics have gained great interest in drug delivery and diagnosis applications. These nanotherapeutics are designed to respond to specific internal stimuli including pH, ionic strength, redox, reactive oxygen species, glucose, enzymes, ATP and hypoxia for site-specific and responsive or triggered release of payloads and/or biomarker detections. This review systematically and comprehensively addresses up-to-date technological and design strategies, and challenges nanomaterials to be used for triggered release and sensing in response to chemical stimuli.
Topics: Adenosine Triphosphate; Animals; Drug Delivery Systems; Enzymes; Glucose; Humans; Hydrogen-Ion Concentration; Hypoxia; Nanostructures; Osmolar Concentration; Oxidation-Reduction
PubMed: 30292916
DOI: 10.1016/j.drudis.2018.09.019 -
Contemporary Clinical Trials Feb 2021The nucleotide analogue prodrug remdesivir was among the first antiviral therapies to be tested in randomized controlled trials (RCTs) for COVID-19. We performed a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The nucleotide analogue prodrug remdesivir was among the first antiviral therapies to be tested in randomized controlled trials (RCTs) for COVID-19. We performed a meta-analysis to understand efficacy and safety.
METHODS
We searched PubMed, EMBASE, Cochrane library, and ClinicalTrials.gov databases (from January 1, 2020 to November 5, 2020). We included RCTs comparing the efficacy and safety of remdesivir to control/placebo in COVID-19. Two independent investigators abstracted data, assessed the quality of evidence, and rated the certainty of evidence.
RESULTS
A total of 4 RCTs with 7334 patients with COVID-19 were included. At a follow-up of 28-29 days from randomization, very low certainty evidence showed that use of remdesivir compared with control group (placebo and/or standard of care) was not associated with a significant decrease in time to clinical improvement (standardized mean difference -0.80 day; [CI, -2.12, 0.53]). However, moderate certainty of evidence showed that remdesivir was associated with higher rates of recovered patients (risk difference [RD] 0.07 [0.05, 0.08]) and discharged patients (RD 0.07 [0.03, 0.11]) and lower rates of developing serious adverse events (RD -0.05 [-0.10, -0.01]) compared with control. Moderate and very low certainty of evidence showed there was no significant difference in deaths at 28-29 days follow-up (RD -0.01 [-0.03, 0.01]) and developing any adverse events (RD 0.01 [-0.17, 0.19]) between both groups, respectively.
CONCLUSION
Patients given remdesivir are more likely to demonstrate recovery and were associated with higher rates of hospital discharge, but not with significant reduction in mean time to clinical improvement or mortality.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; COVID-19; Humans; Randomized Controlled Trials as Topic; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 33422642
DOI: 10.1016/j.cct.2021.106272 -
Sports Medicine (Auckland, N.Z.) Jun 2022The 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a cellular energy sensor that is activated by increases in the cellular AMP/adenosine... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a cellular energy sensor that is activated by increases in the cellular AMP/adenosine diphosphate:adenosine triphosphate (ADP:ATP) ratios and plays a key role in metabolic adaptations to endurance training. The degree of AMPK activation during exercise can be influenced by many factors that impact on cellular energetics, including exercise intensity, exercise duration, muscle glycogen, fitness level, and nutrient availability. However, the relative importance of these factors for inducing AMPK activation remains unclear, and robust relationships between exercise-related variables and indices of AMPK activation have not been established.
OBJECTIVES
The purpose of this analysis was to (1) investigate correlations between factors influencing AMPK activation and the magnitude of change in AMPK activity during cycling exercise, (2) investigate correlations between commonly reported measures of AMPK activation (AMPK-α2 activity, phosphorylated (p)-AMPK, and p-acetyl coenzyme A carboxylase (p-ACC), and (3) formulate linear regression models to determine the most important factors for AMPK activation during exercise.
METHODS
Data were pooled from 89 studies, including 982 participants (93.8% male, maximal oxygen consumption [[Formula: see text]] 51.9 ± 7.8 mL kg min). Pearson's correlation analysis was performed to determine relationships between effect sizes for each of the primary outcome markers (AMPK-α2 activity, p-AMPK, p-ACC) and factors purported to influence AMPK signaling (muscle glycogen, carbohydrate ingestion, exercise duration and intensity, fitness level, and muscle metabolites). General linear mixed-effect models were used to examine which factors influenced AMPK activation.
RESULTS
Significant correlations (r = 0.19-0.55, p < .05) with AMPK activity were found between end-exercise muscle glycogen, exercise intensity, and muscle metabolites phosphocreatine, creatine, and free ADP. All markers of AMPK activation were significantly correlated, with the strongest relationship between AMPK-α2 activity and p-AMPK (r = 0.56, p < 0.001). The most important predictors of AMPK activation were the muscle metabolites and exercise intensity.
CONCLUSION
Muscle glycogen, fitness level, exercise intensity, and exercise duration each influence AMPK activity during exercise when all other factors are held constant. However, disrupting cellular energy charge is the most influential factor for AMPK activation during endurance exercise.
Topics: AMP-Activated Protein Kinases; Acetyl-CoA Carboxylase; Adenosine Diphosphate; Adenosine Monophosphate; Female; Glycogen; Humans; Male; Muscle, Skeletal
PubMed: 34878641
DOI: 10.1007/s40279-021-01610-x -
Andrology Jan 2021A pandemic outbreak of COVID-19 has been sweeping the world since December. It begins as a respiratory infection that, mainly in men with diabetes or renal impairment,...
BACKGROUND
A pandemic outbreak of COVID-19 has been sweeping the world since December. It begins as a respiratory infection that, mainly in men with diabetes or renal impairment, evolves into a systemic disease, with SARDS, progressive endothelial cell damage, abnormal clotting and impaired cardiovascular and liver function. Some clinical trials are testing biological drugs to limit the immune system dysregulation, "cytokines storm," that causes the systemic complications of COVID-19. The contraindications of these drugs and their cost raise concerns over the implications of their widespread availability.
OBJECTIVES
Numerous clinical and experimental studies have revealed a role for the nitric oxide (NO)-cyclic GMP-phosphodiesterase type 5 (PDE5) pathway in modulating low-grade inflammation in patients with metabolic diseases, offering cardiovascular protection. PDE5 inhibition favors an anti-inflammatory response by modulating activated T cells, reducing cytokine release, lowering fibrosis, increasing oxygen diffusion, stimulating vascular repair. PDE5 is highly expressed in the lungs, where its inhibition improves pulmonary fibrosis, a complication of severe COVID-19 disease.
MATERIALS AND METHODS
We performed a systematic review of all evidence documenting any involvement of the NO-cGMP-PDE5 axis in the pathophysiology of COVID-19, presenting the ongoing clinical trials aimed at modulating this axis, including our own "silDEnafil administration in DiAbetic and dysmetaboLic patients with COVID-19 (DEDALO trial)."
RESULTS
The reviewed evidence suggests that PDE5 inhibitors could offer a new strategy in managing COVID-19 by (i) counteracting the Ang-II-mediated downregulation of AT-1 receptor; (ii) acting on monocyte switching, thus reducing pro-inflammatory cytokines, interstitial infiltration and the vessel damage responsible for alveolar hemorrhage-necrosis; (iii) inhibiting the transition of endothelial and smooth muscle cells to mesenchymal cells in the pulmonary artery, preventing clotting and thrombotic complications.
DISCUSSION AND CONCLUSION
If the ongoing trials presented herein should provide positive findings, the low cost, wide availability and temperature stability of PDE5 inhibitors could make them a major resource to combat COVID-19 in developing countries.
Topics: Antiviral Agents; COVID-19; Clinical Trials as Topic; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Host-Pathogen Interactions; Humans; Molecular Targeted Therapy; Nitric Oxide; Phosphodiesterase 5 Inhibitors; SARS-CoV-2; Signal Transduction; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 32526061
DOI: 10.1111/andr.12837 -
Drugs Dec 2020Based on current evidence, recent guidelines of the National Institute of Health, USA indicated the use of remdesivir and dexamethasone for the treatment of COVID-19...
BACKGROUND
Based on current evidence, recent guidelines of the National Institute of Health, USA indicated the use of remdesivir and dexamethasone for the treatment of COVID-19 patients with mild-moderate disease, not requiring high-flow oxygen. No therapeutic agent directed against the immunologic pathogenic mechanisms related to the cytokine release syndrome complicating the disease was indicated.
OBJECTIVES
The purpose of this review was to assess the clinical impact of different therapies for COVID-19; thus, helping to identify the optimal management of the disease. To explain the rationale for the different therapeutic approaches, the characteristics of SARS-CoV-2, the pathogenesis of COVID-19, and the immune response triggered by SARS-CoV-2 infection were reported.
METHODS
The efficacy assessment of the different treatments was performed by a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Available English language published articles including randomised controlled trials, open-label trials of antivirals and immune therapies extracted from Medline, Google Scholar, and MedRxiv databases were analysed. For inclusion, the primary end point of the trials had to be the efficacy as measured by the improvement of clinical features, or mortality, or the Intensive Care Unit Admission rate, or the discharge number. Case reports, paediatric studies, and studies without control group were excluded. The literature search was extended up to August 15, 2020.
RESULTS
After the removal of duplicate articles, and the exclusion of studies not meeting the eligibility criteria, 2 trials of lopinavir/ritonavir, 1 of favipiravir, 3 of remdesivir, 1 of dexamethasone, 3 of hydroxychloroquine, 2 of colchicine, 6 of tocilizumab, 1 of sarilumab, 1 of siltuximab, 2 of anakinra, 3 of baricitinib, 1 of ruxolitinib, 1 of mavrilimumab, and 1 of itolizumab were suitable for the review. Among antivirals, only remdesivir significantly reduced the time to recovery, and mortality. Data for chloroquine and hydroxychloroquine were largely inconclusive. In a large trial, dexamethasone 6 mg/day reduced mortality by one-third. Trials of tocilizumab and sarilumab did not definitively demonstrate efficacy. Anakinra significantly reduced the mortality in 2 trials. Three retrospective trials on a cumulative number of 145 patients, reported the efficacy of baricitinib, with significant reduction of intensive care unit admission, and deaths. These results were recently confirmed by the ACTT-2 trial. Due to paucity of studies and to the small size clinical series, the results of other immune therapies were not conclusive.
CONCLUSIONS
Beyond the supportive therapy, up to now the best therapeutic approach for COVID-19 may be a three-step combination therapy, including remdesivir 100 mg/day (200 mg loading dose on first day) in the first stage of the disease, and combined dexamethasone 6 mg/day plus baricitinib 4 mg/day to target the immune dysregulation triggered by the SARS-CoV-2 infection. The promising results of anakinra should be confirmed by the ongoing RCTs.
Topics: Adenosine Monophosphate; Alanine; Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Antiviral Agents; Biological Products; COVID-19; Cytokines; Dexamethasone; Drug Therapy, Combination; Humans; Inflammation Mediators; Intensive Care Units; Pandemics; Retrospective Studies; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33068263
DOI: 10.1007/s40265-020-01421-w -
Clinical Cardiology Apr 2013There is considerable debate about whether concomitant use of proton pump inhibitors (PPIs) should be recommended for patients who are prescribed clopidogrel after acute... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
There is considerable debate about whether concomitant use of proton pump inhibitors (PPIs) should be recommended for patients who are prescribed clopidogrel after acute coronary syndrome. Most pharmacokinetic and pharmacodynamic studies in vivo were conducted using small sample sizes and were single centered, resulting in conflicting data.
HYPOTHESIS
PPIs may attenuate the antiplatelet effect of clopidogrel in vivo and lead to an increased risk of cardiovascular events.
METHODS
PubMed, the Cochrane Library, Embase, Web of Science, and China Biology Medicine Disc were searched. Randomized controlled trials that compared pharmacodynamic impacts of a PPI on the efficacy of clopidogrel in vivo were included. Two independent reviewers evaluated study quality and extracted data for meta-analysis.
RESULTS
We identified 8 eligible studies. Compared to clopidogrel treatment alone, patients who received both a PPI and clopidogrel had less of a decrease in the platelet reactivity index (weighted mean difference [WMD]: 8.18; 95% confidence interval [CI]: 6.81-9.56; P<0.00001), less adenosine 5'-diphosphate-induced platelet aggregation inhibition (WMD: 7.28; 95% CI: 2.44-12.11; P=0.003), higher P2Y12 reaction units (WMD: 40.58; 95% CI: 19.31-61.86; P=0.0002), and higher risks of clopidogrel resistance (odds ratio [OR]: 2.49; 95% CI: 1.49-4.14; P=0.0005). There were no significant differences, however, for the incidences of major adverse cardiovascular events between the 2 groups (OR: 1.07; 95% CI: 0.44-2.59; P=0.88), and treatment with a PPI and clopidogrel significantly reduced the risk of adverse gastrointestinal events (OR: 0.16; 95% CI: 0.04-0.62; P=0.008).
CONCLUSIONS
Concomitant use of a PPI with clopidogrel attenuated the antiplatelet effect of clopidogrel, but may be clinically unimportant because there were no clinical differences in the risk for major adverse cardiovascular events.
Topics: Adenosine Diphosphate; Blood Platelets; Cardiovascular Diseases; Clopidogrel; Drug Interactions; Drug Resistance; Gastrointestinal Diseases; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Proton Pump Inhibitors; Receptors, Purinergic P2Y12; Ticlopidine
PubMed: 23450832
DOI: 10.1002/clc.22094 -
BMJ Supportive & Palliative Care Mar 2021Because of the lack of vaccination, it is urgent to find effective antiviral agents for COVID-19 treatment. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Because of the lack of vaccination, it is urgent to find effective antiviral agents for COVID-19 treatment.
METHOD
Online databases were searched for articles published before or on 22 June 2020. Studies reporting the effectiveness and safety of antiviral agents for COVID-19 were analysed.
RESULTS
A total of 42 studies were included in this analysis. Hydroxychloroquine (HCQ) was not associated with the incidence of death (risk ratio (RR)=1.08; 95% CI 0.81 to 1.44) and severe cases (RR=1.05; 95% CI 0.61 to 1.81). Patients treated with HCQ obtained few benefits with respect to the clearance of viral RNA and were more likely to have adverse reactions. HCQ treatment could shorten the body temperature recovery time (weighted mean difference = -1.04; 95% CI -1.64 to -0.45). Lopinavir/ritonavir (LPV/r) (RR=0.90; 95% CI 0.76 to 1.07) and Arbidol (RR=1.09; 95% CI 0.92 to 1.29) were not associated with the negative conversion rate. Integrative Chinese-Western medicine alleviated clinical symptoms and decreased the incidence of severe cases (RR=0.38; 95% CI 0.25 to 0.59). Remdesivir treatment reduced the 14-day mortality rate of patients with severe COVID-19 (RR=0.64; 95% CI 0.44 to 0.94). Convalescent plasma (CP) tended to increase the negative conversion rate (RR=2.47; 95% CI 1.70 to 3.57).
CONCLUSION
HCQ, LPV/r and Arbidol bring little benefit in COVID-19 treatment. Integrative Chinese-Western medicine improved the clinical symptoms of patients with COVID-19. Remdesivir and CP might be the potential treatments for patients with severe COVID-19. However, large-scale clinical randomised trials are needed to validate our conclusions.
Topics: Adenosine Monophosphate; Alanine; Antirheumatic Agents; Antiviral Agents; COVID-19; Drug Combinations; Humans; Hydroxychloroquine; Immunization, Passive; Immunoglobulins, Intravenous; Immunologic Factors; Indoles; Lopinavir; Medicine, Chinese Traditional; Ritonavir; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment; COVID-19 Serotherapy
PubMed: 32958501
DOI: 10.1136/bmjspcare-2020-002554 -
Recenti Progressi in Medicina Mar 2021SARS-CoV-2 is a coronavirus that causes a disease which can leads to a severe form of fatal pneumonia. At december 2020 in Italy, more than 2 million people have...
BACKGROUND
SARS-CoV-2 is a coronavirus that causes a disease which can leads to a severe form of fatal pneumonia. At december 2020 in Italy, more than 2 million people have contracted the virus and 78,755 people have died. The scientific community is studying and testing numerous compounds that can be effective and safe for treating people with covid-19.
AIM
To synthesize and evaluate the quality of evidence of efficacy and safety for the treatment. The available evidence is summarized in a living systematic review, a review that is constantly updated on the basis of the results of the new clinical studies.
METHODS
A bibliographic search is launched weekly on the electronic databases and on the main clinical trial registers. Two researchers independently select the articles and assess the quality of the studies using the criteria developed by the Cochrane Collaboration, the certainty of the overall quality of the evidence is assessed using the GRADE criteria.
RESULTS
At 31/12/2020, 101 randomized controlled studies were included that consider 72 different comparisons and include a total of 55,281 patients. 37 drugs are tested with respect to the standard treatment, 6 are evaluated against placebo and finally 29 compare different drugs with each other. By selecting studies that evaluate the efficacy and safety of a drug compared to standard treatment, which include at least 2 studies and which have low to high certainty of evidence, results show that corticosteroids, remdesivir, favipiravir, immunoglobulins, colchicine, and umbilical cord mesenchymal stem cell infusion could reduce overall mortality. No differences for the risk of any adverse events are observed between convalescent plasma and remdesivir compared to standard treatment. Remdesivir probably reduces the risk of serious adverse events; a similar effect, although less strong, is also noted for tocilizumab and the lopinavir-ritonavir combination. In contrast, hydroxychloroquine, corticosteroids and convalescent plasma transfusion are associated with safety concerns with respect to the risk of serious adverse events.
CONCLUSIONS
The 101 studies included consider 72 comparisons and numerous outcomes, the results often coming from single studies and of small dimensions, and for 61% with a very low certainty of evidence, are difficult to summarize and the final result is to increase the uncertainty rather than providing useful information to the clinic and research. From all the work carried out it seems to us that the pandemic has highlighted the many shadows of scientific literature as tool to improve knowledge.
Topics: Adenosine Monophosphate; Adrenal Cortex Hormones; Alanine; Amides; Antibodies, Monoclonal, Humanized; Antiviral Agents; COVID-19; Combined Modality Therapy; Drug Combinations; Drug Repositioning; Humans; Hydroxychloroquine; Immunization, Passive; Immunoglobulins, Intravenous; Lopinavir; Mesenchymal Stem Cell Transplantation; Pandemics; Pyrazines; Randomized Controlled Trials as Topic; Ritonavir; SARS-CoV-2; Treatment Outcome; Uncertainty; COVID-19 Drug Treatment; COVID-19 Serotherapy
PubMed: 33687358
DOI: 10.1701/3565.35458 -
Journal of Cancer Research and... Dec 2021To evaluate the efficacy, safety, and potential advantages of Poly (ADP-ribose) polymerase inhibitors (PARPi) in treating BRCA-mutated breast cancer, we performed a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
To evaluate the efficacy, safety, and potential advantages of Poly (ADP-ribose) polymerase inhibitors (PARPi) in treating BRCA-mutated breast cancer, we performed a meta-analysis of published studies.
MATERIALS AND METHODS
Four randomized controlled trials (RCTs) were included in the meta-analysis. Data analysis was conducted in Review Manager 5.4.
RESULTS
The progression-free survival (PFS) of the patients with triple-negative (hazard ratio [HR] 0.81; 95% confidence interval [CI] 0.74-0.88; P < 0.00001) or hormone receptor-positive (HR 0.83; 95% CI 0.77-0.91; P < 0.0001) BRCA-mutated breast cancer was significantly extended in the containing PARPi therapy arm versus the chemotherapy arm. PFS of the patients who did not receive platinum-based therapy (HR 0.78; 95% CI 0.70-0.86; P < 0.0001) was significantly extended in the PARPi monotherapy arm versus the chemotherapy arm. The objective response rate of patients treated by PARPi monotherapy (risk ratio [RR] 2.51; 95% CI 1.81-3.47; P < 0.00001) was significantly higher than that of patients treated by chemotherapy. The incidence of thrombocytopenia in patients received PARPi combined therapy was obviously increased compared with chemotherapy group (RR 1.36; 95% CI 1.07-1.72; P = 0.01). PARPi monotherapy markedly increased the incidence of anemia (RR 5.83; 95% CI 2.64-12.88; P < 0.0001) versus chemotherapy. However, the risk of neutropenia (RR 0.48; 95% CI 0.29-0.81; P = 0.006) was reduced in the PARPi monotherapy arm. There were no statistical differences in other adverse events among these three groups.
CONCLUSIONS
PARPi combined therapy and monotherapy improved PFS of patients with BRCA-mutated breast cancer compared with standard chemotherapy, which was unrelated to type of BRCA mutation and status of hormone receptor. PARPi therapy has slightly higher hematological toxicity and better overall safety and tolerance.
PROSPERO REGISTRATION NUMBER
CRD42020204385.
Topics: Adenosine Diphosphate; Breast Neoplasms; Female; Humans; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Ribose
PubMed: 35381738
DOI: 10.4103/jcrt.jcrt_2085_21 -
Journal of Neurochemistry Oct 2018Microdialysis is a method to study the extracellular space in vivo, based on the principle of diffusion. It can be used to measure various small molecules including the... (Meta-Analysis)
Meta-Analysis
Microdialysis is a method to study the extracellular space in vivo, based on the principle of diffusion. It can be used to measure various small molecules including the neuroregulator adenosine. Baseline levels of the compounds measured with microdialysis vary over studies. We systematically reviewed the literature to investigate the full range of reported baseline concentrations of adenosine and adenosine monophosphate in microdialysates. We performed a meta-regression analysis to study the influence of flow rate, probe membrane surface area, species, brain area and anaesthesia versus freely behaving, on the adenosine concentration. Baseline adenosine concentrations in microdialysates ranged from 0.8 to 2100 nM. There was limited evidence on baseline adenosine monophosphate concentrations in microdialysates. Across studies, we found effects of flow rate and anaesthesia versus freely behaving on dialysate adenosine concentrations (p ≤ 0.001), but not of probe membrane surface, species, or brain area (p ≥ 0.14). With increasing flow rate, adenosine concentrations decreased. With anaesthesia, adenosine concentrations increased. The effect of other predictor variables on baseline adenosine concentrations, for example, post-surgical recovery time, could not be analysed because of a lack of reported data. This study shows that meta-regression can be used as an alternative to new animal experiments to answer research questions in the field of neurochemistry. However, current levels of reporting of primary studies are insufficient to reach the full potential of this approach; 63 out of 133 studies could not be included in the analysis because of insufficient reporting, and several potentially relevant factors had to be excluded from the analyses. The level of reporting of experimental detail needs to improve.
Topics: Adenosine; Adenosine Monophosphate; Animals; Brain Chemistry; Humans; Microdialysis
PubMed: 30025168
DOI: 10.1111/jnc.14552