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Medicine Nov 2023We compared the efficacy and safety of low-intensity atorvastatin and ezetimibe combination therapy with moderate-intensity atorvastatin monotherapy in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
Effectiveness of low-intensity atorvastatin 5 mg and ezetimibe 10 mg combination therapy compared with moderate-intensity atorvastatin 10 mg monotherapy: A randomized, double-blinded, multi-center, phase III study.
BACKGROUND
We compared the efficacy and safety of low-intensity atorvastatin and ezetimibe combination therapy with moderate-intensity atorvastatin monotherapy in patients requiring cholesterol-lowering therapy.
METHODS
At 19 centers in Korea, 290 patients were randomized to 4 groups: atorvastatin 5 mg and ezetimibe 10 mg (A5E), ezetimibe 10 mg (E), atorvastatin 5 mg (A5), and atorvastatin 10 mg (A10). Clinical and laboratory examinations were performed at baseline, and at 4-week and 8-week follow-ups. The primary endpoint was percentage change from baseline in low-density lipoprotein (LDL) cholesterol levels at the 8-week follow-up. Secondary endpoints included percentage changes from baseline in additional lipid parameters.
RESULTS
Baseline characteristics were similar among the study groups. At the 8-week follow-up, percentage changes in LDL cholesterol levels were significantly greater in the A5E group (49.2%) than in the E (18.7%), A5 (27.9%), and A10 (36.4%) groups. Similar findings were observed regarding the percentage changes in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B levels. Triglyceride levels were also significantly decreased in the A5E group than in the E group, whereas high-density lipoprotein levels substantially increased in the A5E group than in the E group. In patients with low- and intermediate-cardiovascular risk, 93.3% achieved the target LDL cholesterol levels in the A5E group, 40.0% in the E group, 66.7% in the A5 group, and 92.9% in the A10 group. In addition, 31.4% of patients in the A5E group, 8.1% in E, 9.7% in A5, and 7.3% in the A10 group reached the target levels of both LDL cholesterol < 70 mg/dL and reduction of LDL ≥ 50% from baseline.
CONCLUSIONS
The addition of ezetimibe to low-intensity atorvastatin had a greater effect on lowering LDL cholesterol than moderate-intensity atorvastatin alone, offering an effective treatment option for cholesterol management, especially in patients with low and intermediate risks.
Topics: Humans; Atorvastatin; Anticholesteremic Agents; Cholesterol, LDL; Hypercholesterolemia; Azetidines; Heptanoic Acids; Pyrroles; Drug Therapy, Combination; Ezetimibe; Cholesterol; Treatment Outcome; Double-Blind Method; Hydroxymethylglutaryl-CoA Reductase Inhibitors
PubMed: 38013289
DOI: 10.1097/MD.0000000000036122 -
The Medical Letter on Drugs and... Dec 2023
Topics: Humans; Esophagitis; Proton Pump Inhibitors; Pyrroles; Sulfonamides; Esomeprazole
PubMed: 38133593
DOI: 10.58347/tml.2023.1692b -
Environmental Research Aug 2023The Northern Antarctic Peninsula (NAP) shows shifts in phytoplankton distribution and composition along its warming marine ecosystems. However, despite recent efforts to...
The Northern Antarctic Peninsula (NAP) shows shifts in phytoplankton distribution and composition along its warming marine ecosystems. However, despite recent efforts to mechanistically understand these changes, little focus has been given to the phytoplankton seasonal succession, remaining uncertainties regarding to distribution patterns of emerging taxa along the NAP. To fill this gap, we collected phytoplankton (pigment and microscopy analysis) and physico-chemical datasets during spring and summer (November, February and March) of 2013/2014 and 2014/2015 off the NAP. Satellite measurements (sea surface temperature, sea ice concentration and chlorophyll-a) were used to extend the temporal coverage of analysis associated with the in situ sampling. We improved the quantification and distribution pattern of emerging taxa, such as dinoflagellates and cryptophytes, and described a contrasting seasonal behavior and distinct fundamental niche between centric and pennate diatoms. Cryptophytes and pennate diatoms preferentially occupied relatively shallower mixing layers compared with centric diatoms and dinoflagellates, suggesting differences between these groups in distribution and environment occupation over the phytoplankton seasonal succession. Under colder conditions, negative sea surface temperature anomalies were associated with positive anomalies of sea ice concentration and duration. Therefore, based on sea ice-phytoplankton growth relationship, large phytoplankton biomass accumulation was expected during the spring/summer of 2013/2014 and 2014/2015 along the NAP. However, there was a decoupling between sea ice concentration/duration and phytoplankton biomass, characterizing two seasonal periods of low biomass accumulation (negative chlorophyll-a anomalies), associated with the top-down control in the region. These results provide an improved mechanistic understanding on physical-biological drivers modulating phytoplankton seasonal succession along the Antarctic coastal waters.
Topics: Antarctic Regions; Chlorophyll; Chlorophyll A; Dinoflagellida; Ecosystem; Phytoplankton; Seasons
PubMed: 37257748
DOI: 10.1016/j.envres.2023.116273 -
Indian Journal of Gastroenterology :... Aug 2023Proton-pump inhibitors (PPIs) are the mainstay of treatment in erosive esophagitis (EE). An alternative to PPIs in EE is Vonoprazan, a potassium competitive acid... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Proton-pump inhibitors (PPIs) are the mainstay of treatment in erosive esophagitis (EE). An alternative to PPIs in EE is Vonoprazan, a potassium competitive acid blocker. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing vonoprazan to lansoprazole.
METHODS
Multiple databases searched through November 2022. Meta-analysis was performed to assess endoscopic healing at two, four and eight weeks, including for patients with severe EE (Los Angeles C/D). Serious adverse events (SAE) leading to drug discontinuation were assessed. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.
RESULTS
Four RCTs with 2208 patients were included in the final analysis. Vonoprazan 20 mg once-daily was compared to lansoprazole 30 mg once-daily dosing. Among all patients, at two and eight weeks post-treatment, vonoprazan resulted in significantly higher rates of endoscopic healing as compared to lansoprazole, risk ratios (RR) 1.1, p<0.001 and RR 1.04, p=0.03. The same effect was not observed at four weeks, RR 1.03 (CI 0.99-1.06, I=0%) following therapy. Among patients with severe EE, vonoprazan resulted in higher rates of endoscopic healing at two weeks, RR 1.3 (1.2-1.4, I=47%), p=<0.001, at four weeks, RR 1.2 (1.1-1.3, I=36%), p=<0.001 and at eight weeks post-treatment, RR 1.1 (CI 1.03-1.3, I=79%), p=0.009. We found no significant difference in the overall pooled rate of SAE and pooled rate of adverse events leading to drug discontinuation. Finally, the overall certainty of evidence for our main summary estimates was rated as high (grade A).
CONCLUSION
Based on limited number of published non-inferiority RCTs, our analysis demonstrates that among patients with EE, vonoprazan 20 mg once-daily dosing achieves comparable and in those with severe EE, higher endoscopic healing rates as compared to lansoprazole 30 mg once-daily dosing. Both drugs have a comparable safety profile.
Topics: Humans; Lansoprazole; Randomized Controlled Trials as Topic; Esophagitis; Proton Pump Inhibitors; Pyrroles; Peptic Ulcer
PubMed: 37418052
DOI: 10.1007/s12664-023-01384-2 -
Journal of Clinical Oncology : Official... Apr 2024.
Endocrine and Targeted Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer-Capivasertib-Fulvestrant: ASCO Rapid Recommendation Update.
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Topics: Female; Humans; Breast Neoplasms; Fulvestrant; Pyrimidines; Pyrroles; Receptor, ErbB-2; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38478799
DOI: 10.1200/JCO.24.00248 -
Journal of Medicinal Chemistry Apr 2024Akt kinase is vital in cell growth, survival, metabolism, and migration. Dysregulation of Akt signaling is implicated in cancer and metabolic disorders. In the context... (Review)
Review
Akt kinase is vital in cell growth, survival, metabolism, and migration. Dysregulation of Akt signaling is implicated in cancer and metabolic disorders. In the context of cancer, overactive Akt promotes cell survival and proliferation. This has spurred extensive research into developing Akt inhibitors as potential therapeutic agents to disrupt aberrant Akt signaling. Akt inhibitors are classified into three main types: ATP-competitive, allosteric, and covalent-allosteric inhibitors (CAAIs). ATP-competitive inhibitors compete with ATP for binding to Akt, allosteric inhibitors interact with the Pleckstrin homology (PH) domain, and covalent-allosteric inhibitors form covalent bonds, making them more potent and selective. Notably, capivasertib (AZD5363), a potent ATP-competitive Akt inhibitor, received FDA approval in November 2023 for use in combination with the estrogen receptor degrader fulvestrant to treat breast cancer. Challenges remain, including improving selectivity, identifying biomarkers to tailor treatments, and enhancing therapeutic efficacy while minimizing adverse effects. Particularly covalent-allosteric inhibitors hold promise for future more effective and personalized treatments.
Topics: Humans; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrimidines; Allosteric Regulation; Drug Approval; Antineoplastic Agents; Pyrroles; Animals
PubMed: 38592948
DOI: 10.1021/acs.jmedchem.4c00075 -
World Journal of Gastroenterology Mar 2024() infects over half the global population, causing gastrointestinal diseases like dyspepsia, gastritis, duodenitis, peptic ulcers, G-MALT lymphoma, and gastric... (Meta-Analysis)
Meta-Analysis
BACKGROUND
() infects over half the global population, causing gastrointestinal diseases like dyspepsia, gastritis, duodenitis, peptic ulcers, G-MALT lymphoma, and gastric adenocarcinoma. Eradicating is crucial for treating and preventing these conditions. While conventional proton pump inhibitor (PPI)-based triple therapy is effective, there's growing interest in longer acid suppression therapies. Potassium competitive acid blocker (P-CAB) triple and dual therapy are new regimens for eradication. Initially used in Asian populations, vonoprazan (VPZ) has been recently Food and Drug Administration-approved for eradication.
AIM
To assess the efficacy of regimens containing P-CABs in eradicating infection.
METHODS
This study, following PRISMA 2020 guidelines, conducted a systematic review and meta-analysis by searching MEDLINE and Scopus libraries for randomized clinical trials (RCTs) or observational studies with the following command: [("" OR "H pylori") AND ("Treatment" OR "Therapy" OR "Eradication") AND ("Vonaprazan" OR "Potassium-Competitive Acid Blocker" OR "P-CAB" OR "PCAB" OR "Revaprazan" OR "Linaprazan" OR "Soraprazan" OR "Tegoprazan")]. Studies comparing the efficacy of P-CABs-based treatment to classical PPIs in eradicating were included. Exclusion criteria included case reports, case series, unpublished trials, or conference abstracts. Data variables encompassed age, diagnosis method, sample sizes, study duration, intervention and control, and eradication method were gathered by two independent reviewers. Meta-analysis was performed in R software, and forest plots were generated.
RESULTS
A total of 256 references were initially retrieved through the search command. Ultimately, fifteen studies (7 RCTs, 7 retrospective observational studies, and 1 comparative unique study) were included, comparing P-CAB triple therapy to PPI triple therapy. The intention-to-treat analysis involved 8049 patients, with 4471 in the P-CAB intervention group and 3578 in the PPI control group across these studies. The analysis revealed a significant difference in eradication between VPZ triple therapy and PPI triple therapy in both RCTs and observational studies [risk ratio (RR) = 1.17, 95% confidence interval (CI): 1.11-1.22, < 0.0001] and (RR = 1.13, 95%CI: 1.09-1.17, < 0.0001], respectively. However, no significant difference was found between tegoprazan (TPZ) triple therapy and PPI triple therapy in both RCTs and observational studies (RR = 1.04, 95%CI: 0.93-1.16, = 0.5) and (RR = 1.03, 95%CI: 0.97-1.10, = 0.3), respectively.
CONCLUSION
VPZ-based triple therapy outperformed conventional PPI-based triple therapy in eradicating , positioning it as a highly effective first-line regimen. Additionally, TPZ-based triple therapy was non-inferior to classical PPI triple therapy.
Topics: Humans; Anti-Bacterial Agents; Clarithromycin; Helicobacter pylori; Proton Pump Inhibitors; Drug Therapy, Combination; Helicobacter Infections; Pyrroles; Amoxicillin; Treatment Outcome; Randomized Controlled Trials as Topic; Observational Studies as Topic; Benzene Derivatives; Imidazoles; Sulfonamides
PubMed: 38577188
DOI: 10.3748/wjg.v30.i9.1213 -
Journal of Cellular Physiology Nov 2023Oxidative stress has been considered to be closely related to spaceflight-induced bone loss; however, mechanism is elusive and there are no effective countermeasures....
Oxidative stress has been considered to be closely related to spaceflight-induced bone loss; however, mechanism is elusive and there are no effective countermeasures. Using cultured rat calvarial osteoblasts exposed to microgravity simulated by a random positioning machine, this study addressed the hypotheses that microgravity-induced shortening of primary cilia leads to oxidative stress and that primary cilium protection prevents oxidative stress and osteogenesis loss. Microgravity was found to induce oxidative stress (as represented by increased levels of reactive oxygen species (ROS) and malondialdehyde production, and decreased activities of antioxidant enzymes), which was perfectly replicated in osteoblasts growing in NG with abrogated primary cilia (created by transfection of an interfering RNA), suggesting the possibility that shortening of primary cilia leads to oxidative stress. Oxidative stress was accompanied by mitochondrial dysfunction (represented by increased mitochondrial ROS and decreased mitochondrial membrane potential) and intracellular Ca overload, and the latter was found to be caused by increased activity of Ca channel transient receptor potential vanilloid 4 (TRPV4), as also evidenced by TRPV4 agonist GSK1016790A-elicited Ca influx. Supplementation of HC-067047, a specific antagonist of TRPV4, attenuated microgravity-induced mitochondrial dysfunction, oxidative stress, and osteogenesis loss. Although TRPV4 was found localized in primary cilia and expressed at low levels in NG, microgravity-induced shortening of primary cilia led to increased TRPV4 levels and Ca influx. When primary cilia were protected by miR-129-3p overexpression or supplementation with a natural flavonoid moslosooflavone, microgravity-induced increased TRPV4 expression, mitochondrial dysfunction, oxidative stress, and osteogenesis loss were all prevented. Our data revealed a new mechanism that primary cilia function as a controller for TRPV4 expression. Microgravity-induced injury on primary cilia leads to increased expression and overactive channel of TRPV4, causing intracellular Ca overload and oxidative stress, and primary cilium protection could be an effective countermeasure against microgravity-induced oxidative stress and loss of osteogenic potential of osteoblasts.
Topics: Animals; Rats; Cilia; Osteoblasts; Osteogenesis; Oxidative Stress; Reactive Oxygen Species; TRPV Cation Channels; Weightlessness; Cells, Cultured; Morpholines; Pyrroles; Gravitation
PubMed: 37796139
DOI: 10.1002/jcp.31127 -
Applied Microbiology and Biotechnology Dec 2024Heme is an iron-containing porphyrin compound widely used in the fields of healthcare, food, and medicine. Compared to animal blood extraction, it is more advantageous... (Review)
Review
Heme is an iron-containing porphyrin compound widely used in the fields of healthcare, food, and medicine. Compared to animal blood extraction, it is more advantageous to develop a microbial cell factory to produce heme. However, heme biosynthesis in microorganisms is tightly regulated, and its accumulation is highly cytotoxic. The current review describes the biosynthetic pathway of free heme, its fermentation production using different engineered bacteria constructed by metabolic engineering, and strategies for further improving heme synthesis. Heme synthetic pathway in Bacillus subtilis was modified utilizing genome-editing technology, resulting in significantly improved heme synthesis and secretion abilities. This technique avoided the use of multiple antibiotics and enhanced the genetic stability of strain. Hence, engineered B. subtilis could be an attractive cell factory for heme production. Further studies should be performed to enhance the expression of heme synthetic module and optimize the expression of heme exporter and fermentation processes, such as iron supply. KEY POINTS: • Strengthening the heme biosynthetic pathway can significantly increase heme production. • Heme exporter overexpression helps to promote heme secretion, thereby further promoting excessive heme synthesis. • Engineered B. subtilis is an attractive alternative for heme production.
Topics: Animals; Heme; Fermentation; Porphyrins; Anti-Bacterial Agents; Iron
PubMed: 38194135
DOI: 10.1007/s00253-023-12968-5 -
Journal of Applied Microbiology Sep 2023The purpose was to characterize Salmonella Heidelberg (SH) and Minnesota (SM) isolates in terms of their resistance and persistence profile and to assess the...
AIMS
The purpose was to characterize Salmonella Heidelberg (SH) and Minnesota (SM) isolates in terms of their resistance and persistence profile and to assess the antimicrobial effect of benzoic acid (BA) and polypyrrole (PPy).
METHODS AND RESULTS
The 20 isolates from broiler litter drag swabs were submitted to antibiogram and efflux pump expression. The minimum inhibitory/bactericidal concentration (MIC/MBC) of the compounds, synergistic activity, time kill, biofilm production, presence of related genes, and molecular docking between compounds and bacterial target sites were evaluated. All isolates showed multidrug resistance (MDR) and BA and PPy showed mean MIC (1750 and 342 µg ml-1) and MBC (3167 and 1000 µg ml-1), respectively. None of the isolates expressed an efflux pump. The compounds showed synergism against an SH isolate and reduced the count by 3 logs in the presence of the compounds after 4 h. Most isolates (16/20) produced weak to moderate biofilm and 17 showed genes related to biofilm. The compounds interacted with two essential proteins, 3,4-dihydroxy-2-butanone 4-phosphate synthase proteins and ferritin-like domain-containing protein, in bacterial metabolism at different target sites.
CONCLUSIONS
It can be concluded that BA and PPy showed activity on SH and SM, MDR, and biofilm producers, with a potential synergistic effect.
Topics: Animals; Benzoic Acid; Chickens; Manure; Molecular Docking Simulation; Polymers; Pyrroles; Anti-Bacterial Agents
PubMed: 37656886
DOI: 10.1093/jambio/lxad186